[{"id":"acinic-cell-carcinoma-salivary","kind":"cancer","name":"Acinic cell carcinoma of the salivary glands","aka":["Acinic cell carcinoma","Acinic cell carcinoma (NR4A3)","Acinar cell carcinoma of the parotid","Acinic cell adenocarcinoma"],"tldr":"Acinic cell carcinoma is a salivary gland cancer, almost always of the parotid gland, whose cells resemble the gland's normal enzyme-making cells. It is usually low grade and slow, presenting as a painless lump that is easily mistaken for a benign tumour, and surgery cures most; a high-grade minority behaves aggressively and needs radiotherapy too.","summary":"Acinic cell carcinoma is a malignant epithelial neoplasm of the salivary glands defined in the WHO head and neck classification by serous acinar differentiation, with a recurrent NR4A3 rearrangement noted on the parent page; the most common presentation is a well-defined painless solid mass, diagnosis is complicated by its similarity to benign tumours, imaging has no clear characteristics, radical surgery is the best treatment, the role of radiotherapy remains controversial and literature on chemotherapy for metastatic disease is insufficient (Eur Arch Otorhinolaryngol 2020). In 2,362 National Cancer Database cases, most patients were women (61.3 percent) with a median age of 54; age over 70, high grade, size over 3 cm, four or more positive nodes and T4 stage were significant adverse prognosticators (Oral Oncology 2018).\n\nHow it differs from its parent: the salivary gland page covers all types; acinic cell carcinoma is the low-grade type with the best outlook after adenoid cystic and mucoepidermoid carcinoma are set aside, with a defined high-grade transformed variant that changes the plan.\n\nHow common: the third or fourth most common salivary malignancy; no UK share in the sources read.\n\nTreatment: parotidectomy with facial nerve preservation where possible and neck dissection for node-positive or high-grade disease; postoperative radiotherapy for high grade, positive margins or nodes; systemic therapy for metastatic disease has no evidence base and follows the parent page (Eur Arch Otorhinolaryngol 2020).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Acinic_cell_carcinoma","links":[{"label":"NCI PDQ: salivary gland cancer treatment","url":"https://www.cancer.gov/types/head-and-neck/patient/adult/salivary-gland-treatment-pdq"},{"label":"Oral Oncology 2018: parotid acinic cell carcinoma, National Cancer Database study of 2,362 cases","url":"https://doi.org/10.1016/j.oraloncology.2018.05.002"},{"label":"Eur Arch Otorhinolaryngol 2020: acinic cell carcinoma of the parotid gland, from pathogenesis to management (review)","url":"https://doi.org/10.1007/s00405-020-05998-6"}],"tags":["subtype-page","wave4","rare"],"related":["salivary-gland","carcinoma-ex-pleomorphic-adenoma","secretory-carcinoma-breast","adenoid-cystic-carcinoma","salivary-duct-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"2,362 cases of parotid acinic cell carcinoma in the US National Cancer Database over 2004 to 2012, 61.3 percent women, median age 54 (Oral Oncology 2018). Cancer Research UK counts salivary gland cancers together.","subtypes":["Low-grade acinic cell carcinoma of the parotid (the usual form)","Acinic cell carcinoma with high-grade transformation (aggressive)","Acinic cell carcinoma of the submandibular or minor salivary glands (rare)"],"biomarkers":["Serous acinar differentiation; DOG1 and SOX10 positive","NR4A3 rearrangement","Grade, size over 3 cm, node number and T stage (prognostic)","Distinction from secretory carcinoma (ETV6-NTRK3)"],"standardOfCare":[{"setting":"All stages","approach":"Parotidectomy with nerve preservation; neck dissection and postoperative radiotherapy for high grade, positive margins or nodes; metastatic disease as on the parent page.","refs":["salivary-gland"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"salivary-gland"},{"id":"acral-melanoma","kind":"cancer","name":"Acral melanoma","aka":["Acral lentiginous melanoma","Melanoma of the palms, soles and nail beds","Subungual melanoma"],"tldr":"Acral melanoma grows on the soles, palms or under a nail, places without sun exposure, and it is the commonest melanoma in people with darker skin. It is often mistaken for a wart, bruise or fungal nail and so found late; treatment follows skin melanoma, but immunotherapy works less often because the tumour carries fewer mutations.","summary":"Acral melanoma arises on the glabrous skin of the palms, soles and nail apparatus and is not caused by ultraviolet light; its genome has few point mutations but frequent amplifications of CCND1, CDK4 and TERT and other structural changes. BRAF V600 mutations occur in about one in six tumours, NRAS in a similar share and KIT alterations in around one in ten. Delay in diagnosis is the rule, since lesions are mistaken for warts, calluses, haematomas or fungal nail infection, and thick, ulcerated primaries with nodal spread are common at presentation; stage for stage, outcomes are somewhat worse than for other cutaneous melanomas.\n\nManagement follows cutaneous melanoma: excision with margins set by thickness, which for digits may mean amputation of the distal phalanx, sentinel node biopsy for primaries over 0.8 millimetres, and adjuvant anti-PD-1 antibody or, for BRAF-mutant disease, dabrafenib-trametinib after resection of stage III disease. Reconstruction of weight-bearing soles is a particular surgical problem. No adjuvant or advanced-disease trial has been run in acral melanoma alone; the evidence is extrapolated from trials in which acral tumours were a small minority.\n\nResponse to PD-1 blockade is lower than in melanoma of sun-damaged skin: a Japanese multicentre series of 193 patients found responses in 17 percent, and a United States series found responses in about a third. Combination immunotherapy is preferred where tolerated. Imatinib produces responses in roughly a quarter of KIT-mutant tumours, tunlametinib is approved in China for NRAS-mutant melanoma, and CDK4/6 inhibitors are being tested against the CDK4 pathway amplifications that characterise the subtype.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Acral_lentiginous_melanoma","links":[{"label":"Anti-PD-1 in 193 Japanese patients with acral melanoma (Annals of Oncology 2020)","url":"https://doi.org/10.1016/j.annonc.2020.05.031"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Acral_lentiginous_melanoma"}],"tags":["subtype-page"],"related":["mucosal-melanoma","advanced-melanoma","stage-iii-melanoma","uveal-melanoma","braf-v600-melanoma"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","sentinel-node","dermoscopy-ai","kinase-inhibitors"],"targets":["kit","pd1","braf","mek"],"drugs":["nivolumab","ipilimumab","pembrolizumab","imatinib","tunlametinib","palbociclib"],"companies":[],"institutions":[],"pathways":["ras-mapk"],"terms":["breslow-thickness","ulceration-melanoma","sf3b1-mutation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-nadina-nejm-2024","paper-hayward-melanoma-whole-genome-nature-2017","paper-curtin-melanoma-genetic-alterations-nejm-2005","paper-nakamura-anti-pd1-acral-melanoma-ann-oncol-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"skin","burden":"Acral melanoma arises on the palms, soles and under the nails; its absolute incidence is similar in every population, so it is a small minority of melanomas in people with fair skin but the commonest melanoma subtype in people of African and Asian ancestry, accounting for about four in ten melanomas in China.","subtypes":["Acral lentiginous melanoma of the sole (commonest site)","Subungual melanoma (nail apparatus, often with Hutchinson sign)","Palmar melanoma","KIT-mutant acral melanoma (imatinib candidates)","BRAF V600-mutant acral melanoma (targeted therapy eligible)","CDK4 pathway-amplified acral melanoma (CDK4/6 inhibitor trials)"],"biomarkers":["Breslow thickness and ulceration","BRAF V600 mutation","NRAS mutation","KIT mutation or amplification","CCND1, CDK4 and TERT amplification (research)","Low tumour mutational burden"],"standardOfCare":[{"setting":"Diagnosis","approach":"Dermoscopy of the parallel ridge pattern and biopsy of any changing pigmented lesion of the palm, sole or nail; nail matrix biopsy for longitudinal melanonychia with Hutchinson sign.","refs":["dermoscopy-ai","skin-cancer-screening"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Localised disease","approach":"Wide local excision with thickness-based margins, distal amputation for subungual disease when needed, sentinel lymph node biopsy for primaries over 0.8 mm.","refs":["wide-local-excision","sentinel-node","breslow-thickness"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Resected stage III","approach":"Adjuvant nivolumab or pembrolizumab; dabrafenib-trametinib for BRAF V600-mutant disease; neoadjuvant immunotherapy for macroscopic nodes as in NADINA.","refs":["nivolumab","pembrolizumab","dabrafenib-trametinib","nadina"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Advanced disease","approach":"Nivolumab plus ipilimumab or anti-PD-1 monotherapy; BRAF-MEK inhibitors for BRAF-mutant tumours; imatinib for KIT-mutant tumours; tunlametinib for NRAS-mutant disease in China; trials of CDK4/6 inhibitors.","refs":["nivolumab","ipilimumab","pembrolizumab","dabrafenib-trametinib","imatinib","tunlametinib","palbociclib"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}}],"stateOfArt":["Treatment is extrapolated from cutaneous melanoma trials in which acral tumours were a small minority.","Response rates to PD-1 blockade are lower and the subtype's amplification-driven biology has no approved drug yet.","Chinese and Japanese cohorts, where the subtype is common, now supply most of the evidence."],"history":[{"year":1976,"title":"Reed describes acral lentiginous melanoma as a distinct subtype","refs":[]},{"year":2005,"title":"Curtin and Bastian: distinct genetic pattern with few mutations and many amplifications in acral melanoma","refs":["kit"]},{"year":2011,"title":"Imatinib phase 2 trials in KIT-mutant melanoma, many of them acral","refs":["imatinib"]},{"year":2020,"title":"Japanese multicentre series: 17 percent response to anti-PD-1 in acral melanoma","refs":["nivolumab","pembrolizumab"]},{"year":2024,"title":"Tunlametinib approved in China for NRAS-mutant melanoma","refs":["tunlametinib"]}],"pipeline":["tunlametinib","nct06008106","palbociclib","imatinib","seacraft-2","lifileucel"],"openProblems":["Late diagnosis remains the main cause of poor outcomes and awareness in people with darker skin is low.","No trial has been designed for acral melanoma alone outside East Asia.","The amplification-driven genome offers targets (CDK4, CCND1) without a proven drug."],"parent":"melanoma"},{"id":"all-leukemia","kind":"cancer","name":"Acute lymphoblastic leukaemia","aka":[],"tldr":"Acute lymphoblastic leukaemia is the childhood cancer success story, and was the first disease treated with CAR-T and with a T-cell engager.","summary":"Acute lymphoblastic leukaemia is the commonest childhood cancer and a rarer, harder disease in adults. B-cell precursor ALL (85%) is classified by genetics into favourable (ETV6::RUNX1, high hyperdiploidy), intermediate, and adverse groups (KMT2A rearrangement, hypodiploidy, Ph-like/CRLF2, iAMP21, TCF3::HLF); Ph-positive (BCR::ABL1) disease accounts for a quarter of adult cases. T-ALL (15%) has its own genetics and, since 2023, its own targeted options (nelarabine, BCL-2 inhibition in trials). Measurable residual disease after induction is the strongest predictor of relapse in every subgroup.\n\nChildren are cured in over 90% with risk-adapted multi-agent chemotherapy over two to three years, and since 2024 with blinatumomab woven into consolidation (AALL1731: 3-year DFS 96% vs 88%). Adults do worse with chemotherapy alone, but three immunotherapies changed the picture: blinatumomab (E1910: 3-year OS 85% vs 68% when added frontline; standard in MRD-positive and relapsed disease), the CD22 ADC inotuzumab ozogamicin (INO-VATE: 81% remission in relapse), and CD19 CAR-T (tisagenlecleucel for patients up to 25; obe-cel for adults, 2024). Ph-positive ALL is treated with a BCR::ABL1 inhibitor (ponatinib preferred since PhALLCON, 2024) and increasingly with TKI plus blinatumomab and no chemotherapy at all (D-ALBA), while KMT2A-rearranged disease now has menin inhibitors.\n\nAllogeneic transplant remains standard for high-risk or MRD-persistent disease but is being pushed back by MRD-negative remissions achieved with immunotherapy. The unsolved problems are CD19-negative relapse after CAR-T and blinatumomab, T-ALL relapse, Ph-like ALL, infant KMT2A-rearranged ALL, the late toxicities of paediatric therapy, and the very different outcomes for adolescents and adults treated outside specialised centres.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia","links":[{"label":"NCCN ALL guidelines","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1410"}],"tags":["heme"],"related":["paediatric-oncology-roadmap","aml","bpdcn","cll"],"cancers":[],"sections":[],"technologies":["t-cell-engager","car-t","kinase-inhibitors","adc","allogeneic-hsct","flow-cytometry-mrd","ngs-mrd-clonoseq","cytogenetics-fish"],"targets":["cd19","cd3","menin","cd7","cd22","bcr-abl","kmt2a"],"drugs":["clonoseq","clofarabine","nelarabine","prednisone","dexrazoxane","rasburicase","dorocubicel","aminopterin"],"companies":["amgen","pfizer","novartis","autolus","takeda","bms","adaptive-biotechnologies","ecog-acrin","childrens-oncology-group"],"institutions":[],"pathways":[],"terms":["ph-positive-all","mrd-negative-cr","crs","icans","pci-term"],"trials":["ccss","nct07570173","aall0434"],"people":["gertrude-elion"],"bottlenecks":[],"keyPapers":[],"journals":["journal-of-pediatric-hematology-oncology","journal-of-pediatric-hematology-oncology-nursing","pediatric-hematology-and-oncology"],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About 6,500 US cases a year, 60% in children; 5-year survival above 90% in children and about 40-50% in adults, better in those under 40 treated on paediatric-style regimens.","subtypes":["B-cell precursor ALL (85%): ETV6::RUNX1, high hyperdiploidy (favourable); Ph-positive BCR::ABL1 (25% of adults); Ph-like/CRLF2 (adverse, targetable in trials); KMT2A-rearranged (infants); hypodiploid, iAMP21, TCF3::HLF, DUX4/ZNF384 fusions","T-cell ALL (15%): early T-precursor (ETP) subtype adverse; NOTCH1 mutated majority","Mixed-phenotype acute leukaemia","Burkitt-type (mature B) leukaemia, treated as lymphoma"],"biomarkers":["BCR-ABL (Ph+)","KMT2A","Ph-like signature","MRD (flow/NGS)","MRD by flow (10^-4) or clonoSEQ/PCR (10^-5 to 10^-6) at end of induction and consolidation","BCR::ABL1 (Ph+) and transcript type","KMT2A rearrangement (menin inhibitor eligibility; infants)","Ph-like signature (CRLF2, ABL-class fusions, JAK mutations)","IKZF1 deletion / IKZF1-plus (adverse, especially in Ph+)","Hypodiploidy (<44 chromosomes) and TP53 germline testing","CD19 and CD22 expression and density (immunotherapy targets and escape)","CNS involvement at diagnosis","Age and white count (NCI risk in children)"],"standardOfCare":[{"setting":"Frontline","approach":"Risk-adapted chemotherapy + blinatumomab consolidation; TKI if Ph+.","refs":["blinatumomab"],"guideline":{"version":"NCCN Guidelines: Acute Lymphoblastic Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1410"}},{"setting":"Relapsed","approach":"CAR-T (tisagenlecleucel, obe-cel), inotuzumab, transplant.","refs":["car-t","revumenib"],"guideline":{"version":"NCCN Guidelines: Acute Lymphoblastic Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1410"}},{"setting":"Children, standard risk B-ALL","approach":"Risk-adapted multi-agent chemotherapy (induction, consolidation, interim maintenance, delayed intensification, 2-3 years maintenance) with two cycles of blinatumomab in consolidation (AALL1731, approved June 2024); intrathecal CNS prophylaxis; cranial radiation abandoned for most.","refs":["blinatumomab","aall1731","flow-cytometry-mrd"],"guideline":{"nccn":"Category 1 (blinatumomab in consolidation)","version":"NCCN Pediatric ALL 2026"}},{"setting":"Children, high risk or MRD-positive","approach":"Intensified chemotherapy; blinatumomab for MRD persistence (AALL1331 in relapse); inotuzumab and CAR-T (tisagenlecleucel) for relapse; allogeneic transplant for very high risk or MRD persistence.","refs":["blinatumomab","inotuzumab-ozogamicin","tisagenlecleucel","allogeneic-hsct","aall1331"],"guideline":{"nccn":"Category 2A","version":"NCCN Pediatric ALL 2026"}},{"setting":"Infants (<1 year), KMT2A-rearranged","approach":"Interfant-21 backbone with blinatumomab; transplant for high-risk; menin inhibitors in trials.","refs":["blinatumomab","interfant-06","idea-menin-infant-all","kmt2a"],"guideline":{"nccn":"Clinical trial preferred","version":"NCCN Pediatric ALL 2026"}},{"setting":"Adolescents and young adults (15-39), Ph-negative","approach":"Paediatric-inspired regimens (CALGB 10403, GRAALL, UKALL) with asparaginase; blinatumomab consolidation (E1910); MRD-guided transplant.","refs":["blinatumomab","e1910","ngs-mrd-clonoseq","graall-2005"],"guideline":{"nccn":"Category 1 (blinatumomab consolidation)","version":"NCCN ALL 2026"}},{"setting":"Adults 40-70, Ph-negative","approach":"Hyper-CVAD or age-adapted multi-agent chemotherapy with blinatumomab interleaved in consolidation (E1910); inotuzumab-containing lower-intensity regimens (Mini-hyper-CVD + InO ± blinatumomab) for older adults; MRD-driven transplant.","refs":["blinatumomab","inotuzumab-ozogamicin","e1910","allogeneic-hsct"],"guideline":{"nccn":"Category 1 (E1910 regimen)","version":"NCCN ALL 2026"}},{"setting":"Ph-positive ALL, newly diagnosed","approach":"Ponatinib (PhALLCON) or dasatinib with reduced-intensity chemotherapy, or chemotherapy-free TKI + blinatumomab (D-ALBA); BCR::ABL1 PCR monitoring; transplant for MRD persistence or IKZF1-plus, increasingly omitted for MRD-negative patients.","refs":["ponatinib","dasatinib","blinatumomab","phallcon","d-alba","tki-plus-blinatumomab-ph-all"],"guideline":{"nccn":"Category 2A (ponatinib preferred TKI)","version":"NCCN ALL 2026"}},{"setting":"MRD-positive after induction or consolidation","approach":"Blinatumomab (BLAST; full approval 2018) to convert to MRD negativity, then transplant or continued blinatumomab-based therapy.","refs":["blinatumomab","mrd-negative-cr","allogeneic-hsct"],"guideline":{"nccn":"Category 1","version":"NCCN ALL 2026"}},{"setting":"Relapsed or refractory B-ALL","approach":"Blinatumomab (TOWER) or inotuzumab (INO-VATE) as salvage and bridge; CD19 CAR-T (tisagenlecleucel ≤25 years; obe-cel or brexucabtagene in adults) for second salvage or as definitive therapy; transplant for those not previously transplanted; CD22 or dual CAR-T for CD19-negative relapse in trials.","refs":["blinatumomab","inotuzumab-ozogamicin","tisagenlecleucel","obecabtagene-autoleucel","tower","ino-vate","felix","eliana"],"guideline":{"nccn":"Category 2A","version":"NCCN ALL 2026"}},{"setting":"T-cell ALL","approach":"Intensive paediatric-type chemotherapy with nelarabine for high-risk (AALL0434); relapse: nelarabine, venetoclax combinations, CD7 CAR-T and daratumumab in trials; transplant in CR2.","refs":["venetoclax","allogeneic-hsct"],"guideline":{"nccn":"Category 2A","version":"NCCN ALL 2026"}}],"stateOfArt":["Immunotherapy in frontline paediatric therapy.","Blinatumomab in frontline consolidation improves survival in adults (E1910) and children (AALL1731) regardless of MRD; approved June 2024.","Ph-positive ALL: ponatinib is the preferred TKI (PhALLCON) and chemotherapy-free TKI + blinatumomab regimens achieve 18-month survival near 95%.","Two CD19 CAR-T products for ALL (tisagenlecleucel, obe-cel) with obe-cel showing markedly lower severe CRS and neurotoxicity; REMS removed for CAR-T in 2025.","Inotuzumab ozogamicin gives ~80% remission in relapse and is moving into frontline lower-intensity regimens for older adults and children.","MRD at 10^-5 to 10^-6 (clonoSEQ, PCR) is the organising principle for transplant, blinatumomab, and de-escalation decisions.","Menin inhibitors reach KMT2A-rearranged ALL, the first targeted therapy for infant leukaemia."],"history":[{"year":1948,"title":"Farber: aminopterin remissions, birth of chemotherapy","refs":[]},{"year":1948,"title":"Farber induces the first leukaemia remissions","note":"Aminopterin in children with ALL; the birth of cancer chemotherapy.","refs":[]},{"year":1962,"title":"Combination chemotherapy and CNS prophylaxis","note":"Pinkel's 'total therapy' at St. Jude: multi-agent induction, cranial irradiation, maintenance; first cures.","refs":[]},{"year":1990,"title":"Risk-adapted therapy standardised","note":"NCI/Rome criteria (age, white count); paediatric cooperative groups reach ~70% cure.","refs":[]},{"year":2000,"title":"Imatinib transforms Ph-positive leukaemia","note":"First BCR::ABL1 inhibitor; Ph+ ALL survival doubles when added to chemotherapy.","refs":["imatinib","bcr-abl"]},{"year":2009,"title":"MRD becomes the key risk factor","note":"AIEOP-BFM 2000 and UKALL 2003 show end-of-induction MRD outperforms every clinical factor; MRD-directed therapy adopted.","refs":["flow-cytometry-mrd","mrd-negative-cr"]},{"year":2012,"title":"First CAR-T cures: Emily Whitehead","note":"CTL019 at CHOP/Penn; durable remission of refractory paediatric ALL.","refs":["tisagenlecleucel"]},{"year":2014,"title":"Blinatumomab: first BiTE","refs":["blinatumomab"]},{"year":2014,"title":"Blinatumomab: first bispecific T-cell engager approved","note":"Accelerated approval in relapsed/refractory Ph-negative B-ALL.","refs":["blinatumomab"]},{"year":2016,"title":"INO-VATE: CD22 ADC beats chemotherapy in relapse","note":"CR/CRi 81% vs 29%; approval 2017.","refs":["inotuzumab-ozogamicin","ino-vate"]},{"year":2017,"title":"Tisagenlecleucel: first CAR-T","refs":[]},{"year":2017,"title":"Kymriah: first CAR-T approved; TOWER confirms blinatumomab OS benefit","note":"ELIANA-based approval for ALL up to age 25; TOWER OS 7.7 vs 4.0 months.","refs":["tisagenlecleucel","eliana","tower"]},{"year":2018,"title":"Blinatumomab approved for MRD-positive ALL","note":"First approval based on an MRD endpoint (BLAST).","refs":["blinatumomab","mrd-negative-cr"]},{"year":2020,"title":"D-ALBA: chemotherapy-free Ph+ ALL","note":"Dasatinib then blinatumomab, 18-month OS 95%.","refs":["d-alba","dasatinib"]},{"year":2024,"title":"Blinatumomab frontline","refs":[]},{"year":2024,"title":"Blinatumomab frontline (E1910, AALL1731), ponatinib frontline (PhALLCON), obe-cel approved","note":"Immunotherapy becomes part of standard first-line therapy for adults and children; second CAR-T for adult ALL; revumenib approved for KMT2Ar leukaemia.","refs":["e1910","aall1731","phallcon","obecabtagene-autoleucel","revumenib"]},{"year":2025,"title":"REMS removed for CAR-T; menin inhibitor combinations enter ALL trials","note":"FDA lifts REMS for approved CAR-T products; ziftomenib and revumenib studied in KMT2Ar ALL.","refs":["tisagenlecleucel","ziftomenib"]},{"year":2026,"title":"Subcutaneous blinatumomab and Interfant-21 progress","note":"Subcutaneous blinatumomab trials (including the first in mixed-phenotype leukaemia) aim to replace continuous infusion; infant trials integrate blinatumomab.","refs":["blinatumomab","interfant-06"]}],"pipeline":["revumenib","mk-1045","ucart22","crc01","tbi-1501","obecabtagene-autoleucel","ponatinib","asciminib","tki-plus-blinatumomab-ph-all","idea-transplant-free-ph-all","idea-menin-infant-all","ziftomenib","inotuzumab-ozogamicin","ngs-mrd-clonoseq","blinatumomab-frontline-consolidation","allogeneic-hsct"],"openProblems":["Adult ALL outcomes.","CD19-negative relapse.","CD19-negative relapse after blinatumomab or CAR-T; CD22 and dual-antigen CARs are early.","T-cell ALL has no approved immunotherapy; CD7 CAR-T (fratricide) and venetoclax combinations are experimental.","Ph-like ALL (CRLF2, JAK) has poor outcomes and only trial access to JAK/ABL-class inhibitors.","Infant KMT2A-rearranged ALL still has EFS under 50% on chemotherapy alone.","Continuous-infusion blinatumomab is burdensome; subcutaneous formulation not yet approved.","Which adults can safely skip transplant after MRD-negative immunotherapy remission is untested in randomised trials.","Late effects of curative paediatric therapy (neurocognitive, cardiac, second cancers) and survivorship care.","Adults treated outside academic centres have markedly worse survival; access to CAR-T and paediatric-inspired protocols is uneven."],"parent":"leukaemia"},{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","aka":[],"tldr":"Acute myeloid leukaemia is an aggressive blood cancer where, after 40 years of the same chemotherapy, a wave of targeted drugs (FLT3, IDH, BCL-2, menin) arrived.","summary":"Acute myeloid leukaemia is a cancer of immature myeloid cells that floods the marrow and blood within weeks. It is defined molecularly: WHO 2022 and ICC 2022 classify by driver genetics, and ELN 2022 assigns favourable, intermediate, or adverse risk from NPM1, CEBPA, core-binding-factor fusions, FLT3, TP53, KMT2A, and myelodysplasia-related mutations. Median age at diagnosis is 68, and outcomes diverge sharply by age and fitness.\n\nTreatment split into two paradigms. Fit patients receive intensive 7+3 induction (unchanged since 1973) with a targeted add-on chosen by genetics: midostaurin or quizartinib for FLT3, gemtuzumab ozogamicin for CD33+ favourable and intermediate risk, CPX-351 for secondary AML, then high-dose cytarabine consolidation and allogeneic transplant for adverse or MRD-positive disease. Unfit patients, once offered only supportive care, now receive venetoclax with azacitidine (VIALE-A) or, since May 2026, an all-oral regimen with decitabine-cedazuridine; IDH1-mutated patients may receive ivosidenib-azacitidine (AGILE). Relapse is treated by genotype: gilteritinib (FLT3), ivosidenib, olutasidenib or enasidenib (IDH), and the new menin inhibitors revumenib and ziftomenib (NPM1-mutated or KMT2A-rearranged), with transplant as the consolidating cure.\n\nMeasurable residual disease by flow cytometry, NPM1 qPCR, or error-corrected NGS now decides transplant and maintenance, and platform trials such as myeloMATCH assign therapy from rapid genomics at diagnosis. The unsolved problems are TP53-mutated and complex-karyotype AML, where every new class has failed so far, relapse after transplant, early death from infection in older patients, and the cost and logistics of the increasingly individualised pathway.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Acute_myeloid_leukemia","links":[{"label":"ELN 2022 recommendations","url":"https://ashpublications.org/blood/article/140/12/1345/485817"},{"label":"NCCN AML guidelines","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}],"tags":["heme"],"related":["all-leukemia","bpdcn","cmml","cml"],"cancers":[],"sections":[],"technologies":["epigenetic-drugs","adc","kinase-inhibitors","allogeneic-cell-therapy","allogeneic-hsct","flow-cytometry-mrd","ngs-mrd-clonoseq","cytogenetics-fish","bh3-profiling"],"targets":["flt3","idh","menin","bcl2","cd33","cd123","cd47","tp53","cd70","npm1","kmt2a"],"drugs":["decitabine","idarubicin","mitoxantrone","rasburicase","histamine-dihydrochloride","dorocubicel","aminopterin"],"companies":["treadwell-therapeutics","molecular-partners","orca-bio","abbvie","novartis","daiichi-sankyo","astellas","servier","syndax","kura-oncology","taiho-oncology","jazz","rigel-pharmaceuticals","bms"],"institutions":[],"pathways":["apoptosis-bcl2","aml-signalling"],"terms":["eln-risk","flt3-itd-allelic-ratio","mrd-negative-cr","differentiation-syndrome","tumor-lysis-syndrome"],"trials":["aaml0531","nct06387069","nct05586074","nct06852222","nct05429632","nct06788756","nct07007312","nct07211958","nct04229979","nct04256317","nct05907057","nct07581002","nct07255872","nct06389292","nct03182244","apl0406","viale-a"],"people":["hartmut-dohner","uwe-platzbecker","pierre-fenaux"],"bottlenecks":[],"keyPapers":[],"journals":["blood-cancer-discovery","blood-cancer-journal","clinical-lymphoma-myeloma-and-leukemia","current-hematologic-malignancy-reports","haematologica","hematology-oncology-and-stem-cell-therapy","journal-of-hematology-and-oncology","leukemia-and-lymphoma","leukemia-research"],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About 20,000 new cases a year in the US and 120,000 worldwide; median age 68. Genotype-directed drugs and venetoclax combinations have made most patients treatable, and outcomes diverge by genetics. 5-year survival is roughly 30% overall, above 60% in favourable-risk younger adults and below 10% in TP53-mutated disease.","subtypes":["AML with defining genetic abnormalities (WHO 2022): NPM1-mutated, CEBPA bZIP, RUNX1::RUNX1T1, CBFB::MYH11, KMT2A-rearranged, DEK::NUP214, BCR::ABL1, MECOM","Acute promyelocytic leukaemia (PML::RARA), curable without chemotherapy in most cases (ATRA + arsenic)","AML, myelodysplasia-related (mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2 or MDS-type cytogenetics)","TP53-mutated AML / complex karyotype (adverse; ~10-15%)","Therapy-related AML after alkylators or topoisomerase II inhibitors","FLT3-ITD or FLT3-TKD (30%; targetable)","IDH1 or IDH2-mutated (15-20%; targetable)","Blastic plasmacytoid dendritic cell neoplasm (CD123-high; related entity)"],"biomarkers":["FLT3-ITD/TKD","NPM1","IDH1/2","KMT2A","TP53","CD33","ELN risk","MRD","ELN 2022 genetic risk group","FLT3-ITD and TKD (midostaurin, quizartinib, gilteritinib)","NPM1 (favourable risk without FLT3-ITD; MRD marker; menin inhibitor eligibility)","IDH1 / IDH2 (ivosidenib, olutasidenib, enasidenib)","KMT2A rearrangement (revumenib)","TP53 and complex karyotype (adverse; venetoclax less effective)","CD33 (gemtuzumab), CD123 (tagraxofusp, pivekimab)","Measurable residual disease (flow, NPM1 qPCR, NGS) after cycles 2 and before transplant","Karyotype/FISH at diagnosis","Myelodysplasia-related mutation set"],"standardOfCare":[{"setting":"Fit","approach":"7+3 ± targeted agent; consolidation; allogeneic transplant by risk.","refs":["gemtuzumab-ozogamicin","cytotoxic-chemotherapy"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Unfit","approach":"Azacitidine + venetoclax.","refs":["venetoclax"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Relapsed","approach":"Genotype-directed: gilteritinib, IDH inhibitors, menin inhibitors; transplant.","refs":["revumenib"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Diagnosis and risk assignment","approach":"Marrow morphology, flow, karyotype/FISH, rapid FLT3/NPM1/IDH testing (results within days), NGS panel; ELN 2022 risk; fitness assessment. Menin-inhibitor and FLT3-inhibitor eligibility depends on these results.","refs":["cytogenetics-fish","cgp","eln-risk","flow-cytometry-mrd"],"guideline":{"nccn":"Category 2A","version":"NCCN AML 2026","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Fit, FLT3-mutated","approach":"7+3 plus midostaurin (ITD or TKD) or quizartinib (ITD only), consolidation with continued inhibitor, allogeneic transplant for most FLT3-ITD in CR1, post-transplant FLT3-inhibitor maintenance if MRD-positive.","refs":["cytarabine-7-3","midostaurin","quizartinib","ratify","quantum-first","allogeneic-hsct"],"guideline":{"nccn":"Category 1 (midostaurin, quizartinib)","esmoMcbs":"A (RATIFY)","version":"NCCN AML 2026 / ESMO 2020"}},{"setting":"Fit, favourable or intermediate risk, CD33-positive","approach":"7+3 plus fractionated gemtuzumab ozogamicin (ALFA-0701); high-dose cytarabine consolidation; MRD-guided transplant for intermediate risk.","refs":["gemtuzumab-ozogamicin","alfa-0701","cytarabine-7-3"],"guideline":{"nccn":"Category 2A","version":"NCCN AML 2026"}},{"setting":"Fit, secondary or therapy-related AML","approach":"CPX-351 induction (Study 301) then transplant in CR1; alternatives include 7+3 or venetoclax-based therapy in trials.","refs":["cpx-351","cpx-351-301","allogeneic-hsct"],"guideline":{"nccn":"Category 1 (age 60-75)","version":"NCCN AML 2026"}},{"setting":"Fit, adverse risk (TP53, complex karyotype, MDS-related)","approach":"Intensive induction or venetoclax-azacitidine to remission, then allogeneic transplant as the only realistic cure; clinical trial strongly preferred; TP53-mutated disease has no effective targeted therapy after the magrolimab and eprenetapopt failures.","refs":["allogeneic-hsct","venetoclax","azacitidine","magrolimab"],"guideline":{"nccn":"Category 2A (clinical trial preferred)","version":"NCCN AML 2026"}},{"setting":"Unfit for intensive chemotherapy (most patients over 75)","approach":"Venetoclax + azacitidine (VIALE-A) or venetoclax + oral decitabine-cedazuridine (ASCERTAIN-V, 2026); ivosidenib + azacitidine if IDH1-mutated (AGILE); low-dose cytarabine + venetoclax as an alternative. Continue until progression; consider transplant in responders who become fit.","refs":["venetoclax","azacitidine","decitabine-cedazuridine","ivosidenib","viale-a","agile","ascertain-v"],"guideline":{"nccn":"Category 1 (venetoclax + HMA)","esmoMcbs":"4 (VIALE-A)","version":"NCCN AML 2026"}},{"setting":"Maintenance after intensive therapy","approach":"Oral azacitidine (Onureg) for patients not transplanted (QUAZAR AML-001); FLT3 inhibitor maintenance after transplant in FLT3-ITD (MORPHO for MRD-positive); menin inhibitor maintenance in trials.","refs":["azacitidine","gilteritinib","quizartinib","quazar-aml-001","morpho"],"guideline":{"nccn":"Category 1 (oral azacitidine)","version":"NCCN AML 2026"}},{"setting":"Relapsed or refractory, FLT3-mutated","approach":"Gilteritinib monotherapy (ADMIRAL) or gilteritinib + venetoclax/azacitidine, then transplant; quizartinib in Japan.","refs":["gilteritinib","admiral","allogeneic-hsct"],"guideline":{"nccn":"Category 1","version":"NCCN AML 2026"}},{"setting":"Relapsed or refractory, IDH-mutated","approach":"Ivosidenib or olutasidenib (IDH1), enasidenib (IDH2), often with azacitidine or venetoclax; differentiation-syndrome monitoring.","refs":["ivosidenib","olutasidenib","enasidenib","differentiation-syndrome"],"guideline":{"nccn":"Category 2A","version":"NCCN AML 2026"}},{"setting":"Relapsed or refractory, NPM1-mutated or KMT2A-rearranged","approach":"Menin inhibitor: revumenib (KMT2Ar 2024; NPM1 2025) or ziftomenib (NPM1, November 2025), as a bridge to transplant; triplets with venetoclax-azacitidine in trials.","refs":["revumenib","ziftomenib","augment-101","komet-001","menin-plus-venetoclax-hma"],"guideline":{"nccn":"Category 2A","version":"NCCN AML 2026"}},{"setting":"Acute promyelocytic leukaemia","approach":"ATRA + arsenic trioxide without chemotherapy for standard risk (cure >95%); ATRA + arsenic + idarubicin or gemtuzumab for high risk. Differentiation syndrome prophylaxis.","refs":["differentiation-syndrome"],"guideline":{"nccn":"Category 1","version":"NCCN AML 2026"}}],"stateOfArt":["Menin inhibitors.","Venetoclax combinations.","Genotype-directed induction: FLT3 inhibitors (two positive phase 3 trials), gemtuzumab for CD33+ favourable/intermediate risk, CPX-351 for secondary AML.","Venetoclax + hypomethylating agent made unfit AML treatable, and since May 2026 the regimen can be fully oral.","Menin inhibitors (revumenib 2024/2025, ziftomenib 2025) opened NPM1-mutated and KMT2A-rearranged leukaemia, ~40% of adult AML, to a new drug class within one year.","MRD by flow and molecular methods now guides transplant, maintenance, and pre-emptive therapy; ELN 2021 MRD standards are in routine use.","Platform trials (myeloMATCH) assign therapy from rapid genomics at diagnosis and re-assign at each MRD checkpoint.","Allogeneic transplant is safer (post-transplant cyclophosphamide, haploidentical donors) and increasingly followed by targeted maintenance."],"history":[{"year":1948,"title":"First chemotherapy remissions in leukaemia","note":"Farber's aminopterin in childhood ALL; AML remissions follow with 6-MP and cytarabine in the 1960s.","refs":[]},{"year":1973,"title":"7+3 regimen","refs":[]},{"year":1973,"title":"7+3 induction defined","note":"Cytarabine 7 days + daunorubicin 3 days (Yates et al.); still the intensive backbone.","refs":["cytarabine-7-3"]},{"year":1977,"title":"First allogeneic transplants cure refractory leukaemia","note":"Thomas (Seattle) reports long-term survival after HLA-matched sibling transplant; Nobel Prize 1990.","refs":["allogeneic-hsct"]},{"year":1988,"title":"ATRA induces differentiation in APL","note":"Shanghai group shows all-trans retinoic acid remissions; arsenic follows in the 1990s. First differentiation therapy.","refs":["differentiation-syndrome"]},{"year":2000,"title":"Gemtuzumab: first ADC","refs":["gemtuzumab-ozogamicin"]},{"year":2000,"title":"Gemtuzumab ozogamicin, the first ADC","note":"Accelerated approval in relapsed CD33+ AML; withdrawn 2010 after SWOG S0106 toxicity.","refs":["gemtuzumab-ozogamicin"]},{"year":2004,"title":"Azacitidine approved (MDS)","note":"First hypomethylating agent; later the AML backbone for venetoclax and IDH/menin combinations.","refs":["azacitidine"]},{"year":2012,"title":"ALFA-0701 rescues gemtuzumab","note":"Fractionated dosing with 7+3 improves EFS; re-approval 2017.","refs":["alfa-0701","gemtuzumab-ozogamicin"]},{"year":2017,"title":"Midostaurin, enasidenib, gemtuzumab re-approval","refs":[]},{"year":2017,"title":"Four approvals in one year","note":"Midostaurin (RATIFY), enasidenib, CPX-351, gemtuzumab re-approval; the first new AML drugs since 2000.","refs":["midostaurin","ratify","enasidenib","cpx-351"]},{"year":2018,"title":"Ivosidenib, gilteritinib, and venetoclax combinations","note":"Ivosidenib (IDH1) and gilteritinib (ADMIRAL) approved; venetoclax + HMA/LDAC gets accelerated approval for unfit AML.","refs":["ivosidenib","gilteritinib","admiral","venetoclax"]},{"year":2020,"title":"VIALE-A: venetoclax-azacitidine improves survival in unfit AML","note":"OS 14.7 vs 9.6 months; full approval October 2020; oral azacitidine maintenance approved (QUAZAR).","refs":["viale-a","venetoclax","azacitidine"]},{"year":2022,"title":"ELN 2022 risk, WHO/ICC classifications, AGILE, olutasidenib","note":"Genetics-first classification; ivosidenib-azacitidine OS HR 0.44; second IDH1 inhibitor approved.","refs":["eln-risk","agile","olutasidenib"]},{"year":2023,"title":"Quizartinib approved in frontline FLT3-ITD AML","note":"QuANTUM-First OS 31.9 vs 15.1 months, including patients to age 75.","refs":["quizartinib","quantum-first"]},{"year":2024,"title":"Revumenib: first menin inhibitor","refs":["revumenib"]},{"year":2024,"title":"Revumenib: first menin inhibitor; magrolimab fails","note":"Approved for KMT2A-rearranged acute leukaemia (AUGMENT-101). Magrolimab (CD47) discontinued after ENHANCE trials, a setback for TP53-mutated AML.","refs":["revumenib","augment-101","magrolimab"]},{"year":2025,"title":"Menin inhibitors reach NPM1-mutated AML","note":"Revumenib NPM1 label (October) and ziftomenib approval (13 November, KOMET-001).","refs":["ziftomenib","komet-001","revumenib"]},{"year":2026,"title":"First all-oral AML regimen","note":"Decitabine-cedazuridine + venetoclax approved 13 May 2026 (ASCERTAIN-V, CR 41.6%).","refs":["decitabine-cedazuridine","ascertain-v"]}],"pipeline":["revumenib","venetoclax","ak117","hmpl-306","clifutinib","bleximenib","cusatuzumab","cart84","rvu120","bexmarilimab","ard103","ziftomenib","menin-plus-venetoclax-hma","myelomatch","gilteritinib","quizartinib","decitabine-cedazuridine","cpx-351","bh3-profiling","ngs-mrd-clonoseq","idea-mrd-guided-transplant-aml","idea-shortened-venetoclax","tagraxofusp","allogeneic-hsct"],"openProblems":["TP53-mutant AML: no drug class has yet improved survival, so it is the priority for new mechanisms.","Older patients.","TP53-mutated and complex-karyotype AML: no class has improved survival; magrolimab (CD47) and eprenetapopt (p53 reactivator) both failed in phase 3.","Relapse after allogeneic transplant is the main way treatment fails; which maintenance (FLT3, menin, azacitidine) helps whom is unresolved.","Menin-inhibitor resistance through MEN1 mutations appears within months in a third of relapsing patients; combinations and next-generation inhibitors are needed.","Infections and low blood counts early in venetoclax-based therapy are the main risk in the very old; optimal venetoclax duration is untested in randomised trials.","MRD thresholds and assays are not harmonised across labs, and CHIP-associated mutations confound NGS MRD.","Whether triplets (menin or FLT3 inhibitor + venetoclax + HMA) improve survival over doublets, and at what toxicity, awaits phase 3.","Access: rapid genomics within 72 hours and menin/FLT3 inhibitors are unavailable in most low- and middle-income settings."],"parent":"leukaemia"},{"id":"aml-paediatric","kind":"cancer","name":"Acute myeloid leukaemia in children","aka":["Childhood AML","Paediatric AML","Pediatric acute myeloid leukemia"],"tldr":"Acute myeloid leukaemia in children carries gene fusions rather than the mutations of ageing, is treated with four or five intensive courses of chemotherapy, and cures around two thirds of children. Adding gemtuzumab ozogamicin lowered relapse in the AAML0531 trial, and the menin inhibitor revumenib is the first targeted drug approved for the KMT2A-rearranged form common in young children.","summary":"Childhood AML is defined by chromosomal rearrangements: KMT2A fusions in about a fifth, more in infants; the core-binding-factor leukaemias RUNX1::RUNX1T1 and CBFB::MYH11 in about a quarter, with the best prognosis; NUP98 fusions, CBFA2T3::GLIS2 and RBM15::MRTFA in infants and young children, with the worst; and FLT3 internal tandem duplications in about 15 percent, more in adolescents. NPM1, DNMT3A, TP53 and spliceosome mutations, which dominate adult AML, are rare. Down syndrome brings a distinct GATA1-mutated myeloid leukaemia in the first four years of life that is highly curable with reduced chemotherapy. Risk is assigned by these lesions and by flow cytometry measurable residual disease after the first course.\n\nThe backbone came from the UK MRC AML10 and AML12 trials of the 1990s, which set four intensive courses of cytarabine and anthracycline-based chemotherapy with no maintenance, and from the Berlin-Frankfurt-Münster and Nordic groups. COG AAML0531 randomised 1,022 children to gemtuzumab ozogamicin, a CD33 antibody-drug conjugate, added to the first induction and second intensification course: three-year event-free survival 53.1 percent against 46.9 percent, driven by lower relapse, with no significant overall survival gain but a clear benefit in children with high CD33 expression; gemtuzumab was approved for newly diagnosed CD33-positive AML in children from one month of age in 2020. AAML1031 found no benefit from adding bortezomib, and showed that sorafenib added to chemotherapy for FLT3-ITD disease with a high allelic ratio improved event-free survival compared with the FLT3-ITD children on AAML0531. Allogeneic transplant in first remission is reserved for high-risk genetics or persistent residual disease, and the European MyeChild01 trial has been settling gemtuzumab dosing and the choice of anthracycline.\n\nRelapse occurs in about a third of children and is cured in about half of them with fludarabine and cytarabine reinduction and transplant. Revumenib, approved in November 2024 for relapsed or refractory KMT2A-rearranged acute leukaemia from the age of one, is the first targeted therapy for the commonest genetic subgroup; gilteritinib for FLT3-mutated disease and venetoclax with cytarabine, which gave responses in the majority of relapsed children in a St Jude phase 1 study, are in paediatric trials. Anthracycline cardiotoxicity is the defining late effect, so dexrazoxane cardioprotection, liposomal anthracyclines and cumulative-dose limits run through every trial, and infection during the profound neutropenia of each course still kills more children than the leukaemia in many centres.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Acute_myeloid_leukemia","links":[{"label":"Wikipedia: Acute myeloid leukaemia","url":"https://en.wikipedia.org/wiki/Acute_myeloid_leukemia"},{"label":"NCI PDQ: Childhood AML Treatment","url":"https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq"}],"tags":["subtype-page","paediatric"],"related":["aml-npm1-kmt2a","aml-flt3","apl","all-infant","aml-secondary"],"cancers":[],"sections":[],"technologies":["adc","allogeneic-hsct","flow-cytometry-mrd","cardio-oncology"],"targets":["cd33","flt3","kmt2a","menin"],"drugs":[],"companies":["childrens-oncology-group"],"institutions":["st-jude"],"pathways":["menin-kmt2a"],"terms":["late-effects","mrd","secondary-malignancy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-aaml0531-gemtuzumab-gamis-jco-2014","paper-aaml1031-sorafenib-flt3-pollard-jco-2022","paper-bolouri-paediatric-aml-genomics-nat-med-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Acute myeloid leukaemia is about one in five childhood leukaemias, a few hundred children a year in the United Kingdom and United States; cure rates have climbed from under a third in the 1970s to around two thirds through more intensive chemotherapy and better supportive care.","subtypes":["Core-binding-factor AML (RUNX1::RUNX1T1, CBFB::MYH11; low risk)","KMT2A-rearranged AML (about a fifth; partner-dependent risk; menin inhibitors)","FLT3-ITD AML (about 15 percent; sorafenib or gilteritinib added)","Infant AML with NUP98, CBFA2T3::GLIS2 or RBM15::MRTFA fusions (high risk)","Myeloid leukaemia of Down syndrome (GATA1-mutated; reduced-intensity chemotherapy)","Acute promyelocytic leukaemia in children (retinoic acid and arsenic as in adults)","Therapy-related and secondary AML in children"],"biomarkers":["Karyotype and FISH for recurrent fusions","RNA fusion panel (KMT2A, NUP98, CBFA2T3::GLIS2)","FLT3-ITD and allelic ratio","CD33 expression","Flow cytometry MRD after course 1 and course 2","GATA1 mutation in Down syndrome","Germline predisposition (GATA2, RUNX1, CEBPA)"],"standardOfCare":[{"setting":"Induction (two courses)","approach":"Cytarabine with daunorubicin or mitoxantrone and etoposide; gemtuzumab ozogamicin added to the first course for CD33-positive disease (AAML0531); MRD after course 1.","refs":["cytarabine","daunorubicin","mitoxantrone","etoposide","gemtuzumab-ozogamicin","aaml0531","flow-cytometry-mrd"],"guideline":{"version":"NCI PDQ: Childhood Acute Myeloid Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq"}},{"setting":"Consolidation (two or three courses)","approach":"High-dose cytarabine-based courses; no maintenance.","refs":["cytarabine","etoposide","mitoxantrone","gemtuzumab-ozogamicin"],"guideline":{"version":"NCI PDQ: Childhood Acute Myeloid Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq"}},{"setting":"FLT3-ITD","approach":"Sorafenib added to chemotherapy for high allelic ratio (AAML1031); gilteritinib in paediatric trials.","refs":["sorafenib","gilteritinib","flt3","aaml1031"],"guideline":{"version":"NCI PDQ: Childhood Acute Myeloid Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq"}},{"setting":"High-risk genetics or persistent residual disease","approach":"Allogeneic transplant in first remission.","refs":["allogeneic-hsct","flow-cytometry-mrd"],"guideline":{"version":"NCI PDQ: Childhood Acute Myeloid Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq"}},{"setting":"Relapsed or refractory","approach":"Fludarabine and cytarabine reinduction; revumenib for KMT2A-rearranged disease; gilteritinib for FLT3; venetoclax combinations in trials; transplant.","refs":["fludarabine","cytarabine","revumenib","augment-101","gilteritinib","venetoclax","allogeneic-hsct"],"guideline":{"version":"NCI PDQ: Childhood Acute Myeloid Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq"}},{"setting":"Supportive care and late effects","approach":"Dexrazoxane cardioprotection with anthracyclines, transfusion and antimicrobial support, cardio-oncology follow-up.","refs":["dexrazoxane","cardio-oncology","transfusion-support"],"guideline":{"version":"NCI PDQ: Childhood Acute Myeloid Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq"}}],"stateOfArt":["Gemtuzumab ozogamicin added to intensive chemotherapy lowered relapse in AAML0531 and is approved for children from one month of age.","Revumenib is the first targeted therapy approved for KMT2A-rearranged leukaemia, the commonest genetic subgroup in young children.","Flow cytometry residual disease after the first course, with genetics, decides who is transplanted in first remission."],"history":[{"year":1998,"title":"MRC AML10: four intensive courses without maintenance become the paediatric standard","refs":[]},{"year":2014,"title":"AAML0531: gemtuzumab ozogamicin lowers relapse in childhood AML","refs":["aaml0531","gemtuzumab-ozogamicin"]},{"year":2017,"title":"Gemtuzumab ozogamicin returns to the market after withdrawal in 2010","refs":["gemtuzumab-ozogamicin"]},{"year":2020,"title":"Gemtuzumab ozogamicin approved for newly diagnosed CD33-positive AML in children from one month","refs":["gemtuzumab-ozogamicin"]},{"year":2022,"title":"AAML1031: sorafenib improves event-free survival in high allelic ratio FLT3-ITD AML; bortezomib adds nothing","refs":["sorafenib","bortezomib"]},{"year":2024,"title":"Revumenib approved for relapsed KMT2A-rearranged acute leukaemia from the age of one","refs":["revumenib","augment-101"]}],"pipeline":["revumenib","gilteritinib","venetoclax","ziftomenib","menin-inhibitors","dexrazoxane","flow-cytometry-mrd","cpx-351"],"openProblems":["A third of children relapse and only half of those are cured.","Infant AML with NUP98 or CBFA2T3::GLIS2 fusions has no effective therapy.","Anthracycline cardiotoxicity and infection deaths from the most intensive chemotherapy given to children."],"parent":"aml"},{"id":"aml-older-unfit","kind":"cancer","name":"Acute myeloid leukaemia in older or unfit patients","aka":["Unfit AML","AML in the elderly","AML ineligible for intensive chemotherapy","Low-intensity AML therapy"],"tldr":"Most people with acute myeloid leukaemia are over 65, and many cannot take intensive chemotherapy. Venetoclax with azacitidine, two gentler drugs, doubled remission rates and lengthened life in this group, replacing the old choice between supportive care and low-dose chemotherapy.","summary":"Fitness for intensive induction is judged on age, performance status, organ function and comorbidity (the Ferrara criteria and geriatric assessment) rather than on a birthday. Older patients also carry worse biology: more adverse karyotypes, TP53 mutations and secondary disease, and fewer favourable NPM1 or core-binding-factor leukaemias. Until 2018 the options were azacitidine or decitabine alone, low-dose cytarabine or supportive care, with median survival under a year.\n\nVIALE-A, reported in 2020, randomised 431 newly diagnosed patients unfit for intensive therapy to venetoclax or placebo with azacitidine: composite complete remission 66.4 percent versus 28.3 percent, median overall survival 14.7 versus 9.6 months (hazard ratio 0.66), and 37.5 percent versus 16.7 percent alive at two years on longer follow-up. The benefit was largest in IDH-mutated and NPM1-mutated disease and smallest in TP53-mutated and FLT3-ITD disease. Venetoclax-azacitidine received full approval in 2020 and is the global standard; glasdegib with low-dose cytarabine is a lesser alternative, and ivosidenib-azacitidine competes in IDH1-mutated disease.\n\nThe regimen brings its own problems: prolonged neutropenia and infections, cycles that must be shortened or delayed, tumour lysis at the start, and azole antifungals that raise venetoclax levels. Current trials shorten the venetoclax course, add FLT3, IDH or menin inhibitors as triplets, take responders to reduced-intensity transplant, and test whether some fit older patients do better with venetoclax-azacitidine than with 7+3.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Acute_myeloid_leukemia","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Acute_myeloid_leukemia"},{"label":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}],"tags":["subtype-page"],"related":["aml-flt3","aml-idh","aml-npm1-kmt2a","aml-secondary"],"cancers":[],"sections":[],"technologies":["bcl2-inhibitors","geriatric-assessment","g8-geriatric-screening"],"targets":["bcl2"],"drugs":[],"companies":[],"institutions":[],"pathways":["apoptosis-bcl2"],"terms":["hma","tumor-lysis-syndrome","eln-risk"],"trials":["viale-a"],"people":[],"bottlenecks":[],"keyPapers":["paper-viale-a-venetoclax-azacitidine-nejm-2020","paper-agile-ivosidenib-azacitidine-nejm-2022","paper-aza-aml-001-dombret-blood-2015","paper-eln-2022-aml-dohner-blood-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"The median age at diagnosis of acute myeloid leukaemia is about 68, and roughly half of patients are judged unable to withstand intensive chemotherapy because of age, frailty or other illnesses.","subtypes":["Newly diagnosed AML unfit for intensive chemotherapy (age 75 or over, or comorbidity)","AML in fit older patients (60 to 75) eligible for intensive therapy or CPX-351","IDH- or NPM1-mutated AML in unfit patients (best responders to venetoclax-azacitidine)","TP53-mutated AML in unfit patients","Relapsed AML after venetoclax-azacitidine"],"biomarkers":["Performance status and geriatric assessment","Comorbidity index and organ function","ELN 2022 risk group","IDH1/2, NPM1, FLT3 and TP53 mutations","Measurable residual disease by flow cytometry","Azole co-medication (venetoclax dose)"],"standardOfCare":[{"setting":"Newly diagnosed, unfit for intensive chemotherapy","approach":"Venetoclax plus azacitidine (VIALE-A) or venetoclax plus decitabine; ivosidenib plus azacitidine for IDH1-mutated disease; targeted triplets in trials.","refs":["venetoclax","azacitidine","decitabine","viale-a","ivosidenib","agile","venetoclax-plus-hma"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Fit older patients, 60 to 75","approach":"7+3 or CPX-351 for secondary disease, with a FLT3 inhibitor where indicated, and reduced-intensity allogeneic transplant in remission.","refs":["cytarabine-7-3","cpx-351","midostaurin","quizartinib","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Not a candidate for any leukaemia-directed therapy","approach":"Hydroxyurea for count control, transfusion support and palliative care; low-dose cytarabine or glasdegib combinations where tolerated.","refs":["hydroxyurea","transfusion-support","glasdegib","cytarabine"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Relapse after venetoclax-azacitidine","approach":"Genotype-directed drugs (gilteritinib, IDH inhibitors, menin inhibitors) or trials; transplant for the few who respond.","refs":["gilteritinib","ivosidenib","revumenib","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}}],"stateOfArt":["Venetoclax with azacitidine is the worldwide standard for unfit newly diagnosed patients, giving remission to two in three.","Geriatric assessment, not age alone, decides fitness for intensive treatment.","Reduced-intensity transplant after low-intensity remission is extending cure to patients in their seventies."],"history":[{"year":2004,"title":"Azacitidine approved for myelodysplastic syndromes, then adopted for low-blast AML","refs":["azacitidine"]},{"year":2018,"title":"Venetoclax and glasdegib combinations gain accelerated approval for unfit AML","refs":["venetoclax","glasdegib"]},{"year":2020,"title":"VIALE-A: venetoclax plus azacitidine lengthens life; full approval","refs":["viale-a","venetoclax","azacitidine"]},{"year":2022,"title":"AGILE: ivosidenib plus azacitidine for unfit IDH1-mutated patients","refs":["agile","ivosidenib"]}],"pipeline":["venetoclax","idea-shortened-venetoclax","myelomatch","g8-geriatric-screening","geriatric-assessment"],"openProblems":["How long venetoclax needs to be given, and whether MRD-negative patients can stop.","Whether fit older patients do better with venetoclax-azacitidine than with intensive chemotherapy.","Infections and cytopenias that keep older patients in hospital during a treatment meant to be gentle."],"parent":"aml"},{"id":"apl","kind":"cancer","name":"Acute promyelocytic leukaemia","aka":["APL","AML-M3","PML::RARA acute leukaemia","Promyelocytic leukaemia"],"tldr":"Acute promyelocytic leukaemia is caused by a single fused gene that freezes blood cells at an immature stage and triggers dangerous bleeding. Two non-chemotherapy drugs, a vitamin A derivative and arsenic trioxide, make the cells mature and cure more than nine in ten patients.","summary":"The t(15;17) translocation fuses PML to the retinoic acid receptor alpha gene. The PML::RARA protein blocks differentiation at the promyelocyte stage, and the promyelocytes release procoagulants that cause a bleeding and clotting disorder responsible for most early deaths. Diagnosis is a clinical emergency: all-trans retinoic acid (ATRA) is started on suspicion, before the fusion is confirmed, together with aggressive platelet and fibrinogen replacement. Risk is set by the white count at presentation, above 10 x 10^9/L being high risk.\n\nATRA, introduced in Shanghai in 1988, was the first differentiation therapy for any cancer; with anthracycline chemotherapy it lifted cure rates above 70 percent. Arsenic trioxide, developed in Harbin and Shanghai in the 1990s and approved in the United States for relapsed disease in 2000, degrades the fusion protein itself. The Italian-German APL0406 trial, reported in 2013, randomised low- and intermediate-risk patients to ATRA plus arsenic or ATRA plus chemotherapy: two-year event-free survival 97 percent versus 86 percent, with fewer infections and no secondary leukaemias, and the chemotherapy-free regimen became the standard, approved for first-line use in Europe in 2016 and the United States in 2018. High-risk patients receive ATRA and arsenic with an anthracycline or gemtuzumab ozogamicin added for the first weeks.\n\nDifferentiation syndrome, fever, fluid retention and lung infiltrates as the cells mature, affects around a quarter of patients and is treated with dexamethasone; QT prolongation and liver toxicity are watched on arsenic. Molecular monitoring for PML::RARA after consolidation catches the rare relapse, which is treated with arsenic-based regimens and autologous transplant. The remaining deaths are early haemorrhagic deaths before treatment starts, so the research target is recognition and access rather than a new drug.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Acute_promyelocytic_leukemia","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Acute_promyelocytic_leukemia"},{"label":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}],"tags":["subtype-page"],"related":["aml-paediatric","aml-secondary","aml-npm1-kmt2a"],"cancers":[],"sections":[],"technologies":["cytogenetics-fish","transfusion-support"],"targets":["rara"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["differentiation-syndrome","mrd"],"trials":["apl0406"],"people":[],"bottlenecks":[],"keyPapers":["paper-apl0406-lo-coco-nejm-2013","paper-tallman-atra-apl-nejm-1997","paper-eln-apl-sanz-blood-2019"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About one in ten cases of acute myeloid leukaemia; once the most rapidly fatal, it is now the most curable, with more than nine in ten patients cured when early bleeding is prevented.","subtypes":["Low- and intermediate-risk APL (white count 10 x 10^9/L or below)","High-risk APL (white count above 10 x 10^9/L)","Variant APL with RARA fusions other than PML (ZBTB16, NPM1, STAT5B; some resist arsenic or ATRA)","Therapy-related APL"],"biomarkers":["PML::RARA fusion by PCR or FISH","t(15;17) karyotype","White cell count at presentation (Sanz risk)","Fibrinogen, D-dimer and platelet count","PML::RARA transcript MRD after consolidation","FLT3-ITD (common in the microgranular variant)"],"standardOfCare":[{"setting":"Suspected APL, first hours","approach":"Start all-trans retinoic acid on morphological suspicion; transfuse platelets and fibrinogen to targets; avoid invasive procedures until coagulopathy is controlled.","refs":["tretinoin-atra","transfusion-support"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Low- and intermediate-risk","approach":"All-trans retinoic acid plus arsenic trioxide induction and consolidation without chemotherapy (APL0406); dexamethasone prophylaxis or treatment for differentiation syndrome.","refs":["tretinoin-atra","arsenic-trioxide","dexamethasone"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"High-risk","approach":"All-trans retinoic acid plus arsenic trioxide with idarubicin or gemtuzumab ozogamicin added during induction to control the white count.","refs":["tretinoin-atra","arsenic-trioxide","idarubicin","gemtuzumab-ozogamicin"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Molecular relapse","approach":"Arsenic-based salvage to molecular remission, then autologous transplant if PML::RARA negative, allogeneic transplant if not.","refs":["arsenic-trioxide","autologous-stem-cell-transplant","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}}],"stateOfArt":["A chemotherapy-free regimen of all-trans retinoic acid and arsenic trioxide cures more than nine in ten patients with standard-risk disease.","Early death from bleeding, before or during the first days of treatment, is now the main cause of failure.","Oral arsenic formulations are replacing intravenous arsenic in China and in trials elsewhere."],"history":[{"year":1957,"title":"Hillestad describes acute promyelocytic leukaemia","refs":[]},{"year":1977,"title":"t(15;17) translocation identified","refs":["cytogenetics"]},{"year":1988,"title":"All-trans retinoic acid produces remissions in Shanghai: the first differentiation therapy","refs":["tretinoin-atra"]},{"year":2000,"title":"Arsenic trioxide approved for relapsed APL","refs":["arsenic-trioxide"]},{"year":2013,"title":"APL0406: retinoic acid plus arsenic beats retinoic acid plus chemotherapy","refs":["tretinoin-atra","arsenic-trioxide"]},{"year":2018,"title":"Arsenic trioxide approved for first-line standard-risk APL in the United States","refs":["arsenic-trioxide"]}],"pipeline":["arsenic-trioxide","tretinoin-atra"],"openProblems":["Early haemorrhagic death before treatment starts, especially where diagnosis is slow.","Treatment of variant RARA fusions that do not respond to arsenic or retinoic acid.","Whether high-risk patients can also be spared chemotherapy."],"parent":"aml"},{"id":"adamantinoma","kind":"cancer","name":"Adamantinoma of bone","aka":["Adamantinoma of the long bones","Adamantinoma of the tibia","Osteofibrous dysplasia-like adamantinoma"],"tldr":"Adamantinoma is a very rare, slow-growing bone cancer of young adults that almost always affects the shin bone, made of epithelial cells inside fibrous bone, and listed with the bone sarcomas in the WHO classification. It is cured by cutting it out with a margin; chemotherapy and radiotherapy do not work, and a minority spread to the lungs many years later.","summary":"Adamantinoma is a low-grade malignant biphasic bone tumour of epithelial cells in an osteofibrous stroma, classified with the bone tumours of uncertain differentiation in the WHO soft tissue and bone classification; the classic form is distinguished from osteofibrous dysplasia-like (differentiated) adamantinoma, which occurs in children and rarely metastasises (Orthopedics 2007). In 46 consecutive patients followed for a mean of 16 years, the tibia was the commonest site (31), patients presented with pain and swelling at a mean age of 24, 37 had limb-salvage surgery, 39 percent needed reoperation, and ten-year disease-specific and recurrence-free survival were 92 and 72 percent, with three recurrences more than 15 years after treatment (Journal of Surgical Oncology 2018).\n\nHow it differs from its parent: the sarcoma page covers the mesenchymal cancers of bone and soft tissue; adamantinoma is epithelial in lineage, indolent, radiologically distinctive (a multilocular lytic lesion of the anterior tibial cortex) and insensitive to the chemotherapy used for osteosarcoma and Ewing sarcoma.\n\nHow common: no registry figure; under 1 percent of primary bone tumours in the older literature the review cites (Orthopedics 2007).\n\nTreatment: wide en bloc resection with reconstruction, or amputation where resection is impossible; no role for chemotherapy or radiotherapy; lifelong follow-up because recurrence and lung metastasis can occur decades later (Journal of Surgical Oncology 2018; Orthopedics 2007).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Adamantinoma","links":[{"label":"NCI PDQ: rare cancers of childhood","url":"https://www.cancer.gov/types/childhood-cancers/patient/rare-childhood-cancers-pdq"},{"label":"Journal of Surgical Oncology 2018: adamantinoma of bone, long-term follow-up of 46 consecutive patients","url":"https://doi.org/10.1002/jso.25269"},{"label":"Orthopedics 2007: clinicopathological features, diagnosis and treatment of adamantinoma of the long bones","url":"https://doi.org/10.3928/01477447-20070301-04"}],"tags":["subtype-page","wave4","rare"],"related":["sarcoma","chordoma","osteosarcoma","ewing-sarcoma","optic-pathway-glioma","conjunctival-melanoma","desmoplastic-small-round-cell-tumour"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"Very rare: a single institution saw 46 histologically confirmed cases between 1939 and 2012, 31 of them in the tibia, mean age 24 (Journal of Surgical Oncology 2018). No registry figure exists.","subtypes":["Classic adamantinoma of the long bones (tibia; young adults)","Osteofibrous dysplasia-like (differentiated) adamantinoma of bone (children; rarely metastatic)","Dedifferentiated adamantinoma (very rare)"],"biomarkers":["Cytokeratin-positive epithelial nests in fibro-osseous stroma","Anterior tibial cortical location on imaging","Margin status after resection"],"standardOfCare":[{"setting":"All cases","approach":"Wide en bloc resection with reconstruction; no chemotherapy or radiotherapy; decades of follow-up for late recurrence and lung metastasis.","refs":["sarcoma"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"sarcoma"},{"id":"lung-adenocarcinoma-in-situ-and-minimally-invasive","kind":"cancer","name":"Adenocarcinoma in situ and minimally invasive adenocarcinoma of the lung","aka":["Adenocarcinoma in situ of the lung","AIS","Minimally invasive adenocarcinoma","MIA","Lepidic adenocarcinoma, preinvasive","Bronchioloalveolar carcinoma (term retired in 2011)","Ground-glass nodule adenocarcinoma"],"tldr":"Adenocarcinoma in situ and minimally invasive adenocarcinoma are the earliest forms of lung cancer of the adenocarcinoma type: small tumours, usually seen as ground-glass spots on a CT scan, that have not yet invaded, or have invaded less than five millimetres. When removed they are effectively cured, with no recurrences in the large series, so the question is how little surgery is enough.","summary":"The IASLC/ATS/ERS classification introduced adenocarcinoma in situ (a solitary adenocarcinoma of 3 cm or less with pure lepidic growth along intact alveolar walls) and minimally invasive adenocarcinoma (the same with an invasive component of 5 mm or less) in place of the term bronchioloalveolar carcinoma, and the WHO classifications of 2015 and 2021 keep both entities and stage them by invasive size only (Travis 2011; Nicholson 2022). They present as ground-glass or part-solid nodules on CT.\n\nHow it differs from its parent: outcome. In 1,038 stage I adenocarcinomas, none of the 36 patients with adenocarcinoma in situ or minimally invasive adenocarcinoma recurred, lepidic predominant invasive tumours had a five-year cumulative recurrence of 8 percent, and non-lepidic tumours 19 percent (Kadota 2014). In 524 resected cases in Japan (65 percent women, 64 percent never-smokers, mean tumour diameter 15.2 mm, 44 percent treated by sublobar resection) there was no recurrence over a median follow-up of 100 months, and the clinical problem was second primary lung cancers rather than relapse (Yotsukura 2021).\n\nHow common: about 11 percent of lung cancers coming to resection in the Japanese series (Yotsukura 2021); a growing share where CT screening is used.\n\nTreatment: surgical removal, increasingly by sublobar resection (wedge or segmentectomy) rather than lobectomy, with no adjuvant therapy; the parent's resectable page holds the trials of sublobar surgery for small peripheral tumours (CALGB 140503, JCOG0802). Small pure ground-glass nodules are often watched on CT before any surgery.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Adenocarcinoma_of_the_lung","links":[{"label":"Travis 2011, JTO: IASLC/ATS/ERS international multidisciplinary classification of lung adenocarcinoma","url":"https://doi.org/10.1097/jto.0b013e318206a221"},{"label":"Nicholson 2022, JTO: the 2021 WHO classification of lung tumours","url":"https://doi.org/10.1016/j.jtho.2021.11.003"},{"label":"Kadota 2014, Am J Surg Pathol: prognosis of adenocarcinoma in situ, minimally invasive and lepidic predominant adenocarcinoma in 1,038 stage I cases","url":"https://doi.org/10.1097/pas.0000000000000134"},{"label":"Yotsukura 2021, JTO: long-term prognosis of 524 resected adenocarcinoma in situ and minimally invasive adenocarcinoma","url":"https://doi.org/10.1016/j.jtho.2021.04.007"}],"tags":["subtype-page","wave4","lung"],"related":["nsclc","lung-adenocarcinoma","resectable-nsclc","invasive-mucinous-adenocarcinoma-lung"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["lobectomy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"Of 1,038 resected stage I adenocarcinomas at Memorial Sloan Kettering, 2 were adenocarcinoma in situ and 34 minimally invasive (Kadota 2014); of 4,768 lung cancer resections in Japan between 1998 and 2010, 524 (11 percent) were one or the other (Yotsukura 2021).","subtypes":["Adenocarcinoma in situ, non-mucinous (pure lepidic, 3 cm or less)","Minimally invasive adenocarcinoma, non-mucinous (invasion 5 mm or less)","Mucinous adenocarcinoma in situ and minimally invasive adenocarcinoma (rare)","Lepidic predominant invasive adenocarcinoma (over 5 mm invasion; not preinvasive)"],"biomarkers":["Invasive size on the resection specimen (5 mm threshold)","Ground-glass and solid components on CT","EGFR mutation (common in lepidic tumours; not treated at this stage)"],"standardOfCare":[{"setting":"All cases","approach":"Surgical resection, sublobar where the tumour is small and peripheral, with no adjuvant therapy; the parent's resectable page holds the sublobar-surgery trials.","refs":["resectable-nsclc","lobectomy"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"nsclc"},{"id":"lung-adenocarcinoma","kind":"cancer","name":"Adenocarcinoma of the lung","aka":["Lung adenocarcinoma","Pulmonary adenocarcinoma","Adenocarcinoma","Adenocarcinoma (~50%)","Non-squamous non-small-cell lung cancer (in trial entry criteria)","Bronchioloalveolar carcinoma (term retired in 2011)"],"tldr":"Lung adenocarcinoma is the most common type of lung cancer and the form that non-smokers usually get; it starts in the mucus-making gland cells of the small airways, most often at the edge of the lung. It is the type in which testing for a driver mutation matters most, because half of cases have one that a tablet can target.","summary":"Adenocarcinoma is defined by glandular differentiation or mucin production, or by expression of the pneumocyte markers TTF-1 and napsin A in a poorly differentiated tumour. The IASLC/ATS/ERS classification of 2011, carried into the WHO classifications of 2015 and 2021, retired the terms bronchioloalveolar carcinoma and mixed subtype, introduced adenocarcinoma in situ and minimally invasive adenocarcinoma for small lepidic tumours, and classifies invasive tumours by predominant pattern (lepidic, acinar, papillary, micropapillary, solid) after recording the percentage of each; the 2021 edition adds a formal grading system built from those patterns, counts only the invasive component for T size, and recognises spread through air spaces as a prognostic feature (Travis 2011; Nicholson 2022). Invasive mucinous adenocarcinoma has its own page.\n\nHow it differs from its parent: the non-small-cell lung cancer page and its driver subpages describe treatment by mutation; this page is the histology in which those mutations concentrate. In 2,142 adenocarcinomas at Memorial Sloan Kettering, EGFR exon 19 deletions and L858R were found in 15 percent of tumours from former smokers and 6 percent from current smokers, with higher rates in never-smokers (NCI PDQ). The corpus's EGFR, ALK, ROS1, RET, MET, HER2, NTRK and KRAS G12C pages are, in practice, pages about adenocarcinoma.\n\nHow common: about 40 percent of lung cancers (NCI PDQ), against 25 percent squamous and 10 percent large cell.\n\nTreatment follows the parent's pathway with two histology-specific points: pemetrexed and bevacizumab are used in non-squamous disease only, and every advanced adenocarcinoma is tested for the drivers listed above before first-line therapy. For driver-negative metastatic disease the standard is pembrolizumab with platinum and pemetrexed (KEYNOTE-189: median overall survival 22.0 against 10.7 months with chemotherapy alone, hazard ratio 0.56 in the 2020 update of the trial linked here). The TROP2 antibody-drug conjugate datopotamab deruxtecan improved progression-free survival over docetaxel in non-squamous but not squamous disease (TROPION-Lung01), and nintedanib with docetaxel is licensed in the EU for second-line adenocarcinoma.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Adenocarcinoma_of_the_lung","links":[{"label":"NCI PDQ (health professional): non-small cell lung cancer treatment, histological shares","url":"https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq"},{"label":"Cancer Research UK: types of lung cancer","url":"https://www.cancerresearchuk.org/about-cancer/lung-cancer/stages-types/types"},{"label":"Nicholson 2022, JTO: the 2021 WHO classification of lung tumours","url":"https://doi.org/10.1016/j.jtho.2021.11.003"},{"label":"Travis 2011, JTO: IASLC/ATS/ERS international multidisciplinary classification of lung adenocarcinoma","url":"https://doi.org/10.1097/jto.0b013e318206a221"},{"label":"KEYNOTE-189 (Gandhi 2018, NEJM): pembrolizumab plus chemotherapy in metastatic non-squamous NSCLC","url":"https://doi.org/10.1056/nejmoa1801005"},{"label":"Lancet Respir Med 2025: estimated worldwide variation and trends in incidence of lung cancer by histological subtype in 2022 and over time (GLOBOCAN 2022 with Cancer Incidence in Five Continents)","url":"https://doi.org/10.1016/s2213-2600(24)00428-4"},{"label":"Nicholson, J Thorac Oncol 2022: the 2021 WHO classification of lung tumours, impact of advances since 2015","url":"https://doi.org/10.1016/j.jtho.2021.11.003"}],"tags":["subtype-page","wave4","lung"],"related":["nsclc","lung-squamous-cell-carcinoma","large-cell-lung-carcinoma","invasive-mucinous-adenocarcinoma-lung","lung-adenocarcinoma-in-situ-and-minimally-invasive","egfr-mutant-nsclc","kras-g12c-nsclc"],"cancers":[],"sections":[],"technologies":[],"targets":["egfr","kras","met","trop2"],"drugs":["pemetrexed","bevacizumab","pembrolizumab","nintedanib","docetaxel"],"companies":[],"institutions":[],"pathways":[],"terms":["ttf1-p40","spread-through-air-spaces","never-smoker-lung-cancer","pulmonary-nodule"],"trials":["tropion-lung01","keynote-042"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["How common it is, worldwide and by sex. Of 1,572,045 lung cancers in men in 2022, 717,211 (45.6 percent) were adenocarcinoma; of 908,630 in women, 541,971 (59.7 percent). The highest age-standardised rates are in east Asia in both sexes, 27.12 per 100,000 men and 19.04 per 100,000 women. An estimated 114,486 male and 80,378 female adenocarcinomas worldwide in 2022 were attributable to ambient particulate matter pollution, at rates of 2.35 and 1.46 per 100,000 (Lancet Respiratory Medicine 2025).","What the 2021 WHO classification changed about reporting it. Invasive non-mucinous adenocarcinomas are graded by the percentage of each histological growth pattern; only the invasive component counts towards the T size in part-lepidic tumours; and spread through air spaces is recognised as a prognostic feature. The two-stain panel of TTF-1 and p40 assigns the type on small samples, which is where most of these tumours are diagnosed (Nicholson 2022)."],"group":"lung","burden":"About 40 percent of all lung cancers, the commonest histological type in many countries (NCI PDQ); Cancer Research UK also lists it as the most common type. GLOBOCAN counts it within the 2,480,675 lung cancers of 2022.","subtypes":["Lepidic predominant adenocarcinoma","Acinar predominant adenocarcinoma","Papillary predominant adenocarcinoma","Micropapillary predominant adenocarcinoma (pattern with shorter survival)","Solid predominant adenocarcinoma","Invasive mucinous adenocarcinoma (own page)","Colloid, fetal and enteric-type adenocarcinoma (rare variants)","Adenocarcinoma in situ and minimally invasive adenocarcinoma (own page)"],"biomarkers":["TTF-1 and napsin A on immunohistochemistry","EGFR, ALK, ROS1, BRAF, MET exon 14, RET, KRAS G12C, HER2 and NTRK testing before first-line therapy","PD-L1 tumour proportion score","Predominant pattern and WHO 2021 grade; spread through air spaces"],"standardOfCare":[{"setting":"Advanced, driver-negative","approach":"Pembrolizumab with platinum and pemetrexed (KEYNOTE-189), or the parent's PD-L1-high pathway when the score is 50 percent or more; datopotamab deruxtecan after chemotherapy (TROPION-Lung01).","refs":["pembrolizumab","pemetrexed","carboplatin","cisplatin","tropion-lung01","pdl1-high-nsclc"]},{"setting":"Advanced with a driver","approach":"Treated on the parent's driver pages (EGFR, ALK, ROS1, RET, MET, KRAS G12C, HER2, NTRK, BRAF).","refs":["nsclc","egfr-mutant-nsclc","alk-positive-nsclc","kras-g12c-nsclc","met-altered-nsclc"]},{"setting":"Early stage","approach":"Treated as the parent's resectable and stage III pages describe; histology does not change the surgery.","refs":["resectable-nsclc","stage-iii-unresectable-nsclc","lobectomy"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"nsclc"},{"id":"urethral-adenocarcinoma","kind":"cancer","name":"Adenocarcinoma of the urethra (including clear cell adenocarcinoma)","aka":["Urethral adenocarcinoma","Clear cell adenocarcinoma of the urethra","Adenocarcinoma (including clear cell adenocarcinoma of the female urethra)","Skene gland adenocarcinoma","Urethral diverticulum carcinoma"],"tldr":"Adenocarcinoma of the urethra is a gland-forming type of urethral cancer, more often seen in women, that can start in the small glands beside the urethra or in a pouch (diverticulum) in its wall. The clear cell form is its own entity in the WHO classification. No trial has been run in it, so it is treated by surgery at a specialist urological centre, advanced disease as on the parent page.","summary":"Adenocarcinoma of the urethra arises from the periurethral (Skene and Littre) glands or from glandular metaplasia of the urethral lining, and the WHO classification of urinary and male genital tumours separates clear cell adenocarcinoma as a distinct entity. In the defining pathology series of 19 clear cell adenocarcinomas of the urethra, 18 patients were women and one a man, aged 35 to 80 (average 58); 12 tumours, all in women, arose within a urethral diverticulum, and the tumours showed the tubulocystic, papillary and diffuse patterns with hobnail and clear cells that characterise the type (Oliva and Young 1996). The main diagnostic pitfall is nephrogenic adenoma, a benign lesion that shares clear cells and tubules (Young and Scully 1985).\n\nHow it differs from its parent: it is the histology in which women predominate, in which a urethral diverticulum is a recognised site of origin, and in which the parent's bladder-cancer and anal-cancer treatment analogies fit least well because neither urothelial chemotherapy nor squamous chemoradiation has been tested in it. Clear cell adenocarcinoma is morphologically the same tumour that occurs in the vagina and cervix, which the corpus covers on the vaginal adenocarcinoma page.\n\nHow common: no incidence figure for the type alone is published; the parent page's fewer than one case per million a year covers all urethral cancer.\n\nTreatment follows the EAU guideline for the parent: complete surgical excision, from diverticulectomy with a margin for small tumours to anterior exenteration for advanced disease, with radiotherapy for positive margins; systemic therapy has no evidence base of its own and is chosen case by case, which in practice means a specialist urological cancer centre, tumour profiling for a tumour-agnostic option, and a search for open trials (EAU Guidelines: primary urethral carcinoma; NCI PDQ).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Urethral_cancer","links":[{"label":"NCI PDQ: urethral cancer treatment","url":"https://www.cancer.gov/types/urethral/patient/urethral-treatment-pdq"},{"label":"EAU Guidelines: primary urethral carcinoma","url":"https://uroweb.org/guidelines/primary-urethral-carcinoma"},{"label":"Gakis 2016, World J Urol: international collaboration on primary urethral carcinoma, 154 patients","url":"https://doi.org/10.1007/s00345-015-1583-7"},{"label":"Oliva and Young 1996, Modern Pathology: clear cell adenocarcinoma of the urethra, 19 cases (PMID 8733766)","url":"https://europepmc.org/article/MED/8733766"},{"label":"Young and Scully 1985, Am J Surg Pathol: clear cell adenocarcinoma of the bladder and urethra","url":"https://doi.org/10.1097/00000478-198511000-00005"}],"tags":["subtype-page","wave4","rare"],"related":["urethral","urethral-urothelial-carcinoma","urethral-squamous-cell-carcinoma","vaginal-adenocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Adenocarcinoma was 17 of 154 patients (11 percent) in the international collaboration's series (Gakis 2016). Clear cell adenocarcinoma is rarer still: the largest pathology series holds 19 cases, 18 of them in women (Oliva and Young 1996).","subtypes":["Clear cell adenocarcinoma of the urethra (women; often in a urethral diverticulum)","Adenocarcinoma of Skene or Littre gland origin","Enteric-type (columnar or mucinous) adenocarcinoma of the urethra"],"biomarkers":["Histological pattern (tubulocystic, papillary, diffuse) and distinction from nephrogenic adenoma","Association with a urethral diverticulum","Margin status after excision"],"standardOfCare":[{"setting":"All stages","approach":"Treated as the parent page describes: complete surgical excision, radiotherapy for positive margins, and case-by-case systemic therapy in the absence of trials.","refs":["urethral"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"urethral"},{"id":"adenoid-cystic-carcinoma","kind":"cancer","name":"Adenoid cystic carcinoma","aka":["ACC","Cylindroma (historical)","Adenoid cystic carcinoma of the salivary glands"],"tldr":"Adenoid cystic carcinoma is a slow-growing cancer of the salivary glands that spreads along nerves and can come back years after treatment, often in the lungs. Surgery with radiotherapy is the treatment that cures it, chemotherapy has little effect, and the tablets lenvatinib and axitinib can hold spreading disease still for months rather than shrink it.","summary":"Adenoid cystic carcinoma arises in the minor salivary glands of the palate and sinonasal tract, the submandibular gland and the parotid, and occasionally in the lacrimal gland, trachea or breast. It is defined by a MYB-NFIB (or MYBL1) fusion in most cases, grows in cribriform, tubular or solid patterns, and invades nerves, so facial numbness or pain is a common first symptom. A subset with activating NOTCH1 mutations and solid histology behaves aggressively and spreads to bone and liver; the rest progress slowly, with lung metastases that may be watched for years.\n\nCure depends on surgery with the widest margins the anatomy allows, often sacrificing nerves, followed by radiotherapy, which reduces local recurrence but cannot be shown to improve survival in a disease that recurs so late. Unresectable tumours are treated with radiotherapy alone, and heavy-particle therapy has a particular place: the Heidelberg COSMIC trial of intensity-modulated radiotherapy with a carbon-ion boost and the older fast-neutron series reported better local control than photons, and proton and carbon-ion therapy are offered where available.\n\nCytotoxic chemotherapy rarely produces responses. Multikinase inhibitors that block VEGF receptors are the drugs with evidence: lenvatinib produced responses in 15.6 percent of 32 patients with median progression-free survival of 17.5 months in a Memorial Sloan Kettering phase 2, and a randomised phase 2 of axitinib against observation in progressive disease found median progression-free survival of 10.8 against 2.8 months, so both appear in the NCCN guideline for progressive disease while indolent metastases are observed. Immune checkpoint inhibitors have little activity; NOTCH inhibitors gave modest responses in NOTCH1-mutant disease; and the MYB messenger RNA degrader REM-422 and the drug HG146 are in early trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Adenoid_cystic_carcinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Adenoid_cystic_carcinoma"}],"tags":["subtype-page","head-and-neck"],"related":["mucoepidermoid-carcinoma","salivary-duct-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-tchekmedyian-lenvatinib-adenoid-cystic-jco-2019","paper-persson-myb-nfib-pnas-2009","paper-laurie-licitra-salivary-systemic-jco-2006"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"Rare, but the second commonest salivary gland malignancy; it grows slowly along nerves, can recur years after treatment and can spread to the lungs, which is why follow-up runs well past the usual five years and why five-year survival overstates the long-term picture.","subtypes":["Cribriform and tubular pattern (classical, indolent)","Solid pattern or high-grade transformation (aggressive)","NOTCH1-mutant adenoid cystic carcinoma (bone and liver spread, shorter survival)","MYB-NFIB or MYBL1 fusion-positive disease (the majority)","Adenoid cystic carcinoma of the minor salivary glands, palate and sinonasal tract","Adenoid cystic carcinoma outside the head and neck (lacrimal gland, trachea, breast)"],"biomarkers":["MYB immunohistochemistry or MYB-NFIB fusion by FISH or sequencing","NOTCH1 mutation (aggressive subset, NOTCH inhibitor trials)","Perineural invasion and margin status","Solid component and grade","Ki-67","PD-L1 (usually absent)"],"standardOfCare":[{"setting":"Localised, resectable","approach":"Wide resection including involved nerves where needed, with neck dissection for node-positive disease, followed by postoperative radiotherapy to the bed and nerve pathways.","refs":["imrt-igrt","proton-therapy"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Unresectable or inoperable","approach":"Definitive radiotherapy; carbon-ion or proton therapy where available (COSMIC, Heidelberg; fast-neutron series).","refs":["carbon-ion","proton-therapy","imrt-igrt"],"guideline":{"version":"ESMO salivary gland cancer guideline 2022","url":"https://doi.org/10.1016/j.annonc.2022.04.011"}},{"setting":"Slow-growing metastatic disease","approach":"Observation with scans every few months; stereotactic radiotherapy or resection for isolated symptomatic metastases.","refs":["sbrt"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Progressive metastatic disease","approach":"Lenvatinib or axitinib (phase 2 evidence); clinical trials preferred.","refs":["lenvatinib","axitinib","kinase-inhibitors"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Chemotherapy","approach":"Cisplatin with doxorubicin and cyclophosphamide, or single agents, for symptomatic disease after kinase inhibitors; responses are uncommon.","refs":["cisplatin","doxorubicin","cyclophosphamide"],"guideline":{"nccn":"Category 2B","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Trials","approach":"MYB-directed REM-422, HG146 and NOTCH inhibitors for NOTCH1-mutant disease.","refs":["rem-422","nct06118086","nct06781567"]}],"stateOfArt":["Surgery and radiotherapy cure a minority; most patients live with slowly growing metastases for years.","Lenvatinib and axitinib are the first drugs with randomised or reproducible phase 2 evidence of delaying progression.","MYB and NOTCH1 biology has produced the first rational targets and the first trials designed for this disease alone."],"history":[{"year":1859,"title":"Billroth describes the tumour as cylindroma","refs":[]},{"year":2009,"title":"MYB-NFIB fusion identified as the defining genetic event","refs":[]},{"year":2013,"title":"Genomic landscape shows NOTCH1 and chromatin-remodelling mutations","refs":[]},{"year":2019,"title":"Lenvatinib phase 2: median progression-free survival 17.5 months","refs":["lenvatinib"]},{"year":2022,"title":"Randomised phase 2: axitinib delays progression versus observation","refs":["axitinib"]}],"pipeline":["rem-422","nct06118086","nct06781567","lenvatinib","axitinib","carbon-ion"],"openProblems":["No drug shrinks the disease reliably; kinase inhibitors only slow it.","When to start treatment for indolent lung metastases.","Trials are small because the disease is rare and slow.","Perineural spread makes clear margins impossible at the skull base."],"parent":"salivary-gland"},{"id":"adenoid-cystic-carcinoma-breast","kind":"cancer","name":"Adenoid cystic carcinoma of the breast","aka":["Breast adenoid cystic carcinoma","Breast-ACC","Classic adenoid cystic carcinoma of the breast","Solid-basaloid adenoid cystic carcinoma"],"tldr":"Adenoid cystic carcinoma of the breast is a very rare breast cancer that is triple-negative on testing but behaves almost the opposite of usual triple-negative disease: it seldom reaches the lymph nodes, and nearly everyone is alive at ten years. It is the same tumour type as adenoid cystic carcinoma of the salivary glands and shares its gene fusion.","summary":"Adenoid cystic carcinoma of the breast is a special type of basal-like carcinoma with a cribriform, tubular or solid pattern of epithelial and myoepithelial cells. In SEER (1977 to 2006) 338 women were diagnosed, an incidence of 0.92 per million person-years, constant over 30 years; 95 percent presented with localised disease, the highest rates were in ER- and PR-negative tumours, age-specific rates rose until midlife and plateaued as for other ER-negative tumours, and relative survival was 98.1 percent at five years, 94.9 percent at ten and 91.4 percent at fifteen, with no excess of other cancers before or after (Ghabach 2010). The t(6;9) translocation fusing MYB to NFIB is a hallmark of adenoid cystic carcinoma of both breast and head and neck, deleting the microRNA target sites that normally repress MYB (Persson 2009). The European Working Group for Breast Screening Pathology lists classical adenoid cystic carcinoma first among the triple-negative special types with indolent behaviour whose patients are unlikely to benefit from chemotherapy, while noting that the solid-basaloid variant behaves more aggressively (Cserni 2021; Thomas 2023). Its 15-year survival above 90 percent is the clearest illustration that triple-negative is a laboratory category, not a prognosis.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Adenoid_cystic_carcinoma","links":[{"label":"Ghabach, Breast Cancer Res 2010: adenoid cystic carcinoma of the breast in the United States 1977 to 2006 (SEER)","url":"https://doi.org/10.1186/bcr2613"},{"label":"Persson, PNAS 2009: recurrent MYB-NFIB fusion in adenoid cystic carcinomas of the breast and head and neck","url":"https://doi.org/10.1073/pnas.0909114106"},{"label":"Cserni, Cancers 2021: triple-negative breast cancer histological subtypes with a favourable prognosis (European Working Group for Breast Screening Pathology)","url":"https://doi.org/10.3390/cancers13225694"},{"label":"Thomas, NPJ Breast Cancer 2023: rare subtypes of triple-negative breast cancer","url":"https://doi.org/10.1038/s41523-023-00554-x"}],"tags":["breast","tnbc","subtype-page"],"related":["tnbc","adenoid-cystic-carcinoma","secretory-carcinoma-breast"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["basal-like","tumour-grade"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"0.92 cases per million women a year in the United States: 338 women in SEER between 1977 and 2006, 95 percent localised at diagnosis, with rates 39 percent lower in Black than White women (Ghabach 2010).","subtypes":["Classic adenoid cystic carcinoma (cribriform and tubular; basal-like immunophenotype, indolent)","Solid-basaloid adenoid cystic carcinoma (higher grade, more aggressive)","Adenoid cystic carcinoma with high-grade transformation"],"biomarkers":["Triple-negative receptor status with low grade","MYB-NFIB fusion or MYB overexpression","Myoepithelial markers (p63, CD117) on the basaloid component"],"standardOfCare":[{"setting":"Localised disease","approach":"Surgery with clear margins, radiotherapy after breast conservation, and no chemotherapy for the classical type in the European working group consensus; the solid-basaloid variant is managed as high-grade triple-negative disease.","refs":["lumpectomy","mastectomy","sentinel-node"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"tnbc"},{"id":"colorectal-adenoma-like-adenocarcinoma","kind":"cancer","name":"Adenoma-like adenocarcinoma of the colon and rectum","aka":["Adenoma-like adenocarcinoma of the colon and rectum (invasive cancer that looks like an adenoma on biopsy; better outlook)","Adenoma-like colorectal adenocarcinoma","Villous adenoma-like adenocarcinoma","Invasive papillary adenocarcinoma of the colon"],"tldr":"Adenoma-like adenocarcinoma is a form of bowel cancer whose invasive part still looks like a harmless polyp under the microscope, which is why it is often reported as an adenoma on biopsy and only recognised once the bowel is removed. Despite frequently growing deep into the bowel wall, it spreads to lymph nodes less often than ordinary bowel cancer and does better.","summary":"What it is. The fifth edition of the World Health Organization classification of digestive tumours added adenoma-like adenocarcinoma as a subtype of colorectal adenocarcinoma (Nagtegaal 2020). The invasive component keeps the low-grade villous or tubulovillous architecture and cytology of an adenoma, with pushing rather than infiltrative invasion and little or no desmoplastic stroma, so material taken at endoscopy does not look malignant.\n\nHow it differs from its parent. In a series of 35 such carcinomas, 43 percent had been reported as an adenoma on the preceding biopsy and 60 percent of the resections showed no residual conventional adenoma; despite an advanced T category in 66 percent, only 20 percent had nodal metastases and 15 percent developed distant metastases, and KRAS mutation was frequent (Histopathology 2016). A later review of resected stage I to III colonic adenocarcinomas from one institution classified 91 as adenoma-like, 71 percent of them purely so, and compared them with 251 adenocarcinomas of no special type (Hum Pathol 2021).\n\nHow common it is. Ninety-one tumours against 251 of no special type in the single-institution series above, which is the only published frequency. Because the diagnosis rests on recognising the pattern, it depends on the pathologist and on whether a partial component counts; no national registry records it.\n\nHow it is treated. No trial has been run in this histology. Treated as colorectal adenocarcinoma: resection with adjuvant chemotherapy by stage when removable, the systemic rows of the parent page when not; the parent record carries the trials. The clinically important point is diagnostic rather than therapeutic: a biopsy reported as adenoma in a patient whose scan or endoscopy shows a mass should not close the question, and the possibility of this subtype is the reason why.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Colorectal_cancer","links":[{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"Histopathology 2016: adenoma-like adenocarcinoma, a subtype of colorectal carcinoma with good prognosis and deceptive appearance on biopsy (35 tumours)","url":"https://doi.org/10.1111/his.12725"},{"label":"Hum Pathol 2021: adenoma-like adenocarcinoma, clinicopathological characterisation of a newly recognised subtype (91 cases against 251 controls)","url":"https://doi.org/10.1016/j.humpath.2020.09.008"},{"label":"NICE NG151: colorectal cancer, recommendations (Lynch 1.1, local disease 1.3, biomarkers 1.4, metastatic disease 1.5, ongoing care and support including follow-up 1.6)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"}],"tags":["gi","colorectal","subtype-page"],"related":["colorectal","colorectal-micropapillary-carcinoma","colorectal-serrated-adenocarcinoma","colorectal-mucinous-adenocarcinoma","colon-cancer","rectal-cancer"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","endoscopy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["adenoma-carcinoma-sequence","colorectal-polyp-types","tumour-grade","tnm-staging"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"In one American series of resected stage I to III colonic adenocarcinomas from 2013 to 2016, 91 tumours were classified as adenoma-like against 251 of no special type, and 71 percent of the adenoma-like tumours were composed entirely of adenoma-like tissue. No registry count is published.","subtypes":["Pure adenoma-like adenocarcinoma of the colon or rectum (the whole invasive component is adenoma-like; 71 percent of cases in the 2021 series)","Mixed adenoma-like adenocarcinoma of the colon or rectum (more than half but not all of the invasive component is adenoma-like)"],"biomarkers":["Low-grade adenoma-like architecture in the invasive component, recorded in the pathology report","KRAS mutation, frequent in the published series"],"standardOfCare":[{"setting":"Localised disease","approach":"Resection with adjuvant chemotherapy decided by stage as for colorectal adenocarcinoma of no special type; the deceptive biopsy appearance means the diagnosis is often made only on the resection specimen.","refs":["colectomy","capox","folfox","colonoscopy"],"guideline":{"version":"NICE NG151: colorectal cancer (published January 2020, last updated December 2021, last reviewed April 2026)","url":"https://www.nice.org.uk/guidance/ng151"}}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"colorectal"},{"id":"gallbladder-adenosquamous-squamous-carcinoma","kind":"cancer","name":"Adenosquamous and squamous carcinoma of the gallbladder","aka":["Adenosquamous carcinoma of the gallbladder","Squamous cell carcinoma of the gallbladder","Gallbladder cancer with squamous differentiation"],"tldr":"Adenosquamous carcinoma is a gallbladder cancer that mixes gland-forming and squamous (skin-like) cancer cells; pure squamous carcinoma is rarer still. These tumours are larger and more advanced when found and do worse than ordinary adenocarcinoma, but they are treated in the same way because no trial has studied them separately.","summary":"Squamous differentiation arises through metaplasia in the chronically inflamed gallbladder lining. A tumour is called adenosquamous when the squamous component exceeds 25 percent (Gasparello 2026); pure squamous cell carcinoma has no glandular component. In the National Cancer Database analysis of 13,158 patients, the 703 adenosquamous tumours (5 percent) were larger, more often poorly differentiated and more often stage III or IV (75 versus 69 percent), and overall survival was worse both overall and after curative-intent resection; adjuvant chemoradiation was associated with benefit (Murimwa 2021). A SEER series identified 388 patients between 1975 and 2018 and found surgery, node dissection, radiotherapy and chemotherapy each associated with better cancer-specific survival (Fang 2023). In a Chinese surgical series of 411 gallbladder cancers, 10 squamous and 24 adenosquamous tumours were all T3 or T4, with more T4 disease (61.8 versus 34.0 percent) and more node involvement (58.8 versus 39.0 percent) than adenocarcinoma; only complete (R0) resection gave one-year survivors (30 percent) (Song 2015). A 2026 molecular study of 25 European cases found PD-L1 positivity (combined positive score above 1) in 96 percent and claudin 18.2 expression in 28 percent (Gasparello 2026).\n\nWhat differs in treatment: staging, surgery and chemotherapy follow the adenocarcinoma pathway (Cancer Research UK: treated in the same way as adenocarcinomas), but the expectation is of bulkier, more invasive disease, so complete resection is harder to achieve, and the high PD-L1 expression is a reason to study immunotherapy in this subtype specifically. No approved treatment is specific to it.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Adenosquamous_carcinoma","links":[{"label":"Murimwa, J Gastrointest Surg 2021: adenosquamous carcinoma of the gallbladder in the National Cancer Database","url":"https://doi.org/10.1007/s11605-020-04729-w"},{"label":"Song, J Surg Oncol 2015: squamous and adenosquamous carcinoma of the gallbladder, 34 cases","url":"https://doi.org/10.1002/jso.24065"},{"label":"Gasparello, Histopathology 2026: molecular profile of adenosquamous gallbladder carcinoma","url":"https://doi.org/10.1111/his.70179"},{"label":"Fang, J Gastrointest Oncol 2023: adenosquamous gallbladder carcinoma in SEER","url":"https://doi.org/10.21037/jgo-22-1292"},{"label":"CRUK: types of gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/types"}],"tags":["gallbladder","biliary","subtype-page"],"related":["gallbladder","gallbladder-adenocarcinoma","gallbladder-neuroendocrine-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":["pdl1"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["squamous-cell-carcinoma","tumour-grade"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Around 5 percent: 703 of 13,158 gallbladder adenocarcinoma or adenosquamous cases in the US National Cancer Database 2004 to 2015 were adenosquamous (Murimwa 2021); Cancer Research UK puts squamous cell cancers at about 5 in 100.","subtypes":["Adenosquamous carcinoma of the gallbladder (squamous component above 25 percent)","Pure squamous cell carcinoma of the gallbladder","Gallbladder adenocarcinoma with minor squamous differentiation"],"biomarkers":["Share of squamous component (25 percent threshold)","Grade, T category (usually T3 or T4 at presentation) and node status","PD-L1 combined positive score (above 1 in 96 percent of one cohort)","Claudin 18.2 (28 percent of one cohort)"],"standardOfCare":[{"setting":"All stages","approach":"As for gallbladder adenocarcinoma; complete resection is the only setting with long-term survivors in the surgical series, and adjuvant chemoradiation was associated with benefit in the National Cancer Database.","refs":["gallbladder-adenocarcinoma","radical-cholecystectomy","chemoradiation","gemcitabine-cisplatin"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"gallbladder"},{"id":"cervical-adenosquamous-carcinoma","kind":"cancer","name":"Adenosquamous carcinoma of the cervix","aka":["Adenosquamous carcinoma","Adenosquamous cervical cancer","Mixed adenocarcinoma and squamous cell carcinoma of the cervix"],"tldr":"Adenosquamous carcinoma of the cervix is an uncommon cervical cancer containing both gland-forming and squamous cancer cells. Like cervical adenocarcinoma it is caught less well by smear screening and does somewhat worse than squamous cancer stage for stage, but it is treated the same way, with surgery when early and chemoradiation when advanced.","summary":"The WHO classification of female genital tumours lists adenosquamous carcinoma among the HPV-associated cervical carcinomas, defined by both malignant glandular and squamous components. Cytology screening often fails to prevent adenocarcinoma; in a case-control study of 12,418 women with cervical cancer in England and Wales, being up to date with screening halved the odds of adenocarcinoma (odds ratio 0.46) and reduced advanced-stage adenocarcinoma more, and the paper treats adenosquamous carcinoma with adenocarcinoma (International Journal of Cancer 2016). In 148 patients with stage I to IVA adenocarcinoma or adenosquamous carcinoma treated with definitive radiotherapy, five-year relapse-free survival was 68 percent for non-bulky IB/IIA, 38 percent bulky IB/IIA, 49 percent IIB, 30 percent III and 0 percent IVA, inferior to squamous cell carcinoma, with distant failure common (Int J Radiat Oncol Biol Phys 2011).\n\nHow it differs from its parent: the parent page covers cervical cancer overall, three quarters squamous; adenosquamous carcinoma shares adenocarcinoma's screening blind spot and its worse radiotherapy outcomes, and its glandular component may raise the risk of ovarian and distant spread.\n\nHow common: no separate share in the sources read.\n\nTreatment: as cervical cancer by stage on the parent and its early and recurrent pages: radical hysterectomy for early disease, cisplatin-based chemoradiation with brachytherapy for locally advanced disease, and platinum with pembrolizumab or bevacizumab for recurrent or metastatic disease; no histology-specific trial exists.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Cervical_cancer","links":[{"label":"NCI PDQ: cervical cancer treatment","url":"https://www.cancer.gov/types/cervical/treatment"},{"label":"International Journal of Cancer 2016: is cervical screening preventing adenocarcinoma and adenosquamous carcinoma of the cervix?","url":"https://doi.org/10.1002/ijc.30152"},{"label":"Int J Radiat Oncol Biol Phys 2011: outcome of adenocarcinoma and adenosquamous carcinoma of the cervix after definitive radiotherapy, 148 patients","url":"https://doi.org/10.1016/j.ijrobp.2010.02.009"}],"tags":["subtype-page","wave4","rare"],"related":["cervical","early-cervical-cancer","recurrent-metastatic-cervical-cancer","cervical-small-cell-neuroendocrine-carcinoma","vaginal-adenocarcinoma"],"cancers":[],"sections":[],"technologies":["brachytherapy"],"targets":[],"drugs":["cisplatin","pembrolizumab","bevacizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["hpv-p16","chemoradiation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"A minority of cervical cancers grouped with adenocarcinoma in most series; in England and Wales adenocarcinoma has become more common as squamous carcinoma declined under screening (International Journal of Cancer 2016). No separate share is in the sources read.","subtypes":["HPV-associated adenosquamous carcinoma of the cervix (the usual form)","Adenosquamous carcinoma with glassy cell features","Adenosquamous carcinoma, early stage (surgery)","Adenosquamous carcinoma, locally advanced (chemoradiation; inferior control to squamous)"],"biomarkers":["p16 and HPV status","Both glandular and squamous components on histology","FIGO stage and tumour bulk","PD-L1 for recurrent disease"],"standardOfCare":[{"setting":"All stages","approach":"Treated as cervical cancer by stage: radical hysterectomy when early, cisplatin chemoradiation with brachytherapy when locally advanced, platinum with pembrolizumab or bevacizumab when recurrent.","refs":["cervical","early-cervical-cancer","recurrent-metastatic-cervical-cancer","cisplatin","pembrolizumab","bevacizumab","brachytherapy"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"cervical"},{"id":"lung-adenosquamous-carcinoma","kind":"cancer","name":"Adenosquamous carcinoma of the lung","aka":["Adenosquamous carcinoma of the lung","Adenosquamous cell lung cancer","Mixed adenocarcinoma and squamous cell carcinoma of the lung"],"tldr":"Adenosquamous carcinoma is an uncommon lung cancer that contains both gland-forming and squamous cancer cells, each making up at least a tenth of the tumour. It behaves worse than either pure type, but its gland-forming part often carries an EGFR mutation, so it is tested and treated like adenocarcinoma.","summary":"The WHO classification defines adenosquamous carcinoma as a carcinoma with at least 10 percent each of adenocarcinoma and squamous cell carcinoma, a diagnosis that can be made reliably only on a resection specimen; small biopsies usually capture one component (Li 2018). In the Japanese multi-institutional cohort adenosquamous cases had worse survival curves than adenocarcinoma or squamous cell carcinoma for all stages and for stage IA, IB and IIIA (Maeda 2012).\n\nHow it differs from its parent: it is the histology in which the treatment rules of adenocarcinoma and squamous cell carcinoma collide. The review evidence favours treating it as adenocarcinoma: EGFR mutations are frequent enough that EGFR inhibitors such as erlotinib and gefitinib are effective in EGFR-mutant advanced disease, platinum-based adjuvant chemotherapy for at least four cycles improved survival in stage III, data on ALK inhibitors are very limited, and checkpoint inhibitors are a potential option (Li 2018).\n\nHow common: 2.4 percent of resected lung cancers in the Japanese series (Maeda 2012); no population figure was found in the sources read.\n\nTreatment: as the parent by stage, with driver testing as for adenocarcinoma and EGFR inhibitors when a mutation is found; pemetrexed-based regimens are generally used because of the glandular component (Li 2018).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Adenosquamous_carcinoma","links":[{"label":"Nicholson 2022, JTO: the 2021 WHO classification of lung tumours","url":"https://doi.org/10.1016/j.jtho.2021.11.003"},{"label":"Li 2018, OncoTargets and Therapy: adenosquamous carcinoma of the lung (review)","url":"https://doi.org/10.2147/ott.s164574"},{"label":"Maeda 2012, Eur J Cardiothorac Surg: adenosquamous carcinoma of the lung, surgical results in 4,668 resections","url":"https://doi.org/10.1016/j.ejcts.2011.05.050"}],"tags":["subtype-page","wave4","lung"],"related":["nsclc","lung-adenocarcinoma","lung-squamous-cell-carcinoma","egfr-mutant-nsclc"],"cancers":[],"sections":[],"technologies":[],"targets":["egfr"],"drugs":["erlotinib","gefitinib","pemetrexed"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"2.4 percent of resected primary lung cancers (114 of 4,668 operations, Japan National Hospital Organization, 1997 to 2003), against 64.2 percent adenocarcinoma and 29.3 percent squamous cell carcinoma in the same series (Maeda 2012).","subtypes":["Adenosquamous carcinoma with EGFR mutation (treated on the EGFR page)","Adenosquamous carcinoma, driver-negative","Adenocarcinoma or squamous cell carcinoma with a minor (under 10 percent) second component (not adenosquamous)"],"biomarkers":["At least 10 percent each of glandular and squamous components on resection","EGFR and other adenocarcinoma drivers","PD-L1"],"standardOfCare":[{"setting":"All stages","approach":"Treated as lung adenocarcinoma: driver testing, EGFR inhibitors when mutated, platinum-based chemotherapy with immunotherapy otherwise.","refs":["lung-adenocarcinoma","egfr-mutant-nsclc","erlotinib","gefitinib","pemetrexed"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"nsclc"},{"id":"pancreatic-adenosquamous-carcinoma","kind":"cancer","name":"Adenosquamous carcinoma of the pancreas","aka":["Adenosquamous carcinoma of the pancreas (squamous component of at least 30 percent; about 1 percent of cases; body and tail; worse after resection)","Pancreatic adenosquamous carcinoma","ASCP","Adenosquamous pancreatic cancer","Mixed adenocarcinoma and squamous cell carcinoma of the pancreas"],"tldr":"Adenosquamous carcinoma is a rare form of pancreatic cancer in which at least three tenths of the tumour has turned into squamous cells, the flat cells of skin-like linings. It is found more often in the body and tail, tends to be larger and poorly differentiated, and does worse after surgery than ordinary pancreatic cancer, though surgery remains the strongest predictor of survival.","summary":"What it is. The 2019 WHO classification of digestive tumours lists adenosquamous carcinoma as a variant of pancreatic ductal adenocarcinoma in which a squamous component makes up at least 30 percent of the tumour (Nagtegaal 2020); pure squamous cell carcinoma of the pancreas is exceptional and most such tumours prove to be adenosquamous on wider sampling.\n\nHow it differs from its parent. In 415 SEER patients (1988 to 2007) compared with 45,693 with adenocarcinoma, adenosquamous tumours were more often in the body and tail, more often poorly differentiated, larger and node positive, and long-term survival after resection was significantly worse, although resection was still the strongest predictor of survival (Boyd 2012). In the National Cancer Database (2004 to 2012), 1,745 adenosquamous carcinomas (1 percent of 207,073 pancreatic cancers) were larger and more often in the body or tail (36 against 24 percent); survival was similar to adenocarcinoma when operated and unoperated patients were pooled, but worse among resected stage I and II patients (Hester 2018).\n\nHow common it is. About 1 percent of pancreatic cancers in both US series above; no UK registry count is published.\n\nHow it is treated. No trial has been run in this histology. It is staged by the same TNM 8th edition and treated as pancreatic ductal adenocarcinoma: resection with adjuvant chemotherapy when removable, the chemotherapy rows of the parent page when not, with the squamous component sometimes prompting platinum-based regimens by analogy with squamous cancers elsewhere, on case-series evidence only.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Adenosquamous_carcinoma","links":[{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"Boyd, J Surg Res 2012: 415 patients with adenosquamous carcinoma of the pancreas, SEER analysis","url":"https://doi.org/10.1016/j.jss.2011.06.015"},{"label":"Hester, J Surg Oncol 2018: comparative outcomes of adenosquamous carcinoma of the pancreas, National Cancer Database","url":"https://doi.org/10.1002/jso.25112"},{"label":"NCCN Guidelines: Pancreatic Adenocarcinoma (resectability criteria)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}],"tags":["gi","pancreatic","subtype-page"],"related":["pancreatic","pancreatic-colloid-carcinoma","pancreatic-undifferentiated-carcinoma-ogc","gallbladder-adenosquamous-squamous-carcinoma","lung-adenosquamous-carcinoma"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","histopathology-ihc"],"targets":["kras","tp53"],"drugs":["folfirinox","gemcitabine-nab-paclitaxel","nalirifox"],"companies":[],"institutions":[],"pathways":["ras-mapk","pancreatic-cancer-signalling"],"terms":["tumour-grade","whipple","distal-pancreatectomy","resection-margins"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 1 percent of pancreatic cancers: 415 of 46,108 pancreatic carcinomas in SEER (1988 to 2007) and 1,745 of 207,073 in the US National Cancer Database (2004 to 2012). No UK count is published.","subtypes":["Adenosquamous carcinoma with a dominant ductal (PDAC) component","Adenosquamous carcinoma with a dominant squamous component (the 30 percent rule still applies)"],"biomarkers":["Squamous component of at least 30 percent on histology (p40 and p63 immunohistochemistry mark the squamous cells)","KRAS and TP53 as in ductal adenocarcinoma","CA 19-9 for monitoring, as in the parent"],"standardOfCare":[{"setting":"Resectable","approach":"Pancreatoduodenectomy or distal pancreatectomy with adjuvant chemotherapy as for ductal adenocarcinoma; surgery is the strongest predictor of survival in the population series.","refs":["whipple","distal-pancreatectomy","folfirinox","neoadjuvant-adjuvant"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Advanced","approach":"Chemotherapy as for metastatic pancreatic ductal adenocarcinoma; no histology-specific trial exists.","refs":["folfirinox","gemcitabine-nab-paclitaxel","nalirifox"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Recognised as a WHO variant with a worse outcome after resection than ductal adenocarcinoma in two US population series."],"history":[{"year":2012,"title":"SEER analysis of 415 adenosquamous carcinomas defines the phenotype","refs":["tumour-grade"]},{"year":2018,"title":"National Cancer Database comparison: worse survival in resected stage I and II disease","refs":["whipple"]}],"pipeline":[],"openProblems":["No prospective trial; whether platinum or squamous-directed regimens help is unknown.","The 30 percent threshold depends on sampling, so small biopsies under-diagnose it."],"parent":"pancreatic"},{"id":"aya-cancers","kind":"cancer","name":"Adolescent and young adult cancers (ages 15 to 39)","aka":["AYA cancers","Teenage and young adult cancer","TYA cancer","Young adult cancer"],"tldr":"People aged 15 to 39 get a different mix of cancers from children or older adults: leukaemia, lymphoma, testicular and thyroid cancer, melanoma, sarcoma and brain tumours in the younger years, then breast, cervical and bowel cancer towards 40. For decades their survival improved more slowly than anyone else's: they fell between children's and adults' hospitals and joined few trials.","summary":"The National Cancer Institute and LIVESTRONG Progress Review Group defined the adolescent and young adult (AYA) population as 15 to 39 in 2006 after Bleyer and colleagues showed that five-year survival for this age band had improved far less between 1975 and 1997 than for children or for adults over 40, and that fewer than one in ten were treated in a clinical trial against more than half of children. The cancers differ by age: acute lymphoblastic leukaemia, Hodgkin lymphoma, germ cell tumours, osteosarcoma and Ewing sarcoma, thyroid cancer, melanoma and gliomas dominate the teenage years; breast, cervical, colorectal and thyroid cancer take over through the thirties. Several behave differently from the same diagnosis at other ages: young-adult breast cancer is more often triple-negative or BRCA-associated, early-onset colorectal cancer is rising by about two percent a year, and AYA acute lymphoblastic leukaemia carries more Ph-like and fewer favourable genetic subtypes than childhood disease.\n\nThe clearest treatment lesson is in acute lymphoblastic leukaemia. Retrospective comparisons in France, the United States and the Netherlands found that 16 to 20-year-olds treated on paediatric protocols did far better than those on adult ones, and the prospective CALGB 10403 study of a paediatric regimen in 295 patients aged 17 to 39 gave three-year event-free survival of 59 percent and overall survival of 73 percent, roughly double the historical adult figures; paediatric-inspired therapy is now standard to age 40 and blinatumomab consolidation (E1910) adds to it. Ewing sarcoma and osteosarcoma outcomes fall with age partly through dose intensity and partly through biology; Hodgkin lymphoma in AYA is highly curable and the trial question is de-escalation; germ cell tumours have a cure rate over 90 percent but were the disease in which the survival gap was first documented in young men treated outside specialist centres. The United Kingdom built dedicated teenage and young adult units from 1990 through the Teenage Cancer Trust and made specialist referral national policy in 2005; the NCCN issued AYA guidelines in 2012.\n\nThe needs that cut across diagnoses are fertility preservation before treatment, which guidelines have required since 2006 and which is still offered unevenly; psychosocial support during education, early careers and young parenthood; financial toxicity in people with no savings and, in the United States, patchy insurance; and survivorship, since a 25-year-old cured of Hodgkin lymphoma has sixty years to develop the cardiac and second-cancer consequences of treatment. The research gaps are trial eligibility ages that exclude 12 to 17-year-olds from adult trials and over-18s from paediatric ones, which the FDA's 2019 guidance on including adolescents in adult cancer trials began to close; molecular studies of why the same cancer differs at different ages; and registries able to follow a population that moves house, hospital and country more than any other.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Adolescent_and_young_adult_oncology","links":[{"label":"Wikipedia: Adolescent and young adult oncology","url":"https://en.wikipedia.org/wiki/Adolescent_and_young_adult_oncology"},{"label":"NCI: Adolescents and Young Adults with Cancer","url":"https://www.cancer.gov/types/aya"}],"tags":["umbrella","subtype-page","aya"],"related":["childhood-cancers","all-leukemia","hodgkin-lymphoma","testicular","thyroid","melanoma","breast-cancer","cervical","early-onset-colorectal","osteosarcoma","ewing-sarcoma","brain-tumours"],"cancers":["all-leukemia","all-ph-like","hodgkin-lymphoma","testicular","paediatric-germ-cell-tumours","thyroid","melanoma","ewing-sarcoma","osteosarcoma","brain-tumours","breast-cancer","cervical","early-onset-colorectal"],"sections":[],"technologies":["fertility-preservation","survivorship-care-plan","psycho-oncology"],"targets":[],"drugs":[],"companies":["childrens-oncology-group"],"institutions":["teenage-cancer-trust"],"pathways":[],"terms":["aya-oncology","late-effects","financial-toxicity","cancer-in-pregnancy"],"trials":["e1910","ccss"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"adolescent and young adult","burden":"Cancer in people aged 15 to 39 is uncommon but not rare, about 90,000 diagnoses a year in the United States, and for decades survival gains in this age band lagged those in children and older adults.","subtypes":[],"biomarkers":["Germline testing (BRCA1/2, Lynch syndrome, TP53) in young-onset cancers","Ph-like signature screening in AYA acute lymphoblastic leukaemia","Mismatch repair status in early-onset colorectal cancer","Ovarian reserve (anti-Mullerian hormone) before gonadotoxic therapy"],"standardOfCare":[{"setting":"Acute lymphoblastic leukaemia, 15 to 39","approach":"Paediatric-inspired regimen with asparaginase (CALGB 10403 model) and blinatumomab consolidation for MRD-negative B-ALL (E1910); Ph-like screening at diagnosis.","refs":["asparaginase","vincristine","dexamethasone","methotrexate","blinatumomab","e1910","ngs-mrd-clonoseq","paper-e1910-blinatumomab-mrd-negative-all-nejm-2024"],"guideline":{"version":"NCI: Adolescents and Young Adults with Cancer","url":"https://www.cancer.gov/types/aya"}},{"setting":"Before any gonadotoxic treatment","approach":"Fertility preservation referral (sperm banking, oocyte or embryo cryopreservation, ovarian tissue) as a default step.","refs":["fertility-preservation"],"guideline":{"version":"NCI: Adolescents and Young Adults with Cancer","url":"https://www.cancer.gov/types/aya"}},{"setting":"Psychosocial and financial","approach":"Age-specific units or teams, distress screening, education and employment support, financial navigation.","refs":["psycho-oncology","financial-toxicity","teenage-cancer-trust"],"guideline":{"version":"NCI: Adolescents and Young Adults with Cancer","url":"https://www.cancer.gov/types/aya"}},{"setting":"Survivorship","approach":"Treatment summary and risk-based follow-up for cardiac, second-cancer, endocrine and fertility late effects over decades.","refs":["survivorship-care-plan","late-effects","cardio-oncology","idea-acc-aya-survivorship-passport","ccss"],"guideline":{"version":"NCI: Adolescents and Young Adults with Cancer","url":"https://www.cancer.gov/types/aya"}},{"setting":"Hereditary risk","approach":"Germline testing in young-onset breast, colorectal, sarcoma and other cancers, with cascade testing of relatives.","refs":["germline-testing"],"guideline":{"version":"NCI: Adolescents and Young Adults with Cancer","url":"https://www.cancer.gov/types/aya"}}],"stateOfArt":["Paediatric-inspired regimens roughly doubled survival in AYA acute lymphoblastic leukaemia and are standard to age 40.","Dedicated teenage and young adult units are national policy in the United Kingdom and spreading elsewhere.","Trial eligibility is being widened to include adolescents in adult trials and young adults in paediatric ones."],"history":[{"year":1990,"title":"Teenage Cancer Trust opens the first dedicated teenage cancer unit in the United Kingdom","refs":["teenage-cancer-trust"]},{"year":2006,"title":"NCI and LIVESTRONG Progress Review Group defines AYA oncology as ages 15 to 39 and documents the survival gap","refs":["aya-oncology"]},{"year":2006,"title":"ASCO guideline requires fertility preservation discussion before cancer treatment","refs":["fertility-preservation"]},{"year":2012,"title":"NCCN publishes the first adolescent and young adult oncology guidelines","refs":[]},{"year":2019,"title":"CALGB 10403: paediatric regimen in adults 17 to 39 published; FDA guidance on including adolescents in adult cancer trials","refs":["asparaginase"]},{"year":2024,"title":"Blinatumomab consolidation approved for adults and children with B-ALL after E1910","refs":["blinatumomab","e1910"]}],"pipeline":["blinatumomab","e1910","idea-acc-aya-survivorship-passport","idea-acc-default-fertility-preservation-referral","idea-acc-national-late-effects-registry","fertility-preservation","ngs-mrd-clonoseq"],"openProblems":["Trial enrolment in AYA remains far below that of children.","Fertility preservation is offered unevenly and paid for inconsistently.","Why the same cancer behaves differently at different ages is largely unexplained."]},{"id":"adrenocortical","kind":"cancer","name":"Adrenocortical carcinoma","aka":["ACC"],"tldr":"Adrenocortical carcinoma is a rare, aggressive cancer of the adrenal gland that often over-produces hormones. Surgery is the only cure, mitotane is the one drug specific to it (with real toxicity), and chemotherapy or immunotherapy help only a minority.","summary":"Adrenocortical carcinoma (ACC) arises from the adrenal cortex, with TP53 (germline in most childhood cases; R337H founder mutation in Brazil), CTNNB1, ZNRF3, and IGF2 overexpression as recurrent alterations, and molecular subgroups (CIMP-high, C1A) predicting outcome. Diagnosis relies on the Weiss score and Ki-67; staging on ENSAT (I-IV). Hormone excess is present in ~60% and complicates management.\n\nComplete open adrenalectomy (R0) is the only curative treatment; adjuvant mitotane is recommended for high-risk resected disease (Ki-67 >10%, stage III, R1), while ADIUVO (2023) showed no benefit in low-risk patients. Advanced disease is treated with etoposide-doxorubicin-cisplatin plus mitotane (EDP-M, FIRM-ACT 2012: response ~23%, no OS gain over streptozocin-mitotane), with mitotane monotherapy for indolent disease. PD-1 blockade (pembrolizumab, ~15-23% response) and cabozantinib have phase 2 activity; no targeted therapy is approved. Cortisol excess is controlled with metyrapone, osilodrostat or mifepristone. Survival is ~80% for stage I-II and ~15% for stage IV.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Adrenocortical_carcinoma","links":[{"label":"ESE/ENSAT ACC guideline 2018","url":"https://doi.org/10.1530/EJE-18-0608"},{"label":"FIRM-ACT (NEJM 2012)","url":"https://doi.org/10.1056/NEJMoa1200966"},{"label":"NCI PDQ: adrenocortical carcinoma","url":"https://www.cancer.gov/types/adrenocortical/patient/adrenocortical-treatment-pdq"}],"tags":["gap-fill","endocrine","rare"],"related":[],"cancers":[],"sections":[],"technologies":["robotic-surgery","cytotoxic-chemotherapy","checkpoint-inhibitor","kinase-inhibitors","germline-testing","thermal-ablation","sbrt"],"targets":["tp53","pd1","vegf"],"drugs":["mitotane","etoposide","doxorubicin","cisplatin","pembrolizumab","cabozantinib","relacorilant"],"companies":["merck","exelixis","corcept"],"institutions":[],"pathways":["wnt","p53-cell-cycle"],"terms":["germline-vs-somatic"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"About 1-2 per million per year, with peaks in early childhood (Li-Fraumeni, TP53 R337H in southern Brazil) and in the fifth decade; half present with hormone excess (Cushing, virilisation).","subtypes":["Hormone-secreting (cortisol, androgens, mixed) vs non-functioning","Adult ACC (sporadic; Lynch, Li-Fraumeni, MEN1 associations)","Paediatric ACC (TP53 germline, often virilising, better prognosis if localised)","Oncocytic, myxoid and sarcomatoid variants","Molecular: CIMP-high / C1A (poor) vs C1B (better)"],"biomarkers":["Weiss score ≥3, Ki-67 index (>10% and >20% thresholds)","ENSAT stage and R status","Hormone work-up (cortisol, DHEAS, androgens, aldosterone, precursors)","Germline TP53 (all children), Lynch syndrome testing","Urinary steroid metabolomics (diagnosis, emerging)","MSI/TMB (rare; immunotherapy)"],"standardOfCare":[{"setting":"Localised (ENSAT I-III)","approach":"Open en bloc adrenalectomy by an experienced surgeon with locoregional lymphadenectomy; adjuvant mitotane for high-risk (Ki-67 >10%, stage III, R1) for 2-5 years; adjuvant radiotherapy for R1.","refs":["mitotane","imrt-igrt"],"guideline":{"version":"ESE/ENSAT guideline 2018","url":"https://doi.org/10.1530/EJE-18-0608"}},{"setting":"Advanced, aggressive","approach":"EDP-M (etoposide, doxorubicin, cisplatin + mitotane) ×6-8 with surgery for responders; streptozocin-mitotane second line.","refs":["etoposide","doxorubicin","cisplatin","mitotane"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Advanced, indolent","approach":"Mitotane monotherapy (target level 14-20 mg/L) with glucocorticoid replacement; local therapies (ablation, radiotherapy) for oligometastases.","refs":["mitotane","thermal-ablation","sbrt"],"guideline":{"version":"ESE/ENSAT 2018"}},{"setting":"Progressive after chemotherapy","approach":"Pembrolizumab, cabozantinib, gemcitabine-capecitabine; control hormone excess; clinical trials.","refs":["pembrolizumab","cabozantinib"],"guideline":{"nccn":"Category 2B","version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors"}}],"stateOfArt":["Mitotane, an insecticide derivative from 1959, is still the only ACC-specific drug and needs therapeutic drug monitoring.","ADIUVO spared low-risk patients adjuvant mitotane; risk stratification by Ki-67 is now decisive.","Immunotherapy and cabozantinib give a minority durable benefit; no molecular target has translated.","Steroid metabolomics and TP53 founder-mutation screening (Brazil) are the diagnostic advances."],"history":[{"year":1959,"title":"Mitotane (o,p'-DDD) first used in ACC (Bergenstal)","refs":["mitotane"]},{"year":1984,"title":"Weiss histologic criteria","refs":[]},{"year":2007,"title":"Adjuvant mitotane associated with longer recurrence-free survival (Terzolo, NEJM)","refs":["mitotane"]},{"year":2009,"title":"ENSAT staging","refs":[]},{"year":2012,"title":"FIRM-ACT: EDP-M vs streptozocin-mitotane (NEJM)","refs":["etoposide","doxorubicin","cisplatin","mitotane"]},{"year":2016,"title":"TCGA/ENSAT genomic classification of ACC (Zheng, Cancer Cell)","refs":[]},{"year":2019,"title":"Pembrolizumab phase 2 in ACC (Raj, JCO)","refs":["pembrolizumab"]},{"year":2023,"title":"ADIUVO: no benefit of adjuvant mitotane in low-risk disease","refs":["mitotane"]}],"pipeline":["cabozantinib","pembrolizumab","mitotane"],"openProblems":["No targeted therapy despite defined genomic subgroups.","Mitotane toxicity and narrow therapeutic window.","Hormone excess drives morbidity and immunosuppression (cortisol blunts immunotherapy).","Rarity: FIRM-ACT took 8 years and 40 centres for 300 patients."]},{"id":"granulosa-cell-tumour","kind":"cancer","name":"Adult granulosa cell tumour of the ovary","aka":["Granulosa cell tumor","AGCT","Sex cord-stromal tumour of the ovary"],"tldr":"Granulosa cell tumours, a rare form of ovarian cancer, make oestrogen, so they often announce themselves with abnormal bleeding, and almost all carry the same single FOXL2 mutation. Surgery cures most; relapses come late and are treated with further surgery, hormone-blocking drugs, bevacizumab or chemotherapy.","summary":"Adult granulosa cell tumours arise from the hormone-producing cells of the ovarian follicle and carry a FOXL2 C134W mutation in about 97 percent of cases, one of the most specific mutations in oncology. Oestrogen production causes irregular bleeding, endometrial hyperplasia and occasionally endometrial cancer, and inhibin B and anti-Mullerian hormone serve as tumour markers. Surgery, fertility-sparing where appropriate, cures most stage I disease; adjuvant chemotherapy for higher stages is debated. Relapse, typically in the pelvis and abdomen years or decades later, is managed with repeat surgery, aromatase inhibitors or other hormonal therapy, bevacizumab, or platinum-based chemotherapy such as carboplatin-paclitaxel or BEP.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Granulosa_cell_tumour","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Granulosa_cell_tumour"}],"tags":["subtype-page"],"related":["low-grade-serous-ovarian-cancer","mucinous-ovarian-cancer","clear-cell-ovarian-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-shah-foxl2-granulosa-nejm-2009","paper-esmo-non-epithelial-ovarian-ray-coquard-ann-oncol-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"The commonest malignant sex cord-stromal tumour but only two to five percent of ovarian cancers; most are found at stage I and cured, yet a third relapse, sometimes twenty or thirty years later, so follow-up is lifelong.","subtypes":["Adult granulosa cell tumour (FOXL2 C134W)","Juvenile granulosa cell tumour (children and young women, different biology)","Other sex cord-stromal tumours (Sertoli-Leydig, DICER1-related)"],"biomarkers":["FOXL2 C134W mutation (diagnostic)","Inhibin B and anti-Mullerian hormone (monitoring)","Oestradiol","Stage and rupture at surgery (prognosis)"],"standardOfCare":[{"setting":"Stage I","approach":"Surgical staging with hysterectomy and bilateral salpingo-oophorectomy, or unilateral oophorectomy to preserve fertility; endometrial sampling because of oestrogen exposure; no adjuvant therapy.","refs":["ovarian"]},{"setting":"Advanced or relapsed","approach":"Repeat cytoreduction; aromatase inhibitors such as letrozole; bevacizumab; carboplatin-paclitaxel or BEP chemotherapy.","refs":["letrozole","bevacizumab","carboplatin","paclitaxel"]},{"setting":"Follow-up","approach":"Lifelong monitoring with inhibin B and imaging because relapses occur decades later.","refs":["ovarian"]}],"stateOfArt":["The FOXL2 mutation, found in 2009, gives a definitive diagnosis and a target for research.","Hormonal therapy and bevacizumab have added low-toxicity options for relapse.","Registries and rare-tumour networks are replacing case series as the evidence base."],"history":[{"year":1855,"title":"Rokitansky describes granulosa cell tumour","refs":[]},{"year":2009,"title":"FOXL2 C134W mutation found in almost all adult granulosa cell tumours","refs":[]},{"year":2020,"title":"ALIENOR: bevacizumab tested with paclitaxel in relapsed sex cord-stromal tumours","refs":["bevacizumab"]}],"pipeline":["bevacizumab","letrozole"],"openProblems":["No randomised trials guide adjuvant or relapse treatment.","Late relapse makes follow-up long and uncertain.","FOXL2 is not yet druggable."],"parent":"ovarian"},{"id":"adult-t-cell-leukaemia-lymphoma","kind":"cancer","name":"Adult T-cell leukaemia/lymphoma","aka":["ATLL","ATL","Adult T-cell leukemia/lymphoma","Adult T-cell leukaemia","HTLV-1-associated lymphoma","Adult T-cell leukaemia/lymphoma (HTLV-1)","Smouldering ATL","Chronic ATL","Acute ATL","Lymphoma-type ATL"],"tldr":"A T-cell lymphoma caused by a virus, HTLV-1, which is usually caught in infancy through breast milk and causes the lymphoma decades later in a small minority of the people it infects. It occurs in people from south-western Japan, the Caribbean, west and central Africa, parts of South America, Iran and Romania, and it comes in four forms that are treated very differently.","summary":"What it is. A cancer of mature CD4-positive T cells caused by human T-lymphotropic virus type 1, the first human retrovirus shown to cause a cancer. The virus is acquired mainly through breastfeeding in infancy, and also through sexual contact and transfusion of cellular blood products. It then sits in the T cells for decades. Only a small minority of the people it infects ever develop the lymphoma, and the latency is usually measured in decades, which is why this is a disease of middle and later life in people who were infected as babies.\n\nThe four forms, which are really four diseases. The subclassification proposed by Shimoyama and adopted by the international consensus meetings divides it into acute, lymphoma, chronic and smouldering types. The chronic and smouldering types without unfavourable features are indolent and are watched, in the same way an early chronic lymphocytic leukaemia is watched. The acute and lymphoma types are aggressive and are treated at once. Getting the type right is the first decision and it changes everything that follows.\n\nHow it differs from the rest of the T-cell family. Four things recur and none of them belongs to ordinary peripheral T-cell lymphoma. High calcium, often very high, caused by the tumour making parathyroid hormone-related protein; it was found in the blood cells of all 13 patients tested in the study that established the mechanism, and it can present as confusion, thirst and kidney failure before the lymphoma is recognised. Profound suppression of cell-mediated immunity, so that opportunistic infection, and particularly hyperinfection with the worm Strongyloides stercoralis, is a common cause of harm and is looked for before treatment. Involvement of the skin, which may be the only sign for a long time and which the 2019 consensus meeting singled out for a classification of its own. And involvement of the central nervous system, which is common in the aggressive types.\n\nWho should be tested. HTLV-1 serology belongs in the work-up of any T-cell lymphoma or leukaemia in a person who comes from, or whose parents come from, an endemic region. Without the test, the disease is reported as peripheral T-cell lymphoma not otherwise specified and treated on a pathway that does not fit it.\n\nWhat is known about treating it, honestly. The 2019 international consensus report states the position of the evidence in its own words: as a result of lower-quality clinical evidence, a best practice approach was adopted and the statements were agreed by more than 90 per cent of the authors. That is a consensus, not a trial result, and it applies to the choice of chemotherapy, to the use of antiviral therapy with zidovudine and interferon in the leukaemic types, and to the place of allogeneic stem cell transplant. The treatment rows on this page were moved here from the peripheral T-cell lymphoma page once this record existed.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Adult_T-cell_leukemia/lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"Definition, prognostic factors, treatment and response criteria of adult T-cell leukaemia-lymphoma: a proposal from an international consensus meeting (Tsukasaki, J Clin Oncol 2009)","url":"https://doi.org/10.1200/JCO.2008.18.2428"},{"label":"Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report (Cook, J Clin Oncol 2019)","url":"https://doi.org/10.1200/JCO.18.00501"},{"label":"Increase in incidence of adult T-cell leukaemia/lymphoma in non-endemic areas of Japan and the United States (Chihara, Cancer Science 2012)","url":"https://doi.org/10.1111/j.1349-7006.2012.02373.x"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["peripheral-t-cell-lymphoma","extranodal-nk-t-cell-lymphoma","t-cell-prolymphocytic-leukaemia","non-hodgkin-lymphoma","cutaneous-t-cell-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","allogeneic-hsct"],"targets":[],"drugs":["mogamulizumab","interferon-alfa"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-htlv-1","oncogenic-viruses","lymphoma-classification-2022","lymphoma-pit-score","lymphoma-b-versus-t-cell","lymphoma-tx-transplant-role","lymphoma-tx-regimen-alphabet"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Concentrated where the virus is. In the registry study that compared endemic and non-endemic areas, 2,055 patients were diagnosed in three prefectures of Kyushu in south-western Japan between 1993 and 2006 against 1,380 in twelve prefectures of Honshu, and 140 patients were recorded in the United States SEER registries between 1993 and 2008. Incidence rose significantly in the non-endemic areas over that period (an average annual change of plus 4.6 per cent in Honshu and plus 6.2 per cent in the United States) while remaining unchanged in endemic Kyushu, which the authors read as the virus travelling with its carriers. A systematic review of HTLV-1 among immigrants and refugees worldwide found a pooled prevalence of 1.28 per cent, rising to 7.27 per cent among people from the Western Pacific region.","subtypes":["Acute type, the commonest aggressive form, with circulating tumour cells, high calcium and rapid progression","Lymphoma type, with lymph node disease and few circulating cells, which does not respond to antiviral therapy","Chronic type, indolent unless unfavourable features are present","Smouldering type, indolent, often with skin disease and few circulating cells","Cutaneous variants, which the 2019 consensus meeting singled out for their own classification"],"biomarkers":["HTLV-1 serology, and confirmation that the virus is clonally integrated in the tumour cells","The Shimoyama type (acute, lymphoma, chronic or smouldering), which is the main treatment decision","Serum calcium and lactate dehydrogenase, both part of the subtype definition","A CD4-positive, CD25-positive, CCR4-positive phenotype with loss of CD7","Strongyloides screening before immunosuppressive treatment, because hyperinfection is fatal","Examination of the spinal fluid in the aggressive types, in which involvement of the central nervous system is common"],"standardOfCare":[{"setting":"Testing for the virus, which decides the diagnosis","approach":"HTLV-1 serology belongs in the work-up of any T-cell lymphoma or leukaemia in a person who comes from, or whose parents come from, south-western Japan, the Caribbean, west or central Africa, parts of South America, Iran or Romania. Without the test the disease is reported as peripheral T-cell lymphoma not otherwise specified and treated on a pathway that does not fit it. A positive test is followed by confirmation that the virus is clonally integrated in the tumour cells, because asymptomatic infection is common in those populations and does not by itself mean lymphoma.","refs":["lymphoma-htlv-1","histopathology-ihc","oncogenic-viruses"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Working out which of the four types it is","approach":"The subclassification proposed by Shimoyama and adopted by the international consensus meetings divides the disease into acute, lymphoma, chronic and smouldering types, using the count of circulating tumour cells, the lactate dehydrogenase, the calcium and the sites involved. It is the first decision and it changes everything: the chronic and smouldering types without unfavourable features are watched, while the acute and lymphoma types are treated at once. The consensus report sets out prognostic factors and a set of response criteria specific to this disease, which is why trials in it are not reported like trials in other lymphomas.","refs":["lymphoma-htlv-1","lugano-classification","lymphoma-tx-watch-and-wait"],"guideline":{"version":"International consensus meeting report (J Clin Oncol 2009) and its 2019 revision; NCI PDQ","url":"https://doi.org/10.1200/JCO.2008.18.2428"}},{"setting":"What has to be looked for before and during treatment","approach":"Three things that belong to this disease and not to the rest of the family. Calcium, which can be very high because the tumour makes parathyroid hormone-related protein, and which may present as confusion, thirst or kidney failure before the lymphoma is recognised. Strongyloides stercoralis, because the immune suppression caused by the virus allows hyperinfection, which is fatal and is prevented by screening and treating before immunosuppressive therapy. And the central nervous system, which is commonly involved in the aggressive types and is examined by lumbar puncture.","refs":["lymphoma-htlv-1","intrathecal-therapy","lymphoma-tx-pjp-and-infection-prophylaxis"],"guideline":{"version":"Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report (J Clin Oncol 2019)","url":"https://doi.org/10.1200/JCO.18.00501"}},{"setting":"Adult T-cell leukaemia/lymphoma (HTLV-1)","approach":"Caused by human T-lymphotropic virus type 1, acquired in infancy through breastfeeding and causing lymphoma after a latency of decades in a small percentage of those infected. It occurs in people from south-western Japan, the Caribbean, west and central Africa, parts of South America, Romania and Iran, and it is the reason HTLV-1 serology belongs in the work-up of any T-cell lymphoma in a person from those populations.\n\nFour clinical types, and they are treated differently. Smouldering and chronic types without unfavourable features are watched, or treated with zidovudine and interferon alfa, which produces long remissions in the leukaemic types; antiviral therapy does not work in the lymphoma type. Acute and lymphoma types are treated with intensive chemotherapy. JCOG9801 randomised 118 patients with aggressive disease to six courses of VCAP-AMP-VECP or eight courses of biweekly CHOP, both with G-CSF and intrathecal prophylaxis: the complete response rate was 40 against 25 per cent and three-year overall survival 24 against 13 per cent, with more toxicity in the intensive arm (grade 4 neutropenia 98 against 83 per cent, grade 3 or 4 infection 32 against 15 per cent). VCAP-AMP-VECP is standard in Japan; outside Japan, CHOP or CHOEP with early referral for allogeneic transplant is more usual.\n\nAllogeneic stem cell transplant is the only treatment that cures a minority, and it is offered early because remissions are short. Mogamulizumab, an anti-CCR4 antibody first approved in Japan in 2012, produces responses in relapsed aggressive disease: in the updated phase 2 analysis of 26 relapsed patients, median progression-free survival was 5.2 months and median overall survival 14.4 months, and outcomes were better in patients who developed a rash of grade 2 or more, a signal that is being read as an immune effect rather than a side effect alone. Central nervous system involvement is common and intrathecal prophylaxis is given.","refs":["mogamulizumab","interferon-alfa","cyclophosphamide","doxorubicin","vincristine","prednisone","etoposide","carboplatin","allogeneic-hsct","intrathecal-therapy","lymphoma-tx-transplant-role"],"guideline":{"version":"NCCN T-Cell Lymphomas; JCOG9801; Japanese consensus","url":"https://doi.org/10.1200/JCO.2007.11.9958"}}],"stateOfArt":[],"history":[{"year":1977,"title":"Described as a distinct disease in south-western Japan","note":"A cluster of T-cell leukaemias in Kyushu was recognised as a single disease, which led to the search for its cause.","refs":[]},{"year":1990,"title":"The mechanism of the high calcium established","note":"Parathyroid hormone-related protein was found to be abundantly expressed in the blood cells of all 13 patients tested, and in HTLV-1 carriers without symptoms, and the viral Tax protein was shown to switch its gene on.","refs":[]},{"year":2009,"title":"An international consensus defines the four types","note":"The consensus meeting set out the acute, lymphoma, chronic and smouldering types, the prognostic factors and a set of response criteria specific to the disease, which became the standard reference for trials.","refs":[]},{"year":2019,"title":"The consensus revised, on best practice rather than trials","note":"The revised report added the classification of cutaneous disease, disease in the central nervous system, the management of older and transplant-ineligible patients, upfront allogeneic transplant and newer agents, and stated that a best practice approach was adopted because the clinical evidence was of lower quality.","refs":[]}],"pipeline":[],"openProblems":["The treatment of this disease rests on consensus rather than on randomised evidence, and the authors of the consensus say so.","The virus is preventable. Antenatal screening and avoidance of breastfeeding where it is safe to do so reduce transmission, and most of the world does not screen.","The incidence is rising in the places that do not expect it, including the United States and non-endemic Japan, while remaining stable where it is endemic.","Drugs approved for this disease in Japan, including mogamulizumab and later agents, are not approved in much of the world, so the people least likely to be offered them are those who moved away from where the disease is studied."],"parent":"peripheral-t-cell-lymphoma"},{"id":"advanced-adrenocortical-carcinoma","kind":"cancer","name":"Advanced and metastatic adrenocortical carcinoma (ENSAT stage IV or unresectable)","aka":["Metastatic ACC","Stage IV adrenocortical carcinoma","Unresectable adrenal cortical carcinoma","Recurrent adrenocortical carcinoma"],"tldr":"Advanced adrenocortical carcinoma is adrenal cortex cancer that has spread to distant organs or cannot be removed. The standard is mitotane with etoposide, doxorubicin and cisplatin, established by the FIRM-ACT trial in 304 patients; limited spread is treated locally, hormone excess with steroid-blocking drugs, and immunotherapy helps a minority.","summary":"Metastatic adrenocortical carcinoma is often a double problem: a fast-growing cancer and, in the majority of patients, uncontrolled cortisol or androgen excess that itself causes muscle wasting, infections, thrombosis and diabetes. Mitotane, which destroys adrenocortical cells and blocks steroid synthesis, is the backbone of treatment and is started at diagnosis in all patients, with adrenal enzyme inhibitors such as metyrapone or osilodrostat added when cortisol needs to fall quickly; the glucocorticoid receptor antagonist relacorilant is being tested for the same purpose. Tumours with a low burden of disease and a slow course can be treated with mitotane alone or with resection, ablation or stereotactic radiotherapy of metastases, and the ESE/ENSAT guideline advises against debulking surgery unless most of the disease can be removed.\n\nFIRM-ACT (New England Journal of Medicine 2012), the first randomised phase 3 trial in the disease, compared mitotane with etoposide, doxorubicin and cisplatin (EDP-M) against mitotane with streptozocin in 304 patients: EDP-M produced more responses (23.2 against 9.2 percent) and longer progression-free survival (5.0 against 2.1 months) without a significant difference in overall survival, and it has been the first-line standard since. Nothing has matched it in second line. Gemcitabine with capecitabine gives modest disease control; the multikinase inhibitor cabozantinib produced disease stabilisation and a few responses in retrospective series and a phase 2 trial; pembrolizumab produced responses in about one in five patients in two phase 2 trials, more often in the minority of tumours that are mismatch-repair deficient from Lynch syndrome, but most carcinomas are immunologically cold, in part because cortisol suppresses immunity, so trials now combine checkpoint inhibitors with cortisol blockade or with cabozantinib. The steroidogenic enzyme CYP11B1 is a target for radiolabelled tracers and the IGF-2 pathway that drives many tumours proved undruggable in the linsitinib phase 3 trial. Median survival in metastatic disease remains poor, and referral to an ENSAT centre and to trials is recommended for every patient.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Adrenocortical_carcinoma","links":[{"label":"FIRM-ACT (NEJM 2012)","url":"https://doi.org/10.1056/NEJMoa1200966"},{"label":"ESE/ENSAT guideline 2018","url":"https://doi.org/10.1530/EJE-18-0608"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Adrenocortical_carcinoma"}],"tags":["subtype-page","endocrine"],"related":["localised-adrenocortical-carcinoma","adrenocortical","metastatic-ppgl"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","checkpoint-inhibitor","kinase-inhibitors","thermal-ablation","sbrt"],"targets":["tp53","pd1","vegf"],"drugs":["mitotane","etoposide","doxorubicin","cisplatin","gemcitabine","capecitabine","cabozantinib","pembrolizumab","relacorilant"],"companies":[],"institutions":[],"pathways":[],"terms":["adrenalectomy","germline-vs-somatic","msi","tmb"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-firm-act-edp-mitotane-adrenocortical-carcinoma-nejm-2012","paper-ese-ensat-adrenocortical-carcinoma-guideline-eur-j-endocrinol-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"A third or more of patients present with metastases, usually to the liver, lungs and peritoneum, and many more relapse after surgery. Referral to an ENSAT centre and to a trial is recommended for every patient.","subtypes":["Synchronous metastatic adrenocortical carcinoma (liver, lung, peritoneum)","Recurrent adrenocortical carcinoma after resection","Low-burden, slow-growing metastatic disease (mitotane alone, local therapy)","High-burden or rapidly progressing disease (EDP-M)","Cortisol-secreting metastatic adrenocortical carcinoma (steroid blockade needed)","Mismatch-repair-deficient adrenocortical carcinoma (Lynch syndrome; checkpoint inhibitor responsive)"],"biomarkers":["Ki-67 index and tumour burden (pace of disease)","Hormone profile, above all cortisol (steroid blockade)","Plasma mitotane level (14 to 20 mg/L)","Mismatch repair status and tumour mutational burden (immunotherapy)","Germline TP53 and Lynch syndrome testing","Molecular subgroups (CIMP-high, C1A) as prognostic markers in research"],"standardOfCare":[{"setting":"All patients","approach":"Mitotane from diagnosis with glucocorticoid replacement; adrenal enzyme inhibitors (metyrapone, osilodrostat, ketoconazole) for cortisol excess; thromboprophylaxis and infection vigilance.","refs":["mitotane"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}},{"setting":"Low-burden, indolent disease","approach":"Mitotane alone, with resection, thermal ablation or stereotactic radiotherapy of limited metastases.","refs":["mitotane","thermal-ablation","sbrt","adrenalectomy"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}},{"setting":"High-burden or progressive disease, first line","approach":"Etoposide, doxorubicin and cisplatin with mitotane (EDP-M, FIRM-ACT).","refs":["etoposide","doxorubicin","cisplatin","mitotane","cytotoxic-chemotherapy"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}},{"setting":"After EDP-M","approach":"Gemcitabine with capecitabine; cabozantinib; pembrolizumab, especially for mismatch-repair-deficient tumours; streptozocin-mitotane; clinical trials.","refs":["gemcitabine","capecitabine","cabozantinib","pembrolizumab","checkpoint-inhibitor","kinase-inhibitors"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}},{"setting":"Trials","approach":"Relacorilant with checkpoint inhibition for cortisol-secreting tumours; cabozantinib with immunotherapy; radiolabelled CYP11B tracers.","refs":["relacorilant","cabozantinib","pembrolizumab"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}}],"stateOfArt":["FIRM-ACT gave the disease its only randomised first-line standard.","Controlling cortisol excess is as important as controlling the tumour.","Immunotherapy helps a minority, and combinations that overcome cortisol-driven immunosuppression are the main hope."],"history":[{"year":1990,"title":"Etoposide, doxorubicin and cisplatin with mitotane (Berruti regimen) developed in Italy","refs":["etoposide","doxorubicin","cisplatin","mitotane"]},{"year":2012,"title":"FIRM-ACT: EDP-M beats streptozocin-mitotane on response and progression-free survival","refs":["etoposide","doxorubicin","cisplatin","mitotane"]},{"year":2015,"title":"Linsitinib phase 3 fails: IGF-1 receptor blockade does not work","refs":[]},{"year":2020,"title":"Pembrolizumab phase 2 trials report responses in about a fifth of patients","refs":["pembrolizumab"]},{"year":2024,"title":"Cabozantinib phase 2 reports disease control in advanced adrenocortical carcinoma","refs":["cabozantinib"]}],"pipeline":["cabozantinib","pembrolizumab","relacorilant","mitotane"],"openProblems":["No second-line therapy has randomised evidence.","Most tumours are immunologically cold and cortisol excess worsens that.","Mitotane's narrow therapeutic window and slow onset limit it in fast disease.","The rarity of the disease has meant only one completed phase 3 trial in fifty years."],"parent":"adrenocortical"},{"id":"advanced-small-bowel-adenocarcinoma","kind":"cancer","name":"Advanced and metastatic small bowel adenocarcinoma","aka":["Metastatic small bowel adenocarcinoma","Stage IV SBA","Unresectable small intestine adenocarcinoma","Recurrent small bowel adenocarcinoma"],"tldr":"Advanced small bowel adenocarcinoma is cancer of the small intestine that has spread to the liver, peritoneum or elsewhere, treated with the chemotherapy used for bowel cancer, oxaliplatin with a fluoropyrimidine, then taxanes or irinotecan. The exception is the sizeable minority with mismatch-repair-deficient tumours, for whom the immunotherapy pembrolizumab works far better than chemotherapy.","summary":"Metastatic small bowel adenocarcinoma has been treated for two decades with regimens borrowed from colorectal cancer, guided by phase 2 trials rather than randomised evidence. Capecitabine with oxaliplatin (CAPOX) produced responses in about half of patients in a phase 2 trial at MD Anderson (Journal of Clinical Oncology 2009) and, with FOLFOX, became the first-line standard; FOLFIRI is used in second line, and a randomised Japanese phase 2 and a French cohort supported these choices. Bevacizumab is added by analogy with colon cancer, while anti-EGFR antibodies are not used because the tumours behave more like gastric than colorectal cancer in that respect and are usually KRAS mutant or otherwise unresponsive. In the BALLAD era, the NCCN guideline lists taxane-based regimens as a further option, reflecting the tumour's kinship with gastric adenocarcinoma.\n\nThe molecular exceptions matter more than in colon cancer. Mismatch repair deficiency, found in a larger proportion of small bowel than colorectal adenocarcinomas, predicts benefit from pembrolizumab, approved for all mismatch-repair-deficient solid tumours in 2017 and recommended in first line for these patients; the ZEBRA phase 2 trial of pembrolizumab in unselected small bowel adenocarcinoma found responses concentrated in the mismatch-repair-deficient minority. HER2 amplification or mutation occurs in a subset and responds to trastuzumab-based therapy or trastuzumab deruxtecan in tumour-agnostic trials, and comprehensive genomic profiling is recommended for every patient with advanced disease. Resection of limited liver or peritoneal metastases and cytoreductive surgery with HIPEC are considered in selected patients, and circulating tumour DNA is being explored for monitoring. Survival remains shorter than in colorectal cancer, in part because the tumours respond less and in part because they are diagnosed late.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Small_intestine_cancer","links":[{"label":"CAPOX phase 2 in small bowel adenocarcinoma (JCO 2009)","url":"https://doi.org/10.1200/JCO.2008.19.7145"},{"label":"NCCN Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Small_intestine_cancer"}],"tags":["subtype-page","gastrointestinal"],"related":["localised-small-bowel-adenocarcinoma","small-bowel","colorectal","msi-high-colorectal"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","checkpoint-inhibitor","cgp","hipec"],"targets":["her2","kras","pd1"],"drugs":["capox","folfox","folfiri","bevacizumab","paclitaxel","pembrolizumab","nivolumab","trastuzumab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":["msi","tumour-agnostic","peritoneal-metastasis"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-overman-capox-small-bowel-adenocarcinoma-jco-2009","paper-zebra-pembrolizumab-small-bowel-adenocarcinoma-ccr-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About a third of patients present with metastases, to the liver, peritoneum and distant nodes, and many more relapse after surgery; survival is shorter than in colorectal cancer stage for stage.","subtypes":["Synchronous metastatic small bowel adenocarcinoma (liver, peritoneum, distant nodes)","Recurrent small bowel adenocarcinoma after resection","Mismatch-repair-deficient advanced small bowel adenocarcinoma (pembrolizumab first line)","HER2-positive advanced small bowel adenocarcinoma (HER2-directed therapy)","Peritoneal metastases from small bowel adenocarcinoma (cytoreduction and HIPEC in selected patients)","Duodenal versus jejunoileal advanced adenocarcinoma"],"biomarkers":["Mismatch repair and microsatellite status (pembrolizumab)","HER2 amplification or ERBB2 mutation (HER2-directed therapy)","KRAS, BRAF and other alterations on comprehensive genomic profiling","Tumour mutational burden","CEA and CA 19-9 for monitoring","Circulating tumour DNA (investigational)"],"standardOfCare":[{"setting":"First line, mismatch-repair proficient","approach":"CAPOX or FOLFOX, with bevacizumab considered; taxane-based regimens as an alternative.","refs":["capox","folfox","bevacizumab","paclitaxel","cytotoxic-chemotherapy"],"guideline":{"version":"NCCN Guidelines: Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"}},{"setting":"First line, mismatch-repair deficient","approach":"Pembrolizumab (tumour-agnostic approval); nivolumab with ipilimumab as an alternative.","refs":["pembrolizumab","nivolumab","msi","mismatch-repair-msi","checkpoint-inhibitor"],"guideline":{"version":"NCCN Guidelines: Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"}},{"setting":"Second line","approach":"FOLFIRI or a taxane; pembrolizumab if mismatch-repair deficient and not yet given; trastuzumab-based therapy or trastuzumab deruxtecan for HER2-positive tumours.","refs":["folfiri","paclitaxel","pembrolizumab","trastuzumab-deruxtecan"],"guideline":{"version":"NCCN Guidelines: Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"}},{"setting":"Limited metastases","approach":"Resection of liver metastases or cytoreductive surgery with HIPEC for limited peritoneal disease in selected patients.","refs":["hepatectomy","hipec","peritoneal-metastasis"],"guideline":{"version":"NCCN Guidelines: Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"}},{"setting":"All patients","approach":"Comprehensive genomic profiling to find HER2, mismatch repair deficiency and rare actionable alterations; referral to trials.","refs":["cgp","tumour-agnostic"],"guideline":{"version":"NCCN Guidelines: Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"}}],"stateOfArt":["Oxaliplatin-fluoropyrimidine doublets remain first line on phase 2 evidence.","Pembrolizumab transforms outcomes for the mismatch-repair-deficient minority.","Genomic profiling finds HER2 and other targets in a further subset."],"history":[{"year":2009,"title":"CAPOX phase 2 establishes oxaliplatin-fluoropyrimidine as first-line therapy","refs":["capox"]},{"year":2017,"title":"Pembrolizumab approved for mismatch-repair-deficient solid tumours including small bowel adenocarcinoma","refs":["pembrolizumab","msi"]},{"year":2021,"title":"ZEBRA: pembrolizumab responses in unselected small bowel adenocarcinoma confined largely to mismatch-repair-deficient tumours","refs":["pembrolizumab"]},{"year":2024,"title":"Trastuzumab deruxtecan receives tumour-agnostic approval for HER2-positive solid tumours","refs":["trastuzumab-deruxtecan"]}],"pipeline":["pembrolizumab","trastuzumab-deruxtecan","signatera"],"openProblems":["No randomised phase 3 trial has ever been completed in advanced small bowel adenocarcinoma.","Mismatch-repair-proficient tumours have no effective immunotherapy.","Anti-EGFR and other colorectal targeted drugs do not translate.","Rarity makes trials slow and most evidence is retrospective."],"parent":"small-bowel"},{"id":"advanced-cutaneous-scc","kind":"cancer","name":"Advanced cutaneous squamous cell carcinoma","aka":["Locally advanced cutaneous squamous cell carcinoma","Metastatic cutaneous squamous cell carcinoma","Advanced cSCC","Unresectable skin squamous cell carcinoma"],"tldr":"Advanced cutaneous squamous cell carcinoma is a skin cancer that has grown beyond what surgery or radiotherapy can remove or has spread to lymph nodes or organs. Because sun damage gives it more mutations than almost any other cancer, immunotherapy works well: cemiplimab or pembrolizumab shrinks about half of tumours, often for years, and cemiplimab before surgery can make large tumours vanish.","summary":"Cutaneous squamous cell carcinoma arises from keratinocytes of sun-damaged skin and carries one of the highest mutation burdens of any human cancer, with TP53, NOTCH1 and CDKN2A mutations in most tumours. High-risk features are size over 2 centimetres, depth beyond fat, perineural or lymphovascular invasion, poor differentiation, ear or lip site and immunosuppression; these tumours recur, spread to parotid and cervical nodes and account for most deaths. Advanced disease is defined as locally advanced disease not curable by surgery or radiotherapy, or nodal or distant metastasis. Before 2018 the only systemic options were cetuximab, with responses in about a quarter of patients, and platinum-based chemotherapy with short-lived responses.\n\nEMPOWER-CSCC-1 (2018) showed the PD-1 antibody cemiplimab produced responses in 47 percent of patients with metastatic disease and 46 percent in the pooled analysis of 193 patients, most of them durable, and it became the first approved drug for the disease in September 2018. KEYNOTE-629 (2020) found pembrolizumab produced responses in 34 percent of recurrent or metastatic and 50 percent of locally advanced tumours, and cosibelimab, a PD-L1 antibody, was approved in December 2024. Responses are less frequent in transplant recipients, in whom PD-1 blockade also risks graft rejection, and switching immunosuppression to a mammalian target of rapamycin inhibitor is one strategy.\n\nImmunotherapy is now moving earlier. Neoadjuvant cemiplimab for stage II to IV resectable disease produced pathological complete responses in 51 percent and major pathological responses in 63 percent of 79 patients (2022), allowing smaller operations and sometimes omission of radiotherapy. C-POST (2025) randomised patients with high-risk disease after surgery and radiotherapy to adjuvant cemiplimab or placebo and cut the risk of recurrence or death by about two thirds, making it the first positive adjuvant trial in the disease. Intratumoural oncolytic virus RP1 with cemiplimab, photoimmunotherapy with cemiplimab, an EGFR-directed antibody-drug conjugate and intralesional cemiplimab for early lesions are in trials.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Squamous-cell_carcinoma_of_the_skin","links":[{"label":"EMPOWER-CSCC-1 (NEJM 2018)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa1805131"},{"label":"Neoadjuvant cemiplimab (NEJM 2022)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2209813"},{"label":"C-POST (NEJM 2025)","url":"https://doi.org/10.1056/NEJMoa2502449"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Squamous-cell_carcinoma_of_the_skin"}],"tags":["subtype-page"],"related":["cutaneous-scc","head-and-neck","locally-advanced-bcc","merkel-cell-carcinoma"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","mohs-surgery","imrt-igrt","superficial-radiotherapy","oncolytic-virus","photoimmunotherapy"],"targets":["pd1","pdl1","egfr"],"drugs":["cemiplimab","pembrolizumab","cosibelimab","cetuximab"],"companies":[],"institutions":[],"pathways":[],"terms":["tmb","neoadjuvant-adjuvant","pcr","skin-cancer-after-organ-transplant","radiotherapy-for-skin-cancer"],"trials":["empower-cscc-1","keynote-629","nct04050436","c-post","neoadjuvant-cemiplimab-cscc","cemiplimab-kidney-transplant-cscc"],"people":[],"bottlenecks":[],"keyPapers":["paper-empower-cscc-1-cemiplimab-migden-nejm-2018","paper-keynote-629-pembrolizumab-cscc-grob-jco-2020","paper-c-post-adjuvant-cemiplimab-nejm-2025","paper-gross-neoadjuvant-cemiplimab-cscc-nejm-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"skin","burden":"Cutaneous squamous cell carcinoma is the second commonest skin cancer and most are cured by excision, but a few percent recur locally beyond surgical control or spread to lymph nodes and distant sites; the risk is highest in organ-transplant recipients and other immunosuppressed people, in whom the disease is many times commoner and more aggressive.","subtypes":["Locally advanced cutaneous squamous cell carcinoma (unresectable, not curable by radiotherapy)","Nodal metastatic cutaneous squamous cell carcinoma (parotid and cervical nodes)","Distant metastatic cutaneous squamous cell carcinoma","High-risk resectable disease (neoadjuvant cemiplimab, adjuvant C-POST)","Cutaneous squamous cell carcinoma in organ-transplant recipients and other immunosuppressed patients","Keratinocyte cancer with perineural invasion"],"biomarkers":["Tumour mutational burden (very high; ultraviolet signature)","Perineural and lymphovascular invasion","Depth of invasion and differentiation grade","Immunosuppression status (transplant, chronic lymphocytic leukaemia, HIV)","PD-L1 expression (not required for treatment)","Pathological response after neoadjuvant immunotherapy"],"standardOfCare":[{"setting":"High-risk resectable disease","approach":"Excision with margin control or Mohs surgery, nodal evaluation, and postoperative radiotherapy for perineural invasion, positive margins or nodal disease; neoadjuvant cemiplimab to shrink large tumours before surgery.","refs":["mohs-surgery","imrt-igrt","cemiplimab","sentinel-node"],"guideline":{"version":"NCCN Guidelines: Squamous Cell Skin Cancer"}},{"setting":"Adjuvant after surgery and radiotherapy","approach":"Cemiplimab for high-risk disease (C-POST, 2025).","refs":["cemiplimab"],"guideline":{"version":"C-POST (NEJM 2025)","url":"https://doi.org/10.1056/NEJMoa2502449"}},{"setting":"Locally advanced or metastatic, first line","approach":"Cemiplimab (EMPOWER-CSCC-1), pembrolizumab (KEYNOTE-629) or cosibelimab; radiotherapy for symptomatic sites.","refs":["empower-cscc-1","keynote-629","cemiplimab","pembrolizumab","cosibelimab","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Squamous Cell Skin Cancer"}},{"setting":"Immunotherapy-ineligible or refractory","approach":"Cetuximab with or without radiotherapy, platinum-based chemotherapy, capecitabine; clinical trials of RP1 with cemiplimab or photoimmunotherapy.","refs":["cetuximab","carboplatin","nct04050436","nct04305795","vusolimogene-oderparepvec"],"guideline":{"version":"NCCN Guidelines: Squamous Cell Skin Cancer"}},{"setting":"Transplant recipients","approach":"Reduce immunosuppression and switch to sirolimus or everolimus where possible; PD-1 blockade only after weighing graft rejection risk; surgery and radiotherapy preferred.","refs":["everolimus","cemiplimab"],"guideline":{"version":"NCCN Guidelines: Squamous Cell Skin Cancer"}}],"stateOfArt":["PD-1 blockade produces durable responses in about half of patients with advanced disease, where chemotherapy and cetuximab gave brief responses in a quarter.","Neoadjuvant cemiplimab eliminates the tumour in about half of resectable high-risk cases and adjuvant cemiplimab (C-POST) is the first proven adjuvant therapy.","Immunosuppressed patients remain the hardest group because the drugs that work best threaten the transplanted organ."],"history":[{"year":2011,"title":"Cetuximab phase 2: responses in about a quarter of unresectable tumours","refs":["cetuximab"]},{"year":2018,"title":"EMPOWER-CSCC-1: cemiplimab is the first approved systemic therapy","refs":["empower-cscc-1","cemiplimab"]},{"year":2020,"title":"KEYNOTE-629: pembrolizumab approved for recurrent or metastatic disease","refs":["keynote-629","pembrolizumab"]},{"year":2022,"title":"Neoadjuvant cemiplimab: pathological complete response in 51 percent (NEJM)","refs":["cemiplimab"]},{"year":2024,"title":"Cosibelimab approved","refs":["cosibelimab"]},{"year":2025,"title":"C-POST: adjuvant cemiplimab cuts recurrence after surgery and radiotherapy","refs":["cemiplimab"]}],"pipeline":["nct04050436","nct04305795","nct06585410","hmbd-001","cosibelimab","vusolimogene-oderparepvec","cemiplimab"],"openProblems":["Transplant recipients, who have the highest incidence, cannot safely receive the most effective drugs.","About half of patients do not respond to PD-1 blockade and there is no approved second-line therapy.","How much surgery and radiotherapy can be omitted after a complete neoadjuvant response is unsettled."],"parent":"cutaneous-scc"},{"id":"hcc-advanced","kind":"cancer","name":"Advanced hepatocellular carcinoma (BCLC C)","aka":["Advanced-stage HCC","Unresectable hepatocellular carcinoma","Metastatic hepatocellular carcinoma","HCC with portal vein invasion","BCLC C"],"tldr":"Advanced hepatocellular carcinoma has invaded the liver's veins or spread beyond it. Sorafenib was the only drug for a decade; now the combination of the immunotherapy atezolizumab with the anti-angiogenic antibody bevacizumab, or the two-antibody regimen durvalumab with tremelimumab, is standard first line, and several further drugs follow it.","summary":"BCLC stage C is defined by macrovascular invasion, extrahepatic spread or cancer-related symptoms in a patient with preserved liver function (Child-Pugh A) and good performance status; patients with decompensated cirrhosis are stage D and are treated for the liver disease alone. Diagnosis by imaging is usual, but biopsy is increasingly taken for trials and to exclude combined hepatocellular-cholangiocarcinoma. Because outcomes depend on the liver as much as the tumour, ALBI grade, portal hypertension, varices and hepatitis B control are assessed before any drug is started.\n\nSorafenib, a multikinase inhibitor, was the first drug to extend survival: SHARP (NEJM 2008) improved median overall survival from 7.9 to 10.7 months, and nothing beat it for ten years until lenvatinib proved non-inferior in REFLECT (Lancet 2018) with a median of 13.6 against 12.3 months. IMbrave150 (NEJM 2020) then showed that atezolizumab with bevacizumab beat sorafenib, with a median overall survival of 19.2 months against 13.4 in the updated analysis, and it became the first-line standard; endoscopy for varices is required before starting because bevacizumab raises bleeding risk. HIMALAYA (NEJM Evidence 2022) showed that a single priming dose of tremelimumab with durvalumab (the STRIDE regimen) also beat sorafenib, with a median of 16.4 against 13.8 months and about one in five patients alive at five years, giving a chemotherapy-free option for patients who cannot have bevacizumab. CheckMate 9DW (Lancet 2025) added nivolumab with ipilimumab, which beat lenvatinib or sorafenib with a median of 23.7 against 20.6 months, and in China camrelizumab with rivoceranib beat sorafenib in CARES-310.\n\nAfter first-line therapy the evidence is thinner, because the second-line drugs were tested after sorafenib: regorafenib (RESORCE, 10.6 against 7.8 months), cabozantinib (CELESTIAL, 10.2 against 8.0 months) and ramucirumab for patients with alpha-fetoprotein of 400 or above (REACH-2, 8.5 against 7.3 months). Lenvatinib or sorafenib is commonly given after immunotherapy, and trials now test the sequence properly. Radiotherapy or radioembolisation to a portal vein tumour thrombus, hepatic artery infusion chemotherapy in Asia and treatment of bone or brain metastases are added as needed, with liver function the constant limit.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Hepatocellular_carcinoma","links":[{"label":"SHARP (NEJM 2008)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa0708857"},{"label":"IMbrave150 (NEJM 2020)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa1915745"},{"label":"HIMALAYA (NEJM Evidence 2022)","url":"https://evidence.nejm.org/doi/full/10.1056/EVIDoa2100070"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Hepatocellular_carcinoma"}],"tags":["subtype-page"],"related":["hcc-early","hcc-intermediate"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["reach-2"],"people":[],"bottlenecks":[],"keyPapers":["paper-imbrave150-nejm-2020","paper-himalaya-nejm-evidence-2022","paper-sharp-sorafenib-nejm-2008","paper-reflect-lenvatinib-lancet-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Hepatocellular carcinoma that has invaded the portal or hepatic veins, spread outside the liver or caused symptoms, while liver function is still preserved; the stage most patients reach in countries without surveillance, and the one where drug therapy has changed most in the last decade.","subtypes":["HCC with portal vein invasion (macrovascular invasion, BCLC C)","HCC with extrahepatic spread (lung, bone, nodes)","Symptomatic HCC with preserved liver function","Advanced HCC after progression on immunotherapy","Advanced HCC in hepatitis B carriers (antiviral cover during treatment)"],"biomarkers":["Child-Pugh A and ALBI grade (eligibility for all trials)","Alpha-fetoprotein 400 or above (ramucirumab)","Portal vein tumour thrombus extent","Varices on endoscopy before bevacizumab","Hepatitis B DNA and antiviral cover","Aetiology (viral versus non-viral) as a possible modifier of immunotherapy benefit"],"standardOfCare":[{"setting":"First line","approach":"Atezolizumab with bevacizumab (IMbrave150) after endoscopic assessment of varices, or durvalumab with a single dose of tremelimumab (HIMALAYA); nivolumab with ipilimumab (CheckMate 9DW) where approved.","refs":["imbrave150","himalaya","checkmate-9dw","atezolizumab","bevacizumab","durvalumab","tremelimumab","nivolumab","ipilimumab","child-pugh"]},{"setting":"First line when immunotherapy is unsuitable","approach":"Lenvatinib (REFLECT) or sorafenib (SHARP), for example after liver transplantation or with active autoimmune disease.","refs":["reflect","sharp","lenvatinib","sorafenib"]},{"setting":"Second line and beyond","approach":"Lenvatinib or sorafenib after immunotherapy; regorafenib (RESORCE), cabozantinib (CELESTIAL) or ramucirumab when alpha-fetoprotein is 400 or above, all proven after sorafenib.","refs":["resorce","celestial","regorafenib","cabozantinib","ramucirumab","lenvatinib","sorafenib","afp"]},{"setting":"Portal vein tumour thrombus","approach":"Radiotherapy or radioembolisation to the thrombus alongside systemic therapy; hepatic artery infusion chemotherapy in Asian centres.","refs":["portal-vein-tumour-thrombus","sbrt","radioembolisation-tare"]},{"setting":"Liver disease during treatment","approach":"Antiviral therapy for hepatitis B, variceal management and monitoring of liver function, which decides whether further lines are possible.","refs":["hbv-hcv","child-pugh"]}],"stateOfArt":["Immunotherapy combinations have roughly doubled median survival compared with the sorafenib era and produce a tail of long-term survivors.","Four positive first-line regimens now exist, and the choice rests on bleeding risk, autoimmune disease and transplant history.","Every second-line drug was proven after sorafenib, so sequencing after immunotherapy is guided by inference rather than trials."],"history":[{"year":2008,"title":"SHARP: sorafenib is the first drug to extend survival in advanced HCC","refs":["sharp","sorafenib"]},{"year":2017,"title":"RESORCE: regorafenib works after sorafenib","refs":["resorce","regorafenib"]},{"year":2018,"title":"REFLECT: lenvatinib non-inferior to sorafenib; CELESTIAL: cabozantinib in later lines","refs":["reflect","lenvatinib","celestial","cabozantinib"]},{"year":2020,"title":"IMbrave150: atezolizumab plus bevacizumab beats sorafenib","refs":["imbrave150","atezolizumab","bevacizumab"]},{"year":2022,"title":"HIMALAYA: durvalumab plus tremelimumab (STRIDE) beats sorafenib","refs":["himalaya","durvalumab","tremelimumab"]},{"year":2025,"title":"CheckMate 9DW: nivolumab plus ipilimumab beats lenvatinib or sorafenib","refs":["checkmate-9dw","nivolumab","ipilimumab"]}],"pipeline":["checkmate-9dw","camrelizumab-rivoceranib","ivonescimab","livmoniplimab","cobolimab","gpc3","car-t","cabozantinib"],"openProblems":["No trial has defined the best drug after progression on immunotherapy.","Patients with Child-Pugh B liver function are excluded from trials yet make up a large share of the clinic.","Non-viral (metabolic) HCC may benefit less from immunotherapy, and the reason is unclear."],"parent":"hcc"},{"id":"advanced-melanoma","kind":"cancer","name":"Advanced melanoma (unresectable stage III and stage IV)","aka":["Metastatic melanoma","Stage IV melanoma","Unresectable melanoma","First-line advanced melanoma"],"tldr":"Advanced melanoma has spread beyond what surgery can remove, and it is the cancer in which immunotherapy first proved it could cure some people: about half of those given nivolumab with ipilimumab are alive ten years later. If immunotherapy fails, options include a cell therapy grown from the patient's own immune cells, a virus injected into the tumour, and targeted pills for BRAF-mutant disease.","summary":"Until 2011 advanced melanoma was treated with dacarbazine, which shrank about one tumour in ten, or high-dose interleukin-2, which produced rare durable remissions at great toxicity; median survival was six to nine months. Ipilimumab (2010) was the first drug to lengthen survival, from 6.4 to 10.1 months, and produced a plateau with about one in five patients alive long term. PD-1 blockade then transformed the disease: in KEYNOTE-006 pembrolizumab beat ipilimumab with ten-year survival of 34.0 against 23.6 percent, and in CheckMate 067 nivolumab plus ipilimumab, nivolumab and ipilimumab gave ten-year survival of 43, 37 and 19 percent. RELATIVITY-047 (2022) added the LAG-3 antibody relatlimab to nivolumab and lengthened progression-free survival from 4.6 to 10.1 months with about a third of the severe toxicity of the ipilimumab combination.\n\nFirst-line choice therefore lies between nivolumab-ipilimumab (deepest and longest data, most toxic), nivolumab-relatlimab (less toxic, no proven survival advantage over nivolumab alone) and anti-PD-1 monotherapy for frail patients, with treatment stopped after two years or after a confirmed complete response (KEYNOTE-006). BRAF-mutant patients are treated with immunotherapy first and BRAF-MEK inhibitors second on the DREAMseq result, unless rapid control is needed. Asymptomatic brain metastases respond to nivolumab-ipilimumab (intracranial clinical benefit 57 percent in CheckMate 204) and are treated with drugs first, with radiosurgery for symptomatic or progressing lesions; the details are on the brain metastases page.\n\nAfter PD-1 failure, tumour-infiltrating lymphocyte therapy produced responses in 31 percent of heavily pretreated patients in C-144-01, and the Dutch randomised trial found progression-free survival of 7.2 against 3.1 months for TIL versus ipilimumab; lifileucel became the first approved cell therapy for a solid tumour in February 2024. The oncolytic virus RP1 (vusolimogene oderparepvec) with nivolumab was approved in 2026 for PD-1-refractory disease, and ipilimumab-based combinations, clinical trials and, for the rare KIT-mutant tumour, imatinib remain options. Fianlimab plus cemiplimab, the PRAME-directed bispecific brenetafusp, the PRAME TCR-T cell therapy IMA203, faecal microbiota transplantation to reverse PD-1 resistance and first-line lifileucel with pembrolizumab (TILVANCE-301) are in phase 3 or pivotal trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Melanoma","links":[{"label":"CheckMate 067 ten-year results (NEJM 2025)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2407417"},{"label":"KEYNOTE-006 ten-year follow-up (Annals of Oncology 2024)","url":"https://www.annalsofoncology.org/article/S0923-7534(24)03910-3/fulltext"},{"label":"Dutch TIL trial (NEJM 2022)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2210233"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Melanoma"}],"tags":["subtype-page"],"related":["secondary-brain-tumours","braf-v600-melanoma","uveal-melanoma","stage-iii-melanoma","mucosal-melanoma","acral-melanoma"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","til-therapy","oncolytic-virus","lag3-blockade","tcr-t","radiosurgery-srs"],"targets":["pd1","ctla4","lag3","braf","kit","prame"],"drugs":["nivolumab","ipilimumab","pembrolizumab","relatlimab-nivolumab","lifileucel","vusolimogene-oderparepvec","talimogene-laherparepvec","dacarbazine","aldesleukin"],"companies":[],"institutions":[],"pathways":["pd1-checkpoint","ras-mapk"],"terms":["fixed-duration","brain-metastases","irae","interferon-gamma-signature"],"trials":["checkmate-067","relativity-047","keynote-006","dreamseq","checkmate-204","c-144-01","combi-d","cobrim","columbus"],"people":["jedd-wolchok","james-larkin","caroline-robert","hussein-tawbi","f-stephen-hodi","michael-postow","antoni-ribas"],"bottlenecks":[],"keyPapers":["paper-checkmate-067-10-year-nejm-2025","paper-relativity-047-nejm-2022","paper-keynote-006-pembrolizumab-ipilimumab-melanoma-nejm-2015","paper-c-144-01-lifileucel-melanoma-jco-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"skin","burden":"Roughly one in ten melanomas presents with or progresses to unresectable or metastatic disease; before 2011 median survival was under a year, and about half of patients treated with the nivolumab and ipilimumab combination are now alive at ten years.","subtypes":["Unresectable stage III (in-transit or nodal disease beyond surgery)","Stage IV M1a to M1c (skin, nodes, lung, other viscera)","Stage IV M1d (brain metastases; see the brain metastases page)","BRAF V600-mutant advanced melanoma (targeted therapy option)","PD-1-refractory melanoma (cell therapy, oncolytic virus, trials)","Acral and mucosal primaries (lower immunotherapy response rates)"],"biomarkers":["BRAF V600 mutation (decides the targeted-therapy option)","Lactate dehydrogenase (prognostic and part of staging)","PD-L1 expression (weakly predictive; not used to withhold therapy)","Tumour mutational burden and interferon-gamma signature (exploratory)","NRAS and KIT mutations (trial eligibility, imatinib in KIT-mutant disease)","HLA-A*02:01 (tebentafusp eligibility in uveal melanoma only)"],"standardOfCare":[{"setting":"First line, fit patient","approach":"Nivolumab plus ipilimumab (CheckMate 067) or nivolumab plus relatlimab (RELATIVITY-047); anti-PD-1 monotherapy where toxicity must be minimised (KEYNOTE-006). Immunotherapy first even when BRAF-mutant (DREAMseq).","refs":["checkmate-067","relativity-047","keynote-006","dreamseq","nivolumab","ipilimumab","relatlimab-nivolumab","pembrolizumab"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"BRAF V600-mutant, after immunotherapy or when rapid control is needed","approach":"Dabrafenib-trametinib, encorafenib-binimetinib or vemurafenib-cobimetinib.","refs":["braf-v600-melanoma","dabrafenib-trametinib","encorafenib","binimetinib","columbus","combi-d","cobrim"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Brain metastases","approach":"Nivolumab plus ipilimumab first for asymptomatic lesions (CheckMate 204); radiosurgery for symptomatic or progressing lesions; dabrafenib-trametinib in BRAF-mutant disease needing fast control. See the brain metastases page.","refs":["checkmate-204","secondary-brain-tumours","radiosurgery-srs","nivolumab","ipilimumab"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"After PD-1 failure","approach":"Lifileucel TIL therapy (C-144-01); RP1 with nivolumab; ipilimumab-based combinations; clinical trials; imatinib for KIT-mutant tumours.","refs":["lifileucel","c-144-01","til-therapy","vusolimogene-oderparepvec","ipilimumab","imatinib"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Treatment duration","approach":"Stop anti-PD-1 therapy after two years or after a confirmed complete response; most remissions hold off treatment (KEYNOTE-006).","refs":["keynote-006","fixed-duration"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Oligometastatic disease","approach":"Surgery or radiosurgery for isolated metastases alongside systemic therapy; isolated limb perfusion for limb-confined disease.","refs":["radiosurgery-srs","isolated-limb-perfusion"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}}],"stateOfArt":["About half of patients treated with nivolumab plus ipilimumab are alive at ten years, the longest immunotherapy follow-up in any cancer.","Lifileucel is the first approved cell therapy for a solid tumour and RP1 the second approved oncolytic virus, both for PD-1-refractory disease.","Immunotherapy first, targeted therapy second is the settled sequence for BRAF-mutant disease."],"history":[{"year":1975,"title":"Dacarbazine approved: about one in ten tumours respond","refs":["dacarbazine"]},{"year":1998,"title":"High-dose interleukin-2 approved for rare durable remissions","refs":["aldesleukin"]},{"year":2010,"title":"Ipilimumab is the first drug to lengthen survival in advanced melanoma","refs":["ipilimumab"]},{"year":2014,"title":"Pembrolizumab and nivolumab approved; KEYNOTE-006 shows PD-1 beats CTLA-4 blockade","refs":["pembrolizumab","nivolumab","keynote-006"]},{"year":2015,"title":"CheckMate 067: nivolumab plus ipilimumab; T-VEC first oncolytic virus","refs":["checkmate-067","talimogene-laherparepvec"]},{"year":2018,"title":"CheckMate 204: immunotherapy doublet works in the brain","refs":["checkmate-204"]},{"year":2022,"title":"RELATIVITY-047: nivolumab plus relatlimab approved; Dutch trial shows TIL beats ipilimumab","refs":["relativity-047","relatlimab-nivolumab","til-therapy"]},{"year":2024,"title":"Lifileucel: first approved cell therapy for a solid tumour","refs":["lifileucel","c-144-01"]},{"year":2025,"title":"CheckMate 067 ten-year results: 43 percent alive on the combination","refs":["checkmate-067"]},{"year":2026,"title":"RP1 with nivolumab approved for PD-1-refractory melanoma","refs":["vusolimogene-oderparepvec"]}],"pipeline":["fianlimab-phase3-melanoma","fianlimab","prism-mel-301","brenetafusp","nct06743126","ima203","nct05727904","lifileucel","vusolimogene-oderparepvec","fmt-checkpoint-nonresponders","nct05155254","io102-io103","nct06697301","eik1001","seacraft-2","nct06008106","tunlametinib","nct05625399"],"openProblems":["About four in ten patients never respond to PD-1 blockade and no biomarker reliably identifies them.","Who needs the ipilimumab component and its toxicity, and whether relatlimab can replace it, has not been settled.","Acral, mucosal and uveal melanomas respond far less well and have few dedicated trials."],"parent":"melanoma"},{"id":"advanced-recurrent-endometrial-cancer","kind":"cancer","name":"Advanced or recurrent endometrial cancer","aka":["Stage III to IV endometrial cancer","Metastatic endometrial cancer","Relapsed endometrial cancer","Primary advanced endometrial cancer"],"tldr":"Advanced or recurrent endometrial cancer has spread beyond the uterus or come back after treatment. Chemotherapy plus an immune checkpoint antibody is now the first treatment for everyone, with the biggest gains in mismatch-repair-deficient tumours, and lenvatinib with pembrolizumab is the standard when platinum chemotherapy stops working.","summary":"Advanced disease means stage III with nodal or adnexal spread or stage IV with bladder, bowel or distant metastasis, and recurrence after primary treatment behaves in the same way. Treatment begins with surgery where debulking is feasible, then systemic therapy chosen by mismatch-repair status and, increasingly, HER2 and hormone receptor status. Carboplatin-paclitaxel had been the first-line standard since GOG-0209 showed it as effective as and less toxic than the older three-drug regimen, and for pelvic-confined recurrence radiotherapy or exenteration can still be curative.\n\nThree phase 3 trials reported in 2023 changed first-line care. RUBY added dostarlimab to carboplatin-paclitaxel and extended median overall survival in the whole population from 28.2 to 44.6 months, with a hazard ratio of 0.69 and a progression-free survival hazard ratio of 0.28 in mismatch-repair-deficient tumours. NRG-GY018 added pembrolizumab and cut the hazard of progression to 0.30 in deficient and 0.54 in proficient tumours. DUO-E added durvalumab, with a hazard ratio of 0.42 in deficient tumours, and durvalumab plus olaparib maintenance gave 0.57 in proficient tumours. Regulators approved pembrolizumab and dostarlimab with chemotherapy for all comers in 2024, and the gain in proficient disease, though real, is smaller and the subject of debate about cost and toxicity.\n\nAfter platinum, KEYNOTE-775 established lenvatinib with pembrolizumab, which extended median survival from 11.4 to 18.3 months against doxorubicin or weekly paclitaxel in mismatch-repair-proficient disease, at the price of hypertension, fatigue and diarrhoea that force dose reductions in most patients. Trastuzumab deruxtecan gives responses in HER2-expressing tumours after DESTINY-PanTumor02, endocrine therapy suits low-grade receptor-positive disease, and antibody-drug conjugates against TROP2 and folate receptor alpha (sacituzumab tirumotecan, rinatabart sesutecan) are in phase 3. Maintenance selinexor in TP53-wild-type disease failed in XPORT-EC-042 in 2026, and the sequencing of these agents after first-line immunotherapy is the open clinical question.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Endometrial_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Endometrial_cancer"}],"tags":["subtype-page"],"related":["endometrial-nsmp","endometrial-mmr-deficient","endometrial-p53-abnormal","endometrial-pole-ultramutated","uterine-carcinosarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-ruby-nejm-2023","paper-nrg-gy018-nejm-2023","paper-keynote-775-nejm-2022","paper-duo-e-jco-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"Around one in five endometrial cancers present at stage III or IV or relapse after treatment; this is the group in which mortality from the disease is rising in many countries, and the group that immunotherapy has transformed since 2023.","subtypes":["Primary stage III to IV endometrial cancer","First recurrence after surgery with or without adjuvant therapy","Mismatch-repair-deficient advanced disease (largest immunotherapy benefit)","Mismatch-repair-proficient, p53-abnormal or NSMP advanced disease","HER2-expressing advanced serous carcinoma","Isolated vaginal or pelvic recurrence (radiotherapy or surgery with curative intent)","Endometrioid low-grade recurrence (endocrine therapy)"],"biomarkers":["MMR and MSI status (drives the size of immunotherapy benefit)","p53 and POLE (molecular class)","HER2 immunohistochemistry (trastuzumab deruxtecan)","Oestrogen and progesterone receptors (endocrine therapy)","PD-L1 (not required)","TROP2 and folate receptor alpha (antibody-drug conjugate trials)","CA-125 for monitoring"],"standardOfCare":[{"setting":"First line, dMMR","approach":"Carboplatin-paclitaxel with dostarlimab (RUBY) or pembrolizumab (NRG-GY018), then maintenance immunotherapy for up to three years or two years respectively.","refs":["dostarlimab","pembrolizumab","carboplatin","paclitaxel","ruby","nrg-gy018-keynote-868","chemo-io-first-line-endometrial","msi"]},{"setting":"First line, pMMR","approach":"Carboplatin-paclitaxel with pembrolizumab or dostarlimab, or durvalumab followed by durvalumab-olaparib maintenance (DUO-E); trastuzumab added for HER2-positive serous carcinoma.","refs":["pembrolizumab","dostarlimab","durvalumab","olaparib","duo-e","trastuzumab","mss-pmmr"]},{"setting":"After platinum, pMMR","approach":"Lenvatinib with pembrolizumab (KEYNOTE-775); trastuzumab deruxtecan for HER2-expressing tumours; aromatase inhibitors or progestins for low-grade receptor-positive disease.","refs":["lenvatinib","pembrolizumab","keynote-775","trastuzumab-deruxtecan","destiny-pantumor02","letrozole","megestrol-progestins"]},{"setting":"After platinum, dMMR without prior immunotherapy","approach":"Single-agent dostarlimab or pembrolizumab.","refs":["dostarlimab","pembrolizumab","checkpoint-inhibitor"]},{"setting":"Isolated pelvic recurrence","approach":"Radiotherapy with brachytherapy for vaginal recurrence after surgery alone; exenteration in selected central recurrences after radiotherapy.","refs":["imrt-igrt","brachytherapy","radiotherapy"]}],"stateOfArt":["Chemo-immunotherapy is first-line standard for every advanced endometrial cancer since 2023, with RUBY showing a median survival gain of more than a year overall.","KEYNOTE-775 made lenvatinib-pembrolizumab the standard after platinum in proficient disease.","Antibody-drug conjugates against HER2, TROP2 and folate receptor alpha are the next wave."],"history":[{"year":1971,"title":"Progestins approved for advanced endometrial cancer","refs":["megestrol-progestins"]},{"year":2012,"title":"GOG-0209: carboplatin-paclitaxel as effective as and less toxic than TAP","refs":["carboplatin","paclitaxel"]},{"year":2021,"title":"KEYNOTE-775: lenvatinib-pembrolizumab extends survival after platinum","refs":["keynote-775"]},{"year":2023,"title":"RUBY, NRG-GY018 and DUO-E: chemo-immunotherapy first line","refs":["ruby","nrg-gy018-keynote-868","duo-e"]},{"year":2024,"title":"Pembrolizumab and dostarlimab approved with chemotherapy for all comers","refs":["pembrolizumab","dostarlimab"]},{"year":2026,"title":"XPORT-EC-042: maintenance selinexor fails in TP53-wild-type disease","refs":["xport-ec-042"]}],"pipeline":["sacituzumab-tirumotecan","rinatabart-sesutecan","rainfol-01","trastuzumab-deruxtecan","nct06989112","nct05173987","luveltamab-tazevibulin","saruparib","abemaciclib"],"openProblems":["What to give after progression on first-line immunotherapy.","The small benefit and real toxicity of immunotherapy in proficient tumours.","Rising mortality, especially among Black women in the United States, that new drugs have not yet reversed."],"parent":"endometrial"},{"id":"advanced-systemic-mastocytosis","kind":"cancer","name":"Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia)","aka":["AdvSM","Aggressive systemic mastocytosis","ASM","SM-AHN","Mast cell leukaemia","MCL"],"tldr":"Advanced systemic mastocytosis is the dangerous form of this rare blood cancer, in which KIT-mutant mast cells damage the marrow, liver, gut or bones, grow alongside a second blood cancer such as chronic myelomonocytic leukaemia, or flood the blood as mast cell leukaemia. The KIT-blocking tablets midostaurin and avapritinib have replaced older chemotherapy, and fit patients may have a transplant.","summary":"Advanced systemic mastocytosis comprises three WHO entities united by KIT D816V-driven mast cell proliferation with organ damage or an accompanying neoplasm. Aggressive systemic mastocytosis is defined by C findings: cytopenias from marrow infiltration, liver dysfunction with ascites, hypoalbuminaemia and weight loss from gut involvement, or large lytic bone lesions. Systemic mastocytosis with an associated haematological neoplasm (SM-AHN), the commonest advanced form, pairs mastocytosis with a myeloid neoplasm, usually chronic myelomonocytic leukaemia, a myelodysplastic or myeloproliferative neoplasm or acute myeloid leukaemia, which arises from the same KIT-mutant or an earlier clone and often carries SRSF2, ASXL1 or RUNX1 mutations that predict shorter survival on the MARS and IPSM scores. Mast cell leukaemia, with 20 percent or more mast cells in the marrow aspirate, is the rarest and most lethal form. Serum tryptase is usually very high and KIT D816V allele burden in blood reflects the whole disease.\n\nBefore 2017 treatment was cladribine, interferon alfa or hydroxycarbamide, with responses in a minority. Midostaurin, a multikinase inhibitor active against KIT D816V, produced responses in 60 percent of 116 patients with advanced disease in a phase 2 trial (New England Journal of Medicine 2016) and was approved in 2017; avapritinib, a selective KIT D816V inhibitor, produced responses in three quarters of patients in the EXPLORER and PATHFINDER trials with deep falls in tryptase and allele burden and was approved in June 2021 for advanced disease, restricted to patients with platelets of 50 x 10^9/L or more because of intracranial haemorrhage at higher doses in thrombocytopenic patients. Avapritinib is now the preferred first-line agent in the NCCN guideline, midostaurin the alternative, and bezuclastinib is in the Apex trial as a further selective inhibitor. The associated neoplasm is treated on its own merits, for example with azacitidine for chronic myelomonocytic leukaemia or intensive chemotherapy for acute myeloid leukaemia, and allogeneic transplantation is the only curative option, considered for mast cell leukaemia, aggressive disease responding to a KIT inhibitor and SM-AHN with a high-risk neoplasm. Supportive care for mediator symptoms, bone disease and anaphylaxis continues throughout.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Mastocytosis","links":[{"label":"Midostaurin in advanced SM (NEJM 2016)","url":"https://doi.org/10.1056/NEJMoa1513098"},{"label":"NCCN Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Mastocytosis"}],"tags":["subtype-page","haematologic"],"related":["indolent-systemic-mastocytosis","systemic-mastocytosis","cmml","aml-secondary"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","allogeneic-hsct","cgp","histopathology-ihc","liquid-biopsy"],"targets":["kit","flt3"],"drugs":["avapritinib","midostaurin","cladribine","interferon-alfa","azacitidine","bezuclastinib"],"companies":[],"institutions":[],"pathways":[],"terms":["cytopenias","molecular-response","driver-mutation"],"trials":["nct04996875"],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2022-myeloid-khoury-leukemia-2022","paper-gotlib-midostaurin-advanced-systemic-mastocytosis-nejm-2016","paper-pathfinder-avapritinib-advanced-systemic-mastocytosis-nat-med-2021","paper-explorer-avapritinib-advanced-systemic-mastocytosis-nat-med-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"A minority of systemic mastocytosis, mostly in older adults; survival was measured in months for mast cell leukaemia and a few years for aggressive disease before KIT inhibitors, and the associated haematological neoplasm often determines the outcome.","subtypes":["Aggressive systemic mastocytosis (C findings: cytopenias, liver, gut or bone damage)","Systemic mastocytosis with an associated haematological neoplasm (SM-AHN; usually CMML, MDS or MPN)","Systemic mastocytosis with acute myeloid leukaemia (SM-AML)","Mast cell leukaemia (20 percent or more marrow mast cells; acute or chronic)","Advanced systemic mastocytosis with SRSF2, ASXL1 or RUNX1 mutations (high-risk)","Advanced systemic mastocytosis with thrombocytopenia (avapritinib restricted)"],"biomarkers":["C findings (cytopenias, liver dysfunction, hypoalbuminaemia, malabsorption, lytic bone lesions)","Serum tryptase and KIT D816V allele burden (response and molecular remission)","Mast cell percentage in marrow aspirate (20 percent defines mast cell leukaemia)","SRSF2, ASXL1 and RUNX1 mutations; MARS and IPSM prognostic scores","Platelet count (avapritinib eligibility above 50 x 10^9/L)","Molecular and morphological characterisation of the associated neoplasm"],"standardOfCare":[{"setting":"Diagnosis and risk assessment","approach":"Bone marrow biopsy and aspirate, KIT D816V allele burden, myeloid mutation panel, tryptase, imaging for organomegaly and bone lesions, MARS or IPSM score.","refs":["histopathology-ihc","cgp","kit","cytopenias"],"guideline":{"version":"NCCN Guidelines: Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"First line","approach":"Avapritinib 200 mg daily when platelets are 50 x 10^9/L or more (EXPLORER, PATHFINDER, approved 2021); midostaurin as the alternative (approved 2017).","refs":["avapritinib","midostaurin","kit","kinase-inhibitors","explorer"],"guideline":{"version":"NCCN Guidelines: Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Associated haematological neoplasm","approach":"Treat the neoplasm on its own merits (azacitidine for CMML or MDS, intensive chemotherapy for AML) alongside or after KIT inhibition.","refs":["azacitidine","midostaurin"],"guideline":{"version":"NCCN Guidelines: Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Relapsed or intolerant","approach":"Switch between avapritinib and midostaurin; cladribine; interferon alfa; bezuclastinib in the Apex trial.","refs":["cladribine","interferon-alfa","bezuclastinib","nct04996875"],"guideline":{"version":"NCCN Guidelines: Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Fit patients, especially mast cell leukaemia or high-risk SM-AHN","approach":"Allogeneic haematopoietic cell transplantation after response to a KIT inhibitor.","refs":["allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}}],"stateOfArt":["KIT-selective inhibition with avapritinib produces deep molecular responses in most patients.","Midostaurin and avapritinib gave the disease its first approved drugs within four years.","Prognostic scores incorporating myeloid mutations guide the decision to transplant."],"history":[{"year":1991,"title":"Mast cell leukaemia and aggressive mastocytosis defined as distinct categories","refs":[]},{"year":2007,"title":"Cladribine reported as active in advanced mastocytosis","refs":["cladribine"]},{"year":2016,"title":"Midostaurin phase 2: 60 percent response rate in advanced systemic mastocytosis","refs":["midostaurin"]},{"year":2017,"title":"Midostaurin approved for advanced systemic mastocytosis","refs":["midostaurin"]},{"year":2021,"title":"Avapritinib approved for advanced systemic mastocytosis after EXPLORER and PATHFINDER","refs":["avapritinib"]},{"year":2022,"title":"WHO and ICC classifications update advanced disease criteria","refs":["kit"]}],"pipeline":["avapritinib","bezuclastinib","nct04996875","allogeneic-hsct"],"openProblems":["The associated myeloid neoplasm, not the mast cells, now causes most deaths in SM-AHN.","Whether KIT inhibitors improve survival has not been shown in a randomised trial.","Thrombocytopenic patients cannot receive avapritinib safely.","Transplant outcomes rest on small retrospective series."],"parent":"systemic-mastocytosis"},{"id":"advanced-stage-classical-hodgkin-lymphoma","kind":"cancer","name":"Advanced-stage classical Hodgkin lymphoma (stage III to IV)","aka":["Stage III to IV classical Hodgkin lymphoma","Advanced Hodgkin lymphoma","Disseminated Hodgkin lymphoma","High-risk Hodgkin lymphoma (IPS 4 or more)"],"tldr":"Advanced-stage classical Hodgkin lymphoma is Hodgkin lymphoma involving nodes on both sides of the diaphragm or organs such as the liver, lungs or bone marrow. It is treated with six cycles of combination chemotherapy, and two trials changed the standard: replacing bleomycin with brentuximab vedotin (ECHELON-1) and then with nivolumab (SWOG S1826), which cured more patients with less toxicity.","summary":"Advanced classical Hodgkin lymphoma was the first disseminated cancer cured by chemotherapy, with MOPP in the 1960s and then ABVD from 1975, and for forty years the argument was between ABVD and the more intensive escalated BEACOPP of the German Hodgkin Study Group, which cures more patients up front at the cost of infertility, leukaemia and toxicity. PET-adapted therapy eased the trade-off: the RATHL trial (New England Journal of Medicine 2016) showed bleomycin can be dropped after two cycles in PET-negative patients without loss of efficacy, and HD18 showed escalated BEACOPP can be shortened to four cycles in PET-negative patients. The International Prognostic Score, the Deauville score on interim PET and baseline metabolic tumour volume stratify risk.\n\nTwo trials then rebuilt the regimen. ECHELON-1 (New England Journal of Medicine 2018) randomised 1,334 patients to ABVD or to brentuximab vedotin with AVD (A+AVD), replacing bleomycin with the CD30 antibody-drug conjugate; modified progression-free survival improved and, in the six-year update (New England Journal of Medicine 2022), overall survival was higher with A+AVD (93.9 against 89.4 percent), the first survival gain in advanced Hodgkin lymphoma in a generation. SWOG S1826 (New England Journal of Medicine 2024) then randomised 994 patients aged 12 and over to A+AVD or to nivolumab with AVD (N+AVD): one-year progression-free survival was 94 against 86 percent with fewer peripheral neuropathy and infection problems and almost no radiotherapy, making N+AVD the preferred regimen in the NCCN guideline for adults and adolescents. In Europe, GHSG HD21 (Lancet 2024) showed that BrECADD, a brentuximab-containing variant of escalated BEACOPP, was less toxic and at least as effective as escalated BEACOPP with four-year progression-free survival of 94.3 against 90.9 percent, giving a second intensive PET-guided option. Paediatric groups are testing brentuximab vedotin and PD-1 antibodies in children with advanced disease, older patients receive AVD-based or brentuximab-sequenced regimens because bleomycin and BEACOPP are too toxic, and consolidation radiotherapy is now limited to residual PET-positive bulky disease.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Hodgkin_lymphoma","links":[{"label":"SWOG S1826 (NEJM 2024)","url":"https://doi.org/10.1056/NEJMoa2405888"},{"label":"ECHELON-1 (NEJM 2018)","url":"https://doi.org/10.1056/NEJMoa1708984"},{"label":"HD21 (Lancet 2024)","url":"https://doi.org/10.1016/S0140-6736(24)01315-1"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Hodgkin_lymphoma"},{"label":"Lymphoma Action: helpline services","url":"https://lymphoma-action.org.uk/information-and-support/support-you/helpline-services"},{"label":"Lymphoma Action: questions to ask your medical team about lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/questions-ask-your-medical-team-about-lymphoma"},{"label":"Lymphoma Action: follow-up after lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/follow-after-lymphoma-treatment"},{"label":"Lymphoma Action: infections, risk and prevention","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/infections-risk-and-prevention"},{"label":"Lymphoma Action: neutropenia (low neutrophils)","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/neutropenia-low-neutrophils"},{"label":"Lymphoma Action: cancer-related fatigue","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/cancer-related-fatigue"},{"label":"Lymphoma Action: lymphoma, work and you","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/day-day-living/lymphoma-work-and-you"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Lymphoma Action: classical Hodgkin lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/types-lymphoma/hodgkin-lymphoma/classical-hodgkin-lymphoma"},{"label":"Lymphoma Action: late effects of lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/late-effects-lymphoma-treatment"},{"label":"Johnson et al., adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma (RATHL), New England Journal of Medicine 2016","url":"https://doi.org/10.1056/NEJMoa1510093"},{"label":"Borchmann et al., PET-guided BrECADD versus escalated BEACOPP in advanced-stage classical Hodgkin lymphoma (HD21), Lancet 2024","url":"https://doi.org/10.1016/S0140-6736(24)01315-1"},{"label":"Behringer et al., gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin Study Group HD13 to HD15 trials, Journal of Clinical Oncology 2013 (1,323 survivors)","url":"https://doi.org/10.1200/JCO.2012.44.3721"},{"label":"NHS: Hodgkin lymphoma, treatment","url":"https://www.nhs.uk/conditions/hodgkin-lymphoma/treatment/"}],"tags":["subtype-page","haematologic"],"related":["early-stage-classical-hodgkin-lymphoma","relapsed-refractory-hodgkin-lymphoma","nodular-lymphocyte-predominant-hodgkin-lymphoma","hodgkin-lymphoma","dlbcl","lymphoma-roadmap"],"cancers":[],"sections":[],"technologies":["adc","checkpoint-inhibitor","fdg-pet","pet-adapted-therapy","imrt-igrt","cardio-oncology","fertility-preservation","ctdna-lymphoma-monitoring","g-csf-growth-factors","palliative-care","psycho-oncology","peer-support-groups","survivorship-care-plan","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","multidisciplinary-tumour-board","oncology-nutrition","prehabilitation","pet-ct"],"targets":["cd30","pd1","pdl1"],"drugs":["nivolumab","brentuximab-vedotin","doxorubicin","vinblastine","dacarbazine","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["deauville-score","lugano-classification","abvd-beacopp","reed-sternberg-cell","late-effects","lymphoma-tx-radiotherapy","lymphoma-tx-hodgkin-late-effects","lymphoma-tx-fertility-preservation","lymphoma-tx-transplant-role","lymphoma-tx-uk-versus-us","lymphoma-tx-uk-access","lymphoma-tx-regimen-alphabet","cancer-related-fatigue","febrile-neutropenia","neutropenia","financial-toxicity","central-venous-access","hypogammaglobulinaemia","performance-status","quality-of-life","lymphoma-decision-beacopp-or-abvd","lymphoma-decision-fertility-timing","lymphoma-decision-trial","lymphoma-living-hodgkin-survivorship-screening","lymphoma-living-fatigue","secondary-malignancy","cardiotoxicity","deauville"],"trials":["echelon-1","swog-s1826","hd21","rathl","nct02979522","hd18","ahl2011"],"people":[],"bottlenecks":[],"keyPapers":["paper-swog-s1826-nivolumab-avd-nejm-2024","paper-echelon-1-brentuximab-avd-nejm-2018","paper-rathl-interim-pet-adapted-abvd-advanced-hodgkin-nejm-2016","paper-ghsg-hd21-brecadd-vs-ebeacopp-advanced-hodgkin-lancet-2024"],"journals":[],"dependsOn":[],"notes":["Advanced Hodgkin lymphoma, what the escalation decision costs and what it buys: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the 24-hour number they gave you come first, and no figure here is a prediction about you. The decision records, the question sets, the first 60 days checklist and the red cards on this page were written from the NHS, Lymphoma Action, Macmillan and Cancer Research UK patient pages, from NICE NG52, NG47, CG151 and NG234, from the NHS Breast Screening Programme protocols and the Green Book, and from the trial reports named beside each figure, all read on 1 October 2026."],"group":"haematologic","burden":"About half of classical Hodgkin lymphoma at diagnosis; most patients are cured, but a fifth to a quarter relapse after ABVD, and older patients fare worse.","subtypes":["Stage III classical Hodgkin lymphoma (nodes on both sides of the diaphragm)","Stage IV classical Hodgkin lymphoma (extranodal spread to liver, lung, bone or marrow)","Advanced classical Hodgkin lymphoma with a high International Prognostic Score (4 or more)","Advanced classical Hodgkin lymphoma in adolescents and young adults (S1826 population)","Advanced classical Hodgkin lymphoma in older adults (over 60; bleomycin-free regimens)","Interim PET-positive advanced classical Hodgkin lymphoma (escalation or consolidation)"],"biomarkers":["International Prognostic Score (IPS 0 to 7)","Interim FDG-PET after cycle two (Deauville score, RATHL and HD18 escalation or de-escalation)","Baseline metabolic tumour volume","CD30 expression (universal; brentuximab target)","9p24.1 amplification and PD-L1 expression (PD-1 responsiveness)","Circulating tumour DNA (research)"],"standardOfCare":[{"setting":"Staging and risk","approach":"FDG-PET/CT with Lugano staging, International Prognostic Score, fertility counselling and cardiac and pulmonary baselines.","refs":["fdg-pet","lugano-classification","fertility-preservation","cardio-oncology"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"First line, adults and adolescents 12 and over","approach":"Nivolumab with AVD for six cycles (SWOG S1826, preferred); brentuximab vedotin with AVD (ECHELON-1) as an alternative; PET-adapted ABVD with bleomycin omission after two cycles (RATHL) where antibodies are unavailable.","refs":["nivolumab","swog-s1826","brentuximab-vedotin","echelon-1","doxorubicin","vinblastine","dacarbazine","rathl","pd1-plus-avd-hodgkin","bleomycin-omission-caution"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"First line, intensive European option","approach":"BrECADD for four to six cycles guided by interim PET (GHSG HD21), replacing escalated BEACOPP.","refs":["hd21","brentuximab-vedotin","abvd-beacopp","pet-adapted-therapy"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Children","approach":"Response-adapted Children's Oncology Group or EuroNet regimens; brentuximab vedotin with AVD in advanced paediatric disease; radiotherapy for slow responders only.","refs":["nct02979522","brentuximab-vedotin","childrens-oncology-group","pet-adapted-therapy"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Older or frail patients","approach":"AVD with brentuximab vedotin sequenced before and after, or nivolumab-AVD; avoid bleomycin and BEACOPP.","refs":["brentuximab-vedotin","nivolumab","doxorubicin","cardio-oncology"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"End of treatment","approach":"PET-directed consolidation radiotherapy only for residual PET-positive bulky disease; long-term survivorship follow-up.","refs":["fdg-pet","imrt-igrt","deauville-score","late-effects"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Advanced Hodgkin lymphoma in the United States: nivolumab with AVD","approach":"SWOG S1826 randomised 994 patients aged 12 and over with untreated stage III or IV classical Hodgkin lymphoma to nivolumab with AVD or to brentuximab vedotin with AVD, the regimen that had itself displaced ABVD. Two-year progression-free survival was 92 against 83 per cent (hazard ratio 0.45), and any-grade peripheral neuropathy was 28.1 against 54.2 per cent. It is the first trial in this disease to include adolescents and adults in a single protocol, and the FDA approved nivolumab with doxorubicin, vinblastine and dacarbazine for previously untreated stage III or IV classical Hodgkin lymphoma in adults and children of 12 and over on 20 March 2026, converting the two earlier relapsed-disease accelerated approvals to traditional approval at the same time.\n\nIt is a genuinely gentler regimen as well as a more effective one: less neuropathy, less growth-factor requirement, and no bleomycin. The subset analysis of the 99 eligible patients aged 60 and over reported two-year progression-free survival of 89 per cent with nivolumab-AVD against 64 per cent with brentuximab-AVD (hazard ratio 0.24) and two-year overall survival of 96 against 85 per cent (hazard ratio 0.16), with non-relapse mortality of 6 against 16 per cent, 55 per cent discontinuing brentuximab vedotin against 14 per cent discontinuing nivolumab, and six cycles delivered without dose reduction in 69 against 26 per cent. That matters, because older patients tolerate brentuximab-AVD badly and are the group in which first-line treatment most often fails.\n\nWhat is not yet known: overall survival has not separated, follow-up is short for a disease measured in decades, and the long-term consequences of PD-1 blockade in a 20-year-old who will live another 60 years are unknown. That last point is the honest counter-argument to adopting it everywhere.","refs":["swog-s1826","nivolumab","brentuximab-vedotin","doxorubicin","vinblastine","dacarbazine","abvd-beacopp","lymphoma-tx-uk-versus-us","paper-swog-s1826-nivolumab-avd-nejm-2024"],"guideline":{"nccn":"Category 1","version":"NCCN Hodgkin Lymphoma; SWOG S1826","url":"https://doi.org/10.1200/JCO-25-00204"}},{"setting":"Advanced Hodgkin lymphoma in Germany and much of Europe: PET-guided BrECADD","approach":"GHSG HD21 randomised about 1,500 patients aged 18 to 60 with untreated advanced-stage classical Hodgkin lymphoma to PET-guided BrECADD or PET-guided escalated BEACOPP. Four-year progression-free survival was 94.3 against 90.9 per cent (hazard ratio 0.66) and treatment-related morbidity, a composite of organ toxicity, infection and haematological toxicity, was 42 against 59 per cent. BrECADD replaces the bleomycin, vincristine and procarbazine of escalated BEACOPP with brentuximab vedotin and dacarbazine, which removes the lung toxicity, most of the neuropathy and much of the infertility risk, and PET guidance means most patients receive four cycles rather than six.\n\nThis is the highest progression-free survival reported in advanced Hodgkin lymphoma. It is also intensive treatment that requires an experienced unit, hospital admission for febrile neutropenia in a substantial minority, and growth-factor support throughout.\n\nThe earlier PET-guided BEACOPP trials, HD18 and AHL2011, established the principle: HD18 reduced treatment from eight cycles to four in PET-negative patients, and AHL2011 switched PET-negative patients from escalated BEACOPP to ABVD, in both cases without losing disease control.","refs":["hd21","brentuximab-vedotin","etoposide","cyclophosphamide","doxorubicin","dacarbazine","dexamethasone","procarbazine","bleomycin","vincristine","abvd-beacopp","fdg-pet","pet-adapted-therapy","lymphoma-tx-fertility-preservation","paper-ghsg-hd21-brecadd-vs-ebeacopp-advanced-hodgkin-lancet-2024"],"guideline":{"version":"GHSG HD21; ESMO; HD18 and AHL2011 for the PET-guided principle","url":"https://doi.org/10.1016/S0140-6736(17)32134-7"}},{"setting":"Advanced Hodgkin lymphoma with ABVD and brentuximab: what the earlier standards showed","approach":"The two regimens that the current standards displaced are still used, and still reasonable where the newer ones are not available.\n\nABVD with PET adaptation. RATHL enrolled 1,214 patients and showed that in those whose PET after two cycles was negative, bleomycin could be omitted from cycles 3 to 6 without loss of control: three-year progression-free survival 85.7 per cent for continued ABVD against 84.4 per cent for AVD, with less lung toxicity. This remains common British practice and is a perfectly defensible treatment.\n\nBrentuximab vedotin with AVD. ECHELON-1 randomised 1,334 patients with untreated stage III or IV disease to A+AVD or ABVD: two-year modified progression-free survival was 82.1 against 77.2 per cent (hazard ratio 0.77) and, at six years, overall survival was 93.9 against 89.4 per cent (hazard ratio 0.59). It is the only first-line trial in advanced Hodgkin lymphoma to show an overall survival advantage. The cost is peripheral neuropathy, which is commoner and more severe than with ABVD; in SWOG S1826 any-grade peripheral neuropathy was 54.2 per cent with brentuximab-AVD against 28.1 per cent with nivolumab-AVD. Growth-factor support is mandatory. In England, NICE TA1059 recommends brentuximab vedotin with doxorubicin, dacarbazine and vinblastine for untreated stage 3 or 4 CD30-positive Hodgkin lymphoma in adults, so this is the regimen that is funded first line; there is no NICE appraisal of nivolumab with AVD.\n\nOlder and frail patients tolerate none of these well. Options are ABVD with bleomycin omitted, sequential brentuximab vedotin before and after AVD, or a reduced-intensity regimen, and the choice is made on comorbidity rather than on chronological age.","refs":["rathl","echelon-1","brentuximab-vedotin","doxorubicin","bleomycin","vinblastine","dacarbazine","g-csf-growth-factors","abvd-beacopp","paper-rathl-interim-pet-adapted-abvd-advanced-hodgkin-nejm-2016","paper-echelon-1-brentuximab-avd-nejm-2018"],"guideline":{"nccn":"Category 1","version":"NCCN Hodgkin Lymphoma; ESMO; RATHL, ECHELON-1","url":"https://www.cancer.gov/types/lymphoma/hp/adult-hodgkin-treatment-pdq"}}],"stateOfArt":["Nivolumab-AVD is the new standard, curing more patients with less toxicity than brentuximab-AVD.","ECHELON-1 delivered the first overall survival gain in advanced disease in decades.","PET-guided BrECADD gives Europe a less toxic intensive alternative."],"history":[{"year":1964,"title":"MOPP chemotherapy cures advanced Hodgkin lymphoma at the NCI","refs":["cytotoxic-chemotherapy"]},{"year":1975,"title":"ABVD introduced in Milan and later shown superior to MOPP","refs":["abvd-beacopp","doxorubicin"]},{"year":2003,"title":"GHSG HD9: escalated BEACOPP improves outcomes over standard regimens","refs":["abvd-beacopp","gbg"]},{"year":2016,"title":"RATHL: PET-guided omission of bleomycin","refs":["rathl","pet-adapted-therapy"]},{"year":2018,"title":"ECHELON-1: brentuximab vedotin with AVD beats ABVD","refs":["echelon-1","brentuximab-vedotin"]},{"year":2022,"title":"ECHELON-1 six-year update shows an overall survival advantage","refs":["echelon-1"]},{"year":2024,"title":"SWOG S1826 (nivolumab-AVD) and HD21 (BrECADD) published; nivolumab-AVD becomes the preferred regimen","refs":["swog-s1826","hd21","nivolumab","brentuximab-vedotin"]}],"pipeline":["swog-s1826","hd21","nct02979522","pd1-plus-avd-hodgkin","ctdna-lymphoma-monitoring","idea-chemo-free-hodgkin"],"openProblems":["Long-term outcomes of nivolumab-AVD beyond a few years are not yet known.","Nivolumab-AVD and BrECADD have never been compared.","Older patients still have worse survival and more toxicity.","Whether chemotherapy can be reduced further with PD-1 antibodies is the next trial question."],"parent":"hodgkin-lymphoma"},{"id":"alk-negative-anaplastic-large-cell-lymphoma","kind":"cancer","name":"ALK-negative anaplastic large cell lymphoma","aka":["ALK-negative ALCL","ALK- ALCL","Anaplastic large cell lymphoma, ALK-negative","ALK-negative ALCL (DUSP22, TP63 subsets)","Systemic ALK-negative anaplastic large cell lymphoma"],"tldr":"An aggressive T-cell lymphoma that looks like its ALK-positive sibling under the microscope and carries the same CD30 marker, but lacks the broken ALK gene. It affects older people and is cured less often, and several genetic changes inside it predict very different outcomes.","summary":"What it is. A lymphoma of T cells that looks anaplastic, carries uniform strong CD30 and has no ALK rearrangement. The definition is therefore partly negative, which is why WHO-HAEM5 describes it as a heterogeneous entity: it is what is left when ALK-positive disease, breast implant-associated disease and the skin lymphomas have been excluded.\n\nHow it differs from its ALK-positive sibling. In age, and in outcome. ALK-positive disease affects people in their twenties and thirties; this affects people around 70. Both carry CD30, both are treated with the same first-line regimen, and ALK-positive disease is cured considerably more often. Where the appearance is identical, only the ALK stain tells them apart, which is why it is done on every anaplastic lymphoma.\n\nWhat is inside it, and what that is worth. Sequencing has found several genetic contexts within ALK-negative disease, and WHO-HAEM5 is careful about how much weight to put on them: it says there are not currently enough data to decide whether they are prognostic markers or genuine molecular subtypes. Rearrangement of TP63, loss of TP53 and overexpression of the interleukin-2 receptor alpha chain are each associated with worse outcomes. DUSP22 rearrangement was initially reported to carry a five-year survival as good as ALK-positive disease, and WHO-HAEM5 notes that more recent studies have not confirmed that association, which is the sort of reversal worth knowing about before a prognosis is given on the strength of it.\n\nSome of the genetics show in the appearance. Tumours with a DUSP22 rearrangement have cells with a doughnut-like shape and grow in sheets with less variation in size, and LEF1 staining may be a surrogate for the rearrangement. A group with a Hodgkin-like appearance shows aberrant ERBB4 protein, and the cells look more anaplastic where JAK2 is rearranged.\n\nHow it is treated. The same as the other CD30-positive nodal T-cell lymphomas: brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone, on the strength of ECHELON-2, and consolidation of a first remission with an autologous stem cell transplant in people fit for it, which is convention rather than demonstrated benefit. The detail is on the peripheral T-cell lymphoma page and in the treatment layer of this family.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Anaplastic_large-cell_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"ECHELON-2: brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma, five-year results (Horwitz, Annals of Oncology 2022)","url":"https://doi.org/10.1016/j.annonc.2021.12.002"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["alk-positive-anaplastic-large-cell-lymphoma","primary-cutaneous-anaplastic-large-cell-lymphoma","breast-implant-associated-alcl","peripheral-t-cell-lymphoma","non-hodgkin-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","fdg-pet","adc","autologous-stem-cell-transplant"],"targets":["cd30","tp53"],"drugs":["brentuximab-vedotin"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-classification-2022","lymphoma-pit-score","ipi-score","lymphoma-tx-regimen-alphabet","lymphoma-tx-transplant-role","lymphoma-b-versus-t-cell"],"trials":["echelon-2"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"In the United Kingdom population series that reports lymphoma by subtype, 27 of 5,796 lymphomas were ALK-negative anaplastic large cell lymphoma, a European age-standardised rate of 0.08 per 100,000 a year, with a median age at diagnosis of 69.0 years, more than thirty years older than the ALK-positive form. Across all anaplastic large cell lymphomas in that series, five-year relative survival was 50.8 per cent; the published table's figure for the ALK-negative subgroup alone is internally inconsistent and is not quoted here.","subtypes":["With DUSP22 rearrangement","With TP63 rearrangement, which is associated with worse outcomes","With JAK2 rearrangement","Not otherwise characterised"],"biomarkers":["Uniform strong CD30 on every tumour cell","Absence of ALK protein by immunohistochemistry, which is the defining negative","DUSP22 rearrangement, whose prognostic meaning is disputed; WHO-HAEM5 records that the favourable association first reported has not been confirmed","TP63 rearrangement, loss of TP53 and overexpression of the interleukin-2 receptor alpha chain, each associated with worse outcomes","The Prognostic Index for T-cell lymphoma and the International Prognostic Index"],"standardOfCare":[{"setting":"Making the diagnosis","approach":"CD30 and ALK immunohistochemistry on the biopsy. The diagnosis is partly a negative one: uniform strong CD30 with an anaplastic appearance and no ALK, in a lymphoma that is not confined to the skin and is not associated with a breast implant. Those two exclusions matter because both of them are treated very differently. Testing for DUSP22 and TP63 rearrangements is done where it is available, with the caution that WHO-HAEM5 does not regard the resulting groups as established subtypes.","refs":["histopathology-ihc","cd30","alk","lymphoma-classification-2022","fdg-pet"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"First-line treatment","approach":"Brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone, the same regimen as for ALK-positive disease and on the same trial: in ECHELON-2, five-year progression-free survival was 51.4 per cent against 43.0 with chemotherapy alone and overall survival 70.1 against 61.0. Consolidating a first remission with high-dose therapy and an autologous stem cell transplant is standard practice here, unlike in ALK-positive disease, and it rests on a single-arm study and registry comparisons rather than on a randomised trial; a patient is entitled to be told that. The regimens are on the peripheral T-cell lymphoma page.","refs":["echelon-2","brentuximab-vedotin","cyclophosphamide","doxorubicin","prednisone","autologous-stem-cell-transplant","lymphoma-tx-transplant-role","peripheral-t-cell-lymphoma"],"guideline":{"version":"ECHELON-2 five-year results (Annals of Oncology 2022); NCCN T-Cell Lymphomas; NCI PDQ","url":"https://doi.org/10.1016/j.annonc.2021.12.002"}}],"stateOfArt":[],"history":[{"year":2008,"title":"Separated from ALK-positive disease","note":"The fourth edition of the WHO classification made ALK-negative anaplastic large cell lymphoma a distinct entity rather than a variant, on the strength of its different biology and clinical course.","refs":["alk"]},{"year":2014,"title":"Genetic subgroups described","note":"Rearrangements of DUSP22 and TP63 were identified within ALK-negative disease and reported to carry very different outcomes, which raised the question of whether the entity should be split again.","refs":[]},{"year":2022,"title":"The classification declines to split it, and records a reversal","note":"WHO-HAEM5 states that there are not yet enough data to decide whether the genetic contexts are prognostic markers or molecular subtypes, and that the favourable outcome first reported for DUSP22 rearrangement has not been confirmed by more recent studies.","refs":["lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["The entity is defined by what it is not, and WHO-HAEM5 says so. Whether its genetic subgroups are real subtypes or prognostic markers is unresolved.","The prognostic meaning of DUSP22 rearrangement reversed between the first reports and the later ones, and treatment decisions have been made on the earlier version.","Autologous transplant consolidation in first remission is standard practice here on the strength of registry comparisons and a single-arm study, and has never been tested against continuing observation."],"parent":"peripheral-t-cell-lymphoma"},{"id":"alk-positive-anaplastic-large-cell-lymphoma","kind":"cancer","name":"ALK-positive anaplastic large cell lymphoma","aka":["ALK-positive ALCL","ALK+ ALCL","Anaplastic large cell lymphoma, ALK-positive","ALK-positive anaplastic large-cell lymphoma","Systemic ALK-positive anaplastic large cell lymphoma"],"tldr":"An aggressive T-cell lymphoma, mostly of children and young adults, whose cells carry a broken ALK gene and a protein called CD30 on the surface. Despite looking alarming down the microscope it is the T-cell lymphoma most often cured, and both of its markers are things that drugs can aim at.","summary":"What it is. A lymphoma of T cells in which a piece of chromosome 2 carrying the ALK gene has joined another gene, most often NPM1 on chromosome 5, producing a fusion protein that is permanently switched on and drives the cell to divide. Every cell also carries CD30, strongly and uniformly, which is the second thing that makes this disease unusual.\n\nHow it differs from the rest of the family. WHO-HAEM5 recognises three anaplastic large cell lymphomas: this one, the ALK-negative form and the breast implant-associated form, with the primary cutaneous form filed among the skin lymphomas. ALK-positive disease has been separated from ALK-negative disease since the fourth edition because its cause and its course are different, and the difference is large: it occurs in much younger people and is cured far more often.\n\nHow it presents. Often dramatically, with fevers, weight loss, enlarged lymph nodes and disease outside the lymph nodes, in skin, bone, soft tissue, lung or liver. The cells are large and strange-looking, including the hallmark cells with kidney-shaped nuclei, and a pathologist who does not stain for CD30 and ALK can mistake the disease for a carcinoma or a sarcoma. That is a real and recorded error, and it is the reason the two stains are done.\n\nWhy CD30 matters more here than anywhere else. Brentuximab vedotin is an antibody against CD30 carrying a chemotherapy drug. ECHELON-2 randomised 452 people with untreated CD30-positive peripheral T-cell lymphoma, with the trial deliberately targeting 75 per cent with systemic anaplastic large cell lymphoma, to brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone or to the same chemotherapy with vincristine instead of the antibody. At five years, progression-free survival was 51.4 against 43.0 per cent and overall survival 70.1 against 61.0 per cent. It is the only randomised first-line trial in the whole T-cell family to improve survival, and most of its patients had this disease or its ALK-negative sibling.\n\nWhat ALK offers that nothing else in this family does. ALK inhibitors, developed for lung cancer, work here too; crizotinib has activity in relapsed ALK-positive disease and is used particularly in children. That is unusual in T-cell lymphoma, where targeted drugs have mostly disappointed, and it exists only because the same gene was broken in a much commoner cancer.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Anaplastic_large-cell_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"ECHELON-2: brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma, five-year results (Horwitz, Annals of Oncology 2022)","url":"https://doi.org/10.1016/j.annonc.2021.12.002"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["alk-negative-anaplastic-large-cell-lymphoma","primary-cutaneous-anaplastic-large-cell-lymphoma","breast-implant-associated-alcl","peripheral-t-cell-lymphoma","non-hodgkin-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","fdg-pet","adc"],"targets":["alk","cd30"],"drugs":["brentuximab-vedotin"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-classification-2022","lymphoma-b-versus-t-cell","lymphoma-pit-score","ipi-score","lymphoma-tx-regimen-alphabet","lymphoma-tx-transplant-role"],"trials":["echelon-2"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare and young. In the United Kingdom population series that reports lymphoma by subtype, 16 of 5,796 lymphomas were ALK-positive anaplastic large cell lymphoma, a European age-standardised rate of 0.06 per 100,000 a year, with men affected about three times as often as women and a median age at diagnosis of 35.6 years, the youngest of any lymphoma in that series apart from Hodgkin lymphoma and Burkitt lymphoma. Five-year relative survival in that series was 75.2 per cent.","subtypes":["Common pattern, the great majority","Lymphohistiocytic, small cell and Hodgkin-like patterns, which look different and behave the same"],"biomarkers":["ALK rearrangement, most often NPM1::ALK from t(2;5)(p23;q35), detected by immunohistochemistry for the ALK protein and confirmed by fluorescence in situ hybridisation","Uniform strong CD30 on every tumour cell, which is what brentuximab vedotin attaches to","Loss of several T-cell markers, which is characteristic and can make the lineage hard to establish","Epithelial membrane antigen, often positive, which contributes to the mistaken diagnosis of carcinoma","The International Prognostic Index, which separates outcomes here as it does in B-cell lymphoma"],"standardOfCare":[{"setting":"Making the diagnosis, and the mistake to avoid","approach":"Immunohistochemistry for CD30 and for ALK protein on the biopsy, with fluorescence in situ hybridisation to confirm the rearrangement where the stain is equivocal. The large pleomorphic cells, the frequent expression of epithelial membrane antigen and the loss of several T-cell markers mean that a tumour stained with a short panel can be reported as a carcinoma or a sarcoma; CD30 and ALK are what prevent that. Staging covers the sites this disease reaches outside the lymph nodes: skin, bone, soft tissue, lung and liver.","refs":["histopathology-ihc","cd30","alk","fdg-pet","lugano-classification"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"First-line treatment","approach":"Brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone, on the strength of ECHELON-2, which randomised 452 people with untreated CD30-positive peripheral T-cell lymphoma, three-quarters of them with systemic anaplastic large cell lymphoma: five-year progression-free survival 51.4 per cent against 43.0 and overall survival 70.1 against 61.0 with chemotherapy alone. Vincristine is left out because brentuximab vedotin is itself a tubulin-directed agent and giving both causes unacceptable nerve damage. Unlike the other nodal T-cell lymphomas, ALK-positive disease does well enough that consolidating a first remission with an autologous transplant is generally not offered. The regimens and the cycle detail are on the peripheral T-cell lymphoma page.","refs":["echelon-2","brentuximab-vedotin","cyclophosphamide","doxorubicin","prednisone","peripheral-t-cell-lymphoma","lymphoma-tx-regimen-alphabet"],"guideline":{"version":"ECHELON-2 five-year results (Annals of Oncology 2022); NCCN T-Cell Lymphomas; NCI PDQ","url":"https://doi.org/10.1016/j.annonc.2021.12.002"}},{"setting":"Relapse","approach":"Brentuximab vedotin is highly active in relapsed systemic anaplastic large cell lymphoma, with response rates well above those seen in other peripheral T-cell lymphomas, and it is the usual choice for anyone who has not already had it. ALK inhibitors developed for lung cancer, crizotinib in particular, produce responses here and are used especially in children and young adults. Allogeneic transplant is offered to fit patients who respond. The detail is on the peripheral T-cell lymphoma page.","refs":["brentuximab-vedotin","peripheral-t-cell-lymphoma","allogeneic-hsct","lymphoma-tx-transplant-role","alk"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":1994,"title":"The ALK fusion identified","note":"NPM1::ALK was found in anaplastic large cell lymphoma, which split the disease into two and made the ALK-positive form the one with the better outlook.","refs":["alk"]},{"year":2011,"title":"Brentuximab vedotin approved for relapsed disease","note":"The CD30 antibody-drug conjugate was approved for systemic anaplastic large cell lymphoma after failure of previous treatment, on high response rates in a small single-arm trial.","refs":["brentuximab-vedotin"]},{"year":2022,"title":"Five-year results of ECHELON-2","note":"In 452 patients with CD30-positive peripheral T-cell lymphoma, three-quarters of them with systemic anaplastic large cell lymphoma, five-year progression-free survival was 51.4 per cent with brentuximab vedotin and chemotherapy against 43.0 per cent with chemotherapy alone, and overall survival 70.1 against 61.0 per cent.","refs":["echelon-2","brentuximab-vedotin"]}],"pipeline":[],"openProblems":["ECHELON-2 enrolled CD30-positive peripheral T-cell lymphoma and was weighted towards anaplastic large cell lymphoma, so the benefit in the other CD30-positive entities is extrapolated rather than demonstrated.","Whether an ALK inhibitor should be added to first-line treatment, or substituted for part of it, has not been tested in a randomised trial.","Most of the ALK-positive patients are young, and the late effects of anthracycline chemotherapy in a cured 30-year-old are measured in decades and are not recorded in the trials."],"parent":"peripheral-t-cell-lymphoma"},{"id":"alk-positive-nsclc","kind":"cancer","name":"ALK-positive non-small-cell lung cancer","aka":["ALK-rearranged lung cancer","ALK fusion NSCLC","EML4-ALK lung cancer","ALK+ NSCLC"],"tldr":"ALK-positive lung cancer is driven by a fused ALK gene and is treated with a pill from the start. The newest inhibitors keep the disease under control for years, with lorlatinib holding six in ten patients progression-free at five years, and two years of alectinib after surgery cuts recurrence by three quarters.","summary":"The EML4-ALK fusion was found in lung cancer in Japan in 2007, and crizotinib, a MET inhibitor that happened to block ALK, was approved four years later on the strength of response rates around 60 percent, one of the fastest paths from discovery to approval in oncology. PROFILE 1014 (2014) showed crizotinib beat chemotherapy first line, but most patients progressed within a year, frequently in the brain, which crizotinib penetrates poorly. Ceritinib, alectinib and brigatinib were developed against crizotinib-resistant disease and then moved to the front.\n\nALEX (2017) showed alectinib beat crizotinib first line, with median progression-free survival of 34.8 versus 10.9 months, brain progression cut from 41 to 9 percent at one year and five-year survival of 62.5 versus 45.5 percent. ALTA-1L (2018) showed the same for brigatinib (24.0 versus 11.1 months), and CROWN (2020) for lorlatinib, a third-generation inhibitor designed to cover every known resistance mutation and to enter the brain: at five years 60 percent of lorlatinib patients were progression-free against 8 percent with crizotinib (hazard ratio 0.19), a result without precedent in metastatic lung cancer, though lorlatinib's cognitive, mood, weight and lipid effects need active management. Resistance to second-generation drugs is dominated by the G1202R solvent-front mutation, which lorlatinib covers; resistance to lorlatinib produces compound mutations that neladalkib (NVL-655, ALKOVE-1) is designed to overcome. Oligoprogression is often treated with local radiotherapy while the inhibitor continues.\n\nIn resected stage IB to IIIA disease ALINA (2024) showed that two years of adjuvant alectinib cut recurrence by 76 percent compared with platinum chemotherapy (hazard ratio 0.24), and it was approved in April 2024. Checkpoint inhibitors are ineffective in ALK-positive disease and carry excess liver toxicity with ALK inhibitors. Open questions are the sequence of inhibitors, whether ALK-positive cancers can be cured with prolonged therapy, and how long adjuvant treatment should last.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Anaplastic_lymphoma_kinase","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Anaplastic_lymphoma_kinase"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":["egfr-mutant-nsclc","ros1-positive-nsclc","ret-fusion-nsclc","ntrk-fusion-nsclc","met-altered-nsclc","kras-g12c-nsclc"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","radiosurgery-srs","liquid-biopsy","cgp"],"targets":["alk"],"drugs":["alectinib","brigatinib","lorlatinib","crizotinib","ceritinib","ensartinib","iruplinalkib","neladalkib"],"companies":["roche-genentech","pfizer","takeda","novartis","nuvalent"],"institutions":[],"pathways":["nsclc-signalling","rtk-activation"],"terms":["gene-fusion","oncogene-addiction","gatekeeper-mutation","brain-metastases","oligoprogression","tki-term","resistance"],"trials":["alex","alta-1l","crown","alina","alkove-1"],"people":["solomon-benjamin","ross-camidge","solange-peters","tony-mok","ahn-myung-ju","wu-yi-long","justin-gainor"],"bottlenecks":[],"keyPapers":["paper-shaw-crown-lorlatinib-crizotinib-nejm-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"About 3 to 5 percent of non-small-cell lung cancers carry an ALK fusion, most often EML4-ALK; patients are on average a decade younger than other lung cancer patients and most have never smoked or smoked lightly. Brain metastases develop in over half over the course of the disease.","subtypes":["EML4-ALK fusion adenocarcinoma (variants 1, 2 and 3 differ in resistance patterns)","ALK-positive adenocarcinoma with brain metastases at diagnosis","Crizotinib-resistant ALK-positive disease (second-generation inhibitors)","G1202R solvent-front resistance (lorlatinib)","Compound ALK mutations after lorlatinib (neladalkib)"],"biomarkers":["ALK fusion by immunohistochemistry, fluorescence in situ hybridisation or RNA sequencing","ALK resistance mutations at progression (G1202R, compound mutations) by tissue or plasma sequencing","EML4-ALK variant (prognostic, research)","TP53 co-mutation (worse outcome)","Brain MRI at diagnosis and during follow-up","Lipids, weight and mood on lorlatinib"],"standardOfCare":[{"setting":"Advanced, first line","approach":"Alectinib (ALEX), brigatinib (ALTA-1L) or lorlatinib (CROWN); lorlatinib gives the longest control and the best brain protection, with dose adjustment for cognitive, mood and metabolic effects.","refs":["alectinib","alex","brigatinib","alta-1l","lorlatinib","crown","brain-metastases"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, after a second-generation inhibitor","approach":"Lorlatinib, guided where possible by the resistance mutation; local radiotherapy for oligoprogression; platinum-pemetrexed once inhibitors are exhausted.","refs":["lorlatinib","oligoprogression","sbrt","pemetrexed","carboplatin","gatekeeper-mutation"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, after lorlatinib","approach":"Neladalkib in trials (ALKOVE-1); chemotherapy; clinical trial.","refs":["neladalkib","alkove-1","pemetrexed"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Resected stage IB to IIIA","approach":"Surgery then two years of adjuvant alectinib (ALINA) in place of platinum chemotherapy.","refs":["alectinib","alina","neoadjuvant-adjuvant"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Brain metastases","approach":"Next-generation inhibitors control most brain metastases without radiotherapy; stereotactic radiosurgery for large or symptomatic lesions; whole-brain radiotherapy avoided.","refs":["lorlatinib","alectinib","radiosurgery-srs","brain-metastases","wbrt"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Lorlatinib first line: 60 percent progression-free at five years in CROWN, the longest control reported in any metastatic lung cancer trial.","Adjuvant alectinib (ALINA) replaces chemotherapy after resection.","Sequencing of inhibitors by resistance mutation, with neladalkib designed for compound mutations after lorlatinib.","Brain metastases managed largely with drugs rather than radiotherapy."],"history":[{"year":2007,"title":"EML4-ALK fusion discovered in lung cancer (Soda and Mano, Japan)","refs":["alk","gene-fusion"]},{"year":2011,"title":"Crizotinib approved four years after the fusion was found","refs":["crizotinib"]},{"year":2014,"title":"PROFILE 1014: crizotinib beats chemotherapy first line","refs":["crizotinib","solomon-benjamin"]},{"year":2017,"title":"ALEX: alectinib beats crizotinib first line with far less brain progression","refs":["alex","alectinib","solange-peters"]},{"year":2018,"title":"ALTA-1L: brigatinib beats crizotinib first line","refs":["alta-1l","brigatinib","ross-camidge"]},{"year":2020,"title":"CROWN: lorlatinib first line; five-year update in 2024 shows 60 percent progression-free","refs":["crown","lorlatinib","solomon-benjamin"]},{"year":2024,"title":"ALINA: two years of adjuvant alectinib cuts recurrence by 76 percent","refs":["alina","alectinib","wu-yi-long"]}],"pipeline":["neladalkib","alkove-1","iruplinalkib","ensartinib","idea-bio1-ctdna-adaptive-tki"],"openProblems":["Whether any sequence of inhibitors cures metastatic ALK-positive disease or only holds it is unknown.","Lorlatinib's cognitive, mood and metabolic effects are managed by dose reduction without trials of the optimal dose.","Resistance after lorlatinib is compound mutations and bypass pathways with no approved option.","The right duration of adjuvant alectinib is untested; recurrences after stopping are being watched."],"parent":"nsclc"},{"id":"alveolar-soft-part-sarcoma","kind":"cancer","name":"Alveolar soft part sarcoma","aka":["ASPS","ASPSCR1-TFE3 sarcoma"],"tldr":"Alveolar soft part sarcoma is a rare, slow-growing cancer of young adults driven by a single fusion gene, ASPSCR1-TFE3, that switches on blood vessel growth. Chemotherapy does not work, but drugs that block the tumour's blood supply shrink it, and in 2023 the immunotherapy atezolizumab became the first drug approved for it.","summary":"Alveolar soft part sarcoma is defined by the unbalanced translocation der(17)t(X;17) that fuses ASPSCR1 to the transcription factor TFE3, driving a programme of angiogenesis and metabolic genes; the same TFE3 fusion partner occurs in translocation renal cell carcinoma. The tumour is richly vascular, grows slowly in deep muscle of the limbs of young adults or in the orbit and tongue of children, and metastasises early to the lungs, bone and, unusually for a sarcoma, the brain. Because it is indolent, patients with metastases often survive many years, and the disease is followed with regular brain imaging.\n\nLocalised tumours are treated with wide resection, with radiotherapy for close margins, and isolated metastases with surgery or stereotactic radiotherapy. Conventional chemotherapy is ineffective. VEGFR-directed kinase inhibitors are active: sunitinib produced responses in Italian series, cediranib improved progression-free survival against placebo in the randomised CASPS trial, pazopanib is used in Europe, and anlotinib, approved in China for soft tissue sarcoma, showed benefit in the alveolar soft part sarcoma cohort of the APROMISS phase 3 trial.\n\nDespite a low mutational burden, the tumour responds to PD-L1 blockade: the NCI-sponsored phase 2 study of atezolizumab produced durable objective responses in a substantial minority of patients, leading to the first FDA approval for any drug in this disease in December 2023 for unresectable or metastatic alveolar soft part sarcoma in patients aged two and over. Combinations of checkpoint inhibitors with anti-angiogenic drugs, including benmelstobart plus anlotinib, are the main line of current trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Alveolar_soft_part_sarcoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Alveolar_soft_part_sarcoma"}],"tags":["subtype-page"],"related":["extremity-soft-tissue-sarcoma","synovial-sarcoma","epithelioid-sarcoma","pecoma","rhabdomyosarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["cediranib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-atezolizumab-alveolar-soft-part-sarcoma-chen-nejm-2023","paper-ladanyi-aspl-tfe3-oncogene-2001"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"Under one percent of soft tissue sarcomas, arising in adolescents and young adults, usually in the thigh or buttock and in children in the head and neck; it grows slowly but has often already spread to the lungs, bone or brain at diagnosis, and patients live for years with metastatic disease.","subtypes":["Alveolar soft part sarcoma of the deep soft tissue of the limbs (adolescents and young adults)","Head and neck (orbit, tongue) alveolar soft part sarcoma in children","Metastatic disease to lung, bone and brain (indolent course)"],"biomarkers":["ASPSCR1-TFE3 fusion (FISH or RNA sequencing; TFE3 immunohistochemistry)","PAS-positive, diastase-resistant crystals","Brain imaging surveillance for metastases"],"standardOfCare":[{"setting":"Localised","approach":"Wide resection with radiotherapy for close or positive margins; surveillance of lungs and brain.","refs":["limb-salvage-surgery","imrt-igrt","mri"]},{"setting":"Advanced, first line","approach":"Atezolizumab (FDA approved 2023) or a VEGFR kinase inhibitor (sunitinib, pazopanib; anlotinib in China); conventional chemotherapy is not used.","refs":["atezolizumab","checkpoint-inhibitor","sunitinib","pazopanib","anlotinib","nct03016819"]},{"setting":"Oligometastatic","approach":"Metastasectomy or stereotactic radiotherapy to lung and brain lesions in slowly progressing disease.","refs":["sbrt","limb-salvage-surgery"]}],"stateOfArt":["Atezolizumab is the first approved therapy, with durable responses despite a low mutational burden.","Anti-angiogenic kinase inhibitors remain active alternatives and partners for immunotherapy.","The slow course means long survival with metastases and a need for decades of surveillance."],"history":[{"year":1952,"title":"Christopherson, Foote and Stewart name alveolar soft part sarcoma","refs":[]},{"year":2001,"title":"ASPSCR1-TFE3 fusion identified as the defining alteration","refs":[]},{"year":2009,"title":"Sunitinib shows activity in alveolar soft part sarcoma","refs":["sunitinib"]},{"year":2019,"title":"CASPS: cediranib improves progression-free survival against placebo","refs":[]},{"year":2023,"title":"Atezolizumab approved by the FDA, the first drug for the disease","refs":["atezolizumab"]}],"pipeline":["atezolizumab","anlotinib","nct07548177","nct03016819","checkpoint-inhibitor"],"openProblems":["Why a low-mutation fusion sarcoma responds to immunotherapy is not understood.","Brain metastases are common and hard to treat.","No cure for metastatic disease despite long survival."],"parent":"sarcoma"},{"id":"ampullary","kind":"cancer","name":"Ampullary cancer (ampulla of Vater)","aka":["Ampulla of Vater carcinoma","Periampullary cancer","Ampullary adenocarcinoma"],"tldr":"Ampullary cancer, a biliary tract cancer, starts where the bile and pancreatic ducts empty into the small bowel. Because it blocks bile flow early it is often caught while still removable, and the Whipple operation cures a good share of patients. Tumours come in two flavours, intestinal-like and pancreas-like, and chemotherapy is increasingly chosen by which one the pathologist sees.","summary":"Ampullary adenocarcinoma arises from the ampulla of Vater, the papilla where the common bile duct and main pancreatic duct open into the duodenum. It is grouped with periampullary cancers (distal cholangiocarcinoma, duodenal adenocarcinoma, pancreatic head cancer) at surgery but behaves better than pancreatic cancer because it obstructs the bile duct and is diagnosed early. Two histomolecular subtypes matter: intestinal-type tumours resemble colorectal cancer (CDX2, MUC2; APC and KRAS mutations) and pancreatobiliary-type tumours resemble pancreatic cancer (MUC1, CK7; KRAS, TP53, SMAD4), with the latter behaving more aggressively. Familial adenomatous polyposis carries a large relative risk of ampullary adenoma and carcinoma, and endoscopic surveillance of the duodenum is part of FAP care.\n\nCurative treatment is pancreatoduodenectomy (Whipple); small adenomas and some early T1 lesions can be removed endoscopically by papillectomy. Adjuvant chemotherapy is extrapolated: ESPAC-3 periampullary (JAMA 2012) showed a survival advantage for adjuvant gemcitabine or fluorouracil in multivariable analysis, and practice now leans on subtype, with oxaliplatin-fluoropyrimidine (FOLFOX or CAPOX) for intestinal-type and gemcitabine-based or modified FOLFIRINOX regimens for pancreatobiliary-type tumours. For metastatic disease the same logic applies, and tumour-agnostic biomarkers (MSI-high, HER2, NTRK, BRAF) should be tested because they are found more often than in pancreatic cancer.\n\nThe active questions are prospective subtype-directed adjuvant trials, ctDNA to guide adjuvant decisions, and neoadjuvant therapy for node-positive disease.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Ampullary_cancer","links":[{"label":"NCI PDQ: pancreatic cancer (ampullary cancers are covered with periampullary tumours)","url":"https://www.cancer.gov/types/pancreatic"},{"label":"NCCN: Ampullary Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1520"},{"label":"ESPAC-3 periampullary (JAMA 2012)","url":"https://doi.org/10.1001/jama.2012.7352"}],"tags":["nci-coverage","rare","gastrointestinal"],"related":["pancreatic","cholangiocarcinoma","small-bowel","colorectal","gallbladder"],"cancers":[],"sections":[],"technologies":["endoscopic-resection","cytotoxic-chemotherapy","biliary-stenting-drainage","cgp","liquid-biopsy"],"targets":["kras","her2","ntrk","braf"],"drugs":["folfox","capox","gemcitabine","folfirinox","gemcitabine-nab-paclitaxel","pembrolizumab"],"companies":[],"institutions":[],"pathways":["wnt","ras-mapk","p53-cell-cycle"],"terms":["whipple","obstructive-jaundice","ca19-9","hereditary-cancer-syndromes","endoscopy"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers","b-trial-enrolment"],"keyPapers":["paper-neoptolemos-jama"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Rare: well under one case per 100,000 per year, but it makes up a disproportionate share of resectable pancreatoduodenectomies because it obstructs the bile duct early and presents with jaundice.","subtypes":["Intestinal-type adenocarcinoma","Pancreatobiliary-type adenocarcinoma","Mixed type","Ampullary adenoma (precursor; sporadic or FAP-associated)","Ampullary neuroendocrine tumour (rare; see neuroendocrine)"],"biomarkers":["Histomolecular subtype by IHC (CDX2, MUC2 vs MUC1, CK7)","Lymph node status and margin status after Whipple","MSI / mismatch repair","HER2, BRAF V600E, NTRK fusions","KRAS, TP53, SMAD4 (pancreatobiliary), APC (intestinal)","CA 19-9 and CEA for monitoring","Germline APC (FAP) where duodenal polyposis is present"],"standardOfCare":[{"setting":"Ampullary adenoma or early T1 lesion","approach":"Endoscopic papillectomy with surveillance; surgery if invasive cancer or unfavourable features on pathology.","refs":["endoscopic-resection","endoscopy"]},{"setting":"Resectable carcinoma","approach":"Pancreatoduodenectomy with regional lymphadenectomy; biliary stenting first only if cholangitis or delayed surgery.","refs":["whipple","biliary-stenting-drainage","lymphadenectomy"],"guideline":{"version":"NCCN Guidelines: Ampullary Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1520"}},{"setting":"Adjuvant","approach":"Six months of chemotherapy chosen by subtype: oxaliplatin-fluoropyrimidine (FOLFOX or CAPOX) for intestinal-type; gemcitabine-based or modified FOLFIRINOX for pancreatobiliary-type; evidence is from ESPAC-3 periampullary and retrospective series.","refs":["folfox","capox","gemcitabine","folfirinox","espac-3"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Ampullary Adenocarcinoma; ESPAC-3 (JAMA 2012)","url":"https://doi.org/10.1001/jama.2012.7352"}},{"setting":"Metastatic","approach":"Subtype-directed chemotherapy; pembrolizumab for MSI-high; HER2-, BRAF- or NTRK-directed therapy where present; clinical trials.","refs":["folfox","gemcitabine-nab-paclitaxel","pembrolizumab","dabrafenib-trametinib","larotrectinib"]}],"stateOfArt":["Ampullary cancer got its own NCCN guideline in 2022, separating it from pancreatic cancer and formalising subtype-directed chemotherapy.","Histomolecular subtyping is the key advance: it tells the oncologist whether to treat the tumour like a bowel cancer or like a pancreatic cancer.","Endoscopic papillectomy spares many patients with adenomas or early lesions a Whipple operation.","Because the disease is rare, most systemic-therapy evidence is retrospective; prospective subtype-stratified trials and ctDNA-guided adjuvant studies are the next step."],"history":[{"year":1899,"title":"Halsted resects an ampullary cancer","note":"First successful local resection of a periampullary tumour.","refs":[]},{"year":1935,"title":"Whipple's pancreatoduodenectomy","note":"Allen Whipple reports the operation that became the standard for periampullary cancer.","refs":["whipple"]},{"year":1994,"title":"Intestinal and pancreatobiliary subtypes described","note":"Kimura and colleagues link histological type to prognosis.","refs":[]},{"year":2012,"title":"ESPAC-3 periampullary","note":"Adjuvant chemotherapy after resection of periampullary cancer; survival benefit in adjusted analysis.","refs":["gemcitabine"]},{"year":2022,"title":"NCCN publishes a dedicated ampullary adenocarcinoma guideline","note":"Subtype-directed treatment recommendations formalised.","refs":[]}],"pipeline":["folfirinox","pembrolizumab","signatera"],"openProblems":["No prospective randomised trial has compared subtype-directed adjuvant regimens; retrospective consortia and the NCCN guideline are the current basis.","Which patients with node-positive disease benefit from neoadjuvant therapy; extrapolation from pancreatic trials is being tested.","Surveillance intensity after Whipple and the role of ctDNA to select adjuvant therapy.","FAP-associated duodenal disease: timing of prophylactic surgery versus endoscopic control."],"parent":"biliary-tract-cancer"},{"id":"anal","kind":"cancer","name":"Anal cancer (squamous cell carcinoma)","aka":[],"tldr":"An HPV-caused cancer of the anal canal that is usually cured without surgery by combined chemotherapy and radiation. Prevention (HPV vaccination, screening of high-risk groups) and immunotherapy for advanced disease are the new fronts.","summary":"Anal squamous cell carcinoma is an HPV-driven cancer (HPV16 in most), biologically closer to cervical cancer than to rectal adenocarcinoma. Risk factors are HPV persistence, HIV, immunosuppression, receptive anal intercourse and smoking; high-grade anal intraepithelial neoplasia is the precursor, and the ANCHOR trial (2022) showed treating it in people with HIV cuts progression to cancer by more than half.\n\nDefinitive chemoradiation with mitomycin and 5-fluorouracil (Nigro regimen 1974; ACT II confirmed mitomycin-5-FU and no benefit of maintenance) cures ~70-80% and preserves the sphincter; salvage abdominoperineal resection is reserved for persistent or recurrent disease. Metastatic disease was treated with carboplatin-paclitaxel (InterAAct, 2020); PD-1 blockade showed activity in refractory disease (nivolumab NCI9673, pembrolizumab KEYNOTE-158), and POD1UM-303 (2024) established retifanlimab plus carboplatin-paclitaxel as first-line standard (FDA approval 2025). Response-adapted radiotherapy dose (PLATO trials) and ctHPV DNA monitoring are being developed.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Anal_cancer","links":[{"label":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"},{"label":"ANCHOR (NEJM 2022)","url":"https://doi.org/10.1056/NEJMoa2201048"},{"label":"NCI PDQ: anal cancer","url":"https://www.cancer.gov/types/anal/patient/anal-treatment-pdq"}],"tags":["gap-fill","gastrointestinal","hpv"],"related":["urethral"],"cancers":[],"sections":[],"technologies":["imrt-igrt","cytotoxic-chemotherapy","checkpoint-inhibitor","hpv-vaccine","hpv-testing","precancer-ablation","cthpv-dna"],"targets":["pd1","pdl1"],"drugs":["mitomycin","fluorouracil","carboplatin","paclitaxel","retifanlimab","nivolumab","pembrolizumab","gardasil-9"],"companies":["incyte","merck","bms","oncolytics-biotech"],"institutions":[],"pathways":["pd1-checkpoint"],"terms":["hpv-p16","clinical-complete-response"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 50,000 cases per year worldwide and rising ~2-3% a year in high-income countries; over 90% caused by HPV; higher in people living with HIV and in women.","subtypes":["Anal canal SCC (HPV-positive, ~90%)","Perianal skin SCC","HPV-negative anal SCC (worse prognosis, TP53-mutant)","Anal adenocarcinoma (treated as rectal cancer)","High-grade anal intraepithelial neoplasia (precursor)"],"biomarkers":["HPV / p16 status","HIV status and CD4 count","T and N stage (MRI, PET-CT)","PD-L1 (not required)","ctHPV DNA (emerging)","Anal cytology / high-resolution anoscopy (screening in high-risk groups)"],"standardOfCare":[{"setting":"Precancer (HSIL) in people with HIV","approach":"Screening with anal cytology / high-resolution anoscopy and treatment of HSIL (ablation, topical therapy) reduces progression to cancer by 57% (ANCHOR).","refs":["hpv-testing","precancer-ablation","hpv-vaccine","anchor"],"guideline":{"version":"ANCHOR (NEJM 2022)","url":"https://doi.org/10.1056/NEJMoa2201048"}},{"setting":"Localised (stage I-III)","approach":"Definitive IMRT chemoradiation with concurrent mitomycin + 5-FU (or capecitabine); small T1 perianal lesions may be excised; assess response at 26 weeks before declaring failure (ACT II).","refs":["mitomycin","fluorouracil","imrt-igrt"],"guideline":{"nccn":"Category 1 (5-FU/mitomycin + RT)","version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}},{"setting":"Persistent or recurrent local disease","approach":"Salvage abdominoperineal resection with permanent colostomy; flap reconstruction.","refs":["robotic-surgery"]},{"setting":"Metastatic, first line","approach":"Retifanlimab + carboplatin-paclitaxel (POD1UM-303, PFS and OS benefit); carboplatin-paclitaxel alone if immunotherapy contraindicated.","refs":["retifanlimab","carboplatin","paclitaxel","pod1um-303"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Anal Carcinoma"}},{"setting":"Metastatic, later lines","approach":"Nivolumab or pembrolizumab if not previously given; clinical trials.","refs":["nivolumab","pembrolizumab"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Anal Carcinoma"}}],"stateOfArt":["Chemoradiation cures most patients with sphincter preservation; the 1974 Nigro insight still holds.","ANCHOR proved that anal cancer is preventable in the highest-risk group by screening and treating precancer.","Retifanlimab-chemotherapy is the first immunotherapy standard in first-line metastatic disease.","Radiotherapy dose de-escalation for small tumours and escalation for bulky disease (PLATO) is under test."],"history":[{"year":1974,"title":"Nigro: chemoradiation instead of surgery","note":"Three patients with complete response to 5-FU, mitomycin and radiation; abdominoperineal resection abandoned as first treatment.","refs":["fluorouracil","mitomycin"]},{"year":1996,"title":"UKCCCR ACT I and EORTC: chemoradiation beats radiation alone","refs":[]},{"year":2013,"title":"ACT II: mitomycin-5-FU standard; no maintenance benefit","refs":["mitomycin","fluorouracil"]},{"year":2017,"title":"Nivolumab active in refractory disease (NCI9673)","refs":["nivolumab"]},{"year":2020,"title":"InterAAct: carboplatin-paclitaxel first-line standard","refs":["carboplatin","paclitaxel"]},{"year":2022,"title":"ANCHOR: treating HSIL prevents anal cancer in people with HIV","refs":["precancer-ablation"]},{"year":2024,"title":"POD1UM-303: retifanlimab + chemotherapy improves PFS/OS","note":"FDA approval 2025.","refs":["retifanlimab"]}],"pipeline":["retifanlimab","cthpv-dna","hpv-vaccine"],"openProblems":["Screening programmes for high-risk groups exist almost nowhere despite ANCHOR.","Late toxicity of pelvic chemoradiation (bowel, sexual, bone).","HPV-negative anal cancer does poorly.","Stigma and delayed diagnosis."]},{"id":"anal-hsil-precursor","kind":"cancer","name":"Anal high-grade squamous intraepithelial lesions (precursor)","aka":["Anal HSIL","High-grade anal intraepithelial neoplasia","AIN 2 to 3","Anal dysplasia","Anal precancer"],"tldr":"Anal high-grade squamous intraepithelial lesions are the HPV-driven precancer that anal cancer grows from, found by screening people at high risk with cytology and high-resolution anoscopy. The ANCHOR trial showed that treating these lesions, mostly by ablation in the clinic, cuts the number that become anal cancer, so screening and treatment are now recommended for people living with HIV.","summary":"Anal high-grade squamous intraepithelial lesions (HSIL, formerly anal intraepithelial neoplasia grades 2 and 3) are the precursor of anal squamous cell carcinoma in the same way that cervical HSIL precedes cervical cancer, and are caused by the same persistent high-risk HPV types, above all HPV 16. They are commonest in people living with HIV, in transplant recipients and in women with a history of cervical, vaginal or vulvar HPV disease. They cause no symptoms and are found by anal cytology followed by high-resolution anoscopy with biopsy, the anal equivalent of colposcopy, and p16 immunohistochemistry helps the pathologist separate HSIL from low-grade change.\n\nWhether treating HSIL prevents cancer was uncertain until the ANCHOR trial (New England Journal of Medicine 2022) randomised 4,459 people living with HIV to treatment or active monitoring: treatment, mostly office-based electrocautery or infrared coagulation with topical fluorouracil or imiquimod for extensive disease, reduced progression to anal cancer by 57 percent. On that evidence the 2024 International Anal Neoplasia Society guidelines recommend screening from age 35 for men who have sex with men and transgender women living with HIV and from 45 for other people with HIV, and HPV vaccination remains the primary prevention. Lesions recur often after treatment, so surveillance continues, and biomarkers such as HPV 16 typing and methylation markers are being studied to decide which lesions most need treatment.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Anal_cancer","links":[{"label":"ANCHOR (NEJM 2022)","url":"https://doi.org/10.1056/NEJMoa2201048"},{"label":"IANS screening guidelines 2024","url":"https://doi.org/10.1002/ijc.34850"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Anal_cancer"}],"tags":["subtype-page","gastrointestinal"],"related":["localised-anal-cancer","metastatic-anal-cancer","anal"],"cancers":[],"sections":[],"technologies":["hpv-testing","precancer-ablation","hpv-vaccine","cthpv-dna"],"targets":[],"drugs":["fluorouracil","gardasil-9"],"companies":[],"institutions":[],"pathways":[],"terms":["hpv-p16","cin-hsil","hpv-status"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-anchor-anal-hsil-treatment-nejm-2022","paper-ians-anal-cancer-screening-guidelines-ijc-2024"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Common in people living with HIV, especially men who have sex with men, and in women with a history of cervical or vulvar HPV disease; only a minority of lesions progress, but anal cancer rates in these groups are many times those of the general population.","subtypes":["Anal canal HSIL (HPV 16 in most, p16 positive)","Perianal HSIL (perianal skin, treated with topical agents or excision)","HSIL in people living with HIV (highest progression risk, ANCHOR population)","HSIL in women with prior cervical or vulvar HPV disease","Low-grade squamous intraepithelial lesion (LSIL, AIN 1, not a cancer precursor in itself)"],"biomarkers":["Anal cytology (screening)","High-resolution anoscopy with biopsy (diagnosis)","p16 immunohistochemistry (confirms HSIL)","HPV 16 typing (highest progression risk, investigational triage)","HIV status and CD4 count","Host and viral DNA methylation markers (investigational)"],"standardOfCare":[{"setting":"Screening","approach":"Anal cytology or high-risk HPV testing followed by high-resolution anoscopy in people living with HIV and other high-risk groups, following the 2024 International Anal Neoplasia Society guidelines.","refs":["hpv-testing","hpv-p16","cthpv-dna"],"guideline":{"version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}},{"setting":"Treatment of HSIL","approach":"Office-based ablation (electrocautery, infrared coagulation) for discrete lesions; topical fluorouracil or imiquimod for extensive or perianal disease; excision for lesions where invasion is suspected (ANCHOR).","refs":["precancer-ablation","fluorouracil","anchor"],"guideline":{"version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}},{"setting":"Prevention","approach":"HPV vaccination, which protects against the HPV types that cause almost all anal cancer.","refs":["hpv-vaccine","gardasil-9"],"guideline":{"version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}},{"setting":"After treatment","approach":"Repeat high-resolution anoscopy because recurrence is common; biopsy of any lesion that changes or ulcerates.","refs":["hpv-testing","hpv-p16"],"guideline":{"version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}}],"stateOfArt":["ANCHOR is the first randomised proof that treating an HPV precancer outside the cervix prevents cancer.","Screening programmes for people living with HIV now have guideline backing, though high-resolution anoscopy capacity is the limiting step.","HPV vaccination prevents the infection that starts the whole sequence."],"history":[{"year":2006,"title":"Quadrivalent HPV vaccine approved; later trials show protection against anal precancer","refs":["hpv-vaccine","gardasil-9"]},{"year":2012,"title":"Lower Anogenital Squamous Terminology (LAST) unifies HSIL and LSIL across anogenital sites","refs":["hpv-p16"]},{"year":2022,"title":"ANCHOR: treating anal HSIL in people living with HIV cuts progression to anal cancer by 57 percent","refs":["precancer-ablation"]},{"year":2024,"title":"International Anal Neoplasia Society screening guidelines for people at high risk","refs":["hpv-testing"]}],"pipeline":["cthpv-dna","hpv-vaccine","hpv-testing"],"openProblems":["Most HSIL never progresses, and no marker yet says which lesions to treat and which to watch.","High-resolution anoscopy is scarce outside specialist centres.","Recurrence after ablation is common and the best retreatment strategy is untested.","Whether screening helps people at high risk who do not have HIV is unproven."],"parent":"anal"},{"id":"anaplastic-thyroid-cancer","kind":"cancer","name":"Anaplastic thyroid cancer","aka":["Anaplastic thyroid carcinoma","ATC","Undifferentiated thyroid carcinoma"],"tldr":"Anaplastic thyroid cancer is the rare, fast-growing form that presents as a rapidly enlarging neck mass threatening the airway. Few patients lived more than a few months; combining BRAF-targeted drugs, immunotherapy, surgery and radiotherapy has lifted survival for the first time.","summary":"Anaplastic thyroid cancer is an undifferentiated carcinoma that usually arises from a pre-existing papillary or follicular cancer through the accumulation of TP53 and TERT mutations; about 40 percent carry BRAF V600E. It presents in older adults as a hard, rapidly growing neck mass with hoarseness, breathing or swallowing difficulty, and it does not take up iodine. Every case is staged IV. Rapid molecular testing is now urged at diagnosis because BRAF V600E tumours respond to dabrafenib plus trametinib, approved in 2018 on the ROAR basket trial, and neoadjuvant use has made some inoperable tumours resectable; pembrolizumab added to targeted therapy and chemoradiation for resectable disease are part of the multimodal approach that raised one-year survival at MD Anderson from about a fifth to over half. Airway management and early palliative care remain central.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Anaplastic_thyroid_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Anaplastic_thyroid_cancer"}],"tags":["subtype-page"],"related":["follicular-thyroid-cancer","medullary-thyroid-cancer","papillary-thyroid-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-subbiah-dabrafenib-trametinib-atc-jco-2018","paper-ata-anaplastic-thyroid-guideline-bible-thyroid-2021","paper-maniakas-neoadjuvant-braf-atc-jama-oncol-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"One to two percent of thyroid cancers but a large share of thyroid cancer deaths; median survival in registry series before targeted treatment was historically about six months, meaning half of those patients lived longer, and every case is stage IV by definition.","subtypes":["BRAF V600E-mutant (about 40 percent)","RAS-mutant","Arising from differentiated thyroid cancer","Squamous and other rare patterns"],"biomarkers":["BRAF V600E (urgent testing at diagnosis)","TP53 and TERT promoter mutations","PD-L1 expression","NTRK, RET and ALK fusions (rare)"],"standardOfCare":[{"setting":"Diagnosis","approach":"Core biopsy with rapid BRAF testing, airway assessment, staging CT and PET; multidisciplinary planning within days.","refs":["braf"]},{"setting":"BRAF V600E-mutant","approach":"Dabrafenib plus trametinib, with pembrolizumab in many centres; neoadjuvant use to make tumours resectable, then surgery and radiotherapy.","refs":["dabrafenib","trametinib","pembrolizumab"]},{"setting":"BRAF wild-type, resectable","approach":"Surgery followed by chemoradiation (paclitaxel- or doxorubicin-based).","refs":["paclitaxel","doxorubicin","imrt-igrt"]},{"setting":"Unresectable BRAF wild-type","approach":"Chemoradiation or immunotherapy in trials; lenvatinib in some countries; palliative radiotherapy and airway support.","refs":["lenvatinib","palliative-radiotherapy","palliative-care"]}],"stateOfArt":["Dabrafenib-trametinib was the first drug approval ever for anaplastic thyroid cancer and turns some inoperable tumours into operable ones.","Immunotherapy with BRAF inhibition and multimodal treatment has more than doubled one-year survival in specialist centres.","Rapid molecular testing at diagnosis, within days, is now the standard of care because the window for treatment is short."],"history":[{"year":1990,"title":"Anaplastic cancer classified as stage IV in every case","refs":[]},{"year":2018,"title":"Dabrafenib plus trametinib approved (ROAR)","note":"The first drug approval for this cancer.","refs":["dabrafenib","trametinib"]},{"year":2020,"title":"MD Anderson reports survival gains with targeted therapy, immunotherapy and surgery","refs":[]}],"pipeline":["pembrolizumab","lenvatinib"],"openProblems":["Most people diagnosed still die within a year, and the MD Anderson series that lifted one-year survival from about a fifth to over half came from one centre combining BRAF-targeted drugs, immunotherapy, surgery and radiotherapy; whether that holds outside specialist centres is what prospective work has to establish.","BRAF wild-type disease has no targeted option.","Trials are tiny because the disease is rare and fast."],"parent":"thyroid"},{"id":"angiosarcoma","kind":"cancer","name":"Angiosarcoma","aka":["Haemangiosarcoma","Lymphangiosarcoma","Stewart-Treves syndrome (lymphoedema-associated angiosarcoma)","Radiation-associated angiosarcoma"],"tldr":"Angiosarcoma is an aggressive vascular tumour, a cancer of the cells that line blood and lymph vessels. It grows as bruise-like patches on the scalp of older people, in breasts treated years earlier with radiotherapy, or inside organs. Surgery and radiotherapy are used where possible, weekly paclitaxel is the most active drug, and immunotherapy helps a minority with the sun-damaged scalp form.","summary":"Angiosarcoma is a high-grade endothelial malignancy with three main clinical settings: cutaneous angiosarcoma of the scalp and face in elderly patients, carrying an ultraviolet mutational signature and high tumour mutational burden; secondary angiosarcoma after breast radiotherapy or in chronic lymphoedema, typically driven by MYC amplification; and primary visceral angiosarcoma of the liver, heart, spleen and breast. Tumours are multifocal and infiltrative, margins are hard to secure, and local recurrence and lung metastasis are common even after apparently complete treatment.\n\nLocalised disease is treated with wide surgery and radiotherapy, often combined because neither alone controls the diffuse scalp form. For advanced disease, weekly paclitaxel established itself through the French ANGIOTAX phase 2 trial and is used first line or as neoadjuvant treatment for scalp disease; doxorubicin and liposomal doxorubicin are alternatives, and gemcitabine and pazopanib are used later. Adding bevacizumab to paclitaxel (ANGIOTAX-PLUS) and the endoglin antibody TRC105 to pazopanib (TAPPAS) did not improve outcomes.\n\nCheckpoint inhibitors produce durable responses in a subset of cutaneous scalp and face angiosarcomas, consistent with their ultraviolet-driven mutational load, in the DART ipilimumab-nivolumab basket and in case series, but the randomised Alliance A091902 trial did not show that adding nivolumab to paclitaxel improved progression-free survival across all angiosarcomas. Propranolol, targeted anti-angiogenic combinations and the international Angiosarcoma Project patient-partnered genomics effort are the main lines of research.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Angiosarcoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Angiosarcoma"}],"tags":["subtype-page"],"related":["vascular-tumours","kaposi-sarcoma","epithelioid-haemangioendothelioma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["carotuximab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["tappas"],"people":[],"bottlenecks":[],"keyPapers":["paper-angiotax-paclitaxel-angiosarcoma-penel-jco-2008","paper-young-angiosarcoma-review-lancet-oncol-2010"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"About one to two percent of soft tissue sarcomas; arises in the sun-damaged scalp and face of older people, in the irradiated breast, in chronically swollen limbs and in the liver, heart and spleen. It spreads early and median survival with metastatic disease is under a year in most series.","subtypes":["Cutaneous angiosarcoma of the scalp and face (ultraviolet signature, high mutational burden)","Radiation-associated angiosarcoma of the breast (MYC-amplified)","Lymphoedema-associated angiosarcoma (Stewart-Treves)","Primary breast angiosarcoma (younger women)","Visceral angiosarcoma (liver, heart, spleen, bone)"],"biomarkers":["MYC amplification (secondary angiosarcoma)","Tumour mutational burden and ultraviolet signature (scalp and face; immunotherapy response)","CD31, ERG and FLI1 endothelial markers","KDR and PLCG1 mutations","PTPRB and PLCG1 in secondary breast tumours"],"standardOfCare":[{"setting":"Localised cutaneous (scalp, face)","approach":"Wide excision where feasible plus wide-field radiotherapy; neoadjuvant or definitive weekly paclitaxel with radiotherapy when surgery is not possible.","refs":["imrt-igrt","paclitaxel"]},{"setting":"Radiation-associated breast angiosarcoma","approach":"Total mastectomy with wide skin excision; consider neoadjuvant paclitaxel; re-irradiation is limited by prior dose.","refs":["paclitaxel","doxorubicin"]},{"setting":"Advanced, first line","approach":"Weekly paclitaxel (ANGIOTAX) or doxorubicin-based chemotherapy; liposomal doxorubicin in frail patients.","refs":["paclitaxel","angiotax","doxorubicin","pegylated-liposomal-doxorubicin"]},{"setting":"Later lines","approach":"Gemcitabine, pazopanib; checkpoint inhibitors (nivolumab plus ipilimumab) for cutaneous scalp and face disease, off label or in trials.","refs":["gemcitabine","pazopanib","nivolumab","ipilimumab","checkpoint-inhibitor"]}],"stateOfArt":["Weekly paclitaxel is the reference systemic therapy, with responses concentrated in cutaneous scalp and face disease.","Sun-damaged scalp angiosarcoma responds to checkpoint blockade, making it one of the few sarcomas where immunotherapy works.","The patient-partnered Angiosarcoma Project has sequenced hundreds of tumours from home-shipped samples, defining the MYC-amplified and ultraviolet-driven groups."],"history":[{"year":1948,"title":"Stewart and Treves describe angiosarcoma in the lymphoedematous arm after mastectomy","refs":[]},{"year":2008,"title":"ANGIOTAX: weekly paclitaxel established as active in angiosarcoma","refs":["angiotax","paclitaxel"]},{"year":2010,"title":"MYC amplification found in radiation-associated and lymphoedema angiosarcoma","refs":[]},{"year":2015,"title":"ANGIOTAX-PLUS: adding bevacizumab to paclitaxel does not improve outcomes","refs":["paclitaxel","bevacizumab"]},{"year":2020,"title":"Angiosarcoma Project reports ultraviolet signature and immunotherapy responses in scalp and face tumours","refs":["checkpoint-inhibitor"]},{"year":2022,"title":"TAPPAS: TRC105 plus pazopanib fails to beat pazopanib","refs":["pazopanib"]}],"pipeline":["checkpoint-inhibitor","nivolumab","ipilimumab","pazopanib"],"openProblems":["Multifocal scalp disease escapes even wide surgery and radiotherapy.","Median survival with metastases remains under a year.","Immunotherapy benefit is limited to the ultraviolet-driven subset and has not been confirmed in a randomised trial."],"parent":"vascular-tumours"},{"id":"apocrine-carcinoma-breast","kind":"cancer","name":"Apocrine carcinoma of the breast","aka":["Carcinoma with apocrine differentiation","Apocrine breast cancer","Molecular apocrine carcinoma (overlapping expression subtype)"],"tldr":"Apocrine breast cancers are made of large cells resembling sweat-gland cells. They lack oestrogen and progesterone receptors but carry the androgen receptor, so the triple-negative ones sit in the luminal androgen receptor group and are the tumours in which androgen-blocking drugs have been tried.","summary":"Apocrine carcinoma shows distinct morphology (abundant eosinophilic granular cytoplasm and prominent nucleoli) with a characteristic steroid receptor profile that is oestrogen and progesterone receptor negative and androgen receptor positive; strictly defined, apocrine carcinomas express either HER2 or EGFR, which with androgen receptor positivity makes them candidates for targeted therapies (Vranic 2013). In the 5th edition of the WHO classification the entity is discussed as carcinoma with apocrine differentiation, reflecting debate about how much apocrine morphology is needed (Cserni 2020). The transcriptionally defined molecular apocrine group, ESR1-negative and AR- and FOXA1-positive, was 67 percent HER2 3+ and 57 percent GCDFP15-positive by immunohistochemistry and clinically aggressive, and almost all (94 percent) carried the HER2 3+ or GCDFP15-positive signature that none of the basal-like controls did (Lehmann-Che 2013). The HER2-negative apocrine tumours are therefore the histological face of the luminal androgen receptor subtype, whose phase 2 trials of bicalutamide and enzalutamide are on that page; the HER2-positive ones are treated as HER2-positive breast cancer.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Breast_cancer_classification","links":[{"label":"Vranic, Histol Histopathol 2013: apocrine carcinoma of the breast, a comprehensive review","url":"https://doi.org/10.14670/hh-28.1393"},{"label":"Lehmann-Che, Breast Cancer Res 2013: molecular apocrine breast cancers overexpress HER2 or GCDFP15","url":"https://doi.org/10.1186/bcr3421"},{"label":"Cserni, Pathologica 2020: histological type and typing of breast carcinomas and WHO classification changes","url":"https://doi.org/10.32074/1591-951x-1-20"},{"label":"Thomas, NPJ Breast Cancer 2023: rare subtypes of triple-negative breast cancer","url":"https://doi.org/10.1038/s41523-023-00554-x"}],"tags":["breast","tnbc","subtype-page"],"related":["tnbc","tnbc-luminal-androgen-receptor","breast-her2-positive"],"cancers":[],"sections":[],"technologies":[],"targets":["androgen-receptor","her2","egfr"],"drugs":["bicalutamide","enzalutamide"],"companies":[],"institutions":[],"pathways":[],"terms":["androgen-receptor-positive-tnbc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"A rare special type; the WHO classification counts carcinomas with apocrine differentiation among the special types and the molecular apocrine expression group overlaps the luminal androgen receptor subtype (Cserni 2020; Lehmann-Che 2013).","subtypes":["HER2-negative apocrine carcinoma (triple-negative, luminal androgen receptor subtype)","HER2-positive apocrine carcinoma (treated as HER2-positive breast cancer)","Invasive carcinoma of no special type (ductal) with apocrine differentiation"],"biomarkers":["ER and PR negative with androgen receptor positive","HER2 status (3+ in two thirds of molecular apocrine tumours)","GCDFP15 (gross cystic disease fluid protein 15) and FOXA1 expression"],"standardOfCare":[{"setting":"Triple-negative apocrine carcinoma","approach":"As for triple-negative disease of no special type; androgen receptor antagonists only within trials (clinical benefit rates 19 to 33 percent in phase 2).","refs":["bicalutamide","enzalutamide","androgen-receptor"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"tnbc"},{"id":"appendiceal-adenocarcinoma","kind":"cancer","name":"Appendiceal adenocarcinoma (mucinous and non-mucinous, including signet ring cell)","aka":["Appendix adenocarcinoma","Colonic-type appendiceal adenocarcinoma","Mucinous appendiceal adenocarcinoma","Signet ring cell carcinoma of the appendix","High-grade appendiceal cancer"],"tldr":"Appendiceal adenocarcinoma is the invasive, gland-forming form of appendix cancer that behaves more like bowel cancer than the jelly-producing low-grade tumours, spreading to lymph nodes and the abdominal lining. It is treated with right hemicolectomy and bowel-cancer chemotherapy, and peritoneal spread with cytoreductive surgery and heated intraperitoneal chemotherapy in fit patients.","summary":"Appendiceal adenocarcinoma invades the wall of the appendix as a carcinoma and is subdivided into mucinous adenocarcinoma (more than half the tumour is extracellular mucin), non-mucinous or colonic-type adenocarcinoma, and signet ring cell carcinoma when half or more of the cells are signet ring cells. Most are found after appendicectomy for suspected appendicitis or at operation for peritoneal disease, and staging follows the colorectal TNM system. The genetics differ from colorectal cancer: KRAS and GNAS mutations are common, APC mutations rare, microsatellite instability uncommon, and TP53 and SMAD4 mutations mark high-grade tumours; a 2025 analysis of appendiceal cancers also found that many were diagnosed in people under 50, mirroring early-onset colorectal cancer.\n\nBecause the disease is rare, treatment is extrapolated from colon cancer. Right hemicolectomy with lymphadenectomy is recommended for all adenocarcinomas, and adjuvant FOLFOX or CAPOX for node-positive or high-risk disease, without trial evidence specific to the appendix. Peritoneal metastases, the dominant pattern of spread, are treated with cytoreductive surgery and HIPEC in patients with a limited peritoneal cancer index and non-signet-ring histology, where series report median survival of several years, and with perioperative systemic chemotherapy; signet ring cell carcinoma with a high peritoneal cancer index does poorly even after cytoreduction. Unresectable or distant metastatic disease receives FOLFOX or CAPOX with or without bevacizumab, then FOLFIRI, and the rare mismatch-repair-deficient tumour is a candidate for pembrolizumab. Retrospective data suggest that non-mucinous tumours respond to chemotherapy like colorectal cancer while mucinous tumours respond less, and prospective trials in appendiceal cancer specifically are only now beginning.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Appendix_cancer","links":[{"label":"NCCN Colon Cancer (appendiceal adenocarcinoma)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Appendix_cancer"}],"tags":["subtype-page","gastrointestinal"],"related":["low-grade-appendiceal-mucinous-neoplasm","goblet-cell-adenocarcinoma","appendiceal","colorectal"],"cancers":[],"sections":[],"technologies":["hipec","cytotoxic-chemotherapy","ct","mri","checkpoint-inhibitor"],"targets":["kras","tp53"],"drugs":["folfox","capox","folfiri","bevacizumab","mitomycin","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["hipec-procedure","peritoneal-metastasis","colectomy","lymphadenectomy","msi"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-chicago-consensus-appendiceal-neoplasms-cancer-2020","paper-who-2019-digestive-system-tumours-nagtegaal-histopathology-2020","paper-psogi-pseudomyxoma-appendiceal-classification-am-j-surg-pathol-2016"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"A minority of appendiceal tumours but the group that behaves like a true carcinoma, spreading to lymph nodes and the peritoneum; signet ring cell histology carries the worst outlook.","subtypes":["Mucinous appendiceal adenocarcinoma (extracellular mucin, GNAS and KRAS mutant)","Non-mucinous (colonic-type) appendiceal adenocarcinoma","Signet ring cell carcinoma of the appendix (worst prognosis)","Appendiceal adenocarcinoma with peritoneal metastases (cytoreduction and HIPEC in selected patients)","Node-positive appendiceal adenocarcinoma (right hemicolectomy and adjuvant chemotherapy)","Mismatch-repair-deficient appendiceal adenocarcinoma (rare; immunotherapy)"],"biomarkers":["Histological subtype and grade (mucinous, non-mucinous, signet ring)","TNM stage after right hemicolectomy","Peritoneal cancer index and completeness of cytoreduction","KRAS, GNAS, TP53 and SMAD4 mutations","Mismatch repair and microsatellite status (uncommon deficiency)","CEA, CA 19-9 and CA-125"],"standardOfCare":[{"setting":"Localised disease","approach":"Right hemicolectomy with lymphadenectomy; adjuvant FOLFOX or CAPOX for node-positive or high-risk stage II disease, extrapolated from colon cancer.","refs":["colectomy","lymphadenectomy","folfox","capox"],"guideline":{"version":"NCCN Guidelines: Colon Cancer (appendiceal section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Peritoneal metastases, resectable","approach":"Cytoreductive surgery with HIPEC (mitomycin or oxaliplatin) in fit patients with limited disease and favourable histology, with perioperative systemic chemotherapy.","refs":["hipec","hipec-procedure","mitomycin","folfox","capox","peritoneal-metastasis"],"guideline":{"version":"NCCN Guidelines: Colon Cancer (appendiceal section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Unresectable or distant metastatic disease","approach":"FOLFOX or CAPOX with or without bevacizumab; FOLFIRI in second line; pembrolizumab for mismatch-repair-deficient tumours.","refs":["folfox","capox","bevacizumab","folfiri","pembrolizumab","msi"],"guideline":{"version":"NCCN Guidelines: Colon Cancer (appendiceal section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Signet ring cell carcinoma with extensive peritoneal disease","approach":"Systemic chemotherapy first; cytoreduction only for exceptional responders.","refs":["folfox","capox","hipec"],"guideline":{"version":"NCCN Guidelines: Colon Cancer (appendiceal section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}}],"stateOfArt":["Right hemicolectomy and colorectal-style chemotherapy are the accepted standards, on extrapolated evidence.","Cytoreductive surgery with HIPEC extends survival in selected patients with peritoneal disease.","Molecular profiling shows appendiceal adenocarcinoma is not simply colon cancer of the appendix."],"history":[{"year":1998,"title":"Sugarbaker reports cytoreduction with intraperitoneal chemotherapy for appendiceal carcinomatosis","refs":["hipec"]},{"year":2010,"title":"WHO classification separates appendiceal mucinous neoplasms from adenocarcinoma","refs":[]},{"year":2016,"title":"PSOGI consensus defines mucinous adenocarcinoma and signet ring cell carcinoma grades","refs":[]},{"year":2019,"title":"Genomic studies show KRAS and GNAS mutations and few APC mutations, distinguishing appendiceal from colorectal cancer","refs":[]},{"year":2025,"title":"Analysis shows a large share of appendiceal cancers now arise in adults under 50","refs":[]}],"pipeline":["folfox","hipec","pembrolizumab"],"openProblems":["No adjuvant chemotherapy trial has ever been run in appendiceal adenocarcinoma.","Which patients with peritoneal disease benefit from HIPEC is defined only by retrospective series.","Signet ring cell carcinoma has no effective therapy.","Mucinous tumours respond poorly to standard chemotherapy and have no targeted option."],"parent":"appendiceal"},{"id":"appendiceal","kind":"cancer","name":"Appendiceal cancer and pseudomyxoma peritonei","aka":["Appendix cancer","PMP","Low-grade appendiceal mucinous neoplasm (LAMN)"],"tldr":"Rare tumours of the appendix that range from slow mucin-producing growths that fill the abdomen (pseudomyxoma peritonei) to aggressive adenocarcinomas. The slow forms are treated by extensive surgery with heated chemotherapy in the abdomen; the fast ones like colon cancer.","summary":"Appendiceal neoplasms include low-grade appendiceal mucinous neoplasms (LAMN) that rupture and seed the peritoneum as pseudomyxoma peritonei (PMP), mucinous and non-mucinous adenocarcinomas, goblet cell adenocarcinoma, and neuroendocrine tumours (the most common appendix tumour, usually cured by appendicectomy). PSOGI grading (acellular mucin, low-grade, high-grade, signet ring) predicts outcome. GNAS mutations mark low-grade mucinous disease; KRAS, TP53 and SMAD4 mark higher grade.\n\nFor PMP and peritoneal disease, cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC, usually mitomycin C) at an experienced centre gives 10-year survival of ~60-70% for low-grade disease (Sugarbaker, Chua 2012). Systemic chemotherapy (FOLFOX/CAPOX) is used for high-grade and unresectable disease but a randomised trial (2024) showed no benefit in low-grade mucinous carcinoma peritonei. Iterative CRS, mucolytics (bromelain-acetylcysteine) and intraperitoneal therapies are under study. Appendiceal adenocarcinoma is otherwise managed like colorectal cancer, with right hemicolectomy and stage-based chemotherapy.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Pseudomyxoma_peritonei","links":[{"label":"PSOGI consensus (Am J Surg Pathol 2016)","url":"https://doi.org/10.1097/PAS.0000000000000535"},{"label":"Appendix Cancer / PMP Research Foundation","url":"https://www.acpmp.org/"}],"tags":["gap-fill","gastrointestinal","rare"],"related":[],"cancers":[],"sections":[],"technologies":["hipec","cytotoxic-chemotherapy","ct","mri"],"targets":["kras","tp53"],"drugs":["folfox","capox","bevacizumab","mitomycin"],"companies":[],"institutions":[],"pathways":["ras-mapk"],"terms":["peritoneal-metastasis","colectomy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 1-2 per 100,000 per year and rising, especially in adults under 50; most are found incidentally at appendicectomy.","subtypes":["LAMN / HAMN (low- and high-grade appendiceal mucinous neoplasm)","Pseudomyxoma peritonei (low- vs high-grade, PSOGI)","Mucinous and non-mucinous adenocarcinoma","Goblet cell adenocarcinoma","Signet ring cell carcinoma","Appendiceal neuroendocrine tumour"],"biomarkers":["PSOGI histologic grade","Peritoneal cancer index (PCI) and completeness of cytoreduction (CC score)","GNAS (low-grade), KRAS, TP53, SMAD4","CEA, CA19-9, CA-125","MSI (rare)"],"standardOfCare":[{"setting":"Localised LAMN / adenocarcinoma","approach":"Appendicectomy (LAMN without perforation) or right hemicolectomy (adenocarcinoma, goblet cell); adjuvant chemotherapy for node-positive adenocarcinoma by colorectal analogy.","refs":["folfox","capox"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Colon Cancer (appendiceal section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Pseudomyxoma peritonei / peritoneal disease","approach":"Cytoreductive surgery with HIPEC at a peritoneal-surface-malignancy centre; repeat CRS for recurrence when feasible.","refs":["hipec"],"guideline":{"version":"PSOGI consensus (2016); Chicago Consensus (2020)"}},{"setting":"High-grade or unresectable peritoneal disease","approach":"FOLFOX/CAPOX ± bevacizumab; systemic chemotherapy has no proven benefit in low-grade disease (randomised 2024).","refs":["folfox","capox","bevacizumab"]}],"stateOfArt":["CRS-HIPEC turned PMP from a disease with no effective treatment into one with long survival for low-grade histology.","Grade, not stage, drives therapy: the 2024 randomised trial ended routine chemotherapy for low-grade mucinous carcinomatosis.","Molecular profiling (GNAS vs KRAS/TP53) is beginning to formalise the low/high grade split."],"history":[{"year":1842,"title":"Rokitansky describes a mucocele of the appendix","refs":[]},{"year":1884,"title":"Werth coins 'pseudomyxoma peritonei'","refs":[]},{"year":1995,"title":"Sugarbaker's peritonectomy procedures and HIPEC","refs":["hipec"]},{"year":2012,"title":"Multi-institutional CRS-HIPEC outcomes: 10-year survival 63% (Chua, JCO)","refs":["hipec"]},{"year":2016,"title":"PSOGI classification of appendiceal mucinous neoplasms and PMP","refs":[]},{"year":2024,"title":"Randomised trial: no benefit of systemic chemotherapy in low-grade mucinous carcinoma peritonei","refs":["folfox"]}],"pipeline":["hipec","folfox"],"openProblems":["No effective systemic therapy for high-grade or signet-ring disease.","Selection for CRS-HIPEC and management of recurrence after maximal surgery.","Rising incidence in young adults is unexplained.","Centralisation: outcomes depend heavily on centre experience."]},{"id":"idh-mutant-astrocytoma","kind":"cancer","name":"Astrocytoma, IDH-mutant (grades 2 to 4)","aka":["IDH-mutant astrocytoma","Diffuse astrocytoma, IDH-mutant","Anaplastic astrocytoma, IDH-mutant","Lower-grade glioma","Low-grade glioma (adult)"],"tldr":"IDH-mutant astrocytoma is the slow-growing form of adult glioma, defined by a mutation in the IDH1 or IDH2 gene that makes the tumour produce a chemical which rewires its own cells. Surgery first, and then either watchful waiting, the new pill vorasidenib, or radiotherapy with chemotherapy, depending on grade and how much tumour is left.","summary":"Astrocytoma, IDH-mutant is a single WHO 2021 tumour type graded 2, 3 or 4, defined by an IDH1 or IDH2 mutation without 1p/19q codeletion and usually with ATRX loss and TP53 mutation. Grade 4 is assigned on necrosis, microvascular proliferation or homozygous CDKN2A/B deletion, and the old term glioblastoma is no longer used for IDH-mutant tumours. The mutant enzyme produces 2-hydroxyglutarate, which blocks demethylases and gives the tumour its hypermethylated (G-CIMP) phenotype; that dependence is the target of vorasidenib.\n\nMaximal safe resection comes first, with awake mapping where language or motor cortex is close. For grade 2 disease with residual or recurrent tumour and no urgent need for radiotherapy, INDIGO (NEJM 2023) showed vorasidenib prolonged progression-free survival to a median of 27.7 months against 11.1 months on placebo and delayed the next intervention; the FDA approved it in August 2024 for grade 2 astrocytoma and oligodendroglioma from the age of 12. For higher-risk grade 2 disease (age 40 or over, or subtotal resection) RTOG 9802 showed radiotherapy followed by PCV chemotherapy lengthened median survival from 7.8 to 13.3 years compared with radiotherapy alone; EORTC 22033-26033 found temozolomide alone was not superior to radiotherapy alone. For grade 3 (1p/19q non-codeleted) tumours CATNON established radiotherapy followed by twelve cycles of adjuvant temozolomide; concurrent temozolomide added nothing overall. Grade 4 IDH-mutant tumours are treated with radiotherapy and temozolomide by extrapolation from glioblastoma.\n\nAt recurrence the options are re-resection, re-irradiation, lomustine or temozolomide re-challenge and bevacizumab for symptom control. Hypermutation after temozolomide, CDKN2A/B loss and methylation class shape prognosis. Open questions are whether vorasidenib should replace or merely defer radiotherapy, how to treat grade 3 and 4 IDH-mutant tumours with IDH inhibitors (safusidenib, olutasidenib and others are in trials), and how to weigh the cognitive cost of radiotherapy in people who will live with the disease for decades.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Astrocytoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Astrocytoma"},{"label":"INDIGO: vorasidenib in IDH-mutant grade 2 glioma (NEJM 2023)","url":"https://doi.org/10.1056/NEJMoa2304194"},{"label":"RTOG 9802: radiation plus PCV in low-grade glioma (NEJM 2016)","url":"https://doi.org/10.1056/NEJMoa1500925"}],"tags":["subtype-page","cns"],"related":["glioblastoma","oligodendroglioma","brain-tumours","dipg-dmg","paediatric-high-grade-glioma","paediatric-low-grade-glioma"],"cancers":[],"sections":[],"technologies":["methylation-profiling","imrt-igrt","extent-of-resection"],"targets":["idh","tp53"],"drugs":["vorasidenib","temozolomide","lomustine","procarbazine","vincristine"],"companies":["servier"],"institutions":[],"pathways":["glioma-signalling"],"terms":["mgmt","re-irradiation","blood-brain-barrier","1p19q-codeletion","cdkn2a-homozygous-deletion"],"trials":["indigo","catnon","eortc-22033","nct05303519"],"people":[],"bottlenecks":[],"keyPapers":["paper-indigo-nejm-2023","paper-who-2021-cns-louis-neuro-oncology-2021","paper-rtog-9802-buckner-nejm-2016","paper-catnon-lancet-2017"],"journals":[],"dependsOn":[],"notes":[],"group":"central nervous system","burden":"A minority of adult diffuse gliomas, presenting mostly in people in their twenties to forties, often with a seizure; it grows slowly for years and then transforms, so patients live with it for a long time and treatment is timed as much as chosen.","subtypes":["Astrocytoma, IDH-mutant, grade 2 (diffuse, slow growing)","Astrocytoma, IDH-mutant, grade 3 (anaplastic features)","Astrocytoma, IDH-mutant, grade 4 (necrosis, microvascular proliferation or CDKN2A/B homozygous deletion)","Gemistocytic astrocytoma (IDH-mutant morphological variant)"],"biomarkers":["IDH1 R132H immunohistochemistry, with sequencing of IDH1 and IDH2 for non-canonical mutations","1p/19q status (intact; codeletion defines oligodendroglioma)","ATRX loss and TP53 mutation","CDKN2A/B homozygous deletion (assigns grade 4)","DNA methylation class and G-CIMP status","MGMT promoter methylation (less informative than in glioblastoma)","Extent of resection on post-operative MRI"],"standardOfCare":[{"setting":"Newly diagnosed, all grades","approach":"Maximal safe resection with awake or functional mapping where needed; integrated histological and molecular diagnosis (IDH, 1p/19q, ATRX, CDKN2A/B, methylation class).","refs":["extent-of-resection","methylation-profiling","mri"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Grade 2, residual or recurrent, low risk","approach":"Observation with serial MRI, or vorasidenib for grade 2 tumours not needing immediate radiotherapy or chemotherapy (INDIGO).","refs":["vorasidenib","indigo","active-surveillance"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Grade 2, high risk (age 40 or over, subtotal resection)","approach":"Radiotherapy followed by PCV (procarbazine, lomustine, vincristine) as in RTOG 9802, or radiotherapy with temozolomide; temozolomide alone was not better than radiotherapy alone in EORTC 22033.","refs":["imrt-igrt","procarbazine","lomustine","vincristine","temozolomide","eortc-22033"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Grade 3","approach":"Radiotherapy followed by twelve cycles of adjuvant temozolomide (CATNON); concurrent temozolomide is not needed in non-codeleted tumours.","refs":["imrt-igrt","temozolomide","catnon"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Grade 4","approach":"Radiotherapy with concurrent and adjuvant temozolomide, extrapolated from glioblastoma; trials of IDH inhibitors preferred where available.","refs":["imrt-igrt","temozolomide","eortc-26981"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Recurrence","approach":"Re-resection, re-irradiation, lomustine or temozolomide re-challenge, bevacizumab for oedema and symptoms; clinical trials.","refs":["lomustine","temozolomide","bevacizumab-glioma","re-irradiation"]}],"stateOfArt":["Vorasidenib is the first drug to act on the defining mutation of a diffuse glioma and the first new systemic therapy for low-grade glioma in decades.","Grading now integrates CDKN2A/B deletion, so a tumour that looks grade 2 under the microscope can be treated as grade 4.","Radiotherapy plus PCV or temozolomide remains the backbone for higher-risk and higher-grade disease, and the trials that set it took a decade or more to read out."],"history":[{"year":2008,"title":"IDH1 mutations found in glioma","note":"Parsons and colleagues sequence glioblastoma exomes (Science) and find IDH1 mutations concentrated in younger patients and secondary tumours.","refs":["idh"]},{"year":2009,"title":"IDH1 and IDH2 mutations define a glioma lineage","note":"Yan and colleagues (NEJM) show IDH mutations in most grade 2 and 3 gliomas and their better prognosis.","refs":["idh"]},{"year":2016,"title":"RTOG 9802: radiotherapy plus PCV doubles survival in high-risk low-grade glioma","note":"Buckner and colleagues (NEJM) report median overall survival of 13.3 years against 7.8 years with radiotherapy alone.","refs":["procarbazine","lomustine","vincristine"]},{"year":2016,"title":"WHO 2016 classification makes IDH status part of the diagnosis","refs":["idh"]},{"year":2017,"title":"CATNON: adjuvant temozolomide after radiotherapy for grade 3 non-codeleted glioma","refs":["catnon","temozolomide"]},{"year":2021,"title":"WHO 2021 renames the type astrocytoma, IDH-mutant, grades 2 to 4, with CDKN2A/B deletion as a grade 4 criterion","refs":[]},{"year":2023,"title":"INDIGO: vorasidenib delays progression in grade 2 IDH-mutant glioma","note":"Mellinghoff and colleagues (NEJM): median progression-free survival 27.7 versus 11.1 months.","refs":["vorasidenib","indigo"]},{"year":2024,"title":"FDA approves vorasidenib for grade 2 IDH-mutant astrocytoma and oligodendroglioma","refs":["vorasidenib"]}],"pipeline":["vorasidenib","safusidenib","olutasidenib","methylation-profiling"],"openProblems":["Whether vorasidenib should replace radiotherapy and chemotherapy or only defer them, and what to do at progression on it.","No IDH inhibitor has yet shown benefit in grade 3 or 4 IDH-mutant astrocytoma.","Cognitive decline after radiotherapy in people who live decades with the disease.","Temozolomide-induced hypermutation at recurrence has no specific treatment."],"parent":"glioblastoma"},{"id":"atrt","kind":"cancer","name":"Atypical teratoid/rhabdoid tumour (ATRT)","aka":["AT/RT","Rhabdoid tumour of the CNS","Rhabdoid tumour predisposition syndrome"],"tldr":"ATRT is an aggressive brain tumour of babies and toddlers caused by loss of a single gene, SMARCB1, part of the machinery that opens and closes DNA. Intensive chemotherapy with stem-cell rescue, and radiotherapy where age allows, now cure a meaningful share of children who once had little chance, and drugs aimed at the epigenetic consequence of SMARCB1 loss (EZH2 inhibitors) are in trials.","summary":"Atypical teratoid/rhabdoid tumour is a WHO grade 4 embryonal tumour defined by biallelic inactivation of SMARCB1 (INI1) or, rarely, SMARCA4, both core subunits of the SWI/SNF chromatin-remodelling complex. It is one of the genetically simplest human cancers, often with no other recurrent mutation, yet it splits into three epigenetic subgroups (ATRT-TYR, ATRT-SHH, ATRT-MYC) with different locations, ages and outcomes. About a third of children carry a germline SMARCB1 or SMARCA4 alteration (rhabdoid tumour predisposition syndrome), which matters for siblings and for the risk of synchronous renal or soft-tissue rhabdoid tumours. Median age at diagnosis is under two years, which limits radiotherapy.\n\nFew children survived until intensive multimodal protocols were adopted. The COG trial ACNS0333 combined maximal resection, induction chemotherapy (including high-dose methotrexate), three cycles of high-dose chemotherapy with autologous stem-cell rescue, and focal radiotherapy adapted to age, and reported markedly better survival than historical controls (JCO 2020). The European EU-RHAB registry-based regimen (conventional chemotherapy with intraventricular methotrexate, radiotherapy for older children) gives comparable results and forms the basis of the SIOPE ATRT01 trial. Extent of resection, age, metastatic disease and subgroup all predict outcome.\n\nThe biology points to therapy: loss of SMARCB1 leaves the PRC2 methyltransferase EZH2 unopposed, and the EZH2 inhibitor tazemetostat, already approved for SMARCB1-negative epithelioid sarcoma in adults, has shown responses in children with ATRT and other rhabdoid tumours in a paediatric phase 1 and is being combined with chemotherapy. Other avenues include CDK4/6 inhibition, aurora kinase A inhibitors (alisertib) and the EZHIP-independent dependency on the residual SWI/SNF subunit BRG1. Methylation-based subgrouping is expected to stratify the next generation of trials.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Atypical_teratoid_rhabdoid_tumor","links":[{"label":"NCI PDQ: childhood CNS atypical teratoid/rhabdoid tumour","url":"https://www.cancer.gov/types/brain/hp/child-cns-atrt-treatment-pdq"},{"label":"ACNS0333: intensive multimodal therapy for ATRT (JCO 2020)","url":"https://doi.org/10.1200/JCO.19.01776"},{"label":"EU-RHAB registry outcomes (Neuro-Oncology 2020)","url":"https://doi.org/10.1093/neuonc/noz244"}],"tags":["nci-coverage","paediatric","cns"],"related":["epithelioid-sarcoma","medulloblastoma","wilms-tumor","ependymoma","cns-germ-cell-tumours"],"cancers":[],"sections":[],"technologies":["autologous-stem-cell-transplant","methylation-profiling","proton-therapy","cytotoxic-chemotherapy","germline-testing"],"targets":["ezh2"],"drugs":["tazemetostat","methotrexate","cyclophosphamide","cisplatin","carboplatin","vincristine"],"companies":["childrens-oncology-group"],"institutions":["siop-europe","dkfz","st-jude"],"pathways":["swi-snf-chromatin","epigenetic-reprogramming","hedgehog","myc"],"terms":["hereditary-cancer-syndromes","late-effects"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers","b-survivorship"],"keyPapers":["paper-fruhwald-neuro-oncol"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Rare: a small fraction of childhood brain tumours overall, but among the most common malignant brain tumours in infants under one year (NCI PDQ).","subtypes":["ATRT-TYR (infants, infratentorial, melanosomal markers)","ATRT-SHH (supratentorial and infratentorial, SHH and NOTCH signalling)","ATRT-MYC (older children, supratentorial, MYC expression; overlaps with extracranial rhabdoid tumours)","SMARCA4-deficient ATRT (rare, often germline)"],"biomarkers":["Loss of SMARCB1 (INI1) nuclear staining by immunohistochemistry","SMARCB1 or SMARCA4 sequencing, somatic and germline","Methylation subgroup (TYR, SHH, MYC)","Metastatic stage on MRI and cerebrospinal-fluid cytology","Age (radiotherapy eligibility)","Extent of resection"],"standardOfCare":[{"setting":"Newly diagnosed, any age","approach":"Maximal safe resection followed by an intensive multimodal protocol: ACNS0333-style induction, high-dose chemotherapy with autologous stem-cell rescue, and age-adapted focal radiotherapy; or the EU-RHAB regimen with intraventricular methotrexate. Enrolment in SIOPE ATRT01 or a COG successor where available.","refs":["autologous-stem-cell-transplant","methotrexate","cyclophosphamide","cisplatin","carboplatin","vincristine","proton-therapy","acns0333"],"guideline":{"version":"COG ACNS0333 (JCO 2020); EU-RHAB","url":"https://doi.org/10.1200/JCO.19.01776"}},{"setting":"Germline SMARCB1 or SMARCA4 alteration","approach":"Genetic counselling and testing of parents and siblings; surveillance imaging for synchronous or second rhabdoid tumours in the kidney and soft tissue.","refs":["germline-testing"],"guideline":{"version":"NCI PDQ: childhood CNS atypical teratoid/rhabdoid tumour","url":"https://www.cancer.gov/types/brain/hp/child-cns-atrt-treatment-pdq"}},{"setting":"Relapsed or refractory","approach":"Aurora kinase A inhibition and re-irradiation where feasible, with enrolment in a relapse trial the preferred route; EZH2 inhibition with tazemetostat was used in trials and on compassionate grounds until the drug was withdrawn from all markets in March 2026. No regimen is standard at relapse, and symptom and supportive care run alongside from the start.","refs":["tazemetostat","palliative-care"]}],"stateOfArt":["Intensive multimodal therapy (ACNS0333, EU-RHAB) turned ATRT from an infant tumour almost no child survived into one that is cured in a meaningful share of children.","Three methylation subgroups (TYR, SHH, MYC) explain much of the heterogeneity and are being built into trial stratification.","SMARCB1 loss creates an EZH2 dependency; tazemetostat produced responses in paediatric rhabdoid tumours before its 2026 withdrawal, so the dependency is validated but a next EZH2 inhibitor is needed.","Germline testing is routine because a third of children carry a predisposition that affects the whole family."],"history":[{"year":1987,"title":"ATRT described as distinct from medulloblastoma","note":"Rorke and colleagues recognise the rhabdoid tumour of the CNS.","refs":[]},{"year":1998,"title":"SMARCB1 (hSNF5/INI1) identified as the rhabdoid tumour gene","note":"Versteege and colleagues (Nature) find biallelic loss, the first chromatin-remodelling tumour suppressor.","refs":[]},{"year":2016,"title":"Three molecular subgroups defined","note":"Johann and Torchia (Cancer Cell) describe ATRT-TYR, ATRT-SHH and ATRT-MYC by methylation and expression.","refs":["methylation-profiling"]},{"year":2020,"title":"ACNS0333 reports improved survival with intensive therapy","note":"COG phase 3 with high-dose chemotherapy and autologous rescue (JCO 2020).","refs":["autologous-stem-cell-transplant"]},{"year":2020,"title":"Tazemetostat approved for SMARCB1-negative epithelioid sarcoma","note":"First EZH2 inhibitor approval; paediatric rhabdoid tumour responses in the phase 1 programme.","refs":["tazemetostat","ezh2"]}],"pipeline":["methylation-profiling","proton-therapy","pediatric-match"],"openProblems":["Infants too young for radiotherapy and children with metastatic or ATRT-MYC disease still do poorly; SIOPE ATRT01 and COG successors are testing intensified and subgroup-directed therapy.","Long-term neurocognitive and endocrine cost of intensive therapy in the first years of life; proton therapy and radiation-sparing arms aim to reduce it.","Translating the EZH2 dependency into cures: tazemetostat combinations with chemotherapy are in early trials.","Rarity: international registries (EU-RHAB) and shared protocols are the only route to adequately powered trials."],"parent":"brain-tumours"},{"id":"bartholin-gland-carcinoma","kind":"cancer","name":"Bartholin gland carcinoma","aka":["Bartholin gland cancer","Carcinoma of the Bartholin gland","Adenoid cystic carcinoma of the Bartholin gland"],"tldr":"Bartholin gland carcinoma is a very rare vulvar cancer arising in the lubricating glands at the entrance to the vagina, often mistaken at first for a cyst or abscess in a postmenopausal woman. It can be a squamous cancer, an adenocarcinoma or an adenoid cystic carcinoma, each behaving differently; it is treated with surgery and radiotherapy borrowed from vulvar cancer, having no trials of its own.","summary":"Bartholin gland carcinoma is an extremely rare condition with no phase 3 trials, consensus or guidelines; of 275 reported cases with histology specified in 90.4 percent, 30.7 percent were squamous cell carcinoma, 29.6 percent adenoid cystic carcinoma and 25 percent adenocarcinoma, and adenocarcinoma histotype and positive nodes correlated with worse prognosis (Critical Reviews in Oncology/Hematology 2017). Adenoid cystic carcinoma of the Bartholin gland, with about 60 cases reported by 2007, is a slow-growing but locally very aggressive tumour with cribriform architecture, perineural and lymphatic invasion and a high capacity for recurrence and pain (Archives of Pathology 2007). Bartholin gland tumours are 0.1 to 5 percent of vulvar neoplasms (Archives of Pathology 2007).\n\nHow it differs from its parent: the vulvar cancer page covers HPV-associated and HPV-independent squamous carcinoma; Bartholin gland carcinoma is deep rather than surface disease, presents as a mass in the posterior labium, includes glandular and adenoid cystic types with their own spread patterns (perineural for adenoid cystic, nodal for adenocarcinoma) and needs deeper surgical margins.\n\nHow common: 0.1 to 5 percent of vulvar neoplasms (Archives of Pathology 2007).\n\nTreatment: wide or radical local excision with inguinofemoral node assessment, postoperative radiotherapy for close margins, node involvement or adenoid cystic histology, and chemoradiation for advanced disease, following the vulvar cancer page; centralisation to referral centres is recommended (Critical Reviews in Oncology/Hematology 2017).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Bartholin_gland_carcinoma","links":[{"label":"NCI PDQ: vulvar cancer treatment","url":"https://www.cancer.gov/types/vulvar/treatment"},{"label":"Critical Reviews in Oncology/Hematology 2017: Bartholin gland cancer, 275 reported cases","url":"https://doi.org/10.1016/j.critrevonc.2017.06.005"},{"label":"Archives of Pathology 2007: adenoid cystic carcinoma of the Bartholin gland, an overview","url":"https://doi.org/10.5858/2007-131-796-accotb"}],"tags":["subtype-page","wave4","rare"],"related":["vulvar","hpv-associated-vulvar-cancer","hpv-independent-vulvar-cancer","adenoid-cystic-carcinoma","vulvar-melanoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["chemoradiation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"0.1 to 5 percent of vulvar neoplasms (Archives of Pathology 2007); 275 cases had been reported in 133 publications by 2017, so no phase 3 trial exists (Critical Reviews in Oncology/Hematology 2017).","subtypes":["Squamous cell carcinoma of the Bartholin gland (30.7 percent; treated as vulvar squamous carcinoma)","Adenoid cystic carcinoma of the Bartholin gland (29.6 percent; perineural spread, late recurrence)","Adenocarcinoma of the Bartholin gland (25 percent; worse prognosis)","Transitional cell and other rare carcinomas of the Bartholin gland"],"biomarkers":["Histological type (squamous, adenoid cystic, adenocarcinoma)","Perineural and lymphatic invasion (adenoid cystic)","Inguinofemoral node status","HPV and p16 in the squamous type"],"standardOfCare":[{"setting":"All types","approach":"Wide or radical excision with node assessment; postoperative radiotherapy for close margins, nodes or adenoid cystic histology; chemoradiation for advanced disease as on the vulvar cancer page.","refs":["vulvar","hpv-associated-vulvar-cancer","chemoradiation"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"vulvar"},{"id":"basal-cell-carcinoma","kind":"cancer","name":"Basal cell carcinoma","aka":["BCC","Basal Cell Carcinoma of the Skin","Basal cell skin cancer","Rodent ulcer","Basalioma","Keratinocyte carcinoma, basal cell type","BCC of the skin"],"tldr":"Basal cell carcinoma is a skin cancer and the most common cancer of all, caused by sun exposure and almost never life-threatening. Nearly all are removed surgically; the rare advanced cases are treated with drugs that block the hedgehog signalling pathway, and with immunotherapy if those fail.","summary":"Basal cell carcinoma arises from hedgehog-pathway activation in nearly every case, through loss of PTCH1 (~70%) or activating SMO mutations (~10-20%); germline PTCH1 loss causes Gorlin (basal cell nevus) syndrome. Subtypes range from indolent nodular and superficial to infiltrative, morphoeic and basosquamous tumours with higher recurrence risk.\n\nTreatment is surgical (excision, Mohs for high-risk sites), with curettage, topical imiquimod or 5-fluorouracil, photodynamic therapy and radiotherapy as alternatives for low-risk or inoperable lesions. Vismodegib (ERIVANCE, 2012) and sonidegib (BOLT, 2015) are oral SMO inhibitors for locally advanced or metastatic BCC with ~45-60% response; their class toxicities (muscle spasms, dysgeusia, alopecia, weight loss) cause many to stop, and resistance arises through SMO mutations. Cemiplimab (2021) is approved after hedgehog-inhibitor failure or intolerance. Nicotinamide and sun protection reduce new BCCs in high-risk patients.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Basal-cell_carcinoma","links":[{"label":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"},{"label":"ERIVANCE (NEJM 2012)","url":"https://doi.org/10.1056/NEJMoa1113713"},{"label":"NCI PDQ: skin cancer","url":"https://www.cancer.gov/types/skin/patient/skin-treatment-pdq"},{"label":"Thomson et al., interventions for basal cell carcinoma of the skin: Cochrane review of 52 randomised trials and 6,690 participants (2020)","url":"https://doi.org/10.1002/14651858.CD003412.pub3"},{"label":"Bath-Hextall et al., surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma, SINS (Lancet Oncology 2014)","url":"https://doi.org/10.1016/S1470-2045(13)70530-8"},{"label":"Williams et al., surgery versus 5% imiquimod for nodular and superficial basal cell carcinoma, 5-year results of the SINS randomised controlled trial (J Invest Dermatol 2017)","url":"https://doi.org/10.1016/j.jid.2016.10.019"},{"label":"Arits et al., photodynamic therapy versus topical imiquimod versus topical fluorouracil for superficial basal-cell carcinoma, randomised trial of 601 patients (Lancet Oncology 2013)","url":"https://doi.org/10.1016/S1470-2045(13)70143-8"},{"label":"Jansen et al., five-year results of a randomised controlled trial comparing photodynamic therapy, topical imiquimod and topical 5-fluorouracil in superficial basal cell carcinoma (J Invest Dermatol 2018)","url":"https://doi.org/10.1016/j.jid.2017.09.033"},{"label":"van Loo et al., surgical excision versus Mohs micrographic surgery for basal cell carcinoma of the face: randomised clinical trial with 10-year follow-up (Eur J Cancer 2014)","url":"https://doi.org/10.1016/j.ejca.2014.08.018"},{"label":"Marcil and Stern, risk of developing a subsequent non-melanoma skin cancer in patients with a history of non-melanoma skin cancer: review and meta-analysis (Arch Dermatol 2000)","url":"https://doi.org/10.1001/archderm.136.12.1524"},{"label":"British Association of Dermatologists: basal cell carcinoma, patient information leaflet (updated July 2025)","url":"https://www.skinhealthinfo.org.uk/condition/basal-cell-carcinoma/"},{"label":"British Association of Dermatologists and British Society for Dermatological Surgery: Mohs micrographic surgery, patient information leaflet (updated June 2025)","url":"https://www.skinhealthinfo.org.uk/condition/mohs-micrographic-surgery/"},{"label":"Cancer Research UK: types of surgery for non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/treatment/surgery/treatment-surgery-types"},{"label":"Cancer Research UK: follow-up after non-melanoma skin cancer treatment","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/treatment/follow-up-appointments"},{"label":"Cancer Research UK: photodynamic therapy for non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/treatment/photodynamic-therapy"},{"label":"Cancer Research UK: chemotherapy cream for non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/treatment/chemotherapy-cream"},{"label":"NHS: treatment for non-melanoma skin cancer","url":"https://www.nhs.uk/conditions/non-melanoma-skin-cancer/treatment/"},{"label":"Royal College of Pathologists G123: dataset for histopathological reporting of primary cutaneous basal cell carcinoma, version 4, February 2019 (Slater and Barrett)","url":"https://www.rcpath.org/resourceLibrary/g123-dataset-basal.html"},{"label":"Cancer Research UK: basal cell carcinoma","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/types/basal-cell-carcinoma"},{"label":"Nasr et al., British Journal of Dermatology 2021;185(5):899 to 920: British Association of Dermatologists guidelines for the management of adults with basal cell carcinoma 2021","url":"https://doi.org/10.1111/bjd.20524"},{"label":"Royal College of Pathologists appendix A, version 3, 6 November 2025: UICC TNM 9 pathological staging of primary cutaneous carcinoma (basal cell), combining the UICC chapters for skin carcinoma of the head and neck and carcinoma of the skin","url":"https://www.rcpath.org/resourceLibrary/basal-cell-tnm9.html"},{"label":"Cancer Research UK: non-melanoma skin cancer incidence statistics (UK)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/non-melanoma-skin-cancer/incidence"},{"label":"Mistry, Levell, Karponis, Wakkee, Whiteman, Proby and Venables, British Journal of Dermatology 2026: trends in keratinocyte cancers in England 2013 to 2022, basal cell carcinoma incidence, cutaneous squamous cell carcinoma incidence and non-melanoma skin cancer mortality","url":"https://doi.org/10.1093/bjd/ljag315"},{"label":"Kwiatkowska et al., Skin Health and Disease 2021;1(4):e61: an updated report on the incidence and epidemiological trends of keratinocyte cancers in the United Kingdom 2013 to 2018","url":"https://doi.org/10.1002/ski2.61"},{"label":"Venables et al., British Journal of Dermatology 2019;181(3):474 to 482: epidemiology of basal and cutaneous squamous cell carcinoma in the UK 2013 to 2015, a cohort study (the paper that introduced the first-per-person-per-annum count)","url":"https://doi.org/10.1111/bjd.17873"},{"label":"Ahmed et al., British Journal of Dermatology 2026;194:273 to 282: ethnicity and the epidemiology of skin cancer incidence, a national retrospective population-based study in England, 2013 to 2020","url":"https://doi.org/10.1093/bjd/ljaf352"},{"label":"NHS: non-melanoma skin cancer, symptoms","url":"https://www.nhs.uk/conditions/non-melanoma-skin-cancer/symptoms/"}],"tags":["gap-fill","skin"],"related":["cutaneous-scc","melanoma","merkel-cell-carcinoma","bowens-disease"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","checkpoint-inhibitor","imrt-igrt","chemoprevention","dermoscopy-ai","black-salve-escharotics","psycho-oncology","survivorship-care-plan","multidisciplinary-tumour-board"],"targets":["smoothened","pd1"],"drugs":["vismodegib","sonidegib","cemiplimab","fluorouracil","imiquimod","aminolevulinic-acid","nicotinamide"],"companies":["roche-genentech","sanofi","regeneron","philogen-s-p-a"],"institutions":[],"pathways":["basal-cell-carcinoma-signalling"],"terms":["irae","curettage-and-cautery","second-primary-skin-cancer","sun-protection-after-skin-cancer","facial-scar-after-skin-cancer","skin-graft-and-flap-reconstruction","mohs-surgery","wide-local-excision","keratinocyte-cancer","actinic-keratosis","bcc-growth-pattern","skin-cancer-high-risk-features","tnm-skin-carcinoma","keratinocyte-cancer-counting","inherited-skin-cancer-syndromes","perineural-invasion","resection-margins","field-cancerisation","topical-and-destructive-treatment-bcc","surgical-margins-keratinocyte-cancer","hedgehog-inhibitor-tolerability","radiotherapy-for-skin-cancer"],"trials":["nct06050122","mohs-versus-excision-facial-bcc","sins-trial","mal-pdt-imiquimod-fluorouracil-superficial-bcc","scin-trial","mal-pdt-versus-surgery-nodular-bcc","mal-pdt-versus-cryotherapy-superficial-bcc","avril-surgery-versus-radiotherapy-bcc","stevie","vismoneo","cemiplimab-advanced-bcc","patidegib-gel-gorlin-phase-2"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Basal cell carcinoma, the choice and what follows it: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the number they gave you come first, and no figure on this page is a prediction about you. The two rows above quote the randomised evidence rather than summarising it, because the choice between an operation and a cream is routinely presented as a matter of preference when the trials show a 15 percentage point difference in five-year success and an opposite difference in how the result looks.","The decision aid at /tools/bcc-low-risk-treatment/ walks the same evidence a question at a time. It gives no score and makes no prediction, because none of the sources it quotes gives one.","What this page does not carry: hedgehog inhibitors, cemiplimab and the management of locally advanced or metastatic disease, which belong to the locally advanced and metastatic basal cell carcinoma record; and everything about the face, Mohs as a day, the sun, the mind and immunosuppression, which is true of squamous cell carcinoma too and is written once on the skin cancer family page.","Every number on this page rests on a counting rule. Basal cell carcinoma is the cancer the registries handle worst, because people get several and the rules were written for cancers people get once. UK registration long recorded only the first one in a lifetime; counting one per person per year instead found 67 percent more over 2013 to 2022 in England, and validation suggests that even the annual count misses about 14 tumours per 100 patients. Scotland still collects only the first occurrence per person, in its own words because they are so common. The Office for National Statistics excludes the whole group from the national cancer total because it is greatly under-registered. Read every incidence figure here as a floor (see `keratinocyte-cancer-counting`).","The commonest cancer there is, and the one most often left out of the list. Basal cell carcinoma is about 75 in every 100 non-melanoma skin cancers (Cancer Research UK). In England in 2019 the registered rate was 282.36 per 100,000 person-years; on the annual counting method it was 295 per 100,000 in 2022, and rates stabilised after 2015 rather than continuing to rise. Across the UK the annual-method estimate is 184,280 basal cell carcinomas a year for 2016 to 2018. About one person in five in England will develop at least one keratinocyte cancer in their lifetime.","Why the growth pattern is the most important word on the report. It decides the operation, the margin, who performs it and where. Nodular and superficial tumours have edges that can be seen; infiltrating, sclerosing and micronodular tumours grow as strands and specks that extend further than they look, which is why they recur after an excision that appeared complete and why they are the tumours Mohs surgery exists for. The UK dataset combines those three under one term because there is no clinical value in separating them, and reads the risk from the worst pattern present whatever its percentage.","Why so few people with this cancer are ever given a stage, and why that is not an oversight. A stage exists to say how far a cancer has travelled and to predict what it will do. A cancer that metastasises in well under one in a thousand cases has almost nothing for a stage to predict, so what gets recorded instead is a binary, low risk or high risk, that predicts local recurrence. Britain does have a staging system for it, which is more than the American manual offers outside the head and neck, and it is used for registration and for the rare destructive tumour rather than for the ordinary one.","This is not the same thing as a rodent ulcer being harmless. The old name comes from what a neglected basal cell carcinoma does: it erodes. Because it sits most often on the face, and because it grows slowly enough to be ignored for years, the harm it causes is the loss of a nose, an eyelid or an ear rather than a metastasis. That is the reason a small tumour in a difficult place is treated more aggressively than a larger one on the trunk, and the reason the locally advanced page exists.","Who is at risk, and the gap in what is known. Incidence in England is about 26 to 27 times higher in the White ethnic group than in the Asian or Black groups, and ethnicity was unknown for 19.2 percent of registered basal cell carcinomas, the highest proportion of any skin tumour studied (Ahmed 2026). People of every skin tone can get skin cancer, and the near-absence of data on darker skin is itself a finding rather than a reassurance."],"group":"skin","burden":"The most common human cancer: several million cases per year in the US alone; metastasis is exceptionally rare (<0.1%), but locally advanced disease can be destructive.","subtypes":["Nodular (most common)","Superficial","Infiltrative / morphoeic (high-risk)","Basosquamous","Gorlin syndrome (germline PTCH1/SUFU)","Low-risk growth patterns: nodular (the commonest), superficial, and fibroepithelial (of Pinkus) (RCPath G123, following WHO)","High-risk growth patterns, reported together in the UK as infiltrative basal cell carcinoma: infiltrating, sclerosing or morphoeic, and micronodular (nodules under 0.15 mm across)","Basosquamous carcinoma, a basal cell carcinoma with a moderately or severely atypical or malignant squamous component, treated as high risk","Composite basal cell carcinoma, meaning a tumour containing low-risk and high-risk patterns at once, which is usual; the risk is read from the highest-risk pattern present","Gorlin syndrome (naevoid basal cell carcinoma syndrome), in which germline loss of PTCH1 or SUFU causes many tumours from a young age","Locally advanced and metastatic basal cell carcinoma, which is a treatment setting rather than a type and has its own page"],"biomarkers":["Histologic subtype and high-risk location (H-zone of face)","PTCH1 / SMO / SUFU alterations (research; SMO mutations predict hedgehog-inhibitor resistance)","Perineural invasion","Germline PTCH1 (Gorlin)","Growth pattern, low or high risk, which is the single most consequential line on the report (RCPath G123)","Squamous differentiation, reported when moderate or severe, because basosquamous tumours recur and metastasise more often","Level of invasion and thickness: beyond subcutaneous fat, or more than 6 mm, are high-risk features and upstage to pT3","Perineural invasion, which is collected for nodular but not for superficial tumours because superficial tumours cannot show it","Margins: involved at 0 mm, or clear but under 1 mm, both count as high risk","PTCH1, SMO and SUFU alterations, which are the biology rather than a routine test; germline PTCH1 or SUFU indicates Gorlin syndrome"],"standardOfCare":[{"setting":"Low-risk","approach":"Standard excision with 4 mm margin, curettage and electrodesiccation, or topical imiquimod / 5-FU / photodynamic therapy for superficial lesions.","refs":["fluorouracil"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}},{"setting":"High-risk or recurrent","approach":"Mohs micrographic surgery or excision with complete margin assessment; radiotherapy if surgery not feasible.","refs":["imrt-igrt"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Basal Cell Skin Cancer"}},{"setting":"Locally advanced or metastatic","approach":"Vismodegib or sonidegib; cemiplimab after hedgehog-inhibitor failure or intolerance; multidisciplinary review for surgery/radiotherapy after response.","refs":["vismodegib","sonidegib","cemiplimab"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Basal Cell Skin Cancer"}},{"setting":"Choosing between surgery, curettage, freezing, a cream and photodynamic therapy","approach":"For a superficial or low-risk nodular basal cell carcinoma this is a real choice and not a formality, so here are the numbers instead of the phrase several options are available. Surgery has the highest cure rate: the Cochrane review of 52 randomised trials and 6,690 participants concluded that surgical interventions have the lowest recurrence rates. In the UK SINS trial, 501 people with primary nodular or superficial disease at low-risk sites were randomised between imiquimod cream (once daily, six weeks for superficial and twelve for nodular) and excision with a 4 mm margin: treatment succeeded in 83.6 percent against 98.4 percent at three years and 82.5 percent against 97.7 percent at five, and most cream failures happened in the first year. Among the non-surgical options, a Dutch trial of 601 people with superficial disease gives the ranking at five years: imiquimod 80.5 percent tumour-free, fluorouracil cream 70.0 percent, photodynamic therapy 62.7 percent. Curettage and cautery, scraping the lesion away and sealing the surface with heat, usually repeated two or three times in one sitting, is a surgical option for low-risk disease; the BAD notes that unlike an excision it leaves no margins for a pathologist to check but is generally considered effective for a low-risk basal cell carcinoma. Cryotherapy is offered for superficial lesions and the BAD says it generates a wound that usually heals with a scar. Now the other side, because cure rate is not the only axis. Creams take weeks of a visibly inflamed, itching, weeping face (in SINS, itching in 211 of the imiquimod group against 129 of the surgery group); photodynamic therapy causes moderate to severe pain and burning during the treatment itself; and the cosmetic result of the non-surgical options is better, not worse. The Cochrane review found observers rated the outcome good or excellent in 60.6 percent after imiquimod against 35.6 percent after excision, and after photodynamic therapy against excision 87.1 percent against 46.6 percent, while patients rated imiquimod and surgery the same. So: surgery is one appointment and the highest cure rate and a scar; a cream is six to twelve weeks of a sore face, a one-in-six chance of failure, and usually a better-looking result. Both are defensible. Not treating at all is a third option the BAD names for a slow-growing lesion on a non-critical site or where someone could not tolerate treatment.","refs":["wide-local-excision","curettage-and-cautery","mohs-surgery","imiquimod","fluorouracil","methyl-aminolevulinate","aminolevulinic-acid","cryoablation","photodynamic-therapy-lasers","curative-intent","multidisciplinary-tumour-board"],"guideline":{"version":"Cochrane review of interventions for basal cell carcinoma (2020), with the SINS and Dutch randomised trials and the British Association of Dermatologists patient information on basal cell carcinoma (updated July 2025)","url":"https://doi.org/10.1002/14651858.CD003412.pub3"}},{"setting":"Will it come back, and will I get another one","approach":"Two different questions get muddled here and they have different answers. Will this one come back: usually not, and the risk depends on what it was and how it was treated. In the Dutch randomised trial of high-risk facial basal cell carcinoma, ten-year recurrence was 4.4 percent after Mohs and 12.2 percent after standard excision for primary tumours, and 3.9 against 13.5 percent for recurrent ones; the same trial found that 56 percent of the recurrences of primary tumours appeared more than five years after treatment, which is why a clear five years is reassuring but is not the end of the story for a high-risk lesion on the face. Will I get another one: probably, and sooner than you would guess. In a meta-analysis of 17 studies, the three-year cumulative risk of a further basal cell carcinoma after a first was 44 percent, at least ten times the rate of first tumours in a comparable population, while the risk of a squamous cell carcinoma after a basal cell carcinoma was 6 percent. Those are cohort figures rather than a prediction for you, and they are about new cancers on damaged skin rather than this one returning. What follow-up is offered follows from that, and it is lighter than most people expect. The BAD says not everyone needs it, that people are usually discharged if the recurrence risk is low and they are not at high risk of future skin cancers, and that it is considered for advanced disease, a high risk of recurrence, or a high risk of multiple cancers such as people with weakened immune systems or genetic syndromes. Cancer Research UK says an early basal cell carcinoma may mean a single follow-up appointment and then none. Being discharged is not being dropped: it is a transfer of the surveillance to you, and both the BAD and Cancer Research UK are explicit about what you are then meant to do. The BAD puts a frequency on it, once a month, with someone else looking at the places you cannot see; Cancer Research UK asks you to know what your skin normally looks like and does not name an interval. Both say to go to the GP for any mark that is growing, changing, bleeding or not healing, including a change where this one was treated.","refs":["second-primary-skin-cancer","sun-protection-after-skin-cancer","mohs-surgery","wide-local-excision","survivorship-care-plan","late-effects","field-cancerisation"],"guideline":{"version":"British Association of Dermatologists patient information: basal cell carcinoma (updated July 2025), with Cancer Research UK on follow-up (reviewed July 2026) and the 10-year randomised trial of facial basal cell carcinoma","url":"https://www.skinhealthinfo.org.uk/condition/basal-cell-carcinoma/"}},{"setting":"Choosing between an operation and a cream for a superficial tumour","approach":"This is a real choice and the numbers for it exist. In 601 Dutch patients with superficial basal cell carcinoma, five-year tumour-free survival was 80.5 per cent with imiquimod cream, 70.0 per cent with fluorouracil cream and 62.7 per cent with methyl aminolevulinate photodynamic therapy; imiquimod beat photodynamic therapy with a hazard ratio for failure of 0.48 and fluorouracil with 0.65. Against surgery all of them lose: SINS randomised 501 people in the United Kingdom and found clinical success at five years of 82.5 per cent with imiquimod against 97.7 per cent with excision, a relative risk of 0.84 whose confidence interval fell below the non-inferiority margin, so imiquimod is inferior rather than unproven. Cryotherapy matched photodynamic therapy on five-year recurrence, 20 against 22 per cent, and lost badly on appearance, 16 against 60 per cent excellent. Failures come early in every one of these trials, so a lesion still clear at a year is likely to stay clear.","refs":["topical-and-destructive-treatment-bcc","mal-pdt-imiquimod-fluorouracil-superficial-bcc","sins-trial","mal-pdt-versus-cryotherapy-superficial-bcc","imiquimod","fluorouracil"],"guideline":{"nccn":"Category 2A for superficial tumours only","version":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}},{"setting":"The same choice for a nodular tumour, where it goes worse","approach":"The creams and the light are licensed for the thin superficial form, and stretching them to the thicker nodular form has been tested twice with the same answer. Methyl aminolevulinate photodynamic therapy against excision gave five-year recurrence of 14 against 4 per cent and a sustained complete response of 76 against 96 per cent, with an excellent or good cosmetic outcome in 87 against 54 per cent. Scraping the tumour off first and then applying imiquimod, tested in the SCIN trial, gave freedom from treatment failure at five years of 77.8 against 98.2 per cent, a relative risk of failure of 15.93. Both are defensible for someone who cannot or will not have facial surgery, and neither is equivalent to it.","refs":["mal-pdt-versus-surgery-nodular-bcc","scin-trial","topical-and-destructive-treatment-bcc","curettage-and-cautery"],"guideline":{"version":"Five-year follow-up of photodynamic therapy against surgery (Archives of Dermatology 2007)","url":"https://doi.org/10.1001/archderm.143.9.1131"}},{"setting":"Shrinking a tumour before the operation","approach":"For a large facial basal cell carcinoma where the operation would cost an eyelid or a nostril, a hedgehog inhibitor can be given first. VISMONEO gave vismodegib for a mean of 6.0 months to 55 patients with a mean lesion size of 47.3 mm and downstaged the planned surgery in 44 of them (80 per cent, 67 to 90), with 27 complete responses of which 25 were proved on biopsy. The part usually left out belongs in the conversation: at three years 16 of those 44 patients had a known recurrence, 36 per cent. The drug changes the operation, it does not replace it.","refs":["vismoneo","vismodegib","hedgehog-inhibitor-tolerability","mohs-surgery"],"guideline":{"version":"VISMONEO (EClinicalMedicine 2021)","url":"https://doi.org/10.1016/j.eclinm.2021.100844"}},{"setting":"Living with a hedgehog inhibitor","approach":"Vismodegib and sonidegib work and most people stop taking them. STEVIE gave vismodegib to 1,215 patients in ordinary practice: response was 68.5 per cent in locally advanced disease, 98 per cent had a treatment-emergent adverse event, 23.8 per cent had a serious one, and the median treatment duration was 8.6 months, with only 12 per cent still taking it at the analysis. The characteristic events are muscle spasms, loss of taste, hair loss and weight loss, none dangerous and all wearing. Most of them resolve within a year of stopping. Intermittent dosing, neoadjuvant courses and topical delivery are the three attempts to get round it.","refs":["stevie","hedgehog-inhibitor-tolerability","vismodegib","sonidegib","hedgehog-inhibitors"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}},{"setting":"After a hedgehog inhibitor has failed or cannot be tolerated","approach":"Cemiplimab, a PD-1 antibody. In 84 patients with locally advanced disease who had progressed on, could not tolerate, or had no better than stable disease after nine months of a hedgehog inhibitor, objective response by independent central review was 31 per cent (21 to 42) with five complete responses; grade 3 or 4 treatment-emergent adverse events occurred in 48 per cent and serious events in 35 per cent. It was approved in February 2021 on that single-arm evidence and there is no randomised comparison. That basal cell carcinoma responds to checkpoint blockade at all is not obvious for a tumour that almost never spreads, and is explained by its very high ultraviolet mutational burden.","refs":["cemiplimab-advanced-bcc","cemiplimab","checkpoint-inhibitor","tmb","irae"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}},{"setting":"What is available in England","approach":"Less than the approvals suggest. NICE technology appraisal TA489 recommendation 1.1 does not recommend vismodegib within its marketing authorisation for metastatic basal cell carcinoma or for locally advanced disease unsuitable for surgery or radiotherapy: the committee found the comparison with best supportive care not good enough for decision-making and the cost per quality-adjusted life year much higher than 30,000 pounds. Recommendation 1.2 allows anyone already on it to continue. There is no NICE appraisal of sonidegib, and none of cemiplimab in basal cell carcinoma. The commonest cancer in human beings has one NICE technology appraisal and it is a refusal.","refs":["vismodegib","sonidegib","cemiplimab","hedgehog-inhibitor-tolerability"],"guideline":{"version":"NICE TA489 recommendations 1.1 and 1.2 (vismodegib not recommended)","url":"https://www.nice.org.uk/guidance/ta489"}}],"stateOfArt":["Hedgehog inhibitors are among the few targeted drugs whose rationale came straight from a developmental-biology pathway and a hereditary syndrome (Gorlin).","Cemiplimab gives a second line after hedgehog-inhibitor failure.","Neoadjuvant vismodegib can shrink tumours to make surgery less destructive (VISMONEO).","Chemoprevention (nicotinamide) reduces new keratinocyte cancers in high-risk patients."],"history":[{"year":1996,"title":"PTCH1 identified as the Gorlin syndrome gene","note":"Hahn et al. and Johnson et al.: links human BCC to the Drosophila hedgehog pathway.","refs":[]},{"year":2009,"title":"Vismodegib phase 1 shows responses in advanced BCC (NEJM)","refs":["vismodegib"]},{"year":2012,"title":"Vismodegib approved (ERIVANCE)","note":"First hedgehog-pathway inhibitor.","refs":["vismodegib"]},{"year":2013,"title":"The three non-surgical treatments are ranked against each other","note":"601 Dutch patients randomised between photodynamic therapy, imiquimod and fluorouracil; imiquimod superior and fluorouracil non-inferior to the light treatment that had been assumed best.","refs":["mal-pdt-imiquimod-fluorouracil-superficial-bcc"]},{"year":2015,"title":"Sonidegib approved (BOLT)","refs":["sonidegib"]},{"year":2015,"title":"Nicotinamide reduces new keratinocyte cancers (ONTRAC, NEJM)","refs":[]},{"year":2017,"title":"STEVIE measures what the hedgehog pill is like to take","note":"1,215 patients in 36 countries: response 68.5 per cent in locally advanced disease, adverse events in 98 per cent and a median treatment duration of 8.6 months.","refs":["stevie"]},{"year":2017,"title":"NICE refuses to fund vismodegib","note":"TA489 recommendation 1.1 does not recommend vismodegib for metastatic or locally advanced basal cell carcinoma, on uncertain evidence and a cost per quality-adjusted life year far above 30,000 pounds.","refs":["vismodegib"]},{"year":2021,"title":"Cemiplimab approved after hedgehog-inhibitor failure","refs":["cemiplimab"]},{"year":2021,"title":"Cemiplimab gives a second line after hedgehog failure","note":"Objective response in 26 of 84 patients (31 per cent) whose disease had progressed on or who could not tolerate a hedgehog inhibitor.","refs":["cemiplimab-advanced-bcc"]}],"pipeline":["cemiplimab","vismodegib"],"openProblems":["Hedgehog-inhibitor tolerability leads most patients to stop within a year.","Resistance via SMO mutations has no approved next-in-class agent.","Huge volume: dermatology and Mohs capacity, and cost of treating millions of low-risk lesions.","Nobody knows how many there are. The registration rule recorded only the first basal cell carcinoma per person for two decades, the annual method that replaced it finds 67 percent more, and that method still misses about 14 tumours per 100 patients. Dermatology and Mohs capacity is commissioned against the smaller number.","Risk stratification depends on a pattern that is often mixed and not always reproducible. Most tumours are composite, there is no evidence about what proportion of a high-risk pattern is biologically significant, and the joint Royal College of Pathologists and British Association of Dermatologists audit found risk status among the most frequently omitted core items in skin cancer reports.","Superficial basal cell carcinoma has no agreed definition and may not be invasive at all. The UK dataset records that there is no consensus on whether it is in situ or invasive, no consensus on its exact definition, and that studies quote various thicknesses, all under 1 mm; that is why the dataset deliberately avoids the phrase invasive basal cell carcinoma in its own title.","The volume is the problem. Millions of low-risk lesions have to be treated to prevent the small number of destructive ones, and the whole cost of that falls on a disease that is left out of the national cancer statistics.","The first drug ever approved for the commonest cancer in human beings is not recommended by NICE for it, and neither sonidegib nor cemiplimab in this disease has been appraised at all.","Hedgehog inhibitors are stopped by most people who start them, with a median treatment duration of 8.6 months in the largest study, and neither intermittent dosing nor topical delivery has yet produced a licensed alternative.","Acquired smoothened mutations restore hedgehog signalling downstream of the drug and there is no approved next-in-class agent; the working answer is to change pathway entirely and use a PD-1 antibody."],"basics":{"symptoms":["Basal cell carcinoma is usually slow growing. It may look like a smooth firm lump, a patch of scaly skin, or an area of shiny skin that looks like a scar; on brown or black skin it may look like a dark growth resembling a mole (Cancer Research UK)","It develops mostly on areas of skin most exposed to the sun, especially the head and neck, but it can appear anywhere on the body (Cancer Research UK)","It is very rare for a basal cell carcinoma to spread to another part of the body, but it is possible to have more than one at the same time, and having one makes another more likely (Cancer Research UK)","A morphoeic or sclerosing tumour can look like nothing much: a pale, slightly firm, scar-like patch with no clear edge, which is exactly why it is classed as high risk","See a GP if you have a growth on your skin that is getting bigger or has changed colour or texture, or a growth or area of skin that hurts, itches, bleeds, crusts or scabs for more than 4 weeks (NHS)"],"diagnosis":["The diagnosis is histological. A punch, incisional or shave biopsy taken to establish the diagnosis can be reported with the diagnosis and the high-risk indicators alone; a full dataset is completed when the procedure was done with therapeutic intent (RCPath G123)","The report gives the growth pattern under low-risk or high-risk headings, any squamous differentiation, the level of invasion, the thickness, perineural and lymphovascular invasion where relevant, and the margins","Because most tumours contain more than one pattern and there is no evidence about what proportion matters, the UK rule is that the highest-risk pattern present decides the risk status, irrespective of percentage or location; once a high-risk component is recorded the low-risk ones need not be","Many differentiations a basal cell carcinoma can show, pigmented, adenoid, keratotic, clear cell, granular and the adnexal ones, are not recorded at all because they do not change management","Cytology has only a limited role; imprints or aspirates can be used in one-stop clinics, where basal cell carcinoma may show so-called elephant trunk cellular clusters (RCPath G123)"],"staging":["Most basal cell carcinomas do not need staging because it is very rare for them to spread (Cancer Research UK)","Britain nevertheless has a staging system for it, and America does not. UICC TNM covers basal cell carcinoma of the head and neck and of the trunk and limbs; the AJCC 8 cutaneous carcinoma chapter covers the head and neck only. The Royal College of Pathologists chose UICC on exactly this ground, and its reporting dataset carries a UICC TNM 9 appendix for basal cell carcinoma (RCPath G123, appendix A dated 6 November 2025)","The categories: pT1 20 mm or less, pT2 over 20 up to 40 mm, pT3 over 40 mm or minor bone erosion or perineural invasion or deep invasion, pT4a gross cortical or marrow invasion, pT4b axial skeleton invasion","AJCC states that the upstaging risk factors apply less to basal cell carcinoma but does not exclude them; UICC includes them for both body regions without qualification, so the UK dataset uses them (RCPath G123)","What is actually used is the binary: low risk or high risk. The published feature list is short and any one feature is enough (see `skin-cancer-high-risk-features`)","The consequence of that binary is where treatment happens. Low-risk tumours can be treated in primary care by appropriately trained and accredited practitioners; all others in secondary care, with multidisciplinary team referral for high-risk tumours with involved margins, for Mohs surgery, for immunocompromised people, and for metastatic disease or genetic susceptibility"],"sources":[{"label":"Cancer Research UK: basal cell carcinoma","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/types/basal-cell-carcinoma"},{"label":"NHS: non-melanoma skin cancer, symptoms","url":"https://www.nhs.uk/conditions/non-melanoma-skin-cancer/symptoms/"},{"label":"Royal College of Pathologists G123: dataset for histopathological reporting of primary cutaneous basal cell carcinoma, version 4, February 2019 (Slater and Barrett)","url":"https://www.rcpath.org/resourceLibrary/g123-dataset-basal.html"},{"label":"Royal College of Pathologists appendix A, version 3, 6 November 2025: UICC TNM 9 pathological staging of primary cutaneous carcinoma (basal cell), combining the UICC chapters for skin carcinoma of the head and neck and carcinoma of the skin","url":"https://www.rcpath.org/resourceLibrary/basal-cell-tnm9.html"}]},"prognosis":{"text":"Cancer Research UK states that doctors can almost always cure basal cell carcinomas, that it is extremely rare for one to spread to another part of the body, and that people almost never die from this type of cancer; in a small number of people it comes back in the skin and needs further treatment. Three-year net survival in the English registry study was reported as 101.9 percent, a figure above 100 percent because net survival compares people with the cancer against the general population and people who present with a basal cell carcinoma are, as a group, alive and attending a clinic. That number is best read as saying that having a basal cell carcinoma does not shorten life, rather than as a survival rate at all. What the disease does instead is recur locally and destroy tissue where it sits, which is why a tumour on a nose or an eyelid is a bigger problem than a larger one on a back, and why the growth pattern and the margin matter more here than the size. These are population figures and not a personal prognosis.","sources":[{"label":"Cancer Research UK: basal cell carcinoma","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/types/basal-cell-carcinoma"},{"label":"Cancer Research UK: survival for non-melanoma skin cancer (net survival for skin squamous cell carcinoma, England, first tumours diagnosed 2014 to 2016, from the NDRS Get Data Out programme)","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/survival"},{"label":"Venables et al., British Journal of Dermatology 2019;181(3):474 to 482: epidemiology of basal and cutaneous squamous cell carcinoma in the UK 2013 to 2015, a cohort study (the paper that introduced the first-per-person-per-annum count)","url":"https://doi.org/10.1111/bjd.17873"}]},"parent":"skin-cancer"},{"id":"tnbc-basal-like-1","kind":"cancer","name":"Basal-like 1 triple-negative breast cancer (BL1)","aka":["BL1 subtype","Basal-like 1 TNBC","Cell-cycle and DNA damage response subtype of TNBC"],"tldr":"Basal-like 1 is the subtype of triple-negative breast cancer whose cancer cells are busiest dividing and worst at repairing DNA. In the studies that defined it, these tumours were the most likely to disappear completely with chemotherapy before surgery, about four in ten, and their cell lines responded best to platinum drugs.","summary":"Lehmann and colleagues analysed gene expression from 587 triple-negative cancers across 21 datasets and found six clusters; basal-like 1 (BL1) and basal-like 2 (BL2) had higher expression of cell-cycle and DNA damage response genes, and cell lines representing them preferentially responded to cisplatin (Lehmann 2011). The 2016 refinement to four tumour-specific subtypes (BL1, BL2, M and LAR) kept BL1 and showed the subtypes differ in age at diagnosis, grade, progression and histopathology; across five neoadjuvant chemotherapy datasets, 41 percent of BL1 patients reached a pathological complete response against 18 percent for BL2 and 29 percent for LAR (Lehmann 2016). In the MD Anderson series of 130 patients the BL1 subtype had the highest pathological complete response rate, 52 percent (Masuda 2013). Burstein's independent four-way classification splits the basal-like tumours by immune state instead, into basal-like immune-activated (best prognosis) and basal-like immunosuppressed (worst) (Burstein 2015). The DNA repair signature is why BL1 tumours are the natural home of the homologous recombination deficiency biology described in the glossary: HR-deficient triple-negative tumours had pathological complete response rates of 63.5 percent with carboplatin against 33.9 percent without in GeparSixto (Loibl 2018).\n\nA research classification by gene expression (Lehmann 2011, refined 2016), not a test the NHS runs; treatment follows the triple-negative rows on the parent page.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Triple-negative_breast_cancer","links":[{"label":"Lehmann, J Clin Invest 2011: identification of human triple-negative breast cancer subtypes (BL1, BL2, IM, M, MSL, LAR)","url":"https://doi.org/10.1172/jci45014"},{"label":"Lehmann, PLoS One 2016: refinement of triple-negative breast cancer molecular subtypes to four (TNBCtype-4)","url":"https://doi.org/10.1371/journal.pone.0157368"},{"label":"Masuda, Clin Cancer Res 2013: differential response to neoadjuvant chemotherapy among 7 triple-negative subtypes","url":"https://doi.org/10.1158/1078-0432.ccr-13-0799"},{"label":"Burstein, Clin Cancer Res 2015: four triple-negative subtypes (LAR, MES, BLIS, BLIA) with distinct prognoses","url":"https://doi.org/10.1158/1078-0432.ccr-14-0432"},{"label":"Loibl, Ann Oncol 2018: GeparSixto survival and HRD score as predictor of response","url":"https://doi.org/10.1093/annonc/mdy460"}],"tags":["breast","tnbc","subtype-page"],"related":["tnbc","tnbc-basal-like-2","brca-associated-tnbc","tnbc-early"],"cancers":[],"sections":[],"technologies":[],"targets":["brca","parp","tp53"],"drugs":[],"companies":[],"institutions":[],"pathways":["ddr","p53-cell-cycle"],"terms":["basal-like","hrd-in-breast-cancer","pcr"],"trials":["geparsixto","keynote-522"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"One of the four tumour-intrinsic triple-negative subtypes in the refined Lehmann classification; the share varies by cohort and the classification is used in research, not in NHS pathology reports.","subtypes":["Basal-like immune-activated (BLIA, Burstein 2015; best prognosis)","Basal-like immunosuppressed (BLIS, Burstein 2015; worst prognosis)"],"biomarkers":["Cell-cycle and DNA damage response gene expression (research)","HRD score of 42 or more or tumour BRCA mutation, the response marker for platinum in GeparSixto","Germline BRCA1 (enriched in basal-like disease)"],"standardOfCare":[{"setting":"Stage II to III","approach":"As for triple-negative disease: pembrolizumab with carboplatin and paclitaxel then an anthracycline before surgery (KEYNOTE-522); the subtype is not used to choose treatment.","refs":["keynote-522","pembrolizumab","carboplatin","platinum"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"tnbc"},{"id":"tnbc-basal-like-2","kind":"cancer","name":"Basal-like 2 triple-negative breast cancer (BL2)","aka":["BL2 subtype","Basal-like 2 TNBC","Growth-factor signalling subtype of TNBC"],"tldr":"Basal-like 2 is a subtype of triple-negative breast cancer that shares the basal identity of basal-like 1 but is driven more by growth-factor signalling than by DNA damage, and it responded worst to standard chemotherapy before surgery in the studies that defined it, with pathological complete response in about one in five patients or fewer.","summary":"In the six-subtype classification, BL2 tumours showed enrichment for growth factor signalling (EGF, NGF, MET, Wnt and IGF1R pathways), glycolysis and gluconeogenesis, and expressed myoepithelial markers, alongside the cell-cycle signature they share with BL1 (Lehmann 2011). Their chemotherapy response is the poorest of the intrinsic subtypes: 18 percent pathological complete response across five neoadjuvant datasets (Lehmann 2016) and 0 percent in the 130-patient MD Anderson series (Masuda 2013). No BL2-specific treatment exists; the growth-factor dependence is the rationale for trials of EGFR, MET and PI3K-pathway agents in triple-negative disease, none of which is approved.\n\nA research classification by gene expression (Lehmann 2011, refined 2016), not a test the NHS runs; treatment follows the triple-negative rows on the parent page.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Triple-negative_breast_cancer","links":[{"label":"Lehmann, J Clin Invest 2011: identification of human triple-negative breast cancer subtypes (BL1, BL2, IM, M, MSL, LAR)","url":"https://doi.org/10.1172/jci45014"},{"label":"Lehmann, PLoS One 2016: refinement of triple-negative breast cancer molecular subtypes to four (TNBCtype-4)","url":"https://doi.org/10.1371/journal.pone.0157368"},{"label":"Masuda, Clin Cancer Res 2013: differential response to neoadjuvant chemotherapy among 7 triple-negative subtypes","url":"https://doi.org/10.1158/1078-0432.ccr-13-0799"}],"tags":["breast","tnbc","subtype-page"],"related":["tnbc","tnbc-basal-like-1","tnbc-mesenchymal"],"cancers":[],"sections":[],"technologies":[],"targets":["egfr"],"drugs":[],"companies":[],"institutions":[],"pathways":["pi3k-akt-mtor"],"terms":["basal-like","pcr"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"One of the four tumour-intrinsic triple-negative subtypes in the refined Lehmann classification; a research category.","subtypes":["Basal-like tumours with growth factor pathway activation (EGFR, MET, IGF1R, Wnt)"],"biomarkers":["Growth factor pathway gene expression (research)","EGFR expression"],"standardOfCare":[{"setting":"Stage II to III","approach":"As for triple-negative disease (KEYNOTE-522 regimen); the low pathological complete response rate in this subtype is a research observation, not a reason to change treatment.","refs":["keynote-522","pembrolizumab"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"tnbc"},{"id":"basaloid-squamous-cell-carcinoma-lung","kind":"cancer","name":"Basaloid squamous cell carcinoma of the lung","aka":["Basaloid squamous cell lung carcinoma","Basaloid carcinoma of the lung","Basaloid squamous cell carcinoma","Basaloid variant of squamous cell carcinoma"],"tldr":"Basaloid squamous cell carcinoma is a variant of squamous lung cancer made of small, dark, tightly packed cells that grow in nests; survival in the source series was lower than in other squamous cell carcinoma. No trial exists in the variant alone, so the parent's evidence applies: it is treated as squamous lung cancer by stage, and its high PD-L1 is why checkpoint inhibitors are used.","summary":"The WHO classification lists basaloid carcinoma as a form of squamous cell carcinoma (a pure form and a mixed variant with more than 50 percent basaloid pattern), having moved it out of large cell carcinoma in 2015 once immunohistochemistry showed squamous lineage in every case (Travis 2015; Pelosi 2014). Copy-number and expression profiling of 93 squamous cell carcinomas, 42 of them basaloid, showed that pure basaloid tumours have a specific expression profile, with cell-cycle, transcription, chromatin and splicing genes up and squamous differentiation genes down, from which a two-gene (SOX4, IVL) immunohistochemistry predictor separated basaloid from non-basaloid tumours with 94 percent accuracy (Brambilla 2014). In 56 resected basaloid carcinomas PD-L1 expression correlated with CD8-positive and PD-1-positive infiltrating T cells, with fair to poor agreement between some antibody clones (Modern Pathology 2016).\n\nHow it differs from its parent: the source series calls its prognosis \"dismal\" compared with other squamous cell carcinoma, and its molecular profile is distinct; but no therapy has been shown to work better in it (Brambilla 2014).\n\nHow common: no incidence figure is published; it is a minority of squamous cell carcinomas.\n\nTreatment: as squamous cell carcinoma of the lung by stage, including chemotherapy with pembrolizumab in metastatic disease; there is no trial in the variant.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Squamous-cell_carcinoma_of_the_lung","links":[{"label":"Travis 2015, JTO: the 2015 WHO classification of lung tumours","url":"https://doi.org/10.1097/jto.0000000000000630"},{"label":"Pelosi 2014, Virchows Archiv: large cell carcinoma of the lung reclassified by immunohistochemistry and molecular biology","url":"https://doi.org/10.1007/s00428-013-1501-6"},{"label":"Brambilla 2014, Clin Cancer Res: lung squamous cell carcinomas with basaloid histology are a specific molecular entity","url":"https://doi.org/10.1158/1078-0432.ccr-14-0459"},{"label":"Modern Pathology 2016: PD-L1 expression in 56 basaloid squamous cell lung carcinomas","url":"https://doi.org/10.1038/modpathol.2016.149"}],"tags":["subtype-page","wave4","lung"],"related":["nsclc","lung-squamous-cell-carcinoma","large-cell-lung-carcinoma","lymphoepithelial-carcinoma-lung"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"A minority of squamous cell carcinomas: 42 of 93 in the defining molecular series were basaloid (24 pure, 18 mixed), but that series was enriched for the type (Brambilla 2014). No registry share was found in the sources read.","subtypes":["Pure basaloid squamous cell carcinoma","Mixed basaloid squamous cell carcinoma (over 50 percent basaloid pattern)"],"biomarkers":["p40 positive, TTF-1 negative","SOX4 and IVL immunohistochemistry (research predictor)","PD-L1 and CD8-positive infiltrate"],"standardOfCare":[{"setting":"All stages","approach":"Treated as squamous cell carcinoma of the lung; no trial in the variant.","refs":["lung-squamous-cell-carcinoma","pembrolizumab","keynote-407"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"nsclc"},{"id":"biliary-tract-cancer","kind":"cancer","name":"Biliary tract cancer (all types)","aka":["Biliary cancer","Cancers of the bile ducts, gallbladder and ampulla"],"tldr":"Biliary tract cancers arise in the bile ducts inside or outside the liver, the gallbladder or the ampulla where the duct meets the bowel. They share short survival and the same first-line chemotherapy with immunotherapy, but differ in causes and in the targetable mutations they carry. Each has its own page.","summary":"Biliary tract cancers are adenocarcinomas of the bile duct system. Intrahepatic cholangiocarcinoma arises within the liver, perihilar and distal cholangiocarcinoma along the main ducts, gallbladder cancer in the gallbladder and ampullary cancer at the junction with the duodenum. Causes include liver fluke infection, primary sclerosing cholangitis, gallstones and, in Chile and India, a high background rate of gallbladder cancer. Surgery is the only cure and is possible in a minority; gemcitabine-cisplatin with durvalumab or pembrolizumab is the first-line treatment for advanced disease, and intrahepatic tumours often carry FGFR2 fusions or IDH1 mutations with approved targeted drugs. The subtype pages carry the detail.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Biliary_tract_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Biliary_tract_cancer"},{"label":"NCI PDQ: bile duct cancer","url":"https://www.cancer.gov/types/liver/patient/bile-duct-treatment-pdq"}],"tags":["parent-page"],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Around 200,000 cases a year worldwide, rare in the West and common in parts of Asia and South America; most present late and five-year survival is under 20 percent overall.","subtypes":["Cholangiocarcinoma (intrahepatic, perihilar and distal bile duct)","Gallbladder cancer","Ampullary cancer (ampulla of Vater)"],"biomarkers":["FGFR2 fusions and IDH1 mutations (intrahepatic)","HER2 amplification (gallbladder, extrahepatic)","Microsatellite instability","CA 19-9"],"standardOfCare":[{"setting":"Resectable disease","approach":"Surgery followed by six months of capecitabine (BILCAP).","refs":["bilcap","capecitabine"]},{"setting":"Advanced disease","approach":"Gemcitabine-cisplatin with durvalumab (TOPAZ-1) or pembrolizumab; targeted therapy for FGFR2 and IDH1 alterations on progression.","refs":["cholangiocarcinoma","gemcitabine","cisplatin","durvalumab"]},{"setting":"Second line by biology","approach":"Pemigatinib or futibatinib for FGFR2 fusions, ivosidenib for IDH1 mutations, FOLFOX otherwise.","refs":["pemigatinib","futibatinib","ivosidenib","oxaliplatin"]}],"stateOfArt":["Immunotherapy added to chemotherapy improved survival for the first time in a decade (TOPAZ-1, KEYNOTE-966).","FGFR2 and IDH1 inhibitors made intrahepatic cholangiocarcinoma a model for molecular selection in a rare cancer.","Liver transplantation for selected perihilar tumours and liver-directed therapy for intrahepatic disease are expanding."],"history":[{"year":1965,"title":"Klatskin describes perihilar cholangiocarcinoma","refs":[]},{"year":2010,"title":"ABC-02: gemcitabine-cisplatin becomes standard","refs":["abc-02"]},{"year":2020,"title":"Pemigatinib: first FGFR2 inhibitor approved","refs":["pemigatinib"]},{"year":2022,"title":"Durvalumab added to chemotherapy (TOPAZ-1)","refs":["durvalumab"]}],"pipeline":["pemigatinib","futibatinib","ivosidenib"],"openProblems":["Most patients are diagnosed too late for surgery.","No screening even in high-incidence regions.","Resistance to FGFR2 inhibitors within a year.","Gallbladder cancer lacks any approved targeted drug."]},{"id":"cholangiocarcinoma","kind":"cancer","name":"Biliary tract cancer (cholangiocarcinoma)","aka":["Bile Duct Cancer"],"tldr":"Cholangiocarcinoma is cancer of the bile ducts or gallbladder. It is rare and often found late, but it turned out to carry more targetable mutations than almost any other gastrointestinal cancer, and immunotherapy now adds to chemotherapy from the first treatment.","summary":"Biliary tract cancers comprise intrahepatic cholangiocarcinoma (iCCA, rising in incidence), perihilar and distal extrahepatic cholangiocarcinoma, and gallbladder cancer. They share late presentation (jaundice, weight loss) and dependence on surgical resection as the only cure, achievable in a minority, which keeps five-year survival under 20%. Risk factors differ by region: liver flukes and hepatolithiasis in East Asia, primary sclerosing cholangitis in the West, gallstones and chronic inflammation for gallbladder cancer. Biliary drainage is usually a prerequisite for any treatment.\n\nThe systemic landscape was gemcitabine-cisplatin alone from ABC-02 (2010) until TOPAZ-1 (durvalumab, 2022) and KEYNOTE-966 (pembrolizumab, 2023) added PD-(L)1 blockade with a modest median benefit but a doubling of two-year survival. Adjuvant capecitabine (BILCAP) is standard after resection. What sets biliary cancer apart is its genomic actionability: roughly 40% of intrahepatic tumours carry FGFR2 fusions (pemigatinib, futibatinib), IDH1 mutations (ivosidenib), HER2 amplification or overexpression (zanidatamab, trastuzumab deruxtecan), NRG1 fusions (zenocutuzumab, approved 2026), BRAF V600E, or MSI-high status, so molecular profiling at diagnosis is guideline-mandated.\n\nThe frontier is moving targeted agents into first line (HERIZON-BTC-302 for zanidatamab), overcoming FGFR-inhibitor resistance (tinengotinib in FIRST-308, lirafugratinib), ctDNA-guided sequencing, and finding a biomarker for the immunotherapy long-tail. Liver transplantation for unresectable perihilar tumours (Mayo protocol) and for selected intrahepatic disease is expanding. Open problems include second-line therapy after chemo-immunotherapy, gallbladder cancer's neglect in trials, and early detection in high-risk groups such as primary sclerosing cholangitis.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Cholangiocarcinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Cholangiocarcinoma"}],"tags":["gi","spike"],"related":["gemcis-plus-io-btc","gallbladder","ampullary"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","bispecific-antibody","checkpoint-inhibitor","cgp","biliary-stenting-drainage","liver-transplant-oncology","radioembolisation-tare","rna-seq","liquid-biopsy","sbrt"],"targets":["fgfr2","idh","her2","her3","pd1","pdl1","braf","ntrk","cldn18-2"],"drugs":["oncomine-dx-target-test"],"companies":["shenzhen-ionova-life-sciences","hangzhou-hanx-biopharmaceuticals","tiumbio","astrazeneca","merck","incyte","taiho","servier","jazz","zymeworks","merus","transthera"],"institutions":["mayo-clinic","mskcc","cruk","royal-marsden","asan-medical-center"],"pathways":[],"terms":["biliary-anatomy-subtypes","fgfr2-fusion","ca19-9","gene-fusion","tumour-agnostic"],"trials":["nct07229625","nct05065957","nct06622057","nct05987358","nct04353375","companion-002","nct07265674","nct07710885","nct05771480","nct06467357","nct05876754","nct06109779","nct07582315","nct07606599","nct03478488","nct05948475","nct07221253","nct06591520","abc-06","fight-302"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 210,000 cases per year worldwide; incidence of intrahepatic cholangiocarcinoma has roughly doubled in Western countries over 30 years; gallbladder cancer is endemic in Chile, northern India, and among Indigenous Americans.","subtypes":["Intrahepatic cholangiocarcinoma (FGFR2 fusion ~10-15%, IDH1 ~15%)","Perihilar (Klatskin) cholangiocarcinoma","Distal extrahepatic cholangiocarcinoma","Gallbladder carcinoma (HER2 ~15-20%)","Fluke-associated (Opisthorchis, Clonorchis)","PSC-associated"],"biomarkers":["FGFR2 fusions (~15% intrahepatic)","IDH1 (~15%)","HER2 (~15% extrahepatic/gallbladder)","NRG1","MSI","BRAF","FGFR2 fusions/rearrangements (RNA or DNA NGS)","IDH1 mutation","HER2 amplification / IHC 3+","NRG1 fusion","BRAF V600E","MSI/dMMR","KRAS, TP53 (prognostic)","CA 19-9 (monitoring)","PD-L1 (not predictive so far)"],"standardOfCare":[{"setting":"Resectable","approach":"Surgery + adjuvant capecitabine.","refs":[],"guideline":{"version":"NCCN Guidelines: Biliary Tract Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1517"}},{"setting":"Advanced","approach":"Gem-cis + PD-(L)1; targeted therapy by genotype second line.","refs":["durvalumab","pembrolizumab","zanidatamab","zenocutuzumab","trastuzumab-deruxtecan"],"guideline":{"version":"NCCN Guidelines: Biliary Tract Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1517"}},{"setting":"Diagnosis and staging","approach":"Contrast CT/MRI with MRCP; ERCP or EUS-guided biopsy; molecular profiling (DNA + RNA NGS) for all advanced disease; biliary drainage if jaundiced.","refs":["cgp","rna-seq","biliary-stenting-drainage","mri"],"guideline":{"nccn":"Molecular testing recommended (category 2A)","version":"NCCN Biliary Tract Cancers 2026"}},{"setting":"Resectable","approach":"Margin-negative resection (hepatectomy, Whipple, or radical cholecystectomy) with lymphadenectomy; adjuvant capecitabine 6 months (BILCAP).","refs":["bilcap","robotic-surgery"],"guideline":{"nccn":"Capecitabine category 2A (preferred)","esmoMcbs":"B"}},{"setting":"Unresectable perihilar in selected patients","approach":"Neoadjuvant chemoradiation then liver transplantation (Mayo protocol) at experienced centres.","refs":["liver-transplant-oncology"],"guideline":{"nccn":"Category 2B, transplant centres only"}},{"setting":"Advanced, first line","approach":"Gemcitabine-cisplatin + durvalumab (TOPAZ-1) or + pembrolizumab (KEYNOTE-966); zanidatamab added in HER2+ disease within HERIZON-BTC-302.","refs":["topaz-1","keynote-966","gemcitabine-cisplatin","durvalumab","pembrolizumab","herizon-btc-302"],"guideline":{"nccn":"Category 1 (preferred)","esmoMcbs":"TOPAZ-1 grade 3"}},{"setting":"Advanced, FGFR2 fusion after chemotherapy","approach":"Pemigatinib or futibatinib; tinengotinib in FIRST-308 after progression.","refs":["pemigatinib","futibatinib","tinengotinib","fight-202","foenix-cca2","first-308"],"guideline":{"nccn":"Category 2A"}},{"setting":"Advanced, IDH1 mutation after chemotherapy","approach":"Ivosidenib (ClarIDHy).","refs":["ivosidenib","claridhy"],"guideline":{"nccn":"Category 1"}},{"setting":"Advanced, HER2-positive after chemotherapy","approach":"Zanidatamab (IHC 3+ or amplified); trastuzumab deruxtecan (IHC 3+, tumour-agnostic).","refs":["zanidatamab","trastuzumab-deruxtecan"],"guideline":{"nccn":"Category 2A"}},{"setting":"Advanced, other alterations","approach":"Zenocutuzumab (NRG1 fusion, approved 2026); dabrafenib-trametinib (BRAF V600E); pembrolizumab or dostarlimab (MSI-H/dMMR); larotrectinib/entrectinib (NTRK).","refs":["zenocutuzumab","dabrafenib-trametinib","pembrolizumab","dostarlimab"],"guideline":{"nccn":"Category 2A (tumour-agnostic)"}},{"setting":"Second-line, no target","approach":"FOLFOX (ABC-06, modest benefit); liposomal irinotecan/5-FU had conflicting results (NIFTY positive, NALIRICC negative); clinical trials preferred.","refs":["naliricc","cytotoxic-chemotherapy"],"guideline":{"nccn":"FOLFOX category 1"}},{"setting":"Locoregional (intrahepatic, liver-confined)","approach":"Y-90 radioembolisation, hepatic arterial infusion pump chemotherapy, or SBRT at specialised centres; no phase 3 proof of survival benefit.","refs":["radioembolisation-tare","sbrt"],"guideline":{"nccn":"Category 2B"}}],"stateOfArt":["Genotype-directed therapy in ~40% of patients.","Chemo-immunotherapy first line with a doubling of two-year survival (TOPAZ-1, KEYNOTE-966).","Four biomarker-directed drug classes approved (FGFR2, IDH1, HER2, NRG1), plus tumour-agnostic BRAF, MSI-H and NTRK options: ~40% of intrahepatic tumours have an actionable alteration.","Next-generation FGFR inhibitors targeting resistance mutations are in phase 3 (FIRST-308).","Zanidatamab moving into first line for HER2-positive disease (HERIZON-BTC-302).","Liver transplantation protocols extend curative options to selected unresectable perihilar tumours."],"history":[{"year":1965,"title":"Klatskin describes perihilar cholangiocarcinoma","note":"Distinct clinicopathologic entity at the hepatic duct confluence.","refs":[]},{"year":1993,"title":"Mayo Clinic begins neoadjuvant chemoradiation and transplant for perihilar cholangiocarcinoma","refs":["liver-transplant-oncology"]},{"year":2010,"title":"ABC-02: gemcitabine-cisplatin becomes standard","refs":["abc-02","gemcitabine-cisplatin"]},{"year":2013,"title":"FGFR2 fusions and IDH1 mutations characterised as drivers of intrahepatic cholangiocarcinoma","refs":["fgfr2-fusion","idh"]},{"year":2017,"title":"BILCAP: adjuvant capecitabine adopted","refs":["bilcap"]},{"year":2020,"title":"Pemigatinib: first FGFR2 inhibitor","refs":[]},{"year":2020,"title":"Pemigatinib: first targeted approval in biliary cancer","refs":["pemigatinib","fight-202"]},{"year":2021,"title":"Ivosidenib approved (ClarIDHy); infigratinib approved then withdrawn (2022)","refs":["ivosidenib","claridhy"]},{"year":2022,"title":"TOPAZ-1: immunotherapy first line","refs":["durvalumab"]},{"year":2022,"title":"TOPAZ-1: first immunotherapy approval; futibatinib approved","refs":["topaz-1","durvalumab","futibatinib","foenix-cca2"]},{"year":2023,"title":"KEYNOTE-966: pembrolizumab confirms chemo-IO","refs":["keynote-966"]},{"year":2024,"title":"Zanidatamab for HER2+ BTC","refs":["zanidatamab"]},{"year":2024,"title":"Zanidatamab: first HER2 approval in biliary cancer; T-DXd tumour-agnostic HER2 IHC3+; NALIRICC negative","refs":["zanidatamab","trastuzumab-deruxtecan","naliricc"]},{"year":2025,"title":"TOPAZ-1 three-year survival update; FIRST-308 doses first US patient","refs":["topaz-1","first-308"]},{"year":2026,"title":"Zenocutuzumab approved for NRG1-fusion cholangiocarcinoma; HERIZON-BTC-302 enrolling","refs":["zenocutuzumab","herizon-btc-302"]}],"pipeline":["zenocutuzumab","shr-8068","tqb2102","d07001","tqb3454","hmpl-453","tovecimig","xnw27011","azd4360","cgt4859","spevatamig","vb15010","herizon-btc-302","first-308","tinengotinib","zanidatamab","trastuzumab-deruxtecan","idea-btc-ctdna-fgfr-resistance","liquid-biopsy","liver-transplant-oncology","radioembolisation-tare","fapi-pet","cmg901"],"openProblems":["FGFR inhibitor resistance.","Late diagnosis.","Median survival in advanced disease is still barely a year; the immunotherapy benefit is a small tail with no predictive biomarker.","FGFR inhibitor resistance (polyclonal kinase-domain mutations) limits benefit to ~7-9 months; sequencing next-generation agents is unproven.","Second-line chemotherapy is weak (FOLFOX) and evidence for liposomal irinotecan is contradictory.","Gallbladder cancer is under-represented in trials despite distinct biology and high HER2 prevalence.","Early detection in primary sclerosing cholangitis and fluke-endemic regions is unsolved; CA 19-9 is non-specific.","Molecular testing is slow and tissue is scarce from brushings; liquid biopsy adoption lags.","Adjuvant evidence rests on a technically negative trial (BILCAP); immunotherapy adjuvant trials are ongoing."],"parent":"biliary-tract-cancer"},{"id":"prostate-bcr","kind":"cancer","name":"Biochemical recurrence of prostate cancer","aka":["Biochemically recurrent prostate cancer","PSA recurrence","Rising PSA after local therapy","nmHSPC","Hormone-relapsed prostate cancer, PSA-only","Rising PSA after treatment"],"tldr":"Biochemical recurrence of prostate cancer is a rising PSA after surgery or radiotherapy with nothing yet visible on scans. Salvage radiotherapy can still cure it after surgery, and for a fast-doubling PSA the EMBARK trial showed that enzalutamide with or without hormone therapy delays spread.","summary":"Biochemical recurrence is defined as a PSA of 0.2 ng/mL or more, confirmed, after radical prostatectomy, or a rise of 2 ng/mL above the nadir after radiotherapy (the Phoenix definition). It is found by routine PSA follow-up; PSMA PET now locates the recurrence in most men once PSA passes about 0.5 ng/mL, and often shows disease that conventional imaging misses. After prostatectomy, early salvage radiotherapy to the prostate bed, started before PSA reaches 0.5, cures many men, with short-term hormone therapy added for higher-risk features. After radiotherapy, local salvage by surgery, brachytherapy, cryotherapy or high-intensity focused ultrasound is possible for confirmed local recurrence. Men with a PSA doubling time under nine months are at high risk of metastasis: EMBARK randomised 1,068 such men and showed enzalutamide with leuprolide, or enzalutamide alone, cut metastasis or death by about half compared with leuprolide alone, and the FDA approved enzalutamide for this setting in 2023. Slowly rising PSA can be watched, and PSMA PET-directed stereotactic radiotherapy to a few metastases is under study.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Biochemical_recurrence","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Biochemical_recurrence"},{"label":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"},{"label":"NICE NG131: prostate cancer, diagnosis and management (recommendations, including the Cambridge Prognostic Group table at 1.2.15)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"}],"tags":["subtype-page"],"related":["prostate-high-risk","prostate-intermediate-risk","prostate-nmcrpc","prostate-mhspc"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["psa-kinetics","cambridge-prognostic-group","extraprostatic-extension","tnm-prostate-cancer","psa-density","metastasis-free-survival","intermittent-androgen-deprivation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-embark-nejm-2023","paper-radicals-rt-lancet-2020","paper-propsma-hofman-lancet-2020"],"journals":[],"dependsOn":[],"notes":["The findings on the prostatectomy report that raise the chance of arriving here are extraprostatic extension (pT3a), seminal vesicle invasion (pT3b) and a positive surgical margin, which are three different things: the first two say how far the cancer grew, the third says whether the surgeon's cut passed through cancer, and a man can have one without the others."],"group":"genitourinary","burden":"A rising PSA follows a quarter to a third of prostatectomies and radiotherapy courses; only a minority of these men develop metastases on scans within ten years, and the PSA doubling time tells the two apart.","subtypes":["Biochemical recurrence after prostatectomy (PSA 0.2 or more)","Biochemical recurrence after radiotherapy (nadir plus 2)","High-risk biochemical recurrence (PSA doubling time under 9 months, non-metastatic hormone-sensitive)","PSMA PET-detected oligorecurrence"],"biomarkers":["PSA and PSA doubling time","PSMA PET (positive in most men above 0.5 ng/mL)","Decipher on the prostatectomy specimen","Interval from local therapy to recurrence"],"standardOfCare":[{"setting":"After prostatectomy","approach":"Early salvage radiotherapy to the prostate bed, with or without pelvic nodes and four to six months of androgen deprivation for adverse features; observation for slow doubling times.","refs":["imrt-igrt","androgen-deprivation","psa","decipher-prostate"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"After radiotherapy, local recurrence","approach":"Salvage prostatectomy, brachytherapy, cryotherapy or high-intensity focused ultrasound in fit men with biopsy-proven local disease and no metastases on PSMA PET.","refs":["robotic-surgery","brachytherapy","hifu-histotripsy","psma-pet"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"High-risk biochemical recurrence (doubling time under 9 months)","approach":"Enzalutamide with leuprolide, or enzalutamide alone (EMBARK); PSMA PET before starting; intermittent therapy with treatment suspension when PSA becomes undetectable.","refs":["enzalutamide","leuprolide","embark","psma-pet"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"PSMA PET-detected oligorecurrence","approach":"Stereotactic radiotherapy to the visible metastases, usually within trials or with hormone therapy; the survival benefit is unproven.","refs":["sbrt","oligometastatic","idea-psma-pet-guided-mdt"]}],"stateOfArt":["PSMA PET has turned biochemical recurrence from an invisible number into a map, though it also finds disease the trials never saw.","EMBARK is the first trial to show that treating a fast-rising PSA with an androgen receptor inhibitor delays metastasis.","Intermittent therapy with a treatment holiday is built into the approved EMBARK regimen."],"history":[{"year":1997,"title":"ASTRO consensus defines PSA failure after radiotherapy","refs":["psa"]},{"year":2005,"title":"Phoenix definition: nadir plus 2 ng/mL","refs":["psa"]},{"year":2017,"title":"RTOG 9601: bicalutamide with salvage radiotherapy improves survival","refs":["bicalutamide"]},{"year":2020,"title":"PSMA PET approved for recurrence","refs":["psma-pet"]},{"year":2023,"title":"EMBARK: enzalutamide delays metastasis in high-risk biochemical recurrence","refs":["embark","enzalutamide"]}],"pipeline":["psma-pet","enzalutamide","sbrt","idea-psma-pet-guided-mdt"],"openProblems":["Whether treating PSMA PET-detected metastases early lengthens life or only lowers PSA.","How to spare men with slow doubling times from years of hormone therapy.","The trials that defined recurrence used conventional imaging; PSMA PET restages many of these men as metastatic."],"parent":"prostate"},{"id":"urothelial","kind":"cancer","name":"Bladder & urothelial cancer","aka":["BLCA","TCGA-BLCA","bladder urothelial carcinoma (TCGA BLCA cohort)","Transitional Cell Cancer of the Renal Pelvis and Ureter"],"tldr":"Bladder cancer went from 40 years of cisplatin to an ADC-immunotherapy combination that nearly doubled survival, and in 2026 the first blood-test-guided drug approval.","summary":"Urothelial carcinoma of the bladder is the tenth most common cancer worldwide and the most expensive to manage per patient, because three quarters present as non-muscle-invasive disease that recurs for years and demands lifelong cystoscopy. Smoking causes about half of cases. Muscle-invasive disease (25%) has required radical cystectomy with neoadjuvant cisplatin since the 2000s, and metastatic disease relied on platinum chemotherapy for four decades.\n\nBetween 2019 and 2026 the field was rebuilt. In metastatic disease, enfortumab vedotin plus pembrolizumab nearly doubled survival over chemotherapy (EV-302, 2023). The same pair then moved around surgery: EV-303 in cisplatin-ineligible patients (EFS HR 0.40, approved November 2025) and EV-304 in cisplatin-eligible patients (positive December 2025), after NIAGARA had already established perioperative durvalumab (approved March 2025). Adjuvant nivolumab (CheckMate 274) and ctDNA-guided adjuvant atezolizumab (IMvigor011, the first ctDNA-based approval, 2026) cover the post-cystectomy space. In non-muscle-invasive disease, the BCG-unresponsive population gained four bladder-sparing options (pembrolizumab, nadofaragene firadenovec, N-803 + BCG, and the gemcitabine-eluting device TAR-200), with the oncolytic virus cretostimogene filing in 2026, and durvalumab + BCG became the first systemic immunotherapy in BCG-naive disease (POTOMAC, May 2026). Erdafitinib remains the only targeted drug, for FGFR3-altered tumours after immunotherapy.\n\nWhat is next: bladder preservation for complete responders to perioperative EV + pembrolizumab; sequencing after EV + pembrolizumab (platinum, HER2 ADCs such as disitamab vedotin, TROP2 and bispecific ADCs, sac-TMT); urine tumour DNA to reduce cystoscopy; resolving BCG shortages with recombinant strains and alternatives; and understanding why some intravesical immunotherapies (durvalumab, sasanlimab) add to BCG while others (atezolizumab) did not.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Bladder_cancer","links":[{"label":"NCI PDQ: bladder cancer treatment","url":"https://www.cancer.gov/types/bladder/hp/bladder-treatment-pdq"},{"label":"FDA: durvalumab + BCG approval (May 2026)","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-combination-bacillus-calmette-guerin-high-risk-non-muscle-invasive-bladder"}],"tags":["gu"],"related":["urethral","src-urotoday"],"cancers":[],"sections":[],"technologies":["adc","checkpoint-inhibitor","mrd-testing","bispecific-adc","bcg-and-intravesical-therapy","cystoscopy-turbt","oncolytic-virus","cytokine-therapy","kinase-inhibitors","robotic-surgery","imrt-igrt","peptide-drug-conjugate"],"targets":["nectin4","pd1","pdl1","fgfr2","her2","trop2"],"drugs":["therascreen-cdx","ventana-pd-l1-sp142","thiotepa","valrubicin","vinflunine"],"companies":["mabwell-shanghai-bioscience","molecular-partners","suzhou-forlong-biotechnology","astellas","pfizer","merck","astrazeneca","bms","roche-genentech","johnson-johnson","cg-oncology","immunitybio","ferring","bicycle-therapeutics"],"institutions":["mskcc","md-anderson","dana-farber","mount-sinai","the-christie"],"pathways":["ras-mapk","bladder-cancer-signalling","pd1-checkpoint","p53-cell-cycle"],"terms":["nmibc-vs-mibc","bcg-unresponsive","fgfr3","pcr","mrd","neoadjuvant-adjuvant"],"trials":["ev-302","ev-303","ev-304","nct04658862","hr-nmibc","nct07424287","nct07726992","nct05754853","nct07480356","nct06331299","nct06919965","nct04165317","companion-002","nct07218380","nct06774131","nct05243550","nct07815665","nct05302284","nct07720284","nct05037279","nct07419295","nct07129993","nct03682068","nct06111235","nct06857175","nct06319820","nct06211764","nct07566156","nct03036098","nct05704244","nct02516241","nct06510374","nct05943106","nct06960577","nct06545955","nct04241185","nct06592326","nct03967977","nct05911295","nct07393542","nct03711032","nct06879145","nct04960709","nct06493552","nct07106762","nct06196736"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["clinical-genitourinary-cancer","urologic-oncology"],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"About 600,000 cases a year worldwide and the fourth most common cancer in men in the US. Three quarters are non-muscle-invasive and managed for years with bladder-sparing treatment, which is why it has the highest lifetime treatment cost per patient of any cancer; ~220,000 deaths a year.","subtypes":["Non-muscle-invasive (Ta, T1, CIS; ~75%)","Muscle-invasive (T2-T4; ~25%)","Upper-tract urothelial carcinoma (renal pelvis, ureter; ~5-10%)","Molecular: luminal-papillary (FGFR3-altered), luminal-infiltrated, basal/squamous, neuroendocrine-like","Variant histologies (squamous, micropapillary, plasmacytoid, sarcomatoid, small-cell)"],"biomarkers":["FGFR3","PD-L1 (limited utility now)","HER2","Nectin-4 (not required)","ctDNA (Signatera)","Stage and grade (NMIBC risk group; MIBC)","BCG-unresponsive status (FDA definition)","FGFR3/FGFR2 alterations (erdafitinib)","Nectin-4 (not required for enfortumab)","HER2 (disitamab vedotin trials)","PD-L1 (no longer decisive after EV-302)","ctDNA (Signatera; IMvigor011 selection)","Urine tumour DNA (surveillance, research)","Cisplatin eligibility (renal function, hearing, neuropathy, performance status)"],"standardOfCare":[{"setting":"NMIBC","approach":"Non-muscle-invasive: transurethral resection (TURBT) then intravesical BCG; novel intravesical agents for BCG-unresponsive disease; durvalumab + BCG for high-risk disease (2026).","refs":["nmibc-vs-mibc","turbt","intravesical-therapy","durvalumab","oncolytic-virus","cytokine-therapy"],"guideline":{"version":"NCCN Guidelines: Bladder Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1417"}},{"setting":"MIBC","approach":"Muscle-invasive: neoadjuvant chemotherapy ± durvalumab → radical cystectomy → ctDNA-guided atezolizumab or nivolumab; perioperative enfortumab vedotin + pembrolizumab for cisplatin-ineligible patients (EV-303), with EV-304 positive in cisplatin-eligible patients.","refs":["nmibc-vs-mibc","cystectomy","imvigor011","atezolizumab","signatera","ev-303","ev-304"],"guideline":{"version":"NCCN Guidelines: Bladder Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1417"}},{"setting":"Metastatic","approach":"Enfortumab vedotin (an antibody-drug conjugate) + pembrolizumab (immunotherapy); erdafitinib for FGFR3 alterations; platinum chemotherapy + nivolumab.","refs":["ev-302","enfortumab-vedotin","pembrolizumab"],"guideline":{"esmoMcbs":"4 (EV-301 enfortumab vedotin); 3 (TROPHY-U-01)","version":"NCCN Guidelines: Bladder Cancer","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11163648/"}},{"setting":"Diagnosis and surveillance","approach":"Cystoscopy (white or blue light) and TURBT with muscle in the specimen; re-resection for T1; CT urography; urine cytology; surveillance cystoscopy every 3-12 months by risk.","refs":["cystoscopy-turbt","ct"],"guideline":{"nccn":"Bladder cancer guideline","version":"NCCN Bladder v3.2026"}},{"setting":"Low / intermediate-risk NMIBC","approach":"TURBT with single immediate intravesical chemotherapy instillation; intermediate risk adds 1 year of intravesical chemotherapy (gemcitabine/mitomycin) or BCG.","refs":["cystoscopy-turbt","bcg-and-intravesical-therapy"],"guideline":{"nccn":"1 (single postoperative instillation)"}},{"setting":"High-risk NMIBC, BCG-naive","approach":"TURBT then BCG induction and 1-3 years maintenance; durvalumab + BCG approved May 2026 (POTOMAC); radical cystectomy for very high-risk (T1 + CIS, variant histology).","refs":["bcg-intravesical","durvalumab","potomac","durvalumab-plus-bcg"],"guideline":{"nccn":"1 (BCG maintenance); durvalumab + BCG newly approved"}},{"setting":"BCG-unresponsive NMIBC (CIS ± papillary)","approach":"Radical cystectomy remains the oncologic gold standard; bladder-sparing options: TAR-200 (Inlexzo, 2025), N-803 + BCG (Anktiva, 2024), nadofaragene firadenovec (2022), pembrolizumab (2020); cretostimogene in registration.","refs":["tar-200","nogapendekin-alfa","nadofaragene-firadenovec","pembrolizumab","cretostimogene","sunrise-1","bond-003","quilt-3-032"],"guideline":{"nccn":"2A (intravesical options); cystectomy preferred","version":"NCCN Bladder v3.2026"}},{"setting":"Muscle-invasive, cisplatin-eligible","approach":"Perioperative EV + pembrolizumab (EV-304, positive 2025; filing) or neoadjuvant durvalumab + gemcitabine-cisplatin with adjuvant durvalumab (NIAGARA, approved 2025), then radical cystectomy with lymph node dissection; trimodality bladder preservation (TURBT + chemoradiation) for selected patients.","refs":["enfortumab-vedotin","pembrolizumab","ev-304","durvalumab","niagara","imrt-igrt","ev-pembro-continuum"],"guideline":{"nccn":"1 (NIAGARA regimen); EV+pembro pending label","esmoMcbs":"A (NIAGARA)"}},{"setting":"Muscle-invasive, cisplatin-ineligible","approach":"Perioperative EV + pembrolizumab with cystectomy (EV-303, approved Nov 2025); or cystectomy alone / chemoradiation.","refs":["enfortumab-vedotin","pembrolizumab","ev-303"],"guideline":{"nccn":"1","esmoMcbs":"A"}},{"setting":"After cystectomy (no perioperative IO)","approach":"Adjuvant nivolumab for high-risk pathology (CheckMate 274); or ctDNA-guided adjuvant atezolizumab (IMvigor011, approved 2026).","refs":["nivolumab","checkmate-274","atezolizumab","imvigor011","signatera"],"guideline":{"nccn":"1 (nivolumab); ctDNA-guided atezolizumab new"}},{"setting":"Metastatic, first line","approach":"Enfortumab vedotin + pembrolizumab (EV-302); if contraindicated, platinum-gemcitabine followed by avelumab maintenance (JAVELIN Bladder 100) or nivolumab + gemcitabine-cisplatin (CheckMate 901).","refs":["enfortumab-vedotin","pembrolizumab","ev-302","avelumab","javelin-bladder-100","nivolumab"],"guideline":{"nccn":"1 (preferred: EV + pembrolizumab)","esmoMcbs":"4"}},{"setting":"Metastatic, later lines","approach":"Erdafitinib if FGFR3-altered (THOR); platinum chemotherapy if not yet given; disitamab vedotin ± toripalimab (HER2, China); sacituzumab govitecan (US indication withdrawn 2024); trials of TROP2/HER2/bispecific ADCs and sac-TMT.","refs":["erdafitinib","thor","disitamab-vedotin","sacituzumab-tirumotecan","izalontamab-brengitecan","ak146d1"],"guideline":{"nccn":"1 (erdafitinib, FGFR3+)"}}],"stateOfArt":["Antibody-drug conjugate (ADC) plus immunotherapy (IO) first line: enfortumab vedotin with pembrolizumab (EV-302).","First circulating tumour DNA (ctDNA)-guided adjuvant approval: atezolizumab after IMvigor011.","EV + pembrolizumab across metastatic, cisplatin-ineligible perioperative (approved 2025), and cisplatin-eligible perioperative (positive 2025) settings.","Perioperative durvalumab (NIAGARA) and adjuvant nivolumab (CheckMate 274) with overall survival benefit.","First ctDNA-guided drug approval in any cancer: adjuvant atezolizumab for ctDNA-positive MIBC (IMvigor011, 2026).","Five bladder-sparing options for BCG-unresponsive disease, including a drug-eluting device and an oncolytic virus in registration.","Durvalumab + BCG: first systemic immunotherapy approved in BCG-naive NMIBC (May 2026).","Erdafitinib: the only biomarker-directed targeted therapy, with a survival benefit after immunotherapy."],"history":[{"year":1976,"title":"BCG immunotherapy for bladder cancer","refs":[]},{"year":1976,"title":"Morales reports intravesical BCG for bladder cancer","refs":["bcg-intravesical"]},{"year":1990,"title":"BCG approved for carcinoma in situ; SWOG maintenance schedule follows (2000)","refs":["bcg-intravesical"]},{"year":2003,"title":"SWOG 8710: neoadjuvant MVAC before cystectomy improves survival","refs":[]},{"year":2012,"title":"Global BCG shortage begins after Sanofi production halt","refs":["bcg-intravesical"]},{"year":2016,"title":"Atezolizumab: first new bladder drug in 30 years","refs":[]},{"year":2016,"title":"Atezolizumab: first new bladder cancer drug in 30 years (later withdrawn)","refs":["atezolizumab"]},{"year":2017,"title":"Pembrolizumab beats chemotherapy in second line (KEYNOTE-045)","refs":["pembrolizumab"]},{"year":2019,"title":"Erdafitinib (first targeted therapy) and enfortumab vedotin (first ADC) approved","refs":["erdafitinib","enfortumab-vedotin"]},{"year":2020,"title":"Avelumab maintenance (JAVELIN Bladder 100); pembrolizumab for BCG-unresponsive CIS","refs":["javelin-bladder-100","avelumab"]},{"year":2021,"title":"Adjuvant nivolumab (CheckMate 274)","refs":["checkmate-274"]},{"year":2022,"title":"Nadofaragene firadenovec: first bladder gene therapy","refs":["nadofaragene-firadenovec"]},{"year":2023,"title":"EV-302 doubles survival","refs":["ev-302"]},{"year":2023,"title":"EV-302: EV + pembrolizumab nearly doubles metastatic survival","refs":["ev-302","ev-pembro-continuum"]},{"year":2024,"title":"Anktiva (N-803 + BCG) approved; erdafitinib full approval (THOR)","refs":["nogapendekin-alfa","thor"]},{"year":2025,"title":"NIAGARA perioperative durvalumab (March); Inlexzo/TAR-200 (September); EV-303 perioperative EV + pembrolizumab (November); EV-304 positive (December)","refs":["niagara","tar-200","ev-303","ev-304"]},{"year":2026,"title":"IMvigor011: ctDNA-guided atezolizumab approved","refs":["imvigor011"]},{"year":2026,"title":"IMvigor011 ctDNA-guided atezolizumab and POTOMAC durvalumab + BCG approved; cretostimogene BLA under way","refs":["imvigor011","potomac","cretostimogene"]}],"pipeline":["izalontamab-brengitecan","ak146d1","disitamab-vedotin","intismeran-autogene","pf-08634404","shr-8068","shr-a2102","domvanalimab","cetrelimab","budigalimab","livmoniplimab","shr-1501","gotistobart","mrg002","tara-002","ugn-103","tar-210","sasanlimab","tovecimig","vepugratinib","ugn-104","t3011","tyra-300","absk061","jk08","ev-304","cretostimogene","bond-003","tar-200","idea-bladder-preservation-mibc","idea-urine-ctdna-surveillance","sacituzumab-tirumotecan","zelenectide-pevedotin","durvalumab-plus-bcg","ev-pembro-continuum","mrd-testing","cystoscopy-turbt"],"openProblems":["BCG supply.","Bladder preservation strategies.","Nectin-4 ADC resistance.","BCG supply remains inadequate a decade after shortages began; alternatives are unproven for BCG-naive high-risk disease.","What to give after EV + pembrolizumab fails: platinum rechallenge, HER2 or TROP2 ADCs, and bispecific ADCs are untested in sequence.","Whether perioperative therapy's high complete response rates permit bladder preservation in MIBC.","Cystoscopic surveillance burden and cost; urine biomarkers not yet guideline-endorsed to replace cystoscopy.","Overtreatment risk with systemic immunotherapy (durvalumab + BCG) in a disease many patients survive with BCG alone.","Peripheral neuropathy and skin toxicity of enfortumab vedotin limit duration; safer Nectin-4 conjugates stalled in 2026.","Upper-tract urothelial carcinoma and variant histologies are under-represented in trials.","Only one biomarker (FGFR3) is actionable; HER2 and Nectin-4 selection remain unresolved."],"basics":{"symptoms":["Blood in the urine (haematuria), often rusty to bright red, is the most common sign and can come and go","Passing urine often or urgently, pain or burning on passing urine, or feeling the need to go when the bladder is empty","Later: being unable to pass urine, pain in one side of the lower back, bone pain, weight loss, swollen feet or tiredness","Infections and stones cause the same symptoms far more often than cancer; the tests below tell them apart"],"diagnosis":["Urine tests for blood, abnormal cells (cytology) and infection","Cystoscopy: a thin lit scope passed through the urethra to look at the bladder lining","Transurethral resection (TURBT): the tumour is shaved away through the scope and examined by a pathologist, which gives the diagnosis, the grade and whether the muscle is involved","CT urogram or other imaging of the kidneys, ureters and bladder; once cancer is confirmed, CT, MRI, chest imaging or a bone scan look for spread"],"staging":["Stage 0a (papillary) and 0is (carcinoma in situ, always high grade): confined to the lining","Stage I: into the connective tissue under the lining but not the muscle; stages 0 and I together are non-muscle-invasive bladder cancer (NMIBC)","Stage II: into the muscle wall, muscle-invasive bladder cancer (MIBC)","Stage III: through the bladder wall into the surrounding fat or nearby organs, or to pelvic lymph nodes","Stage IV: into the pelvic or abdominal wall, to lymph nodes above the pelvis, or to distant organs","Grade matters as much as stage: low-grade tumours grow slowly and rarely invade; high-grade tumours grow and spread faster"],"sources":[{"label":"NCI: bladder cancer symptoms","url":"https://www.cancer.gov/types/bladder/symptoms"},{"label":"NCI: bladder cancer diagnosis","url":"https://www.cancer.gov/types/bladder/diagnosis"},{"label":"NCI: bladder cancer stages","url":"https://www.cancer.gov/types/bladder/stages"}]}},{"id":"bpdcn","kind":"cancer","name":"Blastic plasmacytoid dendritic cell neoplasm (BPDCN)","aka":[],"tldr":"Blastic plasmacytoid dendritic cell neoplasm is a rare aggressive leukaemia-like blood cancer of dendritic-cell precursors, a few hundred US cases a year, that often first appears as bruise-like skin lesions. Two CD123-directed drugs, tagraxofusp and pivekimab sunirine, are the first targeted therapies; allogeneic transplant in first remission is still the only route to long-term control.","summary":"BPDCN derives from plasmacytoid dendritic cell precursors, expresses CD4, CD56, CD123 (IL-3 receptor alpha), TCF4 and TCL1, and presents with skin lesions, marrow involvement and cytopenias, often evolving to a leukaemic phase. Historically it was treated with ALL- or AML-type chemotherapy with brief responses and a median survival around a year.\n\nTagraxofusp (CD123-directed IL-3/diphtheria toxin fusion) was the first BPDCN-specific drug (2018), with ~70% response in untreated patients and capillary leak syndrome as its signature toxicity. Pivekimab sunirine (CD123 ADC) was approved in 2026 (CADENZA). Venetoclax-based regimens and hyper-CVAD are alternatives, and allogeneic transplant in first remission is the only route to long-term survival. CNS prophylaxis is recommended because of frequent occult CNS involvement.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Blastic_plasmacytoid_dendritic_cell_neoplasm","links":[{"label":"Tagraxofusp pivotal (NEJM 2019)","url":"https://doi.org/10.1056/NEJMoa1815105"}],"tags":["gap-fill","haematologic","rare"],"related":["aml","all-leukemia"],"cancers":[],"sections":[],"technologies":["adc","allogeneic-hsct","cytokine-therapy"],"targets":["cd123","bcl2"],"drugs":["tagraxofusp","pivekimab-sunirine","venetoclax"],"companies":["abbvie","menarini"],"institutions":[],"pathways":["apoptosis-bcl2"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-pemmaraju-n-engl-j-med"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"BPDCN is very rare (a few hundred cases per year in the US); median age ~65-70, male predominance; skin lesions in most.","subtypes":["Skin-only presentation","Leukaemic / marrow-involving disease","Cases arising with or from CMML/MDS"],"biomarkers":["CD123, CD4, CD56, TCF4, TCL1 immunophenotype","Absence of MPO, lysozyme, CD3","MYC rearrangement (8q24)","TET2, ASXL1, ZRSR2 mutations","CSF examination"],"standardOfCare":[{"setting":"First line","approach":"Tagraxofusp (monitor albumin for capillary leak) or pivekimab sunirine (2026); alternatives hyper-CVAD or venetoclax-based regimens; CNS prophylaxis.","refs":["tagraxofusp","pivekimab-sunirine","venetoclax"],"guideline":{"nccn":"Category 2A (tagraxofusp)","version":"NCCN Guidelines: AML (BPDCN section)"}},{"setting":"Consolidation","approach":"Allogeneic HSCT in first complete remission for eligible patients; autologous transplant in selected cases (Japanese data).","refs":["allogeneic-hsct","autologous-stem-cell-transplant"]},{"setting":"Relapsed","approach":"Alternative CD123 agent, venetoclax combinations, clinical trials; prognosis poor.","refs":["venetoclax","pivekimab-sunirine"]}],"stateOfArt":["Two CD123-directed approvals (tagraxofusp 2018, pivekimab 2026) give a rare disease dedicated therapies.","Transplant in first remission remains essential for cure; response to CD123 agents makes more patients eligible.","BCL2 dependence makes venetoclax a rational partner."],"history":[{"year":2008,"title":"WHO names BPDCN","note":"Reclassified from 'CD4+/CD56+ haematodermic neoplasm' as a distinct entity.","refs":[]},{"year":2018,"title":"Tagraxofusp approved","note":"First CD123-targeted therapy and first drug approved for BPDCN.","refs":["tagraxofusp"]},{"year":2019,"title":"Tagraxofusp NEJM pivotal data (Pemmaraju)","refs":["tagraxofusp"]},{"year":2026,"title":"Pivekimab sunirine approved","note":"CD123 ADC (CADENZA), FDA May 2026.","refs":["pivekimab-sunirine"]}],"pipeline":["pivekimab-sunirine","venetoclax","allogeneic-hsct"],"openProblems":["No randomised trials; sequencing of CD123 agents unknown.","Capillary leak syndrome with tagraxofusp.","Relapse after transplant."],"parent":"leukaemia"},{"id":"borderline-resectable-pdac","kind":"cancer","name":"Borderline resectable pancreatic ductal adenocarcinoma","aka":["Borderline resectable pancreatic cancer","BRPC","Marginally resectable pancreatic cancer"],"tldr":"Borderline resectable pancreatic cancer touches the big blood vessels behind the pancreas, so an operation straight away would probably leave cancer behind. Chemotherapy first, usually FOLFIRINOX for several months and sometimes radiotherapy, shrinks the edge of the tumour, and patients whose disease has not spread go on to surgery with a better chance of a clean removal.","summary":"Borderline resectable disease is defined anatomically: tumour contact with the superior mesenteric or portal vein that is reconstructable, abutment of the superior mesenteric artery of 180 degrees or less, or limited contact with the hepatic artery. The MD Anderson, NCCN and international consensus definitions differ in detail and some add biological criteria, such as a very high CA 19-9 or suspicious regional nodes, and conditional criteria such as poor performance status. The point of the category is that upfront surgery leaves a positive margin in a large share of patients and that neoadjuvant treatment selects those who will benefit from a difficult operation.\n\nNeoadjuvant therapy is standard. PREOPANC-1 (2020, long-term follow-up 2022) randomised resectable and borderline patients to gemcitabine-based chemoradiation before surgery or upfront surgery and found more clear-margin resections and better long-term survival, with the benefit concentrated in the borderline group. PREOPANC-2 then compared neoadjuvant FOLFIRINOX with gemcitabine chemoradiation and found no difference, and ESPAC-5 found that neoadjuvant chemotherapy beat immediate surgery for borderline disease. Modified FOLFIRINOX for two to four months is the usual regimen, with gemcitabine plus nab-paclitaxel for less fit patients. The role of radiotherapy after chemotherapy is disputed: ALLIANCE A021501 (2022) stopped its stereotactic radiotherapy arm early because outcomes were worse than with chemotherapy alone, while other groups use conventional or ablative chemoradiation to secure the arterial margin.\n\nAfter neoadjuvant treatment patients are restaged with CT and CA 19-9; radiological shrinkage is often modest even when the tumour has responded, so surgeons operate on patients with stable disease, falling CA 19-9 and good fitness. Resection with venous reconstruction is routine in specialist centres and arterial resection is done selectively. Pathological response predicts survival, and patients complete a total of six months of chemotherapy after surgery where possible. Germline testing is offered to all, and a BRCA or PALB2 variant argues for a platinum-containing regimen. Trials are adding RAS inhibitors and vaccines to neoadjuvant chemotherapy and testing circulating tumour DNA to decide who should proceed to surgery.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Pancreatic_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Pancreatic_cancer"},{"label":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}],"tags":["subtype-page","gastrointestinal"],"related":["resectable-pdac","locally-advanced-pdac","metastatic-pdac","brca-palb2-pdac","kras-g12c-pdac"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","sbrt","mr-linac","robotic-surgery","ct","biliary-stenting-drainage","kras-inhibitors","pdac-organoid-pharmacotyping","liquid-biopsy"],"targets":["kras","brca"],"drugs":["folfirinox","gemcitabine-nab-paclitaxel","gemcitabine","capecitabine","daraxonrasib","autogene-cevumeran"],"companies":["revolution-medicines","biontech"],"institutions":[],"pathways":["pancreatic-cancer-signalling","caf-activation-desmoplasia"],"terms":["resectability","whipple","ca19-9","chemoradiation","sbrt-term","resection-margins","neoadjuvant-adjuvant","locally-advanced","ctdna"],"trials":["preopanc","prodige-24","nct07252232","nct02843945"],"people":["marc-besselink","theodore-hong","albert-koong","richard-schulick","jurgen-weitz","eileen-oreilly"],"bottlenecks":[],"keyPapers":["paper-preopanc-neoadjuvant-chemoradiotherapy-long-term-jco-2022","paper-espac-5-neoadjuvant-borderline-resectable-pancreatic-lancet-gastro-hep-2023","paper-alliance-a021501-mfolfirinox-radiotherapy-borderline-resectable-jama-oncol-2022","paper-conroy-folfirinox-pancreatic-nejm-2011"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"A fifth or so of newly diagnosed pancreatic cancers touch a major vein or artery enough to make a clear-margin operation uncertain; how many are called borderline depends on the surgeon and the definition used.","subtypes":["Borderline resectable PDAC with venous involvement only (reconstructable portal or superior mesenteric vein)","Borderline resectable PDAC with limited arterial abutment (superior mesenteric or hepatic artery)","Biologically borderline PDAC (very high CA 19-9 or suspicious nodes with resectable anatomy)","Borderline resectable PDAC converted to resection after FOLFIRINOX","Borderline resectable PDAC that progresses during neoadjuvant therapy (treated as advanced disease)"],"biomarkers":["Pancreas-protocol CT with degrees of vessel contact (defines the category)","CA 19-9 trend during neoadjuvant chemotherapy (falling levels predict a useful operation)","Restaging CT after chemotherapy (stable disease is acceptable; shrinkage is often modest)","Germline BRCA1, BRCA2, PALB2 and ATM status (platinum choice)","Pathological response grade and margin status after resection","Circulating tumour DNA before surgery (investigational selection marker)"],"standardOfCare":[{"setting":"Neoadjuvant chemotherapy","approach":"Modified FOLFIRINOX for two to four months in fit patients, gemcitabine plus nab-paclitaxel otherwise; restage with CT and CA 19-9 before deciding on surgery (PREOPANC, ESPAC-5).","refs":["folfirinox","gemcitabine-nab-paclitaxel","preopanc","ca19-9","neoadjuvant-adjuvant","espac-5"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Radiotherapy after chemotherapy","approach":"Optional; conventional chemoradiation or stereotactic radiotherapy to secure an arterial margin in selected patients, with ALLIANCE A021501 as the caution against routine use.","refs":["chemoradiation","sbrt","mr-linac","capecitabine"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Surgery","approach":"Pancreatoduodenectomy or distal pancreatectomy with venous resection and reconstruction where needed, arterial resection only in specialist centres; proceed on stable or improved disease with falling CA 19-9.","refs":["whipple","resection-margins","resectability","robotic-surgery"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"After surgery","approach":"Complete six months of chemotherapy in total, usually with the regimen the tumour responded to.","refs":["folfirinox","gemcitabine-nab-paclitaxel","gemcitabine","capecitabine"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Progression during neoadjuvant therapy","approach":"Manage as locally advanced or metastatic disease; switch chemotherapy backbone, RAS inhibitor trials, biliary stenting for jaundice.","refs":["nalirifox","daraxonrasib","biliary-stenting-drainage"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Neoadjuvant chemotherapy is the standard for borderline disease, with modified FOLFIRINOX the usual regimen (PREOPANC, ESPAC-5).","Venous resection and reconstruction is routine in high-volume centres and no longer a reason to call a tumour unresectable.","The role of radiotherapy is being redefined after ALLIANCE A021501, with ablative and MR-guided techniques in trials.","RAS inhibitors and vaccines are entering neoadjuvant trials for the first time."],"history":[{"year":2006,"title":"MD Anderson defines borderline resectable disease by degrees of vessel contact","refs":["resectability"]},{"year":2011,"title":"FOLFIRINOX proves active in metastatic disease and is taken up as a neoadjuvant regimen","refs":["folfirinox","paper-conroy-folfirinox-pancreatic-nejm-2011"]},{"year":2020,"title":"PREOPANC-1: neoadjuvant chemoradiation improves clear-margin resection and long-term survival","refs":["preopanc","chemoradiation"]},{"year":2022,"title":"ALLIANCE A021501: adding stereotactic radiotherapy to neoadjuvant FOLFIRINOX gives worse outcomes","refs":["sbrt","folfirinox"]},{"year":2023,"title":"ESPAC-5: neoadjuvant chemotherapy beats immediate surgery for borderline disease","refs":["gemcitabine","capecitabine","folfirinox"]},{"year":2024,"title":"PREOPANC-2: neoadjuvant FOLFIRINOX and gemcitabine chemoradiation give similar survival","refs":["preopanc","folfirinox"]}],"pipeline":["nct07252232","nct02843945","daraxonrasib","autogene-cevumeran","idea-ras-inhibitor-neoadjuvant-pdac","mr-linac","pdac-organoid-pharmacotyping","idea-tr2-organoid-coclinical-arms"],"openProblems":["Definitions of borderline disease differ between centres, so trial populations are not comparable.","CT underestimates response after chemotherapy, and there is no validated marker to tell fibrosis from viable tumour before surgery.","Whether radiotherapy adds anything after modern chemotherapy is unresolved.","Arterial resection carries high morbidity and its benefit is unproven outside expert centres."],"parent":"pancreatic"},{"id":"bowens-disease","kind":"cancer","name":"Bowen's disease (squamous cell carcinoma in situ)","aka":["Bowen disease","Bowen's disease","squamous cell carcinoma in situ","SCC in situ","cutaneous squamous cell carcinoma in situ","intraepidermal carcinoma","intraepidermal squamous cell carcinoma","in situ skin cancer","stage 0 skin cancer","D04"],"tldr":"Bowen's disease is the earliest form of squamous cell skin cancer: abnormal cells fill the outer layer of the skin but have not broken through it, so it cannot spread. It looks like a red, scaly patch, often on the lower leg, and it is usually cured by a cream, freezing, light treatment or a small operation.","summary":"What it is. Bowen's disease is squamous cell carcinoma in situ of the skin. The keratinocytes of the epidermis have become malignant across its full thickness, but the basement membrane beneath them is intact, so there is nothing for the cancer to spread through: no blood vessels and no lymphatics reach into the epidermis. Cancer Research UK describes it as pre-invasive and as a very early form of non-melanoma skin cancer that grows very slowly. In the staging system UK reports use it is the pTis category, which is stage 0.\n\nHow it differs from its parent. Invasive cutaneous squamous cell carcinoma has broken through the basement membrane into the dermis and can therefore reach lymph nodes; Bowen's disease has not and cannot. That single structural difference is the whole of the difference in outlook, and it is why the treatments are different: a lesion that cannot spread can be treated with something that destroys the epidermis, such as a cream, cryotherapy or photodynamic therapy, where an invasive cancer needs the tissue beneath it removed and examined. It differs from actinic keratosis in the other direction: an actinic keratosis is dysplasia in sun-damaged skin and is not a neoplasm at all in ICD-10, while Bowen's disease is a carcinoma, coded in the neoplasm chapter.\n\nHow it looks and where. Usually red scaly patches; the skin may look red and sore, and as the patches enlarge they can become crusty or turn into an open sore. It most often appears on the head, neck, arms, trunk and the legs, particularly the lower legs, although it can occur anywhere. The lower leg in an older woman is the classic site and also the most awkward, because skin there heals slowly, which is one of the reasons treatment is often chosen to avoid surgery.\n\nHow it is treated and what happens next. Cancer Research UK lists topical fluorouracil or imiquimod, cryotherapy, curettage and cautery, surgical excision, Mohs surgery, photodynamic therapy, radiotherapy and laser, and says that all of these can work well, with high cure rates. It has a UK national guideline of its own, the British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma in situ, published in 2022, whose first line of definition is that Bowen disease is a form of intraepidermal, in situ, squamous cell carcinoma, originally described in 1912.\n\nHow often it becomes invasive, and why two very different numbers are both right. The figure most often quoted is per lesion: the earlier British guideline stated that most studies suggest a risk of invasive carcinoma of about 3 to 5 percent for typical squamous cell carcinoma in situ, and about 10 percent for erythroplasia of Queyrat, the form on the glans penis (Morton 2014); Cancer Research UK gives the same 3 to 5 in 100 and says that most Bowen's disease does not progress. The figure the 2022 guideline cites instead is per person and counts a cancer anywhere on the body: in a Dutch national cohort of 88,754 people with squamous cell carcinoma in situ, the cumulative risk of developing an invasive squamous cell carcinoma at any site within 5 years was 11.7 percent in men and 6.9 percent in women, and the excess over the general population was highest in the first year of follow-up (Tokez 2020). Those two statements are not in conflict. The patch on the leg is very unlikely to turn into a cancer; the person who grew that patch has skin that is likely to grow a cancer somewhere.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Bowen%27s_disease","links":[{"label":"Cancer Research UK: Bowen's disease","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/types/bowens-disease"},{"label":"Sharma et al., British Journal of Dermatology 2023;188:186 to 194: British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma in situ (Bowen disease) 2022","url":"https://doi.org/10.1093/bjd/ljac042"},{"label":"Morton et al., British Journal of Dermatology 2014;170(2):245 to 260: British Association of Dermatologists' guidelines for the management of squamous cell carcinoma in situ (Bowen's disease) 2014, superseded by the 2022 version","url":"https://doi.org/10.1111/bjd.12766"},{"label":"Tokez, Wakkee, Kuijpers et al., JAMA Dermatology 2020;156(9):973 to 981: incidence of cutaneous squamous cell carcinoma in situ and the risk of developing invasive disease, 88,754 patients, the Netherlands 1989 to 2017","url":"https://doi.org/10.1001/jamadermatol.2020.1988"},{"label":"Royal College of Pathologists G124: dataset for histopathological reporting of primary invasive cutaneous squamous cell carcinoma and regional lymph nodes, version 4, February 2019 (Slater and Barrett)","url":"https://www.rcpath.org/resourceLibrary/g124datasetsquamous-pdf.html"},{"label":"WHO ICD-10 (2019): C43 to C44 melanoma and other malignant neoplasms of skin; D04 carcinoma in situ of skin; L57.0 actinic keratosis, under skin changes due to chronic exposure to nonionizing radiation","url":"https://icd.who.int/browse10/2019/en"},{"label":"IARC and the International Association of Cancer Registries: ICD-O-3.2 morphology and behaviour codes (actinic keratosis 8070/0; Bowen disease 8081/2; keratoacanthoma a related term under 8071/3; micronodular basal cell carcinoma shares 8097/3 with nodular, and sclerosing or morphoeic shares 8092/3 with infiltrating)","url":"http://www.iacr.com.fr/index.php?option=com_content&view=category&layout=blog&id=100&Itemid=577"},{"label":"van Bodegraven et al., British Journal of Dermatology 2023;188(6):777 to 784: 'Get Data Out' Skin, national cancer registry incidence and survival rates for all registered skin tumour groups for 2013 to 2019 in England","url":"https://doi.org/10.1093/bjd/ljad033"},{"label":"Royal College of Pathologists appendix A, version 3, 6 November 2025: UICC TNM 9 pathological staging of primary cutaneous carcinoma (basal cell), combining the UICC chapters for skin carcinoma of the head and neck and carcinoma of the skin","url":"https://www.rcpath.org/resourceLibrary/basal-cell-tnm9.html"},{"label":"WHO Classification of Tumours Editorial Board: Skin tumours, 5th edition, volume 12 (IARC, Lyon, 2025), ISBN 978-92-832-4535-3","url":"https://publications.iarc.who.int/Book-And-Report-Series/Who-Classification-Of-Tumours/Skin-Tumours-2025"},{"label":"Office for National Statistics: cancer registration statistics quality and methodology information (the statement that non-melanoma skin cancer is greatly under-registered, and that all-cancer figures are ICD-10 C00 to C97 excluding C44), last revised 23 February 2016","url":"https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/methodologies/cancerregistrationstatisticsqmi"}],"tags":["skin","subtype-page"],"related":["cutaneous-scc","basal-cell-carcinoma","skin-cancer","advanced-cutaneous-scc"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","dermoscopy-ai"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["actinic-keratosis","keratinocyte-cancer","keratinocyte-cancer-counting","cscc-subtype-and-grade","tnm-skin-carcinoma","skin-cancer-high-risk-features","carcinoma-in-situ","in-situ"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Is Bowen's disease cancer? The honest answer is that it is a carcinoma that cannot spread. It is coded 8081/2 in ICD-O, where the final digit means in situ, and D04, carcinoma in situ of skin, in the neoplasm chapter of ICD-10; it is staged as pTis, stage 0, by the system UK reports use; and pathologists call it squamous cell carcinoma in situ. And it is described by Cancer Research UK as pre-invasive, because the malignant cells are trapped above the basement membrane. Both halves of that are true at once, and a person told they have it has been told something that needs treating and not something that threatens their life.","Why this has a page and actinic keratosis does not, and why the answer did not change when WHO changed its mind. The corpus draws the line at the behaviour code and the registration: actinic keratosis is 8070/0, benign, and L57.0, outside the neoplasm chapter, and is registered as cancer nowhere in the UK; Bowen's disease is 8081/2, in situ, and D04, and the Office for National Statistics states that all in-situ neoplasms, D00 to D09, are registered. That line held when the fifth edition of the WHO skin classification, published in 2025, moved squamous cell carcinoma in situ out of the carcinomas section of its skin chapter and in beside actinic keratosis under carcinoma precursors and benign simulants, where the fourth edition of 2018 had filed it with the carcinomas. WHO moved the heading; the behaviour code, the registration and the guideline did not move, and neither did this page. The reasoning is set out in docs/CANCER-PAGES.md so the next borderline case is decided the same way.","Registered is not the same as counted. The Office for National Statistics registers in-situ neoplasms, and then defines all cancers as ICD-10 C00 to C97 excluding C44, which excludes both the invasive keratinocyte cancers and, being a range of C codes, anything coded D04. So Bowen's disease is recorded and then does not appear in any headline cancer figure, which is the same fate as its invasive parent for a different reason.","Why the name is a person's. John Templeton Bowen described the condition in 1912, and the eponym has outlived several attempts to replace it with the accurate description, squamous cell carcinoma in situ. Both appear on British letters, and they mean the same thing. If the report says intraepidermal carcinoma, that is also the same thing."],"group":"skin","burden":"There is no dependable UK figure, and the reason is structural rather than accidental. Bowen's disease is carcinoma in situ, coded D04 in ICD-10 and not C44, so it falls outside the non-melanoma skin cancer totals, which are themselves counted on a rule that misses repeat tumours; and it falls outside the all-cancer total too, which the Office for National Statistics defines as C00 to C97 excluding C44. The English registry registers it, because all in-situ neoplasms D00 to D09 are registered, but registration is not the same as appearing in a published figure. Any number quoted for how common it is should be read beside the counting caveat that governs this whole family.","subtypes":[],"biomarkers":["The word 'in situ' or 'intraepidermal' on the report, which is the whole diagnosis: the basement membrane is intact","pTis in the UICC staging system UK reports use, which is stage 0","Basaloid Bowen's disease, which may be the origin of the basaloid variant of invasive squamous cell carcinoma and stains weakly to focally with BerEP4 (RCPath G124)","Whether invasive squamous cell carcinoma is present alongside it, which changes the diagnosis to the invasive cancer and is itself treated as a high-risk feature"],"standardOfCare":[{"setting":"Typical lesion","approach":"Topical fluorouracil or imiquimod, cryotherapy, curettage and cautery, photodynamic therapy, surgical excision, Mohs surgery, radiotherapy or laser; Cancer Research UK states that all of these can work well and that cure rates are high. The choice is driven by the site, the size, how well the skin there heals and what the person can manage at home. The treatment layer of this family carries the detail.","refs":["fluorouracil","imiquimod","aminolevulinic-acid","mohs-surgery"],"guideline":{"version":"British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma in situ (Bowen disease) 2022","url":"https://doi.org/10.1093/bjd/ljac042"}},{"setting":"If invasion is found","approach":"The diagnosis becomes invasive cutaneous squamous cell carcinoma and is managed on that pathway, with the adjacent Bowen's disease itself usually counted as a high-risk feature of the invasive tumour (RCPath G124). See the cutaneous squamous cell carcinoma page.","refs":["wide-local-excision","mohs-surgery"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":["Nobody knows how common it is. Carcinoma in situ of the skin sits outside the non-melanoma skin cancer totals, and those totals are themselves counted on a rule that misses repeat tumours, so there is no dependable national figure for a diagnosis many thousands of people are given every year.","The 3 to 5 percent who progress cannot be identified in advance. There is no marker that separates the lesion that will become invasive from the one that will not, so everybody is treated, and most of that treatment is for lesions that would never have caused harm.","The lower leg is the commonest site and the hardest to treat, because wounds there heal slowly in the people who most often have the disease. The evidence base for choosing between the destructive treatments at that site is thin."],"parent":"cutaneous-scc"},{"id":"braf-v600-melanoma","kind":"cancer","name":"BRAF V600-mutant melanoma","aka":["BRAF-mutant melanoma","BRAF V600E melanoma","BRAF V600K melanoma","BRAF-positive melanoma"],"tldr":"BRAF V600-mutant melanoma has a single faulty switch that drives it to grow, and two pills, a BRAF inhibitor with a MEK inhibitor, can shut that switch off and shrink the cancer within weeks. Immunotherapy is usually given first because its effect lasts longer, and the pills are kept for later or given for a year after surgery to prevent relapse.","summary":"BRAF V600 mutations lock the BRAF kinase on and drive the MAPK pathway, and every melanoma beyond stage I is tested for them. Vemurafenib was the first inhibitor (BRIM-3, 2011): it shrank about half of tumours where dacarbazine shrank one in twenty, but responses lasted a median of six to seven months, resistance came through MAPK reactivation, and paradoxical pathway activation in normal skin caused squamous cell carcinomas. Adding a MEK inhibitor deepened the responses and removed most of that toxicity.\n\nCOMBI-d (dabrafenib-trametinib, median overall survival 25.1 against 18.7 months), coBRIM (vemurafenib-cobimetinib, 22.3 against 17.4 months) and COLUMBUS (encorafenib-binimetinib, progression-free survival 14.9 against 7.3 months and median overall survival 33.6 months) established three doublets; a pooled analysis of COMBI-d and COMBI-v found 34 percent of patients alive at five years. DREAMseq then settled the order question: starting with nivolumab plus ipilimumab and switching to dabrafenib-trametinib at progression gave two-year survival of 71.8 percent against 51.5 percent for the reverse sequence, because targeted therapy still works after immunotherapy while immunotherapy after targeted-therapy failure works poorly. Targeted therapy is now used first only when the disease is growing so fast or so symptomatically that a response within weeks is needed. IMspire150 added atezolizumab to vemurafenib-cobimetinib and lengthened progression-free survival (15.1 against 10.6 months) without a clear survival gain, and the triplet is little used.\n\nAfter surgery for stage III disease a year of dabrafenib-trametinib halved the relapse risk in COMBI-AD (ten-year relapse-free survival 48 against 32 percent) and is the alternative to adjuvant PD-1 blockade for BRAF-mutant patients. In the brain, dabrafenib-trametinib produced intracranial responses in 58 percent of patients in COMBI-MB, though shorter-lived than in the body. Resistance arises through NRAS mutations, BRAF amplification or splice variants and MEK1 mutations that reactivate the pathway, and rechallenge after a break can work again; next-generation RAF dimer inhibitors and combinations with ERK inhibitors are in trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/BRAF_(gene)","links":[{"label":"COMBI-d final analysis (Lancet 2015)","url":"https://doi.org/10.1016/S0140-6736(15)60898-4"},{"label":"DREAMseq (JCO 2023)","url":"https://ascopubs.org/doi/10.1200/JCO.22.01763"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/BRAF_(gene)"}],"tags":["subtype-page"],"related":["secondary-brain-tumours","advanced-melanoma","stage-iii-melanoma","stage-ii-melanoma","acral-melanoma","mucosal-melanoma"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","checkpoint-inhibitor"],"targets":["braf","mek"],"drugs":["dabrafenib","trametinib","dabrafenib-trametinib","encorafenib","binimetinib","vemurafenib","cobimetinib"],"companies":[],"institutions":[],"pathways":["ras-mapk","melanoma-signalling"],"terms":["braf-v600-mutation"],"trials":["combi-d","cobrim","columbus","combi-ad","dreamseq","imspire150"],"people":["keith-flaherty","georgina-long","paolo-ascierto"],"bottlenecks":[],"keyPapers":["paper-dreamseq-jco-2023","paper-combi-d-long-lancet-2015","paper-columbus-lancet-oncol-2018","paper-combi-ad-nejm-2017","paper-chapman-vemurafenib-nejm-2011"],"journals":[],"dependsOn":[],"notes":[],"group":"skin","burden":"About half of cutaneous melanomas carry a BRAF V600 mutation, most often V600E, less often V600K; it is commoner in younger patients and in melanomas on skin without chronic sun damage, and rare in acral and mucosal melanoma.","subtypes":["BRAF V600E-mutant melanoma (about nine in ten BRAF-mutant cases)","BRAF V600K-mutant melanoma (older patients, more sun damage, shorter responses)","BRAF non-V600 or class 2 and 3 mutations (do not respond to V600 inhibitors)","BRAF-mutant melanoma after immunotherapy (targeted therapy second line)","BRAF-mutant melanoma with brain metastases (COMBI-MB)"],"biomarkers":["BRAF V600 mutation by sequencing or immunohistochemistry (required for targeted therapy)","Lactate dehydrogenase (prognostic for targeted therapy benefit)","Number of metastatic sites (fewer than three predicts long-term benefit)","NRAS, MEK1 and BRAF splice variants at resistance","Circulating tumour DNA BRAF V600 for response monitoring (trials)"],"standardOfCare":[{"setting":"Advanced, first line","approach":"Nivolumab plus ipilimumab or nivolumab plus relatlimab first (DREAMseq); dabrafenib-trametinib, encorafenib-binimetinib or vemurafenib-cobimetinib first only when a rapid response is needed.","refs":["dreamseq","checkmate-067","relatlimab-nivolumab","dabrafenib-trametinib","encorafenib","binimetinib","vemurafenib","cobimetinib"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Advanced, after immunotherapy","approach":"BRAF plus MEK inhibitor doublet (COMBI-d, coBRIM, COLUMBUS); encorafenib-binimetinib has the longest median survival and least fever of the three.","refs":["combi-d","cobrim","columbus","dabrafenib","trametinib","encorafenib","binimetinib"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Resected stage III","approach":"A year of adjuvant dabrafenib-trametinib (COMBI-AD) or of adjuvant nivolumab or pembrolizumab; neoadjuvant immunotherapy for macroscopic nodal disease.","refs":["combi-ad","dabrafenib-trametinib","nivolumab","pembrolizumab","nadina"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Brain metastases","approach":"Nivolumab plus ipilimumab for asymptomatic lesions (CheckMate 204); dabrafenib-trametinib when a fast intracranial response is needed (COMBI-MB); radiosurgery for symptomatic or progressing lesions.","refs":["checkmate-204","dabrafenib-trametinib","radiosurgery-srs","secondary-brain-tumours"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Triplet therapy","approach":"Atezolizumab with vemurafenib-cobimetinib (IMspire150) is approved but little used because it lengthened progression-free survival without a clear survival gain.","refs":["atezolizumab","vemurafenib","cobimetinib"]}],"stateOfArt":["Three BRAF plus MEK doublets give response rates of about two thirds and a third of patients alive at five years in metastatic disease.","DREAMseq established immunotherapy first and targeted therapy second as the standard sequence.","Adjuvant dabrafenib-trametinib halves relapse risk after surgery for stage III disease with benefit still visible at ten years."],"history":[{"year":2002,"title":"BRAF mutations found in about half of melanomas (Davies and colleagues, Nature)","refs":["braf"]},{"year":2011,"title":"BRIM-3: vemurafenib beats dacarbazine; first BRAF inhibitor approved","refs":["vemurafenib","dacarbazine"]},{"year":2013,"title":"Dabrafenib and trametinib approved as single agents","refs":["dabrafenib","trametinib"]},{"year":2014,"title":"COMBI-d and coBRIM: BRAF plus MEK doublets beat BRAF inhibitor alone","refs":["combi-d","cobrim","dabrafenib-trametinib"]},{"year":2017,"title":"COMBI-AD: adjuvant dabrafenib-trametinib halves relapse risk; COMBI-MB shows intracranial responses","refs":["combi-ad","dabrafenib-trametinib"]},{"year":2018,"title":"COLUMBUS: encorafenib-binimetinib approved","refs":["columbus","encorafenib","binimetinib"]},{"year":2020,"title":"IMspire150: atezolizumab triplet approved on progression-free survival","refs":["atezolizumab"]},{"year":2021,"title":"DREAMseq: immunotherapy first, targeted therapy second","refs":["dreamseq"]}],"pipeline":["seacraft-2","naporafenib","nct07449754","nct04417621","nct04657991","idea-ctdna-guided-adjuvant-melanoma"],"openProblems":["Responses to targeted therapy are almost universal but most are not durable, and resistance through MAPK reactivation has no approved answer.","Whether a short targeted-therapy induction before immunotherapy helps has not been settled in a phase 3 trial.","BRAF V600K and non-V600 mutations respond less well and have no dedicated drugs."],"parent":"melanoma"},{"id":"braf-v600e-colorectal","kind":"cancer","name":"BRAF V600E-mutant colorectal cancer","aka":["BRAF-mutant colorectal cancer","BRAF V600E metastatic colorectal cancer","BRAF-mutated bowel cancer"],"tldr":"BRAF V600E bowel cancer carries the same mutation as many melanomas, but BRAF drugs alone did nothing here because the tumour re-routes its growth signal through EGFR. Blocking both with encorafenib and cetuximab, now given with chemotherapy from the start, has doubled survival in a subtype that used to be the worst.","summary":"BRAF V600E locks the RAS-MAPK pathway on, and in colorectal cancer it arises in the serrated pathway with CpG island methylation; about a third of localised BRAF-mutant tumours are also mismatch-repair deficient, in which case the immunotherapy of that subtype applies and the outlook is good. Microsatellite-stable BRAF V600E disease is different: it is often right-sided, presents with peritoneal and nodal spread, responds poorly to chemotherapy, and anti-EGFR antibodies alone do not work. Non-V600 BRAF mutations, about 2 percent of cancers, behave as a separate and less aggressive group.\n\nSingle-agent vemurafenib failed in 2011 because inhibiting BRAF in bowel cells releases feedback activation of EGFR; blocking both proved the answer. BEACON CRC (2019) randomised 665 previously treated patients to encorafenib and cetuximab with or without binimetinib against chemotherapy plus cetuximab: median survival was 9.3 months with either targeted regimen against 5.9 months, response rates were 20 to 27 percent against 2 percent, and the FDA approved encorafenib with cetuximab in April 2020. BREAKWATER (2024 to 2025) then moved the doublet into first line with mFOLFOX6: the response rate was 61 percent against 40 percent for chemotherapy and median survival 30.3 months against 15.1 months, which brought accelerated approval in December 2024 and full approval in 2026.\n\nThe next questions are whether to add a PD-1 antibody (SEAMARK, encorafenib-cetuximab-pembrolizumab in mismatch-repair deficient BRAF disease), how to treat after progression on the targeted doublet, when MAPK reactivation and MET amplification drive resistance, and whether the triplet should be given in the adjuvant setting for stage III disease.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/BRAF_(gene)","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/BRAF_(gene)"},{"label":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}],"tags":["subtype-page"],"related":["early-onset-colorectal","her2-amplified-colorectal","kras-g12c-colorectal","msi-high-colorectal","rectal-cancer"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","monoclonal-antibody","checkpoint-inhibitor","liquid-biopsy"],"targets":["braf","egfr","mek","pd1"],"drugs":["encorafenib","cetuximab","binimetinib","folfox","pembrolizumab"],"companies":[],"institutions":[],"pathways":["ras-mapk","colorectal-cancer-signalling"],"terms":["msi","sidedness","cms-subtypes","ctdna"],"trials":["beacon-crc","breakwater","nct05217446","nct06008119"],"people":["scott-kopetz","josep-tabernero","elena-elez"],"bottlenecks":[],"keyPapers":["paper-breakwater-nejm-2025","paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019","paper-cms-guinney-nat-med-2015"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 8 to 10 percent of colorectal cancers carry BRAF V600E; they are commoner in older women and right-sided tumours, are often mismatch-repair deficient when localised, and when metastatic and microsatellite-stable have had among the shortest survival of any colorectal subtype.","subtypes":["BRAF V600E, microsatellite-stable (the aggressive majority; targeted therapy with encorafenib and cetuximab)","BRAF V600E with mismatch-repair deficiency (right-sided; immunotherapy first)","BRAF non-V600 (class 2 and 3) mutations, a distinct and less aggressive group","Right-sided serrated-pathway tumours with CpG island methylation"],"biomarkers":["BRAF V600E by sequencing or VE1 immunohistochemistry","Mismatch repair status (immunotherapy if deficient)","RAS wild-type by definition; co-mutations rare","Consensus molecular subtype 1 enrichment","Circulating tumour DNA to track MAPK reactivation on treatment"],"standardOfCare":[{"setting":"Metastatic, microsatellite-stable, first line","approach":"Encorafenib plus cetuximab plus mFOLFOX6 (BREAKWATER); encorafenib plus cetuximab alone for patients unfit for chemotherapy.","refs":["breakwater","encorafenib","cetuximab","folfox","kinase-inhibitors"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Metastatic, previously treated","approach":"Encorafenib plus cetuximab (BEACON CRC) if not already given; then trifluridine-tipiracil with bevacizumab, fruquintinib or regorafenib.","refs":["beacon-crc","encorafenib","cetuximab","trifluridine-tipiracil","fruquintinib","regorafenib"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Metastatic, mismatch-repair deficient","approach":"Checkpoint blockade first (pembrolizumab, or nivolumab plus ipilimumab); BRAF-targeted therapy at progression.","refs":["pembrolizumab","nivolumab","ipilimumab","keynote-177","checkmate-8hw"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Localised","approach":"Surgery and stage-based adjuvant FOLFOX or CAPOX as for colorectal cancer; BRAF status does not yet change adjuvant treatment outside trials.","refs":["folfox","capox","oxaliplatin"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}}],"stateOfArt":["Encorafenib plus cetuximab with FOLFOX in first line (BREAKWATER) doubles survival against chemotherapy.","The EGFR-feedback mechanism explained a decade of failed BRAF monotherapy and is the template for vertical pathway blockade.","Mismatch-repair deficient BRAF tumours get immunotherapy, not targeted therapy, first."],"history":[{"year":2002,"title":"BRAF mutations discovered in human cancer (Davies, Nature)","refs":["braf"]},{"year":2011,"title":"Vemurafenib alone fails in BRAF-mutant colorectal cancer; EGFR feedback identified the next year","refs":["braf","egfr","scott-kopetz"]},{"year":2019,"title":"BEACON CRC: encorafenib plus cetuximab improves survival after prior therapy","refs":["beacon-crc","encorafenib","cetuximab"]},{"year":2020,"title":"FDA approves encorafenib with cetuximab, the first targeted therapy for the subtype","refs":["encorafenib"]},{"year":2024,"title":"BREAKWATER: encorafenib-cetuximab-FOLFOX first line; accelerated approval in December","refs":["breakwater"]},{"year":2025,"title":"BREAKWATER overall survival 30.3 versus 15.1 months","refs":["breakwater","scott-kopetz","elena-elez"]},{"year":2026,"title":"Full approval of the first-line triplet","refs":["encorafenib","breakwater"]}],"pipeline":["nct05217446","nct06008119","breakwater","encorafenib"],"openProblems":["No standard therapy after progression on encorafenib and cetuximab.","Resistance through MAPK reactivation and MET amplification is common and untargeted.","Adjuvant use of the targeted doublet in stage III disease is untested.","Non-V600 BRAF mutations have no approved targeted option."],"parent":"colorectal"},{"id":"braf-v600e-nsclc","kind":"cancer","name":"BRAF V600E-mutant non-small-cell lung cancer","aka":["BRAF-mutant lung cancer","BRAF V600E NSCLC","BRAF V600-mutated lung adenocarcinoma"],"tldr":"BRAF V600E lung cancer carries the same mutation as many melanomas and is treated with the same pairs of pills that block BRAF and MEK together. Dabrafenib with trametinib and encorafenib with binimetinib each shrink about two thirds to three quarters of untreated tumours.","summary":"BRAF V600E lung cancer was recognised as a targetable subtype after the melanoma experience, in which BRAF inhibitors alone produced responses that were quickly lost through MEK reactivation and paradoxical pathway activation, so combined BRAF and MEK blockade became the rule. In the phase 2 BRF113928 study dabrafenib plus trametinib produced response rates of 64 percent in treatment-naive and 63 percent in previously treated patients with median progression-free survival of about 10 months, and the FDA approved the combination for BRAF V600E lung cancer in June 2017, the first targeted therapy for this driver.\n\nPHAROS (2023) tested encorafenib plus binimetinib in the same population: response rates of 75 percent in 59 treatment-naive and 46 percent in 39 previously treated patients, with fewer of the fevers that interrupt dabrafenib and trametinib, and the combination was approved in October 2023. Both pairs are given until progression; pyrexia, fatigue, nausea, rash and cardiac and eye toxicity are monitored. BRAF V600E lung cancers often express PD-L1 and, unlike EGFR or ALK disease, respond to checkpoint inhibitors, so chemoimmunotherapy is a reasonable alternative first line and the standard afterwards.\n\nNon-V600 BRAF mutations (class II and III), the other half of BRAF-mutant lung cancers, do not respond to BRAF plus MEK inhibitors and are treated as driver-negative disease; MEK inhibitors and pan-RAF inhibitors are in trials for them. Open questions are the sequence of targeted therapy and immunotherapy and how to treat resistance, which usually arises through reactivation of the MAPK pathway.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/BRAF_(gene)","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/BRAF_(gene)"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":["kras-g12c-nsclc","egfr-mutant-nsclc","her2-mutant-nsclc","met-altered-nsclc","ret-fusion-nsclc","ros1-positive-nsclc"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","checkpoint-inhibitor","cgp"],"targets":["braf","pd1","pdl1"],"drugs":["dabrafenib-trametinib","dabrafenib","trametinib","encorafenib","binimetinib","pembrolizumab"],"companies":["novartis","pfizer"],"institutions":[],"pathways":["ras-mapk","nsclc-signalling"],"terms":["braf-v600-mutation","driver-mutation","resistance","tps"],"trials":["pharos"],"people":["david-planchard"],"bottlenecks":[],"keyPapers":["paper-planchard-dabrafenib-trametinib-braf-nsclc-lancet-oncol-2016","paper-planchard-dabrafenib-trametinib-first-line-lancet-oncol-2017","paper-pharos-encorafenib-binimetinib-riely-jco-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"BRAF mutations occur in 2 to 4 percent of non-small-cell lung cancers, about half of them V600E; unlike most drivers they are found in current or former smokers as often as in never-smokers.","subtypes":["BRAF V600E adenocarcinoma, treatment-naive (BRAF plus MEK inhibitor or chemoimmunotherapy)","BRAF V600E adenocarcinoma after chemotherapy or immunotherapy","Non-V600 BRAF mutations, class II and III (not sensitive to BRAF inhibitors)"],"biomarkers":["BRAF V600E by sequencing (immunohistochemistry as a screen)","BRAF mutation class (V600 versus non-V600)","PD-L1 tumour proportion score (immunotherapy is active in BRAF-mutant disease)","Left ventricular function, eye examination and temperature on BRAF plus MEK inhibitors"],"standardOfCare":[{"setting":"Advanced BRAF V600E, first line","approach":"Dabrafenib plus trametinib or encorafenib plus binimetinib (PHAROS); pembrolizumab with platinum doublet is an alternative, particularly with high PD-L1.","refs":["dabrafenib-trametinib","dabrafenib","trametinib","encorafenib","binimetinib","pharos","pembrolizumab","braf-v600-mutation"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced BRAF V600E, after targeted therapy","approach":"Pembrolizumab plus platinum doublet, or the other BRAF plus MEK pair if the first was stopped for toxicity rather than progression.","refs":["pembrolizumab","carboplatin","pemetrexed","encorafenib","binimetinib"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Non-V600 BRAF mutations","approach":"Treated as driver-negative disease with chemoimmunotherapy; MEK or pan-RAF inhibitor trials.","refs":["pembrolizumab","carboplatin","pemetrexed","trametinib"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Two approved BRAF plus MEK inhibitor pairs with response rates of 64 to 75 percent in untreated disease.","Immunotherapy is active, giving a genuine choice of sequence unlike most driver subtypes.","Non-V600 mutations remain without a targeted drug."],"history":[{"year":2002,"title":"BRAF V600E mutations discovered across cancers, including a small share of lung cancers","refs":["braf","braf-v600-mutation"]},{"year":2017,"title":"Dabrafenib plus trametinib approved for BRAF V600E lung cancer after BRF113928","refs":["dabrafenib-trametinib","david-planchard","novartis"]},{"year":2023,"title":"PHAROS: encorafenib plus binimetinib approved","refs":["pharos","encorafenib","binimetinib","pfizer"]}],"pipeline":["pharos","encorafenib","binimetinib"],"openProblems":["No randomised trial compares BRAF plus MEK inhibitors with chemoimmunotherapy first line or settles the sequence.","Non-V600 BRAF mutations, half of cases, have no approved targeted therapy.","Resistance through MAPK reactivation has no established next step."],"parent":"nsclc"},{"id":"brain-tumours","kind":"cancer","name":"Brain and spinal cord tumours (all types)","aka":["Brain Tumors","Brain tumors","CNS tumours","Central nervous system tumours","Brain cancer"],"tldr":"Brain and spinal cord tumours range from slow-growing meningiomas and low-grade gliomas to glioblastoma, the commonest malignant brain tumour in adults, and a distinct set of childhood tumours such as medulloblastoma and diffuse midline glioma. Molecular markers now define them, and treatment is surgery, radiotherapy and, for some, drugs chosen by those markers.","summary":"Tumours of the brain and spinal cord are classified by the WHO by cell type and, since 2016 and more so in 2021, by molecular markers such as IDH mutation, 1p/19q codeletion, H3 K27 alteration and MGMT methylation. In adults the main groups are gliomas (from IDH-mutant low-grade astrocytomas and oligodendrogliomas to IDH-wildtype glioblastoma), meningiomas, pituitary tumours and primary CNS lymphoma; in children, medulloblastoma, ependymoma, low-grade gliomas, diffuse midline glioma and rare embryonal tumours dominate. Surgery as complete as function allows, radiotherapy and temozolomide remain the backbone; targeted drugs such as vorasidenib for IDH-mutant glioma and BRAF and MEK inhibitors for BRAF-altered paediatric glioma are the first molecular therapies to change practice. The blood-brain barrier and the impossibility of wide margins make these among the hardest cancers to treat, which is why the subtype pages give the detail.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Brain_tumor","links":[{"label":"NCI: Brain tumors","url":"https://www.cancer.gov/types/brain"},{"label":"GLOBOCAN 2020 (Sung 2021)","url":"https://doi.org/10.3322/caac.21660"}],"tags":["umbrella"],"related":["glioblastoma","dipg-dmg","medulloblastoma","ependymoma","craniopharyngioma","atrt","paediatric-low-grade-glioma","primary-cns-lymphoma","idh-mutant-astrocytoma","oligodendroglioma","meningioma","secondary-brain-tumours","paediatric-high-grade-glioma","spinal-cord-tumours","vestibular-schwannoma","cns-germ-cell-tumours","pituitary-tumours"],"cancers":[],"sections":[],"technologies":["bbb-focused-ultrasound"],"targets":["idh","braf","mek"],"drugs":["temozolomide","vorasidenib","dabrafenib","trametinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["alliance-n0574","nrg-cc001","catnon","rtog-9402","eortc-26951","eortc-22033","nct06496971","nct04365374"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"central nervous system","burden":"About 308,000 new cases and 251,000 deaths worldwide in 2020 (GLOBOCAN) for brain and central nervous system cancers; the leading cause of cancer death in children in many high-income countries.","subtypes":["Glioblastoma (IDH-wildtype)","IDH-mutant astrocytoma and oligodendroglioma","Paediatric low-grade glioma","Diffuse midline glioma (DIPG)","Medulloblastoma","Ependymoma","Atypical teratoid/rhabdoid tumour","Craniopharyngioma","Meningioma","Primary CNS lymphoma","Brain metastases (from other cancers)","Paediatric high-grade glioma","Vestibular schwannoma","Spinal cord tumours","CNS germ cell tumours","Pituitary tumours"],"biomarkers":["IDH1/IDH2 mutation","1p/19q codeletion","MGMT promoter methylation","H3 K27M alteration","BRAF V600E and KIAA1549::BRAF fusion in paediatric glioma","Molecular subgroups of medulloblastoma (WNT, SHH, group 3, group 4)"],"standardOfCare":[{"setting":"Glioblastoma","approach":"Maximal safe resection, radiotherapy with concurrent and adjuvant temozolomide (Stupp regimen), tumour-treating fields as an option. See the glioblastoma page.","refs":["temozolomide"]},{"setting":"IDH-mutant low-grade glioma","approach":"Surgery, then observation or vorasidenib for grade 2 tumours, radiotherapy and chemotherapy for higher risk.","refs":["vorasidenib"]},{"setting":"Childhood tumours","approach":"Risk-adapted surgery, radiotherapy and chemotherapy by subgroup; BRAF and MEK inhibitors for BRAF-altered low-grade glioma. See the medulloblastoma, ependymoma and DIPG pages.","refs":["dabrafenib","trametinib"]}],"stateOfArt":[],"history":[{"year":2005,"title":"Temozolomide chemoradiation becomes the glioblastoma standard","note":"The Stupp trial showed radiotherapy with concurrent and adjuvant temozolomide prolonged survival.","refs":["temozolomide"]},{"year":2016,"title":"WHO classification adds molecular markers","note":"IDH mutation, 1p/19q codeletion and H3 K27M began to define brain tumour types alongside microscopy; extended in 2021.","refs":[]},{"year":2024,"title":"Vorasidenib approved for IDH-mutant glioma","note":"First targeted drug for grade 2 astrocytoma and oligodendroglioma after surgery (INDIGO trial).","refs":["vorasidenib"]}],"pipeline":["dordaviprone","tovorafenib","emavusertib"],"openProblems":["Drugs rarely cross the blood-brain barrier at useful concentrations.","Median survival in diffuse midline glioma is still about a year.","Cognitive late effects of radiotherapy in children."]},{"id":"secondary-brain-tumours","kind":"cancer","name":"Brain metastases (secondary brain tumours)","aka":["Brain metastases","Secondary brain cancer","Intracranial metastases","Cerebral metastases","Brain mets"],"tldr":"Brain metastases are cancers that have spread to the brain from elsewhere, most often from the lung, breast or skin. Focused radiation aimed at each spot (radiosurgery) has largely replaced radiation to the whole brain, and for some cancers modern targeted drugs and immunotherapy reach the brain well enough to shrink the deposits on their own.","summary":"Brain metastases seed the grey-white junction and watershed zones through the arterial circulation; they are recognised on contrast MRI and, with a known primary, rarely need biopsy. Prognosis depends on the primary, its molecular subtype, performance status, extracranial disease and number of lesions (graded prognostic assessment). Dexamethasone relieves oedema. Management has moved in twenty years from whole-brain radiotherapy for nearly everyone to a choice among surgery, stereotactic radiosurgery, systemic therapy with brain penetration and, for some, no brain-directed treatment at all.\n\nSurgery is used for a large or symptomatic single lesion or when tissue is needed (Patchell, 1990), followed by radiosurgery to the cavity rather than whole-brain radiotherapy (N107C, 2017). For a limited number of metastases, Alliance N0574 (JAMA 2016) showed that adding whole-brain radiotherapy to radiosurgery worsened cognition at three months in 91.7 percent of patients against 63.5 percent with radiosurgery alone, without lengthening survival, and radiosurgery alone is now standard for up to four lesions and increasingly for more. When whole-brain radiotherapy is still used, NRG CC001 (JCO 2020) showed hippocampal avoidance with memantine preserves cognition. QUARTZ (Lancet 2016) found no meaningful gain in quality-adjusted survival from whole-brain radiotherapy in non-small cell lung cancer patients unsuited to surgery or radiosurgery, so best supportive care alone is legitimate in poor-prognosis patients.\n\nSystemic therapy now controls brain disease in several subtypes: osimertinib in EGFR-mutant and lorlatinib in ALK-positive lung cancer (CROWN), tucatinib with trastuzumab and capecitabine (HER2CLIMB) and trastuzumab deruxtecan (DESTINY-Breast12) in HER2-positive breast cancer, nivolumab plus ipilimumab in melanoma (CheckMate 204) and dabrafenib plus trametinib in BRAF-mutant melanoma (COMBI-MB), so asymptomatic small metastases in these groups are often treated with drugs first and radiosurgery held in reserve. Trials have historically excluded patients with brain metastases; their inclusion, the management of leptomeningeal disease, radionecrosis after radiosurgery, and drugs designed to cross the blood-brain barrier are the open fronts.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Brain_metastasis","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Brain_metastasis"},{"label":"Alliance N0574: radiosurgery with or without whole-brain radiotherapy (JAMA 2016)","url":"https://doi.org/10.1001/jama.2016.9839"},{"label":"QUARTZ (Lancet 2016)","url":"https://doi.org/10.1016/S0140-6736(16)30825-X"}],"tags":["subtype-page","cns"],"related":["brain-tumours","metastatic-cancer","nsclc","breast-her2-positive","melanoma","glioblastoma","meningioma","spinal-cord-tumours"],"cancers":[],"sections":[],"technologies":["radiosurgery-srs","gamma-knife","cyberknife","imrt-igrt","mri","bbb-focused-ultrasound"],"targets":[],"drugs":["dexamethasone","osimertinib","lorlatinib","alectinib","tucatinib","trastuzumab-deruxtecan","nivolumab","ipilimumab","dabrafenib-trametinib","memantine"],"companies":[],"institutions":[],"pathways":[],"terms":["brain-metastases","wbrt","stereotactic-radiosurgery","blood-brain-barrier","her2-brain-metastases","leptomeningeal-disease","graded-prognostic-assessment"],"trials":["alliance-n0574","nrg-cc001","quartz","her2climb","destiny-breast12","crown"],"people":[],"bottlenecks":[],"keyPapers":["paper-alliance-n0574-brown-jama-2016","paper-n107c-brown-lancet-oncol-2017","paper-nrg-cc001-brown-jco-2020","paper-quartz-lancet-2016"],"journals":[],"dependsOn":[],"notes":[],"group":"central nervous system","burden":"The commonest intracranial tumour in adults, many times more frequent than primary brain tumours; lung cancer, breast cancer, melanoma, kidney cancer and bowel cancer account for most, and incidence is rising as people live longer with systemic disease.","subtypes":["Brain metastases from non-small cell lung cancer (EGFR, ALK and other driver subsets)","Brain metastases from breast cancer (HER2-positive, triple-negative)","Brain metastases from melanoma","Brain metastases from kidney, bowel and other cancers","Solitary brain metastasis (surgical candidate)","Multiple brain metastases (radiosurgery or whole-brain radiotherapy)","Leptomeningeal metastases (cerebrospinal fluid spread)"],"biomarkers":["Primary tumour type and its driver (EGFR, ALK, HER2, BRAF, PD-L1)","Number, size and location of lesions on contrast MRI","Graded prognostic assessment (age, performance status, extracranial disease, lesion count, molecular subtype)","Cerebrospinal fluid cytology and cell-free DNA for leptomeningeal disease","Distinguishing radionecrosis from progression (perfusion MRI, amino acid PET)"],"standardOfCare":[{"setting":"Symptomatic oedema","approach":"Dexamethasone, tapered as quickly as symptoms allow; anticonvulsants only after a seizure.","refs":["dexamethasone"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Single large or symptomatic lesion, fit patient","approach":"Surgical resection followed by radiosurgery to the cavity (N107C) rather than whole-brain radiotherapy.","refs":["radiosurgery-srs"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Limited number of metastases","approach":"Stereotactic radiosurgery alone (Alliance N0574); whole-brain radiotherapy withheld because it worsens cognition without lengthening life.","refs":["radiosurgery-srs","gamma-knife","cyberknife","alliance-n0574"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Many metastases or leptomeningeal spread","approach":"Hippocampal-avoidance whole-brain radiotherapy with memantine (NRG CC001) where whole-brain treatment is chosen; radiosurgery to many lesions in selected patients; best supportive care alone in poor-prognosis lung cancer (QUARTZ).","refs":["wbrt","nrg-cc001","quartz","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Driver-positive lung cancer, asymptomatic metastases","approach":"Brain-penetrant targeted therapy first: osimertinib (EGFR), lorlatinib or alectinib (ALK); radiosurgery for progression.","refs":["osimertinib","lorlatinib","alectinib","crown"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"HER2-positive breast cancer","approach":"Tucatinib with trastuzumab and capecitabine (HER2CLIMB) or trastuzumab deruxtecan (DESTINY-Breast12), with local therapy for symptomatic lesions.","refs":["tucatinib","trastuzumab-deruxtecan","her2climb","destiny-breast12"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Melanoma","approach":"Nivolumab plus ipilimumab for asymptomatic metastases (CheckMate 204); dabrafenib plus trametinib for BRAF V600-mutant disease (COMBI-MB); radiosurgery for symptomatic or progressing lesions.","refs":["nivolumab","ipilimumab","dabrafenib-trametinib","radiosurgery-srs"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}}],"stateOfArt":["Radiosurgery alone has replaced whole-brain radiotherapy for limited disease because it spares cognition without costing survival.","Several targeted drugs and immunotherapy doublets now control brain metastases well enough to be used before radiation.","Whole-brain radiotherapy, once universal, is now reserved for extensive disease and given with hippocampal avoidance and memantine."],"history":[{"year":1954,"title":"Whole-brain radiotherapy reported for brain metastases","note":"Chao and colleagues describe palliative irradiation of cerebral metastases.","refs":["wbrt"]},{"year":1990,"title":"Patchell: surgery plus whole-brain radiotherapy beats radiotherapy alone for a single metastasis (NEJM)","refs":[]},{"year":2004,"title":"RTOG 9508: radiosurgery boost improves function and, for single lesions, survival","refs":["radiosurgery-srs"]},{"year":2016,"title":"Alliance N0574: radiosurgery alone preserves cognition","note":"Brown and colleagues (JAMA): cognitive deterioration at three months in 63.5 percent with radiosurgery alone against 91.7 percent with added whole-brain radiotherapy; no survival difference.","refs":["alliance-n0574","radiosurgery-srs"]},{"year":2016,"title":"QUARTZ: no quality-adjusted survival gain from whole-brain radiotherapy in poor-prognosis lung cancer","refs":["quartz","wbrt"]},{"year":2017,"title":"N107C: radiosurgery to the surgical cavity replaces post-operative whole-brain radiotherapy","refs":["radiosurgery-srs"]},{"year":2018,"title":"CheckMate 204: nivolumab plus ipilimumab active in melanoma brain metastases","refs":["nivolumab","ipilimumab"]},{"year":2020,"title":"NRG CC001: hippocampal-avoidance whole-brain radiotherapy with memantine preserves cognition","refs":["nrg-cc001"]},{"year":2020,"title":"HER2CLIMB: tucatinib triplet benefits patients with HER2-positive brain metastases","refs":["tucatinib","her2climb"]},{"year":2024,"title":"DESTINY-Breast12: trastuzumab deruxtecan active in HER2-positive brain metastases","refs":["trastuzumab-deruxtecan","destiny-breast12"]}],"pipeline":["trastuzumab-deruxtecan","tucatinib","lorlatinib","bbb-focused-ultrasound","radiosurgery-srs"],"openProblems":["Trials still often exclude patients with brain metastases, so drug activity in the brain is learned late.","Leptomeningeal disease has no standard treatment and a survival of months.","Radionecrosis after radiosurgery is hard to tell from progression and hard to treat.","Few drugs are designed from the start to cross the blood-brain barrier."],"parent":"brain-tumours"},{"id":"brca-palb2-pdac","kind":"cancer","name":"BRCA or PALB2-mutant pancreatic ductal adenocarcinoma","aka":["BRCA-mutated pancreatic cancer","gBRCA pancreatic cancer","Homologous recombination deficient pancreatic cancer","PALB2-mutant pancreatic cancer"],"tldr":"BRCA or PALB2-mutant pancreatic cancer is pancreatic cancer in someone who inherited a faulty copy of a gene that repairs broken DNA. These tumours respond better to platinum chemotherapy, and the POLO trial showed that the PARP inhibitor olaparib, taken after platinum has held the disease, delays its return; that made it the first targeted drug approved for a pancreatic cancer subgroup.","summary":"BRCA1, BRCA2 and PALB2 encode proteins of homologous recombination repair. Tumours that have lost both copies cannot repair double-strand DNA breaks accurately, which makes them sensitive to platinum drugs that create such breaks and to PARP inhibitors, which trap the repair enzyme PARP on DNA and are lethal to cells without homologous recombination (synthetic lethality). Germline carriers develop pancreatic cancer at a younger age and carry risks of breast, ovarian and prostate cancer for themselves and their relatives, so a diagnosis triggers cascade testing of the family and, for unaffected carriers, consideration of pancreatic surveillance in a research programme.\n\nRetrospective series and the platinum-containing arms of trials showed that carriers live longer on FOLFIRINOX or gemcitabine plus cisplatin than on non-platinum regimens, and a randomised phase 2 found gemcitabine plus cisplatin effective as first line. POLO (2019) randomised germline BRCA carriers whose metastatic disease had not progressed on at least sixteen weeks of platinum chemotherapy to maintenance olaparib or placebo: olaparib roughly doubled progression-free survival without lengthening overall survival, and the FDA approved it in December 2019. Rucaparib produced similar maintenance activity in a phase 2 that included PALB2 carriers and somatic mutations, and niraparib with ipilimumab has shown promise as maintenance in a broader platinum-sensitive population.\n\nResistance to PARP inhibitors arises through reversion mutations that restore the reading frame of BRCA, through loss of PARP trapping and through replication fork protection, and platinum resistance often precedes it. Trials are testing PARP inhibitors earlier and in combination with immunotherapy, ATR inhibitors and chemotherapy, and whether carriers with resectable disease should receive platinum-based neoadjuvant treatment or adjuvant PARP inhibition. ATM, CHEK2 and other repair gene variants are found in a further few percent of patients but respond less predictably to platinum and PARP inhibitors than BRCA and PALB2.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/BRCA_mutation","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/BRCA_mutation"},{"label":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}],"tags":["subtype-page","gastrointestinal"],"related":["metastatic-pdac","resectable-pdac","kras-g12c-pdac","kras-wild-type-pdac","msi-high-pdac","borderline-resectable-pdac","platinum-sensitive-ovarian-cancer"],"cancers":[],"sections":[],"technologies":["parp-inhibitor","germline-testing","cytotoxic-chemotherapy","pancreatic-surveillance","liquid-biopsy","checkpoint-inhibitor"],"targets":["brca","kras"],"drugs":["olaparib","rucaparib","niraparib","talazoparib","folfirinox","nalirifox","gemcitabine-cisplatin","cisplatin","gemcitabine-nab-paclitaxel","ipilimumab","daraxonrasib"],"companies":["astrazeneca","merck","pfizer"],"institutions":[],"pathways":["ddr","homologous-recombination-repair","synthetic-lethality-map","pancreatic-cancer-signalling"],"terms":["gbrca-mutation","hrd","platinum-sensitivity","brca-reversion-mutations","germline-vs-somatic","resistance"],"trials":["polo","prodige-24","preopanc","nct07491445"],"people":["talia-golan","susan-domchek","eileen-oreilly","diane-simeone","bert-vogelstein"],"bottlenecks":[],"keyPapers":["paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019","paper-polo-overall-survival-olaparib-gbrca-pancreatic-jco-2022","paper-oreilly-gemcitabine-cisplatin-veliparib-gbrca-palb2-pancreatic-jco-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 5 to 7 percent of pancreatic ductal adenocarcinomas arise in people carrying an inherited BRCA1, BRCA2 or PALB2 variant, BRCA2 most often, with higher rates in people of Ashkenazi Jewish descent; a further group has somatic alterations or other DNA repair gene defects such as ATM.","subtypes":["Germline BRCA2-mutant PDAC (the commonest; POLO population)","Germline BRCA1-mutant PDAC","Germline PALB2-mutant PDAC (rucaparib phase 2; olaparib label covers BRCA only)","Somatic BRCA or PALB2-altered PDAC (PARP inhibitor benefit less certain)","ATM, CHEK2 or other homologous recombination gene-altered PDAC (variable platinum sensitivity)","Platinum-resistant BRCA-mutant PDAC with reversion mutations (PARP inhibitors ineffective)"],"biomarkers":["Germline BRCA1, BRCA2 and PALB2 testing in every patient at diagnosis","Somatic homologous recombination gene alterations on tumour sequencing","Homologous recombination deficiency signatures (investigational in the pancreas)","Response to at least sixteen weeks of platinum without progression (POLO eligibility)","BRCA reversion mutations in plasma at progression on a PARP inhibitor","Family history and Ashkenazi Jewish ancestry (prior probability of a variant)"],"standardOfCare":[{"setting":"Testing","approach":"Germline testing for BRCA1, BRCA2, PALB2 and other cancer genes for every patient with pancreatic cancer, with cascade testing of relatives and surveillance for unaffected carriers in a research setting.","refs":["germline-testing","gbrca-mutation","germline-vs-somatic","pancreatic-surveillance"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Metastatic, first line","approach":"Platinum-containing chemotherapy: modified FOLFIRINOX, NALIRIFOX or gemcitabine plus cisplatin, chosen by fitness.","refs":["folfirinox","nalirifox","gemcitabine-cisplatin","cisplatin","platinum-sensitivity"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Maintenance","approach":"Olaparib after at least sixteen weeks of first-line platinum without progression in germline BRCA carriers (POLO); rucaparib for PALB2 and somatic alterations on phase 2 evidence; continued chemotherapy as the alternative.","refs":["olaparib","polo","rucaparib","parp-inhibitor"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Resectable or borderline","approach":"Platinum-based neoadjuvant or adjuvant chemotherapy (modified FOLFIRINOX) rather than gemcitabine alone; adjuvant PARP inhibition only in trials.","refs":["folfirinox","prodige-24","preopanc","neoadjuvant-adjuvant"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"After progression on a PARP inhibitor","approach":"Non-platinum chemotherapy (gemcitabine plus nab-paclitaxel) or daraxonrasib after first-line chemotherapy; trials of PARP inhibitor combinations.","refs":["gemcitabine-nab-paclitaxel","daraxonrasib","brca-reversion-mutations"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Olaparib maintenance after platinum (POLO) is the first approved targeted therapy for a pancreatic cancer subgroup.","Universal germline testing at diagnosis is guideline standard and finds carriers who would be missed by family history.","Platinum-based regimens are preferred at every stage for carriers.","PARP inhibitor combinations with immunotherapy and ATR inhibitors and earlier use are in trials."],"history":[{"year":1994,"title":"BRCA1 identified; BRCA2 follows in 1995 and is linked to pancreatic cancer risk","refs":["brca"]},{"year":2005,"title":"PARP inhibition shown to kill BRCA-deficient cells (synthetic lethality)","refs":["parp-inhibitor","synthetic-lethality-map"]},{"year":2014,"title":"Retrospective series show BRCA carriers with pancreatic cancer live longer on platinum chemotherapy","refs":["platinum-sensitivity","cisplatin"]},{"year":2018,"title":"ASCO and NCCN recommend germline testing for every patient with pancreatic cancer","refs":["germline-testing","gbrca-mutation"]},{"year":2019,"title":"POLO: olaparib maintenance delays progression in germline BRCA carriers; FDA approval in December","refs":["polo","olaparib","talia-golan","astrazeneca"]},{"year":2021,"title":"Rucaparib maintenance phase 2 extends the approach to PALB2 and somatic alterations","refs":["rucaparib"]}],"pipeline":["rucaparib","niraparib","talazoparib","ipilimumab","nct07491445","idea-prev-reflex-germline-testing","pancreatic-surveillance"],"openProblems":["Olaparib delays progression but has not lengthened overall survival, and the best duration of maintenance is unknown.","Somatic and non-BRCA repair gene alterations respond unpredictably, and there is no validated homologous recombination deficiency test for the pancreas.","Reversion mutations restore repair and defeat both platinum and PARP inhibitors.","Whether unaffected carriers benefit from pancreatic surveillance is still being established."],"parent":"pancreatic"},{"id":"brca-associated-tnbc","kind":"cancer","name":"BRCA-associated triple-negative breast cancer","aka":["Germline BRCA1 triple-negative breast cancer","gBRCA TNBC","Hereditary triple-negative breast cancer","BRCA1-related basal-like breast cancer"],"tldr":"Some triple-negative breast cancers arise because a person was born with a faulty BRCA1 or BRCA2 gene. This group is diagnosed younger, is found by a blood test NICE recommends for all women under 50 with triple-negative disease, and has options of its own: platinum chemotherapy works well, a year of olaparib lowers relapse, and surgery decisions weigh the risk of a second cancer.","summary":"BRCA1-associated breast cancers are mostly basal-like and triple-negative, high grade and often with a medullary pattern; BRCA2-associated cancers are mostly ER-positive, and the triple-negative share falls with age at diagnosis in BRCA1 carriers but rises in BRCA2 carriers (Mavaddat 2012; Atchley 2008). Among 1,824 triple-negative patients unselected for family history, 14.6 percent carried a deleterious germline mutation: BRCA1 8.5 percent, BRCA2 2.7 percent, PALB2 1.2 percent, and BARD1, RAD51D, RAD51C and BRIP1 0.3 to 0.5 percent each; carriers were younger and had higher-grade tumours, and the authors concluded that all triple-negative patients should be considered for BRCA testing regardless of age or family history (Couch 2015). A prospective US registry found 15.4 percent BRCA1 or BRCA2 carriers, 27.6 percent among those diagnosed at 50 or under and 4.9 percent at 61 or over, with NCCN's rule of testing all triple-negative disease at 60 or under catching every carrier (Sharma 2014); in the UK POSH cohort of 2,733 women diagnosed at 40 or under, 12 percent carried a BRCA mutation (Copson 2018). PALB2 carries a relative risk of 7.18 for breast cancer and a 53 percent risk to age 80 (Yang 2020). Outcome: in POSH, BRCA carriers with triple-negative disease had better overall survival than non-carriers at two years (95 against 91 percent, hazard ratio 0.59) but not at five (81 against 74 percent) or ten years (72 against 69 percent), and the authors advise that decisions on further risk-reducing surgery take the prognosis of the first cancer into account (Copson 2018). Treatment specifics are on the parent and early-disease pages: germline testing under NICE NG101 1.3.6 and CG164; the OlympiA year of adjuvant olaparib for high-risk HER2-negative early disease after chemotherapy, recommended by NICE TA886; olaparib and talazoparib for metastatic disease (OlympiAD, EMBRACA); and the HRD biology that predicts platinum response, on the glossary term. Somatic BRCA mutations and germline PALB2 mutations also predicted olaparib response in TBCRC 048 (Tung 2020). Contralateral risk-reducing mastectomy lowered contralateral breast cancer incidence (relative risk 0.072) and all-cause mortality (hazard ratio 0.512) in carriers with breast cancer in a meta-analysis (Li 2016), and tamoxifen after the first cancer was associated with fewer contralateral cancers in carriers regardless of ER status (Phillips 2013).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/BRCA_mutation","links":[{"label":"Couch, J Clin Oncol 2015: inherited mutations in 17 genes among 1,824 triple-negative breast cancers unselected for family history","url":"https://doi.org/10.1200/jco.2014.57.1414"},{"label":"Sharma, Breast Cancer Res Treat 2014: germline BRCA mutations in a prospective triple-negative breast cancer registry","url":"https://doi.org/10.1007/s10549-014-2980-0"},{"label":"Atchley, J Clin Oncol 2008: clinical and pathological characteristics of BRCA-positive and BRCA-negative breast cancer","url":"https://doi.org/10.1200/jco.2008.16.6231"},{"label":"Mavaddat, Cancer Epidemiol Biomarkers Prev 2012: pathology of breast cancers in BRCA1 and BRCA2 carriers (CIMBA)","url":"https://doi.org/10.1158/1055-9965.epi-11-0775"},{"label":"Copson, Lancet Oncol 2018: germline BRCA mutation and outcome in young-onset breast cancer (POSH)","url":"https://doi.org/10.1016/s1470-2045(17)30891-4"},{"label":"Yang, J Clin Oncol 2020: cancer risks with germline PALB2 pathogenic variants, 524 families","url":"https://doi.org/10.1200/jco.19.01907"},{"label":"Tung, J Clin Oncol 2020: TBCRC 048, olaparib for metastatic breast cancer with germline PALB2 or somatic BRCA mutations","url":"https://doi.org/10.1200/jco.20.02151"},{"label":"Li, Clin Cancer Res 2016: effectiveness of prophylactic surgeries in BRCA1 or BRCA2 carriers, meta-analysis","url":"https://doi.org/10.1158/1078-0432.ccr-15-1465"},{"label":"Phillips, J Clin Oncol 2013: tamoxifen and contralateral breast cancer risk in BRCA1 and BRCA2 carriers","url":"https://doi.org/10.1200/jco.2012.47.8313"},{"label":"NICE NG101: early and locally advanced breast cancer (receptor testing 1.3, genetic testing 1.3.6, triple-negative section 1.8)","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"},{"label":"NICE CG164: familial breast cancer (referral, genetic testing, surveillance, risk-reducing surgery, chemoprevention)","url":"https://www.nice.org.uk/guidance/cg164/chapter/Recommendations"},{"label":"NICE TA886: olaparib for adjuvant treatment of BRCA mutation-positive HER2-negative high-risk early breast cancer (May 2023)","url":"https://www.nice.org.uk/guidance/ta886"}],"tags":["breast","tnbc","subtype-page"],"related":["tnbc","tnbc-early","tnbc-metastatic","tnbc-basal-like-1","medullary-pattern-breast-carcinoma"],"cancers":[],"sections":[],"technologies":["germline-testing","parp-inhibitor","platinum"],"targets":["brca","parp"],"drugs":["olaparib","talazoparib","carboplatin"],"companies":[],"institutions":[],"pathways":["ddr"],"terms":["germline-brca-testing-criteria-tnbc","hrd-in-breast-cancer","risk-reducing-surgery-brca-carriers","germline-vs-somatic","basal-like"],"trials":["olympia","olympiad","embraca"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"About one in nine triple-negative patients unselected for family history carries a germline BRCA1 (8.5 percent) or BRCA2 (2.7 percent) mutation, and one in seven a mutation in one of 17 predisposition genes (Couch 2015); from the other direction, 57.1 percent of breast cancers in BRCA1 carriers are triple-negative (Atchley 2008).","subtypes":["Germline BRCA1-associated triple-negative breast cancer (basal-like, often medullary pattern, the majority)","Germline BRCA2-associated triple-negative breast cancer (a minority of BRCA2 cancers, older at diagnosis)","Germline PALB2-associated triple-negative breast cancer","Somatic (tumour-only) BRCA1 or BRCA2 mutation in triple-negative disease"],"biomarkers":["Germline BRCA1, BRCA2 and PALB2 pathogenic variants (blood test)","Tumour BRCA1 or BRCA2 mutation and HRD score (platinum and PARP inhibitor response)","Age under 50 at diagnosis and family history (testing criteria)"],"standardOfCare":[{"setting":"At diagnosis","approach":"Germline BRCA1 and BRCA2 testing for women under 50 with triple-negative disease including those with no family history (NICE NG101 1.3.6); UK mainstream criteria cover all triple-negative disease under 60; genetic counselling and cascade testing of relatives.","refs":["germline-testing","germline-brca-testing-criteria-tnbc","germline-vs-somatic"],"guideline":{"version":"NICE NG101 1.3.6; NICE CG164","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Early disease after chemotherapy","approach":"One year of adjuvant olaparib for germline BRCA-mutated HER2-negative high-risk early breast cancer (OlympiA; NICE TA886); the same neoadjuvant platinum, taxane and anthracycline regimen as other triple-negative disease (NG101 1.8).","refs":["olaparib","olympia","parp-inhibitor","carboplatin"],"guideline":{"version":"NICE TA886 (May 2023)","url":"https://www.nice.org.uk/guidance/ta886"}},{"setting":"Metastatic disease","approach":"Olaparib or talazoparib (OlympiAD, EMBRACA); platinum chemotherapy; PD-L1 and TROP2 ADC options as for other triple-negative disease.","refs":["olaparib","talazoparib","olympiad","embraca","platinum"]},{"setting":"Surgery and the other breast","approach":"Contralateral risk-reducing mastectomy lowers contralateral cancer incidence and all-cause mortality in carriers with breast cancer (meta-analysis); the decision weighs the prognosis of the first cancer and personal preference (POSH authors; NICE CG164 counselling steps).","refs":["mastectomy","risk-reducing-surgery-brca-carriers"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"tnbc"},{"id":"breast-cancer","kind":"cancer","name":"Breast cancer (all types)","aka":["TCGA-BRCA","breast invasive carcinoma (TCGA BRCA cohort)","Breast carcinoma","Carcinoma of the breast"],"tldr":"Breast cancer is not one disease, and the result that decides which page you need is the receptor result: whether the cancer carries oestrogen and progesterone receptors, and whether it carries too much HER2. Those two answers give four boxes, not three, with a page for each. Grade and stage do not change which page you read; they change what happens on it.","summary":"Breast cancer arises from the milk ducts or lobules and is classified by the receptors on its cells: oestrogen and progesterone receptors, and HER2. Hormone receptor-positive, HER2-negative disease is treated with endocrine therapy and CDK4/6 inhibitors; HER2-positive disease with HER2 antibodies and antibody-drug conjugates; triple-negative disease with chemotherapy, immunotherapy and, for BRCA carriers, PARP inhibitors. Ductal carcinoma in situ is a precursor confined to the duct, and about one percent of cases occur in men. Screening mammography from around age 50, breast-conserving surgery with radiotherapy, sentinel node biopsy and genomic tests that spare chemotherapy are common to all types. Most patients present early and are cured. Metastatic disease is treated in successive lines rather than once, is controlled for years in many people, and is rarely cured; the subtype pages carry the sequence, the trials open in each line and the point at which a trial is a reasonable choice beside standard treatment.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Breast_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Breast_cancer"},{"label":"NCI PDQ","url":"https://www.cancer.gov/types/breast"},{"label":"NICE NG101: early and locally advanced breast cancer, diagnosis and management (published 18 July 2018, last updated 14 April 2025)","url":"https://www.nice.org.uk/guidance/ng101/chapter/recommendations"},{"label":"Royal College of Pathologists G148: dataset for histopathological reporting of breast disease in surgical excision specimens of breast cancer, version 3, November 2024 (full review due November 2026)","url":"https://www.rcpath.org/resourceLibrary/g148-dataset-for-histopathological-reporting-of-breast-disease-in-surgical-excision-specimens-of-breast-cancer.html"},{"label":"NICE CG81: advanced breast cancer, diagnosis and treatment, diagnosis and assessment section (published 23 February 2009, last updated 30 June 2026)","url":"https://www.nice.org.uk/guidance/cg81/chapter/Diagnosis-and-assessment"},{"label":"Brierley et al., International Journal of Cancer 2026: the 9th edition of the UICC TNM classification of malignant tumours, updates and rationale for change (breast: the classification remains unchanged, the yp classification is clarified)","url":"https://doi.org/10.1002/ijc.70561"},{"label":"UICC: TNM Classification of Malignant Tumours, 9th edition, recommended to take effect from 1 January 2026","url":"https://www.uicc.org/what-we-do/sharing-knowledge/tnm"},{"label":"Quinn et al., Histopathology 2026;89(2):199 to 218: World Health Organization classification of tumours of the breast, 6th edition 2026","url":"https://doi.org/10.1111/his.70149"},{"label":"Tan et al., Histopathology 2020: the 2019 WHO classification of tumours of the breast (5th edition)","url":"https://doi.org/10.1111/his.14091"},{"label":"Elston and Ellis, Histopathology 1991;19:403 to 410: pathological prognostic factors in breast cancer, the value of histological grade, with long-term follow-up of 1,831 graded patients","url":"https://doi.org/10.1111/j.1365-2559.1991.tb00229.x"},{"label":"Galea, Blamey, Elston and Ellis, Breast Cancer Research and Treatment 1992;22:207 to 219: the Nottingham Prognostic Index in primary breast cancer","url":"https://doi.org/10.1007/bf01840834"},{"label":"Allison et al., Journal of Clinical Oncology 2020;38:1346 to 1366: oestrogen and progesterone receptor testing in breast cancer, ASCO/CAP guideline update","url":"https://doi.org/10.1200/jco.19.02309"},{"label":"Rakha et al., Journal of Clinical Pathology 2023;76:217 to 227: UK recommendations for HER2 assessment in breast cancer, an update","url":"https://doi.org/10.1136/jcp-2022-208632"},{"label":"Schrijver et al., Journal of the National Cancer Institute 2018: receptor conversion in distant breast cancer metastases, a systematic review and meta-analysis of 39 studies","url":"https://doi.org/10.1093/jnci/djx273"},{"label":"SEER Cancer Stat Facts: female breast cancer subtypes (share of cases and five-year relative survival by receptor subtype and stage, SEER 21)","url":"https://seer.cancer.gov/statfacts/html/breast-subtypes.html"},{"label":"SEER Cancer Stat Facts: female breast cancer (incidence, stage distribution and survival)","url":"https://seer.cancer.gov/statfacts/html/breast.html"},{"label":"GLOBOCAN breast fact sheet (IARC Global Cancer Observatory, 2024 estimates)","url":"https://gco.iarc.who.int/media/globocan/factsheets/cancers/20-breast-fact-sheet.pdf"},{"label":"Cancer Research UK: breast cancer statistics (UK incidence, mortality, survival, stage at diagnosis and routes to diagnosis)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer"},{"label":"Cancer Research UK: types of breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/types"},{"label":"NHS: breast cancer in women, symptoms","url":"https://www.nhs.uk/conditions/breast-cancer/symptoms/"},{"label":"NHS: breast cancer in women","url":"https://www.nhs.uk/conditions/breast-cancer-in-women/"},{"label":"NHS: tests and next steps for breast cancer in women","url":"https://www.nhs.uk/conditions/breast-cancer-in-women/tests-and-next-steps-for-breast-cancer-in-women/"},{"label":"NHS: treatment for breast cancer in women","url":"https://www.nhs.uk/conditions/breast-cancer-in-women/treatment-for-breast-cancer-in-women/"},{"label":"NHS: help and support for breast cancer in women","url":"https://www.nhs.uk/conditions/breast-cancer-in-women/help-and-support-for-breast-cancer-in-women/"},{"label":"NHS: breast cancer in men","url":"https://www.nhs.uk/conditions/breast-cancer-in-men/"},{"label":"NHS: mastectomy","url":"https://www.nhs.uk/tests-and-treatments/mastectomy/"},{"label":"NHS: lymphoedema","url":"https://www.nhs.uk/conditions/lymphoedema/"},{"label":"NHS: lymphoedema, treatment","url":"https://www.nhs.uk/conditions/lymphoedema/treatment/"},{"label":"NHS: cellulitis","url":"https://www.nhs.uk/conditions/cellulitis/"},{"label":"NHS: menopause and perimenopause, symptoms","url":"https://www.nhs.uk/conditions/menopause-and-perimenopause/symptoms/"},{"label":"NHS: sepsis","url":"https://www.nhs.uk/conditions/sepsis/"},{"label":"NHS: clinical trials","url":"https://www.nhs.uk/tests-and-treatments/clinical-trials/"},{"label":"NHS: when to use 111","url":"https://www.nhs.uk/nhs-services/urgent-and-emergency-care-services/when-to-use-111/"},{"label":"NHS: when to call 999","url":"https://www.nhs.uk/nhs-services/urgent-and-emergency-care-services/when-to-call-999/"},{"label":"NHS: carer's assessments","url":"https://www.nhs.uk/social-care-and-support/support-and-benefits-for-carers/carer-assessments/"},{"label":"NHS: benefits for carers","url":"https://www.nhs.uk/social-care-and-support/support-and-benefits-for-carers/benefits-for-carers/"},{"label":"NICE NG101: early and locally advanced breast cancer, recommendations (updated 2025)","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"},{"label":"NICE NG257: fertility problems, fertility preservation for medical indications (2026)","url":"https://www.nice.org.uk/guidance/ng257/chapter/Fertility-preservation-for-medical-indications"},{"label":"NICE NG234: spinal metastases and metastatic spinal cord compression, recommendations","url":"https://www.nice.org.uk/guidance/ng234/chapter/Recommendations"},{"label":"NICE CG151: neutropenic sepsis","url":"https://www.nice.org.uk/guidance/cg151"},{"label":"Macmillan: breast-conserving surgery","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/breast-conserving-surgery-for-breast-cancer"},{"label":"Macmillan: removing the breast (mastectomy)","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/removing-the-breast-mastectomy"},{"label":"Macmillan: breast reconstruction","url":"https://www.macmillan.org.uk/cancer-information-and-support/breast-cancer/breast-reconstruction"},{"label":"Macmillan: surgery to the lymph nodes for breast cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/surgery-to-the-lymph-nodes-for-breast-cancer"},{"label":"Macmillan: radiotherapy for breast cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/radiotherapy-for-breast-cancer"},{"label":"Macmillan: lymphoedema","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/lymphoedema"},{"label":"Macmillan: hair loss","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/hair-loss"},{"label":"Macmillan: fertility","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/fertility"},{"label":"Macmillan: sepsis","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/sepsis"},{"label":"Macmillan: work and cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/work-and-cancer"},{"label":"Macmillan: looking after someone with cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/supporting-someone/looking-after-someone-with-cancer"},{"label":"Macmillan: questions to ask your healthcare team","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatment/your-treatment-options/questions-to-ask-your-healthcare-team"},{"label":"Cancer Research UK: breast reconstruction","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/treatment/surgery/breast-reconstruction"},{"label":"Cancer Research UK: life after breast cancer surgery","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/living-with/life-after-surgery"},{"label":"Cancer Research UK: possible problems after mastectomy","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/treatment/surgery/after-surgery/problems-after-mastectomy"},{"label":"Cancer Research UK: preserving fertility with breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/living-with/preserving-fertility"},{"label":"Cancer Research UK: menopausal symptoms and breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/living-with/menopausal-symptoms"},{"label":"Cancer Research UK: lymphoedema after breast cancer treatment","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/living-with/lymphoedema-after-treatment"},{"label":"Cancer Research UK: having radiotherapy for breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/treatment/radiotherapy/radiotherapy-treatment"},{"label":"Cancer Research UK: prehabilitation","url":"https://www.cancerresearchuk.org/about-cancer/treatment/prehabilitation"},{"label":"Breast Cancer Now: lymphoedema","url":"https://breastcancernow.org/about-breast-cancer/treatment/lymphoedema"},{"label":"Breast Cancer Now: surgery for primary breast cancer","url":"https://breastcancernow.org/about-breast-cancer/treatment/surgery-for-primary-breast-cancer"},{"label":"Breast Cancer Now: secondary breast cancer symptoms","url":"https://breastcancernow.org/about-breast-cancer/secondary-breast-cancer/secondary-breast-cancer-symptoms"},{"label":"Breast Cancer Now: coping with breast cancer emotionally","url":"https://breastcancernow.org/about-breast-cancer/life-after-treatment/coping-with-breast-cancer-emotionally"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Cancer Research UK: breast cancer incidence statistics (invasive)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/incidence-invasive"},{"label":"Veronesi et al., twenty-year follow-up of breast-conserving surgery versus radical mastectomy, Milan trial (NEJM 2002)","url":"https://doi.org/10.1056/NEJMoa020989"},{"label":"Fisher et al., twenty-year follow-up of total mastectomy, lumpectomy, and lumpectomy plus irradiation, NSABP B-06 (NEJM 2002)","url":"https://doi.org/10.1056/NEJMoa022152"},{"label":"EBCTCG, radiotherapy after breast-conserving surgery: meta-analysis of 10,801 women in 17 randomised trials (Lancet 2011)","url":"https://doi.org/10.1016/S0140-6736(11)61629-2"},{"label":"DiSipio et al., incidence of unilateral arm lymphoedema after breast cancer: systematic review and meta-analysis (Lancet Oncology 2013)","url":"https://doi.org/10.1016/S1470-2045(13)70076-7"},{"label":"Bartels et al., radiotherapy or surgery of the axilla after a positive sentinel node, 10-year results of AMAROS (JCO 2023)","url":"https://doi.org/10.1200/JCO.22.01565"},{"label":"Giuliano et al., axillary dissection versus no axillary dissection, 10-year results of ACOSOG Z0011 (JAMA 2017)","url":"https://doi.org/10.1001/jama.2017.11470"},{"label":"de Boniface et al., omitting axillary dissection in breast cancer with sentinel-node metastases, SENOMAC (NEJM 2024)","url":"https://doi.org/10.1056/NEJMoa2313487"},{"label":"Reimer et al., axillary surgery in breast cancer, primary results of the INSEMA trial (NEJM 2025)","url":"https://doi.org/10.1056/NEJMoa2412063"},{"label":"Gartner et al., prevalence of and factors associated with persistent pain following breast cancer surgery (JAMA 2009)","url":"https://doi.org/10.1001/jama.2009.1568"},{"label":"Moore et al., goserelin for ovarian protection during breast cancer adjuvant chemotherapy, POEMS/S0230 (NEJM 2015)","url":"https://doi.org/10.1056/NEJMoa1413204"},{"label":"Lambertini et al., GnRH agonists during chemotherapy for preservation of ovarian function and fertility, individual patient-level meta-analysis of 873 patients (JCO 2018)","url":"https://doi.org/10.1200/JCO.2018.78.0858"},{"label":"Dilawari et al., does scalp cooling have the same efficacy in Black patients receiving chemotherapy for breast cancer? (The Oncologist 2021)","url":"https://doi.org/10.1002/onco.13690"},{"label":"Nangia et al., scalp cooling device and alopecia in women having chemotherapy for breast cancer, SCALP randomised trial (JAMA 2017)","url":"https://doi.org/10.1001/jama.2016.20939"}],"tags":["parent-page"],"related":["her2-low-metastatic-breast-cancer","inflammatory-breast-cancer","paget-disease-of-the-nipple","phyllodes-tumour","male-breast-cancer","ductal-carcinoma-in-situ","breast-hr-positive","breast-her2-positive","tnbc","invasive-breast-carcinoma-no-special-type","invasive-lobular-carcinoma","lobular-carcinoma-in-situ","medullary-pattern-breast-carcinoma"],"cancers":[],"sections":[],"technologies":["mammography","ultrasound","mri","ct","pet-ct","histopathology-ihc","digital-pathology-ai","palliative-care","psycho-oncology","peer-support-groups","oncology-nutrition","pain-management","survivorship-care-plan","multidisciplinary-tumour-board","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","prehabilitation","lymphoedema-decongestive-therapy","scalp-cooling","fertility-preservation"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["terminal-duct-lobular-unit","who-breast-classification","nottingham-grade","nottingham-prognostic-index","tnm-breast-cancer-editions","grade-stage-receptor-breast","er-pr-scoring-breast","her2-testing-uk-breast","receptor-conversion-breast","breast-tumour-size-on-the-report","hormone-receptor-status","her2-positive","her2-low","er-pr-negative-threshold","ajcc-prognostic-stage-breast","tumour-grade","grade-vs-stage","cancer-stage","tnm-staging","carcinoma-in-situ","dcis","lymphovascular-invasion","lymph-node-status","sentinel-lymph-node-biopsy","core-needle-biopsy","ihc","fish","pcr","rcb","basal-like","pam50","interval-breast-cancer","ki-67-in-tnbc","breast-conserving-surgery-versus-mastectomy","oncoplastic-breast-surgery","axillary-surgery-de-escalation","targeted-axillary-dissection","breast-cancer-related-lymphoedema","breast-reconstruction","bia-alcl","radiotherapy-omission-early-breast-cancer","partial-breast-irradiation","tumour-bed-boost","post-mastectomy-radiotherapy","neoadjuvant-versus-adjuvant-breast","late-effects","quality-of-life","curative-intent","cancer-related-fatigue","febrile-neutropenia","bone-metastases","brain-metastases","metastatic-spinal-cord-compression"],"trials":["ibis-i","ibis-ii","agex","start-b","fast-forward","import-low"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Which page is mine? Start with the receptor result, because that is the only one of the three things on your report that chooses a page. If you were told the cancer is oestrogen receptor positive (or progesterone receptor positive) and HER2 negative, your page is HR-positive / HER2-negative breast cancer, and you are in the largest group, 70.1 percent of American cases with a known subtype (SEER 21, 2019 to 2023). If you were told HER2 positive, your page is HER2-positive breast cancer whatever the oestrogen receptor says, because HER2 chooses the treatment backbone; and if you were told you are hormone receptor positive as well, which is true of about seven in ten HER2-positive cancers (9.3 percent of all cases against 4.0 percent hormone receptor negative), you will also have endocrine treatment, and the HR-positive page is where that is explained. If you were told all three are negative, your page is triple-negative breast cancer, 10.8 percent of American cases and around 15 percent on Cancer Research UK's page. If you were told an oestrogen receptor figure between 1 and 10 percent, or the phrase ER low positive, read both the HR-positive and the triple-negative pages and the term on the threshold, because that band behaves more like triple-negative disease and the endocrine benefit is uncertain.","Which page is mine, continued: the answers that are not a receptor result. If you have been told a type rather than a receptor status, the type has a page: invasive carcinoma of no special type, which is the ordinary kind and is what most of this family is written about; invasive lobular carcinoma, about 15 percent of cases; or one of the special types, tubular, mucinous, cribriform, papillary, micropapillary, metaplastic, apocrine, secretory, adenoid cystic, neuroendocrine, or carcinoma with a medullary pattern. If you were told in situ, non-invasive or stage 0, you have ductal carcinoma in situ or lobular carcinoma in situ, which are staged Tis and are not invasive cancer; lobular carcinoma in situ is closer to a risk marker than a cancer. If the breast became red, swollen and hot over weeks, that is inflammatory breast cancer, staged T4d and diagnosed clinically. If the change is an eczema-like nipple, that is Paget disease of the nipple. If the lump turned out to be a fibroepithelial tumour, that is a phyllodes tumour, not a carcinoma, and it is not treated with any of the drugs on the receptor pages. If you are a man, there is a page for male breast cancer. And if you are here because of a screening recall rather than a diagnosis, a recall is not a diagnosis: most people recalled after a mammogram do not have cancer, and the NHS pathway page explains what happens next.","Which page is mine, continued: grade, stage and the words that are not pages. A grade is not a page. Someone told 'grade 3, triple negative' should go to the triple-negative page: grade 3 is the commonest grade in triple-negative disease and it changes the prognosis, not the route. A stage is not a page either, although each receptor page splits into early and advanced disease at the second click, and there are pages for high-risk early hormone receptor-positive disease, for hormone receptor-positive disease after CDK4/6 inhibitors, for early HER2-positive disease, for HER2-positive brain metastases and for early and metastatic triple-negative disease. Luminal A and luminal B, basal-like and claudin-low are names from gene expression profiling rather than from a report, and they live in the glossary. HER2-low and HER2-ultralow are not a fourth receptor status: they describe a HER2-negative cancer with a little HER2 on it, and they change what is available only once the disease is advanced.","What breast cancer is. The breast is a branching tree of fifteen to twenty duct systems, each ending in lobules, the clusters of sacs that make milk. Almost all breast cancer begins where the smallest duct meets its lobule, the terminal duct lobular unit, and the names of the two commonest kinds are therefore misleading in a useful way: neither invasive carcinoma of no special type, still widely called invasive ductal carcinoma, nor invasive lobular carcinoma starts where its name suggests. What really separates them is E-cadherin, the protein that glues cells to their neighbours: lobular cancers have lost it, so they spread in single files instead of forming a lump, which makes them harder to feel, harder to see on a mammogram and harder to measure. While the cancer is still inside the duct or lobule it cannot spread and is called carcinoma in situ; once it has crossed the basement membrane it is invasive, and can reach the lymph nodes in the armpit and, from there or through the blood, the bones, liver, lungs and brain.","Why the receptors decide everything. Breast cancer was the first cancer shown to be driven by a hormone that could be taken away: Beatson removed the ovaries of women with advanced breast cancer in 1896, and it worked in some of them. Most breast cancers are fed by oestrogen through the oestrogen receptor in the nucleus, and blocking that receptor or removing the hormone works; a minority instead make far too much of a growth-signal protein called HER2 on their surface, and antibodies and antibody-drug conjugates aimed at HER2 work; and a minority have neither, so neither treatment applies and chemotherapy, immunotherapy and, for people with an inherited BRCA fault, PARP inhibitors are used. That is why the first question after diagnosis is not how big or how far, but which of these the cancer is, and why NICE asks for all three receptor results to be requested at once on the first biopsy rather than one after another (NG101 1.3.1).","Is grade the same as stage? No, and confusing them is the commonest misunderstanding on a breast report. Grade is how abnormal the cells look under the microscope, from 1 to 3, and it is a property of the cancer's behaviour. Stage is how much cancer there is and how far it has gone, from 0 to IV, and it is a property of the situation. A small grade 3 cancer and a large grade 1 cancer are different problems, and the report gives you both because neither can be worked out from the other. The UK dataset makes the same point about its own staging system: the UICC classification, it says, does not incorporate histological grade or receptor status, which is why the Nottingham Prognostic Index and PREDICT exist to put them back together.","Why the numbers on my report are given to the nearest whole grade and my friend's cancer had an Oncotype score. Grade, size and node status are measured in the hospital laboratory and are on every report. A genomic recurrence score, such as Oncotype DX, MammaPrint, Prosigna or EndoPredict, is an extra test sent away in some hormone receptor-positive, HER2-negative, node-negative cancers to decide whether chemotherapy is worth adding, and it is not done in all cases and not in other subtypes. It is not a better version of the grade; it answers a narrower question, and NICE has separate diagnostics guidance on which of these tests may be used.","How the outlook is described, and how it is not. Population figures for breast cancer are averages over everyone diagnosed in a period, and for this cancer they are unusually favourable: 76.6 percent of UK women survive ten years or more, and five-year relative survival in the United States is 91.9 percent across all breast cancer. They are also unusually stratified: 95.8 percent five-year survival in hormone receptor-positive HER2-negative disease against 78.7 percent in triple-negative disease, and within triple-negative disease 92.8 percent when it is localised against 14.9 percent when it is distant (SEER 21, 2016 to 2022). No one of those numbers is a prediction about a person, and the number that moves them most is not the subtype but the stage at which the cancer was found.","Living with breast cancer, the decisions that are shared: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and 24-hour number come first, and no figure on this page is a prediction about you. The seven decision rows above, the question sets for the surgeon, breast care nurse, oncology, radiotherapy planning, fertility and lymphoedema appointments and for partners and carers, the first 60 days checklist and the red cards were written from NICE NG101, NG257, NG234 and CG151 and from the NHS, Macmillan, Cancer Research UK, Breast Cancer Now and Maggie's, with every trial figure taken from the trial's own publication rather than from a summary of it.","On what is here and what is not. Breast cancer is three diseases wearing one name, and the pages for hormone receptor-positive, HER2-positive and triple-negative disease carry the drug decisions that follow the receptor result. This page carries only what is true whichever result comes back: the operation, the armpit, the arm, fertility and the menopause, the body you are left with, hair, and follow-up. Where a subtype page says it better, this page points there rather than saying it again.","On the survival figures. They come from two randomised trials that followed people for twenty years, the Milan trial of 701 women with cancers under 2 cm and NSABP B-06 with 1,851 women, both started in the 1970s, and from the EBCTCG meta-analysis of 10,801 women in 17 radiotherapy trials. They describe those cohorts, treated with the surgery and drugs of their time. They are quoted because the alternative, the phrase similar outcomes, tells a reader nothing about what is actually being traded. No sentence on this page is a forecast for one person.","On the word women. NICE writes several of these recommendations about women specifically, including the reconstruction and menopause sections, and the wording is kept as NICE wrote it rather than quietly broadened. Everywhere else this page says people, because about 420 of the roughly 59,000 breast cancers diagnosed in the UK each year are in men, and the male breast cancer page exists for them. The lymphoedema section of NG101 says the same thing in its own rationale: the committee recognised that while breast cancer predominantly affects women, men can also be affected, and extrapolated the evidence to make recommendations that address the needs of all breast cancer patients.","On lymphoedema, which is the reason this layer exists in the form it does. It is lifelong, it affects more than one in five people after axillary clearance, it is badly covered on almost every page a newly diagnosed person will read, and nearly everything that reduces it is decided in the first month: which armpit operation, whether radiotherapy replaces clearance, whether anyone measured the arm before surgery, and whether anyone explained the early signs. NICE rewrote its recommendations on it in 2025 and they are quoted at length above for that reason."],"group":"breast","burden":"The commonest cancer in the world and in the UK. Worldwide there are 2,434,087 new breast cancers and 693,660 deaths a year, second for cases among all cancers and fourth for deaths (GLOBOCAN 2024). In the UK there are 59,413 new cases a year, about 59,000 in females and 420 in males, 15 percent of all cancers, and 11,200 deaths a year (Cancer Research UK). In England in 2022, 85 percent of cases with a known stage were stage I or II.","subtypes":["By receptor result, which is what chooses a treatment page: hormone receptor-positive and HER2-negative (70.1 percent of American cases with a known subtype), HER2-positive whatever the hormone receptors say (13.3 percent, of which 9.3 points are also hormone receptor-positive), and triple-negative (10.8 percent) (SEER 21, 2019 to 2023)","By histological type, which the WHO classification decides: invasive carcinoma of no special type (the commonest by far), invasive lobular carcinoma (about 15 percent), and the special types, each with its own page","By whether the cancer has broken out of the duct or lobule: ductal carcinoma in situ and lobular carcinoma in situ are staged Tis and are not invasive cancer","Clinical entities that are defined by how they present rather than by histology: inflammatory breast cancer (staged T4d) and Paget disease of the nipple","Phyllodes tumour, which is not a carcinoma at all but a fibroepithelial tumour of the breast stroma"],"biomarkers":["Oestrogen and progesterone receptors","HER2 (including HER2-low)","Ki-67 and grade","Genomic recurrence scores (Oncotype DX, MammaPrint)","BRCA1/2 and other germline variants","PD-L1 (triple-negative)","ESR1 and PIK3CA mutations (advanced hormone receptor-positive)","Oestrogen receptor, reported as a percentage of stained invasive nuclei with an intensity, positive at 1 percent or more, with 1 to 10 percent reported separately as ER low positive (RCPath G148; ASCO/CAP 2020)","Progesterone receptor, asked for by NICE NG101 1.3.3 on every invasive cancer but not a mandatory item of the UK pathology dataset, and used for prognosis and quality control rather than to predict endocrine benefit","HER2 by immunohistochemistry 0 to 3+, with reflex dual-probe in situ hybridisation for 2+ reporting the HER2 to chromosome 17 ratio, the HER2 copy number and the chromosome 17 copy number; 13 to 20 percent of early breast cancer is positive (RCPath G148)","Nottingham grade, and the three component scores that make it, which are mandatory to record separately","Invasive tumour size and whole tumour size in millimetres, reported as two different numbers","Lymph node status, and whether it came from a sentinel node biopsy, which is written pN0(SN)","Nottingham Prognostic Index from grade, node stage and size, and PREDICT, which NICE NG101 1.6.4 asks clinicians to use"],"standardOfCare":[{"setting":"Early disease, all types","approach":"Breast-conserving surgery with radiotherapy or mastectomy, sentinel node biopsy, then treatment by receptor type on the subtype pages.","refs":["breast-hr-positive","breast-her2-positive","tnbc","hypofractionated-radiotherapy"]},{"setting":"Ductal carcinoma in situ","approach":"Surgery with or without radiotherapy and endocrine therapy; active surveillance under study.","refs":["ductal-carcinoma-in-situ"]},{"setting":"Every invasive breast cancer, at diagnosis","approach":"Oestrogen receptor, progesterone receptor and HER2 assessed simultaneously on the diagnostic biopsy by quality-assured immunohistochemistry, reported quantitatively, with reflex in situ hybridisation for a HER2 score of 2+, and the results available at both the preoperative and the postoperative multidisciplinary meeting. The pathology report also carries the histological type, the Nottingham grade with its three component scores, the invasive and whole tumour size, the node stage and the margins.","refs":["histopathology-ihc","core-needle-biopsy","fish","er-pr-scoring-breast","her2-testing-uk-breast","nottingham-grade"],"guideline":{"version":"NICE NG101 recommendations 1.3.1 to 1.3.5; RCPath G148 version 3 (November 2024)","url":"https://www.nice.org.uk/guidance/ng101/chapter/recommendations"}},{"setting":"Staging and prognostic assessment","approach":"Ultrasound of the axilla with needle sampling of any abnormal node before treatment; MRI only where the extent is unclear, the breast is too dense to assess or a lobular cancer is being sized for breast-conserving surgery. Stage against UICC TNM 8, and put grade, node stage and size together in the Nottingham Prognostic Index and in PREDICT, which estimates the benefit of each adjuvant treatment. In advanced disease, contrast-enhanced CT of chest, abdomen and pelvis or FDG PET-CT.","refs":["ultrasound","mri","ct","pet-ct","tnm-breast-cancer-editions","nottingham-prognostic-index","grade-stage-receptor-breast"],"guideline":{"version":"NICE NG101 1.2.1 to 1.2.3 and 1.6.4 to 1.6.5; NICE CG81 1.3.1 to 1.3.3","url":"https://www.nice.org.uk/guidance/ng101/chapter/recommendations"}},{"setting":"At recurrence","approach":"Consider reassessing hormone receptor and HER2 status on a biopsy of the recurrence where a change in receptor status would change management, because conversion between the primary and a metastasis is common in both directions.","refs":["receptor-conversion-breast","core-needle-biopsy","her2-low"],"guideline":{"version":"NICE CG81 recommendation 1.4.1","url":"https://www.nice.org.uk/guidance/cg81/chapter/Diagnosis-and-assessment"}},{"setting":"Surgery to the breast: conservation or mastectomy","approach":"Breast-conserving surgery with radiotherapy, or mastectomy, depending on the size of the tumour against the size of the breast, whether there is more than one tumour, whether radiotherapy is possible, and what the woman wants. Survival is the same either way and has been for twenty years: NSABP B-06 found a hazard ratio for death of 0.97 (0.83 to 1.14) for lumpectomy with irradiation against mastectomy, Milan I found death from any cause of 41.7 against 41.2 percent at twenty years, and EORTC 10801 found a hazard ratio of 1.11 (0.94 to 1.33) at a median 22.1 years. What differs is recurrence in the conserved breast, which is why radiotherapy goes with conservation. Oncoplastic techniques widen the range of tumours that can be conserved.","refs":["nsabp-b06","milan-i","eortc-10801","nsabp-b04","lumpectomy","mastectomy","breast-conserving-surgery-versus-mastectomy","oncoplastic-breast-surgery"],"guideline":{"version":"NICE NG101 recommendations 1.4.1 to 1.4.6","url":"https://www.nice.org.uk/guidance/ng101"}},{"setting":"Margins and further surgery","approach":"Re-excision or mastectomy when tumour reaches the inked margin. NICE NG101 recommendation 1.4.3 offers further surgery when invasive cancer or ductal carcinoma in situ is present at the radial margin (0 mm), and recommendation 1.4.5, new in 2024, considers it when tumour cells lie within 1 mm of but not at the radial margin. The threshold for invasive cancer was lowered from 2 mm to 1 mm because the evidence could not separate 1 to 2 mm from more than 2 mm on local recurrence, and repeated operations harm appearance and self-image. For ductal carcinoma in situ alone the 2 mm threshold is retained (recommendation 1.4.4).","refs":["resection-margins","lumpectomy","ductal-carcinoma-in-situ","breast-conserving-surgery-versus-mastectomy"],"guideline":{"version":"NICE NG101 recommendations 1.4.3 to 1.4.6","url":"https://www.nice.org.uk/guidance/ng101"}},{"setting":"Staging the axilla when the nodes look clear","approach":"Sentinel lymph node biopsy, not axillary clearance, with dual technique using isotope and blue dye (NICE NG101 recommendations 1.4.9 and 1.4.10). NSABP B-32 randomised 5,611 women and found eight-year overall survival of 90.3 percent with sentinel node biopsy alone against 91.8 percent with added clearance (hazard ratio 1.20, 0.96 to 1.50); ALMANAC measured the gain, with lymphoedema at one year falling from 13 to 5 percent and sensory loss from 31 to 11 percent. In selected patients the sentinel node itself can now be omitted: SOUND (tumours up to 2 cm, clear axillary ultrasound) and INSEMA (T1 and T2, breast-conserving surgery) both showed non-inferiority, with axillary recurrence in INSEMA of 1.0 against 0.3 percent. Omission is only reasonable where the missing nodal information would not change the treatment plan.","refs":["nsabp-b32","almanac","sound","insema","sentinel-lymph-node-biopsy","sentinel-node","axillary-surgery-de-escalation"],"guideline":{"version":"NICE NG101 recommendations 1.4.9 and 1.4.10","url":"https://www.nice.org.uk/guidance/ng101"}},{"setting":"A positive sentinel node","approach":"Isolated tumour cells count as node-negative and need nothing further (NICE NG101 recommendation 1.4.15). Micrometastases need nothing further either: IBCSG 23-01 found ten-year disease-free survival of 76.8 percent without clearance against 74.9 percent with it, and lymphoedema of 4 against 13 percent (recommendation 1.4.14). For one or two macrometastases, NICE recommendation 1.4.12 offers axillary clearance or axillary radiotherapy and recommendation 1.4.13 asks for a discussion of having neither after breast-conserving surgery with whole-breast radiotherapy and systemic therapy. The evidence behind that discussion is Z0011 (ten-year overall survival 86.3 against 83.6 percent) and SENOMAC (five-year recurrence-free survival 89.7 against 88.7 percent in 2,540 patients including mastectomy and T3 disease). Where the axilla is treated, AMAROS makes radiotherapy the gentler choice: ten-year axillary recurrence of 1.82 against 0.93 percent, with lymphoedema halved at 11.9 against 24.5 percent.","refs":["acosog-z0011","senomac","amaros","ibcsg-23-01","posnoc","lymphadenectomy","breast-cancer-related-lymphoedema","axillary-surgery-de-escalation"],"guideline":{"version":"NICE NG101 recommendations 1.4.11 to 1.4.15","url":"https://www.nice.org.uk/guidance/ng101"}},{"setting":"The axilla after chemotherapy given before surgery","approach":"Sentinel node biopsy after chemotherapy is unreliable on its own: ACOSOG Z1071 found a false-negative rate of 12.6 percent against a pre-specified threshold of 10 percent. The fix is targeted axillary dissection, marking the biopsied node before chemotherapy and removing that node as well as the sentinel nodes, which brought the false-negative rate to 1.4 percent when combined with sentinel node dissection and 2.0 percent as a formal procedure. If the nodes are pathologically clear afterwards, NSABP B-51 found that regional nodal irradiation adds nothing (hazard ratio 0.88, 0.60 to 1.28, p=0.51). Whether axillary surgery can also be dropped in that situation is what ATNEC is recruiting to answer.","refs":["acosog-z1071","targeted-axillary-dissection-md-anderson","nsabp-b51","atnec","targeted-axillary-dissection","neoadjuvant-versus-adjuvant-breast"],"guideline":{"version":"NICE NG101 recommendations 1.13.26 to 1.13.29","url":"https://www.nice.org.uk/guidance/ng101"}},{"setting":"Radiotherapy after breast-conserving surgery","approach":"Whole-breast radiotherapy for every woman with invasive cancer and clear margins (NICE NG101 recommendation 1.13.3). The Early Breast Cancer Trialists' Collaborative Group overview of 10,801 women in 17 trials found radiotherapy cut the ten-year risk of any first recurrence from 35.0 to 19.3 percent and the fifteen-year risk of breast cancer death from 25.2 to 21.4 percent, with about one death avoided by year fifteen for every four recurrences avoided by year ten. A boost of 16 Gy to the tumour bed is offered where the risk of local recurrence is high (recommendation 1.13.17): EORTC 22881-10882 found twenty-year recurrence of 12.0 against 16.4 percent with no survival gain and severe fibrosis of 5.2 against 1.8 percent.","refs":["nsabp-b06","eortc-22881-boost","tumour-bed-boost","imrt-igrt","radiotherapy-omission-early-breast-cancer"],"guideline":{"version":"NICE NG101 recommendations 1.13.3 and 1.13.17","url":"https://www.nice.org.uk/guidance/ng101"}},{"setting":"Dose and schedule","approach":"In England, 26 Gy in five fractions over one week for partial-breast, whole-breast or chest-wall radiotherapy without nodal irradiation (NICE NG101 recommendation 1.13.13), and 40 Gy in fifteen fractions over three weeks when the regional nodes are treated (recommendation 1.13.16) or where a diagnosis increases radiosensitivity, an implant-based reconstruction has been done, or a three-week course is simply more acceptable (recommendation 1.13.14). The radiobiology came from three British trials: START-A held the treatment time constant and varied the fraction size, START-B established 40 Gy in fifteen, FAST estimated the alpha to beta ratio at 2.7 Gy and so predicted a five-fraction equivalent of 28 Gy, and FAST-Forward tested 26 Gy in five fractions in 4,096 women and found five-year recurrence of 1.4 against 2.1 percent. Deep inspiratory breath hold is used for left-sided cancers to lower the heart dose (recommendation 1.13.2), because major coronary events rise by 7.4 percent per gray of mean heart dose with no threshold.","refs":["start-a","start-b","fast-trial","fast-forward","hypofractionated-radiotherapy","hypofractionation","deep-inspiration-breath-hold","alpha-beta-ratio"],"guideline":{"version":"NICE NG101 recommendations 1.13.1, 1.13.2, 1.13.13, 1.13.14 and 1.13.16","url":"https://www.nice.org.uk/guidance/ng101"}},{"setting":"Treating less than the whole breast","approach":"Partial-breast radiotherapy is considered for women who have had breast-conserving surgery for invasive cancer excluding lobular type, with clear margins, aged 50 or over with tumours of 3 cm or less, node-negative, oestrogen receptor-positive, HER2-negative, grade 1 to 2, who will take endocrine therapy for at least five years, and it must be given by external beam (NICE NG101 recommendations 1.13.4 to 1.13.6). IMPORT LOW found five-year local relapse of 0.5 against 1.1 percent with fewer changes in breast appearance, while RAPID, which gave the dose twice a day, was non-inferior on recurrence but had late toxicity of 32 against 13 percent. Intraoperative radiotherapy during the lumpectomy met its non-inferiority margin in TARGIT-A and had lower mortality from causes other than breast cancer (hazard ratio 0.59, 0.40 to 0.86), but NICE TA501 does not recommend the Intrabeam system for routine commissioning and permits it only on existing machines under NHS England governance.","refs":["import-low","rapid","nsabp-b39","targit-a","partial-breast-irradiation","intraoperative-radiotherapy"],"guideline":{"version":"NICE NG101 recommendations 1.13.4 to 1.13.6; NICE TA501 (not recommended for routine commissioning)","url":"https://www.nice.org.uk/guidance/ta501"}},{"setting":"Who can leave radiotherapy out","approach":"Women aged 65 and over with clear margins and a very low absolute risk of local recurrence, defined by NICE NG101 recommendation 1.13.7 as T1N0, oestrogen receptor-positive, HER2-negative, grade 1 to 2, who are willing to take endocrine therapy for at least five years. Recommendation 1.13.8 sets out what must be said: without radiotherapy local recurrence occurs in about 50 women per 1,000 at five years and with it in about 10 per 1,000; overall survival at ten years is the same; and there is no increase in serious late effects from having it in this group. CALGB 9343 (aged 70 and over, ten-year locoregional recurrence 10 against 2 percent), PRIME II (aged 65 and over, ten-year local recurrence 9.5 against 0.9 percent) and LUMINA (aged 55 and over with luminal A biology, five-year local recurrence 2.3 percent) are the trials behind it. Outside that group radiotherapy after conservation remains standard.","refs":["calgb-9343","prime-ii","lumina","radiotherapy-omission-early-breast-cancer","active-surveillance"],"guideline":{"version":"NICE NG101 recommendations 1.13.7 and 1.13.8","url":"https://www.nice.org.uk/guidance/ng101"}},{"setting":"Radiotherapy after mastectomy, and to the nodes","approach":"Chest-wall radiotherapy is offered for node-positive macrometastatic disease or involved margins (NICE NG101 recommendation 1.13.10), considered for node-negative T3 or T4 disease (1.13.11) and not offered to people at low risk of local recurrence (1.13.12). SUPREMO tested it in intermediate-risk disease treated with modern systemic therapy and found ten-year overall survival of 81.4 against 81.9 percent (hazard ratio 1.04, p=0.80), with chest-wall recurrence of 1.1 against 2.5 percent. For the nodes: no regional nodal radiotherapy for histologically node-negative disease (1.13.19), no axillary radiotherapy after axillary clearance because the combination is the worst for the arm (1.13.20), supraclavicular fossa radiotherapy for four or more involved nodes (1.13.21) or for one to three with other poor prognostic factors (1.13.22), and the internal mammary chain considered within the nodal target for macrometastatic node-positive disease (1.13.23). MA.20 and EORTC 22922 are the trials behind nodal irradiation.","refs":["supremo","ma-20","eortc-22922","nsabp-b51","post-mastectomy-radiotherapy","mastectomy"],"guideline":{"version":"NICE NG101 recommendations 1.13.10 to 1.13.12 and 1.13.19 to 1.13.23","url":"https://www.nice.org.uk/guidance/ng101"}},{"setting":"Reconstruction","approach":"Reconstruction is offered to everyone having a mastectomy for breast cancer, and both timings, immediate and delayed, are offered whether or not they are available locally (NICE NG101 recommendations 1.5.1 and 1.5.3). Immediate reconstruction is offered even where radiotherapy is planned, unless other illness rules out the surgery (1.5.4). The choice between an implant and the woman's own tissue is a real trade: in the Mastectomy Reconstruction Outcomes Consortium, autologous reconstruction gave higher satisfaction with the breasts at two years (7.94 points, 5.68 to 10.20) but roughly double the odds of a complication, while implants failed more often (7.1 against 1.3 percent). British outcomes after implant reconstruction have been measured and are above the national standards: iBRA found implant loss of 9 percent, infection of 25 percent and return to theatre of 18 percent within three months across 81 units, and Pre-BRA found implant loss of 8.2 percent for the newer pre-pectoral technique. Mesh was used in 65 percent of iBRA reconstructions without randomised evidence; Best-BRA is the pilot trial testing implant placement properly.","refs":["mroc","ibra-study","pre-bra","best-bra","breast-reconstruction","bia-alcl","mastectomy"],"guideline":{"version":"NICE NG101 recommendations 1.5.1 to 1.5.5","url":"https://www.nice.org.uk/guidance/ng101"}},{"setting":"Drugs before or after surgery","approach":"Which drugs are given is decided by receptor status and belongs on the subtype pages; when they are given is shared. The Early Breast Cancer Trialists' Collaborative Group pooled 4,756 women in ten trials of the same chemotherapy before or after surgery and found no difference in distant recurrence (38.2 against 38.0 percent at fifteen years), breast cancer mortality or death from any cause, with breast conservation achieved in 65 against 49 percent and fifteen-year local recurrence higher after chemotherapy first (21.4 against 15.9 percent, rate ratio 1.37). Treating first is chosen to make conservation possible, to make a large or node-positive tumour operable, and to see whether the drugs work, because what remains at surgery now guides what follows, differently for each receptor subtype.","refs":["neoadjuvant-versus-adjuvant-breast","neoadjuvant-adjuvant","breast-hr-positive","breast-her2-positive","tnbc","pcr","rcb"],"guideline":{"version":"NICE NG101 recommendations 1.13.25 to 1.13.29; EBCTCG meta-analysis of ten trials","url":"https://doi.org/10.1016/S1470-2045(17)30777-5"}},{"setting":"Breast-conserving surgery or mastectomy","approach":"This is the decision the whole of early breast cancer turns on, and it is usually presented as a choice with the same outcome. That is true of survival and of almost nothing else, so it is worth having the actual numbers. Two randomised trials followed people for twenty years. In the Milan trial, 701 women with cancers no larger than 2 cm were assigned between 1973 and 1980 to radical (Halsted) mastectomy or to quadrantectomy followed by radiotherapy; after a median 20 years, death from any cause had occurred in 41.2 percent of the mastectomy group and 41.7 percent of the conserving group (P equals 1.0), and death from breast cancer in 24.3 and 26.1 percent (P equals 0.8). In NSABP B-06, 1,851 women were assigned to total mastectomy, lumpectomy alone, or lumpectomy with radiotherapy, and after 20 years there was no significant difference between the three in disease-free, distant-disease-free or overall survival, with a hazard ratio for death of 0.97 (0.83 to 1.14) for lumpectomy with radiotherapy against total mastectomy. Those are the cohorts they are: women treated decades ago, with the surgery and drugs of the time, and they say nothing about what will happen to one person. What they do say is that keeping the breast did not cost survival, which is why it is offered first. What differs is everything else, and this is the part usually summarised away. Radiotherapy: conserving surgery commits you to it. NICE NG101 (1.13.3) says to offer whole-breast radiotherapy after breast-conserving surgery with clear margins, and (1.13.13) 26 Gy in 5 fractions over 1 week where the lymph nodes are not being treated, or (1.13.14) 40 Gy in 15 fractions over 3 weeks where there is a reason including implant-based reconstruction, and (1.13.16) 40 Gy in 15 fractions whenever the nodes are irradiated. Mastectomy does not reliably avoid it: NG101 (1.13.10) offers radiotherapy after mastectomy for node-positive disease or involved margins, and (1.13.12) withholds it from most node-negative disease. What radiotherapy is worth after conserving surgery has been measured: in the EBCTCG meta-analysis of 10,801 women in 17 randomised trials, it cut the 10-year risk of any first recurrence from 35.0 to 19.3 percent and the 15-year risk of breast cancer death from 25.2 to 21.4 percent, with about one breast cancer death avoided by year 15 for every four recurrences avoided by year 10. For a narrow low-risk group NICE offers the choice of leaving it out: NG101 (1.13.7, 1.13.8) says to consider not using radiotherapy for women aged 65 and over with T1N0, ER-positive, HER2-negative, grade 1 to 2 cancer who will take endocrine therapy for at least 5 years, and to tell them that without radiotherapy local recurrence occurs in about 50 women per 1,000 at 5 years against about 10 per 1,000 with it, that overall survival at 10 years is the same, and that there is no increase in serious late effects from having it. A second operation: conserving surgery can need one. NG101 (1.4.3) offers further surgery where cancer is at the inked margin and (1.4.5) considers it within 1 mm, and the 2024 committee lowered that threshold from 2 mm precisely because repeated surgeries damage breast appearance and self-esteem, are traumatic, and vary in frequency across the country. How the breast looks and feels: after conserving surgery the treated breast can be smaller, firmer or dented, and NICE's own radiotherapy evidence records more clinician-assessed adverse events at 5 years and more reports of a harder or firmer breast with the one-week schedule, though it judged the differences not clinically important. After mastectomy the chest is numb over the scar whatever is done next. And what recurrence would mean: in the Milan trial, 30 of 352 women treated by quadrantectomy and radiotherapy had a recurrence in the same breast over 20 years, a crude cumulative incidence of 8.8 percent, against 8 local recurrences among 349 after radical mastectomy, 2.3 percent, with no difference in distant metastases; NSABP B-06 put in-breast recurrence at 14.3 percent over 20 years with radiotherapy and 39.2 percent without. A recurrence in a conserved breast is a further operation and a frightening year; it did not, in these trials, change survival. Finally, some cancers do not offer the choice. Macmillan lists the reasons a mastectomy is recommended: a lump large compared with the rest of the breast, cancer in different parts of the breast, widespread DCIS, cancer on the skin or in the underlying muscle, previous radiotherapy to the chest, or a gene mutation found on testing.","refs":["lumpectomy","mastectomy","breast-margins-and-re-excision","hypofractionated-radiotherapy","fast-forward","start-b","import-low","prime-ii","lumina","curative-intent","multidisciplinary-tumour-board","prehabilitation"],"guideline":{"version":"NICE NG101 (2018, updated 2025)","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Reconstruction surgery, delayed reconstruction, or neither","approach":"Three options, not two, and the third is a real one. NICE NG101 (1.5.1) says to offer breast reconstruction to people after they have had a mastectomy for breast cancer, and immediately afterwards (1.5.2) to be aware that some people may prefer not to have it. It also says (1.5.3) to offer both the immediate and the delayed option whether or not they are available locally, which is the sentence to quote when a local service offers only one, and (1.5.4) to offer immediate reconstruction to women advised to have a mastectomy including those who may need radiotherapy, unless comorbidities rule out reconstructive surgery. On timing, NG101's table 1 is unusually frank. Immediate reconstruction means waking with a breast shape, usually fewer operations and anaesthetics, and less scarring because the existing breast skin is used, but limited time to decide, a longer operation and recovery, and a risk that complications delay chemotherapy or radiotherapy; Cancer Research UK notes that there is good evidence chemotherapy works best started within 6 weeks of cancer surgery. Delayed reconstruction means a period with no breast, which a prosthesis can fill, but more time to choose, time to lose weight or stop smoking first, and a reconstruction that cannot be derailed by the cancer treatment. Both, NICE says, usually need more than one operation to complete, and there are no clear differences in satisfaction with completed reconstructions either way. On what each option asks of the body: an implant is the simplest operation and the shortest recovery, but NICE notes that implant-based reconstructions may be more affected by radiotherapy than flap reconstructions, and where radiotherapy is planned the route is often a tissue expander first and an exchange later, which is two operations. A flap moves skin, fat and sometimes muscle from the tummy or the back, gives a breast that ages and changes weight with you, and costs a second wound, a longer operation, a longer recovery and, where the tummy is used, a risk of hernia that smoking increases. Both carry flap or implant failure, which NICE says may lead to delayed reconstruction and a flat appearance for a period of time. Surgery to the other breast to match, called contralateral symmetrisation, is common and can be done at the same time or later. Whatever is built, Cancer Research UK says plainly that the new breast will feel and look different to the one removed: it is a shape rather than a restored breast, and it has little sensation. Choosing none is not a failure to decide. A prosthesis, specialist mastectomy wear, or nothing at all are all ordinary, and a surgeon can often make a flat chest wall even rather than leaving loose skin. For men the NHS does not routinely do implant reconstruction, because the implants available do not recreate the shape of a man's chest. After breast-conserving surgery there is a smaller version of the same conversation: where a large amount of tissue is removed the breast can be left with a dent, and a partial reconstruction using nearby tissue, or reshaping the breast (therapeutic mammoplasty, often with a reduction on the other side), can be done at the same operation. Radiotherapy still follows.","refs":["breast-reconstruction","mastectomy","lumpectomy","body-image-after-breast-surgery","numbness-after-breast-surgery","male-breast-cancer","psycho-oncology","peer-support-groups"],"guideline":{"version":"NICE NG101 (2018, updated 2025)","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Surgery to the armpit, and the lymphoedema risk that lasts for life","approach":"The armpit operation is decided almost in passing and is the single biggest determinant of how the arm feels for the rest of your life, so it is worth understanding. NICE NG101 (1.2.1) has the axilla scanned before treatment and any abnormal node sampled with a needle. If that is clear, (1.4.9) says to stage the axilla with a sentinel lymph node biopsy rather than a clearance, using (1.4.10) the dual technique of isotope and blue dye; Macmillan says this removes the smallest number of nodes possible, usually 1 to 3. If the needle biopsy already proved cancer in a node, (1.4.11) says to offer axillary node clearance. If a sentinel node turns out to contain cancer, (1.4.12) says to offer further axillary treatment, clearance or radiotherapy, for 1 or more macrometastasis; (1.4.13) says to discuss the benefits and risks of having no further treatment with women who have 1 or 2 macrometastases, have had conserving surgery, and are having whole-breast radiotherapy with systemic therapy; (1.4.14) says not to treat micrometastases further; and (1.4.15) says isolated tumour cells count as node-negative. The reason all of that exists is lymphoedema, and the figures are the part nobody hears. In a meta-analysis of 72 studies, the pooled incidence of arm lymphoedema after breast cancer was 16.6 percent, and 21.4 percent when restricted to 30 prospective cohorts, rising over the first two years; it was about four times higher after axillary lymph node dissection (19.9 percent) than after sentinel node biopsy (5.6 percent), and the risk factors with the strongest evidence were extensive surgery and being overweight or obese. That is where more than one in five comes from. Radiotherapy to the axilla instead of surgery roughly halves it: in AMAROS, 1,425 sentinel node-positive patients were randomised, and at 5 years lymphoedema affected 24.5 percent after clearance against 11.9 percent after axillary radiotherapy, while at 10 years axillary recurrence was 0.93 against 1.82 percent with no difference in survival. Two trials go further and leave the axilla alone: in ACOSOG Z0011, 891 women with 1 or 2 positive sentinel nodes having lumpectomy and whole-breast radiotherapy had 10-year overall survival of 86.3 percent without clearance against 83.6 percent with it, and in SENOMAC, 2,540 patients with 1 or 2 sentinel-node macrometastases, about 90 percent of them having nodal radiotherapy, had 5-year recurrence-free survival of 89.7 against 88.7 percent. What reduces the risk, in NICE's own 2025 words: information before treatment starts in a format to take away, covering risk reduction, early signs, skin changes, how to self-monitor and how to take baseline measurements of the limb (1.14.1); keeping to a healthy weight and keeping the arm moving, because (1.14.3) physical activity does not cause or worsen lymphoedema and may improve quality of life; and skin care, because infection is what tips a vulnerable arm over. NICE also clears away some folklore: (1.14.1) says there is no consistent evidence of increased risk from air travel, travel to hot countries, manicures, hot tub use or sports injuries, nor from blood tests, injections, intravenous medicines or blood pressure measurement on the treated side, and (1.14.2) makes procedures on that arm a shared decision rather than a prohibition. It says (1.14.4) not to offer compression garments as prevention to people who are only at risk. Recognising it early is the whole game. Breast Cancer Now describes swelling that comes and goes and is worse at the end of the day, rings and watches suddenly tight, tightness in the arm or breast without visible swelling, a dull ache, heaviness, tingling or numbness, dry skin, and later hardness or pins and needles. NICE (1.14.6) says to refer anyone who develops it to a specialist lymphoedema service as soon as possible. Treatment exists and works: (1.14.8) assess for other causes such as nodal disease or cellulitis first, (1.14.9) compression therapy as the first stage with a shared decision about the form, (1.14.10) kinesiology tape if compression is not tolerated, and (1.14.11) reassurance that exercise is safe. The NHS calls the whole package decongestive lymphatic therapy: compression, skin care, exercise and specialised massage, then a maintenance phase you run yourself. It is controlled rather than cured, which is why it is worth catching in the first weeks. Alongside lymphoedema sits the shoulder. NG101 (1.14.14) says to identify people as high risk before surgery if they have a pre-existing shoulder problem, a BMI over 30, planned axillary node clearance, or planned radiotherapy to the axilla or supraclavicular nodes, (1.14.16) to offer them supervised support with upper limb exercises, and (1.14.19) to refer anyone with a persistent reduction in arm and shoulder mobility to physiotherapy.","refs":["sentinel-lymph-node-biopsy","lymphadenectomy","sentinel-node","lymphoedema-after-breast-cancer","cording-axillary-web-syndrome","seroma-after-breast-surgery","lymphoedema-decongestive-therapy","hypofractionated-radiotherapy","late-effects"],"guideline":{"version":"NICE NG101 (2018, updated 2025)","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Fertility and early menopause, decided before treatment starts","approach":"This is the decision with a deadline. Chemotherapy can stop the ovaries working, temporarily or permanently, and treatment can bring the menopause forward by decades; once treatment has started, some of the options have gone. NICE NG101 (1.1.5) hands fertility preservation to the NICE fertility guideline, now NG257 (2026), and NG257 (1.53.1) says to discuss it with people preparing for treatment likely to impair their fertility, and that where treatment is urgent the discussion should happen at the earliest possible opportunity. The route it names is (1.53.6) oocyte or embryo cryopreservation for people of reproductive age with female reproductive organs, (1.53.5) sperm cryopreservation for those with male reproductive organs, which matters because men get breast cancer too, and (1.53.7) ovarian tissue cryopreservation where the others are not feasible. Two sentences in NG257 are worth carrying into the room. The first is (1.53.3): for NHS-funded fertility preservation, do not apply the eligibility criteria used for conventional fertility treatment, including the lower age limit. The rules about age, existing children and BMI that govern NHS IVF are not supposed to be applied to preserving fertility before cancer treatment. The second is (1.53.4): those criteria will apply later, when you come to use the stored material, so the funding question has two halves and it is worth asking both. Storage is reviewed at least every 5 years and NHS funding continues for people who remain at significant risk (1.53.8). On timing, Cancer Research UK says collecting and freezing eggs takes about 2 to 3 weeks, that IVF is the most effective method, that letrozole or tamoxifen can be used with lower-dose stimulation, and that IVF is available for some people on the NHS but not everywhere, so the answer varies by where you live. Where there is no time for any of that, the other route is switching the ovaries off during chemotherapy with a GnRH agonist injection. In an individual patient-level meta-analysis of 873 patients from five randomised trials, premature ovarian insufficiency occurred in 14.1 percent of those given a GnRH agonist against 30.9 percent of controls (adjusted odds ratio 0.38), and at least one pregnancy after treatment in 10.3 against 5.5 percent, with no significant difference in disease-free or overall survival. The trial that opened this question, POEMS, randomised 257 premenopausal women with operable hormone receptor-negative breast cancer and found ovarian failure at 2 years in 8 percent on goserelin against 22 percent, with pregnancy in 21 against 11 percent. Whether this is offered as well as, or instead of, egg freezing is a conversation for the fertility clinic rather than a substitute for it. If the menopause arrives anyway, it arrives fast and without the years of warning a natural menopause gives. NICE NG101 (1.14.20) says to offer women information and counselling about the possibility of early menopause and its symptoms, and (1.14.21) to stop systemic HRT at diagnosis. On treating the symptoms it is restrictive and says so: (1.14.22) do not routinely offer HRT to women with a history of breast cancer; (1.14.23) offer it in exceptional circumstances for severe symptoms after discussing the risks; (1.14.24) consider an SSRI for hot flushes, but not for women taking tamoxifen; and (1.14.25) do not offer soy, red clover, black cohosh, vitamin E or magnetic devices. Bone follows: (1.14.26) offer a baseline DEXA scan to women not on adjuvant bisphosphonates who are starting an aromatase inhibitor, have a treatment-induced menopause, or are starting ovarian suppression; (1.14.27) not to those on tamoxifen alone; and (1.14.28) bisphosphonates for those the UK expert group algorithms identify. Whether it is safe to pause endocrine therapy to try for a baby is a question for hormone receptor-positive disease and is answered on that page.","refs":["fertility-preservation","menopause-after-chemotherapy-breast","breast-hr-positive","male-breast-cancer","cbt-fatigue-distress","psycho-oncology"],"guideline":{"version":"NICE NG257 (2026) and NICE NG101 (2018, updated 2025)","url":"https://www.nice.org.uk/guidance/ng257/chapter/Fertility-preservation-for-medical-indications"}},{"setting":"Body image, sensation and sex","approach":"Start with the thing almost nobody is told before they consent. Breast and armpit surgery cuts small sensory nerves, so an area of the chest, the breast, the armpit and the upper inner arm is numb afterwards. Cancer Research UK puts it as numbness, tingling or a shooting pain in the armpit, upper arm, shoulder or chest wall from nerve damage during surgery, and says the nerves usually repair themselves but it can take many weeks or months. The longer-term picture comes from a Danish national survey: of 3,253 women aged 18 to 70 who answered a median of 26 months after surgery, 1,543 (47 percent) reported pain in the treated area, 201 of them severe and 595 moderate; the odds of persistent sensory disturbance were about five times higher after axillary lymph node dissection than after sentinel lymph node dissection (odds ratio 4.97, 3.92 to 6.30) and five times higher in women aged 18 to 39; radiotherapy raised the odds of pain and chemotherapy did not. Only about 1 in 5 of those in pain had spoken to a doctor about it in the previous three months, which is the second half of the problem: it is treatable, and people do not report it because they were never told to expect it. A reconstructed breast has little or no sensation however good it looks, and a spared nipple usually has none. Cancer Research UK says the new breast will feel and look different to the one removed. That is worth asking about separately from appearance, before the operation, because it is not something a photograph shows. On the body you are left with: Cancer Research UK says swelling and bruising go down and scars fade, but it may take up to a year for things to settle, and that the first few months can bring intense feelings. NICE NG101 (1.1.2) says to offer all people with breast cancer prompt access to specialist psychological support and, where appropriate, psychiatric services, which makes asking for it a request for something already promised. Breast Cancer Now's Someone Like Me pairs people with a volunteer who has been through something similar, and Maggie's centres are free and need no appointment. On sex, plainly. Cancer Research UK says breast surgery does not affect your ability to have sex, but that emotions may change sexual feelings for a while and that you might worry about letting a partner see or touch your body. The physical obstacles are usually treatable and usually unmentioned: numbness where the breast used to respond, a chest wall that hurts to lie on, shoulder stiffness that makes positions awkward, fatigue, and, where treatment has forced the menopause, vaginal dryness and pain, which is a symptom with treatments rather than something to endure. NICE NG101 (1.14.20) puts information and counselling about menopausal symptoms into the guideline. Nothing here assumes the reader is a woman, has a partner, is heterosexual, or has stopped wanting sex. Men with breast cancer have their own page and the same conversation is owed to them; the NHS does not routinely offer implant reconstruction to men because the implants available do not recreate the shape of a man's chest, which makes the scar and the sensation the whole of the outcome.","refs":["numbness-after-breast-surgery","body-image-after-breast-surgery","breast-reconstruction","menopause-after-chemotherapy-breast","male-breast-cancer","psycho-oncology","peer-support-groups","quality-of-life"],"guideline":{"version":"NICE NG101 (2018, updated 2025)","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Hair, and whether scalp cooling is worth it","approach":"It is the first question people ask and the one answered with the least detail, so here is what is known. Not every breast cancer treatment causes hair loss: it depends on the drugs, which depend on the receptor result, and the subtype pages list the regimens. Where it happens, Macmillan says it usually starts after the first or second treatment, that eyebrows and eyelashes can go as well, and that hair usually starts to grow back after treatment, sometimes with a different texture or colour. Scalp cooling is the only thing that changes the outcome. In the SCALP randomised trial, 50.5 percent of women cooled during taxane, anthracycline or both kept more than half their hair after the fourth cycle, against none of the controls. That is the honest headline: about half kept enough hair to go without a wig, and about half did not, and the trial counted keeping more than half rather than keeping all of it. The figure is better with taxane-only regimens and worse with anthracyclines. A caveat that belongs beside every one of those numbers: the trials that produced them had few Black participants, and a later phase II study of the Paxman device in Black patients having chemotherapy for stage I to III breast cancer closed early after 15 of a planned 30 participants for lack of efficacy, with hair loss and distress scores rising during cooling and only one participant avoiding significant loss; the authors named hair thickness, hair volume and cap design as the likely reasons. Anyone quoting one in two should say whose hair it was measured on. Practically, cooling means wearing a tight cold cap from before the infusion until some time after it, so treatment days get longer, and it is uncomfortable at the start. Availability varies by unit, so whether it is offered at all is a question for the first chemotherapy appointment rather than the third. If you would want a wig, Macmillan says to get it before treatment starts, because matching your own colour and style is easier while you still have it and you can get used to wearing it; buying and practising with eyebrow and eyelash products beforehand works the same way. Some people shave their heads first for the sense of control. The Little Princess Trust provides free real-hair wigs to people up to the age of 24. None of this is vanity. Hair is how most people are recognised, including by themselves, and losing it is often the moment a diagnosis becomes visible to everyone else.","refs":["hair-loss-and-scalp-cooling-breast","scalp-cooling","psycho-oncology","peer-support-groups"],"guideline":{"version":"NICE NG101 (2018, updated 2025)","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Survivorship: follow-up, and which symptom is worth a phone call","approach":"Follow-up after breast cancer is lighter than most people expect, and the reason is that scans of people without symptoms have never been shown to help. NICE NG101 (1.15.1) says to offer annual mammography for 5 years to everyone who has had or is being treated for breast cancer including DCIS, and for women to continue annual mammography past 5 years until they enter the NHS Breast Screening Programme in England or the Breast Test Wales Screening Programme; (1.15.2) not to do mammography of the ipsilateral soft tissues after a mastectomy; and (1.15.3) not to use routine ultrasound or MRI for post-treatment surveillance. That first rule is under revision: NICE reviewed the guideline on 11 September 2026 and says it will be updating the recommendation on annual mammography, following a surveillance decision taken in June 2026, with no new wording published yet. What replaces the scans is a document and a phone number. NG101 (1.15.4) says to ensure everyone who has had treatment has an agreed written care plan, recorded in the notes by a named professional and copied to them and their GP, that names the designated healthcare professionals, the dates for reviewing any adjuvant therapy, the details of surveillance mammography, the signs and symptoms to look out for and seek advice on, the contact details for immediate referral to specialist care, and the contact details for support services such as lymphoedema. If you do not have that piece of paper, asking for it is asking for something the guideline already promised. Which symptoms count. Breast Cancer Now gives a three-part rule that is easier to hold than a list: talk to your GP or breast care nurse about any symptom that is new, has no obvious cause, and does not go away, and it says the same rule applies to people already living with secondary breast cancer, where a new symptom may mean the cancer is progressing. Its organ-by-organ list is the one to keep: in the bone, pain that does not improve with painkillers and may be worse lying down or at night, a fracture, or unexplained back pain with difficulty walking, numbness or loss of bladder or bowel control; in the lungs, breathlessness on activity or at rest, a cough that does not go away, or chest pain or tightness that persists; in the liver, pain under the right ribs or in the right shoulder, sickness, loss of appetite and weight, hiccups, a swollen abdomen or yellowing of the skin; in the brain, headache, morning sickness or vomiting, weakness or numbness down one side, unsteadiness, seizures, speech or vision problems, or changes in behaviour or memory; in the skin or the chest wall, a rash, a change in skin colour, or a firm painless lump; and in the lymph nodes, a lump or swelling under the arm, breastbone or collarbone. Three general ones sit above the list: constant tiredness, constant nausea, and unexplained weight loss and loss of appetite. The point of writing them down is not to make the reader watch for cancer in every ache. It is that the three-part test, new plus unexplained plus persistent, is what distinguishes the ache that needs a call from the one that does not, and having it in advance is what stops people waiting months out of a wish not to make a fuss. Alongside all of this, NG101 (1.4.16, 1.4.17) asks every breast unit to audit its local, regional, distant and axillary recurrence rates, including radial margins and demographic information such as socioeconomic status, age and ethnicity, which is a fair thing to ask your own unit about.","refs":["survivorship-care-plan","late-effects","bone-metastases","brain-metastases","metastatic-spinal-cord-compression","lymphoedema-after-breast-cancer","palliative-care","financial-navigation","work-and-money-breast-cancer-uk","carers-breast-cancer-uk"],"guideline":{"version":"NICE NG101 (2018, updated 2025)","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}}],"stateOfArt":["Five-year survival above 90 percent in early disease across high-income countries, driven by screening, endocrine therapy and HER2-targeted drugs.","Antibody-drug conjugates such as trastuzumab deruxtecan have redrawn the HER2 boundary and moved into HER2-low disease.","Genomic tests spare most node-negative hormone receptor-positive patients chemotherapy.","Omission of radiotherapy in older low-risk women and one-week hypofractionation are reducing treatment burden.","The operation has shrunk twice over. Breast conservation replaced mastectomy for most early cancers on four trials that all reported at twenty years or more with no survival difference, and the axilla has gone from full clearance to one or two sentinel nodes to, in SOUND and INSEMA, no axillary operation at all for small tumours with a clear ultrasound.","Radiotherapy has gone from five weeks to one. England now gives 26 Gy in five fractions over a week as the default whole-breast, partial-breast or chest-wall schedule when the nodes are not treated, on a chain of British trials running from START-A through START-B and FAST to FAST-Forward.","De-escalation is now guided by response as well as by risk. NSABP B-51 showed that regional nodal irradiation can be dropped when chemotherapy given first clears the nodes, and SUPREMO found no survival gain from chest-wall radiotherapy in intermediate-risk disease treated with modern drugs."],"history":[{"year":1894,"title":"Halsted radical mastectomy","note":"The standard operation for seventy years.","refs":[]},{"year":1985,"title":"NSABP B-06: lumpectomy plus radiotherapy equals mastectomy","refs":[]},{"year":1991,"title":"Elston and Ellis make breast grading reproducible","note":"The Nottingham revision of Bloom and Richardson's grade scores tubule formation, nuclear pleomorphism and mitotic count separately and adds them. Grade was assessed in 1,831 patients of the Nottingham series and separated survival with p less than 0.0001. It is still the only grading system UK practice permits.","refs":["nottingham-grade"]},{"year":1992,"title":"The Nottingham Prognostic Index is published","note":"Nine candidate factors were tested in 387 patients and three survived: size, node stage and grade. In the first 1,629 patients the good prognosis group, 29 percent of the series, had 80 percent fifteen-year survival against 83 percent in an age-matched female population (Galea 1992).","refs":["nottingham-prognostic-index"]},{"year":2000,"title":"Molecular subtypes described","note":"Perou and Sorlie's expression profiling defines luminal, HER2-enriched and basal-like breast cancers.","refs":["basal-like","pam50"]},{"year":2002,"title":"Twenty-year results: keeping the breast costs nothing in survival","note":"NSABP B-06 and Milan I both report at twenty years and NSABP B-04 at twenty-five, none of them finding a survival advantage for the larger operation.","refs":["nsabp-b06","milan-i","nsabp-b04"]},{"year":2010,"title":"NSABP B-32: the sentinel node replaces axillary clearance","note":"5,611 women; eight-year overall survival 90.3 against 91.8 percent, and in ALMANAC lymphoedema at a year fell from 13 to 5 percent.","refs":["nsabp-b32","almanac"]},{"year":2017,"title":"Z0011 at ten years: a positive sentinel node no longer means clearing the axilla","note":"Ten-year overall survival 86.3 percent without completion clearance against 83.6 percent with it.","refs":["acosog-z0011"]},{"year":2018,"title":"UICC TNM 8 becomes the UK staging standard for breast cancer","note":"Used for all breast tumours diagnosed after 1 January 2018. The Royal College of Pathologists reprints it and advises against substituting the American AJCC 8th edition, whose prognostic stage folds grade and receptors into the stage number.","refs":["tnm-breast-cancer-editions","ajcc-prognostic-stage-breast"]},{"year":2019,"title":"WHO classification of breast tumours, 5th edition","note":"Keeps invasive carcinoma of no special type as the default group and folds the former medullary, oncocytic, lipid-rich, glycogen-rich, sebaceous and pleomorphic carcinomas into it as patterns. This is the edition UK reports are written against in 2026.","refs":["who-breast-classification"]},{"year":2020,"title":"FAST-Forward: whole-breast radiotherapy in one week","note":"26 Gy in five fractions non-inferior to 40 Gy in fifteen at five years; adopted across the United Kingdom and accelerated by the pandemic.","refs":["fast-forward","fast-trial"]},{"year":2024,"title":"The UK breast reporting dataset is rewritten","note":"RCPath G148 version 3 (November 2024) adds the ER low positive category, a separate section on male breast disease, updated handling of specimens after neoadjuvant treatment, and an appendix on assessing tumour cellularity for molecular testing. Full review is due November 2026.","refs":["er-pr-scoring-breast","er-pr-negative-threshold"]},{"year":2025,"title":"The de-escalation year: INSEMA, NSABP B-51 and SUPREMO","note":"Axillary surgery omitted in 4,858 patients, regional nodal irradiation dropped after a complete nodal response, and no survival gain from chest-wall radiotherapy in intermediate-risk disease.","refs":["insema","nsabp-b51","supremo"]},{"year":2026,"title":"TNM 9 takes effect, and leaves breast staging alone","note":"Published 3 July 2025 and recommended from 1 January 2026. For breast the classification is unchanged; the yp classification is clarified, basing ypT on the largest continuous focus of residual invasive cancer and recommending that the residual cancer burden be reported beside it.","refs":["tnm-breast-cancer-editions","rcb"]},{"year":2026,"title":"WHO classification of breast tumours, 6th edition","note":"Published April 2026. Reserves 'variant' for molecular alterations and separates subtype from pattern, updates the HER2 reporting categories so that no membrane staining is distinguished from any, recognises lobular carcinoma with extracellular mucin, moves high-grade and receptor-negative mucinous carcinomas into no special type, drops the unified neuroendocrine model for the breast, and lowers malignant phyllodes tumour to four of five adverse criteria.","refs":["who-breast-classification"]}],"pipeline":["trastuzumab-deruxtecan","datopotamab-deruxtecan","oral-serds"],"openProblems":["The receptor result produces four boxes and the world is organised around three. One report gives a hormone receptor answer and a HER2 answer, and the four combinations are unequal: 70.1 percent hormone receptor-positive HER2-negative, 9.3 percent positive for both, 4.0 percent HER2-positive alone and 10.8 percent triple-negative (SEER 21, 2019 to 2023). Guidelines, trials and patient information are written for three subtypes, so the largest HER2-positive group, the people who are hormone receptor-positive as well, have to read two sets of advice and work out where they overlap.","The classification a report is written against is two years behind the classification in print. The sixth edition of the WHO classification of breast tumours appeared in April 2026 and changed the vocabulary of subtype, pattern and variant, the HER2 reporting categories and the criteria for several types; the UK reporting dataset in force was written against the fifth edition and is due for review in November 2026. Every page in this family, and every report a patient is holding, is currently a fifth-edition document, and there is no mechanism that tells a patient which edition her report was written to.","Stage does not contain grade or the receptors, and the tools that patch the gap disagree with each other. The UK dataset says so in its own words, which is why the Nottingham Prognostic Index and PREDICT exist; America solved the same problem inside the stage number with the AJCC prognostic stage, which the UK dataset advises against using. A British and an American clinician can therefore give the same tumour a different stage, and PREDICT is explicitly less accurate in women under 30, women over 70, tumours over 50 mm, and has never been validated in men.","Receptor conversion is measured but not acted on by evidence. On meta-analysis of 39 paired studies, 22.5 percent of oestrogen receptor-positive primaries had become negative in their metastases and 21.3 percent of HER2-positive ones had, with conversion in the other direction too; NICE asks only that reassessment be considered where it would change management. No prospective study has shown what treating on the metastasis rather than the primary does to survival, so the commonest decision in relapsed breast cancer rests on a biological argument rather than a trial (Schrijver 2018).","The measurements underneath every one of these systems are less precise than the decisions they drive. Grade agrees between core biopsy and surgical specimen about 70 percent of the time; the national screening programme's quality assurance scheme finds poor agreement between pathologists on tumour size even on prepared slides; there is no internationally agreed method for scoring oestrogen receptor; and pathologists disagree at the HER2 0 to 1+ boundary that now decides eligibility for an antibody-drug conjugate.","POSNOC is the only trial in which a woman with a positive sentinel node receives no axillary treatment at all, radiotherapy included; until it reports, every de-escalation result rests on an axilla that was quietly irradiated in nine cases out of ten.","Every partial-breast irradiation trial required pathological nodal staging for eligibility, so the women who now have no sentinel node biopsy under SOUND and INSEMA criteria fall outside the evidence for the radiotherapy they are being offered.","Implant-based reconstruction in the United Kingdom runs above the National Quality Standards on implant loss, infection, reoperation and readmission, and mesh was in majority use for years without a randomised trial; Best-BRA is a pilot, not an answer.","The de-escalation portfolio is inefficient. A systematic review of 97 trials in up to 94,866 participants found multiple studies asking nearly the same question, with patients rarely involved in designing them.","Radiotherapy omission is defined by age thresholds that biology does not respect. LUMINA selected by luminal A biology rather than by age and got a lower recurrence rate than the age-based trials, but the guidelines still key the decision to 65 or 70."],"basics":{"symptoms":["A new lump or thickening in the breast or armpit, a change in the size, shape or feel of a breast, skin puckering or dimpling, a rash, redness or crusting on the nipple or the skin, fluid leaking from a nipple you are not breastfeeding from, or a nipple that has turned inwards (NHS)","Most breast changes are not cancer, and most lumps turn out to be benign; the reason to have a change checked is not that it is probably serious but that it cannot be told apart from something serious without looking","Redness and inflammation may look darker or brownish rather than red on brown or black skin, which is one reason inflammatory breast cancer is missed more often in some patients (Cancer Research UK)","Men have breast tissue and get breast cancer too, about 420 UK cases a year against about 59,000 in women; there is a page for it, and there is no screening programme for men, so a lump behind a man's nipple needs the same appointment (Cancer Research UK)","Pain is not a typical symptom. Breast pain without a lump or a skin change is common, is usually hormonal, and is rarely how breast cancer presents (NHS)","The referral rules the GP is working to, and what the appointment involves, are on the NHS pathway page; this page is about what the results mean when they come back"],"diagnosis":["Every invasive breast cancer has its oestrogen receptor, progesterone receptor and HER2 status assessed at the same time, at the initial histopathological diagnosis, by standardised and quality-assured techniques reported quantitatively, and recorded at both the preoperative and the postoperative multidisciplinary meeting (NICE NG101 1.3.1 to 1.3.5)","MRI is not used routinely before surgery. It is offered when the extent of disease is unclear from examination, mammography and ultrasound, when breast density defeats mammography, or to size an invasive lobular cancer before breast-conserving surgery (NG101 1.2.2, 1.2.3)","The axilla is scanned before treatment and any abnormal node is sampled with a needle (NG101 1.2.1)","The pathology report carries the histological type, the Nottingham grade with its three component scores, the invasive and whole tumour size in millimetres, the node stage, the excision margins, the receptor results and the assessment of treatment effect where chemotherapy came first (RCPath G148, version 3, November 2024)","In advanced disease the choice for staging the rest of the body is contrast-enhanced CT of the chest, abdomen and pelvis or FDG PET-CT, with the caution that some lobular and some low-grade cancers take up the tracer poorly (NICE CG81 1.3.1, 1.3.2)","If the cancer comes back, reassessing the hormone receptor and HER2 status is considered where a change would change management, because the receptors of a metastasis are often not those of the primary (NICE CG81 1.4.1)"],"staging":["Three things are measured and they answer three different questions: the grade is how abnormal the cells look, the stage is how far the cancer has gone, and the receptor status is what it will respond to. None can be worked out from the others","Grade: three features, tubule formation, nuclear pleomorphism and mitotic count, each scored 1 to 3 and added. Total 3 to 5 is grade 1, 6 or 7 is grade 2, 8 or 9 is grade 3 (Elston and Ellis; RCPath G148)","Grades are not expected in equal thirds: the expected ratio of grades 1, 2 and 3 is about 2:3:5 in symptomatic breast cancer and about 3:5:2 in screen-detected breast cancer, so a grade 3 is commoner in a cancer found as a lump than in one found by screening (RCPath G148)","Stage: UK reports stage against UICC TNM 8, which the RCPath dataset names and reprints, warning that AJCC TNM 8 should not be used in its place because the two differ significantly. NICE NG101 names no edition at all","TNM 9 was published on 3 July 2025 and UICC recommends it from 1 January 2026. For breast the classification is unchanged; the one change clarifies the post-treatment yp classification, basing ypT on the largest continuous focus of residual invasive cancer and recommending that residual cancer burden be reported beside it (Brierley 2026)","In situ disease is staged Tis with the type in brackets, Tis (DCIS) or Tis (LCIS), and inflammatory carcinoma is T4d, a clinical diagnosis rather than a size","Because stage does not include grade or the receptors, the UK adds the Nottingham Prognostic Index, grade plus node stage plus 0.2 times the size in centimetres, banded from excellent below 2.4 to poor at 5.4 and above (RCPath G148; Galea 1992)","PREDICT is the tool used in the clinic to put stage, grade, receptors, age and detection method together and estimate the benefit of each treatment; NICE NG101 1.6.4 recommends it and 1.6.5 lists where it is less accurate, including that it has not been validated in men","Tumour size is less precise than it looks: the national screening programme's quality assurance scheme finds poor agreement between pathologists on size even on prepared slides, and separate deposits 5 mm or more apart are not added together (RCPath G148)"],"sources":[{"label":"NICE NG101: early and locally advanced breast cancer, diagnosis and management (published 18 July 2018, last updated 14 April 2025)","url":"https://www.nice.org.uk/guidance/ng101/chapter/recommendations"},{"label":"Royal College of Pathologists G148: dataset for histopathological reporting of breast disease in surgical excision specimens of breast cancer, version 3, November 2024 (full review due November 2026)","url":"https://www.rcpath.org/resourceLibrary/g148-dataset-for-histopathological-reporting-of-breast-disease-in-surgical-excision-specimens-of-breast-cancer.html"},{"label":"NICE CG81: advanced breast cancer, diagnosis and treatment, diagnosis and assessment section (published 23 February 2009, last updated 30 June 2026)","url":"https://www.nice.org.uk/guidance/cg81/chapter/Diagnosis-and-assessment"},{"label":"Brierley et al., International Journal of Cancer 2026: the 9th edition of the UICC TNM classification of malignant tumours, updates and rationale for change (breast: the classification remains unchanged, the yp classification is clarified)","url":"https://doi.org/10.1002/ijc.70561"},{"label":"Elston and Ellis, Histopathology 1991;19:403 to 410: pathological prognostic factors in breast cancer, the value of histological grade, with long-term follow-up of 1,831 graded patients","url":"https://doi.org/10.1111/j.1365-2559.1991.tb00229.x"},{"label":"Galea, Blamey, Elston and Ellis, Breast Cancer Research and Treatment 1992;22:207 to 219: the Nottingham Prognostic Index in primary breast cancer","url":"https://doi.org/10.1007/bf01840834"},{"label":"NHS: breast cancer in women, symptoms","url":"https://www.nhs.uk/conditions/breast-cancer/symptoms/"},{"label":"Cancer Research UK: breast cancer statistics (UK incidence, mortality, survival, stage at diagnosis and routes to diagnosis)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer"}]},"prognosis":{"text":"These are population figures, quoted with the group they were measured in. They describe what happened to large numbers of people who were diagnosed years ago and treated with what was available then, and they are not a prediction about any one person.\n\nBy receptor subtype, in American women diagnosed between 2016 and 2022, five-year relative survival was 95.8 percent for hormone receptor-positive HER2-negative disease, 92.2 percent for hormone receptor-positive HER2-positive, 87.0 percent for hormone receptor-negative HER2-positive and 78.7 percent for triple-negative disease, against 91.9 percent for all breast cancer (SEER 21). By stage the same source gives, for hormone receptor-positive HER2-negative disease, 100.0 percent localised, 91.1 percent regional and 38.1 percent distant; for triple-negative disease 92.8, 68.3 and 14.9 percent. The pattern is the point: the subtype matters much less when the cancer is found early than when it is found late.\n\nIn the UK, 76.6 percent of women survive breast cancer for ten years or more (2018 prediction, Cancer Research UK), and mortality rates have fallen 46 percent since the early 1970s. Survival is not evenly distributed: five-year survival in England is 82.6 percent in the most deprived group against 89.6 percent in the least (2018 to 2022).\n\nThe single largest lever on all of these numbers is the stage at which the cancer is found, which is why 85 percent of English cases being diagnosed at stage I or II matters more than any of the treatment comparisons on the pages below.","sources":[{"label":"SEER Cancer Stat Facts: female breast cancer subtypes (share of cases and five-year relative survival by receptor subtype and stage, SEER 21)","url":"https://seer.cancer.gov/statfacts/html/breast-subtypes.html"},{"label":"Cancer Research UK: breast cancer statistics (UK incidence, mortality, survival, stage at diagnosis and routes to diagnosis)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer"},{"label":"SEER Cancer Stat Facts: female breast cancer (incidence, stage distribution and survival)","url":"https://seer.cancer.gov/statfacts/html/breast.html"}]}},{"id":"breast-implant-associated-alcl","kind":"cancer","name":"Breast implant-associated anaplastic large cell lymphoma","aka":["BIA-ALCL","Breast implant-associated ALCL","Breast implant-associated anaplastic large-cell lymphoma","Implant-associated ALCL","Breast implant lymphoma"],"tldr":"A rare lymphoma that grows in the scar capsule the body forms around a breast implant, usually many years after the operation, and usually shows itself as sudden swelling of the breast from fluid around the implant. It is linked to textured implants, and when it is confined to the capsule it is usually cured by removing the implant and the capsule whole.","summary":"What it is. A T-cell lymphoma that arises in the fibrous capsule the body builds around a breast implant. In most women it stays inside that capsule and in the fluid between the capsule and the implant, and does not invade. WHO-HAEM5 describes it as an entity distinct from other ALK-negative anaplastic large cell lymphomas, usually non-invasive, arising in association with textured-surface implants, and associated with an excellent outcome, and adds that invasion of adjacent structures worsens the outlook.\n\nHow it shows itself, and the one thing that must not be missed. The usual presentation is a late seroma: the reconstructed or augmented breast swells, often suddenly, more than a year after the operation and typically many years after it. The rule that follows is simple and is the single most useful sentence on this page. A late seroma around a breast implant is aspirated, and the fluid is sent for cytology and for CD30 immunohistochemistry, rather than simply drained. Less often the disease presents as a mass in the capsule or as contracture of the capsule, and those carry a worse outlook because the disease has left the fluid.\n\nHow it differs from the lymphoma it is named after. It carries CD30 and lacks ALK, like systemic ALK-negative anaplastic large cell lymphoma, and it behaves nothing like it. The systemic disease is treated with combination chemotherapy and is cured in a minority; this one, confined to the capsule, is treated surgically and is cured in almost everybody.\n\nWhy the implant matters. The cases are almost exclusively in women with textured implants. In the Dutch series, 23 of the 28 implants of known type in the lymphoma cases were macrotextured, 82 per cent, against 45 per cent of implants sold in the same country over the same years. The meta-analysis found the same risk whether the implant was placed for reconstruction after cancer or for cosmetic reasons. WHO-HAEM5 describes the biology as involving an allergic inflammatory response, escape from the immune system through amplification at 9p24.1 and overexpression of PD-L1 in more than half of cases, and constant activation of the JAK-STAT pathway through mutations of STAT3, STAT5B, JAK1 and JAK2 and loss-of-function mutations of SOCS1 and SOCS3.\n\nWhat the treatment is. Complete removal of the implant together with the whole capsule, intact where possible, and removal of any mass, which for disease confined to the capsule is usually the whole of the treatment. Disease that has spread beyond the capsule or formed a mass is staged and treated systemically, as a CD30-positive T-cell lymphoma. Women with implants and no symptoms are not advised to have them removed; the advice rests on recognising a late seroma and investigating it properly.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Anaplastic_large-cell_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"Breast implants and the risk of anaplastic large-cell lymphoma in the breast, Dutch nationwide pathology registry (de Boer, JAMA Oncology 2018)","url":"https://doi.org/10.1001/jamaoncol.2017.4510"},{"label":"Risk of breast implant-associated anaplastic large cell lymphoma, systematic review and meta-analysis (Aesthetic Plastic Surgery 2024)","url":"https://doi.org/10.1007/s00266-024-03956-9"}],"tags":["heme","lymphoma","subtype-page"],"related":["alk-negative-anaplastic-large-cell-lymphoma","alk-positive-anaplastic-large-cell-lymphoma","peripheral-t-cell-lymphoma","breast-cancer","non-hodgkin-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc"],"targets":["cd30"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["bia-alcl","lymphoma-classification-2022","lymphoma-nodal-versus-extranodal","lymphoma-b-versus-t-cell"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare in absolute terms, and strongly concentrated in women with textured implants. In the Dutch nationwide pathology registry, which identified every primary breast lymphoma between 1990 and 2016, 32 of 43 women with anaplastic large cell lymphoma of the breast had an implant on the same side, against 1 of 146 women with other primary breast lymphomas. The cumulative risk in women with implants was 29 per million at age 50 and 82 per million at 70, and the authors calculated that 6,920 women would need an implant to cause one case before the age of 75. A later meta-analysis across 525,475 patients with implants and 254 cases put the median time from implant to diagnosis at 13.16 years. The glossary entry written for the breast cancer pages carries the full set of figures.","subtypes":["Confined to the seroma and the capsule, the great majority of breast implant-associated ALCL, usually cured by complete removal","With a mass or invasion beyond the capsule, which carries a worse outlook and needs systemic treatment"],"biomarkers":["CD30 on the large cells in the seroma fluid, which is how the diagnosis is made","Absence of ALK, as in systemic ALK-negative anaplastic large cell lymphoma","Whether the disease is confined to the capsule or has formed a mass or invaded, which is the main determinant of outcome","The implant surface: cases are almost exclusively associated with textured implants","Amplification at 9p24.1 with PD-L1 overexpression in more than half of cases, and activating mutations of STAT3, STAT5B, JAK1 and JAK2"],"standardOfCare":[{"setting":"A late swelling around a breast implant","approach":"A seroma appearing around a breast implant more than a year after the operation is aspirated and the fluid sent for cytology and for CD30 immunohistochemistry, rather than simply drained. That single step is what makes the diagnosis, and draining without testing is how it is missed. The same applies to a new mass in the capsule or to capsular contracture appearing years after surgery. Imaging, usually ultrasound in the first instance, maps the fluid and any mass.","refs":["histopathology-ihc","cd30","bia-alcl"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Disease confined to the capsule","approach":"Complete removal of the implant together with the whole capsule, intact where it can be done, and removal of any associated mass. For disease that has not left the capsule this is usually the whole of the treatment, and WHO-HAEM5 describes the entity as usually non-invasive and associated with an excellent outcome. Removal of an implant on the other side is discussed case by case. Women with implants and no symptoms are not advised to have them removed.","refs":["bia-alcl","histopathology-ihc"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Disease that has formed a mass or spread","approach":"Staged and treated as a CD30-positive T-cell lymphoma, on the pathway used for systemic anaplastic large cell lymphoma, because WHO-HAEM5 records that invasion of adjacent structures worsens the outlook. Radiotherapy to the chest wall is used in some series for disease that cannot be removed completely. The evidence is case series; there are no trials and there will not be, because the great majority of patients are cured by surgery.","refs":["alk-negative-anaplastic-large-cell-lymphoma","brentuximab-vedotin","lymphoma-tx-radiotherapy","peripheral-t-cell-lymphoma"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":2016,"title":"Recognised as a provisional entity","note":"The revised fourth edition of the WHO classification named breast implant-associated anaplastic large cell lymphoma as a provisional entity separate from systemic ALK-negative disease.","refs":[]},{"year":2018,"title":"The size of the risk measured in a national registry","note":"The Dutch pathology registry found an implant on the same side in 32 of 43 women with breast anaplastic large cell lymphoma against 1 of 146 with other primary breast lymphomas, and put the cumulative risk in women with implants at 29 per million by age 50 and 82 per million by 70.","refs":[]},{"year":2022,"title":"Confirmed as a distinct entity","note":"WHO-HAEM5 lists it as one of the three anaplastic large cell lymphomas, describes it as usually non-invasive and associated with an excellent outcome, and records that invasion of adjacent structures worsens the outlook.","refs":["lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["The absolute risk is small and the exposure is very common, so the right advice to a woman who already has textured implants and no symptoms is a question about communication rather than about oncology; current guidance is not to remove them.","Why a textured surface and not a smooth one is not fully explained, and the proposed mechanisms, chronic inflammation and an allergic response to the surface, have not been shown to be the cause.","Because the disease is almost always cured by surgery, there are no randomised trials and there will not be, so the management of the minority with invasive disease rests on case series."],"parent":"peripheral-t-cell-lymphoma"},{"id":"buccal-mucosa-cancer","kind":"cancer","name":"Buccal mucosa and gingivobuccal cancer (oral cancer in India)","aka":["Gingivobuccal complex cancer","Cheek cancer","Betel quid-associated oral cancer","Indian oral cancer"],"tldr":"Cancer of the cheek lining and gums is India's commonest cancer in men, caused by chewing tobacco and areca nut. Surgery with reconstruction is the mainstay, and trials from Tata Memorial in Mumbai have shown that removing the neck nodes up front, cheap oral chemotherapy, tiny doses of immunotherapy and visual screening by health workers all save lives at low cost.","summary":"Squamous cell carcinoma of the buccal mucosa, gingivobuccal sulcus, lower alveolus and retromolar trigone is the characteristic oral cancer of South Asia, where smokeless tobacco (gutka, khaini, mawa) and areca nut are held against the cheek for hours a day. It is often preceded by leukoplakia or by oral submucous fibrosis, the areca-nut induced stiffening of the cheek that limits mouth opening and hides tumours. The Kerala trial, reported by Sankaranarayanan in 2005, showed that visual oral examination by trained health workers cut oral cancer deaths in tobacco or alcohol users by about a third, the only randomised evidence for oral cancer screening.\n\nSurgery is the mainstay: wide excision with marginal or segmental mandibulectomy for bone involvement, clearance of the infratemporal fossa when the masticator space is involved, neck dissection and free-flap reconstruction with anterolateral thigh or fibula flaps. The Tata Memorial trial of elective neck dissection, reported by D'Cruz in 2015 in 596 patients with early node-negative oral cancer, showed three-year overall survival of 80.0 against 67.5 percent, and Tata Memorial surgeons have redefined which tumours invading the masticator space can still be resected; induction docetaxel-cisplatin-fluorouracil is used to make borderline tumours operable. Postoperative radiotherapy or cisplatin chemoradiation follows for advanced stage, extranodal extension or positive margins.\n\nBecause most Indian patients present late and few can afford imported drugs, Tata Memorial trials have built a low-cost palliative pathway: oral methotrexate with celecoxib beat intravenous cisplatin (median survival 7.5 against 6.1 months, with fewer serious side effects); adding nivolumab at one-twentieth of the usual dose raised one-year survival from 16.3 to 43.4 percent; and METRO PLUS in Varanasi doubled median survival from 5 to 10 months by adding metronomic tablets to paclitaxel-carboplatin. Tobacco control, state bans on gutka and screening are the levers for prevention, and incidence is still rising.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Oral_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Oral_cancer"}],"tags":["subtype-page","head-and-neck"],"related":["lip-cancer","oral-tongue-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["celecoxib"],"companies":[],"institutions":["tata-memorial","actrec","homi-bhabha-cancer-hospital-varanasi"],"pathways":[],"terms":["extranodal-extension","depth-of-invasion"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-dcruz-elective-neck-dissection-nejm-2015","paper-sankaranarayanan-oral-screening-lancet-2005","paper-bernier-eortc-22931-nejm-2004","paper-cooper-rtog-9501-nejm-2004"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"India carries about a third of the world's oral cancers, and the gingivobuccal complex (the cheek lining, the gums and the sulcus between them) is the commonest site there because chewed tobacco and areca nut sit in the cheek pouch; it is the leading cancer in Indian men.","subtypes":["Buccal mucosa squamous cell carcinoma","Gingivobuccal sulcus and lower alveolus (gum) cancer","Retromolar trigone cancer","Cancer arising in oral submucous fibrosis (areca nut)","Verrucous carcinoma of the buccal mucosa"],"biomarkers":["Depth of invasion and bone invasion (marginal versus segmental mandibulectomy)","Masticator space involvement (resectability)","Extranodal extension and margin status","Oral submucous fibrosis and leukoplakia (precursors)","TP53 mutation","PD-L1 combined positive score (recurrent disease)"],"standardOfCare":[{"setting":"Screening in high-risk populations","approach":"Visual oral examination by trained health workers for tobacco and alcohol users (Kerala trial); treatment of leukoplakia and management of oral submucous fibrosis.","refs":["kerala-oral-screening","oral-visual-screening"],"guideline":{"version":"Kerala trial (Lancet 2005)","url":"https://doi.org/10.1016/S0140-6736(05)66658-5"}},{"setting":"Resectable disease","approach":"Wide excision with marginal or segmental mandibulectomy as needed, elective or therapeutic neck dissection (Tata Memorial trial), and free-flap reconstruction.","refs":["elective-neck-dissection-tmh","imrt-igrt"],"guideline":{"nccn":"Category 1 (elective neck dissection)","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Borderline resectable (masticator space involvement)","approach":"Induction docetaxel-cisplatin-fluorouracil to shrink technically unresectable tumours, then surgery in responders (Tata Memorial practice); chemoradiation otherwise.","refs":["docetaxel","cisplatin","fluorouracil","chemoradiation"]},{"setting":"After surgery","approach":"Postoperative radiotherapy for advanced stage, perineural invasion or nodes; cisplatin chemoradiation for extranodal extension or positive margins.","refs":["imrt-igrt","cisplatin","chemoradiation"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Palliative and recurrent disease","approach":"Oral metronomic methotrexate with celecoxib; low-dose nivolumab added where affordable; metronomic tablets with paclitaxel-carboplatin (METRO PLUS); pembrolizumab where available.","refs":["methotrexate","metronomic-vs-cisplatin-tmh","nivolumab","low-dose-nivolumab-tmh","metro-plus-varanasi","pembrolizumab"]},{"setting":"Prevention","approach":"Smokeless tobacco and areca nut cessation, gutka bans, and oral screening in high-risk people.","refs":["smoking-cessation-after-diagnosis","oral-visual-screening"]}],"stateOfArt":["Tata Memorial trials have produced category 1 evidence for elective neck dissection and the only randomised evidence for oral cancer screening.","Low-cost metronomic chemotherapy and low-dose immunotherapy are now standards for palliative care across South Asia.","Compartment surgery and free-flap reconstruction have made resection of masticator-space tumours possible."],"history":[{"year":1941,"title":"Tata Memorial Hospital opens in Bombay","refs":[]},{"year":2005,"title":"Kerala trial: visual screening cuts oral cancer deaths in high-risk people","refs":["kerala-oral-screening"]},{"year":2015,"title":"Elective neck dissection improves survival in early oral cancer","refs":["elective-neck-dissection-tmh"]},{"year":2020,"title":"Oral metronomic methotrexate-celecoxib beats cisplatin","refs":["metronomic-vs-cisplatin-tmh"]},{"year":2023,"title":"Low-dose nivolumab nearly triples one-year survival","refs":["low-dose-nivolumab-tmh"]},{"year":2026,"title":"METRO PLUS: metronomic tablets with paclitaxel-carboplatin double survival","refs":["metro-plus-varanasi"]}],"pipeline":["low-dose-nivolumab-tmh","metro-plus-varanasi","oral-visual-screening","nivopostop"],"openProblems":["Late presentation and rising incidence as areca nut and gutka use spread.","Access to pembrolizumab, cetuximab and radiotherapy machines outside big cities.","Whether low-dose immunotherapy matches full-dose treatment.","Trismus and eating after cheek and jaw resection."],"parent":"oral-cavity-cancer"},{"id":"burkitt-leukaemia","kind":"cancer","name":"Burkitt leukaemia","aka":["Burkitt leukemia","Burkitt lymphoma/leukaemia","Mature B-cell acute lymphoblastic leukaemia","B-ALL L3 (retired FAB term)","Burkitt leukaemia (more than 25% marrow blasts)","Burkitt-type (mature B) leukaemia, treated as lymphoma"],"tldr":"Burkitt leukaemia is Burkitt lymphoma presenting mainly in the bone marrow and blood, so that it looks like acute lymphoblastic leukaemia but is a mature B-cell cancer driven by the MYC gene. It is treated as Burkitt lymphoma, with short, very intensive chemotherapy plus rituximab and protection of the brain, and most children and many adults are cured.","summary":"The WHO classification identifies Burkitt lymphoma/leukaemia as one highly aggressive mature B-cell neoplasm with endemic, sporadic and immunodeficiency-associated variants, all carrying MYC rearrangements, and the leukaemic presentation is defined by more than 25 percent marrow blasts (Alaggio 2022; Blum 2004). Brief-duration, high-intensity chemotherapy with aggressive central nervous system prophylaxis achieves complete remission in 75 to 90 percent of adults with overall survival of 50 to 70 percent, and the cells are extremely chemosensitive (Blum 2004). In children, a phase 2 window study of a single dose of rituximab in 136 patients with newly diagnosed mature B-cell lymphoma and Burkitt leukaemia established its activity before it was built into paediatric regimens (Meinhardt 2010).\n\nHow it differs from its parent: presentation by marrow failure and blood involvement rather than an abdominal or jaw mass, a higher tumour burden with tumour lysis risk at the start of treatment, and the need to distinguish it from precursor B-cell acute lymphoblastic leukaemia (which lacks surface immunoglobulin and MYC rearrangement) because the treatments differ entirely.\n\nHow common: no registry figure for the leukaemic presentation alone.\n\nTreatment: as Burkitt lymphoma on the parent page, with the regimens for high-risk or marrow-involved disease (rituximab with CODOX-M/IVAC, dose-adjusted EPOCH-R in adults, LMB or BFM-type regimens with rituximab in children), intrathecal and high-dose methotrexate prophylaxis, and tumour lysis prevention with rasburicase (Blum 2004; Meinhardt 2010).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Burkitt_lymphoma","links":[{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq"},{"label":"NCI PDQ: acute lymphoblastic leukaemia treatment","url":"https://www.cancer.gov/types/leukemia/patient/adult-all-treatment-pdq"},{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"Blum 2004, Blood: adult Burkitt leukaemia and lymphoma","url":"https://doi.org/10.1182/blood-2004-02-0405"},{"label":"Meinhardt 2010, JCO: rituximab window study in paediatric mature B-cell lymphoma and Burkitt leukaemia","url":"https://doi.org/10.1200/jco.2009.26.6791"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["burkitt-lymphoma","all-leukemia","hiv-associated-lymphoma","mixed-phenotype-acute-leukaemia","dlbcl"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["rituximab","methotrexate","cyclophosphamide","cytarabine"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"A minority presentation of Burkitt lymphoma, defined by more than 25 percent marrow blasts; adult Burkitt lymphoma and leukaemia together are a rare, highly aggressive mature B-cell neoplasm (Blum 2004). No registry figure for the leukaemic presentation alone is in the sources read.","subtypes":["Sporadic Burkitt leukaemia (the usual form in Europe and North America)","Endemic Burkitt lymphoma with marrow involvement (EBV-positive)","Immunodeficiency-associated Burkitt leukaemia (HIV)","Burkitt leukaemia with central nervous system involvement"],"biomarkers":["MYC rearrangement (t(8;14) or variants) with surface immunoglobulin and CD20","Marrow blasts over 25 percent; cerebrospinal fluid cytology","Lactate dehydrogenase and uric acid (tumour lysis risk)","EBV status and HIV serology"],"standardOfCare":[{"setting":"All cases","approach":"Treated as high-risk Burkitt lymphoma: short intensive chemotherapy with rituximab, methotrexate-based CNS prophylaxis and tumour lysis prevention.","refs":["burkitt-lymphoma","rituximab","methotrexate","cyclophosphamide"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"burkitt-lymphoma"},{"id":"burkitt-lymphoma","kind":"cancer","name":"Burkitt lymphoma","aka":["Burkitt lymphoma/leukaemia","Endemic Burkitt lymphoma","Sporadic Burkitt lymphoma","Immunodeficiency-associated Burkitt lymphoma"],"tldr":"Burkitt lymphoma is the fastest-growing human tumour, driven by a single rearrangement that switches on the MYC gene. That speed makes it exquisitely sensitive to chemotherapy: short, intense courses, now with the antibody rituximab, cure the great majority of children in well-resourced settings. The remaining task is to bring the same cure to the African children who make up most cases.","summary":"Burkitt lymphoma is a mature B-cell neoplasm defined by translocation of MYC to an immunoglobulin locus, most often t(8;14), with cooperating mutations in ID3, TCF3 and CCND3. It exists in three epidemiological forms: endemic (equatorial Africa and Papua New Guinea, almost always Epstein-Barr virus positive, linked to Plasmodium falciparum malaria, classically presenting in the jaw or abdomen), sporadic (worldwide, usually abdominal, EBV in a minority) and immunodeficiency-associated (HIV). The 2022 WHO classification separates EBV-positive and EBV-negative Burkitt lymphoma. Bone-marrow and CNS involvement define the highest-risk group and are common at presentation.\n\nTreatment is short, dose-intense, CNS-directed multi-agent chemotherapy: the French LMB and German BFM regimens in children (cyclophosphamide, vincristine, prednisone, high-dose methotrexate, cytarabine, etoposide, doxorubicin with intrathecal therapy), CODOX-M/IVAC or dose-adjusted EPOCH-R in adults. The Inter-B-NHL Ritux 2010 trial (NEJM 2020) showed that adding rituximab to LMB chemotherapy in high-risk children and adolescents improved event-free survival, making rituximab part of paediatric standard care. Tumour lysis syndrome at treatment start is a major hazard and rasburicase, hydration and a low-intensity pre-phase are integral to the protocols. Relapse is uncommon but very hard to treat; CD19 CAR-T and bispecific antibodies are being explored.\n\nThe global picture is stark: in sub-Saharan Africa, where most cases occur, cure rates are limited by late presentation, supportive-care capacity and the toxicity of intensive regimens. Cyclophosphamide-based and modified LMB regimens with rituximab (where affordable) have improved outcomes in Malawi, Uganda and elsewhere, and the AfriBL and other consortia are testing risk-adapted, resource-appropriate protocols. Burkitt lymphoma is therefore both a model of curable cancer and a test of whether cures can travel.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Burkitt_lymphoma","links":[{"label":"NCI PDQ: childhood non-Hodgkin lymphoma (Burkitt)","url":"https://www.cancer.gov/types/lymphoma/hp/child-nhl-treatment-pdq"},{"label":"Inter-B-NHL Ritux 2010: rituximab in high-risk paediatric B-NHL (NEJM 2020)","url":"https://doi.org/10.1056/NEJMoa1915315"},{"label":"SIOP PODC adapted treatment guidelines for Burkitt lymphoma in low-income settings","url":"https://doi.org/10.1002/pbc.24407"}],"tags":["nci-coverage","paediatric","haematologic","global-health"],"related":["dlbcl","hiv-associated-lymphoma","all-leukemia","primary-mediastinal-b-cell-lymphoma","primary-cns-lymphoma","double-hit-rearrangement"],"cancers":[],"sections":[],"technologies":["monoclonal-antibody","cytotoxic-chemotherapy","car-t","global-oncology-access","cytogenetics-fish","histopathology-ihc","cgp"],"targets":["cd20","cd19","myc-gene","tcf3","id3","ccnd3","tp53"],"drugs":["rituximab","cyclophosphamide","methotrexate","doxorubicin","vincristine","etoposide","rasburicase"],"companies":["childrens-oncology-group"],"institutions":["siop-europe","uganda-cancer-institute"],"pathways":["myc","oncogenic-viruses","bcr-signalling","pi3k-akt-mtor","cell-cycle-engine-cdks"],"terms":["tumor-lysis-syndrome","ebv-term","lymphoma-type","lymphoma-tx-tumour-lysis","lymphoma-tx-regimen-alphabet","lymphoma-tx-fertility-preservation","lymphoma-tx-pjp-and-infection-prophylaxis","lymphoma-bio-germinal-centre","lymphoma-bio-ebv-latency"],"trials":["inter-b-nhl-ritux-2010"],"people":[],"bottlenecks":["b-global-access"],"keyPapers":["paper-minard-colin-n-engl-j-med","paper-hesseling-pediatr-blood-cancer"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"The most common childhood cancer in equatorial Africa and the most common non-Hodgkin lymphoma of children worldwide; rare in adults (NCI PDQ).","subtypes":["Endemic (EBV-positive, malaria-associated)","Sporadic","Immunodeficiency-associated (HIV)","Burkitt leukaemia (more than 25% marrow blasts)","High-grade B-cell lymphoma with 11q aberration (Burkitt-like, MYC-negative)"],"biomarkers":["MYC rearrangement (t(8;14), t(2;8), t(8;22)) by FISH","EBV status (EBER)","Ki-67 near 100%","ID3, TCF3, CCND3 mutations","Lactate dehydrogenase and uric acid (tumour lysis risk)","Bone marrow and cerebrospinal-fluid involvement (stage IV / leukaemic)"],"standardOfCare":[{"setting":"Children and adolescents, all stages","approach":"Risk-stratified LMB or BFM regimen with intrathecal therapy; rituximab added for high-risk (stage III with high LDH, stage IV, leukaemic) disease per Inter-B-NHL Ritux 2010; low-intensity pre-phase and tumour lysis prophylaxis.","refs":["rituximab","cyclophosphamide","methotrexate","doxorubicin","vincristine","etoposide","inter-b-nhl-ritux-2010"],"guideline":{"version":"Inter-B-NHL Ritux 2010 (NEJM 2020); NCI PDQ","url":"https://doi.org/10.1056/NEJMoa1915315"}},{"setting":"Adults","approach":"Dose-adjusted EPOCH-R (lower toxicity, effective in older and HIV-positive patients) or CODOX-M/IVAC-R or hyper-CVAD-R; CNS prophylaxis in all.","refs":["rituximab","cyclophosphamide","doxorubicin","etoposide","methotrexate"],"guideline":{"nccn":"Category 2A","version":"NCCN B-cell lymphomas"}},{"setting":"Resource-limited settings","approach":"Cyclophosphamide-based or modified LMB regimens with intrathecal therapy, adding rituximab where available; investment in supportive care (transfusion, antimicrobials, tumour lysis management) is the main lever.","refs":["cyclophosphamide","global-oncology-access"],"guideline":{"version":"SIOP PODC adapted treatment guidelines","url":"https://doi.org/10.1002/pbc.24407"}},{"setting":"Relapsed or refractory","approach":"No standard; salvage chemotherapy with autologous or allogeneic transplant in responders, CD19 CAR-T and bispecific antibodies in trials.","refs":["autologous-stem-cell-transplant","allogeneic-hsct","car-t"]},{"setting":"Burkitt lymphoma in adults: which intensive regimen, and the pre-phase that prevents tumour lysis","approach":"The fastest-growing human tumour, with a doubling time measured in hours, and curable in the large majority when treated immediately with an intensive multi-agent regimen that includes central nervous system-directed treatment. R-CHOP is not adequate and should not be used.\n\nThree accepted regimens. Risk-adapted dose-adjusted EPOCH-R, tested in 113 adults across 22 centres: low-risk patients received three cycles with no central nervous system prophylaxis and high-risk patients six cycles with intrathecal prophylaxis; event-free survival was 84.5 per cent and overall survival 87.0 per cent at a median 58.7 months, with event-free survival of 100 per cent in the low-risk group and 82.1 per cent in the high-risk group. It worked equally well regardless of age, HIV status and IPI group, and five patients (4 per cent) died of treatment. CODOX-M/IVAC and hyper-CVAD with high-dose methotrexate and cytarabine are the older, more intensive inpatient alternatives, used particularly where there is central nervous system involvement, for which dose-adjusted EPOCH-R performed least well.\n\nBefore the first full dose: a pre-phase of low-dose cyclophosphamide and prednisolone for about a week to shrink the tumour gradually, intravenous fluids, allopurinol or rasburicase, and electrolyte monitoring every six to eight hours. Tumour lysis syndrome, not the lymphoma, is what kills people in the first week.","refs":["lymphoma-tx-tumour-lysis","rasburicase","lymphoma-tx-regimen-alphabet","rituximab","etoposide","doxorubicin","cyclophosphamide","vincristine","prednisone","methotrexate","cytarabine","ifosfamide","intrathecal-therapy","lymphoma-tx-fertility-preservation"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; risk-adapted DA-EPOCH-R (JCO 2020)","url":"https://doi.org/10.1200/JCO.20.00303"}},{"setting":"Burkitt lymphoma with HIV, and in countries where the endemic form is common","approach":"HIV does not change the regimen. In the 113-adult dose-adjusted EPOCH-R study a quarter of patients were HIV positive and did as well as the rest; antiretroviral therapy is continued through chemotherapy, with attention to interactions, and co-trimoxazole prophylaxis is given. Rituximab is used in HIV-associated Burkitt lymphoma provided the CD4 count is not very low.\n\nThe endemic form, driven by Epstein-Barr virus and malaria and presenting as a jaw or abdominal mass in children in equatorial Africa, is treated with regimens designed for what a unit can actually deliver: reduced-intensity cyclophosphamide-based protocols with intrathecal therapy, given where blood products, dialysis and intensive care may not be available. Cure rates in those settings are lower than in high-income countries, and the limiting factors are late presentation, abandonment of treatment and supportive care rather than the drugs. Where rituximab can be obtained, adding it to chemotherapy improves outcomes in high-risk paediatric mature B-cell lymphoma.","refs":["paper-hesseling-pediatr-blood-cancer","paper-minard-colin-n-engl-j-med","paper-sparano-blood","rituximab","cyclophosphamide","intrathecal-therapy","ebv-term","lymphoma-tx-tumour-lysis","lymphoma-tx-pjp-and-infection-prophylaxis"],"guideline":{"version":"NCI PDQ childhood non-Hodgkin lymphoma; Hesseling et al. for resource-limited settings","url":"https://www.cancer.gov/types/lymphoma/hp/child-nhl-treatment-pdq"}},{"setting":"Burkitt lymphoma that relapses","approach":"Relapse is uncommon, occurs early and is difficult to treat; it is the reason the first regimen must be the right one. Options are a non-cross-resistant salvage regimen such as R-ICE or R-GDP followed by autologous or allogeneic transplant in those who respond, CD19 CAR-T, which has activity but is less well established here than in diffuse large B-cell lymphoma, and a clinical trial. Central nervous system involvement at relapse requires high-dose methotrexate or cytarabine with intrathecal therapy. Early and explicit discussion of what is realistic belongs in this conversation, alongside the offer of a trial.","refs":["lymphoma-tx-regimen-alphabet","lymphoma-tx-transplant-role","autologous-stem-cell-transplant","allogeneic-hsct","car-t","axicabtagene-ciloleucel","methotrexate","cytarabine","palliative-care"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":["Short intensive chemotherapy cures most children; rituximab added a further step in high-risk disease (Inter-B-NHL Ritux 2010).","MYC translocation plus a small set of cooperating mutations make Burkitt one of the best-understood lymphomas at the genomic level.","Dose-adjusted EPOCH-R has made adult and HIV-associated Burkitt lymphoma treatable with far less toxicity.","The largest gap is geographical: most children with Burkitt lymphoma live where intensive protocols and supportive care are hard to deliver, and adapted regimens are closing the gap.","MYC is the defining lesion and has been localisable since 1982, when the gene was mapped to the chromosome 8 region translocated to chromosome 2, 14 or 22 in Burkitt cells. The partner is always an immunoglobulin locus, so the growth driver is run by the enhancer that should be making antibody.","MYC alone is not enough. Burkitt lymphoma needs a second lesion that supplies survival, and it comes from tonic B-cell receptor signalling: TCF3 activation or ID3 inactivation in 70% of sporadic cases, switching on the PI3K pathway. A third, independent lesion drives the cycle directly, with CCND3 mutations producing unusually stable cyclin D3 in 38%.","The uncomfortable gap is that none of this has produced a drug. The regimens that cure Burkitt lymphoma are the most toxic in lymphoma, which is exactly the problem in older patients and in the equatorial regions where the endemic, Epstein-Barr-positive form occurs."],"history":[{"year":1958,"title":"Denis Burkitt describes the jaw tumour of African children","note":"Later maps its distribution to the malaria belt.","refs":[]},{"year":1964,"title":"Epstein-Barr virus discovered in Burkitt lymphoma cells","note":"Epstein, Achong and Barr identify the first human tumour virus.","refs":[]},{"year":1972,"title":"t(8;14) translocation identified (Manolov and Manolova)","refs":[]},{"year":1982,"title":"MYC mapped to the translocation breakpoint","note":"Dalla-Favera and Taub show MYC is juxtaposed to the immunoglobulin heavy-chain locus.","refs":["myc"]},{"year":1990,"title":"LMB89 establishes short intensive therapy","note":"French SFOP protocol cures most children including stage IV.","refs":["cyclophosphamide","methotrexate"]},{"year":2012,"title":"Genomic landscape: ID3, TCF3 and CCND3","note":"Schmitz and Richter (Nature, Nature Genetics) define the cooperating mutations.","refs":[]},{"year":2020,"title":"Inter-B-NHL Ritux 2010: rituximab improves outcomes in children","note":"Minard-Colin and colleagues (NEJM 2020).","refs":["rituximab","inter-b-nhl-ritux-2010"]}],"pipeline":["inter-b-nhl-ritux-2010","car-t","global-oncology-access"],"openProblems":["Relapsed Burkitt lymphoma is rarely curable; CD19-directed CAR-T and bispecifics are being tested.","Cure rates in sub-Saharan Africa remain far below high-income countries; adapted protocols, rituximab access and supportive-care investment are the response.","Acute toxicity (tumour lysis, mucositis, infection) of intensive regimens, particularly in adults and the immunocompromised.","Late effects of anthracyclines and alkylators in survivors treated as children."],"parent":"non-hodgkin-lymphoma"},{"id":"cancer-of-unknown-primary","kind":"cancer","name":"Cancer of unknown primary (CUP)","aka":["CUP","Occult primary"],"tldr":"Cancer found already spread, where doctors cannot find where it started. Genomic profiling finds a drug target in about a third of cases and tumour-agnostic approvals apply directly; the rest still rely on general-purpose chemotherapy, which is what those tests are changing.","summary":"CUP is metastatic cancer with no identifiable primary after standardised work-up (history, examination, CT chest/abdomen/pelvis, immunohistochemistry panel, tumour markers, PET-CT and endoscopy where indicated). About 15-20% fall into favourable subsets treated like the presumed primary: extragonadal germ cell tumours, women with isolated axillary adenocarcinoma (treat as breast), women with peritoneal serous carcinoma (treat as ovarian), squamous carcinoma in cervical nodes (treat as head and neck, often HPV+), isolated inguinal squamous nodes, neuroendocrine carcinomas, and single resectable metastases. The unfavourable majority (adenocarcinoma or poorly differentiated carcinoma with visceral spread) receive empiric platinum-taxane or platinum-gemcitabine chemotherapy with median survival ~9-12 months.\n\nTwo molecular strategies compete: tissue-of-origin classifiers (gene expression or methylation) directing site-specific therapy, which did not improve survival in randomised trials (GEFCAPI 04), and genomic profiling directing targeted or immune therapy, which improved progression-free survival in CUPISCO (2024, Lancet). Nivolumab is approved for CUP in Japan (NivoCUP). ESMO 2023 guidelines recommend comprehensive genomic profiling for all unfavourable CUP.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin","links":[{"label":"ESMO CUP guideline 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"},{"label":"NCCN Guidelines: Occult Primary","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1451"},{"label":"CUP Foundation (Jo's Friends)","url":"https://www.cupfoundjo.org/"}],"tags":["gap-fill","site-agnostic"],"related":[],"cancers":[],"sections":[],"technologies":["cgp","histopathology-ihc","pet-ct","liquid-biopsy","methylation-profiling","platinum","checkpoint-inhibitor"],"targets":["ntrk","braf","her2","pd1"],"drugs":["carboplatin","paclitaxel","gemcitabine-cisplatin","pembrolizumab","nivolumab"],"companies":["roche-genentech","foundation-medicine","bms"],"institutions":[],"pathways":[],"terms":["tumour-agnostic","tmb","msi","ihc"],"trials":[],"people":["jim-valvano"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"other","burden":"About 2-3% of all cancer diagnoses (down from ~5% as imaging and pathology improved); median survival for the unfavourable majority remains under a year.","subtypes":["Favourable subsets (extragonadal germ cell, axillary node adenocarcinoma in women, peritoneal serous carcinoma, cervical node SCC, neuroendocrine, single metastasis)","Unfavourable: adenocarcinoma with liver/multiple metastases","Poorly differentiated carcinoma","Squamous carcinoma of unfavourable sites","Provisional CUP resolved by molecular tissue-of-origin"],"biomarkers":["Immunohistochemistry panel (CK7/CK20, TTF-1, CDX2, GATA3, PAX8, NKX3.1, SOX10, p16)","Comprehensive genomic profiling (targetable alterations in ~30%)","MSI, TMB, PD-L1 (tumour-agnostic immunotherapy)","Tissue-of-origin classifiers (gene expression, methylation)","AFP, hCG (germ cell), PSA (men), CA-125","ctDNA"],"standardOfCare":[{"setting":"Favourable subsets","approach":"Treat as the presumed primary: e.g. axillary node-only adenocarcinoma in women as breast cancer (mastectomy or axillary dissection + radiotherapy, systemic therapy); cervical node SCC with chemoradiation; peritoneal serous carcinoma as ovarian.","refs":["carboplatin","paclitaxel","imrt-igrt"],"guideline":{"version":"ESMO CUP guideline 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}},{"setting":"Unfavourable, first line","approach":"Empiric carboplatin-paclitaxel or cisplatin-gemcitabine ×4-6; comprehensive genomic profiling at diagnosis to find targetable alterations or immunotherapy biomarkers.","refs":["carboplatin","paclitaxel","gemcitabine-cisplatin","cgp"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Occult Primary","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1451"}},{"setting":"Molecularly directed","approach":"Targeted therapy for actionable alterations (e.g. NTRK, BRAF V600E, HER2, ALK) and pembrolizumab for MSI-H/TMB-H; CUPISCO supports molecular-guided therapy after induction chemotherapy.","refs":["pembrolizumab","nivolumab","cgp","liquid-biopsy"],"guideline":{"version":"CUPISCO (Lancet 2024)","url":"https://doi.org/10.1016/S0140-6736(24)00814-6"}}],"stateOfArt":["Genomic profiling finds an actionable alteration in about a third of CUP and improved PFS in a randomised trial (CUPISCO).","Tissue-of-origin prediction is accurate but has not improved survival when used to pick chemotherapy.","Tumour-agnostic approvals (NTRK, MSI-H, TMB-H, BRAF, RET, HER2) apply directly to CUP.","Better imaging and pathology have shrunk the category by half; the residue is biologically aggressive."],"history":[{"year":1979,"title":"Cisplatin-based therapy cures some 'poorly differentiated carcinoma of unknown primary' (Greco, Hainsworth)","note":"Recognition of the extragonadal germ cell subset.","refs":[]},{"year":2003,"title":"Favourable subsets codified (Pavlidis, Fizazi)","refs":[]},{"year":2013,"title":"Tissue-of-origin gene expression tests (CancerTYPE ID) enter practice","refs":[]},{"year":2019,"title":"GEFCAPI 04: site-specific therapy by molecular classifier no better than empiric chemotherapy","refs":[]},{"year":2021,"title":"Nivolumab approved for CUP in Japan (NivoCUP)","refs":["nivolumab"]},{"year":2023,"title":"ESMO guideline recommends comprehensive genomic profiling","refs":[]},{"year":2024,"title":"CUPISCO: molecularly guided therapy improves PFS (Lancet)","refs":["cgp"]}],"pipeline":["cgp","liquid-biopsy","methylation-profiling","pembrolizumab"],"openProblems":["Whether finding the primary matters, or only finding the target.","Median survival under a year for unfavourable CUP despite decades of trials.","Access to genomic profiling for a diagnosis that is over-represented in older and deprived patients.","Trial design when the population is defined by absence."]},{"id":"cup-favourable-subsets","kind":"cancer","name":"Cancer of unknown primary, favourable subsets","aka":["Favourable-risk CUP","Treatable CUP subsets","CUP with a presumed primary","Specific CUP syndromes"],"tldr":"Favourable subsets of cancer of unknown primary are the roughly one in five cases where the pattern of spread, the microscope appearance or blood markers point strongly to a particular cancer even though no primary can be found. They are treated as that cancer would be, for example breast cancer for a woman with cancer only in armpit nodes, and many are curable or controllable for years.","summary":"Cancer of unknown primary is a metastatic cancer whose origin cannot be found despite a full work-up. Within it, decades of clinical observation identified subsets that behave like, and respond to treatment for, a specific cancer. The ESMO 2023 guideline lists them: women with adenocarcinoma confined to axillary nodes (treated as breast cancer with axillary dissection, breast radiotherapy or mastectomy and systemic therapy); women with serous papillary carcinoma of the peritoneum (treated as ovarian cancer with cytoreductive surgery and carboplatin-paclitaxel); squamous cell carcinoma in cervical nodes (treated as head and neck cancer, with HPV or EBV testing, neck dissection and chemoradiotherapy) or in inguinal nodes (treated with node dissection and radiotherapy as anogenital cancer); young men with poorly differentiated carcinoma in a midline distribution or raised markers (treated as extragonadal germ cell tumour with cisplatin-based chemotherapy); men with bone metastases and raised PSA (treated as prostate cancer); neuroendocrine carcinoma of unknown primary (treated as extrapulmonary neuroendocrine carcinoma or, if well differentiated, as a neuroendocrine tumour); adenocarcinoma with a colorectal immunoprofile (CK20 and CDX2 positive, CK7 negative; treated as colorectal cancer); a single resectable metastasis (treated with surgery or radiotherapy); and renal-like carcinoma.\n\nRecognising these patterns depends on a disciplined work-up: histology with a directed immunohistochemistry panel, CT of chest, abdomen and pelvis, mammography or breast MRI and gynaecological examination in women, PSA in men, alpha-fetoprotein and hCG in young patients, and PET-CT in cervical node squamous carcinoma and single-site disease. Gene-expression and DNA-methylation tissue-of-origin classifiers can assign a likely primary in most cases, but two randomised trials (GEFCAPI 04 and a Japanese trial) found that classifier-directed site-specific therapy did not beat empirical chemotherapy in unfavourable disease, so the classifiers are used to support rather than replace clinical judgement. Because the subsets are treated as their presumed cancer, their prognosis approaches that of the corresponding metastatic or node-positive disease, which is why every patient with CUP should be reviewed against the list before empirical chemotherapy is started.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin","links":[{"label":"ESMO CUP guideline 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin"}],"tags":["subtype-page","site-agnostic"],"related":["cup-unfavourable","cancer-of-unknown-primary","extragonadal-germ-cell-tumour","extrapulmonary-nec"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","cgp","methylation-profiling","pet-ct","ct","imrt-igrt","sbrt","germ-cell-tumour-markers"],"targets":[],"drugs":["carboplatin","paclitaxel","cisplatin","etoposide","platinum-etoposide","octreotide-lanreotide","lutathera"],"companies":[],"institutions":[],"pathways":[],"terms":["ihc","tumour-markers","primary-tumour","hpv-p16","chemoradiation","lymphadenectomy","debulking"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-esmo-cancer-of-unknown-primary-guideline-ann-oncol-2023","paper-hayashi-site-specific-vs-empirical-chemotherapy-cup-jco-2019"],"journals":[],"dependsOn":[],"notes":[],"group":"other","burden":"About a fifth of cancers of unknown primary fall into a recognised favourable subset; these patients live far longer than the rest because their disease can be treated as the cancer it most resembles.","subtypes":["Adenocarcinoma confined to axillary nodes in a woman (treated as breast cancer)","Serous papillary peritoneal carcinoma in a woman (treated as ovarian cancer)","Squamous cell carcinoma in cervical nodes (treated as head and neck cancer)","Squamous cell carcinoma in inguinal nodes (treated as anogenital cancer)","Poorly differentiated midline carcinoma in a young man (treated as extragonadal germ cell tumour)","Neuroendocrine carcinoma of unknown primary","Adenocarcinoma with a colorectal immunoprofile (CK20 and CDX2 positive, CK7 negative)","Men with bone metastases and raised PSA (treated as prostate cancer)","Single resectable metastasis of unknown primary"],"biomarkers":["Directed immunohistochemistry panel (CK7, CK20, CDX2, GATA3, PAX8, TTF-1, NKX3.1, p16, SOX10)","Serum PSA (men), alpha-fetoprotein and hCG (young patients), CA-125 (women)","HPV (p16) and EBV testing in cervical node squamous carcinoma","Oestrogen receptor and HER2 in axillary node adenocarcinoma","Tissue-of-origin classifier (gene expression or methylation, supportive)","Ki-67 and neuroendocrine markers where neuroendocrine carcinoma is suspected"],"standardOfCare":[{"setting":"Work-up","approach":"Histology with directed immunohistochemistry, CT of chest, abdomen and pelvis, sex-specific examinations and tumour markers, PET-CT for cervical node squamous carcinoma and single-site disease.","refs":["histopathology-ihc","ihc","ct","pet-ct","tumour-markers","germ-cell-tumour-markers"],"guideline":{"version":"ESMO Clinical Practice Guideline on cancer of unknown primary 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}},{"setting":"Axillary node adenocarcinoma in a woman","approach":"Treat as node-positive breast cancer: axillary dissection, breast radiotherapy or mastectomy, systemic therapy by receptor status.","refs":["lymphadenectomy","imrt-igrt"],"guideline":{"version":"ESMO Clinical Practice Guideline on cancer of unknown primary 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}},{"setting":"Peritoneal serous carcinoma in a woman","approach":"Treat as advanced ovarian cancer: cytoreductive surgery and carboplatin-paclitaxel with maintenance as indicated.","refs":["carboplatin","paclitaxel","debulking"],"guideline":{"version":"ESMO Clinical Practice Guideline on cancer of unknown primary 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}},{"setting":"Cervical node squamous carcinoma","approach":"Treat as head and neck cancer: HPV and EBV testing, neck dissection or chemoradiotherapy with cisplatin.","refs":["cisplatin","imrt-igrt","chemoradiation","hpv-p16"],"guideline":{"version":"ESMO Clinical Practice Guideline on cancer of unknown primary 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}},{"setting":"Midline poorly differentiated carcinoma in a young man","approach":"Treat as extragonadal germ cell tumour with cisplatin-based combination chemotherapy.","refs":["cisplatin","etoposide","germ-cell-tumour-markers"],"guideline":{"version":"ESMO Clinical Practice Guideline on cancer of unknown primary 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}},{"setting":"Neuroendocrine carcinoma of unknown primary","approach":"Platinum-etoposide as for extrapulmonary neuroendocrine carcinoma; somatostatin analogues and radioligand therapy for well-differentiated tumours.","refs":["platinum-etoposide","octreotide-lanreotide","lutathera"],"guideline":{"version":"ESMO Clinical Practice Guideline on cancer of unknown primary 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}},{"setting":"Single metastasis","approach":"Resection or stereotactic radiotherapy with curative intent.","refs":["sbrt"],"guideline":{"version":"ESMO Clinical Practice Guideline on cancer of unknown primary 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}}],"stateOfArt":["Treating a favourable subset as its presumed cancer gives outcomes close to that cancer's.","Immunohistochemistry panels assign most tumours to a lineage within days.","Tissue-of-origin classifiers support but do not replace the clinical subsets."],"history":[{"year":1980,"title":"Cisplatin-based chemotherapy cures young men with midline poorly differentiated carcinoma, defining the first favourable subset","refs":["cisplatin"]},{"year":1990,"title":"Axillary node adenocarcinoma in women recognised as occult breast cancer","refs":[]},{"year":2010,"title":"Gene-expression tissue-of-origin classifiers reach clinical use","refs":[]},{"year":2019,"title":"GEFCAPI 04: classifier-directed therapy does not beat empirical chemotherapy","refs":[]},{"year":2023,"title":"ESMO guideline codifies the favourable subsets and their treatment","refs":["histopathology-ihc"]}],"pipeline":["cgp","methylation-profiling","liquid-biopsy"],"openProblems":["Some favourable subsets rest on small series decades old.","Whether a tissue-of-origin classifier should ever override the clinical picture is unsettled.","Patients outside specialist centres are often given empirical chemotherapy without the subset review.","Biopsy material is frequently too small for the full immunohistochemistry panel and sequencing."],"parent":"cancer-of-unknown-primary"},{"id":"cup-unfavourable","kind":"cancer","name":"Cancer of unknown primary, unfavourable (adenocarcinoma and poorly differentiated carcinoma)","aka":["Unfavourable-risk CUP","Poor-prognosis CUP","CUP adenocarcinoma with liver or multiple metastases","Non-specific CUP"],"tldr":"Unfavourable cancer of unknown primary is the large majority of cases, where a metastatic adenocarcinoma or poorly differentiated carcinoma fits no recognised pattern and its origin cannot be found. Treatment has long been general-purpose platinum chemotherapy, but CUPISCO showed that matching drugs to the tumour's genetic faults after short chemotherapy holds the disease longer.","summary":"Most patients with cancer of unknown primary do not fit a favourable subset. They have adenocarcinoma or poorly differentiated carcinoma in the liver, lungs, bones or several sites at once, are often unwell at diagnosis, and survival is short; performance status and serum lactate dehydrogenase are the strongest predictors of survival. For thirty years treatment has been empirical: carboplatin with paclitaxel or gemcitabine with cisplatin, regimens chosen because they work across many cancers, with response rates around a third and median survival of about nine to twelve months in trial populations and shorter in the clinic. Randomised trials of classifier-directed site-specific chemotherapy (GEFCAPI 04, Lancet Oncology 2019, and a Japanese trial) did not improve on this, and PD-1 antibodies produced responses in about a fifth of patients in the NivoCUP trial (Annals of Oncology 2022) and the CUPISCO immunotherapy arm, leading to nivolumab's approval for CUP in Japan in 2021.\n\nThe CUPISCO trial (Lancet 2024) changed the framing. After three cycles of platinum-based induction chemotherapy, 636 patients with unfavourable CUP whose disease had not progressed were randomised to continue chemotherapy or to switch to molecularly guided therapy chosen by a tumour board from comprehensive genomic profiling, including targeted drugs for actionable alterations and atezolizumab for tumours with high mutational burden or without a target: progression-free survival rose from 4.4 to 6.1 months, a modest but real gain that established genomic profiling as part of the standard work-up. About a third of patients carry an actionable alteration (HER2, BRAF V600E, NTRK fusions, MSI or high tumour mutational burden, and others), and the ESMO 2023 guideline recommends profiling for all patients fit for treatment; circulating tumour DNA is an alternative when tissue is scarce. Trials now test targeted agents, immunotherapy combinations and antibody-drug conjugates with chemotherapy in first line, and DNA-methylation classifiers are being revisited as a route to site-specific immunotherapy choices. Early palliative care and honest discussion of prognosis are part of standard management.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin","links":[{"label":"CUPISCO (Lancet 2024)","url":"https://doi.org/10.1016/S0140-6736(24)00814-6"},{"label":"ESMO CUP guideline 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin"}],"tags":["subtype-page","site-agnostic"],"related":["cup-favourable-subsets","cancer-of-unknown-primary","metastatic-cancer"],"cancers":[],"sections":[],"technologies":["cgp","liquid-biopsy","methylation-profiling","histopathology-ihc","pet-ct","platinum","checkpoint-inhibitor"],"targets":["her2","braf","ntrk","pd1"],"drugs":["carboplatin","paclitaxel","gemcitabine-cisplatin","pembrolizumab","nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":["tumour-agnostic","tmb","msi","ihc","primary-tumour"],"trials":["cupisco","nct07761429"],"people":[],"bottlenecks":[],"keyPapers":["paper-cupisco-molecularly-guided-therapy-cup-lancet-2024","paper-esmo-cancer-of-unknown-primary-guideline-ann-oncol-2023","paper-hayashi-site-specific-vs-empirical-chemotherapy-cup-jco-2019"],"journals":[],"dependsOn":[],"notes":[],"group":"other","burden":"About four fifths of cancers of unknown primary; most are adenocarcinomas or poorly differentiated carcinomas with liver, lung, bone or multiple metastases, and median survival on empirical chemotherapy is under a year.","subtypes":["Adenocarcinoma of unknown primary with liver metastases","Adenocarcinoma of unknown primary with multiple metastatic sites","Poorly differentiated carcinoma of unknown primary (non-midline, marker negative)","Squamous cell carcinoma of unknown primary at non-nodal sites","Cancer of unknown primary with an actionable alteration (HER2, BRAF, NTRK, MSI-high, high tumour mutational burden)","Cancer of unknown primary with poor performance status (best supportive care)"],"biomarkers":["Comprehensive genomic profiling (actionable alterations in about a third)","Microsatellite instability, tumour mutational burden and PD-L1 (immunotherapy)","Performance status and serum lactate dehydrogenase (prognosis)","Immunohistochemistry lineage panel (to exclude favourable subsets)","Circulating tumour DNA where tissue is insufficient","Tissue-of-origin classifier (supportive)"],"standardOfCare":[{"setting":"Work-up","approach":"Exclude favourable subsets; comprehensive genomic profiling of tissue or plasma; assess performance status and lactate dehydrogenase.","refs":["histopathology-ihc","cgp","liquid-biopsy","tumour-agnostic"],"guideline":{"version":"ESMO Clinical Practice Guideline on cancer of unknown primary 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}},{"setting":"First line, fit patients","approach":"Platinum-based doublet (carboplatin-paclitaxel or gemcitabine-cisplatin) for three cycles, then continuation or a switch to molecularly guided therapy where an actionable alteration is found (CUPISCO).","refs":["carboplatin","paclitaxel","gemcitabine-cisplatin","cupisco","platinum"],"guideline":{"version":"ESMO Clinical Practice Guideline on cancer of unknown primary 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}},{"setting":"Actionable alterations","approach":"Tumour-agnostic therapies: pembrolizumab or nivolumab for MSI-high or high tumour mutational burden, NTRK inhibitors, BRAF and MEK inhibitors, HER2-directed therapy.","refs":["pembrolizumab","nivolumab","tumour-agnostic","cgp"],"guideline":{"version":"ESMO Clinical Practice Guideline on cancer of unknown primary 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}},{"setting":"Second line","approach":"Alternative chemotherapy, PD-1 antibody if not given (nivolumab approved in Japan), or trial entry; trials of antibody-drug conjugates and immunotherapy combinations.","refs":["nivolumab","pembrolizumab","nct07761429"],"guideline":{"version":"ESMO Clinical Practice Guideline on cancer of unknown primary 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}},{"setting":"Poor performance status","approach":"Best supportive care with early palliative care involvement.","refs":["b-palliative"],"guideline":{"version":"ESMO Clinical Practice Guideline on cancer of unknown primary 2023","url":"https://doi.org/10.1016/j.annonc.2022.11.013"}}],"stateOfArt":["CUPISCO is the first randomised trial to show a benefit from genomically guided therapy in this disease.","Comprehensive genomic profiling is now recommended for all fit patients.","Immunotherapy produces durable responses in a minority and is approved in Japan."],"history":[{"year":1997,"title":"Carboplatin-paclitaxel established as empirical therapy in phase 2 trials","refs":["carboplatin","paclitaxel"]},{"year":2013,"title":"Hainsworth phase 2: molecular tissue-of-origin assay-directed therapy","refs":[]},{"year":2019,"title":"GEFCAPI 04: site-specific therapy by classifier no better than empirical chemotherapy","refs":[]},{"year":2021,"title":"Nivolumab approved for cancer of unknown primary in Japan after NivoCUP","refs":["nivolumab"]},{"year":2024,"title":"CUPISCO: molecularly guided therapy after induction chemotherapy lengthens progression-free survival","refs":["cupisco","cgp"]}],"pipeline":["cupisco","nct07761429","cgp","liquid-biopsy","methylation-profiling","pembrolizumab"],"openProblems":["Median survival remains under a year for most patients.","Only a third have an actionable alteration and the gain from targeting it is modest.","Patients too unwell for CUPISCO-style induction have no evidence-based option.","The disease is under-studied because it belongs to no organ-based specialty."],"parent":"cancer-of-unknown-primary"},{"id":"carcinoma-ex-pleomorphic-adenoma","kind":"cancer","name":"Carcinoma ex pleomorphic adenoma","aka":["Carcinoma ex pleomorphic adenoma (CXPA)","Malignant mixed tumour of the salivary gland","Carcinoma arising in a pleomorphic adenoma"],"tldr":"Carcinoma ex pleomorphic adenoma is a salivary gland cancer that grows out of a long-standing benign pleomorphic adenoma, the commonest salivary tumour, usually in the parotid. Its outlook depends on how far the cancer has grown beyond the old adenoma's capsule: cancers still inside it are cured by surgery, while widely invasive ones need radiotherapy and do poorly.","summary":"Carcinoma ex pleomorphic adenoma is a carcinoma arising from a primary or recurrent benign pleomorphic adenoma, most often presenting as a firm parotid mass; it is difficult to diagnose preoperatively, pathological assessment is the gold standard, treatment is ablative surgery often followed by radiotherapy, prognosis is poor overall, and molecular studies show a multistep progression from adenoma (Head and Neck Pathology 2012). The WHO classification grades it by the extent of invasion beyond the adenoma capsule (intracapsular, minimally invasive, widely invasive), which drives prognosis. In 619 SEER patients the parotid was the site in 76.9 percent, two- and five-year disease-specific survival were 90.3 and 80.4 percent, facial nerve sacrifice did not predict survival, and size over 4 cm, multiple positive nodes and distant metastasis raised the risk of death two- to four-fold (American Journal of Otolaryngology 2019).\n\nHow it differs from its parent: the carcinoma component can be of any salivary type (salivary duct carcinoma most often), so treatment follows that component once invasion is established, and the history of a slowly growing lump that suddenly enlarges is the clinical clue.\n\nHow common: about 0.6 per million a year in the United States (American Journal of Otolaryngology 2019).\n\nTreatment: complete excision (parotidectomy) for all forms; postoperative radiotherapy and neck dissection for widely invasive, high-grade or node-positive disease; systemic therapy by the carcinoma component, including HER2- and androgen receptor-directed therapy when the component is salivary duct carcinoma, as on that page.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Carcinoma_ex_pleomorphic_adenoma","links":[{"label":"NCI PDQ: salivary gland cancer treatment","url":"https://www.cancer.gov/types/head-and-neck/patient/adult/salivary-gland-treatment-pdq"},{"label":"Head and Neck Pathology 2012: carcinoma ex pleomorphic adenoma, comprehensive review","url":"https://doi.org/10.1007/s12105-011-0281-z"},{"label":"American Journal of Otolaryngology 2019: carcinoma ex pleomorphic adenoma in SEER 1973 to 2015, 619 patients","url":"https://doi.org/10.1016/j.amjoto.2019.102279"}],"tags":["subtype-page","wave4","rare"],"related":["salivary-gland","salivary-duct-carcinoma","acinic-cell-carcinoma-salivary","adenoid-cystic-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"619 patients in the US SEER registry over 1973 to 2015, 76.9 percent in the parotid; the reported incidence rose from 0.24 to 0.63 per million between 2005 and 2015 (American Journal of Otolaryngology 2019).","subtypes":["Intracapsular carcinoma ex pleomorphic adenoma (non-invasive; excellent outlook)","Minimally invasive carcinoma ex pleomorphic adenoma (invasion under 4 to 6 mm)","Widely invasive carcinoma ex pleomorphic adenoma (the poor-prognosis form)","Carcinoma ex pleomorphic adenoma with a salivary duct carcinoma component (HER2, androgen receptor)"],"biomarkers":["Extent of invasion beyond the adenoma capsule","PLAG1 or HMGA2 rearrangement (inherited from the adenoma)","HER2 and androgen receptor when the component is salivary duct carcinoma","Size over 4 cm and node number (prognostic)"],"standardOfCare":[{"setting":"All stages","approach":"Complete excision; postoperative radiotherapy and neck dissection for widely invasive, high-grade or node-positive disease; systemic therapy by the carcinoma component.","refs":["salivary-gland","salivary-duct-carcinoma"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"salivary-gland"},{"id":"gallbladder-carcinoma-in-situ-and-dysplasia","kind":"cancer","name":"Carcinoma in situ and dysplasia of the gallbladder","aka":["Biliary intraepithelial neoplasia of the gallbladder","BilIN","High-grade dysplasia of the gallbladder","Low-grade dysplasia of the gallbladder","Tis gallbladder cancer","Stage 0 gallbladder cancer"],"tldr":"Dysplasia means the cells lining the gallbladder have become abnormal but have not invaded; carcinoma in situ (stage 0) is the most abnormal form, with cancer cells still confined to the lining. Both are found by the pathologist after a gallbladder is removed and are cured by that removal when the margin is clear. Cancer Research UK notes some doctors do not regard stage 0 as a true cancer.","summary":"Gallbladder cancer develops through a metaplasia, dysplasia, carcinoma sequence in chronically inflamed mucosa (Lewis 2007; Hundal 2014). The WHO classification (5th edition, 2019; Nagtegaal 2020) names the flat precursor biliary intraepithelial neoplasia, graded low or high, with high-grade lesions equivalent to carcinoma in situ, and the mass-forming precursor the intracholecystic papillary neoplasm (Adsay 2012). In TNM 8th edition carcinoma in situ is Tis, stage 0: cancer cells confined to the lining with no invasion, rarely found except when a gallbladder is removed for other reasons (CRUK stages and grades). Early carcinomas confined to or above the muscle layer (Tis, T1a, T1b) are usually invisible to the naked eye (60 percent of 190 cases), occur about a decade younger than advanced cancers (mean 57.9 years) and have excellent outcomes: 92.3 percent five-year and 90.4 percent ten-year survival in a high-incidence series that sampled every specimen fully. The exception is extension of the intraepithelial tumour into Rokitansky-Aschoff sinuses, present in 17.8 percent, after which 39 percent died of disease against 4 percent without, often years later (Roa 2013). In primary sclerosing cholangitis dysplasia and carcinoma are common enough (37 and 14 percent of explanted gallbladders) that guidelines advise cholecystectomy for any polyp; a later cohort found most such polyps benign and proposed short-interval surveillance before surgery in the absence of high-risk features (Lewis 2007; van Erp 2020).\n\nWhat differs in treatment: Tis with a clear cystic duct margin needs no operation beyond the cholecystectomy already done. A positive cystic duct margin, or high-grade dysplasia running into the cystic duct, prompts consideration of bile duct margin re-excision, and Rokitansky-Aschoff sinus involvement is a reason to consider further surgery and to follow the patient for years (Roa 2013). The pathology protocol matters: at least three sections and the cystic duct margin from every routine specimen in high-incidence settings, and complete embedding when dysplasia or cancer is found (Aloia 2015).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Carcinoma_in_situ","links":[{"label":"CRUK: stages and grades of gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/stages-and-grades"},{"label":"Roa, Virchows Arch 2013: early gallbladder carcinoma and Rokitansky-Aschoff sinus involvement","url":"https://doi.org/10.1007/s00428-013-1478-1"},{"label":"Lewis, Am J Surg Pathol 2007: gallbladder neoplasia in primary sclerosing cholangitis explants","url":"https://doi.org/10.1097/01.pas.0000213435.99492.8a"},{"label":"van Erp, Liver Int 2020: gallbladder polyps and cancer risk in primary sclerosing cholangitis","url":"https://doi.org/10.1111/liv.14326"},{"label":"Adsay, Am J Surg Pathol 2012: intracholecystic papillary-tubular neoplasms, 123 cases","url":"https://doi.org/10.1097/pas.0b013e318262787c"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"AHPBA expert consensus statement on gallbladder cancer (Aloia, HPB 2015)","url":"https://doi.org/10.1111/hpb.12444"},{"label":"Hundal and Shaffer, Clin Epidemiol 2014: gallbladder cancer epidemiology and outcome","url":"https://doi.org/10.2147/clep.s37357"}],"tags":["gallbladder","biliary","subtype-page"],"related":["gallbladder","incidental-gallbladder-cancer","gallbladder-papillary-carcinoma","gallbladder-adenocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["carcinoma-in-situ","dysplasia","rokitansky-aschoff-sinus","cystic-duct-margin","gallbladder-polyp"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Almost always an incidental pathology finding. In 100 consecutive liver explants for primary sclerosing cholangitis, 37 percent of gallbladders showed dysplasia (15 high grade) and 14 percent adenocarcinoma (Lewis 2007); in the general population the frequency is far lower and not reliably measured.","subtypes":["Low-grade biliary intraepithelial neoplasia (dysplasia) of the gallbladder","High-grade biliary intraepithelial neoplasia, carcinoma in situ of the gallbladder (Tis, stage 0)","Carcinoma in situ extending into Rokitansky-Aschoff sinuses","Gallbladder dysplasia in primary sclerosing cholangitis"],"biomarkers":["Grade of dysplasia (low or high)","Absence of invasion through the basement membrane (Tis) versus lamina propria invasion (T1a)","Cystic duct margin status","Rokitansky-Aschoff sinus involvement","Pyloric and intestinal metaplasia in the background mucosa"],"standardOfCare":[{"setting":"Tis or dysplasia with a clear cystic duct margin","approach":"No further surgery; follow-up because occasional late recurrences reflect a field effect.","refs":["simple-cholecystectomy","cystic-duct-margin"]},{"setting":"Positive cystic duct margin or Rokitansky-Aschoff sinus involvement","approach":"Consider bile duct margin re-excision or further surgery at a hepatobiliary centre.","refs":["cystic-duct-margin","rokitansky-aschoff-sinus","radical-cholecystectomy"]},{"setting":"Gallbladder polyp in primary sclerosing cholangitis","approach":"Cholecystectomy advised for polyps of any size by international guidelines; a 2020 cohort supports short-interval imaging first when no high-risk feature is present.","refs":["gallbladder-polyp","simple-cholecystectomy"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"gallbladder"},{"id":"medullary-pattern-breast-carcinoma","kind":"cancer","name":"Carcinoma with medullary pattern (medullary breast cancer)","aka":["Medullary carcinoma of the breast","Medullary breast cancer","Invasive carcinoma of no special type with medullary pattern","Atypical medullary carcinoma","Basal-like carcinoma with medullary features","Invasive breast carcinoma with medullary pattern","Medullary carcinoma","Carcinoma with medullary features","Medullary-like carcinoma","Atypical medullary carcinoma of the breast"],"tldr":"Medullary breast cancers are high-grade, triple-negative tumours with a sharp border and a heavy immune-cell infiltrate that, despite looking aggressive, do better than ordinary breast cancers of the same grade. They are linked to BRCA1. Pathologists now call them a medullary pattern of common breast cancer rather than a type of their own.","summary":"Medullary carcinoma was defined by a circumscribed, syncytial growth pattern, high nuclear grade and a dense lymphoplasmacytic infiltrate; because pathologists agreed poorly on the diagnosis and the molecular profile overlaps basal-like carcinoma, the 5th edition of the WHO classification (2019) reclassified it as invasive breast carcinoma of no special type with medullary pattern, alongside the other patterns of common ductal-origin carcinoma (Cserni 2020; Thomas 2023). Its behaviour is better than its grade suggests: among 12,409 patients in 13 International Breast Cancer Study Group trials, 14-year distant recurrence-free interval was 76 percent for 127 medullary against 64 percent for 8,096 invasive ductal tumours (hazard ratio 0.52) and overall survival 66 against 57 percent (0.75); restricted to ER-negative grade 3 tumours the figures were 89 against 63 percent (0.24) and 74 against 54 percent (0.55) (Huober 2012). Medullary tumours are BRCA1-related (odds ratio for BRCA2 versus BRCA1 carrier status 0.25 in the CIMBA pathology series, Mavaddat 2012), and the claudin-low subtype shows frequent medullary differentiation (Prat 2010). The immune infiltrate is the same feature now scored as stromal tumour-infiltrating lymphocytes across triple-negative disease.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Medullary_breast_carcinoma","links":[{"label":"Huober, Ann Oncol 2012: prognosis of medullary breast cancer in 13 IBCSG trials","url":"https://doi.org/10.1093/annonc/mds105"},{"label":"Cserni, Pathologica 2020: histological type and typing of breast carcinomas and WHO classification changes","url":"https://doi.org/10.32074/1591-951x-1-20"},{"label":"Thomas, NPJ Breast Cancer 2023: rare subtypes of triple-negative breast cancer","url":"https://doi.org/10.1038/s41523-023-00554-x"},{"label":"Mavaddat, Cancer Epidemiol Biomarkers Prev 2012: pathology of breast cancers in BRCA1 and BRCA2 carriers (CIMBA)","url":"https://doi.org/10.1158/1055-9965.epi-11-0775"},{"label":"Prat, Breast Cancer Res 2010: phenotypic and molecular characterisation of the claudin-low intrinsic subtype","url":"https://doi.org/10.1186/bcr2635"},{"label":"Tan et al., Histopathology 2020: the 2019 WHO classification of tumours of the breast (5th edition)","url":"https://doi.org/10.1111/his.14091"},{"label":"Quinn et al., Histopathology 2026;89(2):199 to 218: World Health Organization classification of tumours of the breast, 6th edition 2026","url":"https://doi.org/10.1111/his.70149"}],"tags":["breast","tnbc","subtype-page"],"related":["tnbc","brca-associated-tnbc","tnbc-immunomodulatory","metaplastic-breast-carcinoma","breast-cancer","invasive-breast-carcinoma-no-special-type"],"cancers":[],"sections":[],"technologies":[],"targets":["brca"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["tils","basal-like","germline-brca-testing-criteria-tnbc","who-breast-classification","nottingham-grade"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Two more series, smaller than the trial cohorts above and quoted with their own denominators. In a Shiraz breast centre's 22-year experience, 179 medullary carcinomas among 3,246 patients (5.5 percent of that centre's series) were of higher grade than the 3,067 ductal carcinomas beside them and yet had a more favourable clinical outcome (Iranian Journal of Medical Sciences 2018). In 165 triple-negative basal-like carcinomas, prominent inflammation and anastomosing sheets in at least 30 percent of the tumour were each associated with better prognosis; their combination, a simplified medullary-like definition, was present in 17 percent of tumours, was an independent prognostic factor and showed good agreement between observers (Modern Pathology 2010). Both are quoted from the series named, and neither is a population figure: with the 2019 definition the pattern is no longer counted separately, so any percentage for how common medullary carcinoma is describes how often it was recognised."],"group":"breast","burden":"About 1 percent of breast cancers in trial populations: 127 of 12,409 patients in 13 IBCSG trials were recorded as medullary (Huober 2012). The 2019 WHO classification no longer lists it as a separate type.","subtypes":["Invasive carcinoma of no special type (ductal) with medullary pattern, the 2019 WHO term","Classic medullary carcinoma by the older strict criteria","Atypical medullary carcinoma (older term for tumours meeting some criteria)"],"biomarkers":["Triple-negative receptor status with grade 3","Dense lymphoplasmacytic infiltrate (high stromal tumour-infiltrating lymphocytes)","Germline BRCA1 (medullary tumours are BRCA1-related)"],"standardOfCare":[{"setting":"Early disease","approach":"As for triple-negative disease of no special type, including germline testing; the medullary pattern is recorded because of its better prognosis but does not change the NICE pathway.","refs":["keynote-522","germline-testing","tils"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"tnbc"},{"id":"cns-germ-cell-tumours","kind":"cancer","name":"Central nervous system germ cell tumours (germinoma and non-germinomatous)","aka":["Intracranial germ cell tumour","CNS germinoma","Pineal germinoma","Suprasellar germinoma","Non-germinomatous germ cell tumour (NGGCT)","Intracranial teratoma"],"tldr":"Germ cell tumours of the brain grow near the pineal gland or above the pituitary in teenagers. The commonest kind, germinoma, is so sensitive to radiation and chemotherapy that most patients are cured; the other kinds need stronger chemotherapy and radiotherapy, and doctors measure two proteins in the blood and spinal fluid to tell them apart and to follow treatment.","summary":"Central nervous system germ cell tumours arise in the midline, in the pineal region (more often in boys) and suprasellar region (with diabetes insipidus and hormone deficits), sometimes at both sites (bifocal). WHO 2021 lists germinoma, embryonal carcinoma, yolk sac tumour, choriocarcinoma, mature and immature teratoma, teratoma with somatic-type malignancy and mixed germ cell tumour; clinically they divide into germinoma and non-germinomatous germ cell tumours (NGGCT). Alpha-fetoprotein and beta-hCG in serum and cerebrospinal fluid are diagnostic and prognostic: marked elevation indicates NGGCT and can spare biopsy, while normal or mildly raised hCG with typical imaging leads to biopsy to confirm germinoma. Staging requires spinal MRI and cerebrospinal fluid cytology. Klinefelter and Down syndromes raise risk, and KIT and RAS pathway mutations are frequent.\n\nGerminoma is exquisitely radiosensitive. Craniospinal irradiation alone cured more than nine in ten patients with localised disease in SIOP CNS GCT 96 (five-year event-free survival above 90 percent), and the same trial showed that carboplatin, etoposide and ifosfamide followed by focal radiotherapy gave similar survival but more relapses in the ventricles; SIOP CNS GCT II and the Children's Oncology Group's ACNS1123 therefore adopted chemotherapy followed by reduced-dose whole-ventricular irradiation with a tumour boost, the current standard for localised germinoma, with craniospinal irradiation kept for disseminated disease. NGGCT is treated with intensive platinum-based chemotherapy (cisplatin or carboplatin with etoposide and ifosfamide), second-look surgery for residual masses, which often prove to be teratoma, and then radiotherapy; ACNS0122 used craniospinal irradiation after chemotherapy with good results, and attempts to reduce to whole-ventricular fields in ACNS1123 were tempered by spinal relapses. High-dose chemotherapy with stem cell rescue is used at relapse.\n\nThe agenda is reducing late effects without losing cure: lowering radiation dose and volume, proton therapy, and defining which NGGCT patients can safely avoid craniospinal irradiation. Long-term survivors need endocrine replacement, neurocognitive support and fertility counselling. International harmonisation of the SIOP and COG approaches, which historically differed on the role of chemotherapy for germinoma, is progressing through joint trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Germinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Germinoma"},{"label":"NCI PDQ: childhood CNS germ cell tumours","url":"https://www.cancer.gov/types/brain/hp/child-cns-germ-cell-treatment-pdq"},{"label":"SIOP CNS GCT 96 germinoma results (Neuro-Oncology 2013)","url":"https://doi.org/10.1093/neuonc/not019"}],"tags":["subtype-page","cns","paediatric"],"related":["brain-tumours","paediatric-germ-cell-tumours","testicular","extragonadal-germ-cell-tumour","pituitary-tumours","medulloblastoma","atrt","craniopharyngioma"],"cancers":[],"sections":[],"technologies":["imrt-igrt","proton-therapy","autologous-stem-cell-transplant","mri"],"targets":[],"drugs":["carboplatin","etoposide","ifosfamide","cisplatin","thiotepa"],"companies":["childrens-oncology-group"],"institutions":["siop-europe"],"pathways":[],"terms":["afp","late-effects","re-irradiation"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers","b-survivorship"],"keyPapers":["paper-who-2021-cns-louis-neuro-oncology-2021","paper-siop-cns-gct-96-calaminus-neuro-oncology-2013","paper-acns1123-germinoma-neuro-oncology-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"central nervous system","burden":"A few percent of childhood and adolescent brain tumours in Western countries and several times commoner in East Asia; peak age is the second decade with a male excess, and germinoma is one of the most curable brain tumours.","subtypes":["Germinoma of the pineal or suprasellar region (bifocal when both)","Non-germinomatous germ cell tumour: embryonal carcinoma, yolk sac tumour, choriocarcinoma, mixed","Mature and immature teratoma (surgical disease; growing teratoma after chemotherapy)","Teratoma with somatic-type malignancy","Metastatic or disseminated CNS germ cell tumour (cerebrospinal fluid spread)"],"biomarkers":["Alpha-fetoprotein in serum and cerebrospinal fluid","Beta-hCG in serum and cerebrospinal fluid","Placental alkaline phosphatase and c-KIT on germinoma cells","Cerebrospinal fluid cytology and spinal MRI for staging","Pituitary hormone panel for suprasellar tumours"],"standardOfCare":[{"setting":"Localised germinoma","approach":"Platinum-based chemotherapy (carboplatin and etoposide, with ifosfamide in the SIOP schedule) followed by reduced-dose whole-ventricular irradiation with a tumour boost (SIOP CNS GCT II, ACNS1123); craniospinal irradiation alone remains an alternative in adults.","refs":["carboplatin","etoposide","ifosfamide","imrt-igrt","proton-therapy","acns1123"],"guideline":{"version":"NCI PDQ: childhood CNS germ cell tumours","url":"https://www.cancer.gov/types/brain/hp/child-cns-germ-cell-treatment-pdq"}},{"setting":"Disseminated germinoma","approach":"Craniospinal irradiation with boosts, with or without chemotherapy.","refs":["imrt-igrt","proton-therapy"],"guideline":{"version":"NCI PDQ: childhood CNS germ cell tumours","url":"https://www.cancer.gov/types/brain/hp/child-cns-germ-cell-treatment-pdq"}},{"setting":"Non-germinomatous germ cell tumour","approach":"Intensive cisplatin or carboplatin, etoposide and ifosfamide chemotherapy, second-look surgery for residual disease, then craniospinal or whole-ventricular irradiation depending on stage and response (ACNS0122, ACNS1123, SIOP CNS GCT II).","refs":["cisplatin","carboplatin","etoposide","ifosfamide","imrt-igrt","proton-therapy","acns0122","acns1123"],"guideline":{"version":"NCI PDQ: childhood CNS germ cell tumours","url":"https://www.cancer.gov/types/brain/hp/child-cns-germ-cell-treatment-pdq"}},{"setting":"Teratoma","approach":"Complete surgical resection; growing teratoma after chemotherapy is also managed surgically.","refs":["mri"]},{"setting":"Relapse","approach":"High-dose chemotherapy (thiotepa-based) with autologous stem cell rescue, with re-irradiation where possible.","refs":["thiotepa","autologous-stem-cell-transplant","re-irradiation"]}],"stateOfArt":["Germinoma is cured in the great majority with chemotherapy and reduced-field radiotherapy, and each trial generation has lowered the radiation dose and volume.","Tumour markers in blood and spinal fluid allow diagnosis and risk assignment with less surgery than any other brain tumour.","Proton therapy is reducing the endocrine and cognitive cost of ventricular and craniospinal irradiation in children."],"history":[{"year":1985,"title":"Jennings reviews intracranial germ cell tumours and their site and age patterns","refs":[]},{"year":1997,"title":"Matsutani proposes the Japanese good, intermediate and poor prognosis grouping","note":"Basis for risk-adapted therapy in Japan and later international trials.","refs":[]},{"year":2013,"title":"SIOP CNS GCT 96: craniospinal irradiation alone or chemotherapy plus focal radiotherapy for germinoma","note":"Calaminus and colleagues (Neuro-Oncology): equivalent survival, more ventricular relapses with focal fields; whole-ventricular irradiation adopted.","refs":["carboplatin","etoposide","ifosfamide"]},{"year":2015,"title":"ACNS0122: chemotherapy then craniospinal irradiation for non-germinomatous tumours","note":"Goldman and colleagues (JCO).","refs":["carboplatin","etoposide","ifosfamide"]},{"year":2021,"title":"WHO 2021 lists CNS germ cell tumour types alongside their gonadal counterparts","refs":[]}],"pipeline":["proton-therapy","autologous-stem-cell-transplant"],"openProblems":["Which non-germinomatous patients can safely avoid craniospinal irradiation.","Late endocrine, cognitive and vascular effects of radiotherapy in survivors treated as teenagers.","Relapsed non-germinomatous tumours have poor salvage rates.","Why incidence is several times higher in East Asia."],"parent":"brain-tumours"},{"id":"cervical","kind":"cancer","name":"Cervical cancer","aka":["CESC","TCGA-CESC","cervical squamous cell carcinoma and endocervical adenocarcinoma (TCGA CESC cohort)"],"tldr":"A cancer that could be eliminated by HPV vaccination and screening. For those who develop it, immunotherapy and a tissue-factor ADC have improved survival.","summary":"Cervical cancer is almost entirely caused by persistent infection with high-risk human papillomavirus, which makes it the one common cancer that could be eliminated: HPV vaccination prevents about 90% of cases, HPV screening finds the precancers that remain, and a minute of thermal ablation or a loop excision cures them. Around 660,000 women are diagnosed and 350,000 die each year, nine in ten of them in low- and middle-income countries where vaccination and screening have not reached. In Sweden, Scotland, and Australia, cohorts vaccinated at 12-13 show near-zero invasive cancer, and Australia expects to pass the WHO elimination threshold (4 per 100,000) around 2035.\n\nFor women who develop cancer, treatment depends on stage. Early disease is treated with open radical hysterectomy (minimally invasive surgery proved worse in the LACC trial) or, for the smallest tumours, fertility-sparing surgery, with sentinel node mapping under evaluation. Locally advanced disease is cured in roughly two-thirds by cisplatin chemoradiation with brachytherapy, and two 2023-24 trials improved on that standard for the first time since 1999: six weeks of induction carboplatin-paclitaxel (INTERLACE, 5-year OS 80% vs 72%) and pembrolizumab with chemoradiation (KEYNOTE-A18, 36-month OS 82.6% vs 74.8%). Metastatic or recurrent disease, once treated with chemotherapy alone, now has first-line chemotherapy plus a checkpoint inhibitor with or without bevacizumab (KEYNOTE-826, BEATcc, COMPASSION-16 in China), the tissue-factor ADC tisotumab vedotin in second line (innovaTV 301), and HER2-directed therapy for the minority with HER2-positive tumours.\n\nWhat comes next is mostly delivery rather than discovery: single-dose HPV vaccination and self-sampled HPV testing to reach the 90-70-90 targets, screen-and-treat with portable ablation devices, AI-read colposcopy, and cheaper immunotherapy access. On the treatment side, HPV ctDNA to guide who needs maintenance therapy, TROP2 ADCs (sacituzumab tirumotecan), TIL therapy, and therapeutic HPV vaccines are in trials. The enduring problem is that the tools already exist and the women who die do not have them.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Cervical_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Cervical_cancer"}],"tags":["gyn","spike"],"related":["induction-chemo-then-crt","io-plus-crt-cervical","caution-mis-radical-hysterectomy","radiation-plus-io","early-detection-roadmap","vaginal"],"cancers":[],"sections":[],"technologies":["hpv-vaccine","brachytherapy","adc","checkpoint-inhibitor","til-therapy","probiotics-treatment-diarrhoea","hpv-testing","colposcopy-excision","precancer-ablation","imrt-igrt","sentinel-node","robotic-surgery","liquid-biopsy"],"targets":["tissue-factor","pd1","trop2","vegf","ctla4","her2","pdl1"],"drugs":[],"companies":["color-health","mabwell-shanghai-bioscience","bio-thera-solutions","neonc-technologies","merck","roche-genentech","genmab","pfizer","akeso","regeneron","nrg-oncology"],"institutions":["tikur-anbessa-hospital","iarc","cruk","md-anderson"],"pathways":[],"terms":["cin-hsil","cps","tumour-agnostic"],"trials":["mumbai-via-screening","nct07418749","nct05027776","nct07216703","nct04422366","nct07168200","nct06459180","nct06123884","nct05235516","nct06079671","nct06692166","nct04906993"],"people":["jade-goody"],"bottlenecks":[],"keyPapers":[],"journals":["international-journal-of-gynecological-cancer","journal-of-gynecologic-oncology"],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"Cervical cancer is almost entirely preventable by HPV vaccination and screening, and cohorts vaccinated at 12-13 show near-zero invasive cancer. It still causes ~660,000 cases and ~350,000 deaths per year, nine in ten in low- and middle-income countries; it is the fourth most common cancer in women worldwide and the leading cause of cancer death among women in many sub-Saharan African countries.","subtypes":["Squamous cell carcinoma (~75%; HPV16 predominant)","Adenocarcinoma (~20-25%; HPV18 enriched; rising share in screened populations)","Adenosquamous carcinoma","HPV-independent adenocarcinoma (gastric-type; ~5% of adenocarcinomas; behaves more aggressively)","Neuroendocrine carcinoma (rare; SCLC-like)","Precursor lesions: CIN2-3/HSIL, adenocarcinoma in situ"],"biomarkers":["HPV type","PD-L1 CPS","Tissue factor (not required)","High-risk HPV type (16, 18, others) and HPV status (HPV-independent tumours behave worse)","PD-L1 CPS (≥1 for pembrolizumab in recurrent disease; not required for KEYNOTE-A18)","p16 IHC (HPV surrogate)","HER2 (IHC 3+ for T-DXd; ~5-10%)","Tissue factor (not required for tisotumab)","Plasma HPV ctDNA (investigational monitoring)","FIGO 2018 stage incorporating imaging and nodal status","MSI/TMB (rare tumour-agnostic eligibility)"],"standardOfCare":[{"setting":"Prevention","approach":"HPV vaccination age 9-14; HPV primary screening.","refs":["hpv-vaccine"],"guideline":{"version":"NCCN Guidelines: Cervical Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1426"}},{"setting":"Locally advanced","approach":"Cisplatin chemoradiation + brachytherapy + pembrolizumab.","refs":["brachytherapy","imrt-igrt","pembrolizumab"],"guideline":{"version":"NCCN Guidelines: Cervical Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1426"}},{"setting":"Recurrent/metastatic","approach":"Pembrolizumab-chemotherapy-bevacizumab; tisotumab vedotin.","refs":["pembrolizumab","tisotumab-vedotin"],"guideline":{"esmoMcbs":"2 (innovaTV 204 tisotumab vedotin, single-arm)","version":"NCCN Guidelines: Cervical Cancer","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11163648/"}},{"setting":"Primary prevention","approach":"HPV vaccination of girls (and boys) at 9-14, one or two doses per WHO; catch-up to 26 (US label to 45). Reduces invasive cancer ~90% when given before exposure.","refs":["hpv-vaccine","gardasil-9","ken-she"],"guideline":{"nccn":"Prevention guideline","url":"https://www.who.int/publications/i/item/9789240014107"}},{"setting":"Screening","approach":"HPV primary testing every 5 years from 25-30 (self-sampling accepted), or cytology every 3 years; VIA or HPV screen-and-treat in low-resource settings; WHO target 70% screened twice in a lifetime.","refs":["hpv-testing","precancer-ablation","colposcopy-excision"],"guideline":{"nccn":"USPSTF Grade A"}},{"setting":"Precancer (HSIL / CIN2-3, AIS)","approach":"Colposcopy-directed biopsy then LEEP/LLETZ or cone excision; thermal ablation or cryotherapy where eligible; HPV test of cure at 6-12 months.","refs":["colposcopy-excision","precancer-ablation","cin-hsil"],"guideline":{"nccn":"ASCCP 2019 risk-based management"}},{"setting":"Stage IA1-IB1 (≤2 cm)","approach":"Simple hysterectomy is non-inferior to radical for low-risk IA2-IB1 ≤2 cm (SHAPE trial, 2024); cone or trachelectomy for fertility preservation; sentinel node mapping in trials (SENTICOL III).","refs":["robotic-surgery","sentinel-node","senticol-iii"],"guideline":{"nccn":"2A"}},{"setting":"Stage IB2-IIA (surgical candidates)","approach":"Open radical hysterectomy with pelvic lymphadenectomy (minimally invasive approach inferior in LACC); adjuvant radiation or chemoradiation for intermediate/high-risk pathology (Sedlis, Peters criteria).","refs":["lacc","caution-mis-radical-hysterectomy","imrt-igrt","cisplatin"],"guideline":{"nccn":"1 (open approach)"}},{"setting":"Locally advanced (IB3, IIB-IVA), standard","approach":"Weekly cisplatin 40 mg/m² with external-beam IMRT/IGRT followed by image-guided brachytherapy to ≥85 Gy EQD2, completed within 56 days.","refs":["cisplatin","imrt-igrt","brachytherapy"],"guideline":{"nccn":"1","esmoMcbs":"A"}},{"setting":"Locally advanced, high risk (node-positive IB2-IIB, III-IVA)","approach":"Add pembrolizumab during chemoradiation and for 15 maintenance cycles (KEYNOTE-A18, approved 2024 for FIGO III-IVA), or induction carboplatin-paclitaxel weekly × 6 before chemoradiation (INTERLACE). Adjuvant chemotherapy after chemoradiation is not recommended (OUTBACK).","refs":["keynote-a18","pembrolizumab","interlace","induction-chemo-then-crt","io-plus-crt-cervical","outback"],"guideline":{"nccn":"1 (pembrolizumab); 2A (induction)","esmoMcbs":"A (KEYNOTE-A18)"}},{"setting":"Persistent, recurrent, or metastatic, first line","approach":"Pembrolizumab + cisplatin/carboplatin-paclitaxel ± bevacizumab (KEYNOTE-826, CPS ≥1 in the US); atezolizumab + chemotherapy + bevacizumab (BEATcc, region-dependent); cadonilimab + chemotherapy in China (COMPASSION-16).","refs":["keynote-826","pembrolizumab","bevacizumab","beatcc","atezolizumab","compassion-16","cadonilimab"],"guideline":{"nccn":"1","esmoMcbs":"4"}},{"setting":"Second line and beyond","approach":"Tisotumab vedotin (innovaTV 301, OS benefit); cemiplimab if immunotherapy-naive (EU); T-DXd for HER2 IHC 3+; pembrolizumab for MSI-H/TMB-high; single-agent chemotherapy; trials of sac-TMT and TIL therapy.","refs":["tisotumab-vedotin","innovatv-301","cemiplimab","empower-cervical-1","trastuzumab-deruxtecan","destiny-pantumor02","sacituzumab-tirumotecan","lifileucel"],"guideline":{"nccn":"1 (tisotumab)"}},{"setting":"Pelvic recurrence after radiation","approach":"Pelvic exenteration in selected patients with central recurrence; re-irradiation with brachytherapy or proton therapy in specialised centres.","refs":["robotic-surgery","brachytherapy","proton-therapy"],"guideline":{"nccn":"2A"}}],"stateOfArt":["Near-elimination in vaccinated cohorts (Scotland, Sweden).","IO in locally advanced and metastatic disease.","Vaccinated cohorts in Sweden and Scotland show a ~90% to near-total reduction in invasive cervical cancer; single-dose schedules (97.5% efficacy in KEN SHE) make global coverage achievable.","HPV primary screening with self-sampling has replaced the Pap smear as the recommended test and reaches women who never attended clinics.","Two curative-intent advances in one year after 24 years of stasis: induction chemotherapy (INTERLACE, OS HR 0.60) and pembrolizumab with chemoradiation (KEYNOTE-A18, OS HR 0.67).","First-line chemo-immunotherapy roughly doubles median survival in metastatic disease compared with the pre-2014 era (KEYNOTE-826 26.4 months; BEATcc 32.1 months).","The first ADC with survival benefit in cervical cancer (tisotumab vedotin) and tumour-agnostic HER2 ADC access.","Surgical evidence now favours less: simple over radical hysterectomy for small tumours (SHAPE) and open over minimally invasive radical hysterectomy (LACC)."],"history":[{"year":1943,"title":"Pap smear introduced","refs":[]},{"year":1943,"title":"Papanicolaou smear introduced","note":"Cytology screening cuts cervical cancer mortality by ~70% where implemented.","refs":[]},{"year":1983,"title":"zur Hausen identifies HPV16 in cervical cancer","note":"HPV18 follows in 1984; Nobel Prize 2008.","refs":["dkfz","hpv-vaccine"]},{"year":1999,"title":"NCI clinical alert: cisplatin with radiation","note":"Five randomised trials show 30-50% mortality reduction; chemoradiation becomes standard for locally advanced disease.","refs":["cisplatin","imrt-igrt"]},{"year":2006,"title":"HPV vaccine approved","refs":["hpv-vaccine"]},{"year":2006,"title":"First HPV vaccine (Gardasil) approved","refs":["gardasil-9","hpv-vaccine"]},{"year":2014,"title":"Bevacizumab extends survival in advanced disease (GOG-0240); Gardasil 9 approved; HPV primary screening approved in the US","refs":["bevacizumab","gardasil-9","hpv-testing"]},{"year":2018,"title":"LACC: minimally invasive radical hysterectomy is inferior","note":"Practice reverses to open surgery within months.","refs":["lacc"]},{"year":2020,"title":"WHO launches the Cervical Cancer Elimination Initiative (90-70-90 by 2030)","note":"Swedish registry study shows ~88% cancer reduction in women vaccinated before 17.","refs":["hpv-vaccine","hpv-testing"]},{"year":2021,"title":"Tisotumab vedotin approved","refs":["tisotumab-vedotin"]},{"year":2021,"title":"KEYNOTE-826: first-line chemo-immunotherapy; tisotumab vedotin accelerated approval; EMPOWER-Cervical 1","refs":["keynote-826","tisotumab-vedotin","empower-cervical-1"]},{"year":2022,"title":"WHO endorses single-dose HPV vaccination (KEN SHE); OUTBACK negative","refs":["ken-she","outback"]},{"year":2023,"title":"KEYNOTE-A18 and INTERLACE positive; BEATcc and innovaTV 301 positive","note":"Four practice-changing phase 3 results presented at ESMO 2023.","refs":["keynote-a18","interlace","beatcc","innovatv-301"]},{"year":2024,"title":"Pembrolizumab approved with chemoradiation (Jan); tisotumab full approval (Apr); FDA approves HPV self-collection (May); COMPASSION-16 published; SHAPE trial supports simple hysterectomy; Scotland reports zero cancers in fully vaccinated cohort","refs":["keynote-a18","tisotumab-vedotin","hpv-testing","compassion-16"]},{"year":2025,"title":"At-home HPV self-test approved in the US; single-dose schedules adopted by 60+ countries","refs":["hpv-testing","gardasil-9"]},{"year":2026,"title":"World Health Assembly calls for accountable elimination systems; sac-TMT and TIL trials in recurrent disease","refs":["sacituzumab-tirumotecan","lifileucel"]}],"pipeline":["sacituzumab-tirumotecan","lifileucel","shr-8068","shr-a2102","yl202","hlx43","gotistobart","hmbd-001","lorigerlimab","vudalimab","np137","cadonilimab","trastuzumab-deruxtecan","senticol-iii","hpv-testing","precancer-ablation","idea-single-dose-hpv-self-sampling-elimination","idea-hpv-ctdna-cervical","gardasil-9","mrd-testing","proton-therapy"],"openProblems":["Vaccine and screening access in LMICs.","Brachytherapy capacity.","Delivery, not discovery: the disease is preventable, yet global HPV vaccination coverage of girls is around 27% and 350,000 women still die of it each year.","Screening reaches under 30% of women in most low- and middle-income countries; brachytherapy capacity is absent in much of Africa.","Pembrolizumab with chemoradiation costs far more than induction chemotherapy; how to combine or choose between KEYNOTE-A18 and INTERLACE is untested.","Recurrent disease after chemo-immunotherapy has few options; tisotumab adds two months of median survival.","HPV-independent (gastric-type) adenocarcinoma and neuroendocrine carcinoma have poor outcomes and no specific therapy.","Minimally invasive surgery's harm mechanism is unresolved; protective-technique trials (RACC, ROCC) are pending.","Therapeutic HPV vaccines (E6/E7-directed) have repeatedly shown immunogenicity without clear clinical benefit in invasive cancer.","Fertility preservation options for tumours over 2 cm remain limited."],"prognosis":{"text":"In the United States, 68.8% of women diagnosed with cervical cancer in 2016-2022 were alive five years later, relative to women of the same age without the disease. 41% of cases are found while confined to the cervix, with five-year relative survival of 91.8%; it is 64% for regional disease (37% of cases) and 20.5% for distant disease (16% of cases). Screening and HPV vaccination prevent most cases altogether, which is why the outlook depends so heavily on where a woman lives.","sources":[{"label":"SEER Cancer Stat Facts: Cervical Cancer","url":"https://seer.cancer.gov/statfacts/html/cervix.html"}]}},{"id":"childhood-cancers","kind":"cancer","name":"Childhood cancers (all types)","aka":["Childhood Cancers","Paediatric cancers","Pediatric cancers","Cancer in children","Young Adults, Cancer in","Adolescent and young adult cancer"],"tldr":"Cancer in children is rare and different from adult cancer: the common types are leukaemias, brain tumours, lymphomas and embryonal tumours such as neuroblastoma and Wilms tumour, most are curable in well-resourced health systems, and the great challenge is bringing the same cures to the majority of children who live where they are not available.","summary":"Childhood cancers are mostly not the carcinomas of adults but leukaemias, brain and spinal cord tumours, lymphomas and embryonal tumours that arise in developing tissue: neuroblastoma, Wilms tumour, retinoblastoma, hepatoblastoma, rhabdomyosarcoma and bone sarcomas. Decades of cooperative group trials made most of them curable in high-income countries with combination chemotherapy, surgery and radiotherapy, and newer approaches such as CAR-T for leukaemia, anti-GD2 antibodies for neuroblastoma and targeted drugs for BRAF- or ALK-driven tumours are improving results further. Survival is far lower in low- and middle-income countries, where most children with cancer live, because of late diagnosis, abandonment of treatment and lack of drugs; the WHO Global Initiative for Childhood Cancer aims to raise survival there to at least 60% by 2030. Survivors carry lifelong late effects, so reducing treatment intensity where cure is secure is a major research theme. Adolescents and young adults (15 to 39) sit between paediatric and adult services and often do worse than either.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Childhood_cancer","links":[{"label":"NCI: Childhood cancers","url":"https://www.cancer.gov/types/childhood-cancers"},{"label":"WHO Global Initiative for Childhood Cancer","url":"https://www.who.int/initiatives/the-global-initiative-for-childhood-cancer"}],"tags":["paediatric","umbrella"],"related":["all-leukemia","aml","medulloblastoma","dipg-dmg","ependymoma","paediatric-low-grade-glioma","atrt","neuroblastoma","retinoblastoma","hepatoblastoma","rhabdomyosarcoma","osteosarcoma","ewing-sarcoma","paediatric-germ-cell-tumours","pleuropulmonary-blastoma","hodgkin-lymphoma","burkitt-lymphoma"],"cancers":[],"sections":[],"technologies":["car-t"],"targets":["cd19","gd2"],"drugs":["blinatumomab","tisagenlecleucel","dinutuximab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["nct05491525","nct04851717","nct05948943","nct06055959","nct06149559"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About 400,000 children and adolescents aged 0 to 19 develop cancer each year worldwide (WHO); leukaemias, brain tumours and lymphomas are the commonest, and the chance of cure depends heavily on where a child lives.","subtypes":["Acute lymphoblastic leukaemia","Acute myeloid leukaemia","Brain and spinal cord tumours (medulloblastoma, gliomas, ependymoma)","Hodgkin and non-Hodgkin lymphoma","Neuroblastoma","Wilms tumour","Retinoblastoma","Hepatoblastoma","Rhabdomyosarcoma and other soft tissue sarcomas","Osteosarcoma and Ewing sarcoma","Germ cell tumours","Rare tumours (pleuropulmonary blastoma, ATRT and others)"],"biomarkers":["Cytogenetics and minimal residual disease in leukaemia","MYCN amplification in neuroblastoma","Molecular subgroups in medulloblastoma","Germline predisposition (Li-Fraumeni, RB1, WT1 and others)"],"standardOfCare":[{"setting":"Leukaemias","approach":"Risk-stratified multi-agent chemotherapy over two to three years for ALL, with immunotherapy (blinatumomab, CAR-T) for high-risk or relapsed disease. See the ALL page.","refs":["blinatumomab","tisagenlecleucel"]},{"setting":"Solid tumours","approach":"Surgery, chemotherapy and radiotherapy by risk group in cooperative group protocols; anti-GD2 antibody for high-risk neuroblastoma. See the neuroblastoma, Wilms, sarcoma and brain tumour pages.","refs":["dinutuximab"]},{"setting":"Survivorship","approach":"Lifelong follow-up for late effects on heart, fertility, growth and second cancers, with a survivorship care plan; trials that reduce therapy where cure rates are high.","refs":["survivorship-care-plan"]}],"stateOfArt":[],"history":[{"year":1965,"title":"Combination chemotherapy first cures childhood leukaemia","note":"Multi-drug regimens at the National Cancer Institute and St Jude turned acute lymphoblastic leukaemia from a disease almost no child survived into a curable one.","refs":["vincristine","methotrexate"]},{"year":2015,"title":"Dinutuximab approved for high-risk neuroblastoma","note":"Anti-GD2 antibody added to maintenance therapy after the Children's Oncology Group trial.","refs":["dinutuximab"]},{"year":2017,"title":"First CAR-T therapy approved","note":"Tisagenlecleucel for children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia.","refs":["tisagenlecleucel"]}],"pipeline":["naxitamab","tovorafenib","obecabtagene-autoleucel"],"openProblems":["Most children with cancer live where cure rates are below 30%.","Late effects affect the majority of long-term survivors.","Few new drugs are developed for children because the markets are small."]},{"id":"pleuropulmonary-blastoma","kind":"cancer","name":"Childhood lung and airway tumours (pleuropulmonary blastoma, tracheobronchial tumours)","aka":["PPB","DICER1 syndrome","Bronchial tumours (childhood)","Tracheobronchial tumours","Childhood bronchial carcinoid","Pleuropulmonary blastoma (childhood)"],"tldr":"Primary lung tumours in children are rare and unlike adult lung cancer. Pleuropulmonary blastoma starts as a lung cyst in infants and results from a faulty DICER1 gene that also predisposes to thyroid, ovarian and kidney tumours; removing cysts early, guided by an international registry and family gene testing, prevents progression to the aggressive solid forms.","summary":"Pleuropulmonary blastoma (PPB) is the archetypal DICER1-related tumour: a mesenchymal malignancy of the lung and pleura in children under about six years. It evolves through recognised stages: type I (purely cystic, infants, excellent outcome with surgery), type Ir (regressed cystic), type II (cystic and solid) and type III (solid), with progressively worse prognosis. About two thirds of children carry a germline loss-of-function DICER1 variant, with a second somatic hotspot mutation in the RNase IIIb domain in the tumour. The same syndrome causes cystic nephroma, Sertoli-Leydig cell tumour of the ovary, multinodular goitre and differentiated thyroid carcinoma, pituitary blastoma, pineoblastoma, embryonal rhabdomyosarcoma of the cervix and nasal chondromesenchymal hamartoma, so a PPB diagnosis triggers testing and surveillance across the family.\n\nTreatment is surgical for type I disease, with adjuvant chemotherapy debated and studied in the registry; types II and III receive multi-agent chemotherapy (ifosfamide, vincristine, dactinomycin and doxorubicin, the IVADo backbone used in rhabdomyosarcoma) plus complete resection, with radiotherapy for residual disease. The International PPB/DICER1 Registry (since 1988) has defined the staging, treatment recommendations and surveillance guidance, including chest imaging for infants known to carry DICER1 variants so that cysts are removed before they become solid tumours.\n\nOther childhood lung and airway tumours are grouped with PPB by the NCI: tracheobronchial carcinoid tumours (the most common primary lung malignancy in children, usually cured by sleeve or lobar resection), mucoepidermoid carcinoma of the bronchus, inflammatory myofibroblastic tumour (ALK-rearranged, see its own record) and rare adult-type carcinomas. The recurring themes are delayed diagnosis because symptoms mimic asthma or pneumonia, the value of bronchoscopy and cross-sectional imaging, and the need for rare-tumour registries rather than randomised trials.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Pleuropulmonary_blastoma","links":[{"label":"NCI PDQ: childhood pleuropulmonary blastoma (in rare cancers of childhood)","url":"https://www.cancer.gov/types/childhood-cancers/patient/rare-childhood-cancers-pdq"},{"label":"International PPB/DICER1 Registry","url":"https://www.ppbregistry.org/"},{"label":"Messinger 2015: PPB types and outcomes (Cancer)","url":"https://doi.org/10.1002/cncr.29062"},{"label":"Schultz 2018: DICER1 syndrome surveillance consensus (Clinical Cancer Research)","url":"https://doi.org/10.1158/1078-0432.CCR-17-3089"}],"tags":["nci-coverage","paediatric","thoracic"],"related":["inflammatory-myofibroblastic-tumour","rhabdomyosarcoma","rare-childhood-cancers","thyroid","wilms-tumor","hepatoblastoma"],"cancers":[],"sections":[],"technologies":["germline-testing","ct","cytotoxic-chemotherapy"],"targets":[],"drugs":["ifosfamide","vincristine","dactinomycin","doxorubicin"],"companies":["childrens-oncology-group"],"institutions":["siop-europe"],"pathways":[],"terms":["hereditary-cancer-syndromes","bronchoscopy","ttf1-p40"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers","b-hereditary-risk"],"keyPapers":["paper-english-cancer","paper-schultz-clin-cancer-res"],"journals":[],"dependsOn":[],"notes":["Where the childhood lung tumours sit. The lung cancer family page names pleuropulmonary blastoma among its subtypes, and this umbrella record is the page that string points at. It is a childhood disease of a different lineage from the carcinomas that make up adult lung cancer, and the DICER1-related entity with its types I to III sits beneath it; neither is a subtype of non-small-cell or small-cell lung cancer, and neither is treated on the adult pathway."],"group":"paediatric","burden":"Very rare: pleuropulmonary blastoma is reported in a few dozen children a year worldwide through the International PPB/DICER1 Registry; tracheobronchial tumours in children are mostly carcinoid and mucoepidermoid tumours (NCI PDQ).","subtypes":["Pleuropulmonary blastoma type I (cystic)","Pleuropulmonary blastoma type Ir (regressed)","Pleuropulmonary blastoma type II (cystic and solid)","Pleuropulmonary blastoma type III (solid)","Tracheobronchial carcinoid tumour","Mucoepidermoid carcinoma of the bronchus","Pulmonary inflammatory myofibroblastic tumour (ALK-rearranged)"],"biomarkers":["Germline DICER1 loss-of-function variant","Somatic DICER1 RNase IIIb hotspot mutation","PPB type (I, Ir, II, III) on pathology","Chest CT for cystic lung lesions in DICER1 carriers","ALK rearrangement (inflammatory myofibroblastic tumour)"],"standardOfCare":[{"setting":"Type I or Ir pleuropulmonary blastoma","approach":"Complete surgical resection of the cystic lesion; adjuvant chemotherapy is optional and registry-guided; germline DICER1 testing for the child and first-degree relatives.","refs":["germline-testing"],"guideline":{"version":"International PPB/DICER1 Registry; NCI PDQ","url":"https://www.cancer.gov/types/childhood-cancers/patient/rare-childhood-cancers-pdq"}},{"setting":"Type II or III pleuropulmonary blastoma","approach":"Neoadjuvant or adjuvant multi-agent chemotherapy (ifosfamide, vincristine, dactinomycin, doxorubicin) with complete resection; radiotherapy for unresectable residual disease.","refs":["ifosfamide","vincristine","dactinomycin","doxorubicin"],"guideline":{"version":"International PPB/DICER1 Registry recommendations (Cancer 2015)","url":"https://doi.org/10.1002/cncr.29062"}},{"setting":"Tracheobronchial carcinoid or mucoepidermoid carcinoma","approach":"Bronchoscopic assessment and parenchyma-sparing surgical resection (sleeve resection); systemic therapy rarely needed.","refs":["bronchoscopy"]},{"setting":"DICER1 carriers","approach":"Surveillance per international consensus: chest imaging in infancy and early childhood, abdominal ultrasound, thyroid ultrasound, and awareness of ovarian and other syndrome tumours.","refs":["hereditary-cancer-syndromes","germline-testing"],"guideline":{"version":"DICER1 surveillance consensus (Clinical Cancer Research 2018)","url":"https://doi.org/10.1158/1078-0432.CCR-17-3089"}}],"stateOfArt":["PPB is understood as a DICER1 syndrome tumour with a staged natural history; early removal of type I cysts prevents the solid, chemotherapy-requiring forms.","A single international registry has defined classification, treatment and surveillance for a tumour too rare for randomised trials.","Germline DICER1 testing and family surveillance turn one diagnosis into prevention across a family.","Childhood carcinoid and mucoepidermoid airway tumours are cured by lung-sparing surgery when recognised; diagnostic delay is the main problem."],"history":[{"year":1988,"title":"Pleuropulmonary blastoma described as a distinct entity","note":"Manivel and colleagues separate PPB from adult pulmonary blastoma; the International PPB Registry is founded.","refs":[]},{"year":2009,"title":"DICER1 germline mutations cause familial PPB","note":"Hill and colleagues (Science) identify the first microRNA-processing gene tumour syndrome.","refs":[]},{"year":2015,"title":"Registry defines types I to III and treatment recommendations","note":"Messinger and colleagues (Cancer 2015) report outcomes by type.","refs":[]},{"year":2018,"title":"International DICER1 surveillance consensus published","refs":["germline-testing"]}],"pipeline":["germline-testing"],"openProblems":["Whether adjuvant chemotherapy helps type I PPB; the registry is comparing outcomes with and without it.","Type III and recurrent PPB have poor outcomes and no targeted therapy; DICER1-dependent biology (miRNA processing) has not yet yielded a drug.","Uptake of germline testing and surveillance across families, and the psychological burden of surveillance in carriers.","Diagnostic delay for childhood airway tumours misdiagnosed as asthma."],"parent":"childhood-cancers"},{"id":"chondrosarcoma","kind":"cancer","name":"Chondrosarcoma","aka":["Cartilage sarcoma","Atypical cartilaginous tumour (grade 1, limbs)","Dedifferentiated chondrosarcoma","Mesenchymal chondrosarcoma"],"tldr":"Chondrosarcoma is a cancer of cartilage-forming cells in bone. It is nearly immune to chemotherapy and radiotherapy, so complete surgery is the treatment, with proton or carbon-ion beams for skull base and spine tumours that cannot be fully removed. Half of conventional tumours carry an IDH mutation, and the IDH1 blocker ivosidenib is in a phase 3 trial.","summary":"Chondrosarcoma arises in bone from cartilage-producing cells and is graded 1 to 3; grade 1 tumours of the limbs were renamed atypical cartilaginous tumours in 2013 because they almost never metastasise, while grade 3 and dedifferentiated tumours spread early to the lungs. About half of conventional and most dedifferentiated tumours carry a mutation in IDH1 or IDH2, the same enzymes mutated in glioma and acute myeloid leukaemia, and mesenchymal chondrosarcoma carries a HEY1-NCOA2 fusion. The tumour's low cell turnover, poor blood supply and abundant cartilage matrix make it resistant to conventional chemotherapy and to standard-dose radiotherapy.\n\nSurgery is the only established curative treatment: curettage for atypical cartilaginous tumours of the limbs, wide resection for higher grades and for all pelvic and axial tumours, with limb-salvage reconstruction where feasible. Skull base and spinal tumours that cannot be resected completely are treated with high-dose proton or carbon-ion radiotherapy, which achieves local control in most cases. Dedifferentiated chondrosarcoma is treated like osteosarcoma with doxorubicin and cisplatin-based chemotherapy despite uncertain benefit, and mesenchymal chondrosarcoma with Ewing-type regimens.\n\nThe 2011 discovery of IDH mutations made chondrosarcoma a targetable disease. In the phase 1 study of ivosidenib in IDH1-mutant chondrosarcoma, most patients had stable disease as their best response with durable control in some, and the placebo-controlled phase 3 CHONQUER trial (NCT06127407) in conventional chondrosarcoma is now recruiting. Immunotherapy has shown occasional responses in dedifferentiated tumours, and there is no approved systemic therapy for any form.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Chondrosarcoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Chondrosarcoma"}],"tags":["subtype-page"],"related":["osteosarcoma","chordoma","ewing-sarcoma","extremity-soft-tissue-sarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["regobone"],"people":[],"bottlenecks":[],"keyPapers":["paper-amary-idh-cartilaginous-tumours-j-pathol-2011","paper-esmo-bone-sarcoma-guideline-strauss-ann-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"The commonest primary bone sarcoma of adults, typically diagnosed between 40 and 70 in the pelvis, proximal femur, shoulder girdle and ribs; low-grade tumours are cured by surgery alone, while dedifferentiated tumours are among the most lethal of all sarcomas.","subtypes":["Conventional central chondrosarcoma, grades 1 to 3 (IDH1/IDH2-mutant in about half)","Atypical cartilaginous tumour (grade 1 of the limbs; curettage)","Peripheral (secondary) chondrosarcoma arising in osteochondroma","Dedifferentiated chondrosarcoma (high-grade component; treated like osteosarcoma)","Mesenchymal chondrosarcoma (HEY1-NCOA2; Ewing-type chemotherapy)","Clear cell chondrosarcoma (epiphyseal, low grade)","Skull base and spinal chondrosarcoma (particle therapy)"],"biomarkers":["IDH1 or IDH2 mutation (ivosidenib eligibility)","Histological grade 1 to 3 and dedifferentiation","HEY1-NCOA2 fusion (mesenchymal)","COL2A1 mutations","Site (limb versus pelvis and axial skeleton)"],"standardOfCare":[{"setting":"Atypical cartilaginous tumour of the limbs","approach":"Intralesional curettage with local adjuvant, or observation of asymptomatic lesions; no chemotherapy or radiotherapy.","refs":["limb-salvage-surgery","active-surveillance","mri"]},{"setting":"Conventional grade 2 to 3, resectable","approach":"Wide en bloc resection with limb-salvage or pelvic reconstruction in a bone sarcoma centre; radiotherapy only for positive margins.","refs":["limb-salvage-surgery","imrt-igrt"]},{"setting":"Skull base and spine, incompletely resectable","approach":"Maximal safe surgery followed by high-dose proton or carbon-ion radiotherapy.","refs":["proton-therapy","carbon-ion","imrt-igrt"]},{"setting":"Dedifferentiated and mesenchymal","approach":"Surgery plus osteosarcoma-type (doxorubicin, cisplatin) or Ewing-type (doxorubicin, ifosfamide) chemotherapy, benefit uncertain.","refs":["doxorubicin","cisplatin","ifosfamide"]},{"setting":"Advanced IDH1-mutant conventional","approach":"Ivosidenib within the CHONQUER phase 3 trial or compassionate access; no approved systemic therapy.","refs":["ivosidenib","nct06127407","idh-inhibitors"]}],"stateOfArt":["Particle therapy gives durable local control of skull base chondrosarcoma that surgery alone cannot achieve.","IDH1 inhibition with ivosidenib produced durable stable disease in the phase 1 study and is being tested against placebo in the CHONQUER phase 3 trial.","Grading by an expert bone pathologist, not imaging alone, decides between curettage and wide resection."],"history":[{"year":1943,"title":"Lichtenstein and Jaffe separate chondrosarcoma from osteosarcoma","refs":[]},{"year":2011,"title":"IDH1 and IDH2 mutations found in chondrosarcoma and enchondroma","refs":["idh"]},{"year":2013,"title":"WHO renames grade 1 limb tumours atypical cartilaginous tumours","refs":[]},{"year":2020,"title":"Phase 1 ivosidenib in IDH1-mutant chondrosarcoma reports durable stable disease","refs":["ivosidenib"]},{"year":2023,"title":"CHONQUER phase 3 trial of ivosidenib opens","refs":["nct06127407"]}],"pipeline":["ivosidenib","nct06127407","idh-inhibitors","carbon-ion"],"openProblems":["No systemic therapy has ever been proven to help.","Dedifferentiated chondrosarcoma kills most patients within two years.","Distinguishing enchondroma from grade 1 chondrosarcoma remains unreliable."],"parent":"sarcoma"},{"id":"chordoma","kind":"cancer","name":"Chordoma","aka":["Childhood chordoma","Clival chordoma","Sacral chordoma"],"tldr":"Chordoma is a slow-growing bone cancer (a sarcoma) of the skull base and spine that arises from leftover embryonic notochord cells. Complete surgery followed by high-dose proton or carbon-ion radiotherapy controls most tumours, and the whole disease depends on a single transcription factor, brachyury, which vaccines and degraders are now trying to hit.","summary":"Chordoma arises from notochordal remnants along the axial skeleton (clivus, mobile spine, sacrum). Nearly all tumours express the T-box transcription factor brachyury (TBXT), a lineage dependency rather than a mutation: a common germline TBXT variant raises risk, and germline TBXT duplication causes familial chordoma. Conventional and chondroid chordomas are indolent but locally destructive; dedifferentiated and poorly differentiated chordomas are aggressive. Poorly differentiated chordoma, seen mainly in children, is defined by SMARCB1 (INI1) loss, placing it in the SWI/SNF-deficient family with epithelioid sarcoma and ATRT.\n\nCurative treatment is en bloc resection with negative margins where anatomy permits, followed by high-dose radiotherapy, because the tumour is radioresistant at conventional doses and sits against the brainstem, cranial nerves or sacral roots. Proton and carbon-ion therapy deliver 70 Gy-equivalent or more while sparing neural tissue, and definitive particle therapy is used when resection is impossible. Systemic options are limited: imatinib (PDGFRB-expressing disease, phase 2 Stacchiotti 2012) and afatinib (EGFR) give disease stabilisation more often than shrinkage, and are not approved. Tazemetostat is being studied in INI1-negative poorly differentiated chordoma on the basis of its epithelioid sarcoma activity.\n\nThe frontier is brachyury itself: a yeast-based brachyury vaccine (GI-6301) and adenoviral brachyury vaccines have been tested with radiotherapy, and brachyury degraders and CDK7/9 inhibitors that lower TBXT expression are in preclinical or early clinical development. The Chordoma Foundation coordinates a global registry, biobank and drug-screening pipeline, a model for how a rare cancer community can run its own research programme.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Chordoma","links":[{"label":"NCI PDQ: childhood chordoma (bone cancer)","url":"https://www.cancer.gov/types/bone"},{"label":"Chordoma Global Consensus Group recommendations (Lancet Oncol 2015)","url":"https://doi.org/10.1016/S1470-2045(14)71190-8"},{"label":"Chordoma Foundation","url":"https://www.chordomafoundation.org/"}],"tags":["nci-coverage","rare","sarcoma","paediatric"],"related":["chondrosarcoma","osteosarcoma","ewing-sarcoma"],"cancers":[],"sections":[],"technologies":["proton-therapy","carbon-ion","imrt-igrt","sbrt","kinase-inhibitors","epigenetic-drugs"],"targets":["ezh2","egfr","pdgfra"],"drugs":["imatinib","afatinib","sorafenib","tazemetostat","gi-6301"],"companies":[],"institutions":[],"pathways":["swi-snf-chromatin","transcription-addiction"],"terms":["rare-cancers"],"trials":["regobone"],"people":[],"bottlenecks":["b-rare-cancers","b-undruggable-targets"],"keyPapers":["paper-stacchiotti-lancet-oncol"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"About one case per million people per year, at any age; skull-base tumours are more common in children, sacral tumours in older adults.","subtypes":["Conventional chordoma","Chondroid chordoma","Dedifferentiated chordoma","Poorly differentiated chordoma (SMARCB1/INI1-deficient, mostly paediatric skull base)"],"biomarkers":["Brachyury (TBXT) nuclear immunostaining (diagnostic)","SMARCB1/INI1 loss (poorly differentiated subtype)","PDGFRB and EGFR expression (drug selection in trials)","Germline TBXT duplication (familial chordoma)","Surgical margin status and location (skull base vs sacrum)"],"standardOfCare":[{"setting":"Resectable, any site","approach":"En bloc resection with negative margins by a spine or skull-base team, followed by high-dose proton or carbon-ion radiotherapy; intralesional surgery is associated with early recurrence.","refs":["proton-therapy","carbon-ion","imrt-igrt"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Bone Cancer; Chordoma Global Consensus Group (Lancet Oncol 2015)","url":"https://doi.org/10.1016/S1470-2045(14)71190-8"}},{"setting":"Unresectable or medically inoperable","approach":"Definitive particle therapy (proton or carbon-ion) to 70 Gy-equivalent or higher; stereotactic photon radiosurgery where particles are unavailable.","refs":["proton-therapy","carbon-ion","sbrt"]},{"setting":"Advanced or metastatic","approach":"Clinical trial preferred. Imatinib (PDGFRB-positive), afatinib or other EGFR inhibitors, or sorafenib give mainly disease stabilisation; tazemetostat was used for INI1-negative poorly differentiated chordoma until Ipsen withdrew it from all markets in March 2026.","refs":["imatinib","afatinib","sorafenib","tazemetostat","kinase-inhibitors"]}],"stateOfArt":["Particle therapy after maximal surgery has made long-term local control the expected outcome for skull-base chordoma, with less neurological injury than photon plans.","Brachyury is now recognised as the lineage dependency of the disease: TBXT knockdown is lethal to chordoma cells, and vaccines plus degraders that target it are the main mechanistic bets.","SMARCB1-deficient poorly differentiated chordoma in children is being treated with EZH2 inhibition borrowed from epithelioid sarcoma, an example of biology-based rather than histology-based drug repurposing.","Patient-led infrastructure (the Chordoma Foundation's registry, cell-line bank and prize-driven drug screens) has produced most of the field's preclinical models."],"history":[{"year":1857,"title":"Virchow describes chordoma","note":"First description of the notochord-derived tumour.","refs":[]},{"year":2006,"title":"Brachyury identified as a chordoma marker","note":"Vujovic and colleagues show near-universal nuclear brachyury expression.","refs":[]},{"year":2009,"title":"Germline TBXT duplication in familial chordoma","note":"Yang and colleagues (Nat Genet).","refs":[]},{"year":2012,"title":"Imatinib phase 2 in advanced chordoma","note":"Stacchiotti and colleagues: disease stabilisation in most patients, few objective responses.","refs":["imatinib"]},{"year":2015,"title":"Chordoma Global Consensus Group","note":"First international recommendations on surgery, radiotherapy and systemic therapy (Lancet Oncol).","refs":[]},{"year":2020,"title":"Poorly differentiated chordoma recognised as SMARCB1-deficient entity","note":"WHO classification of soft tissue and bone tumours, fifth edition.","refs":[]},{"year":2021,"title":"Brachyury vaccine plus radiotherapy tested","note":"Phase 2 of GI-6301 yeast-brachyury vaccine with radiation (NCT02383498).","refs":["proton-therapy"]}],"pipeline":["carbon-ion","proton-therapy","afatinib"],"openProblems":["No approved systemic therapy: trials of brachyury-directed vaccines, degraders and EGFR inhibitors are the response.","Recurrent skull-base disease after full-dose radiotherapy: re-irradiation with particles and salvage surgery are being studied.","Paediatric poorly differentiated chordoma: tazemetostat and SWI/SNF-directed trials.","Access to particle therapy, which remains concentrated in a few countries."],"parent":"sarcoma"},{"id":"testicular-choriocarcinoma","kind":"cancer","name":"Choriocarcinoma of the testis","aka":["Testicular choriocarcinoma","Choriocarcinoma (very high hCG, haemorrhagic metastases)","Pure choriocarcinoma of the testis","Choriocarcinoma-predominant germ cell tumour"],"tldr":"Choriocarcinoma is the rarest and most dangerous form of non-seminoma testicular cancer, made of placenta-like cells that pour out the pregnancy hormone hCG and spread early through the blood to the lungs, liver and brain, where they can bleed. Fewer than eight in ten men survive five years, against more than 95 for testicular cancer overall, so it is treated urgently with intensive chemotherapy.","summary":"Choriocarcinoma is a trophoblastic germ cell tumour of syncytiotrophoblasts and mononucleated trophoblasts, arising from germ cell neoplasia in situ and usually as a component of mixed tumours (Moch 2016). In the 1,010-orchidectomy series, pure and predominant choriocarcinoma together made up 1.5 percent; all patients had markedly raised serum beta-hCG (median 199,000 IU/L), tumours averaged 6.5 cm, and the histology showed expansile haemorrhagic nodules surrounded by trophoblastic cells with plexiform aggregates (Am J Surg Pathol 2014). Five-year survival is under 80 percent against over 95 percent for testicular germ cell tumours overall; the choriocarcinoma syndrome, bleeding from metastatic sites at presentation or on starting chemotherapy, is a medical emergency with high morbidity and mortality (Current Oncology Reports 2015).\n\nHow it differs from its parent: haematogenous rather than lymphatic spread, so lung, liver and brain metastases without bulky retroperitoneal nodes; beta-hCG in the tens or hundreds of thousands, which alone places a patient in the poor-risk group; and a tendency to bleed that shapes the first days of treatment.\n\nHow common: about 1.5 percent of orchidectomies for germ cell tumour when pure and predominant cases are combined (Am J Surg Pathol 2014).\n\nTreatment: as poor-risk non-seminoma with four cycles of BEP or VIP, sometimes with a reduced first cycle to limit bleeding, aiming at marker normalisation; refractory disease goes to high-dose chemotherapy and trials such as TIGER; brain metastases are treated with chemotherapy first and surgery or radiotherapy for residual disease (Current Oncology Reports 2015; the parent page).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Choriocarcinoma","links":[{"label":"NCI PDQ: testicular cancer treatment","url":"https://www.cancer.gov/types/testicular/treatment"},{"label":"Moch 2016, European Urology: the 2016 WHO classification of urinary and male genital tumours, part A","url":"https://doi.org/10.1016/j.eururo.2016.02.029"},{"label":"Am J Surg Pathol 2014: choriocarcinoma as a pure or predominant component of testicular germ cell tumour, 1,010 orchiectomies","url":"https://doi.org/10.1097/pas.0b013e3182a2926e"},{"label":"Current Oncology Reports 2015: testicular choriocarcinoma, a rare variant needing a unique treatment approach","url":"https://doi.org/10.1007/s11912-014-0430-0"}],"tags":["subtype-page","wave4","testicular","rare"],"related":["non-seminoma","testicular","embryonal-carcinoma-testis","yolk-sac-tumour-postpubertal","gestational-trophoblastic","mediastinal-germ-cell-tumour"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["bleomycin","etoposide","cisplatin","ifosfamide","methotrexate"],"companies":[],"institutions":[],"pathways":[],"terms":["tumour-markers"],"trials":["tiger-trial"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Rare: 6 pure (0.6 percent) and 9 choriocarcinoma-predominant (0.9 percent) tumours among 1,010 orchiectomies over 1999 to 2011 at one cancer centre; patients aged 20 to 39, median 29 (Am J Surg Pathol 2014).","subtypes":["Pure choriocarcinoma of the testis (0.6 percent of orchidectomies)","Choriocarcinoma-predominant mixed germ cell tumour","Choriocarcinoma syndrome (haemorrhage from metastases at presentation or on starting treatment)","Non-choriocarcinomatous trophoblastic tumours (placental site and cystic trophoblastic tumour; rare)"],"biomarkers":["Serum beta-hCG (very high; poor-risk marker level)","Beta-hCG and GATA3 on immunohistochemistry","Lung, liver and brain imaging at diagnosis","Haemoglobin and signs of bleeding during induction"],"standardOfCare":[{"setting":"All cases","approach":"Treated as poor-risk non-seminoma: four cycles of BEP or VIP with care for bleeding, resection of residual disease, high-dose chemotherapy or trials for refractory disease.","refs":["non-seminoma","testicular","bleomycin","etoposide","cisplatin","ifosfamide","tiger-trial"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"non-seminoma"},{"id":"choroid-plexus-carcinoma","kind":"cancer","name":"Choroid plexus carcinoma","aka":["Choroid plexus carcinoma (WHO grade 3)","Malignant choroid plexus tumour","CPC"],"tldr":"Choroid plexus carcinoma is a rare, aggressive brain tumour of infants and young children that grows from the tissue that makes spinal fluid inside the brain's ventricles, causing fluid build-up and pressure. It is strongly linked to an inherited TP53 fault (Li-Fraumeni syndrome), so families are tested; treatment is surgery, then chemotherapy and, in older children, radiotherapy.","summary":"Choroid plexus carcinoma is the grade 3 member of the choroid plexus tumours in the WHO central nervous system classification, distinguished from choroid plexus papilloma and atypical papilloma by frequent mitoses, necrosis and invasion (NCI PDQ). Choroid plexus tumours make up about 2 to 5 percent of paediatric brain tumours and most present with severe hydrocephalus; in 39 patients (31 papillomas, 8 carcinomas) perioperative management and oncological care remained debated (J Neurosurg Pediatrics 2012). Of 42 choroid plexus tumour patients at Children's Hospital Los Angeles, 6 (16.7 percent) had features of Li-Fraumeni syndrome (Pediatric Blood and Cancer 2012), and in southern Brazil, where the low-penetrance TP53 R337H founder mutation is common, 9 of 13 children with choroid plexus carcinoma (69 percent) carried it (Cancer 2011).\n\nHow it differs from its parent: a tumour of infancy arising inside the ventricles with hydrocephalus as the presenting problem, extreme vascularity that makes surgery hazardous, and the strongest association with germline TP53 mutation of any childhood brain tumour, so that germline testing is part of the work-up.\n\nHow common: a minority of the 2 to 5 percent of paediatric brain tumours that are choroid plexus tumours (J Neurosurg Pediatrics 2012).\n\nTreatment: maximal safe resection, often in stages after chemotherapy to shrink and devascularise the tumour, then platinum- and etoposide-based chemotherapy with radiotherapy for older children and residual disease, as the PDQ childhood brain tumour summaries describe; TP53 carriers are treated with radiotherapy sparing where possible because of second cancers.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Choroid_plexus_carcinoma","links":[{"label":"NCI PDQ: rare cancers of childhood","url":"https://www.cancer.gov/types/childhood-cancers/patient/rare-childhood-cancers-pdq"},{"label":"J Neurosurg Pediatrics 2012: treatment of choroid plexus tumours, 20-year single-institution experience","url":"https://doi.org/10.3171/2012.8.peds12132"},{"label":"Pediatric Blood and Cancer 2012: choroid plexus tumours and Li-Fraumeni syndrome, Children's Hospital Los Angeles 1991 to 2010","url":"https://doi.org/10.1002/pbc.23349"},{"label":"Cancer 2011: TP53 R337H and paediatric choroid plexus carcinoma in southeast Brazil","url":"https://doi.org/10.1002/cncr.25826"}],"tags":["subtype-page","wave4","rare"],"related":["brain-tumours","childhood-cancers","pineoblastoma","atrt","adrenocortical"],"cancers":[],"sections":[],"technologies":["germline-testing"],"targets":["tp53"],"drugs":["cisplatin","carboplatin","etoposide","cyclophosphamide"],"companies":[],"institutions":[],"pathways":[],"terms":["li-fraumeni"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Choroid plexus tumours are about 2 to 5 percent of paediatric brain tumours, and carcinomas the minority: 8 carcinomas among 39 choroid plexus tumours in one 20-year series (J Neurosurg Pediatrics 2012). No registry figure for the carcinoma alone is in the sources read.","subtypes":[],"biomarkers":["Germline TP53 mutation (Li-Fraumeni syndrome)","Mitotic count, necrosis and brain invasion (grade 3 criteria)","Extent of resection","Hydrocephalus at presentation"],"standardOfCare":[{"setting":"All cases","approach":"Maximal safe resection, staged after chemotherapy where the tumour is too vascular; platinum- and etoposide-based chemotherapy; radiotherapy for older children and residual disease; germline TP53 testing.","refs":["brain-tumours","cisplatin","etoposide","germline-testing","li-fraumeni"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"brain-tumours"},{"id":"chromophobe-rcc","kind":"cancer","name":"Chromophobe renal cell carcinoma","aka":["chRCC"],"tldr":"Chromophobe kidney cancer comes from a different cell of the kidney's tubules, usually behaves gently and is cured by surgery. Its rare metastatic form responds poorly to immunotherapy, so kinase and mTOR inhibitors are used, and it runs in families with Birt-Hogg-Dube syndrome.","summary":"Chromophobe renal cell carcinoma arises from the intercalated cells of the collecting duct and is marked by loss of whole chromosomes (1, 2, 6, 10, 13, 17, 21) with TP53 and PTEN mutations in a minority; it must be told apart from the benign oncocytoma, which it resembles. It is a feature of Birt-Hogg-Dube syndrome, caused by germline FLCN mutations, along with skin fibrofolliculomas and lung cysts. Most tumours are found early and cured by partial nephrectomy, and surveillance is reasonable for small lesions. Metastatic disease is uncommon, responds poorly to PD-1 blockade and is treated with sunitinib or cabozantinib, everolimus, or lenvatinib plus everolimus, drawing on the mTOR pathway activity seen in the disease; sarcomatoid transformation carries the worst prognosis of any kidney cancer.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Chromophobe_renal_cell_carcinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Chromophobe_renal_cell_carcinoma"}],"tags":["subtype-page"],"related":["clear-cell-rcc","papillary-rcc"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2022-gu-moch-eur-urol-2022","paper-tcga-chromophobe-davis-cancer-cell-2014","paper-aspen-armstrong-lancet-oncol-2016"],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"About five percent of kidney cancers, with the best outlook of the common types: fewer than one in ten spread, and those that do are often slow, but sarcomatoid change turns it deadly.","subtypes":["Classic chromophobe","Eosinophilic chromophobe","Birt-Hogg-Dube-associated (germline FLCN, hybrid oncocytic tumours)","Chromophobe with sarcomatoid change (aggressive)"],"biomarkers":["Multiple whole-chromosome losses","TP53 and PTEN mutations (shorter survival)","CK7 and KIT positive, distinguishing it from oncocytoma","Germline FLCN testing when syndromic features are present"],"standardOfCare":[{"setting":"Localised","approach":"Partial nephrectomy or ablation; active surveillance for small tumours; no adjuvant therapy.","refs":["thermal-ablation","active-surveillance"]},{"setting":"Metastatic","approach":"Sunitinib, cabozantinib, everolimus or lenvatinib plus everolimus; immunotherapy has low response rates outside sarcomatoid disease; trials preferred.","refs":["sunitinib","cabozantinib","everolimus","lenvatinib"]},{"setting":"Birt-Hogg-Dube syndrome","approach":"Kidney surveillance with MRI, nephron-sparing surgery at 3 cm, and genetic counselling.","refs":["rcc"]}],"stateOfArt":["Recognition of mTOR pathway dependence gave chromophobe cancer a rational medical option after immunotherapy disappointed.","Molecular tools now reliably separate chromophobe carcinoma from oncocytoma, sparing some patients surgery.","Registries of rare kidney cancers are producing the first subtype-specific outcome data."],"history":[{"year":1985,"title":"Thoenes describes chromophobe renal cell carcinoma","refs":[]},{"year":2002,"title":"FLCN identified as the Birt-Hogg-Dube gene","refs":[]},{"year":2014,"title":"TCGA maps chromosome losses and TP53 and PTEN mutations","refs":[]}],"pipeline":["lenvatinib","everolimus"],"openProblems":["No randomised trial has ever been run in chromophobe cancer.","Immunotherapy rarely works and the reason is not understood.","Sarcomatoid change has no effective treatment."],"parent":"rcc"},{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","aka":[],"tldr":"A slow leukaemia that no longer needs chemotherapy: BTK inhibitors and venetoclax control it for years, often in fixed-duration courses.","summary":"Chronic lymphocytic leukaemia is a slow accumulation of mature B cells in blood, marrow, and lymph nodes, diagnosed at a median age of 70 and often found incidentally. Prognosis is set at diagnosis by IGHV mutational status, TP53 status (del(17p) or mutation), and karyotype, and by the CLL-IPI. Around a third of patients never need treatment; the rest are watched until symptoms, cytopenias, or bulky or rapidly progressive disease meet iwCLL criteria.\n\nTreatment abandoned chemotherapy within a decade. Continuous BTK inhibitors (ibrutinib 2014, then the better-tolerated acalabrutinib and zanubrutinib) and the BCL-2 inhibitor venetoclax replaced FCR and BR after RESONATE, ELEVATE-TN, SEQUOIA, CLL13, and CLL14. Two strategies now compete in first line: indefinite BTK inhibition, or fixed-duration therapy for 12-15 months with venetoclax-obinutuzumab (CLL14) or a BTK inhibitor plus venetoclax (acalabrutinib-venetoclax, the first all-oral fixed-duration regimen approved in the US in February 2026). Undetectable MRD at the end of fixed-duration therapy predicts years of treatment-free remission. Patients with del(17p)/TP53 aberration receive continuous BTK inhibition or venetoclax-based therapy and are excluded from chemoimmunotherapy entirely.\n\nRelapse is treated by switching class: venetoclax after BTK inhibitor failure, or a BTK inhibitor after venetoclax; pirtobrutinib (non-covalent) works after covalent BTK inhibitors and gained full approval in December 2025; CAR-T (liso-cel, 2024) and allogeneic transplant are reserved for double-refractory disease. Next come BTK degraders (BGB-16673, phase 3), the next-generation BCL-2 inhibitor sonrotoclax (approved for mantle cell lymphoma in May 2026; CLL phase 3 reading out), and MRD-guided treatment duration. The unsolved problems are Richter transformation, double-refractory disease, infections and second cancers on long-term therapy, and the cost of indefinite treatment.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia","links":[{"label":"NCCN CLL/SLL Insights v2.2026","url":"https://jnccn.org/view/journals/jnccn/24/3/article-p68.xml"},{"label":"iwCLL guidelines (Blood 2018)","url":"https://ashpublications.org/blood/article/131/25/2745/36953"}],"tags":["heme"],"related":["cml","hairy-cell-leukemia","cmml","all-leukemia"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","car-t","protac-degrader","monoclonal-antibody","flow-cytometry-mrd","ngs-mrd-clonoseq","cytogenetics-fish","bh3-profiling","allogeneic-hsct","cardio-oncology"],"targets":["bcl2","cd19","cd20","ror1","btk","tp53"],"drugs":["clonoseq","alemtuzumab","chlorambucil","fludarabine","prednisone","ofatumumab","rasburicase"],"companies":["curis","abbvie","astrazeneca","beone","eli-lilly","roche-genentech","johnson-johnson","bms","merck","adaptive-biotechnologies"],"institutions":[],"pathways":["apoptosis-bcl2","pi3k-akt-mtor"],"terms":["ighv-status","del17p-tp53","richter-transformation","mrd-negative-cr","tumor-lysis-syndrome"],"trials":["tai-shan6","nct07342478","nct07516093","apex-03","nct07509151","nct06973187","nct06943872","nct05947851","nct05624554","nct04075292","nct07277231","nct06428019","nct02477696","nct06846671","nct05645107","nct05023980","nct02970318","nct05254743","nct04965493","nct05057494","nct06970743","murano"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["blood-cancer-discovery","blood-cancer-journal","clinical-lymphoma-myeloma-and-leukemia","current-hematologic-malignancy-reports","haematologica","journal-of-hematology-and-oncology","leukemia-and-lymphoma"],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About 20,000 US cases a year and 100,000 worldwide, the most common adult leukaemia in Western countries; median age 70; median survival now exceeds 10 years for most, approaching that of the age-matched population for IGHV-mutated patients.","subtypes":["IGHV-mutated (indolent; long remissions after fixed-duration therapy)","IGHV-unmutated (more aggressive; targeted therapy erases much of the gap)","del(17p) and/or TP53-mutated (5-10% at diagnosis, up to 40% at relapse; continuous targeted therapy)","del(11q) (ATM; historically adverse, neutralised by BTK inhibitors)","Trisomy 12 (NOTCH1-associated)","del(13q) alone (favourable)","Complex karyotype (≥3 abnormalities; adverse)","Small lymphocytic lymphoma (same disease, nodal presentation)","Monoclonal B-cell lymphocytosis (precursor; 1-2% per year progress)","Richter transformation (DLBCL or Hodgkin-type; 2-10% of patients)"],"biomarkers":["del(17p)/TP53","IGHV mutation status","del(11q)","BTK/PLCG2 resistance mutations","MRD","IGHV mutational status (<2% deviation = unmutated)","TP53 mutation and del(17p) by FISH","FISH panel: del(13q), del(11q), trisomy 12, del(17p)","Complex karyotype","NOTCH1, SF3B1, BIRC3 mutations","β2-microglobulin and CLL-IPI score","MRD by flow or clonoSEQ at end of fixed-duration therapy","BTK C481S/T474I/L528W and PLCG2 mutations at BTKi progression","BCL2 G101V and other mutations at venetoclax progression","Hepatitis B serology before anti-CD20 therapy"],"standardOfCare":[{"setting":"Frontline","approach":"BTK inhibitor continuous or venetoclax-based fixed duration.","refs":["venetoclax"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Relapsed","approach":"Alternate class; pirtobrutinib; CAR-T.","refs":["car-t"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Early stage, asymptomatic (Rai 0-II, Binet A-B)","approach":"Watch and wait with periodic counts and examination; early treatment with ibrutinib (CLL12) delayed progression but did not improve survival and is not recommended. Vaccinations and infection prevention.","refs":["ibrutinib","ighv-status","cll12"],"guideline":{"nccn":"Category 1 (observation)","version":"NCCN CLL/SLL v2.2026","url":"https://jnccn.org/view/journals/jnccn/24/3/article-p68.xml"}},{"setting":"First-line, TP53-intact, fit or unfit, fixed duration","approach":"Venetoclax + obinutuzumab for 12 months (CLL14, CLL13), or acalabrutinib + venetoclax for 14 cycles (AMPLIFY; approved February 2026), or ibrutinib + venetoclax 15 months (EU; GLOW, CAPTIVATE). uMRD at end of treatment predicts durable remission; retreatment is effective.","refs":["venetoclax","obinutuzumab","acalabrutinib","cll14","cll13-gaia","amplify","btki-plus-venetoclax-fixed-duration"],"guideline":{"nccn":"Category 1 (venetoclax-obinutuzumab); Category 1 (acalabrutinib-venetoclax)","esmoMcbs":"4 (CLL14)","version":"NCCN CLL/SLL v2.2026"}},{"setting":"First-line, continuous BTK inhibition","approach":"Acalabrutinib (± obinutuzumab, ELEVATE-TN) or zanubrutinib (SEQUOIA) until progression; ibrutinib where alternatives are unavailable. Preferred for del(17p)/TP53 and for patients who cannot manage venetoclax ramp-up or TLS monitoring.","refs":["acalabrutinib","zanubrutinib","ibrutinib","elevate-tn","sequoia"],"guideline":{"nccn":"Category 1 (acalabrutinib, zanubrutinib preferred)","version":"NCCN CLL/SLL v2.2026"}},{"setting":"First-line, del(17p) or TP53 mutation","approach":"Continuous second-generation BTK inhibitor (zanubrutinib: 5-year PFS 72%; acalabrutinib) or venetoclax-obinutuzumab; never chemoimmunotherapy; consider clinical trial and early referral for transplant/CAR-T planning if young.","refs":["zanubrutinib","acalabrutinib","venetoclax","sequoia","del17p-tp53","cit-in-del17p-caution"],"guideline":{"nccn":"Category 1","version":"NCCN CLL/SLL v2.2026"}},{"setting":"First-line, chemoimmunotherapy (limited role)","approach":"FCR only for young, fit, IGHV-mutated, TP53-intact patients who decline targeted therapy or lack access; BR in older patients likewise. Outperformed by targeted therapy in CLL13, ELEVATE-TN, SEQUOIA, AMPLIFY.","refs":["rituximab","cll13-gaia"],"guideline":{"nccn":"Category 2A (select patients)","version":"NCCN CLL/SLL v2.2026"}},{"setting":"Relapse after fixed-duration venetoclax","approach":"Retreat with venetoclax-based therapy if remission lasted >2-3 years, or switch to a BTK inhibitor (acalabrutinib, zanubrutinib); pirtobrutinib if prior covalent BTKi as well.","refs":["venetoclax","zanubrutinib","acalabrutinib","pirtobrutinib"],"guideline":{"nccn":"Category 2A","version":"NCCN CLL/SLL v2.2026"}},{"setting":"Progression on a covalent BTK inhibitor","approach":"Venetoclax-based therapy (venetoclax-rituximab 24 months, MURANO) or pirtobrutinib (BRUIN CLL-321; traditional approval December 2025); BTK degraders (BGB-16673 vs pirtobrutinib, CaDAnCe-304) in trials.","refs":["venetoclax","pirtobrutinib","bgb-16673","bruin-cll-321","cadance-304"],"guideline":{"nccn":"Category 1 (venetoclax-rituximab); Category 2A (pirtobrutinib)","version":"NCCN CLL/SLL v2.2026"}},{"setting":"Double-refractory (BTKi and BCL2i)","approach":"Pirtobrutinib if BTK-naive-to-noncovalent; lisocabtagene maraleucel CAR-T (TRANSCEND CLL 004; accelerated approval 2024); allogeneic transplant in fit patients; PI3K inhibitors (idelalisib, duvelisib) rarely; clinical trials of degraders, sonrotoclax, bispecifics.","refs":["pirtobrutinib","lisocabtagene-maraleucel","transcend-cll-004","allogeneic-hsct","sonrotoclax"],"guideline":{"nccn":"Category 2A","version":"NCCN CLL/SLL v2.2026"}},{"setting":"Richter transformation","approach":"Biopsy to confirm and assess clonal relationship; chemoimmunotherapy (R-CHOP) has poor results; checkpoint inhibitor + BTK inhibitor (zanubrutinib-tislelizumab, RT1), pirtobrutinib, venetoclax-based regimens, CD20×CD3 bispecifics (epcoritamab, glofitamab), CAR-T; allogeneic transplant for responders.","refs":["richter-transformation","pirtobrutinib","zanubrutinib","glofitamab","allogeneic-hsct"],"guideline":{"nccn":"Category 2A (clinical trial preferred)","version":"NCCN CLL/SLL v2.2026"}},{"setting":"Supportive care throughout","approach":"Infection prophylaxis and vaccination (non-live; reduced vaccine responses), IVIG for recurrent infections with hypogammaglobulinaemia, HBV screening before anti-CD20, skin cancer surveillance (second cancers), cardio-oncology review before ibrutinib, TLS prophylaxis with venetoclax.","refs":["tumor-lysis-syndrome","cardio-oncology","btki-ibrutinib-cardiac-caution"],"guideline":{"nccn":"Category 2A","version":"NCCN CLL/SLL v2.2026"}}],"stateOfArt":["Chemotherapy-free care with near-normal life expectancy for many.","Chemotherapy is essentially obsolete in CLL; median survival for most patients now approaches that of the general population.","Two first-line philosophies with phase 3 support: indefinite BTK inhibition (acalabrutinib, zanubrutinib) or fixed-duration venetoclax combinations (venetoclax-obinutuzumab; acalabrutinib-venetoclax approved February 2026).","Head-to-head data rank the BTK inhibitors: zanubrutinib beat ibrutinib on PFS and safety (ALPINE); acalabrutinib matched it with less cardiotoxicity (ELEVATE-RR).","Sequencing works: BTKi → venetoclax → pirtobrutinib gives years of additional control; pirtobrutinib fully approved December 2025.","uMRD at end of fixed-duration therapy is the key prognostic readout and is being tested as a stopping rule.","First CAR-T in CLL (liso-cel, 2024), BTK degraders in phase 3, and sonrotoclax approved (MCL 2026) with CLL phase 3 reading out."],"history":[{"year":1975,"title":"Rai staging system","note":"Clinical staging by lymphocytosis, nodes, organomegaly, cytopenias; Binet system follows in 1981.","refs":[]},{"year":1999,"title":"IGHV mutational status predicts outcome","note":"Hamblin and Damle show unmutated IGHV means aggressive disease.","refs":["ighv-status"]},{"year":2000,"title":"Döhner hierarchical FISH model","note":"del(17p) and del(11q) adverse; del(13q) favourable.","refs":["cytogenetics-fish","del17p-tp53"]},{"year":2010,"title":"FCR: first regimen to improve survival","note":"CLL8 shows fludarabine-cyclophosphamide-rituximab beats FC on OS; rituximab approved in CLL.","refs":["rituximab"]},{"year":2013,"title":"Obinutuzumab approved; ibrutinib debuts","note":"CLL11 (obinutuzumab-chlorambucil) and ibrutinib's first approval (MCL).","refs":["obinutuzumab","ibrutinib"]},{"year":2014,"title":"Ibrutinib approved","refs":[]},{"year":2014,"title":"Ibrutinib approved in CLL; RESONATE","note":"PFS HR 0.22 vs ofatumumab; the BTK era begins. Idelalisib approved the same year.","refs":["ibrutinib","resonate"]},{"year":2016,"title":"Venetoclax approved","refs":["venetoclax"]},{"year":2016,"title":"Venetoclax approved (del(17p)); ibrutinib first line","note":"First BCL-2 inhibitor; RESONATE-2 moves ibrutinib to untreated CLL.","refs":["venetoclax","ibrutinib"]},{"year":2019,"title":"Fixed-duration therapy: CLL14; acalabrutinib approved","note":"Venetoclax-obinutuzumab for 12 months; ELEVATE-TN and ASCEND establish acalabrutinib.","refs":["cll14","acalabrutinib","elevate-tn"]},{"year":2022,"title":"Ibrutinib-venetoclax fixed duration (EU); CLL13 and GLOW","note":"Venetoclax combinations beat chemoimmunotherapy in fit patients; ibrutinib-venetoclax approved in Europe.","refs":["cll13-gaia","glow","captivate"]},{"year":2023,"title":"Zanubrutinib approved in CLL; ALPINE; pirtobrutinib accelerated approval","note":"First BTKi to beat ibrutinib head to head; first non-covalent BTKi in CLL (December).","refs":["zanubrutinib","alpine","pirtobrutinib"]},{"year":2024,"title":"First CAR-T in CLL; AMPLIFY presented","note":"Liso-cel accelerated approval (March); AMPLIFY fixed-duration acalabrutinib-venetoclax at ASH.","refs":["lisocabtagene-maraleucel","transcend-cll-004","amplify"]},{"year":2025,"title":"Pirtobrutinib traditional approval; sonrotoclax approved in China","note":"BRUIN CLL-321 confirms benefit after covalent BTKi (3 December); next-generation BCL-2 inhibitor reaches patients.","refs":["pirtobrutinib","bruin-cll-321","sonrotoclax"]},{"year":2026,"title":"Acalabrutinib frontline label expanded","refs":[]},{"year":2026,"title":"First US all-oral fixed-duration regimen; sonrotoclax US approval (MCL); BTK degrader phase 3","note":"Acalabrutinib-venetoclax approved 19 February; sonrotoclax accelerated approval 13 May; CaDAnCe-304 and CELESTIAL-TNCLL enrolling.","refs":["acalabrutinib","amplify","sonrotoclax","bgb-16673","cadance-304"]}],"pipeline":["venetoclax","dzd8586","rocbrutinib","bexobrutideg","icp-248","krt-232","ctx112","emavusertib","sonrotoclax","bgb-16673","nemtabrutinib","celestial-tncll","cadance-304","bellwave-011","pirtobrutinib","lisocabtagene-maraleucel","idea-mrd-guided-stop-cll","idea-btk-degrader-frontline","btki-plus-venetoclax-fixed-duration","bh3-profiling","ngs-mrd-clonoseq"],"openProblems":["Double-refractory disease.","Richter transformation.","Richter transformation: median survival still under a year for clonally related cases; no approved therapy.","Double-refractory disease after BTKi and venetoclax: pirtobrutinib gives ~1 year; CAR-T complete responses are only ~20%.","Fixed duration versus continuous therapy has never been compared head to head for OS; MAJIC and CLL17 will inform.","Infections are the main threat to people living with CLL; vaccine responses are blunted and COVID-19 mortality was high, so prophylaxis and immunoglobulin replacement matter.","Second primary cancers, especially skin, on long-term therapy.","Cost: indefinite BTK inhibition costs more than $150,000 per year; access is limited in most of the world and biosimilar rituximab-based chemoimmunotherapy persists where targeted drugs are unaffordable.","T-cell dysfunction in CLL limits CAR-T and bispecific efficacy; how to restore it (BTKi pre-treatment, allogeneic products) is open.","Optimal MRD assay, compartment (blood vs marrow), and threshold for stopping therapy are not standardised."],"parent":"leukaemia"},{"id":"cll-treatment-naive","kind":"cancer","name":"Chronic lymphocytic leukaemia, first treatment","aka":["Treatment-naive CLL","Front-line CLL","Previously untreated CLL","First-line CLL therapy"],"tldr":"Chronic lymphocytic leukaemia is treated only when it causes problems, and chemotherapy has gone. The first treatment is now either a BTK inhibitor taken indefinitely or a one-year course of venetoclax with obinutuzumab (CLL14), and the two can be combined for a fixed course.","summary":"Diagnosis needs 5 x 10^9/L clonal B cells with the typical CD5, CD19, CD23 phenotype; treatment starts only for iwCLL indications (symptoms, progressive anaemia or thrombocytopenia, bulky or fast-growing disease), because early treatment, even with ibrutinib in CLL12, has not lengthened life. Before the first treatment, every patient has FISH and sequencing for del(17p) and TP53 mutation and testing of IGHV mutational status, since these decide the regimen: TP53-aberrant disease does not respond durably to chemotherapy, and unmutated IGHV disease relapses early after it.\n\nTwo families of drugs replaced chemoimmunotherapy between 2014 and 2023. Continuous BTK inhibitors, ibrutinib and then the better-tolerated acalabrutinib (ELEVATE-TN, versus chlorambucil-obinutuzumab: median progression-free survival not reached at six years against 27.8 months) and zanubrutinib (SEQUOIA, versus bendamustine-rituximab, hazard ratio 0.42), control the disease for years but must be taken indefinitely and carry atrial fibrillation, bleeding and hypertension risks. Fixed-duration venetoclax with obinutuzumab for 12 months (CLL14, versus chlorambucil-obinutuzumab in older unfit patients: six-year progression-free survival 53.1 percent versus 21.7 percent, hazard ratio 0.40) gives most patients undetectable MRD and years off treatment; CLL13/GAIA confirmed the same in fit patients, where venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib beat fludarabine-based chemoimmunotherapy (five-year progression-free survival 69.8 and 81.3 percent against 50.7 percent).\n\nThe third option is an all-oral fixed-duration doublet: ibrutinib-venetoclax (GLOW in older patients, hazard ratio 0.216 for progression; CAPTIVATE; and the UK FLAIR trial with MRD-guided duration) and acalabrutinib-venetoclax with or without obinutuzumab (AMPLIFY, 2025), which in 2026 joined the approved first-line options. Choice now turns on comorbidity, TP53 status (continuous BTK inhibitor favoured), patient preference for a finite course, drug interactions and cost; non-covalent BTK inhibitors, BTK degraders, sonrotoclax and MRD-guided stopping are in first-line trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia"},{"label":"NCCN Guidelines: CLL/SLL","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}],"tags":["subtype-page"],"related":["cll-relapsed","richter-transformation-cll"],"cancers":[],"sections":[],"technologies":["bcl2-inhibitors","cytogenetics-fish","flow-cytometry-mrd"],"targets":["btk","bcl2","cd20"],"drugs":[],"companies":[],"institutions":[],"pathways":["bcr-signalling","apoptosis-bcl2"],"terms":["ighv-status","del17p-tp53","tp53-mutated","umrd","tumor-lysis-syndrome","cll-ipi"],"trials":["elevate-tn","resonate-2"],"people":[],"bottlenecks":[],"keyPapers":["paper-cll14-venetoclax-obinutuzumab-nejm-2019","paper-elevate-tn-acalabrutinib-lancet-2020","paper-amplify-acalabrutinib-venetoclax-nejm-2025"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Chronic lymphocytic leukaemia is the commonest adult leukaemia in Western countries, with a median age at diagnosis of about 70; a third of patients never need treatment, and the rest start it when the disease causes symptoms, cytopenias or bulky nodes.","subtypes":["Treatment-naive CLL without del(17p) or TP53 mutation, IGHV mutated","Treatment-naive CLL, IGHV unmutated","Treatment-naive CLL with del(17p) or TP53 mutation (continuous BTK inhibitor favoured)","Older or unfit patients starting first treatment (CLL14, GLOW)","Fit patients starting first treatment (CLL13, AMPLIFY)","Early-stage CLL under watch and wait"],"biomarkers":["del(17p) by FISH and TP53 mutation","IGHV mutational status","CLL-IPI score","Beta-2 microglobulin","Complex karyotype","Undetectable MRD at end of fixed-duration therapy","Cardiac risk factors before BTK inhibitors"],"standardOfCare":[{"setting":"Asymptomatic early-stage disease","approach":"Watch and wait with counts every three to twelve months; treat only on iwCLL indications.","refs":["flow-cytometry","ighv-status","del17p-tp53","cytogenetics-fish"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"First treatment, fixed duration","approach":"Venetoclax plus obinutuzumab for 12 months (CLL14, CLL13); ibrutinib-venetoclax (GLOW, CAPTIVATE) or acalabrutinib-venetoclax with or without obinutuzumab (AMPLIFY) for fit patients.","refs":["venetoclax","obinutuzumab","cll14","cll13-gaia","ibrutinib","acalabrutinib","glow","captivate","amplify","venetoclax-plus-obinutuzumab","btki-plus-venetoclax-fixed-duration"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"First treatment, continuous","approach":"Acalabrutinib (ELEVATE-TN) or zanubrutinib (SEQUOIA) until progression, preferred for del(17p) or TP53-mutated disease; ibrutinib where the newer agents are unavailable.","refs":["acalabrutinib","zanubrutinib","ibrutinib","elevate-tn","sequoia","btki-ibrutinib-cardiac-caution"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Chemoimmunotherapy","approach":"Fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab only for IGHV-mutated disease without TP53 aberration where targeted drugs are unavailable; never for del(17p).","refs":["fludarabine","cyclophosphamide","rituximab","bendamustine","chlorambucil","cit-in-del17p-caution"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}}],"stateOfArt":["Chemoimmunotherapy has been displaced by BTK inhibitors and venetoclax-based fixed-duration regimens for almost every patient.","One year of venetoclax-obinutuzumab keeps half of older patients progression-free at six years.","All-oral fixed-duration doublets and MRD-guided duration are the current direction."],"history":[{"year":1952,"title":"Chlorambucil introduced; the standard for forty years","refs":["chlorambucil"]},{"year":2010,"title":"CLL8: fludarabine-cyclophosphamide-rituximab lengthens life, the first regimen to do so","refs":["fludarabine","rituximab"]},{"year":2014,"title":"Ibrutinib approved for CLL; obinutuzumab-chlorambucil for unfit patients","refs":["ibrutinib","obinutuzumab"]},{"year":2019,"title":"CLL14: one year of venetoclax-obinutuzumab approved; ELEVATE-TN reports acalabrutinib","refs":["cll14","venetoclax","elevate-tn","acalabrutinib"]},{"year":2022,"title":"SEQUOIA: zanubrutinib beats bendamustine-rituximab; GLOW: ibrutinib-venetoclax approved in Europe","refs":["sequoia","zanubrutinib","glow"]},{"year":2023,"title":"CLL13: venetoclax-obinutuzumab beats chemoimmunotherapy in fit patients","refs":["cll13-gaia"]},{"year":2025,"title":"AMPLIFY: acalabrutinib-venetoclax fixed duration in fit patients","refs":["amplify","acalabrutinib","venetoclax"]}],"pipeline":["sonrotoclax","nemtabrutinib","celestial-tncll","cadance-304","bellwave-011","idea-mrd-guided-stop-cll","idea-btk-degrader-frontline"],"openProblems":["Continuous BTK inhibitor or fixed-duration venetoclax first: no head-to-head survival data.","Whether MRD should decide how long fixed-duration therapy lasts.","Cardiac toxicity, cost and interactions of indefinite BTK inhibition in patients in their seventies and eighties."],"parent":"cll"},{"id":"cml","kind":"cancer","name":"Chronic myeloid leukaemia (CML)","aka":[],"tldr":"Chronic myeloid leukaemia is a blood cancer driven by a single fused gene, BCR-ABL1, and the model for oncogene-targeted treatment: imatinib in 2001 and the tyrosine kinase inhibitors that followed turned it into a condition most people live with long-term. About half of patients with a sustained deep molecular response can now stop treatment altogether.","summary":"CML is defined by the Philadelphia chromosome t(9;22) and its product, the constitutively active BCR-ABL1 tyrosine kinase. It is the paradigm of oncogene addiction: tyrosine kinase inhibitors (TKIs) restore near-normal life expectancy in chronic phase, and treatment response is tracked by quantitative BCR-ABL1 PCR on the International Scale (IS), with milestones at 3, 6 and 12 months (ELN 2020).\n\nFirst-line options are imatinib, the second-generation TKIs dasatinib, nilotinib and bosutinib, and since 2024 asciminib (ASC4FIRST), the first allosteric STAMP inhibitor. Second-generation drugs achieve deeper responses faster but have not improved overall survival over imatinib; choice is driven by comorbidity (cardiovascular risk with nilotinib and ponatinib, pleural effusions with dasatinib) and by the goal of treatment-free remission (TFR). Resistance is largely through ABL1 kinase-domain mutations; T315I is covered by ponatinib and asciminib. Allogeneic transplant is reserved for blast phase or multi-TKI failure.\n\nThe frontier is TFR (about half of patients with sustained deep molecular response can stop, EURO-SKI), safer T315I coverage, olverembatinib in Asia, and the small residue of accelerated/blast-phase disease, where outcomes remain poor.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Chronic_myelogenous_leukemia","links":[{"label":"ELN 2020 recommendations","url":"https://www.nature.com/articles/s41375-020-0776-2"},{"label":"NCI PDQ: CML","url":"https://www.cancer.gov/types/leukemia/patient/cml-treatment-pdq"},{"label":"SEER: CML","url":"https://seer.cancer.gov/statfacts/html/cmyl.html"}],"tags":["gap-fill","haematologic"],"related":["cll","cmml","aml"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","allogeneic-hsct","mrd-testing","cytogenetics-fish"],"targets":["bcr-abl"],"drugs":["imatinib","dasatinib","nilotinib","bosutinib","ponatinib","asciminib","busulfan","omacetaxine"],"companies":["novartis","bms","pfizer","takeda"],"institutions":[],"pathways":["ras-mapk","pi3k-akt-mtor","cml-signalling"],"terms":["oncogene-addiction","mrd","resistance"],"trials":["nct04971226","nct03459534","nct05456191","dasision"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["leukemia-research"],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About 1-2 cases per 100,000 per year; because patients now live near-normal lifespans, prevalence keeps rising (SEER).","subtypes":["Chronic phase (~95% at diagnosis)","Accelerated phase","Blast phase (myeloid or lymphoid)","Atypical CML / BCR-ABL1-negative (separate MDS/MPN entity)"],"biomarkers":["BCR-ABL1 by RT-qPCR on the International Scale (MMR = ≤0.1%, MR4.5 = ≤0.0032%)","ABL1 kinase-domain mutations (T315I, F317L, E255K/V, Y253H)","ELTS score at diagnosis","Additional cytogenetic abnormalities","Cardiovascular risk profile (drug selection)"],"standardOfCare":[{"setting":"Chronic phase, first line","approach":"Imatinib 400 mg, or a second-generation TKI (dasatinib, nilotinib, bosutinib), or asciminib (ASC4FIRST, approved 2024). Choice by comorbidity and treatment goal; monitor BCR-ABL1 IS at 3, 6, 12 months against ELN milestones.","refs":["imatinib","dasatinib","nilotinib","bosutinib","asciminib"],"guideline":{"nccn":"Category 1 (imatinib, dasatinib, nilotinib, bosutinib, asciminib)","version":"NCCN Guidelines: CML; ELN 2020 recommendations","url":"https://www.nature.com/articles/s41375-020-0776-2"}},{"setting":"Resistance or intolerance","approach":"Switch TKI guided by mutation analysis; ponatinib or asciminib for T315I; allogeneic HSCT if two or more TKIs fail or in advanced phase.","refs":["ponatinib","asciminib","allogeneic-hsct","bosutinib"],"guideline":{"version":"ELN 2020","url":"https://www.nature.com/articles/s41375-020-0776-2"}},{"setting":"Sustained deep molecular response","approach":"Treatment-free remission attempt after ≥3-5 years of TKI and ≥2 years of MR4 or better, with monthly PCR for the first six months (EURO-SKI); restart on loss of MMR.","refs":["mrd"],"guideline":{"version":"ELN 2020; EURO-SKI (Lancet Oncol 2018)","url":"https://doi.org/10.1016/S1470-2045(18)30192-X"}},{"setting":"Blast phase","approach":"TKI plus acute-leukaemia-type induction (ponatinib or dasatinib with chemotherapy), then allogeneic HSCT.","refs":["ponatinib","dasatinib","allogeneic-hsct"]}],"stateOfArt":["Life expectancy in chronic phase on TKI is close to the general population; the goal has moved from survival to deep molecular response and treatment-free remission.","Asciminib is the first allosteric BCR-ABL1 inhibitor and, since ASC4FIRST (2024), a first-line option with better tolerability than second-generation TKIs.","Roughly half of eligible patients maintain remission off therapy; predictors are duration of deep response and prior interferon exposure.","Blast-phase CML remains the unsolved problem, and TKI cost is the barrier in low- and middle-income countries despite generic imatinib."],"history":[{"year":1960,"title":"Philadelphia chromosome","note":"Nowell and Hungerford describe a minute chromosome in CML: the first consistent chromosomal abnormality in a human cancer.","refs":[]},{"year":1973,"title":"t(9;22) translocation","note":"Janet Rowley shows the Philadelphia chromosome is a reciprocal translocation.","refs":[]},{"year":1990,"title":"BCR-ABL causes CML in mice","note":"Daley, Van Etten and Baltimore demonstrate the fusion kinase is sufficient to cause a CML-like disease.","refs":[]},{"year":1998,"title":"Imatinib enters the clinic","note":"Druker's phase 1 trial of STI571: complete haematologic responses in nearly every chronic-phase patient.","refs":["imatinib"]},{"year":2001,"title":"Imatinib approved","note":"FDA approval in under three months; IRIS (2003) confirms superiority over interferon-cytarabine.","refs":["imatinib"]},{"year":2006,"title":"Second-generation TKIs","note":"Dasatinib (2006) and nilotinib (2007) approved for resistance; later first line (DASISION, ENESTnd).","refs":["dasatinib","nilotinib"]},{"year":2012,"title":"Ponatinib covers T315I; bosutinib approved","refs":["ponatinib","bosutinib"]},{"year":2018,"title":"Treatment-free remission validated","note":"EURO-SKI: about half of patients stopping TKI stay in remission.","refs":["mrd"]},{"year":2021,"title":"Asciminib: allosteric STAMP inhibitor approved","note":"ASCEMBL vs bosutinib in third line.","refs":["asciminib"]},{"year":2024,"title":"Asciminib first line","note":"ASC4FIRST: higher MMR at 48 weeks than investigator-selected TKI; FDA accelerated approval October 2024.","refs":["asciminib"]}],"pipeline":["asciminib","allogeneic-hsct","radotinib"],"openProblems":["Blast-phase CML: median survival still under a year.","Predicting who can stop TKI safely; second TFR attempts.","Cardiovascular toxicity of nilotinib and ponatinib.","Access to any TKI and to PCR monitoring in LMICs."],"parent":"leukaemia"},{"id":"cml-advanced-phase","kind":"cancer","name":"Chronic myeloid leukaemia, accelerated and blast phase","aka":["CML-AP","CML-BP","Blast crisis","Advanced-phase CML","Accelerated-phase CML"],"tldr":"Chronic myeloid leukaemia can accelerate and then transform into an acute leukaemia called blast crisis. Tyrosine kinase inhibitors are given at full strength, combined with acute leukaemia chemotherapy in blast phase, to bring the disease back to chronic phase quickly enough for a donor stem cell transplant, the only treatment that cures it.","summary":"Accelerated phase is defined by 10 to 19 percent blasts in blood or marrow (WHO; the ELN and ICC use 15 to 29 percent and additional criteria), basophils of 20 percent or more, thrombocytopenia unrelated to treatment, or new clonal chromosomal abnormalities on top of the Philadelphia chromosome; the ICC 2022 classification folds most accelerated-phase features into high-risk chronic phase. Blast phase is 20 percent or more blasts (30 percent by ELN) or an extramedullary blast proliferation, and is myeloid in two thirds and lymphoid in a third. Additional mutations in ASXL1, RUNX1, IKZF1 and TP53 accumulate with progression, and resistance mutations in the BCR::ABL1 kinase domain are common.\n\nTreatment aims to return the disease to a second chronic phase and consolidate with allogeneic transplant, the only curative treatment. In accelerated phase a second- or third-generation inhibitor at the higher dose, chosen by mutation testing (ponatinib for T315I, asciminib in trials), can restore a chronic phase lasting years, and transplant is reserved for poor responders. In blast phase the inhibitor is combined with acute leukaemia induction: 7+3-type chemotherapy for myeloid blast phase, or ALL-type regimens, or blinatumomab and inotuzumab for lymphoid blast phase, where dasatinib and ponatinib are favoured for their activity in the central nervous system. Patients who reach transplant in a second chronic phase have long-term survival in a substantial minority; those transplanted in overt blast phase rarely do.\n\nProgression is now rare enough that trials are small and outcomes come from registries (the CML-IV and ELN blast phase studies). Prevention through early achievement of molecular milestones and prompt switching on failure is the practical strategy, and the biology of the leukaemic stem cell that acquires these extra hits is the research question.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Chronic_myelogenous_leukemia","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Chronic_myelogenous_leukemia"},{"label":"NCCN Guidelines: Chronic Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427"}],"tags":["subtype-page"],"related":["cml-chronic-phase"],"cancers":[],"sections":[],"technologies":["allogeneic-hsct","kinase-inhibitors","cytogenetics-fish"],"targets":["bcr-abl"],"drugs":[],"companies":[],"institutions":[],"pathways":["bcr-abl1-signalling"],"terms":["blasts","philadelphia-chromosome","allogeneic-transplant","tki-term","resistance","abl1-kinase-domain-mutations"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-iris-imatinib-nejm-2003","paper-pace-ponatinib-nejm-2013","paper-eln-2020-cml-hochhaus-leukemia-2020","paper-who-2022-myeloid-khoury-leukemia-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Fewer than one in twenty patients now present in accelerated or blast phase, and progression from chronic phase on treatment has fallen to around one percent a year; blast phase remains the most dangerous form of the disease, with survival historically under a year.","subtypes":["Accelerated phase CML (10 to 19 percent blasts, basophilia or clonal evolution)","Myeloid blast phase CML","Lymphoid blast phase CML (dasatinib or ponatinib with ALL-type therapy)","De novo blast phase at presentation","Extramedullary blast phase (myeloid sarcoma)","Second chronic phase after treatment of blast phase (transplant candidate)"],"biomarkers":["Blast percentage in blood and marrow","Basophil percentage and platelet count","Additional chromosomal abnormalities (clonal evolution)","BCR::ABL1 kinase domain mutations including T315I","Blast lineage by flow cytometry (myeloid or lymphoid)","ASXL1, RUNX1, IKZF1 and TP53 mutations","Donor availability"],"standardOfCare":[{"setting":"Accelerated phase","approach":"Second- or third-generation tyrosine kinase inhibitor at full dose guided by mutation testing (dasatinib, nilotinib, bosutinib, ponatinib for T315I, olverembatinib where approved); allogeneic transplant if response is poor or clonal evolution progresses.","refs":["dasatinib","nilotinib","bosutinib","ponatinib","olverembatinib","asciminib","nct04233346","nct06514534","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Chronic Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427"}},{"setting":"Myeloid blast phase","approach":"Tyrosine kinase inhibitor (ponatinib or dasatinib) with 7+3-type or hypomethylating agent and venetoclax induction, then allogeneic transplant in second chronic phase.","refs":["ponatinib","dasatinib","cytarabine-7-3","cytarabine","azacitidine","venetoclax","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Chronic Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427"}},{"setting":"Lymphoid blast phase","approach":"Dasatinib or ponatinib with ALL-type chemotherapy or with blinatumomab, central nervous system prophylaxis, then allogeneic transplant.","refs":["dasatinib","ponatinib","blinatumomab","cyclophosphamide","allogeneic-hsct","tki-plus-blinatumomab-ph-all"],"guideline":{"version":"NCCN Guidelines: Chronic Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427"}},{"setting":"Consolidation","approach":"Allogeneic stem cell transplant for every eligible patient in second chronic phase, with tyrosine kinase inhibitor maintenance after transplant.","refs":["allogeneic-hsct","allogeneic-transplant","conditioning-regimen"],"guideline":{"version":"NCCN Guidelines: Chronic Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427"}}],"stateOfArt":["Tyrosine kinase inhibitors have made progression rare: around one percent of chronic-phase patients a year.","Blast phase is treated as an acute leukaemia with an inhibitor added, and cured only by transplant in a second chronic phase.","Third-generation inhibitors cover T315I in advanced phase, and chemotherapy-free inhibitor-plus-antibody regimens are being borrowed from Philadelphia-positive ALL."],"history":[{"year":1980,"title":"Blast crisis defined; median survival months with chemotherapy","refs":["blasts"]},{"year":2001,"title":"Imatinib produces responses in blast phase, though short-lived","refs":["imatinib"]},{"year":2012,"title":"Ponatinib approved for advanced phase including T315I","refs":["ponatinib"]},{"year":2021,"title":"Olverembatinib approved in China for T315I chronic and accelerated phase","refs":["olverembatinib"]},{"year":2022,"title":"ICC and WHO redefine accelerated and blast phase thresholds","refs":[]}],"pipeline":["ponatinib","asciminib","olverembatinib","blinatumomab","nct04233346","nct06514534","allogeneic-hsct"],"openProblems":["Blast phase remains largely fatal without transplant, and few patients reach it in remission.","Trials are tiny because progression has become rare.","The mutations that drive progression are known but not targetable."],"parent":"cml"},{"id":"cml-chronic-phase","kind":"cancer","name":"Chronic myeloid leukaemia, chronic phase","aka":["CML-CP","Chronic-phase CML","Newly diagnosed Ph-positive CML","BCR::ABL1-positive chronic phase"],"tldr":"Chronic-phase chronic myeloid leukaemia is the disease that imatinib turned from fatal into manageable: a daily pill blocks the BCR::ABL1 protein that drives it. Blood tests track the leukaemia gene to a millionth, newer pills such as asciminib (ASC4FIRST) reach deeper responses faster, and patients with years of undetectable disease can try stopping.","summary":"The Philadelphia chromosome, t(9;22), fuses BCR to ABL1 and produces a constitutively active tyrosine kinase; in chronic phase the marrow overproduces mature granulocytes with fewer than 10 percent blasts (WHO) and the disease is symptomless in half of patients, found on a routine blood count. Response is measured by quantitative PCR for BCR::ABL1 on the International Scale, with ELN milestones of 10 percent or less at three months, 1 percent or less at six months and 0.1 percent or less (major molecular response) at twelve months; failure to reach them prompts kinase domain mutation testing and a switch of drug.\n\nIRIS (2003) randomised 1,106 newly diagnosed patients to imatinib or interferon plus cytarabine: complete cytogenetic response at 18 months in 76 percent versus 14 percent, and at ten years 83 percent of imatinib patients were alive, most without progression. Second-generation inhibitors dasatinib (DASISION), nilotinib (ENESTnd) and bosutinib (BFORE) produce faster and deeper responses without a survival advantage, at the cost of pleural effusions, vascular events and liver toxicity respectively. Asciminib, which binds the myristoyl pocket rather than the ATP site, beat investigator-selected inhibitors in ASC4FIRST (2024): major molecular response at 48 weeks in 67.7 percent against 49.0 percent, and 69.3 percent against 40.2 percent for imatinib, with fewer side effects, earning accelerated approval for newly diagnosed disease in October 2024.\n\nResistance through kinase domain mutations is handled by switching: ponatinib or asciminib for T315I, and the third-generation olverembatinib in China; allogeneic transplant is reserved for failure of several inhibitors. Treatment-free remission is now a goal: EURO-SKI found about half of patients with at least three years of therapy and a year of deep molecular response stayed in remission two years after stopping. The unsolved problems are the residual stem cell pool that keeps the other half relapsing, cardiovascular toxicity over decades of therapy, and the price and access gap that leaves patients in low-income countries on older drugs or none.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Chronic_myelogenous_leukemia","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Chronic_myelogenous_leukemia"},{"label":"NCCN Guidelines: Chronic Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427"}],"tags":["subtype-page"],"related":["cml-advanced-phase"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","mrd-kinetics-models","cytogenetics-fish"],"targets":["bcr-abl"],"drugs":[],"companies":[],"institutions":[],"pathways":["bcr-abl1-signalling","cml-signalling"],"terms":["molecular-response","philadelphia-chromosome","tki-term","mrd","sokal-elts-scores","abl1-kinase-domain-mutations"],"trials":["dasision","nct04971226"],"people":[],"bottlenecks":[],"keyPapers":["paper-iris-imatinib-nejm-2003","paper-druker-imatinib-phase1-nejm-2001"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About 95 percent of people with chronic myeloid leukaemia are diagnosed in chronic phase; on a tyrosine kinase inhibitor their life expectancy is close to that of the general population, and about half of those who reach a deep, stable molecular response can stop treatment.","subtypes":["Newly diagnosed chronic phase, low ELTS risk","Newly diagnosed chronic phase, high ELTS risk","Chronic phase resistant or intolerant to first tyrosine kinase inhibitor","Chronic phase with T315I mutation (ponatinib, asciminib, olverembatinib)","Chronic phase in sustained deep molecular response (treatment-free remission candidate)","Chronic phase in pregnancy or in children"],"biomarkers":["BCR::ABL1 transcript by quantitative PCR on the International Scale","ELTS and Sokal risk scores","Karyotype and additional chromosomal abnormalities","BCR::ABL1 kinase domain mutations (T315I and others)","Depth of molecular response (MR4, MR4.5) for stopping","Cardiovascular risk profile before nilotinib or ponatinib"],"standardOfCare":[{"setting":"Newly diagnosed chronic phase","approach":"Imatinib 400 mg daily, a second-generation inhibitor (dasatinib, nilotinib, bosutinib) chosen by comorbidity and treatment goal, or asciminib (ASC4FIRST); PCR at 3, 6 and 12 months against ELN milestones.","refs":["imatinib","dasatinib","nilotinib","bosutinib","asciminib","nct04971226","nct05456191","molecular-response"],"guideline":{"version":"NCCN Guidelines: Chronic Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427"}},{"setting":"Resistance or intolerance","approach":"Switch inhibitor guided by kinase domain mutation testing; ponatinib or asciminib for T315I; radotinib or olverembatinib where approved; allogeneic transplant after failure of two or more inhibitors.","refs":["ponatinib","asciminib","olverembatinib","radotinib","nct06423911","nct03459534","nct05384587","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Chronic Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427"}},{"setting":"Sustained deep molecular response","approach":"Attempt treatment-free remission after at least three to five years of therapy and two years of MR4 or better, with monthly PCR for six months; restart on loss of major molecular response.","refs":["mrd","molecular-response","mrd-kinetics-models"],"guideline":{"version":"NCCN Guidelines: Chronic Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427"}}],"stateOfArt":["Life expectancy in chronic-phase CML on tyrosine kinase inhibitors approaches that of the general population.","Asciminib gives the highest first-line molecular response rates yet reported with the fewest side effects.","About half of patients who reach a deep, stable response can stop treatment and stay in remission."],"history":[{"year":1960,"title":"Nowell and Hungerford describe the Philadelphia chromosome","refs":["philadelphia-chromosome"]},{"year":1990,"title":"BCR-ABL shown to cause leukaemia in mice","refs":["bcr-abl"]},{"year":1998,"title":"Imatinib enters the clinic: remissions in nearly every chronic-phase patient","refs":["imatinib"]},{"year":2003,"title":"IRIS: imatinib beats interferon plus cytarabine","refs":["imatinib"]},{"year":2006,"title":"Dasatinib and nilotinib approved for resistant disease, later first line","refs":["dasatinib","nilotinib"]},{"year":2012,"title":"Ponatinib approved, covering T315I","refs":["ponatinib"]},{"year":2018,"title":"EURO-SKI: half of patients stopping treatment stay in remission","refs":["molecular-response"]},{"year":2024,"title":"ASC4FIRST: asciminib approved for newly diagnosed chronic phase","refs":["asciminib","nct04971226"]}],"pipeline":["asciminib","olverembatinib","radotinib","nct04971226","nct05456191","nct06423911","nct06163430"],"openProblems":["The leukaemic stem cells that survive kinase inhibition and cause relapse after stopping.","Cardiovascular toxicity over decades on second- and third-generation inhibitors.","Access to any tyrosine kinase inhibitor, and to PCR monitoring, in low-income countries."],"parent":"cml"},{"id":"cmml","kind":"cancer","name":"Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms","aka":["CMML","MDS/MPN","Myelodysplastic/myeloproliferative neoplasms","Atypical CML (BCR-ABL1-negative)","MDS/MPN with ring sideroblasts and thrombocytosis","MDS/MPN with SF3B1 mutation and thrombocytosis","Juvenile myelomonocytic leukaemia (JMML)"],"tldr":"Chronic myelomonocytic leukaemia and its relatives are bone-marrow cancers that behave partly like myelodysplasia (poorly made blood cells) and partly like a proliferative disease (an excess of monocytes or platelets). Hypomethylating agents produce responses in a minority and stabilise counts in more, transplant can cure the fit, and RAS-pathway and JAK inhibitors are in trials.","summary":"The myelodysplastic/myeloproliferative neoplasms combine dysplasia and cytopenias with proliferation. Chronic myelomonocytic leukaemia (CMML) is the prototype: persistent monocytosis (above 0.5 x 10^9/L and at least 10 percent of leukocytes under WHO 2022) with dysplasia, absence of BCR-ABL1 and of PDGFRA/B, FGFR1 or JAK2 rearrangements, and a characteristic mutational profile: TET2 and SRSF2 co-mutation in around half, with ASXL1, RUNX1, SETBP1 and RAS-pathway (NRAS, KRAS, CBL) mutations driving the proliferative phenotype and worse outcome. The other members are atypical CML (SETBP1, ETNK1; dysplastic neutrophilia), MDS/MPN with SF3B1 mutation and thrombocytosis (ring sideroblasts, often with JAK2 V617F), MDS/MPN not otherwise specified, and in children juvenile myelomonocytic leukaemia (JMML; RAS-pathway, neurofibromatosis type 1 and Noonan syndrome). Risk is scored by CPSS and the molecular CPSS-Mol, which incorporate blast count, white count, transfusion need, cytogenetics and ASXL1, NRAS, RUNX1 and SETBP1 mutations.\n\nAllogeneic transplant is the only curative therapy and is offered to fit patients with higher-risk disease. Hypomethylating agents are the drug standard: azacitidine and decitabine are approved for CMML (the oral decitabine-cedazuridine label also includes CMML), producing responses in a minority and stabilising counts in more, without clear evidence that they change the mutational clone. Hydroxyurea controls proliferative disease and splenomegaly and was as good as etoposide in the only randomised trial. JMML is treated with azacitidine as a bridge to transplant, the only cure. For MDS/MPN with ring sideroblasts, luspatercept and JAK inhibitors are used by extension from MDS and MPN. Trials are testing RAS-pathway inhibition (MEK inhibitors), JAK inhibition (ruxolitinib in proliferative CMML), the anti-GM-CSF antibody lenzilumab, venetoclax combinations for accelerated disease, and hypomethylating-agent combinations.\n\nOpen problems: transformation to AML in a substantial minority, the lack of disease-modifying drugs, and the fact that trials rarely enrol these patients specifically.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Chronic_myelomonocytic_leukemia","links":[{"label":"NCI PDQ: myelodysplastic/myeloproliferative neoplasms","url":"https://www.cancer.gov/types/myeloproliferative/patient/mds-mpn-treatment-pdq"},{"label":"NCCN: Myelodysplastic Syndromes (includes CMML)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"},{"label":"WHO 5th edition haematolymphoid tumours (Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01613-1"},{"label":"Hydroxyurea vs etoposide in CMML (Blood 1996)","url":"https://doi.org/10.1182/blood.V88.7.2480.bloodjournal8872480"}],"tags":["nci-coverage","rare","haematologic"],"related":["mds","myeloproliferative-neoplasms","aml","cml","systemic-mastocytosis","cll"],"cancers":[],"sections":[],"technologies":["allogeneic-hsct","epigenetic-drugs","cytogenetics-fish","flow-cytometry-mrd","ngs-bioinformatics-software","transfusion-support"],"targets":["jak2","kras","bcl2"],"drugs":["azacitidine","decitabine-cedazuridine","hydroxyurea","ruxolitinib","venetoclax","luspatercept","lenzilumab"],"companies":[],"institutions":[],"pathways":["ras-mapk","jak-stat","epigenetic-reprogramming","clonal-haematopoiesis","rna-splicing"],"terms":["hma","blasts","cytopenias","cytogenetics","conditioning-regimen"],"trials":["nct04256317"],"people":[],"bottlenecks":["b-rare-cancers","b-aging-comorbidity"],"keyPapers":["paper-wattel-blood"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"CMML affects roughly four people per million per year, almost all over 60; the overlap neoplasms are together rarer than either MDS or the classical MPNs (SEER; WHO).","subtypes":["CMML, dysplastic type (WBC under 13 x 10^9/L)","CMML, proliferative type (WBC 13 or more; RAS-pathway mutations, splenomegaly)","CMML-1 and CMML-2 by blast percentage","Atypical chronic myeloid leukaemia, BCR-ABL1-negative","MDS/MPN with SF3B1 mutation and thrombocytosis (formerly MDS/MPN-RS-T)","MDS/MPN not otherwise specified","Juvenile myelomonocytic leukaemia (paediatric)"],"biomarkers":["Monocyte count and percentage; flow cytometric monocyte subset partitioning (classical monocytes above 94 percent)","Bone marrow blasts and dysplasia","Cytogenetics (trisomy 8, -7/del(7q), complex)","NGS: TET2, SRSF2, ASXL1, RUNX1, SETBP1, NRAS, KRAS, CBL, JAK2, SF3B1; exclusion of BCR-ABL1 and PDGFRA/B rearrangements","CPSS and CPSS-Mol risk score","Germline NF1, PTPN11, CBL in JMML"],"standardOfCare":[{"setting":"Higher-risk CMML, fit with a donor","approach":"Allogeneic haematopoietic stem cell transplant, often after hypomethylating-agent cytoreduction; the only curative option.","refs":["allogeneic-hsct","azacitidine"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Myelodysplastic Syndromes (CMML section); EHA/ELN CMML recommendations","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}},{"setting":"Higher-risk or symptomatic CMML, not transplant candidate","approach":"Azacitidine or decitabine (or oral decitabine-cedazuridine) until progression; supportive care with transfusion and growth factors.","refs":["azacitidine","decitabine-cedazuridine","hma","transfusion-support"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: MDS (CMML)"}},{"setting":"Proliferative CMML with symptomatic leucocytosis or splenomegaly","approach":"Hydroxyurea (superior to etoposide in the randomised GFM trial); ruxolitinib in trials for symptomatic proliferative disease.","refs":["hydroxyurea","ruxolitinib"],"guideline":{"version":"Wattel et al., Blood 1996 (hydroxyurea vs etoposide)","url":"https://doi.org/10.1182/blood.V88.7.2480.bloodjournal8872480"}},{"setting":"Juvenile myelomonocytic leukaemia","approach":"Allogeneic transplant; azacitidine as bridging therapy (EMA approval 2019 for JMML); watchful waiting for some CBL- or Noonan-associated cases that regress spontaneously.","refs":["azacitidine","allogeneic-hsct"],"guideline":{"version":"EWOG-MDS / COG JMML recommendations"}}],"stateOfArt":["WHO 2022 and the ICC redefined CMML with a lower monocyte threshold and molecular criteria, and split it into dysplastic and proliferative types with distinct biology.","CPSS-Mol brings mutations into risk assessment and guides transplant timing.","Hypomethylating agents remain the only approved drugs; oral decitabine-cedazuridine makes them easier to take but the clone usually persists.","RAS-pathway biology (also the driver of JMML) is the therapeutic target of the decade: MEK inhibitors, GM-CSF blockade and combinations with hypomethylating agents are in trials."],"history":[{"year":1982,"title":"FAB classification includes CMML within MDS","refs":[]},{"year":1996,"title":"Hydroxyurea beats etoposide in CMML","note":"GFM randomised trial (Wattel et al., Blood).","refs":["hydroxyurea"]},{"year":2001,"title":"WHO creates the MDS/MPN category","note":"CMML, atypical CML and JMML grouped as overlap neoplasms.","refs":[]},{"year":2004,"title":"Azacitidine approved for MDS including CMML","refs":["azacitidine"]},{"year":2013,"title":"CPSS risk score for CMML","note":"Such and colleagues; CPSS-Mol adds mutations in 2016.","refs":[]},{"year":2020,"title":"Oral decitabine-cedazuridine approved for MDS and CMML","refs":["decitabine-cedazuridine"]},{"year":2022,"title":"WHO 5th edition and ICC redefine CMML","note":"Monocyte threshold lowered to 0.5 x 10^9/L with molecular support; dysplastic vs proliferative subtypes formalised.","refs":[]}],"pipeline":["ruxolitinib","venetoclax","azacitidine","allogeneic-hsct","jbi-802","tuspetinib","bexmarilimab"],"openProblems":["No drug alters the disease course; RAS-pathway inhibitors, GM-CSF antibodies and venetoclax combinations are in early trials.","Transformation to AML in a substantial minority; sequential mutation tracking to intervene earlier is being studied.","Transplant is curative but most patients are old; reduced-intensity conditioning and better donor availability widen access.","Trials usually lump CMML with MDS or exclude it; dedicated CMML cohorts and registries (such as the European Hematology Association consortium) are the response."],"parent":"leukaemia"},{"id":"gastric-cldn18-2-positive","kind":"cancer","name":"Claudin 18.2-positive gastric cancer","aka":["CLDN18.2-positive gastric cancer","Claudin 18.2-high gastro-oesophageal adenocarcinoma"],"tldr":"Claudin 18.2 is a tight-junction protein normally hidden inside stomach lining cells that becomes exposed on the surface of many stomach cancers. Zolbetuximab, an antibody against it, added to chemotherapy lengthens survival in tumours that express it strongly, and antibody-drug conjugates and CAR-T cells against the same target are in trials.","summary":"Claudin 18.2 is a tight-junction protein confined to the gastric mucosa in normal tissue; during malignant transformation the junctions break down and the protein is exposed on the cell surface, where an antibody can reach it. Expression is tested by immunohistochemistry with the 43-14A antibody, and the trial-defined positive threshold is moderate-to-strong membranous staining in at least 75 percent of tumour cells. Expression is retained in metastases and is as common in diffuse-type as in intestinal-type tumours, so it is the one target that reaches the poor-prognosis diffuse subgroup; HER2 and claudin 18.2 positivity rarely overlap.\n\nZolbetuximab, a chimeric IgG1 antibody that kills claudin 18.2-positive cells through antibody-dependent cytotoxicity and complement, was tested in two phase 3 trials in HER2-negative, claudin 18.2-positive advanced disease. SPOTLIGHT (Lancet 2023) added it to FOLFOX and extended median progression-free survival from 8.7 to 10.6 months and median overall survival from 15.5 to 18.2 months; GLOW (Nature Medicine 2023) added it to CAPOX and extended survival from 12.2 to 14.4 months. Japan approved zolbetuximab in March 2024, the FDA in October 2024 and Europe later that year; nausea and vomiting in the first cycles, from on-target binding to normal stomach lining, are its characteristic toxicity and are managed with slower infusion and antiemetics.\n\nBecause PD-L1 expression is common in the same tumours, the order in which zolbetuximab and PD-1 blockade should be used, or whether they should be combined, is unsettled; trials of zolbetuximab with pembrolizumab or nivolumab and chemotherapy are under way. A second wave of claudin 18.2 agents follows: antibody-drug conjugates such as CMG901 and LM-302, the bispecific ASP2138, and satricabtagene autoleucel, a CAR-T product that produced responses in Chinese patients with heavily pretreated disease.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Zolbetuximab","links":[{"label":"SPOTLIGHT (Lancet 2023)","url":"https://pubmed.ncbi.nlm.nih.gov/37068504/"},{"label":"GLOW (Nature Medicine 2023)","url":"https://pubmed.ncbi.nlm.nih.gov/37524953/"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Zolbetuximab"}],"tags":["subtype-page"],"related":["early-gastric-cancer","gastric-her2-positive","gastric-msi-high","gastric-pdl1-high"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-spotlight-lancet-2023","paper-glow-zolbetuximab-nat-med-2023","paper-rainbow-ramucirumab-paclitaxel-lancet-oncol-2014"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About four in ten HER2-negative advanced gastric and junctional adenocarcinomas show claudin 18.2 on at least 75 percent of tumour cells, the threshold used in the zolbetuximab trials, making it the most widely shared drug target in stomach cancer.","subtypes":["Claudin 18.2-positive (75 percent or more of cells, moderate to strong), HER2-negative","Claudin 18.2-positive diffuse-type gastric cancer","Claudin 18.2-positive with PD-L1 CPS 5 or above (sequencing question)","Claudin 18.2-low (candidates for antibody-drug conjugates)"],"biomarkers":["Claudin 18.2 by immunohistochemistry (VENTANA 43-14A; 75 percent threshold)","HER2 (must be negative for zolbetuximab)","PD-L1 combined positive score","Claudin 18.2 expression in metastases and after prior therapy"],"standardOfCare":[{"setting":"Advanced, first line","approach":"Zolbetuximab with FOLFOX (SPOTLIGHT) or CAPOX (GLOW) in HER2-negative, claudin 18.2-positive disease; nivolumab or pembrolizumab with chemotherapy remains an alternative where PD-L1 is high.","refs":["spotlight-glow","zolbetuximab","folfox","capox","cldn18-2","nivolumab","pembrolizumab"]},{"setting":"Second line","approach":"Ramucirumab with paclitaxel; claudin 18.2 antibody-drug conjugates and CAR-T in trials.","refs":["ramucirumab","paclitaxel","cmg901","satricabtagene-autoleucel","cldn18-antibody-then-adc"]},{"setting":"Toxicity management","approach":"Antiemetic prophylaxis and slowed infusion for the nausea and vomiting of the first cycles.","refs":["zolbetuximab"]}],"stateOfArt":["Zolbetuximab is the first drug approved on a target other than HER2 or PD-L1 in stomach cancer and the first to reach the diffuse subtype.","Two positive phase 3 trials with different chemotherapy backbones give the result unusual robustness.","Antibody-drug conjugates and CAR-T against claudin 18.2 aim to treat tumours with lower expression and later lines."],"history":[{"year":2008,"title":"Claudin 18.2 identified as a tumour-exposed target (Sahin and colleagues)","refs":[]},{"year":2016,"title":"FAST phase 2: claudin 18.2 antibody plus chemotherapy improves survival","refs":[]},{"year":2023,"title":"SPOTLIGHT and GLOW: zolbetuximab plus chemotherapy extends survival","refs":["spotlight-glow","zolbetuximab"]},{"year":2024,"title":"Zolbetuximab approved in Japan, the United States and Europe","refs":["zolbetuximab"]}],"pipeline":["cmg901","satricabtagene-autoleucel","lm-302","asp2138","cldn18-antibody-then-adc","idea-biomarker-quadruplet-gastric"],"openProblems":["Whether zolbetuximab or PD-1 blockade should come first when both PD-L1 and claudin 18.2 are positive.","Tumours below the 75 percent threshold have no approved claudin 18.2 therapy.","Nausea and vomiting lead some patients to stop early."],"parent":"gastric"},{"id":"clear-cell-ovarian-cancer","kind":"cancer","name":"Clear cell ovarian cancer","aka":["Ovarian clear cell carcinoma","OCCC"],"tldr":"Clear cell ovarian cancer grows out of endometriosis, is usually caught early and cured by surgery, but when advanced it resists platinum chemotherapy. Its distinct genetics, with ARID1A and PIK3CA mutations, are the focus of targeted and immune approaches.","summary":"Clear cell carcinoma is strongly associated with endometriosis and is commoner in East Asian women. About half carry ARID1A mutations and a third PIK3CA mutations; TP53 is usually wild-type. It presents as a large unilateral mass, often at stage I, with a raised risk of venous thromboembolism and hypercalcaemia. Surgery is curative for most early disease, with adjuvant carboplatin-paclitaxel for stage IC and above; advanced and recurrent disease respond poorly to chemotherapy and do not benefit from PARP inhibitors. Immune checkpoint inhibitors have produced responses in a minority, and trials target ARID1A loss (ATR and EZH2 inhibitors), PI3K and the hypoxia pathway.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Clear-cell_ovarian_carcinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Clear-cell_ovarian_carcinoma"}],"tags":["subtype-page"],"related":["mucinous-ovarian-cancer","low-grade-serous-ovarian-cancer","high-grade-serous-ovarian-cancer","platinum-resistant-ovarian-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-wiegand-arid1a-clear-cell-nejm-2010","paper-jones-arid1a-clear-cell-science-2010"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"About one in ten ovarian cancers in Western countries and a quarter in Japan; most present at an early stage and are cured, but advanced disease responds poorly to chemotherapy and carries a worse outlook than high-grade serous cancer.","subtypes":["Clear cell carcinoma arising in endometriosis","Stage I clear cell carcinoma (most cases)","Advanced and recurrent clear cell carcinoma (chemoresistant)"],"biomarkers":["ARID1A mutation (about 50 percent)","PIK3CA mutation","HNF1B expression (diagnostic)","Mismatch repair deficiency (a minority)","Wild-type TP53"],"standardOfCare":[{"setting":"Early stage","approach":"Complete staging surgery; adjuvant carboplatin-paclitaxel for stage IC and above; observation may be considered for stage IA.","refs":["carboplatin","paclitaxel"]},{"setting":"Advanced or recurrent","approach":"Cytoreduction and platinum-based chemotherapy despite modest responses; clinical trials of immunotherapy and ARID1A-directed drugs are preferred where available.","refs":["pembrolizumab","atr-chk1-inhibitors"]},{"setting":"Supportive","approach":"Thromboprophylaxis awareness because of the high clot risk.","refs":["ovarian"]}],"stateOfArt":["Recognition of clear cell cancer as a separate disease has ended its lumping into serous trials.","ARID1A loss creates dependencies (ATR, EZH2, immune) now being exploited in dedicated trials.","Early detection through endometriosis follow-up is under study in Japan."],"history":[{"year":1973,"title":"WHO recognises clear cell carcinoma as an ovarian type","refs":[]},{"year":2010,"title":"ARID1A mutations discovered in clear cell carcinoma","refs":[]},{"year":2022,"title":"MOCCA and other trials test immunotherapy in clear cell carcinoma","refs":["pembrolizumab"]}],"pipeline":["atr-chk1-inhibitors","pembrolizumab"],"openProblems":["No effective treatment for platinum-resistant disease.","Which early-stage patients can skip chemotherapy.","Whether treating endometriosis reduces risk."],"parent":"ovarian"},{"id":"clear-cell-papillary-renal-cell-tumour","kind":"cancer","name":"Clear cell papillary renal cell tumour","aka":["Clear cell papillary renal cell carcinoma","Clear cell papillary renal cell tumour (indolent, separate in WHO 2022)","Clear cell tubulopapillary renal cell carcinoma","Renal angiomyoadenomatous tumour (overlapping term)"],"tldr":"Clear cell papillary renal cell tumour is a small, low-grade kidney tumour that looks like a mix of clear cell and papillary kidney cancer but behaves harmlessly: no case has been reported to spread. The WHO renamed it from carcinoma to tumour in 2022 for that reason. It is common in people with kidney failure and is cured by removing it.","summary":"The 2016 WHO classification recognised clear cell papillary renal cell carcinoma as a type, and the 2022 edition renamed it clear cell papillary renal cell tumour because no metastasis has been documented (Moch 2016; Moch 2022). It is composed of clear cells lining cystic, tubular and papillary structures with nuclei aligned away from the basement membrane, is strongly CK7-positive with cup-shaped carbonic anhydrase IX staining, and lacks the VHL alterations and 3p loss of clear cell carcinoma and the trisomies of papillary carcinoma. In 55 tumours from 34 patients (8 with end-stage renal disease), tumours were 0.2 to 7.5 cm (mean 2.0), 87 percent grade 2 and 96 percent stage pT1a, multiple in 9 patients (Modern Pathology 2013). In 290 consecutive nephrectomies it was the fourth most common type, average age 58, a third associated with end-stage renal disease, all pT1, and two cases had been misclassified as clear cell carcinoma (Human Pathology 2014).\n\nHow it differs from its parent: it is the renal cell tumour that is not, in behaviour, a cancer; misclassifying it as clear cell carcinoma can lead to over-treatment and to unnecessary VHL testing.\n\nHow common: 3 to 4 percent of renal tumours coming to surgery (Modern Pathology 2013; Human Pathology 2014).\n\nTreatment: partial nephrectomy or, where appropriate, active surveillance of a small mass; no systemic therapy is needed and none has been studied.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Renal_cell_carcinoma","links":[{"label":"Moch 2016, European Urology: the 2016 WHO classification of urinary and male genital tumours, part A","url":"https://doi.org/10.1016/j.eururo.2016.02.029"},{"label":"Moch 2022, European Urology: the 2022 WHO classification of urinary and male genital tumours, part A (renal, penile, testicular)","url":"https://doi.org/10.1016/j.eururo.2022.06.016"},{"label":"Modern Pathology 2013: clear cell papillary renal cell carcinoma, 55 tumours, differential diagnosis and immunoprofile","url":"https://doi.org/10.1038/modpathol.2012.204"},{"label":"Human Pathology 2014: clear cell papillary RCC is the fourth most common type in 290 nephrectomies","url":"https://doi.org/10.1016/j.humpath.2013.08.004"},{"label":"Cancer Research UK: types and grades of kidney cancer","url":"https://www.cancerresearchuk.org/about-cancer/kidney-cancer/stages-types-grades/types-grades"}],"tags":["subtype-page","wave4","kidney","rare"],"related":["rcc","clear-cell-rcc","papillary-rcc","mucinous-tubular-spindle-cell-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["nephrectomy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"3 percent of adult renal cell carcinoma resections over three years at one centre (Modern Pathology 2013) and 4.1 percent of 290 consecutive nephrectomies for renal cell carcinoma, the fourth most common type after clear cell (70 percent), papillary (16.6) and chromophobe (5.9) (Human Pathology 2014).","subtypes":["Sporadic clear cell papillary renal cell tumour (solitary, pT1a)","Clear cell papillary renal cell tumour in end-stage renal disease (often multiple)","Renal angiomyoadenomatous tumour (smooth muscle-rich variant)"],"biomarkers":["Strong CK7 and cup-shaped carbonic anhydrase IX staining; CD10 and AMACR negative","No VHL mutation or 3p loss","Low grade (WHO/ISUP 1 or 2) and pT1 stage","End-stage renal disease"],"standardOfCare":[{"setting":"All cases","approach":"Partial nephrectomy or active surveillance of a small mass; no systemic therapy.","refs":["rcc","nephrectomy","clear-cell-rcc"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"rcc"},{"id":"clear-cell-rcc","kind":"cancer","name":"Clear cell renal cell carcinoma","aka":["KIRC","TCGA-KIRC","kidney renal clear cell carcinoma (TCGA KIRC cohort)","ccRCC","Conventional renal cell carcinoma"],"tldr":"Clear cell is the common kidney cancer, driven by loss of the VHL gene that leaves the tumour behaving as if starved of oxygen and flooding itself with blood vessels. That biology explains why anti-angiogenic drugs, immunotherapy and the HIF-2 alpha blocker belzutifan all work.","summary":"Clear cell renal cell carcinoma arises from the proximal tubule and in about nine in ten cases has lost the VHL gene on chromosome 3p, stabilising HIF-2 alpha and driving VEGF, so tumours are highly vascular; PBRM1, SETD2 and BAP1 mutations shape its behaviour. Small tumours are removed by partial nephrectomy or ablated, and some are watched. Adjuvant pembrolizumab after nephrectomy improves survival in higher-risk disease (KEYNOTE-564). Metastatic disease is treated first line with an immunotherapy doublet: pembrolizumab with axitinib or lenvatinib, nivolumab with cabozantinib, or nivolumab with ipilimumab for intermediate- and poor-risk patients; cabozantinib, axitinib, tivozanib and belzutifan follow. Belzutifan, the first HIF-2 alpha inhibitor, was approved for VHL disease in 2021 and for previously treated advanced disease in 2023. Cytoreductive nephrectomy is now reserved for selected patients after CARMENA.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Clear-cell_renal_cell_carcinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Clear-cell_renal_cell_carcinoma"}],"tags":["subtype-page"],"related":["chromophobe-rcc","papillary-rcc"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["bap1-loss"],"trials":["carmena","checkmate-025"],"people":[],"bottlenecks":[],"keyPapers":["paper-keynote-564-nejm-2021","paper-clear-nejm-2021","paper-keynote-426-nejm-2019","paper-checkmate-214-nejm-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"About three quarters of kidney cancers and most of the deaths; a third of patients present with or develop metastases, and immunotherapy combinations have lifted median survival in advanced disease to around four years.","subtypes":["Sporadic clear cell (VHL-inactivated)","Clear cell with sarcomatoid or rhabdoid features (aggressive, immunotherapy-responsive)","VHL disease-associated (hereditary, multifocal)","Clear cell papillary renal cell tumour (indolent, separate in WHO 2022)"],"biomarkers":["VHL inactivation and 3p loss","PBRM1, SETD2, BAP1 mutations (prognosis)","IMDC risk group (metastatic disease)","Sarcomatoid features","Germline VHL testing in young or multifocal disease"],"standardOfCare":[{"setting":"Small renal mass","approach":"Partial nephrectomy, thermal ablation or active surveillance by size, growth and patient fitness.","refs":["thermal-ablation","cryoablation","active-surveillance"]},{"setting":"Localised, higher risk","approach":"Radical or partial nephrectomy followed by one year of adjuvant pembrolizumab (KEYNOTE-564, overall survival benefit).","refs":["pembrolizumab","keynote-564"]},{"setting":"Metastatic, first line","approach":"Pembrolizumab plus axitinib (KEYNOTE-426) or lenvatinib, nivolumab plus cabozantinib, or nivolumab plus ipilimumab (CheckMate 214) for intermediate and poor risk; cytoreductive nephrectomy only in selected patients.","refs":["pembrolizumab","axitinib","lenvatinib","nivolumab","cabozantinib","ipilimumab","keynote-426","checkmate-214"]},{"setting":"Later lines","approach":"Cabozantinib, axitinib, belzutifan (LITESPARK-005), lenvatinib plus everolimus, tivozanib.","refs":["cabozantinib","belzutifan","everolimus","hif2a"]},{"setting":"VHL disease","approach":"Belzutifan for kidney, pancreatic and CNS tumours that would otherwise need surgery; surveillance of the kidneys with nephron-sparing surgery when tumours reach 3 cm.","refs":["belzutifan"]}],"stateOfArt":["Immunotherapy doublets cure a small fraction of metastatic patients and control most for years, with the nivolumab-ipilimumab plateau the clearest sign of durable benefit.","Belzutifan is the first drug to target the transcription factor at the root of the disease, forty years after VHL was mapped.","Adjuvant pembrolizumab is the first adjuvant treatment ever to lengthen survival in kidney cancer."],"history":[{"year":1993,"title":"VHL gene identified","refs":[]},{"year":2005,"title":"Sorafenib and sunitinib open the anti-angiogenic era","refs":["sunitinib"]},{"year":2015,"title":"Nivolumab beats everolimus after anti-angiogenic therapy (CheckMate 025)","refs":["nivolumab"]},{"year":2018,"title":"Nivolumab plus ipilimumab first line (CheckMate 214)","refs":["checkmate-214"]},{"year":2019,"title":"Pembrolizumab plus axitinib first line (KEYNOTE-426)","refs":["keynote-426"]},{"year":2021,"title":"Belzutifan approved for VHL disease; adjuvant pembrolizumab (KEYNOTE-564)","refs":["belzutifan","keynote-564"]}],"pipeline":["belzutifan","hif2a"],"openProblems":["No validated biomarker chooses between immunotherapy doublets.","Most metastatic patients still progress within two to three years.","Overtreatment of small renal masses versus the risk of surveillance."],"parent":"rcc"},{"id":"collecting-duct-carcinoma","kind":"cancer","name":"Collecting duct carcinoma of the kidney","aka":["Bellini duct carcinoma","Carcinoma of the collecting ducts of Bellini","Collecting duct renal cell carcinoma","Collecting duct and medullary (SMARCB1)"],"tldr":"Collecting duct carcinoma is a rare, aggressive kidney cancer that starts in the tubes deep in the kidney that collect urine. It is treated with surgery where possible and the platinum chemotherapy used for bladder cancer, not the usual kidney cancer drugs, which do not work in it. It is usually advanced when found: 74.4 percent of 286 US SEER patients were stage III or IV.","summary":"Collecting duct carcinoma is a high-grade adenocarcinoma of the distal nephron, medullary in location, with tubular or tubulopapillary growth and a desmoplastic stroma; the 2022 WHO classification keeps it as a type and separates SMARCB1-deficient renal medullary carcinoma, its closest relative, as a molecularly defined type (Moch 2022). In a series of 39 collecting duct and 13 renal medullary carcinomas, both favoured the right kidney, centred on the medulla, averaged 7 cm, and showed poorly differentiated histology with desmoplasia, inflammation, lymphovascular invasion and perinephric extension in nearly all (Am J Surg Pathol 2012). In SEER, 74.4 percent presented at stage III or IV and most tumours were under 7 cm (Frontiers in Oncology 2021).\n\nHow it differs from its parent: renal cell carcinoma's VEGF and checkpoint pathways do not carry over; a systematic review found a 26 percent objective response to gemcitabine with cisplatin or carboplatin in 23 patients with metastatic disease and no response to immunotherapy in 49 patients treated in two older studies (Current Oncology 2013).\n\nHow common: 286 US cases in 15 years (Frontiers in Oncology 2021).\n\nTreatment: nephrectomy where the disease is resectable; gemcitabine with cisplatin or carboplatin for metastatic disease, borrowed from urothelial cancer, as the review describes; checkpoint inhibitor combinations are used off the renal cell carcinoma pathway without trial evidence in this type (Current Oncology 2013).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Collecting_duct_carcinoma","links":[{"label":"NCI PDQ: renal cell cancer treatment","url":"https://www.cancer.gov/types/kidney/patient/kidney-treatment-pdq"},{"label":"Cancer Research UK: types and grades of kidney cancer","url":"https://www.cancerresearchuk.org/about-cancer/kidney-cancer/stages-types-grades/types-grades"},{"label":"Moch 2022, European Urology: the 2022 WHO classification of urinary and male genital tumours, part A (renal, penile, testicular)","url":"https://doi.org/10.1016/j.eururo.2022.06.016"},{"label":"Frontiers in Oncology 2021: collecting duct carcinoma of the kidney, 286 SEER patients 2004 to 2018","url":"https://doi.org/10.3389/fonc.2021.727222"},{"label":"Current Oncology 2013: management of renal collecting duct carcinoma, systematic review","url":"https://doi.org/10.3747/co.20.1230"},{"label":"Am J Surg Pathol 2012: collecting duct carcinoma and renal medullary carcinoma, 52 cases","url":"https://doi.org/10.1097/pas.0b013e3182635954"}],"tags":["subtype-page","wave4","kidney","rare"],"related":["rcc","renal-medullary-carcinoma","urothelial","papillary-rcc","fh-deficient-renal-cell-carcinoma","tfe3-rearranged-renal-cell-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["gemcitabine-cisplatin","gemcitabine","cisplatin","carboplatin"],"companies":[],"institutions":[],"pathways":[],"terms":["nephrectomy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Very rare and falling: 286 patients in the US SEER registry over 2004 to 2018, median age 59, 67.5 percent men, 74.4 percent stage III or IV at diagnosis (Frontiers in Oncology 2021). Cancer Research UK lists clear cell at 70 to 80 percent, papillary 5 to 10 and chromophobe 3 to 5 percent of renal cell cancers; collecting duct carcinoma is well under 1 percent.","subtypes":["Collecting duct carcinoma, classic (medullary epicentre, desmoplastic; right kidney predilection)","Collecting duct carcinoma with sarcomatoid change","SMARCB1-deficient renal medullary carcinoma (own page; formerly grouped here)"],"biomarkers":["Retained SMARCB1 (INI1) expression, distinguishing it from renal medullary carcinoma","High nuclear grade and lymphovascular invasion","Stage at diagnosis (three quarters III or IV)"],"standardOfCare":[{"setting":"All stages","approach":"Nephrectomy where resectable; gemcitabine with cisplatin or carboplatin for metastatic disease, borrowed from urothelial cancer; renal cell carcinoma drugs have little evidence here.","refs":["nephrectomy","gemcitabine-cisplatin","carboplatin","rcc"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"rcc"},{"id":"pancreatic-colloid-carcinoma","kind":"cancer","name":"Colloid (mucinous non-cystic) carcinoma of the pancreas","aka":["Colloid (mucinous non-cystic) carcinoma of the pancreas (mucin pools; usually the invasive part of an intestinal-type IPMN; better outlook)","Colloid carcinoma of the pancreas","Mucinous non-cystic carcinoma of the pancreas","Mucinous noncystic carcinoma","Colloid carcinoma"],"tldr":"Colloid carcinoma is a rare form of pancreatic cancer in which the cancer cells float in large pools of mucus rather than forming glands in dense scar. It usually grows out of an intestinal-type IPMN in the main pancreatic duct, presents as a larger but lower-stage tumour, and has a clearly better outlook after surgery than ordinary pancreatic cancer.","summary":"What it is. Colloid carcinoma is defined by nodular pools of extracellular mucin containing scanty malignant cells, making up more than 80 percent of the tumour (Adsay 2001); the 2019 WHO classification lists it as a variant of ductal adenocarcinoma (Nagtegaal 2020). In more than half of the defining series it was the invasive component of an IPMN (9 of 17) or an MCN (1 of 17), and KRAS codon 12 mutations were found in only 4 of 12 cases studied, fewer than in ordinary ductal cancer.\n\nHow it differs from its parent. Patients present with larger tumours (mean 5.3 cm) but lower stage; two- and five-year survival were 70 and 57 percent against 28 and 12 percent for 82 resectable ordinary ductal adenocarcinomas at the same centre, and ten patients were alive without disease at a median of 79 months, four of them despite lymph node metastases (Adsay 2001). Among invasive IPMNs, colloid and oncocytic carcinomas kept a favourable outcome after stage matching while tubular carcinomas did not; colloid carcinomas arose only from intestinal-type IPMNs and mostly from main-duct disease (Mino-Kenudson 2011), and in a matched series tubular histology carried 3.7 times the hazard of death of colloid histology (Yopp 2011).\n\nHow common it is. Not counted by registries; 26 to 41 percent of invasive IPMN-associated cancers in the two single-centre series above.\n\nHow it is treated. Resection, usually a pancreatoduodenectomy for main-duct IPMN in the head, with adjuvant chemotherapy as for ductal adenocarcinoma; there is no histology-specific trial. The defining series noted that all seven patients who died with or of tumour had undergone an incisional biopsy before or during surgery, and none of the survivors had, an observation the authors flagged rather than proved.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Mucinous_carcinoma","links":[{"label":"Adsay, Am J Surg Pathol 2001: colloid (mucinous non-cystic) carcinoma of the pancreas","url":"https://doi.org/10.1097/00000478-200101000-00003"},{"label":"Mino-Kenudson, Gut 2011: prognosis of invasive IPMN depends on histological and precursor epithelial subtypes","url":"https://doi.org/10.1136/gut.2010.232272"},{"label":"Yopp, Ann Surg 2011: invasive carcinoma arising in IPMN, matched comparison with ductal adenocarcinoma","url":"https://doi.org/10.1097/sla.0b013e318214bcb4"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"}],"tags":["gi","pancreatic","subtype-page"],"related":["pancreatic","ipmn-associated-carcinoma","ipmn-cystic-precursors","mcn-associated-carcinoma","colorectal-mucinous-adenocarcinoma","gallbladder-mucinous-carcinoma"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","histopathology-ihc","pancreatic-surveillance"],"targets":["kras"],"drugs":["folfirinox","gemcitabine-nab-paclitaxel"],"companies":[],"institutions":[],"pathways":["ras-mapk","pancreatic-cancer-signalling"],"terms":["tumour-grade","whipple","pancreatic-cyst-high-risk-stigmata"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Rare: 17 cases with more than 80 percent colloid pattern in the series that defined it; 16 of 61 (26 percent) invasive cancers arising in IPMNs at one centre and 24 of 59 (41 percent) at another were colloid type. No population count is published.","subtypes":["Colloid carcinoma arising in an intestinal-type IPMN (the usual setting)","Colloid carcinoma arising in a mucinous cystic neoplasm","Colloid carcinoma without an identifiable precursor (distinguished from ductal PDAC with mucinous features)"],"biomarkers":["More than 80 percent extracellular mucin pools with floating malignant cells (histology)","Intestinal-type IPMN background (MUC2 and CDX2 positive)","KRAS mutation in a minority (4 of 12 in the defining series)"],"standardOfCare":[{"setting":"Resectable","approach":"Pancreatoduodenectomy or distal pancreatectomy with the IPMN, followed by adjuvant chemotherapy as for ductal adenocarcinoma; the remaining gland is kept under surveillance because IPMN is a field disease.","refs":["whipple","distal-pancreatectomy","folfirinox","neoadjuvant-adjuvant","pancreatic-surveillance"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Advanced","approach":"Treated as pancreatic ductal adenocarcinoma: resection with adjuvant chemotherapy when removable, the chemotherapy rows of the parent page when not; the parent record carries the trials.","refs":["folfirinox","gemcitabine-nab-paclitaxel"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Recognised since 2001 as a distinct, better-behaved variant; the favourable outcome of invasive IPMN is largely the colloid and oncocytic subtypes."],"history":[{"year":2001,"title":"Adsay and colleagues define colloid carcinoma of the pancreas (17 cases)","refs":["tumour-grade"]},{"year":2011,"title":"Invasive IPMN outcome shown to depend on colloid versus tubular histology","refs":["ipmn-associated-carcinoma"]}],"pipeline":[],"openProblems":["Rarity: no trial, no registry code, so its share and outcomes come from single centres.","Whether the favourable outlook justifies less adjuvant treatment is untested."],"parent":"pancreatic"},{"id":"colon-cancer","kind":"cancer","name":"Colon cancer (adenocarcinoma of the colon)","aka":["Colon cancer","Colonic adenocarcinoma","Cancer of the colon","Right-sided and left-sided colon cancer","Rectal vs colon (different local therapy)"],"tldr":"Colon cancer is bowel cancer arising in the large bowel above the rectum. It shares its biology with colorectal cancer but is treated differently from rectal cancer: surgery comes first without radiotherapy, chemotherapy afterwards is decided by stage and increasingly by a blood test for leftover tumour DNA, and the side the tumour started on changes which drugs work once it has spread.","summary":"The WHO classification of digestive tumours describes adenocarcinoma of the colon and rectum as one chapter, with the site recorded because staging and local treatment differ (Nagtegaal 2020). The colorectal page holds the molecular subtypes; this page is the anatomical entity that the corpus's rectal cancer page mirrors. Two identically designed adjuvant trials in 855 colon and 796 rectal cancer patients showed that adding folinic acid to fluorouracil improved seven-year overall survival in colon but not rectal cancer, with different patterns of recurrence (Clinical Colorectal Cancer 2013). Within the colon, right-sided (proximal) tumours are more often mismatch-repair deficient, BRAF-mutant, mucinous and worse-prognosis in the metastatic setting, and left-sided tumours respond better to EGFR antibodies; a pooled analysis of 2,879 metastatic patients found no outcome difference between left-sided colon and rectal primaries (European Journal of Cancer 2018).\n\nHow it differs from its parent: the colorectal page carries the shared biology and the metastatic drug pathways; colon cancer differs from rectal cancer in having no role for pelvic radiotherapy, in colectomy with regional lymphadenectomy as the operation, and in the stage III adjuvant standard of three or six months of FOLFOX or CAPOX set by the IDEA collaboration and recorded on the FOLFOX and CAPOX pages.\n\nHow common: no separate GLOBOCAN figure; the proximal-colon share above is from one registry.\n\nTreatment follows the colorectal page and the NCI PDQ colon summary: colectomy for stage I to III, adjuvant FOLFOX or CAPOX for stage III and high-risk stage II, with the ctDNA-guided DYNAMIC and CIRCULATE-US trials and the exercise trial CHALLENGE linked here; mismatch-repair deficient colon cancer is treated with checkpoint inhibitors before surgery in NICHE-2 and after surgery in ATOMIC; metastatic disease follows the colorectal page by sidedness and RAS, BRAF and HER2 status.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Colorectal_cancer","links":[{"label":"NCI PDQ: colon cancer treatment","url":"https://www.cancer.gov/types/colorectal/patient/colon-treatment-pdq"},{"label":"Nagtegaal 2020, Histopathology: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"Clinical Colorectal Cancer 2013: two adjuvant trials reveal differences between colon and rectal cancer","url":"https://doi.org/10.1016/j.clcc.2012.07.005"},{"label":"European Journal of Cancer 2018: left-sided colon and rectal cancer in 2,879 ARCAD trial patients","url":"https://doi.org/10.1016/j.ejca.2018.08.020"},{"label":"J Cancer Res Clin Oncol 2016: mucinous and signet ring cell colorectal cancer in 28,056 Munich registry patients","url":"https://doi.org/10.1007/s00432-016-2224-2"}],"tags":["subtype-page","wave4","colorectal"],"related":["colorectal","rectal-cancer","msi-high-colorectal","braf-v600e-colorectal","colorectal-mucinous-adenocarcinoma","colorectal-serrated-adenocarcinoma","colorectal-medullary-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["folfox","capox","oxaliplatin","capecitabine","fluorouracil","bevacizumab","cetuximab","panitumumab","nivolumab","ipilimumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["niche-2","atomic","dynamic","circulate-us","challenge","alascca","paradigm","crystal-fire3"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"GLOBOCAN counts colon and rectum together (1,926,425 new colorectal cancers in 2022); most colorectal cancers arise in the colon. In the Munich registry, 34 percent of ordinary adenocarcinomas were in the proximal colon (J Cancer Res Clin Oncol 2016).","subtypes":["Right-sided (proximal) colon cancer: caecum to transverse colon; more often MSI-high, BRAF-mutant and mucinous","Left-sided (distal) colon cancer: splenic flexure to sigmoid; EGFR-antibody responsive when RAS wild-type","Stage II colon cancer (ctDNA-guided adjuvant decisions)","Stage III colon cancer (three or six months of FOLFOX or CAPOX)","Mismatch-repair deficient colon cancer (neoadjuvant immunotherapy in trials)"],"biomarkers":["Mismatch repair and microsatellite instability","RAS and BRAF V600E mutation, HER2 amplification (metastatic)","Primary tumour side","Circulating tumour DNA after surgery","Carcinoembryonic antigen"],"standardOfCare":[{"setting":"Stage I to III","approach":"Colectomy with regional lymphadenectomy; adjuvant FOLFOX or CAPOX for stage III and high-risk stage II, with ctDNA guidance under study.","refs":["folfox","capox","dynamic","circulate-us","challenge"]},{"setting":"Mismatch-repair deficient, localised","approach":"Neoadjuvant nivolumab and ipilimumab (NICHE-2) and adjuvant atezolizumab with FOLFOX (ATOMIC) in trials.","refs":["niche-2","atomic","nivolumab","ipilimumab"]},{"setting":"Metastatic","approach":"As the colorectal page by sidedness and RAS, BRAF and HER2 status.","refs":["colorectal","cetuximab","panitumumab","bevacizumab","paradigm"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"colorectal"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","aka":["COAD","COADREAD","TCGA-COAD","TCGA-COADREAD","colorectal adenocarcinoma (TCGA COAD and READ cohorts)","Rectal Cancer","Bowel cancer","Colorectal adenocarcinoma","Cancer of the colon and rectum","Large bowel cancer","CRC"],"tldr":"The cancer where screening works best and where immunotherapy can make some tumours disappear entirely; chemotherapy still carries most metastatic disease, now with antibodies and targeted combinations chosen by RAS, BRAF, mismatch repair and which side of the bowel the tumour started on.","summary":"Colorectal cancer is the disease where screening works best: removing adenomas at colonoscopy prevents cancer, stool and blood tests catch it early, and localised disease is cured by surgery. It is the third most common cancer worldwide (about 1.9 million cases a year) and, because many are still found late, the second most common cause of cancer death (900,000 a year). Most cases arise through the adenoma-carcinoma sequence driven by APC loss, KRAS mutation, and TP53 loss (chromosomal instability); about 15% arise through mismatch-repair deficiency (dMMR/MSI-high), either sporadically via MLH1 methylation or through Lynch syndrome. Incidence is rising sharply in adults under 50 for reasons that remain unexplained.\n\nHow common it is, world and United States. The IARC fact sheets, served with the GLOBOCAN 2024 estimates, count the colon and the rectum separately: 1,206,011 new colon cancers a year (the 4th commonest cancer, age-standardised rate 10.8 per 100,000) with 556,774 deaths (the 5th commonest cause of cancer death, 4.7 per 100,000), and 778,594 rectal cancers (8th, 7.3 per 100,000) with 339,370 deaths (9th, 3.0 per 100,000). Added together that is 1,984,605 new cases and 896,144 deaths a year, which is where the familiar round figures of about 1.9 million cases and about 900,000 deaths come from. Asia has 49.3 percent of colon cases, Europe 27.2 percent, Northern America 10.6 percent, Latin America and the Caribbean 8.3 percent, Africa 3.4 percent and Oceania 1.3 percent. In the United States the SEER programme projects 158,850 new cases (7.5 percent of all cancers) and 55,230 deaths (8.8 percent of cancer deaths) for 2026, making colorectal cancer the 4th commonest cancer diagnosed and the 2nd commonest cause of cancer death; the rate of new cases is 37.6 per 100,000 a year (2019 to 2023) and the death rate 12.7 (2020 to 2024); the median age at diagnosis is 66 and at death 72; about 3.9 percent of Americans will be diagnosed in their lifetime; and 1,478,528 people were living with the disease in 2023. Rates differ by group: 59.5 per 100,000 in non-Hispanic American Indian and Alaska Native men and 50.1 in non-Hispanic Black men against 42.9 in non-Hispanic White men (SEER).\n\nHow common it is in the UK. Cancer Research UK counts 48,213 new bowel cancers a year (2019, 2021 to 2022), more than 130 a day, which makes it the 4th commonest cancer and 12 percent of all new cancers: about 26,800 in men and about 21,400 in women. It is the 2nd commonest cause of cancer death, with about 17,700 deaths a year (2022 to 2024), 48 a day. More than two-fifths (43 percent) of new cases are in people aged 75 and over, rates are highest at 85 to 89, and 59 percent of deaths are in the over-75s. The lifetime risk of a diagnosis is 1 in 20 for women and 1 in 17 for men born in 1961. The trends run in opposite directions: incidence rates are up about 6 percent since the early 1990s but down 3 percent in the last decade, and are projected to fall a further 7 percent by 2038 to 2040 (to about 47,700 cases a year), while mortality rates have almost halved (down 46 percent) since the early 1970s and fell 6 percent in the last decade. The rectum is the commonest single site (2016 to 2018). Deprivation shows through: mortality rates for lower gastrointestinal cancer are 22 percent higher in the most deprived fifth than the least for women and 27 percent higher for men, about 1,700 deaths a year in the UK.\n\nThe rise in early-onset disease. Colorectal cancer is becoming a young person's disease at the same time as it retreats in the old. The American Cancer Society's 2026 report finds overall incidence falling 0.9 percent a year over 2013 to 2022, driven by a 2.5 percent annual fall in people aged 65 and over, while incidence rose 3 percent a year in adults aged 20 to 49 and 0.4 percent a year at 50 to 64, dominated by tumours of the distal colon and rectum; rectal cancer incidence overall turned upwards by 1 percent a year from 2018 to 2022 after decades of decline and now accounts for 32 percent of colorectal cancers, up from 27 percent in the mid-2000s. Mortality under 50 has risen 1 percent a year since 2004 and at 50 to 64 by 1 percent a year since 2019, while it fell 2.3 percent a year in the over-65s from 2012. The earlier 2023 report put the same shift another way: the share of cases in people under 55 went from 11 percent in 1995 to 20 percent in 2019, and 60 percent of new cases were advanced in 2019 against 52 percent in the mid-2000s. The pattern is not American. A study of registry data from 36 countries found incidence in adults under 50 rising in 19 of them and, in nine spanning three continents (Australia, Canada, Denmark, Germany, New Zealand, Slovenia, Sweden, the UK and the USA), rising in the young while stable or falling in older adults; the uptick began in the mid-1990s in most high-income countries, and the steepest rises were in Korea and New Zealand (Siegel 2019). No cause has been established. Diet, obesity, type 2 diabetes, inactivity, alcohol, smoking and the microbiome are the candidates, and the generational pattern points at an exposure acting early in life.\n\nWhat raises the risk, at population level. These are the factors that shape how many bowel cancers occur in a country, not an account of why any one person got theirs. Age comes first, and then a list that is unusually modifiable: Cancer Research UK judges 54 percent of UK bowel cancers preventable. Processed meat causes 13 percent of UK cases (risk 18 percent higher per 50 g a day; colon cancer risk 22 percent higher per 100 g a day of red meat, with no association for rectal cancer); too little fibre causes 28 percent (risk 10 percent lower per 10 g a day of total or cereal fibre, 20 percent lower per 90 g a day of whole grains); overweight and obesity cause 11 percent (colon cancer risk 30 percent higher in men and 12 percent higher in women per 5 units of body mass index, 25 percent higher per 10 cm of waist, and adenoma risk 47 percent higher in obesity); alcohol causes 6 percent (risk 7 percent higher per unit a day, 33 percent higher above 6 units a day); smoking causes 7 percent (17 to 21 percent higher risk in current smokers, adenomatous polyp risk about doubled, serrated polyp risk more than doubled); too little physical activity causes 5 percent (colon cancer risk 19 percent lower in the most active); and ionising radiation 2 percent. Medical conditions matter too: type 2 diabetes raises risk 22 to 30 percent, and inflammatory bowel disease (ulcerative or Crohn's colitis) raises it 70 percent, with a 5 percent risk of bowel cancer after 20 years of disease. Family history more than doubles risk with one affected first-degree relative. Inherited syndromes account for a minority but a decisive one: mismatch repair variants (Lynch syndrome) are carried by about 1 in 279 people and cause 1 to 4 percent of colon cancers, familial adenomatous polyposis fewer than 1 percent, and about 1 in 45 people carry a MUTYH variant (Win 2017; Cancer Research UK). Aspirin runs the other way: ever-use is associated with 17 percent lower risk, and longer use with lower risk still.\n\nHow it shows itself, and when to refer. The NHS lists the symptoms as changes in poo (looser, harder or going more or less often than usual), blood in the poo or bleeding from the bottom, a persistent feeling of needing to poo, tummy pain, a lump in the tummy, bloating, unexplained weight loss, and tiredness or breathlessness from anaemia; it advises seeing a GP for any of them, an urgent appointment or NHS 111 for black or dark red poo or bloody diarrhoea, and 999 or A&E for non-stop bleeding or large clots. None of these symptoms is specific, which is why England now puts a test between the symptom and the referral. NICE NG12 (1.3.1, adapted from the HealthTech guidance on quantitative faecal immunochemical testing in primary care) tells GPs to offer a quantitative faecal immunochemical test to adults with an abdominal mass, a change in bowel habit or iron-deficiency anaemia; aged 40 and over with unexplained weight loss and abdominal pain; under 50 with rectal bleeding plus abdominal pain or weight loss; 50 and over with unexplained rectal bleeding, abdominal pain or weight loss; and 60 and over with anaemia even without iron deficiency. A result of at least 10 micrograms of haemoglobin per gram of faeces triggers a suspected cancer pathway referral (1.3.2); below that, safety netting applies and strong clinical concern still overrides the test (1.3.3). A rectal mass goes straight to referral, and people with a rectal mass, an unexplained anal mass or anal ulceration do not need the test first. A previous negative screening result does not exempt a symptomatic person. In England in 2019, 38 percent of bowel cancers were diagnosed through an urgent suspected cancer referral, 22 percent after an emergency presentation and 12 percent through screening; 47 percent of staged cases in 2022 were stage I or II (Cancer Research UK).\n\nScreening: what is offered and what it is worth. England invites everyone aged 50 to 74 every two years for a faecal immunochemical test done at home, with a colonoscopy for an abnormal result; the kit replaced the older guaiac test in June 2019, results come about two weeks after the laboratory receives the sample, and people aged 75 and over can request a kit every two years on the programme helpline (NHS; GOV.UK). The threshold that decides who is called for colonoscopy is a rationing decision as much as a clinical one: the English programme uses 120 micrograms of haemoglobin per gram of faeces, a figure no programme publication states but which the modelling of the English pilot calls the current threshold (Br J Cancer 2022; the same paper's estimates of what it buys are in the glossary). The symptomatic threshold in primary care is twelve times lower, at 10 micrograms per gram. The United States starts earlier: the US Preventive Services Task Force recommends screening from 50 to 75 (grade A) and from 45 to 49 (grade B), with selective screening from 76 to 85, by colonoscopy, faecal testing, stool DNA or computed tomography colonography. The evidence that screening saves lives is randomised. Annual faecal occult blood testing cut 13-year colorectal cancer mortality by 33 percent in 46,551 people in Minnesota (Mandel 1993). A single flexible sigmoidoscopy offered once to people aged 55 to 64 cut incidence by 26 percent and mortality by 30 percent over 17 years, and by 35 and 41 percent in those who actually attended (Atkin 2017). NordICC, the first randomised trial of screening colonoscopy, found a 10-year risk of colorectal cancer of 0.98 percent in the invited group against 1.20 percent in usual care, an 18 percent reduction, with 455 people needing to be invited to prevent one cancer; only 42 percent of those invited attended, and a later instrumental-variable analysis of the same trial estimated a 35 to 41 percent reduction in incidence among those screened (Bretthauer 2022).\n\nHow it is diagnosed and staged. Colonoscopy with biopsy is the test that makes the diagnosis and removes the precursor at the same visit; computed tomography colonography is the alternative when colonoscopy is not possible. Staging is by computed tomography of the chest, abdomen and pelvis, with magnetic resonance imaging of the pelvis for every rectal cancer. The eighth edition of the TNM system is the language: Tis is carcinoma in situ in the mucosa; T1 is into the inner layer, T2 into the muscle, T3 through the muscle into the surrounding tissue, T4a through the outer lining into the peritoneum and T4b into a nearby organ; N1a, N1b and N1c mean one node, two or three nodes, or tumour deposits without node involvement, and N2a and N2b mean four to six or seven or more nodes; M1a, M1b and M1c mean one distant site, two or more, or any spread to the peritoneum (Cancer Research UK). Rectal cancer adds two questions computed tomography cannot answer: how close the tumour comes to the plane the surgeon will cut along (the mesorectal fascia, which becomes the circumferential resection margin in the specimen), and whether tumour has spread into the veins outside the bowel wall. High-resolution magnetic resonance imaging answers the first with 92 percent specificity for predicting a clear margin, and in the 349 patients it predicted clear, 327 were clear at surgery (MERCURY, 408 patients, BMJ 2006). Every metastatic tumour is tested for RAS and BRAF V600E mutations before systemic therapy (NICE NG151 1.4.1), mismatch repair status is tested at diagnosis, and where the tumour started, the right colon or the left colon and rectum, predicts both biology and the benefit of EGFR antibodies. In the United States 34 percent of cases are found localised, 37 percent regional, 23 percent distant and 6 percent unstaged (SEER).\n\nPathology, the two pathways, and prevention. Almost all bowel cancers are adenocarcinomas of the gland cells that line the bowel; mucinous and signet ring cell tumours are rarer forms of adenocarcinoma, and squamous, neuroendocrine, sarcomatous, lymphoid and melanocytic tumours of the bowel are separate diseases with their own records (Cancer Research UK). Grade runs 1 to 4, from cells that look almost normal to cells that look nothing like them. The cancers arise along two routes. The conventional adenoma-carcinoma sequence, mapped in 172 specimens in 1988 and formalised as a model in 1990, runs from normal mucosa through adenoma to carcinoma as mutations accumulate: loss of the chromosome 5 region that carries the polyposis gene, RAS mutation (found in 58 percent of adenomas over 1 cm but only 9 percent of smaller ones), loss of chromosome 18 (73 percent of carcinomas) and loss of chromosome 17p (75 percent of carcinomas) (Vogelstein 1988; Fearon and Vogelstein 1990). The serrated pathway accounts for about 30 percent of colorectal carcinomas and runs instead through hyperplastic polyps, sessile serrated lesions and traditional serrated adenomas, with methylation of promoter islands and BRAF or KRAS mutation, and it produces most of the sporadic mismatch repair-deficient cancers (Bettington 2013). Prevention follows from the first route: in the National Polyp Study, removing adenomas at colonoscopy left 1,418 patients with 76 to 90 percent fewer cancers than expected, and at a median of 15.8 years mortality from colorectal cancer among 2,602 patients whose adenomas were removed was 53 percent lower than the general population would predict (Winawer 1993; Zauber 2012). Aspirin is the drug: in the CAPP2 trial, 600 mg of aspirin daily for at least two years cut colorectal cancer in Lynch syndrome carriers over ten years (hazard ratio 0.65 in the intention-to-treat analysis, 0.56 in those who completed two years), and NICE NG151 (1.1.1) now says to consider daily aspirin for more than two years in Lynch syndrome (Burn 2020).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Colorectal_cancer","links":[{"label":"NCCN Colon Cancer guideline","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"},{"label":"NCCN Rectal Cancer guideline","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461"},{"label":"NCCN Colorectal Cancer Screening guideline","url":"https://www.nccn.org/guidelines/guidelines-detail?category=2&id=1429"},{"label":"ESMO metastatic colorectal cancer guideline","url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-gastrointestinal-cancers/"},{"label":"NCI PDQ colon cancer treatment","url":"https://www.cancer.gov/types/colorectal/hp/colon-treatment-pdq"},{"label":"NHS: bowel cancer","url":"https://www.nhs.uk/conditions/bowel-cancer/"},{"label":"NHS: bowel cancer, symptoms","url":"https://www.nhs.uk/conditions/bowel-cancer/symptoms/"},{"label":"NHS: bowel cancer, tests and next steps","url":"https://www.nhs.uk/conditions/bowel-cancer/tests-and-next-steps/"},{"label":"NHS: bowel cancer, treatment","url":"https://www.nhs.uk/conditions/bowel-cancer/treatment/"},{"label":"NHS: recovery and lifestyle changes after a colostomy","url":"https://www.nhs.uk/tests-and-treatments/colostomy/recovery-and-lifestyle-changes-after-a-colostomy/"},{"label":"NHS: complications of a colostomy","url":"https://www.nhs.uk/tests-and-treatments/colostomy/complications-of-a-colostomy/"},{"label":"NHS: genetic and genomic testing","url":"https://www.nhs.uk/tests-and-treatments/genetic-and-genomic-testing/"},{"label":"NHS: clinical trials","url":"https://www.nhs.uk/tests-and-treatments/clinical-trials/"},{"label":"NICE NG151: colorectal cancer, recommendations","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"},{"label":"Bowel Cancer UK: stomas","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/treatment/surgery/stomas/"},{"label":"Bowel Cancer UK: change in bowel habit after treatment","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/living-with-and-beyond-bowel-cancer/change-in-bowel-habit-after-treatment/"},{"label":"Bowel Cancer UK: long term and late side effects","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/living-with-and-beyond-bowel-cancer/long-term-and-late-side-effects/"},{"label":"Bowel Cancer UK: body image and sex","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/living-with-and-beyond-bowel-cancer/body-image-and-sex/"},{"label":"Bowel Cancer UK: fertility","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/living-with-and-beyond-bowel-cancer/fertility/"},{"label":"Bowel Cancer UK: work, money and travel","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/living-with-and-beyond-bowel-cancer/work,-money-and-travel/"},{"label":"Bowel Cancer UK: sleep and fatigue","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/living-with-and-beyond-bowel-cancer/sleep-and-fatigue/"},{"label":"Bowel Cancer UK: diet after treatment","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/living-with-and-beyond-bowel-cancer/diet-after-treatment/"},{"label":"Bowel Cancer UK: questions to ask at your hospital appointment","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/diagnosis/questions-to-ask/"},{"label":"Bowel Cancer UK: prehabilitation, preparing for treatment","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/treatment/prehabilitation/"},{"label":"Bowel Cancer UK: clinical trials","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/treatment/clinical-trials/"},{"label":"Bowel Cancer UK: getting a second opinion","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/treatment/getting-a-second-opinion/"},{"label":"Bowel Cancer UK: end of life care","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/end-of-life-care/"},{"label":"Bowel Cancer UK: treating advanced bowel cancer","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/advanced-bowel-cancer/treating-advanced-bowel-cancer/"},{"label":"Bowel Cancer UK: Lynch syndrome","url":"https://www.bowelcanceruk.org.uk/campaigning/never-too-young/lynch-syndrome/"},{"label":"Bowel Cancer UK: supporting someone with bowel cancer","url":"https://www.bowelcanceruk.org.uk/about-bowel-cancer/living-with-and-beyond-bowel-cancer/emotional-wellbeing/supporting-someone-with-bowel-cancer/"},{"label":"Macmillan: bowel cancer (including rectal cancer and colon cancer)","url":"https://www.macmillan.org.uk/cancer-information-and-support/bowel-cancer"},{"label":"Macmillan: bowel changes after cancer treatment","url":"https://www.macmillan.org.uk/cancer-information-and-support/bowel-cancer/managing-bowel-changes-after-treatment"},{"label":"Macmillan: surgery for colon cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/surgery-to-remove-colon-cancer"},{"label":"Macmillan: surgery for rectal cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/surgery-to-remove-rectal-cancer"},{"label":"Macmillan: chemotherapy for bowel cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/chemotherapy-for-bowel-cancer"},{"label":"Macmillan: chemoradiation for rectal cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/chemoradiation-for-rectal-cancer"},{"label":"Macmillan: the multidisciplinary team for bowel cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/bowel-cancer/multidisciplinary-team-for-bowel-cancer"},{"label":"Macmillan: tests on the bowel cancer cells","url":"https://www.macmillan.org.uk/cancer-information-and-support/bowel-cancer/tests-on-the-bowel-cancer-cells"},{"label":"Macmillan: treatment for advanced bowel cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/bowel-cancer/treatment-for-advanced-bowel-cancer"},{"label":"Macmillan: sex life after bowel cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/sex-life-and-bowel-cancer"},{"label":"Cancer Research UK: living with bowel cancer","url":"https://www.cancerresearchuk.org/about-cancer/bowel-cancer/living-with"},{"label":"Cancer Research UK: bowel changes after treatment for bowel cancer","url":"https://www.cancerresearchuk.org/about-cancer/bowel-cancer/living-with/bowel-changes-after-treatment"},{"label":"Cancer Research UK: coping with a stoma","url":"https://www.cancerresearchuk.org/about-cancer/bowel-cancer/living-with/having-stoma"},{"label":"Cancer Research UK: eating and bowel cancer","url":"https://www.cancerresearchuk.org/about-cancer/bowel-cancer/living-with/eating"},{"label":"Cancer Research UK: your sex life and bowel cancer","url":"https://www.cancerresearchuk.org/about-cancer/bowel-cancer/living-with/sex-life"},{"label":"Cancer Research UK: coping with bowel cancer","url":"https://www.cancerresearchuk.org/about-cancer/bowel-cancer/living-with/coping"},{"label":"Colostomy UK: managing your colostomy","url":"https://www.colostomyuk.org/information/managing-your-colostomy/"},{"label":"Colostomy UK: diet","url":"https://www.colostomyuk.org/information/diet/"},{"label":"Colostomy UK: obtaining stoma prescription supplies","url":"https://www.colostomyuk.org/information/prescriptions/"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Marie Curie: what is palliative care?","url":"https://www.mariecurie.org.uk/information/getting-care/palliative-care"},{"label":"National Bowel Cancer Audit: State of the Nation 2025","url":"https://www.natcan.org.uk/reports/nboca-state-of-the-nation-report-2025/"},{"label":"Bowel Cancer UK","url":"https://www.bowelcanceruk.org.uk/"},{"label":"GLOBOCAN colon fact sheet (IARC Global Cancer Observatory, 2024 estimates)","url":"https://gco.iarc.who.int/media/globocan/factsheets/cancers/8-colon-fact-sheet.pdf"},{"label":"GLOBOCAN rectum fact sheet (IARC Global Cancer Observatory, 2024 estimates)","url":"https://gco.iarc.who.int/media/globocan/factsheets/cancers/9-rectum-fact-sheet.pdf"},{"label":"SEER Cancer Stat Facts: colorectal cancer (rates, stage distribution, survival by stage, age and race)","url":"https://seer.cancer.gov/statfacts/html/colorect.html"},{"label":"CRUK: bowel cancer statistics (incidence, mortality, survival, early diagnosis, treatment)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer"},{"label":"CRUK: bowel cancer incidence statistics","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer/incidence"},{"label":"CRUK: bowel cancer mortality statistics","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer/mortality"},{"label":"CRUK: bowel cancer survival statistics (professional)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer/survival"},{"label":"CRUK: bowel cancer risk factors (professional)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer/risk-factors"},{"label":"CRUK: TNM staging for bowel cancer","url":"https://www.cancerresearchuk.org/about-cancer/bowel-cancer/stages-types-and-grades/TNM-staging"},{"label":"CRUK: grades and types of bowel cancer","url":"https://www.cancerresearchuk.org/about-cancer/bowel-cancer/stages-types-and-grades/grades-and-types"},{"label":"CRUK: survival for bowel cancer (by stage, England 2016 to 2020)","url":"https://www.cancerresearchuk.org/about-cancer/bowel-cancer/survival"},{"label":"CRUK: symptoms of bowel cancer","url":"https://www.cancerresearchuk.org/about-cancer/bowel-cancer/symptoms"},{"label":"NHS: bowel cancer screening (the home test kit, ages 50 to 74)","url":"https://www.nhs.uk/tests-and-treatments/bowel-cancer-screening/"},{"label":"GOV.UK: NHS bowel cancer screening programme overview (target population and the screening test)","url":"https://www.gov.uk/guidance/bowel-cancer-screening-programme-overview"},{"label":"GOV.UK: bowel cancer screening programme standards, reporting from 1 April 2025 (uptake thresholds)","url":"https://www.gov.uk/government/publications/bowel-cancer-screening-programme-standards/bowel-cancer-screening-programme-standards-reporting-from-1-april-2025"},{"label":"NICE NG12: suspected cancer, recommendations by site (lower gastrointestinal tract 1.3.1 to 1.3.5)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"},{"label":"NICE HealthTech guidance: quantitative faecal immunochemical testing to guide colorectal cancer pathway referral in primary care","url":"https://www.nice.org.uk/guidance/dg56"},{"label":"US Preventive Services Task Force, JAMA 2021: screening for colorectal cancer (start at 45, grade B; 50 to 75, grade A)","url":"https://doi.org/10.1001/jama.2021.6238"},{"label":"Monahan, Gut 2020: BSG, ACPGBI and UKCGG guidelines for the management of hereditary colorectal cancer","url":"https://doi.org/10.1136/gutjnl-2019-319915"},{"label":"Colorectal cancer statistics, 2026 (American Cancer Society, CA: a Cancer Journal for Clinicians)","url":"https://doi.org/10.3322/caac.70067"},{"label":"Colorectal cancer statistics, 2023 (American Cancer Society, CA: a Cancer Journal for Clinicians)","url":"https://doi.org/10.3322/caac.21772"},{"label":"Siegel, Gut 2019: global patterns and trends in colorectal cancer incidence in young adults (36 countries)","url":"https://doi.org/10.1136/gutjnl-2019-319511"},{"label":"Mandel, N Engl J Med 1993: reducing mortality from colorectal cancer by screening for faecal occult blood (Minnesota, 46,551 people)","url":"https://doi.org/10.1056/nejm199305133281901"},{"label":"Atkin, Lancet 2017: UK Flexible Sigmoidoscopy Screening Trial, 17 years of follow-up (170,034 people)","url":"https://doi.org/10.1016/s0140-6736(17)30396-3"},{"label":"Bretthauer, N Engl J Med 2022: NordICC, effect of colonoscopy screening on risks of colorectal cancer and related death (84,585 people)","url":"https://doi.org/10.1056/nejmoa2208375"},{"label":"Br J Cancer 2022: interscreening interval and faecal immunochemical test threshold in the English bowel cancer screening programme (FIT pilot)","url":"https://doi.org/10.1038/s41416-022-01919-y"},{"label":"Vogelstein, N Engl J Med 1988: genetic alterations during colorectal tumour development (172 specimens)","url":"https://doi.org/10.1056/nejm198809013190901"},{"label":"Fearon and Vogelstein, Cell 1990: a genetic model for colorectal tumorigenesis","url":"https://doi.org/10.1016/0092-8674(90)90186-i"},{"label":"Bettington, Histopathology 2013: the serrated pathway to colorectal carcinoma, current concepts and challenges","url":"https://doi.org/10.1111/his.12055"},{"label":"Expert Rev Gastroenterol Hepatol 2025: the serrated pathway and colorectal cancer, what the gastroenterologist should know","url":"https://doi.org/10.1080/17474124.2025.2509797"},{"label":"Winawer, N Engl J Med 1993: prevention of colorectal cancer by colonoscopic polypectomy (National Polyp Study, 1,418 patients)","url":"https://doi.org/10.1056/nejm199312303292701"},{"label":"Zauber, N Engl J Med 2012: colonoscopic polypectomy and long-term prevention of colorectal cancer deaths (National Polyp Study, 2,602 patients)","url":"https://doi.org/10.1056/nejmoa1100370"},{"label":"Rutter, Gut 2020: BSG, ACPGBI and Public Health England post-polypectomy and post-resection surveillance guidelines","url":"https://doi.org/10.1136/gutjnl-2019-319858"},{"label":"ESGE Guideline update 2020: post-polypectomy colonoscopy surveillance","url":"https://doi.org/10.1055/a-1185-3109"},{"label":"Burn, Lancet 2020: CAPP2, cancer prevention with aspirin in Lynch syndrome, 10-year follow-up (861 patients randomised)","url":"https://doi.org/10.1016/s0140-6736(20)30366-4"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"Heald, Br J Surg 1982: the mesorectum in rectal cancer surgery, the clue to pelvic recurrence?","url":"https://doi.org/10.1002/bjs.1800691019"},{"label":"Quirke, Lancet 1986: local recurrence of rectal adenocarcinoma due to inadequate surgical resection (52 specimens sliced transversely)","url":"https://doi.org/10.1016/s0140-6736(86)92612-7"},{"label":"Nagtegaal and Quirke, J Clin Oncol 2008: what is the role for the circumferential margin in the modern treatment of rectal cancer? (more than 17,500 patients)","url":"https://doi.org/10.1200/jco.2007.12.7027"},{"label":"MERCURY Study Group, BMJ 2006: diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer (408 patients)","url":"https://doi.org/10.1136/bmj.38937.646400.55"},{"label":"Battersby, Ann Surg 2016: MERCURY II, prospective validation of a low rectal cancer magnetic resonance imaging staging system (279 patients)","url":"https://doi.org/10.1097/sla.0000000000001193"},{"label":"van der Valk, Lancet 2018: long-term outcomes of clinical complete responders in the International Watch and Wait Database (880 patients)","url":"https://doi.org/10.1016/s0140-6736(18)31078-x"},{"label":"Garcia-Aguilar, J Clin Oncol 2022: OPRA, organ preservation in rectal adenocarcinoma treated with total neoadjuvant therapy (324 patients)","url":"https://doi.org/10.1200/jco.22.00032"},{"label":"Verheij, J Clin Oncol 2024: long-term results of the OPRA trial (median follow-up 5.1 years)","url":"https://doi.org/10.1200/jco.23.01208"},{"label":"Nordlinger, Lancet 2008: EORTC 40983, perioperative FOLFOX4 and surgery versus surgery alone for resectable colorectal liver metastases (364 patients)","url":"https://doi.org/10.1016/s0140-6736(08)60455-9"},{"label":"Folprecht, Lancet Oncol 2010: CELIM, tumour response and secondary resectability of colorectal liver metastases with cetuximab (111 patients)","url":"https://doi.org/10.1016/s1470-2045(09)70330-4"},{"label":"Quenet, Lancet Oncol 2021: PRODIGE 7, cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases (265 patients)","url":"https://doi.org/10.1016/s1470-2045(20)30599-4"},{"label":"Morris, Br J Surg 2010: surgical management and outcomes of colorectal cancer liver metastases (England)","url":"https://doi.org/10.1002/bjs.7032"},{"label":"Hill, Br J Surg 2022: CReST, colorectal endoscopic stenting trial for obstructing left-sided colorectal cancer (245 patients)","url":"https://doi.org/10.1093/bjs/znac141"},{"label":"FOxTROT Collaborative Group, J Clin Oncol 2023: preoperative chemotherapy for operable colon cancer, mature results (699 patients allocated to preoperative chemotherapy, randomised 2:1)","url":"https://doi.org/10.1200/jco.22.00046"},{"label":"Win, Cancer Epidemiol Biomarkers Prev 2017: prevalence and penetrance of major genes and polygenes for colorectal cancer (5,744 families)","url":"https://doi.org/10.1158/1055-9965.epi-16-0693"},{"label":"Moller, Gut 2017: cancer incidence and survival in Lynch syndrome under surveillance, the Prospective Lynch Syndrome Database (1,942 carriers)","url":"https://doi.org/10.1136/gutjnl-2015-309675"},{"label":"Gastrointest Endosc Clin N Am 2022: endoscopic management and surgical considerations for familial adenomatous polyposis","url":"https://doi.org/10.1016/j.giec.2021.08.007"}],"tags":["gi","spike"],"related":["colorectal-cancer-alliance","msi-high","dmmr-ihc","braf-v600e","braf-class-ii-iii","kras-g12c","kras-g12d","her2-ish-amplified","her2-ihc-3-plus","tmb-high","ctdna-mrd-positive","ntrk-fusion","ret-fusion","pik3ca-hotspot-mutation","colorectal-roadmap","idea-crc-early-onset-cause-hunt","idea-crc-screening-uptake-and-age-extension","idea-crc-ctdna-de-escalation-beyond-stage-ii","idea-crc-organ-preservation-randomised-in-pmmr-rectal","idea-crc-mss-immunotherapy-by-biomarker-not-by-line","idea-crc-peritoneal-disease-found-early-and-treated-in-networks","idea-crc-exercise-as-a-funded-treatment","idea-crc-uk-colonoscopy-capacity-and-fit-threshold","idea-crc-uk-young-patient-referral-and-diagnostic-interval","colorectal-micropapillary-carcinoma","colorectal-adenoma-like-adenocarcinoma","lynch-associated-colorectal-cancer","fap-associated-colorectal-cancer","colon-cancer","rectal-cancer","colorectal-mucinous-adenocarcinoma","colorectal-signet-ring-cell-carcinoma","colorectal-medullary-carcinoma","colorectal-serrated-adenocarcinoma","early-onset-colorectal","anal","small-bowel","appendiceal"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","kras-inhibitors","mrd-testing","mced","hipec","thermal-ablation","probiotics-treatment-diarrhoea","hydrazine-sulfate","colorectal-screening","monoclonal-antibody","antiangiogenic","sbrt","germline-testing","exercise-oncology","palliative-care","palliative-radiotherapy","psycho-oncology","peer-support-groups","oncology-nutrition","prehabilitation","eras-perioperative-nutrition","survivorship-care-plan","cea-surveillance-colorectal","msi-mmr-testing","fertility-preservation","financial-navigation","multidisciplinary-tumour-board","cbt-fatigue-distress","exercise-during-chemotherapy","microwave-rf-ablation","oncology-pharmacogenomics","liquid-biopsy","histopathology-ihc","methylation-profiling","cgp","organoids","wes-wgs","rna-seq","tmb-testing","continuous-ctdna-monitoring","cytogenetics-fish","colonoscopy","endoscopy","cologuard","signatera","ngs","radiotherapy","imrt-igrt","adc","hipec-pipac-devices","endoscopic-resection","companion-diagnostic","ct","mri","aspirin-cancer-prevention"],"targets":["kras","braf","egfr","her2","pd1","vegf","ntrk","ctla4","tp53","apc","nras","pik3ca","smad4","fbxw7","mmr","pole","pold1","rnf43","rspo3","ctnnb1","amer1","sox9","arid1a","tgfbr2","b2m","tcf7l2","myc-gene","ret","alk","pten"],"drugs":["therascreen-cdx","tempus-xt-cdx","caris-mi-cancer-seek","oncodetect","ziv-aflibercept","catumaxomab","tegafur-gimeracil-oteracil","cetuximab","panitumumab","encorafenib","trastuzumab","lapatinib","pertuzumab","tucatinib","trastuzumab-deruxtecan","sotorasib","adagrasib","pembrolizumab","nivolumab","botensilimab","balstilimab","atezolizumab","signatera","guardant-reveal","foundationone-cdx","guardant360-cdx","trusight-oncology-comprehensive","ventana-mmr-rxdx","folfoxiri","avelumab","ramucirumab","vemurafenib","cobimetinib","mitomycin","larotrectinib","entrectinib","selpercatinib","dostarlimab"],"companies":["ambagon-therapeutics","mabwell-shanghai-bioscience","multitude-therapeutics","neonc-technologies","oncolytics-biotech","shanghai-kechow-pharma","shenzhen-ionova-life-sciences","mbrace-therapeutics","stcube","tiumbio","vyriad","pfizer","merck","bms","amgen","roche-genentech","takeda","servier","gsk","guardant-health","natera","exact-sciences","eli-lilly","bayer","alliance-oncology"],"institutions":["nki","mskcc","ncc-japan","johns-hopkins","bowel-cancer-uk","bowel-research-uk","leeds-cancer-centre","birmingham-cancer-centre","oxford-cancer","royal-marsden","beatson-glasgow","nottingham-cancer-centre","imperial-cancer-centre"],"pathways":["ras-mapk","wnt","colorectal-cancer-signalling","pi3k-akt-mtor","pd1-checkpoint","vegf-angiogenesis","p53-cell-cycle","tgf-beta","mismatch-repair-msi","replication-stress","chromosomal-instability","epigenetic-reprogramming","swi-snf-chromatin","myc","rtk-activation","antigen-presentation-immunoediting","immune-desert-exclusion","caf-activation-desmoplasia","tumor-microenvironment","clonal-evolution","field-cancerisation","mutagenesis-signatures","cancer-immunity-cycle"],"terms":["msi","sidedness","cms-subtypes","lynch-syndrome","fit-test","clinical-complete-response","mrd","ctdna","neoadjuvant-adjuvant","tumour-agnostic","stoma","colectomy","total-mesorectal-excision","total-neoadjuvant-therapy","organ-preservation","hepatectomy","peripheral-neuropathy","hand-foot-syndrome","rash-skin-toxicity","neutropenia","febrile-neutropenia","mucositis","cancer-related-fatigue","late-effects","financial-toxicity","performance-status","curative-intent","mss-pmmr","mlh1-promoter-methylation","malnutrition-screening","nutrition-impact-symptoms","liver-directed-therapy","colonoscopy","pole-ultramutation","tmb","cfdna","ngs","ihc","fish","wild-type","driver-mutation","germline-vs-somatic","hereditary-cancer-syndromes","neoantigen","cold-vs-hot","immune-exclusion","mutational-signature","somatic-mutations-wxs-wgs","tumour-informed-assay","copy-number-variation-term","gene-fusion","gene-amplification","kras-mutation-subtypes","vus","mmr","chemoradiation","complete-response","colorectal-trials-open-today","colorectal-palliation-obstruction-pain","colorectal-failed-programmes","colorectal-uk-drug-access","cancer-drugs-fund","debulking","radiofrequency-ablation","oligometastatic","adenoma-carcinoma-sequence","serrated-pathway","colorectal-polyp-types","bowel-cancer-screening-uk","colonoscopy-surveillance-intervals","watch-and-wait-rectal-cancer","circumferential-resection-margin","obstructing-colorectal-cancer","liver-limited-metastatic-colorectal","conversion-therapy-colorectal","colorectal-peritoneal-metastases","adenoma-detection-rate","interval-cancer","screening-uptake","faecal-occult-blood-test","cytoreductive-surgery","peritoneal-carcinomatosis-index","colibactin","extended-ras-testing","anti-egfr-rechallenge","cimp","immunoscore","heracles-criteria","rspo-fusion","low-anterior-resection-syndrome","living-with-a-stoma-bowel-cancer","chemotherapy-side-effects-colorectal","urgent-help-bowel-cancer","lynch-syndrome-testing-uk","sex-fertility-after-bowel-cancer","work-and-money-bowel-cancer-uk","carers-bowel-cancer-uk","emergency-presentation","tnm-staging","tumour-grade","peritoneal-metastasis","stage-shift"],"trials":["nordicc","symbiotic-gi-03","nct07525206","nct06614192","nct06997497","nct06686576","nct05141721","nct05945901","nct03659448","proceade-crc-03","nct07284849","cao-aro-aio-94","rapido","nct06199973","nct04854668","nct07221357","nct07775287","nct07219238","nct07228832","nct07412613","nct05425940","nct06252649","nct04547166","nct07462143","nct07454720","nct07722494","nct06497985","nct07702032","nct07361003","nct04793958","nct07676162","nct05890742","nct05709249","nct06951503","nct06662786","nct07669454","nct06750094","mountaineer","nct07669519","nct05855200","nct05239741","nct06968221","quasar","scot","cr07","coin","foxtrot","mercury","star-trec","nottingham-fob","ukfss","heracles","crystal-fire3","circulate-japan","prodige-23","opra","mosaic","idea-collaboration","tosca","petacc-8","n0147","dutch-tme-trial","stockholm-iii","stellar-rectal","cao-aro-aio-12","iwwd","avf2107g","prime","opus","calgb-80405","tribe","tribe2","velour","raise","correct","concur","recourse","fresco","cairo3","cairo5","swog-s1406","destiny-crc01","mountaineer-03","imblaze370","eortc-40983","new-epoc","clocc","prodige-7","colopec","prophylochip","dynamic-iii","altair","chronos","cave","swedish-rectal-cancer-trial","minnesota-fob","funen-fob","national-polyp-study","netherlands-hipec","checkmate-142","co-17","petacc-3","triumph"],"people":["chadwick-boseman","angelita-habr-gama","michael-bretthauer","aimery-de-gramont","david-sebag-montefiore","matt-seymour","dion-morton","john-burn","rachel-kerr","tim-maughan","naureen-starling","ian-chau"],"bottlenecks":["b-early-detection","b-prevention-adoption","b-immunotherapy-response","b-dormancy-mrd","b-workforce","b-care-fragmentation","b-survivorship"],"keyPapers":["paper-capp2-aspirin-lynch-lancet-2020","paper-lynch-frameshift-vaccine-ccr-2020","paper-lengauer-genetic-instability-colorectal-nature-1997","paper-markowitz-tgfbr2-inactivation-msi-colon-science-1995","paper-tcga-colorectal-comprehensive-characterization-nature-2012","paper-seshagiri-rspo-fusions-colon-nature-2012","paper-giannakis-genomic-correlates-immune-colorectal-cell-rep-2016","paper-yaeger-metastatic-colorectal-genomic-landscape-cancer-cell-2018","paper-grasso-immune-evasion-colorectal-cancer-discov-2018","paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998","paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006","paper-ligtenberg-epcam-deletion-msh2-silencing-nat-genet-2009","paper-moreira-lynch-syndrome-identification-jama-2012","paper-koopman-deficient-mismatch-repair-advanced-colorectal-bjc-2009","paper-venderbosch-mmr-braf-metastatic-colorectal-pooled-ccr-2014","paper-palles-germline-pole-pold1-proofreading-nat-genet-2013","paper-domingo-somatic-pole-proofreading-colorectal-lancet-gastro-2016","paper-bettington-serrated-pathway-colorectal-histopathology-2013","paper-crockett-nagtegaal-serrated-neoplasia-gastroenterology-2019","paper-lee-six-somatic-mutation-normal-colorectal-crypts-nature-2019","paper-isella-stromal-contribution-colorectal-transcriptome-nat-genet-2015","paper-calon-stromal-gene-expression-poor-prognosis-colorectal-nat-genet-2015","paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018","paper-lenz-cms-calgb-swog-80405-jco-2019","paper-missiaglia-distal-proximal-colon-cancers-ann-oncol-2014","paper-tejpar-tumour-location-crystal-fire3-jama-oncol-2017","paper-loree-tumour-location-continuum-colorectal-ccr-2018","paper-karapetis-kras-cetuximab-colorectal-nejm-2008","paper-jones-non-v600-braf-colorectal-jco-2017","paper-schirripa-kras-g12c-metastatic-colorectal-clin-colorectal-cancer-2020","paper-misale-kras-acquired-resistance-anti-egfr-colorectal-nature-2012","paper-diaz-molecular-evolution-egfr-resistance-colorectal-nature-2012","paper-bertotti-xenopatients-her2-cetuximab-resistant-colorectal-cancer-discov-2011","paper-valtorta-her2-scoring-colorectal-heracles-mod-pathol-2015","paper-richman-her2-amplification-quasar-focus-piccolo-j-pathol-2016","paper-nakamura-triumph-ctdna-pertuzumab-trastuzumab-her2-colorectal-nat-med-2021","paper-overman-checkmate-142-nivolumab-dmmr-colorectal-lancet-oncol-2017","paper-eng-imblaze370-atezolizumab-cobimetinib-colorectal-lancet-oncol-2019","paper-mlecnik-immunoscore-msi-colorectal-immunity-2016","paper-pages-immunoscore-international-validation-lancet-2018","paper-reinert-ctdna-ultradeep-sequencing-colorectal-jama-oncol-2019","paper-henriksen-ctdna-stage-iii-colorectal-improve-it-ccr-2022","paper-sepulveda-molecular-biomarkers-colorectal-guideline-jco-2017","paper-fearon-cell","paper-cms-guinney-nat-med-2015","paper-keynote-177-nejm-2020","paper-niche-2-nejm-2024","paper-cercek-dostarlimab-rectal-nejm-2022","paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019","paper-breakwater-nejm-2025","paper-krystal-1-crc-yaeger-nejm-2023","paper-codebreak-300-nejm-2023","paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023","paper-destiny-crc02-lancet-oncol-2024","paper-paradigm-jama-2023","paper-dynamic-nejm-2022","paper-galaxy-signatera-nat-med-2023","paper-le-mmr-deficiency-pd1-nejm-2015","paper-le-mmr-deficiency-science-2017","paper-galon-immune-contexture-colorectal-science-2006"],"journals":["clinical-colorectal-cancer","journal-of-gastrointestinal-cancer"],"dependsOn":[],"notes":["Living with bowel cancer, care and decisions: This is orientation from public patient pages and guidelines, not advice for your case: your own team's instructions and 24-hour number come first. The ten decision rows above, the question sets for the surgeon, oncologist, stoma nurse, genomics and palliative care appointments, the first 60 days checklist and the red cards were written from NICE NG151 and the NHS, Bowel Cancer UK, Macmillan, Cancer Research UK, Colostomy UK, Maggie's and Marie Curie patient pages, all read on 24 September 2026.","The science in detail, 1 of 7, in full; the one-sentence version is on the overview. Genomic landscape. WNT signalling is altered in 93% of tumours in the TCGA analysis and 96% once intronic APC splice events and large in-frame CTNNB1 deletions are counted: APC mutated in 58 to 77% by cohort, with RNF43 5 to 12%, CTNNB1 5 to 7%, AMER1 6 to 13%, TCF7L2 7 to 15% and RSPO2 or RSPO3 fusions covering most of the APC-wild-type remainder. TP53 52 to 73%, KRAS 40 to 44%, PIK3CA 20 to 28%, FBXW7 13 to 17%, SMAD4 12 to 16%, ARID1A 9 to 13%, SOX9 10 to 12%, NRAS 4 to 9%, BRAF V600E 6 to 18%, B2M 3 to 7%, ERBB2 amplification 2 to 3% and mutation 4 to 6%, MYC amplification 4 to 5%, IGF2 amplification about 2%, and fusions of NTRK, RET and ALK each at or below 0.3%. Every figure and its cohort is in the molecular table; the cBioPortal rows were computed on the TCGA PanCancer Atlas and 2012 deposits, the DFCI prospective exome cohort, the Genentech discovery set, two MSK-IMPACT cohorts (1,134 and 7,237 samples), the MSK early-onset comparison and the Chinese ChangKang project.","The science in detail, 2 of 7, in full; the one-sentence version is on the overview. Two instability classes. About 16% of colorectal cancers are hypermutated: three-quarters through mismatch repair failure, usually sporadic MLH1 promoter silencing, and one-quarter through somatic mismatch repair gene or POLE mutation. The other 84% are chromosomally unstable, with a persistent segregation defect running above 10^-2 chromosome gains or losses per division and the characteristic 18q, 17p and 8p losses and 8q, 13q and 20q gains. The two classes are near-exclusive, which is why SMAD4 and TP53 loss are rare in MSI-high tumours and why coding-microsatellite frameshift targets (TGFBR2 38.6% against 1.8%, RNF43 63.8% against 3.7%, ARID1A 65.2% against 6.3%, B2M 31.0% against 1.5%) are almost confined to them. Median tumour mutational burden separates three regimes: 5.7 per megabase microsatellite stable, 56.9 MSI-high and 172.1 in POLE exonuclease hotspot tumours.","The science in detail, 3 of 7, in full; the one-sentence version is on the overview. Sidedness as biology. In the 3,483 MSK-IMPACT samples with a named subsite, microsatellite instability was 24.3% on the right against 5.2% on the left, BRAF V600E 19.2% against 2.9%, KRAS 51.9% against 39.7%, PIK3CA 32.4% against 15.5%, APC 65.0% against 77.6% and TP53 56.7% against 79.2%. Right-sided microsatellite-stable tumours carry mitogenic pathway mutations; left-sided ones often carry none and depend on ligand instead, which is the mechanism behind the treatment rule. Across six randomised trials in 2,159 RAS wild-type patients, adding an EGFR antibody improved overall survival on the left (hazard ratio 0.75) and not on the right (1.12), interaction p less than 0.001, while right-sided disease was worse in every arm (overall survival hazard ratio 2.03 in the control arms). The caution is that the bowel is a gradient: RAS mutation falls from 70% at the caecum to 43% at the hepatic flexure, BRAF V600 rises from 10% to 22% across the same stretch, the sigmoid-rectal region is distinct from the rest of the left colon, and the transverse colon clusters with the left.","The science in detail, 4 of 7, in full; the one-sentence version is on the overview. Two routes in, plus two short cuts. The adenoma-carcinoma sequence runs APC, then KRAS, then 18q and SMAD4, then 17p and TP53, and is mostly left-sided; it starts before any visible lesion, since about 1% of normal crypts in middle age already carry a driver. The serrated pathway starts with BRAF V600E or KRAS in a hyperplastic polyp or sessile serrated lesion, proceeds by CpG island methylation rather than chromosome loss, accounts for about 30% of carcinomas, and is where sporadic mismatch repair deficiency comes from through MLH1 promoter silencing; serrated-class polyps are found in 20 to 40% of average-risk people and are the ones most often missed. Lynch syndrome is the inherited short cut, 3.1% of colorectal cancer probands, caused by a germline MLH1, MSH2, MSH6 or PMS2 variant or a 3' EPCAM deletion. Polymerase proofreading failure is the fourth route: 1.0% of cancers, ultramutated but microsatellite stable, with an excellent prognosis.","The science in detail, 5 of 7, in full; the one-sentence version is on the overview. Immunity. Mismatch repair deficient tumours carry a mean of 1,782 somatic mutations against 73 in proficient ones, and that is why they respond: 4 of 10 against 0 of 18 in the first pembrolizumab study, 31.1% with single-agent nivolumab in 74 previously treated patients, 16.5 against 8.2 months of progression-free survival with first-line pembrolizumab, and 68% pathological complete response after four weeks of neoadjuvant nivolumab plus ipilimumab. Microsatellite-stable disease has failed every unselected attempt, most clearly IMblaze370, where atezolizumab with or without a MEK inhibitor matched regorafenib in 363 patients. The mechanism is not only low mutation load: TGF-beta-activated stroma excludes T cells and its blockade makes mouse liver metastases checkpoint-sensitive, and tumour-cell WNT activation independently tracks the absence of T cells. Inside the responsive group, biallelic B2M and HLA loss is the documented escape route. Immunoscore, a digital CD3 and CD8 count, is prognostic across the whole disease independently of stage and microsatellite status (hazard ratio 0.20 high against low in 2,681 patients).","The science in detail, 6 of 7, in full; the one-sentence version is on the overview. Residual disease in blood. Tumour-informed circulating tumour DNA after resection gives recurrence hazard ratios of 7 to 18, after adjuvant chemotherapy 17 to 51, and during surveillance up to 43, with lead times over imaging of about 10 to 16 months; week-4 positivity in 1,039 prospectively followed patients carried a hazard ratio of 10 and 18-month disease-free survival of 38.4% against 90.5%. DYNAMIC randomised 455 patients and cut adjuvant chemotherapy use from 28% to 15% with two-year recurrence-free survival of 93.5% against 92.4%, the only randomised evidence in any solid tumour that a residual disease result can safely change treatment. What is missing is escalation evidence, and the false negatives are real: 16 of 164 ctDNA-negative stage II patients recurred. Plasma sequencing does two other jobs here, watching RAS-mutant clones emerge under EGFR blockade months before imaging, and selecting HER2-amplified patients as accurately as tissue.","The science in detail, 7 of 7, in full; the one-sentence version is on the overview. Testing, in practice. Mismatch repair immunohistochemistry (MLH1, MSH2, MSH6, PMS2) on every colorectal cancer, with MSI PCR where the stain is equivocal, and BRAF V600E or MLH1 promoter methylation as a reflex where MLH1 is lost; extended RAS across KRAS and NRAS exons 2, 3 and 4 before any EGFR antibody, because a codon 12 and 13 assay misses about one in six KRAS mutations and nearly all NRAS ones; BRAF reported as V600E or non-V600, since the two carry median survivals of 11.4 and 60.7 months and only V600E has a regimen; HER2 scored by the colorectal-specific rule of intense membranous staining in more than 50% of cells, which selects about 5% of RAS wild-type patients; and sequencing rather than staining where POLE ultramutation or an NTRK, RET, ALK or RSPO fusion is possible, since none of those is visible to immunohistochemistry. Primary tumour side belongs on the report alongside the genotype.","Frequencies marked cBioPortal were computed from the public API on 24 September 2026 on the sequenced sample lists of coadread_tcga_pan_can_atlas_2018 (534 sequenced of 594), coadread_tcga_pub (224 of 276), coadread_dfci_2016 (619), coadread_genentech (72), crc_msk_2017 (1,134), crc_msk_2026 (7,237), crc_eo_2020 (1,516) and crc_sysucc_2022 (1,015), as sample-level counts of non-synonymous mutation, high-level amplification, deep deletion or structural variant. They are not the papers' own percentages, which are quoted alongside.","Panel content decides what is seen. ACVR2A, BCL9L, RSPO2 and CDX2 read zero in the MSK-IMPACT cohorts because they are not on the panel, not because they are absent from the disease; RSPO3 fusions read 0.44% on a DNA panel against 10% for RSPO2 and RSPO3 together on transcriptome sequencing. Copy-number calls on 20q genes such as PTPRT and GNAS largely reflect the broad chromosome 20q gain of the chromosomally unstable class rather than focal amplification, and the ChangKang copy-number profile calls amplification much more liberally than the others, so its copy-number rows are not used here.","KRAS and BRAF allele shares are counts of mutation records over all mutation records for that gene in a study, so a tumour with two mutations in one gene counts twice. Study-level mutation rates also differ with cohort design: the prospective population cohort reads BRAF V600E at 17.9% and the metastatic referral cohorts at 7.5 to 7.9%, because sporadic right-sided BRAF-mutant disease is over-represented in resected series and under-represented in metastatic ones.","Is bowel cancer the same as colorectal cancer? Yes. Bowel cancer is the everyday British name for cancer of the large bowel, which doctors split into colon cancer and rectal cancer and together call colorectal cancer. Cancer of the small bowel and cancer of the anus are different diseases with their own pages. The colon and rectum are counted separately by the world registries and together by most UK and US statistics, which is why the same disease can be the 4th and the 8th commonest cancer in one paragraph and the 3rd in another.","How common is it? Worldwide, 1,206,011 colon cancers and 778,594 rectal cancers a year with 556,774 and 339,370 deaths (GLOBOCAN 2024), which is about 1.98 million cases and about 896,000 deaths added together. In the UK, 48,213 cases and about 17,700 deaths a year, the 4th commonest cancer and the 2nd commonest cause of cancer death (Cancer Research UK). In the United States, 158,850 cases and 55,230 deaths projected for 2026 (SEER). The lifetime risk in the UK is 1 in 20 for women and 1 in 17 for men.","Why do I keep reading that it is rising in young people when the overall numbers are falling? Both are true, in different age groups. In the United States, incidence fell 0.9 percent a year over 2013 to 2022 overall, but rose 3 percent a year in adults aged 20 to 49 while falling 2.5 percent a year in the over-65s (American Cancer Society, 2026). In the UK, incidence rates are down 3 percent in the last decade. The same divergence appears in 19 of 36 countries with registry data, and in nine of them rates rose in the young while stable or falling in older adults (Siegel 2019). No cause is established.","What raises the risk, and how much of it can I change? Cancer Research UK judges 54 percent of UK cases preventable. Eating too little fibre accounts for 28 percent, processed meat 13 percent, overweight and obesity 11 percent, smoking 7 percent, alcohol 6 percent, too little physical activity 5 percent and ionising radiation 2 percent. Type 2 diabetes raises risk 22 to 30 percent and inflammatory bowel disease 70 percent, with a 5 percent risk of cancer after 20 years of colitis. A first-degree relative with the disease more than doubles risk. Age is the largest factor and cannot be changed: 43 percent of UK cases are in people aged 75 and over.","Who is offered NHS bowel screening, and what does the test do? In England everyone aged 50 to 74 who is registered with a GP is sent a faecal immunochemical test kit through the post every two years; depending on when you turned 50 the first kit arrives at 50, 52 or 54. People aged 75 and over can ask for a kit every two years on the free helpline. The kit looks for blood in a single stool sample you collect at home and post back; results come in about two weeks. Most people are told no further tests are needed. If blood is found you are invited to see a specialist nurse and usually offered a colonoscopy; blood in the poo often turns out to be a fissure or a polyp rather than cancer (NHS; GOV.UK).","Does screening actually save lives? Yes, and it has been shown in randomised trials rather than inferred. Annual faecal occult blood testing cut 13-year colorectal cancer mortality by 33 percent in Minnesota (Mandel 1993). One flexible sigmoidoscopy offered at 55 to 64 cut incidence by 26 percent and mortality by 30 percent over 17 years, and by 35 and 41 percent among those who attended (Atkin 2017). NordICC, the first randomised trial of screening colonoscopy, cut the 10-year risk of colorectal cancer from 1.20 to 0.98 percent on an invitation basis in a trial where only 42 percent of invitees attended (Bretthauer 2022). Removing the polyps is what does most of the work.","My GP gave me a poo test rather than referring me. Is that right? It is what NICE asks for. NG12 (1.3.1) tells GPs to offer a quantitative faecal immunochemical test to people with a change in bowel habit, an abdominal mass, iron-deficiency anaemia and several combinations of bleeding, pain and weight loss by age, and to refer on the suspected cancer pathway at 10 micrograms of haemoglobin per gram of faeces or above (1.3.2). Below the threshold the GP should safety net you, and if clinical concern is strong the referral should not wait for the test (1.3.3). A rectal mass is referred without the test. If you were screened recently and have symptoms now, you should still be tested.","Why does rectal cancer get a magnetic resonance scan when colon cancer does not? Because the rectum sits in a narrow pelvis and the surgeon's plane of dissection runs within millimetres of the tumour. The scan measures how close the tumour comes to that plane, the mesorectal fascia, which becomes the circumferential resection margin in the specimen, and whether tumour has grown into the veins outside the bowel wall. Those two readings decide whether radiotherapy or chemoradiotherapy comes before surgery. In the MERCURY study of 408 patients, magnetic resonance imaging predicted a clear margin with 92 percent specificity, and 327 of the 349 it predicted clear were clear at operation.","What is watch and wait? In some people the rectal tumour disappears completely after chemoradiotherapy, leaving a flat white scar and a normal scan. Instead of removing the rectum, the team watches with regular examination, endoscopy and magnetic resonance imaging and operates only if the tumour comes back. In 880 such patients in the International Watch and Wait Database, 25.2 percent had a regrowth by two years, almost all of it in the bowel wall and 88 percent of it within two years, and five-year overall survival was 85 percent. In the OPRA trial about half of patients kept their rectum at five years. NICE (NG151 1.3.7) says to tell people who defer surgery that there is a risk of recurrence, that no marker predicts who is safe, and to record the outcome in a national registry.","My report says the circumferential resection margin is involved. What does that mean? It means tumour was found within 1 mm of the cut surface at the side of the removed rectum. It matters because that is where rectal cancer recurs: in the 52 specimens Quirke examined in 1986, 14 had tumour at the lateral margin and 12 of those recurred in the pelvis. In more than 17,500 patients reviewed in 2008, an involved margin predicted local recurrence, distant metastases and shorter survival, and its predictive power for local recurrence was higher after preoperative radiotherapy than without it. It usually leads to a discussion about more treatment, not to a conclusion about you.","What happens if the bowel blocks? Where a primary tumour is left in place in metastatic disease, around 20 in 100 people develop obstruction, perforation, bleeding or pain needing surgery (NICE NG151). For acute obstruction on the left side, NICE offers either a stent through the blockage followed by planned surgery a few weeks later, or emergency surgery, when cure is still the aim; for palliative treatment a stent is the option to consider. In the CReST trial, stenting relieved the obstruction in 82.4 percent and reduced the proportion of people left with a stoma from 67.9 to 47.5 percent, with no difference in 30-day mortality, length of stay, recurrence at three years or survival.","The cancer has spread to my liver. Is that the end? Not necessarily. Colorectal cancer that has spread only to the liver, and sometimes only to the lung, is treated with the aim of cure: resection or ablation of the metastases, sometimes at the same operation as the primary, with chemotherapy before and after (NICE NG151 1.5.15 to 1.5.19). In the EORTC 40983 trial, perioperative chemotherapy added about 9 percentage points to three-year progression-free survival in patients who had their liver metastases resected. Where the metastases are not removable at first, chemotherapy with an EGFR antibody raised the proportion that became operable from 32 to 60 percent in the CELIM trial. In England, around 45 percent of people whose liver metastases were operated on survived five years or more (Morris 2010).","What is the outlook? Averages hide a wide range and predate the newest drugs. In the United States 65.4 percent of people are alive at five years, which rises to 91.3 percent for the 34 percent found while the cancer is still confined to the bowel and falls to 16.9 percent for distant disease (SEER). In England, around 90 percent survive five years with stage 1, around 85 percent with stage 2, 65 percent with stage 3 and around 10 percent with stage 4, and almost 55 percent of everyone survives ten years (Cancer Research UK). Survival in the UK has more than doubled since the 1970s. These are population figures, not a personal prognosis."],"group":"gastrointestinal","burden":"1,206,011 new colon cancers and 556,774 deaths, plus 778,594 rectal cancers and 339,370 deaths, a year worldwide (GLOBOCAN 2024; about 1.98 million cases and 896,000 deaths added together). 48,213 UK cases and about 17,700 UK deaths a year, the 4th commonest cancer and the 2nd commonest cause of cancer death (Cancer Research UK); 158,850 US cases and 55,230 deaths projected for 2026 (SEER). Incidence is falling in the over-65s and rising 3 percent a year in adults aged 20 to 49 (American Cancer Society, 2026).","subtypes":["Chromosomal instability / APC-KRAS-TP53 pathway (~80%)","Mismatch-repair deficient / MSI-high (about 15% localised, about 5% metastatic)","Lynch syndrome (hereditary dMMR, ~3%)","BRAF V600E (8 to 10%, right-sided, aggressive; now has a first-line targeted triplet), plus non-V600 BRAF in 2 to 4%","KRAS-mutant (40 to 44%, with NRAS in a further 4 to 9%; G12D about 12%, G12V about 8%, G13D about 8%, G12C about 3%)","HER2-amplified (2 to 3% of all tumours, 5 to 8% of RAS and BRAF wild-type ones, left-sided)","Left-sided vs right-sided (embryologic origin drives biology)","Consensus molecular subtypes CMS1-4","Early-onset (<50 years)","Rectal vs colon (different local therapy)","Micropapillary adenocarcinoma of the colon and rectum (small tumour nests with reversed polarity; heavy lymphatic and vascular invasion)","Adenoma-like adenocarcinoma of the colon and rectum (invasive cancer that looks like an adenoma on biopsy; better outlook)","Lynch syndrome-associated colorectal cancer (inherited mismatch repair variant; about 1 to 4 percent of colon cancers)","Familial adenomatous polyposis-associated colorectal cancer (inherited APC variant; fewer than 1 percent of bowel cancers)"],"biomarkers":["RAS (KRAS and NRAS exons 2-4) for anti-EGFR eligibility","BRAF V600E","MMR/MSI status (universal testing at diagnosis)","HER2 amplification (IHC/ISH or NGS)","Primary tumour sidedness","NTRK fusions (rare)","POLE/POLD1 (ultramutated, IO-responsive)","ctDNA MRD after surgery (Signatera, Guardant Reveal)","CEA (monitoring)","UGT1A1*28 (irinotecan dosing) and DPYD (fluoropyrimidine toxicity)","Germline testing for Lynch when dMMR or young onset","APC inactivating mutation (wnt pathway gatekeeper): 58-77%","TP53 mutation (with 17p loss): 52-73%","KRAS activating mutation (any allele): 40-44%","KRAS G12D g12d allele (share of kras mutation records): 27-29%","KRAS G12V g12v allele (share of kras mutation records): 16-22%","KRAS G13D g13d allele (share of kras mutation records): 16-24%","KRAS G12C g12c allele (share of kras mutation records): 6-9%","KRAS outside exon 2 codon 59, 61, 117 or 146 mutation (share of kras missense records): 16-18%","NRAS activating mutation (codon 12, 13, 59, 61 or 117): 4-9%","BRAF V600E v600e mutation: 6-18%","BRAF non-V600 class ii and class iii mutations (d594, g466, g469, k601, n581) and fusions: 2-4%","PIK3CA hotspot mutation (e542k, e545k, h1047r): 20-28%","SMAD4 mutation or deep deletion (18q loss): 12-16%","FBXW7 inactivating mutation: 13-17%","ERBB2 (HER2) high-level amplification: 2-3%","ERBB2 mutation activating mutation (not amplification): 4-6%","MSI-high / dMMR microsatellite instability or mismatch repair deficiency: 5-15%","POLE exonuclease (proofreading) domain hotspot mutation, ultramutated tumours: 0.7-2%","POLD1 exonuclease domain hotspot mutation; germline p.ser478asn: 0.03%","Tumour mutational burden 10 or more mutations per megabase (panel): 15-19%","Chromosomal instability (CIN) aneuploidy with 18q, 17p and 8p loss and 8q, 13q and 20q gain: 84%","RNF43 inactivating mutation (g659fs hotspot): 5-12%","RSPO2 / RSPO3 gene fusion (ptprk-rspo3, eif3e-rspo2): 0.4-10%","CTNNB1 activating mutation or large in-frame deletion: 5-7%","AMER1 (FAM123B) inactivating mutation: 6-13%","SOX9 inactivating mutation: 10-12%","ARID1A inactivating mutation: 9-13%","TGFBR2 frameshift of the polyadenine coding microsatellite: 3-10%","B2M inactivating mutation or deletion (antigen presentation): 3-7%","TCF7L2 mutation or vti1a-tcf7l2 fusion: 7-15%","MYC high-level amplification (8q24): 4-5%","IGF2 high-level amplification with overexpression: 2%","EGFR high-level amplification (and acquired ectodomain mutation): 1-2%","NTRK1 / NTRK3 gene fusion (lmna-ntrk1, etv6-ntrk3): 0.2-0.3%","RET gene fusion (ncoa4-ret, ccdc6-ret): 0.1%","ALK gene fusion: 0.1%","PTEN inactivating mutation or deep deletion: 6-8%","BCL9L, RBM10, CTCF, KLF5 recurrently mutated genes found only in the large prospective exome cohort: 7%","Faecal haemoglobin by quantitative faecal immunochemical test: 10 micrograms per gram of faeces refers a symptomatic patient in England, 120 micrograms per gram calls a screened person for colonoscopy","Circumferential resection margin on rectal magnetic resonance imaging before surgery and on the specimen after it (1 mm rule)","Extramural venous invasion on rectal magnetic resonance imaging"],"standardOfCare":[{"setting":"The operation and what a stoma means: temporary or permanent","approach":"Removing the cancer with a rim of healthy bowel, and joining the two ends back together, is what cures most bowel cancer. The operation depends on where the tumour sits. Macmillan names the colon operations as a right or left hemi-colectomy, a sigmoid colectomy (also called a high anterior resection), a transverse colectomy or a total colectomy, and the rectal ones as a local excision for a very small stage 1 cancer, an anterior resection or low anterior resection for the upper or middle rectum, usually with a total mesorectal excision, and it says that if the cancer is very low in the rectum and close to the anus you are more likely to need a permanent stoma. NICE NG151 recommends laparoscopic (keyhole) resection as an alternative to open resection for both colon and rectal cancer when both are suitable, says to consider open surgery for locally advanced tumours or after previous abdominal or pelvic surgery, and to use robotic surgery only within established programmes with audited outcomes. It sets volume floors for rectal surgery: at least 10 major resections a year per hospital and at least 5 per surgeon. On the stoma, NICE asks teams to advise people of the likelihood of having one, why it might be necessary and for how long it might be needed, and to have a trained stoma professional provide information on care and on learning to live with it. Bowel Cancer UK puts it plainly: a reversible stoma is formed to let the join heal and a permanent one when the two ends cannot be joined, and the surgeon may not know for certain until the operation has started. A colostomy is formed from the large bowel and the output is more solid; an ileostomy is formed from the small bowel, the output is looser and more fluid and salt are lost. The NHS says recovery from a colostomy usually takes about 8 weeks, with no heavy lifting in that time, and that permanent colostomy supplies come free on prescription. Prehabilitation before the operation and an enhanced recovery programme after it are both worth asking about: NICE says to explain what recovery protocols involve and their value, and Bowel Cancer UK says prehabilitation reduces anxiety, improves fitness and can shorten the stay.","refs":["colectomy","total-mesorectal-excision","stoma","prehabilitation","eras-perioperative-nutrition"],"guideline":{"version":"NICE NG151 (2020, updated)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"}},{"setting":"Chemotherapy after surgery for stage 2 and stage 3, and how the benefit is worked out","approach":"Chemotherapy after the operation is given to kill cells that have already left the bowel but are too few to see, and the whole decision is about how large that risk is against what the treatment costs you. For stage 3 (cancer in the lymph nodes), NICE NG151 is explicit and the same for colon and for rectal cancer treated with short-course radiotherapy or no preoperative treatment: offer capecitabine with oxaliplatin (CAPOX) for 3 months, or if that is not suitable either oxaliplatin with fluorouracil and folinic acid (FOLFOX) for 3 to 6 months, or a single-agent fluoropyrimidine such as capecitabine for 6 months. It then says to base the choice on the person's histopathology (giving pT1 to T3 with pN1 against pT4 or pN2 as the example), performance status, personal preferences, comorbidities and age, which is the guideline's way of saying that three months of a doublet and six months of a single tablet are both defensible and the balance is yours to weigh. For stage 2 (no nodes involved) NICE NG151 makes no adjuvant recommendation at all, so the conversation runs on individual risk features, on the mismatch repair result, and increasingly on whether circulating tumour DNA is detectable after surgery; the ctDNA-guided studies on this record (DYNAMIC and the others) are where that question is being settled, and a trial is a reasonable answer. Two practical points NICE puts in writing: monitor prolonged sensory symptoms after platinum chemotherapy, because they are a sign the dose needs reducing to prevent permanent neuropathy, and a DPD blood test comes before fluorouracil or capecitabine because low DPD raises the risk of severe toxicity. The OnCo decision aid at /tools/colorectal-adjuvant-chemotherapy/ lays the NICE wording out by site, stage and fitness for oxaliplatin.","refs":["capox","folfox","capecitabine","oxaliplatin","ctdna","dynamic"],"guideline":{"version":"NICE NG151 (2020, updated)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"}},{"setting":"Rectal cancer: surgery or chemoradiotherapy first, and watch and wait if the tumour disappears","approach":"Rectal cancer is the part of bowel cancer where the order of treatment is a real choice. NICE NG151 says not to offer preoperative radiotherapy for early rectal cancer (cT1 to T2, cN0, M0) outside a clinical trial, and to offer preoperative radiotherapy or chemoradiotherapy where the cancer is cT1 to T2 with involved nodes, or cT3 to T4 with any node status. Two forms are used: a short course of radiotherapy on its own, and a longer course of radiotherapy given together with chemotherapy (Macmillan says the drug most commonly used is capecitabine tablets, started on the first morning of radiotherapy and taken throughout it, with a DPD test first), and in recent practice both are often followed by several months of chemotherapy before surgery (total neoadjuvant therapy, tested in RAPIDO, PRODIGE 23 and OPRA on this record; PROSPECT asked the opposite question, whether chemotherapy alone can replace radiotherapy in selected tumours). The reason this matters to a patient is that treatment before surgery shrinks the tumour, improves the chance of a clear margin, and in a minority makes the tumour disappear altogether on examination, MRI and endoscopy. NICE NG151 covers that case directly: inform people with a complete clinical and radiological response who wish to defer surgery that there is a risk of recurrence, and that there are no prognostic factors to guide selection for deferral; for those who choose to defer, encourage participation in a clinical trial and ensure data is collected via a national registry. Watch and wait is therefore not less treatment but a different commitment, to frequent examination and scans for years. For early rectal cancer NICE offers a shared decision between transanal excision, endoscopic submucosal dissection and total mesorectal excision, and gives a table comparing them on exactly the points a patient asks about: whether bowel is removed, whether a stoma is possible, hospital stay, scarring and the complications of each.","refs":["total-neoadjuvant-therapy","organ-preservation","total-mesorectal-excision","rapido","prodige-23","opra","prospect","cao-aro-aio-94"],"guideline":{"version":"NICE NG151 (2020, updated)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"}},{"setting":"Which first treatment when the cancer has spread, by RAS, BRAF, mismatch repair and which side of the bowel","approach":"When bowel cancer has spread, the first treatment is chosen by three test results and one piece of anatomy. NICE NG151 says to test for RAS and BRAF V600E mutations in all people with metastatic colorectal cancer suitable for systemic anticancer treatment, and separately recommends immunotherapy where the tumour is MSI-high or mismatch repair deficient. If RAS is wild-type, NICE recommends cetuximab or panitumumab with FOLFOX or FOLFIRI; if RAS is mutated, those antibodies do not work and bevacizumab with fluoropyrimidine-based chemotherapy is recommended where targeted treatment or immunotherapy is unsuitable. The anatomy is sidedness: cancers that start on the left (descending colon, sigmoid, rectum) respond better to the EGFR antibodies than cancers that start on the right, which is why the standard-of-care rows put anti-EGFR treatment with left-sided RAS wild-type disease and bevacizumab with right-sided or RAS-mutant disease (PARADIGM tested that question head to head; CRYSTAL and FIRE-3 are the older comparisons). BRAF V600E is its own group, with encorafenib and cetuximab added to chemotherapy (BREAKWATER). What this means at the appointment is that the first question is not which drug but which result, and that a treatment plan made before the molecular report is back may change. Two further decisions sit alongside: whether the primary tumour should be removed when it is causing no symptoms (NICE says consider it, and supplies a table of advantages and disadvantages to share), and when to take a break from oxaliplatin before the nerve damage becomes permanent.","refs":["folfox","folfiri","cetuximab","panitumumab","bevacizumab","encorafenib","paradigm","crystal-fire3","breakwater","msi","mss-pmmr","sidedness"],"guideline":{"version":"NICE NG151 (2020, updated)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"}},{"setting":"Surgery or ablation when the cancer has spread to the liver","approach":"Bowel cancer that has spread to the liver is one of the few settings in which surgery for metastatic disease is done with the intention of cure, and a meaningful number of people live many years after it. NICE NG151 says to consider resection, either simultaneous with the bowel operation or sequential, after discussion by a multidisciplinary team with expertise in resection of disease in all involved sites, and to consider perioperative systemic anticancer therapy where liver resection is a suitable treatment. Where the liver disease is not resectable, it says to consider chemotherapy with local ablative techniques after discussion by a specialist multidisciplinary team, and not to offer selective internal radiation therapy as first-line treatment for liver metastases unsuitable for local treatment except under the arrangements its HealthTech guidance sets out. The same logic extends to the lungs: consider metastasectomy, ablation or stereotactic body radiation therapy for lung metastases suitable for local treatment, after discussion by a team including a thoracic surgeon and a specialist in non-surgical ablation, and consider a biopsy for a single lung lesion to exclude a primary lung cancer. For disease limited to the peritoneum, NICE says to offer systemic therapy and, within the multidisciplinary team, to discuss referral to a nationally commissioned specialist centre to consider cytoreductive surgery with heated intraperitoneal chemotherapy. The practical consequence for a patient is that the answer to whether an operation is possible depends on which team is looking, so asking whether a specialist liver or peritoneal unit has seen the scans is a fair question, and a second opinion is a recognised step (Bowel Cancer UK has a page on it).","refs":["hepatectomy","thermal-ablation","microwave-rf-ablation","liver-directed-therapy","hipec","sabr-comet"],"guideline":{"version":"NICE NG151 (2020, updated)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"}},{"setting":"Immunotherapy when the tumour is mismatch repair deficient","approach":"A small minority of bowel cancers that have spread have lost the mismatch repair machinery that proof-reads DNA, which leaves the tumour carrying very many mutations and makes it visible to the immune system. For those people, immunotherapy has replaced chemotherapy as the first treatment. NICE NG151 recommends nivolumab with ipilimumab as an option for untreated unresectable or metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency, and pembrolizumab as an option for untreated metastatic disease with the same markers, stopped after 2 years or earlier if the disease progresses; after fluoropyrimidine-based combination chemotherapy it recommends nivolumab with ipilimumab, and pembrolizumab only if that combination cannot be used. KEYNOTE-177 and CheckMate 8HW are the trials behind those recommendations and are on this record. The same biology is being tested before surgery, where a few weeks of immunotherapy has cleared the tumour in a large fraction of mismatch repair deficient colon cancers (NICHE-2) and of rectal cancers (the dostarlimab work and the registrational AZUR-1), but outside those trials NICE does not recommend it, so the question at the clinic is whether a trial is open. Everything therefore turns on the test: ask whether mismatch repair immunohistochemistry or microsatellite instability testing has been done and what the result was, because a mismatch repair deficient result also starts the Lynch syndrome pathway for your family.","refs":["pembrolizumab","nivolumab","ipilimumab","keynote-177","checkmate-8hw","niche-2","azur-1","msi","msi-mmr-testing"],"guideline":{"version":"NICE NG151 (2020, updated)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"}},{"setting":"Later lines, when chemotherapy stops working","approach":"When the cancer grows through the first and second lines, there is still a recognised sequence, and knowing it in advance makes each step less sudden. NICE NG151 points to its appraisals for metastatic colorectal cancer previously treated with fluoropyrimidine-based chemotherapy, anti-VEGF or anti-EGFR therapy: trifluridine with tipiracil plus bevacizumab after 2 systemic treatments (the SUNLIGHT combination), fruquintinib after 2 systemic treatments if trifluridine with tipiracil plus bevacizumab is not suitable (FRESCO-2), regorafenib, and trifluridine with tipiracil alone. It also lists what is not recommended at this point, including aflibercept with irinotecan and fluorouracil after oxaliplatin, and cetuximab or panitumumab monotherapy after first-line chemotherapy. Where a rarer change is present the sequence changes: encorafenib with cetuximab for BRAF V600E after previous systemic treatment, larotrectinib through the Cancer Drugs Fund for NTRK fusion-positive tumours when there are no other satisfactory options, and the HER2 and KRAS G12C options on this record's other rows. These drugs are given to hold the cancer and protect quality of life rather than to cure, so the honest questions are what each is likely to buy, what it costs in side effects and hospital visits, how progression will be recognised, and what the stopping rule is. Bowel Cancer UK has pages on treating advanced bowel cancer and on taking a break from treatment; both are legitimate choices, and so is a trial.","refs":["trifluridine-tipiracil","bevacizumab","fruquintinib","regorafenib","sunlight","fresco-2"],"guideline":{"version":"NICE NG151 (2020, updated)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"}},{"setting":"Lynch syndrome testing, and what it means for your family","approach":"Around 3 in 100 UK bowel cancers are caused by Lynch syndrome, an inherited fault in one of the mismatch repair genes, and Bowel Cancer UK says testing should be offered to everyone at diagnosis because the result changes treatment as well as family risk. The route runs in order: the tumour is stained for the mismatch repair proteins (or tested for microsatellite instability); where MLH1 is lost, the laboratory checks for MLH1 promoter methylation, which usually means the loss is sporadic rather than inherited; and where the pattern still suggests an inherited cause, a germline blood test is offered through the genomics service. A positive result has three consequences. For you, immunotherapy becomes an option in advanced disease, and lifelong colonoscopy surveillance begins. For your relatives, each child, brother and sister has a one in two chance of carrying the same change, and Bowel Cancer UK says they should be offered the same test, which it calls cascade testing; it estimates that most of the 175,000 to 200,000 people in the UK with Lynch syndrome do not know. For prevention, NICE NG151 says to consider aspirin, taken daily and for a period of more than 2 years, to reduce the risk of colorectal cancer in people with Lynch syndrome, noting that in January 2020 this was an off-label use and that NICE has produced a patient decision aid to support the discussion. Bowel Cancer UK says surveillance means colonoscopy every 18 months to two years and can reduce the chance of dying from bowel cancer by as much as 72 percent.","refs":["lynch-syndrome","germline-testing","msi-mmr-testing","mlh1-promoter-methylation","colonoscopy","aspirin"],"guideline":{"version":"NICE NG151 (2020, updated)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"}},{"setting":"A clinical trial or standard treatment","approach":"At several points in bowel cancer a trial is a reasonable choice beside standard treatment rather than a last resort, and NICE NG151 says so itself in two places: preoperative radiotherapy for early rectal cancer should only happen within a clinical trial, and people who defer surgery after a complete response should be encouraged to take part in a trial with data collected via a national registry. The open questions this record follows are the ones a trial would answer for you: whether circulating tumour DNA after surgery should decide who has chemotherapy and for how long; whether immunotherapy before surgery can replace an operation in mismatch repair deficient colon and rectal cancer; whether the newer RAS inhibitors help the large majority whose tumours are RAS-mutant; and how to make immunotherapy work in microsatellite-stable disease, where it so far does not. Bowel Cancer UK says some trials test new treatments and others test new ways of using existing treatments, and that if you would like to take part you should ask your healthcare team whether you are suitable for any current trials in your area; the NHS says you can ask your doctor or a patient organisation about trials you may be eligible to join, and that you can choose to leave at any point without giving a reason and without it affecting the care you receive. Practical points worth settling before you agree: how many extra visits, scans or biopsies are involved, whether travel is reimbursed, whether the trial is open at another hospital if not here, and what the standard alternative would be if you decline.","refs":["focus4","azur-1","dynamic","multidisciplinary-tumour-board"],"guideline":{"version":"NICE NG151 (2020, updated)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"}},{"setting":"When to talk about palliative care","approach":"Palliative care is symptom control and support, and it is not a stage of the illness. Bowel Cancer UK says palliative care may start when you are diagnosed with advanced bowel cancer, or after treatment has stopped working, and that its aim is to improve quality of life; end of life care is a later part of the same service, usually in the last year of life. The NHS says that where bowel cancer cannot be cured you will be referred to a symptom control or palliative care team, who work with you to manage symptoms and help you and your loved ones get other support. A randomised trial in another cancer (Temel 2010) found that early palliative care alongside cancer treatment improved quality of life and mood, which is why the referral belongs alongside treatment rather than after it. In bowel cancer the concrete reasons are specific: pain from pelvic or liver disease, a bowel that is becoming obstructed, high stoma output and dehydration, poor appetite and weight loss, fatigue, low mood, sleep, and the practical questions about work, money and care at home. Bowel Cancer UK says you can choose where you would prefer to be cared for and where you wish to die, that care can be at home with the GP and community nurses, in a hospice (for a day or for a stay), in hospital or in a care home, and that your choices can be documented by your healthcare team and kept with your medical records so that the people close to you know them. Marie Curie sets out what palliative care covers and who provides it, and its support line and nurses are available to families as well as patients.","refs":["palliative-care","palliative-radiotherapy","psycho-oncology","curative-intent"],"guideline":{"version":"NICE NG151 (2020, updated)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"}},{"setting":"Stage I and low-risk stage II colon cancer","approach":"Resection with complete mesocolic excision and at least twelve lymph nodes examined; observation afterwards. Adjuvant chemotherapy is not given for stage I. In stage II the absolute gain from fluorouracil and folinic acid is small: QUASAR (3,239 patients, 2,963 with stage II disease) found a relative risk of death of 0.82 and of recurrence 0.78, translating to about 3.6 percent absolute survival. DYNAMIC showed that a negative circulating tumour DNA result four to seven weeks after surgery identifies patients who can safely have no chemotherapy, cutting adjuvant use from 27.9 to 15.3 percent without worse recurrence-free survival. Mismatch-repair deficient stage II disease gains nothing from fluorouracil alone and is observed.","refs":["quasar","dynamic","mrd-testing","msi","cea-surveillance-colorectal"],"guideline":{"nccn":"Category 1 (observation, stage I)","version":"NCCN Colon Cancer; NICE NG151","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"High-risk stage II colon cancer","approach":"Resection then a discussion about three to six months of a fluoropyrimidine with or without oxaliplatin, weighing T4 disease, obstruction or perforation, fewer than twelve nodes examined, lymphovascular or perineural invasion and poor differentiation against the neuropathy risk. SCOT included high-risk stage II patients and found three months of oxaliplatin-containing chemotherapy non-inferior to six (three-year disease-free survival 76.7 against 77.1 percent) with grade 2 or worse neuropathy halved. Mismatch-repair deficiency remains a reason not to give fluorouracil alone.","refs":["scot","quasar","folfox","capox","msi"],"guideline":{"version":"NCCN Colon Cancer; NICE NG151; ESMO","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Stage III colon cancer, mismatch-repair proficient","approach":"Resection then adjuvant oxaliplatin-fluoropyrimidine chemotherapy. MOSAIC established it (three-year disease-free survival 78.2 against 72.9 percent with fluorouracil alone, hazard ratio 0.77; six-year overall survival gain confined to stage III). Duration follows IDEA: three months of CAPOX for T1-3 N1 disease (three-year disease-free survival 83.1 against 83.3 percent for six months) and six months of FOLFOX or CAPOX for T4 or N2. Cetuximab must not be added: N0147 and PETACC-8 both found no benefit and more toxicity.","refs":["mosaic","idea-collaboration","scot","tosca","folfox","capox","n0147","petacc-8"],"guideline":{"nccn":"Category 1","version":"NCCN Colon Cancer; IDEA; NICE NG151","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Stage III colon cancer, mismatch-repair deficient","approach":"Resection then FOLFOX with atezolizumab for twelve months (ATOMIC, three-year disease-free survival 86 against 77 percent), the first adjuvant immunotherapy success in colorectal cancer. Neoadjuvant nivolumab with ipilimumab is the alternative under test: NICHE-2 produced a 68 percent pathological complete response rate and AZUR-2 (NCT05855200, 892 patients, primary completion March 2029) is the phase 3 that would make perioperative dostarlimab standard.","refs":["atomic","niche-2","nct05855200","atezolizumab","folfox","msi"],"guideline":{"version":"NCCN Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Locally advanced operable colon cancer: chemotherapy before surgery","approach":"Six weeks of preoperative oxaliplatin-fluoropyrimidine chemotherapy followed by surgery and eighteen weeks more is an option for radiologically staged T3 with deep invasion or T4 disease. FOxTROT (1,053 patients) found residual or recurrent disease within two years in 16.9 against 21.5 percent with surgery first (rate ratio 0.72), with fewer serious postoperative complications and 4.3 percent needing expedited surgery for obstruction. Panitumumab added nothing and mismatch-repair deficient tumours gained little, so they are better served by neoadjuvant immunotherapy in a trial.","refs":["foxtrot","folfox","capox","niche-2"],"guideline":{"version":"NCCN Colon Cancer; ESMO","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Locally advanced rectal cancer: radiotherapy and total neoadjuvant therapy","approach":"Total mesorectal excision is the operation (Dutch TME trial) and preoperative rather than postoperative radiotherapy is the sequence (CAO/ARO/AIO-94: five-year local relapse 6 against 13 percent, no survival difference). High-risk disease (cT4, extramural vascular invasion, cN2, threatened mesorectal fascia, lateral nodes) is treated with total neoadjuvant therapy: short-course 5 x 5 Gy then CAPOX or FOLFOX before surgery (RAPIDO: three-year disease-related treatment failure 23.7 against 30.4 percent, hazard ratio 0.75; STELLAR: three-year disease-free survival 64.5 against 62.3 percent) or long-course chemoradiotherapy with FOLFIRINOX before it (PRODIGE 23: three-year disease-free survival 76 against 69 percent, hazard ratio 0.69). Delaying surgery four to eight weeks after short-course radiotherapy is safe (Stockholm III). For sphincter-sparing candidates who do not need radiotherapy, PROSPECT showed neoadjuvant FOLFOX with selective chemoradiotherapy is non-inferior (five-year disease-free survival 80.8 against 78.6 percent).","refs":["dutch-tme-trial","cao-aro-aio-94","rapido","prodige-23","stellar-rectal","stockholm-iii","prospect","total-neoadjuvant-therapy","imrt-igrt","chemoradiation"],"guideline":{"nccn":"Category 1","version":"NCCN Rectal Cancer; NICE NG151; ESMO","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461"}},{"setting":"Rectal cancer: organ preservation and watch and wait","approach":"Consolidation chemotherapy after chemoradiotherapy, not induction before it, is the sequence that preserves the rectum: OPRA gave TME-free survival of 54 against 39 percent at five years (the long-term report, Journal of Clinical Oncology 2024; the first report gave 53 against 41 percent at three years), and CAO/ARO/AIO-12 found pathological complete response 25 against 17 percent with the same ordering. Patients with a clinical complete response on digital examination, endoscopy and MRI are offered watch and wait with endoscopy and MRI every three to four months. The International Watch & Wait Database (880 patients with a clinical complete response from 47 institutes) records two-year local regrowth of 25.2 percent, 88 percent of it within two years and 97 percent in the bowel wall where salvage surgery is possible, with five-year overall survival 85 percent and disease-specific survival 94 percent. In mismatch-repair deficient rectal cancer, dostarlimab for six months has produced complete clinical responses without surgery and AZUR-1 is the registrational trial.","refs":["opra","cao-aro-aio-12","iwwd","azur-1","dostarlimab","clinical-complete-response","organ-preservation"],"guideline":{"version":"NCCN Rectal Cancer; ESMO","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461"}},{"setting":"Metastatic disease, mismatch-repair deficient or MSI-high, first line","approach":"Immunotherapy, not chemotherapy: pembrolizumab (KEYNOTE-177) or nivolumab with ipilimumab (CheckMate 8HW). In England NICE TA709 recommends pembrolizumab stopped at two years and TA1065 recommends nivolumab with ipilimumab; TA914 places pembrolizumab after fluoropyrimidine therapy only where nivolumab with ipilimumab is unsuitable. The FDA approved nivolumab with ipilimumab for this indication on 8 April 2025. Universal mismatch-repair or MSI testing at diagnosis is what makes this route possible.","refs":["keynote-177","checkmate-8hw","pembrolizumab","nivolumab","ipilimumab","msi","colorectal-uk-drug-access"],"guideline":{"nccn":"Category 1","version":"NCCN Colon Cancer; NICE TA709, TA1065, TA914","url":"https://www.nice.org.uk/guidance/ta1065"}},{"setting":"Metastatic disease, RAS and BRAF wild-type, left-sided, first line","approach":"FOLFOX or FOLFIRI with panitumumab or cetuximab. PARADIGM showed panitumumab beats bevacizumab in left-sided RAS wild-type disease; FIRE-3 found overall survival 28.7 against 25.0 months for cetuximab against bevacizumab with FOLFIRI, while CALGB/SWOG 80405 found no overall difference (30.0 against 29.0 months) before sidedness was taken into account. Extended RAS testing of KRAS and NRAS exons 2, 3 and 4 is mandatory: PRIME showed patients with non-exon-2 RAS mutations do worse with panitumumab. In England TA439 funds cetuximab or panitumumab with FOLFOX or FOLFIRI first line only.","refs":["paradigm","crystal-fire3","calgb-80405","prime","opus","panitumumab","cetuximab","folfox","folfiri","sidedness","anti-egfr-left-sided"],"guideline":{"nccn":"Category 1","version":"NCCN Colon Cancer; NICE TA439","url":"https://www.nice.org.uk/guidance/ta439"}},{"setting":"Metastatic disease, RAS-mutant or right-sided, first line","approach":"FOLFOX, FOLFIRI or FOLFOXIRI with bevacizumab; EGFR antibodies are contraindicated. FOLFOXIRI plus bevacizumab gives a higher response rate and longer progression-free survival than a doublet (TRIBE: 12.1 against 9.7 months; TRIBE2 progression-free survival 2 of 19.2 against 16.4 months) at the cost of grade 3-4 neutropenia in about half, and is preferred where deep response matters. After six cycles, maintenance with a fluoropyrimidine and bevacizumab beats observation (CAIRO3: progression-free survival 2 of 11.7 against 8.5 months). In England bevacizumab is funded under TA1136 only when targeted treatment or immunotherapy is unsuitable.","refs":["tribe","tribe2","cairo3","avf2107g","folfoxiri","bevacizumab","sidedness"],"guideline":{"version":"NCCN Colon Cancer; NICE TA1136","url":"https://www.nice.org.uk/guidance/ta1136"}},{"setting":"Metastatic disease, BRAF V600E","approach":"First line encorafenib with cetuximab and mFOLFOX6 (BREAKWATER), which the FDA approved on 20 December 2024 and converted to traditional approval on 24 February 2026. After previous treatment, encorafenib with cetuximab (BEACON CRC), which NICE recommends in England under TA668. The mechanism was established by SWOG S1406: BRAF blockade alone fails because it releases feedback activation of EGFR, so the EGFR antibody is not optional. There is no NICE recommendation for the first-line triplet.","refs":["breakwater","beacon-crc","swog-s1406","encorafenib","cetuximab","folfox"],"guideline":{"version":"NCCN Colon Cancer; NICE TA668","url":"https://www.nice.org.uk/guidance/ta668"}},{"setting":"Metastatic disease, KRAS G12C","approach":"Sotorasib with panitumumab (CodeBreaK 300, FDA approval 16 January 2025) or adagrasib with cetuximab (KRYSTAL-1 colorectal cohort, accelerated approval 21 June 2024) after fluoropyrimidine, oxaliplatin and irinotecan. The confirmatory trials are KRYSTAL-10 (NCT04793958, 461 patients, active but closed) and, for first-line use, CodeBreaK 301 (NCT06252649, 450 patients, recruiting). Neither combination has a NICE recommendation, so they are not routinely funded in England.","refs":["codebreak-300","nct04793958","nct06252649","sotorasib","adagrasib","panitumumab","cetuximab","kras-inhibitors","kras-plus-egfr-crc"],"guideline":{"version":"NCCN Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Metastatic disease, HER2-amplified and RAS wild-type","approach":"Tucatinib with trastuzumab (MOUNTAINEER, confirmed objective response 38.1 percent; FDA accelerated approval 19 January 2023) or trastuzumab deruxtecan at 5.4 mg/kg (DESTINY-CRC02, response 37.8 percent; DESTINY-CRC01 gave 45.3 percent at the higher 6.4 mg/kg dose with interstitial lung disease in 6 percent and two deaths). The tumour-agnostic HER2 IHC 3+ accelerated approval of trastuzumab deruxtecan came on 5 April 2024. MOUNTAINEER-03 (NCT05253651, 400 patients, primary completion December 2027) is testing first-line use. No NICE recommendation exists for either regimen in colorectal cancer.","refs":["mountaineer","mountaineer-03","destiny-crc01","destiny-crc02","tucatinib","trastuzumab","trastuzumab-deruxtecan"],"guideline":{"version":"NCCN Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Metastatic disease, rarer biomarkers: NTRK, RET and POLE","approach":"NTRK fusions occur in well under 1 percent of colorectal cancers, almost always in right-sided, mismatch-repair deficient, RAS and BRAF wild-type tumours, and are treated with larotrectinib, which NICE recommends tumour-agnostically in England through the Cancer Drugs Fund only (TA630); entrectinib is no longer an option there, because TA644 has been withdrawn and its replacement TA1118 was terminated in January 2026. RET fusions are rarer still and are treated with selpercatinib under its tumour-agnostic approval. POLE or POLD1 exonuclease-domain mutations produce an ultramutated, immunotherapy-responsive tumour that is microsatellite-stable, so it is missed unless sequencing is done. All three are reasons to send comprehensive sequencing rather than a small hotspot panel in metastatic disease.","refs":["larotrectinib","entrectinib","selpercatinib","tumour-agnostic","companion-diagnostic"],"guideline":{"version":"NCCN Colon Cancer; NICE TA630, TA644","url":"https://www.nice.org.uk/guidance/ta630"}},{"setting":"Metastatic disease, later lines","approach":"Trifluridine-tipiracil with bevacizumab (SUNLIGHT: overall survival 10.8 against 7.5 months; FDA approval 2 August 2023; NICE TA1008), then fruquintinib (FRESCO-2: 7.4 against 4.8 months; FDA approval 8 November 2023; NICE TA1079 only where trifluridine-tipiracil with bevacizumab is unsuitable) or regorafenib (CORRECT: 6.4 against 5.0 months; NICE TA866). Second-line anti-angiogenic options after an oxaliplatin regimen are ziv-aflibercept (VELOUR: 13.50 against 12.06 months, not recommended by NICE in TA307) and ramucirumab (RAISE: 13.3 against 11.7 months, no NICE recommendation). Anti-EGFR rechallenge guided by circulating tumour DNA is promising and unproven in phase 3.","refs":["sunlight","fresco-2","correct","concur","recourse","fresco","velour","raise","trifluridine-tipiracil","fruquintinib","regorafenib","ziv-aflibercept","ramucirumab"],"guideline":{"version":"NCCN Colon Cancer; NICE TA1008, TA1079, TA866","url":"https://www.nice.org.uk/guidance/ta1008"}},{"setting":"Anti-EGFR resistance and rechallenge","approach":"Resistance to EGFR antibodies is universal and arises through RAS, BRAF and EGFR ectodomain mutant clones that expand under treatment and decay once it stops, which is why rechallenge is worth trying and why it must be selected by a blood test rather than by time alone. CHRONOS screened 52 patients with circulating tumour DNA, excluded the 31 percent with a resistance mutation and rechallenged the rest with panitumumab alone: 30 percent responded and 63 percent had disease control. CAVE rechallenged with cetuximab and avelumab and found median overall survival 17.3 months where baseline plasma RAS and BRAF were wild-type against 10.4 months where they were mutated (hazard ratio 0.49). Both trials are single-arm, so rechallenge is an option to consider in a trial or after discussion, not a standard.","refs":["chronos","cave","panitumumab","cetuximab","liquid-biopsy","ctdna"],"guideline":{"version":"NCCN Colon Cancer (anti-EGFR rechallenge listed as an option in selected patients)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Microsatellite-stable disease and immunotherapy","approach":"Ninety-five percent of metastatic colorectal cancers are microsatellite-stable and do not respond to PD-1 blockade; IMblaze370 confirmed that adding a MEK inhibitor does not change this (overall survival 8.87 against 8.51 months with regorafenib, hazard ratio 1.00). The most promising current approach is Fc-enhanced CTLA-4 blockade: botensilimab with balstilimab gave an objective response rate of 17 percent (17 of 101 response-evaluable patients among 148 treated) with disease control in 61 percent and median progression-free survival 3.5 months in the phase 1 (Bullock, Nature Medicine 2024), and 21 percent with median overall survival 21.2 months in the 123 patients of the later cohort selected for the absence of liver metastases (Clinical Cancer Research 2026). Both are single-arm. Liver metastases deplete tumour-specific CD8 T cells, which is the reason for the restriction and the reason results in unselected populations have been so poor.","refs":["imblaze370","nct05608044","botensilimab","balstilimab","cold-vs-hot","msi","idea-immunotherapy-mss-crc"],"guideline":{"version":"No approved regimen; trials only","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Liver-limited and oligometastatic disease","approach":"Resection with curative intent where all disease can be removed with an adequate remnant; perioperative FOLFOX is the reference, although EORTC 40983 found the progression-free survival gain did not become a survival gain at 8.5 years (61.3 against 54.3 months, hazard ratio 0.88). Thermal ablation is the only local treatment with randomised survival evidence: CLOCC gave eight-year overall survival of 35.9 against 8.9 percent when radiofrequency ablation was added to systemic treatment. For initially unresectable liver metastases, CAIRO5 chose FOLFOXIRI with bevacizumab for right-sided or RAS/BRAF-mutant tumours and found panitumumab no better than bevacizumab for left-sided wild-type tumours, with resectability reviewed by a surgical panel every two months. Cetuximab must not be added around liver resection: New EPOC found median overall survival 55.4 against 81.0 months with it.","refs":["eortc-40983","clocc","cairo5","new-epoc","hepatectomy","thermal-ablation","sbrt","oligometastatic","robotic-surgery"],"guideline":{"version":"NCCN Colon Cancer; ESMO","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Peritoneal metastases","approach":"Complete cytoreductive surgery in selected patients with a Peritoneal Cancer Index of 25 or less gives a median overall survival above three years, but adding heated intraperitoneal oxaliplatin does not: PRODIGE 7 found 41.7 against 41.2 months with more late grade 3 or worse complications. HIPEC also failed as prophylaxis in T4 or perforated colon cancer (COLOPEC) and as systematic second-look surgery (PROPHYLOCHIP). Selection for surgery, and systemic chemotherapy, are what change the outcome; other agents and delivery methods, including pressurised intraperitoneal aerosol chemotherapy, remain investigational.","refs":["prodige-7","colopec","prophylochip","hipec","debulking","colorectal-failed-programmes"],"guideline":{"version":"NCCN Colon Cancer; ESMO","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Circulating tumour DNA after surgery","approach":"A tumour-informed assay four to seven weeks after resection is the strongest single predictor of recurrence: GALAXY within CIRCULATE-Japan and DYNAMIC-III both show a large separation (DYNAMIC-III three-year recurrence-free survival 87 percent if negative against 49 percent if positive). De-escalation on a negative result is proven only in stage II (DYNAMIC, adjuvant chemotherapy use 15.3 against 27.9 percent with equal recurrence-free survival); in stage III, DYNAMIC-III could not show non-inferiority. Escalation on a positive result has failed twice: ALTAIR missed its disease-free survival endpoint (9.30 against 5.55 months, hazard ratio 0.79, p=0.107) and DYNAMIC-III's escalation arm gave no benefit. CIRCULATE-US (NRG-GI008) and TRACC are the trials still running.","refs":["dynamic","dynamic-iii","altair","circulate-japan","circulate-us","bespoke-crc","tracc","mrd-testing","mrd","ctdna"],"guideline":{"version":"NCCN Colon Cancer (ctDNA not yet recommended to guide therapy outside a trial)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"The failed and stopped programmes","approach":"Adjuvant cetuximab (N0147, PETACC-8) gave no benefit and more toxicity; cetuximab around liver resection shortened life (New EPOC, 55.4 against 81.0 months). Oxaliplatin HIPEC failed three times (PRODIGE 7, COLOPEC, PROPHYLOCHIP). Checkpoint inhibition with a MEK inhibitor failed in microsatellite-stable disease (IMblaze370, hazard ratio 1.00 against regorafenib). Treating molecular recurrence with late-line chemotherapy failed (ALTAIR). In access, NICE did not recommend ziv-aflibercept (TA307) despite a positive phase 3 trial.","refs":["colorectal-failed-programmes","n0147","petacc-8","new-epoc","prodige-7","colopec","prophylochip","imblaze370","altair"],"guideline":{"version":"NICE TA307","url":"https://www.nice.org.uk/guidance/ta307"}},{"setting":"UK access to treatments (NICE, September 2026)","approach":"Funded in England: cetuximab and panitumumab first line in RAS wild-type disease (TA439); pembrolizumab first line for MSI-high or dMMR disease (TA709) and after chemotherapy where nivolumab with ipilimumab is unsuitable (TA914); nivolumab with ipilimumab first line (TA1065) and after previous treatment (TA716); encorafenib with cetuximab after previous treatment in BRAF V600E disease (TA668); trifluridine-tipiracil (TA405) and with bevacizumab after two lines (TA1008); regorafenib (TA866); fruquintinib at third line or later where trifluridine-tipiracil with bevacizumab is unsuitable (TA1079); bevacizumab with fluoropyrimidine chemotherapy first and second line where targeted treatment or immunotherapy is unsuitable (TA1136); larotrectinib for NTRK fusions, through the Cancer Drugs Fund rather than routine commissioning (TA630). Withdrawn: entrectinib (TA644, replaced by the terminated TA1118). Not funded: ziv-aflibercept (TA307, not recommended), and, for want of any appraisal, tucatinib with trastuzumab, trastuzumab deruxtecan in colorectal cancer, sotorasib with panitumumab, adagrasib with cetuximab and first-line encorafenib with chemotherapy. The clinical guideline is NG151.","refs":["colorectal-uk-drug-access","cancer-drugs-fund"],"guideline":{"version":"NICE NG151 and the technology appraisals named","url":"https://www.nice.org.uk/guidance/ng151"}},{"setting":"Palliation: obstruction, stents and stomas","approach":"A self-expanding metal stent at colonoscopy relieves a left-sided obstruction within a day or two, either as a bridge to elective resection without a stoma or as definitive palliation; perforation, migration and re-obstruction are the risks and stenting is avoided during bevacizumab treatment. A defunctioning or end colostomy is preferred for right-sided or multi-level obstruction, peritoneal disease and a longer prognosis; right-sided obstruction is usually resected with primary anastomosis. Inoperable malignant bowel obstruction is managed medically with a syringe driver: an anti-emetic, hyoscine butylbromide or octreotide, dexamethasone and opioid analgesia, with a venting gastrostomy if vomiting persists.","refs":["colorectal-palliation-obstruction-pain","stoma","endoscopic-resection","palliative-care"],"guideline":{"version":"NICE NG151","url":"https://www.nice.org.uk/guidance/ng151"}},{"setting":"Palliation: liver capsule pain, pelvic symptoms and early palliative care","approach":"Liver capsule pain from bulky metastases is a position-dependent right upper quadrant pain that usually responds to dexamethasone and, when it does not, to a short course of palliative radiotherapy to the liver. Bleeding, discharge and pain from an unresectable rectal tumour respond to hypofractionated palliative radiotherapy; tenesmus is the hardest symptom and may need a nerve block or a stoma. Opioids are titrated with laxatives, and anaemia from chronic blood loss is treated with iron or transfusion. Early integrated palliative care alongside oncology from the diagnosis of incurable disease is recommended, and dietetic review matters where a stoma or short bowel follows surgery.","refs":["colorectal-palliation-obstruction-pain","palliative-radiotherapy","palliative-care","transfusion-support"],"guideline":{"version":"NICE NG151","url":"https://www.nice.org.uk/guidance/ng151"}},{"setting":"Diagnosis and staging (UK pathway)","approach":"Quantitative faecal immunochemical testing in primary care to decide referral; colonoscopy with biopsy, or computed tomography colonography where colonoscopy is not possible; computed tomography of chest, abdomen and pelvis for everyone and high-resolution pelvic magnetic resonance imaging for every rectal cancer; RAS and BRAF V600E testing in metastatic disease before systemic therapy; mismatch repair testing at diagnosis, which also finds Lynch syndrome; baseline carcinoembryonic antigen.","refs":["fit-test","colonoscopy","ct","mri","msi-mmr-testing","histopathology-ihc","circumferential-resection-margin","germline-testing","cea-surveillance-colorectal"],"guideline":{"version":"NICE NG151: colorectal cancer (published January 2020, last updated December 2021, last reviewed April 2026)","url":"https://www.nice.org.uk/guidance/ng151"}},{"setting":"Acute left-sided large bowel obstruction","approach":"Stenting for people being treated with palliative intent; either stenting or emergency surgery when potentially curative treatment is suitable. In CReST, stenting as a bridge to elective surgery relieved obstruction in 82.4 percent and cut stoma formation from 67.9 to 47.5 percent in patients treated with curative intent, with no difference in 30-day mortality, hospital stay, 3-year recurrence or survival.","refs":["obstructing-colorectal-cancer","endoscopy","colectomy"],"guideline":{"version":"NICE NG151: colorectal cancer (published January 2020, last updated December 2021, last reviewed April 2026)","url":"https://www.nice.org.uk/guidance/ng151"}},{"setting":"Prevention and chemoprevention","approach":"Remove adenomas at colonoscopy and put the person on a surveillance interval set by what was found; consider daily aspirin for more than two years in Lynch syndrome. Population screening from 50 in England and 45 in the United States. Diet, weight, alcohol, smoking and physical activity account for the 54 percent of UK cases Cancer Research UK judges preventable.","refs":["colonoscopy-surveillance-intervals","colorectal-polyp-types","aspirin-cancer-prevention","lynch-syndrome","colorectal-screening","exercise-oncology"],"guideline":{"version":"NICE NG151: colorectal cancer (published January 2020, last updated December 2021, last reviewed April 2026)","url":"https://www.nice.org.uk/guidance/ng151"}},{"setting":"Follow-up after potentially curative surgery","approach":"Follow up for detection of local recurrence and distant metastases for the first three years, including serum carcinoembryonic antigen and computed tomography of the chest, abdomen and pelvis; a clearance colonoscopy at one year and a surveillance colonoscopy three years after that.","refs":["cea-surveillance-colorectal","ct","colonoscopy","colonoscopy-surveillance-intervals"],"guideline":{"version":"NICE NG151: colorectal cancer (published January 2020, last updated December 2021, last reviewed April 2026)","url":"https://www.nice.org.uk/guidance/ng151"}},{"setting":"Referral when symptoms suggest bowel cancer","approach":"Offer a quantitative faecal immunochemical test to the symptom groups NICE lists and refer on the suspected cancer pathway at 10 micrograms of haemoglobin per gram of faeces or above; refer a rectal mass without testing first; safety net people who do not return a sample or test below the threshold, and do not let a low result delay referral where clinical concern is strong.","refs":["fit-test","bowel-cancer-screening-uk","emergency-presentation"],"guideline":{"version":"NICE NG12: suspected cancer, recognition and referral","url":"https://www.nice.org.uk/guidance/ng12"}}],"stateOfArt":["dMMR disease: immunotherapy first line gives median OS over 6 years (KEYNOTE-177); neoadjuvant IO achieves 68% pCR and 100% 3-year DFS in colon (NICHE-2) and complete organ preservation in rectal cancer (dostarlimab, AZUR-1).","BRAF V600E first-line targeted triplet doubled survival to 30 months (BREAKWATER); full approval in 2026.","Adjuvant atezolizumab for dMMR stage III colon cancer halves recurrence (ATOMIC, 2025): the first adjuvant IO success in CRC.","Sidedness plus RAS/BRAF status selects anti-EGFR therapy, yielding median OS near 38 months first line (PARADIGM).","ctDNA-guided de-escalation is proven (DYNAMIC); blood-based screening is FDA-approved (Shield, 2024) and Medicare-covered.","KRAS G12C and HER2 have approved targeted combinations; RAS(ON) inhibitors are entering phase 3 for the remaining KRAS alleles.","Genomic landscape. WNT signalling is on in 93 to 96% of tumours (APC mutated in 58 to 77%, with RNF43, AXIN2, CTNNB1 and RSPO fusions covering most of the rest); TP53 52 to 73%, KRAS 40 to 44%, PIK3CA 20 to 28%, SMAD4 12 to 16%, FBXW7 13 to 17%, NRAS 4 to 9%, BRAF V600E 6 to 18%, HER2 amplification 2 to 3%. Every figure and its cohort is in the molecular table; the full account is in the notes on the Data page.","Two instability classes. About 16% of tumours are hypermutated, three-quarters through mismatch repair failure and one-quarter through somatic mismatch repair or POLE mutation; the other 84% are chromosomally unstable, losing 18q, 17p and 8p and gaining 8q, 13q and 20q. The two are near-exclusive, which is why SMAD4 and TP53 loss are rare in MSI-high disease.","Sidedness is biology. Right-sided tumours are 24.3% MSI-high and 19.2% BRAF V600E against 5.2% and 2.9% on the left, and carry more KRAS and PIK3CA and less APC and TP53. EGFR antibodies improve survival on the left (hazard ratio 0.75) and not on the right (1.12) in RAS wild-type disease, the only place in colorectal oncology where anatomy selects a drug.","Two routes in. The adenoma-carcinoma sequence runs APC, KRAS, 18q, 17p and is mostly left-sided; the serrated pathway starts with BRAF or KRAS and proceeds by CpG island methylation, accounts for about 30% of carcinomas, and is where sporadic mismatch repair deficiency comes from, through MLH1 promoter silencing that accompanies BRAF mutation with an odds ratio of 203.","Immunity. Mismatch repair deficient tumours carry a mean of 1,782 mutations against 73 and respond to checkpoint blockade from 31% (nivolumab, pre-treated) to 68% pathological complete response (four weeks of neoadjuvant nivolumab plus ipilimumab); microsatellite-stable tumours do not, and the phase 3 test against regorafenib failed. T-cell exclusion there is driven by TGF-beta in the stroma and by WNT activation in the cancer cell.","Residual disease. Circulating tumour DNA after surgery carries recurrence hazard ratios of 7 to 18, and after adjuvant chemotherapy 17 to 51, with lead times over imaging of about 10 to 16 months. DYNAMIC is the only randomised trial in any solid tumour to change treatment on the result, cutting adjuvant chemotherapy from 28% to 15% in stage II colon cancer without losing recurrence-free survival.","Testing, in practice. Mismatch repair immunohistochemistry on every tumour (with BRAF V600E or MLH1 methylation reflex where MLH1 is lost), extended RAS across KRAS and NRAS exons 2, 3 and 4 before any EGFR antibody, BRAF V600 separately from non-V600, HER2 by the colorectal-specific more-than-50% rule, and sequencing rather than staining where POLE ultramutation or a fusion is possible."],"history":[{"year":1957,"title":"5-Fluorouracil synthesised","note":"Heidelberger; still the backbone of colorectal chemotherapy 70 years later.","refs":["cytotoxic-chemotherapy"]},{"year":1982,"title":"Total mesorectal excision described","note":"Heald found cancer deposits in the mesorectum several centimetres below the tumour and removed the whole envelope instead of cutting through it; the first 50 curative operations had no pelvic or staple-line recurrence at two years.","refs":["total-mesorectal-excision"]},{"year":1986,"title":"The circumferential resection margin explains local recurrence","note":"Quirke sliced 52 rectal specimens transversely: 14 had tumour at the lateral margin and 12 of those recurred locally, which redefined recurrence as a problem of surgery and pathology rather than of biology alone.","refs":["circumferential-resection-margin"]},{"year":1988,"title":"The genetic model of colorectal tumourigenesis","note":"Four alterations measured across 172 specimens accumulate in step with progression: ras in 58% of adenomas over 1 cm, 18q loss in 73% of carcinomas, 17p loss almost only in carcinomas.","refs":["paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988","apc","kras"]},{"year":1990,"title":"Adjuvant chemotherapy becomes standard for stage III; the Lynch genes are cloned","note":"Fluorouracil with levamisole improved survival after resection of node-positive colon cancer (1990); MSH2 and MLH1 were cloned in 1993. MOSAIC added oxaliplatin in 2004.","refs":["lynch-syndrome","fluorouracil"]},{"year":1993,"title":"Stool blood testing cuts bowel cancer deaths","note":"Nottingham (1996, 152,850 people, 15 percent reduction) and Funen (1996, 18 percent) follow the Minnesota result and build the case for national programmes.","refs":["paper-minnesota-fobt-nejm-1993","paper-hardcastle-nottingham-faecal-occult-blood-lancet-1996","paper-kronborg-funen-faecal-occult-blood-lancet-1996"]},{"year":1993,"title":"Polypectomy prevents cancer, and screening prevents death","note":"The National Polyp Study found 76 to 90 percent fewer cancers than expected in 1,418 patients whose adenomas were removed; in the same year the Minnesota trial showed annual faecal occult blood testing cut 13-year colorectal cancer mortality by 33 percent in 46,551 people.","refs":["adenoma-carcinoma-sequence","colonoscopy","colorectal-screening"]},{"year":1995,"title":"How a repair defect becomes a cancer","note":"TGFBR2, the growth brake, is destroyed by slippage in a short repeat in mismatch repair deficient colon cancer lines.","refs":["paper-markowitz-tgfbr2-inactivation-msi-colon-science-1995","tgfbr2"]},{"year":1997,"title":"Two kinds of instability","note":"Microsatellite-stable colorectal cancers gain or lose chromosomes above 10^-2 per chromosome per division, a dominant and continuing defect distinct from mismatch repair failure.","refs":["paper-lengauer-genetic-instability-colorectal-nature-1997"]},{"year":1997,"title":"Swedish Rectal Cancer Trial: radiotherapy before surgery","note":"1,168 patients; five-year local recurrence 11 versus 27 percent and overall survival 58 versus 48 percent, against surgery that was not standardised.","refs":["paper-swedish-rectal-cancer-trial-preoperative-radiotherapy-nejm-1997"]},{"year":1998,"title":"Sporadic mismatch repair deficiency is epigenetic","note":"MLH1 promoter hypermethylation explains most sporadic microsatellite-unstable cancers and is reversible in the laboratory.","refs":["paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998","mlh1"]},{"year":2000,"title":"Irinotecan and oxaliplatin combinations","note":"FOLFIRI and FOLFOX double median metastatic survival from ~12 to ~20 months.","refs":["folfox","folfiri"]},{"year":2001,"title":"Dutch TME trial separates local control from survival","note":"1,861 patients; two-year local recurrence 2.4 versus 8.2 percent with preoperative radiotherapy, two-year survival identical at 82.0 versus 81.8 percent.","refs":["paper-kapiteijn-dutch-tme-preoperative-radiotherapy-nejm-2001"]},{"year":2003,"title":"Cytoreduction with heated intraperitoneal chemotherapy for peritoneal disease","note":"Verwaal, 105 patients: median survival 22.3 versus 12.6 months, at 8 percent treatment-related mortality.","refs":["paper-verwaal-cytoreduction-hipec-peritoneal-colorectal-jco-2003","hipec"]},{"year":2004,"title":"Bevacizumab and cetuximab approved","note":"First anti-angiogenic and first anti-EGFR antibodies; MOSAIC establishes adjuvant FOLFOX.","refs":["bevacizumab","cetuximab","folfox"]},{"year":2006,"title":"CIMP defined, and tied to BRAF","note":"195 methylation markers across 295 tumours: CIMP-positive tumours are a distinct subset encompassing almost all BRAF-mutant cancers (odds ratio 203), and are where sporadic MLH1 silencing comes from.","refs":["paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006","braf"]},{"year":2006,"title":"MERCURY: magnetic resonance imaging predicts the surgical margin","note":"In 408 patients across 11 European units, high-resolution pelvic magnetic resonance imaging predicted a clear circumferential margin with 92 percent specificity, and the scan started deciding who needs treatment before surgery.","refs":["mri","circumferential-resection-margin"]},{"year":2007,"title":"QUASAR measures the stage II benefit","note":"3,239 patients, 91 percent node-negative: relative risk of death 0.82, an absolute survival gain of about 3.6 percent.","refs":["paper-quasar-adjuvant-chemotherapy-vs-observation-lancet-2007"]},{"year":2008,"title":"KRAS as a negative predictive biomarker","note":"Cetuximab improved survival only in K-ras wild-type tumours (9.5 against 4.8 months) and did nothing in mutant ones, creating the first negative predictive biomarker in solid tumours.","refs":["paper-karapetis-kras-cetuximab-colorectal-nejm-2008","kras"]},{"year":2009,"title":"EPCAM deletions as a cause of Lynch syndrome","note":"Loss of the 3' exons of EPCAM silences the neighbouring MSH2 gene by transcriptional read-through, in EpCAM-expressing tissue only.","refs":["paper-ligtenberg-epcam-deletion-msh2-silencing-nat-genet-2009","epcam"]},{"year":2009,"title":"MRC CR07 settles the timing of rectal radiotherapy","note":"1,350 patients; local recurrence 61 percent lower with short-course radiotherapy before surgery than with selective postoperative chemoradiotherapy, with no survival difference.","refs":["paper-sebag-montefiore-cr07-preoperative-radiotherapy-lancet-2009"]},{"year":2010,"title":"One flexible sigmoidoscopy, and the adenoma detection rate","note":"Atkin, 170,432 people: incidence down 23 percent and mortality 31 percent, still holding at 17 years. Kaminski: endoscopists finding adenomas in under 20 percent of people leave a roughly tenfold higher interval cancer risk.","refs":["paper-atkin-once-only-flexible-sigmoidoscopy-lancet-2010","paper-atkin-flexible-sigmoidoscopy-17-year-follow-up-lancet-2017","paper-kaminski-adenoma-detection-rate-interval-cancer-nejm-2010"]},{"year":2010,"title":"The serrated pathway is accepted as a second route to cancer","note":"Sessile serrated lesions and traditional serrated adenomas, with promoter methylation and BRAF or KRAS mutation, account for about 30 percent of colorectal carcinomas and for most sporadic mismatch repair-deficient tumours.","refs":["serrated-pathway","colorectal-polyp-types"]},{"year":2012,"title":"The molecular portrait, and a second way into WNT","note":"TCGA read 276 tumours on every platform, found 16% hypermutated and added ARID1A, SOX9 and FAM123B to the driver list; the same year, R-spondin fusions were found in 10% of colon tumours, mutually exclusive with APC mutation.","refs":["paper-tcga-colorectal-comprehensive-characterization-nature-2012","paper-seshagiri-rspo-fusions-colon-nature-2012","rspo3"]},{"year":2012,"title":"Resistance to EGFR antibodies is selection, not mutation","note":"KRAS-mutant clones emerge in plasma 5 to 6 months into panitumumab and are detectable up to 10 months before progression; modelling places them in the tumour before treatment.","refs":["paper-diaz-molecular-evolution-egfr-resistance-colorectal-nature-2012","paper-misale-kras-acquired-resistance-anti-egfr-colorectal-nature-2012"]},{"year":2012,"title":"Polypectomy prevents deaths, not just cancers","note":"National Polyp Study at 23 years: colorectal cancer mortality halved against the general population.","refs":["paper-zauber-national-polyp-study-colonoscopic-polypectomy-nejm-2012","paper-tcga-colorectal-comprehensive-characterization-nature-2012"]},{"year":2013,"title":"Extended RAS, and inherited proofreading failure","note":"A further 17% of KRAS exon 2 wild-type patients in PRIME carry another RAS mutation and gain nothing from panitumumab, which moved the label to all RAS; germline POLE and POLD1 proofreading variants are identified as a new predisposition syndrome.","refs":["paper-douillard-prime-panitumumab-ras-nejm-2013","paper-palles-germline-pole-pold1-proofreading-nat-genet-2013","pole"]},{"year":2013,"title":"The first refractory-line drug","note":"CORRECT: regorafenib gave 6.4 against 5.0 months after everything else had been used, the first drug approved for that setting.","refs":["paper-douillard-prime-panitumumab-ras-nejm-2013","paper-grothey-correct-regorafenib-lancet-2013"]},{"year":2015,"title":"Trifluridine/tipiracil approved for refractory disease","note":"RECOURSE established the oral combination after fluoropyrimidine, oxaliplatin, irinotecan and the antibodies had run out.","refs":["trifluridine-tipiracil","recourse"]},{"year":2015,"title":"Four consensus subtypes, and the discovery that the mesenchymal signal is stromal","note":"The consensus molecular subtypes reconcile six classifications across 4,151 samples; two papers published together show the mesenchymal signal comes from fibroblasts rather than cancer cells. The HER2 scoring criteria for colorectal cancer are validated the same year.","refs":["paper-cms-guinney-nat-med-2015","paper-isella-stromal-contribution-colorectal-transcriptome-nat-genet-2015","paper-calon-stromal-gene-expression-poor-prognosis-colorectal-nat-genet-2015","paper-valtorta-her2-scoring-colorectal-heracles-mod-pathol-2015"]},{"year":2015,"title":"Mismatch repair deficiency predicts response to PD-1 blockade","note":"Four of 10 deficient colorectal cancers responded to pembrolizumab and none of 18 proficient ones, with a mean of 1,782 against 73 mutations per tumour.","refs":["paper-le-mmr-deficiency-pd1-nejm-2015","msi-high"]},{"year":2016,"title":"Blood after surgery predicts relapse","note":"Circulating tumour DNA after resection of stage II colon cancer gave a recurrence hazard ratio of 18 in 230 patients, the measurement every later trial of residual disease is built on.","refs":["paper-tie-ctdna-minimal-residual-disease-stage-ii-colon-sci-transl-med-2016","paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016","ctdna-mrd-positive","her2-ish-amplified"]},{"year":2016,"title":"HER2 becomes a colorectal target","note":"HERACLES treated RAS wild-type patients with HER2 amplification using trastuzumab and lapatinib and got responses in 8 of 27.","refs":["paper-tie-ctdna-minimal-residual-disease-stage-ii-colon-sci-transl-med-2016","ctdna","mrd"]},{"year":2017,"title":"Pembrolizumab: first tumour-agnostic approval, dMMR","note":"Based on KEYNOTE-016/164 and others; dMMR CRC becomes the model immunotherapy-responsive GI tumour.","refs":["pembrolizumab","msi","tumour-agnostic"]},{"year":2017,"title":"Side becomes a treatment decision, and non-V600 BRAF a separate disease","note":"Across six randomised trials, EGFR antibodies helped left-sided RAS wild-type tumours (hazard ratio 0.75) and not right-sided ones (1.12); non-V600 BRAF mutations, 22% of all BRAF mutations, carry median survival of 60.7 months against 11.4. Universal molecular testing is codified in guideline form.","refs":["paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017","paper-tejpar-tumour-location-crystal-fire3-jama-oncol-2017","paper-jones-non-v600-braf-colorectal-jco-2017","paper-sepulveda-molecular-biomarkers-colorectal-guideline-jco-2017"]},{"year":2017,"title":"A single flexible sigmoidoscopy still protects 17 years later","note":"The UK Flexible Sigmoidoscopy Screening Trial, 170,034 people, reported a 26 percent lower incidence and a 30 percent lower mortality in those invited, and 35 and 41 percent lower in those who attended.","refs":["colorectal-screening","colonoscopy"]},{"year":2018,"title":"IDEA: 3 months of adjuvant CAPOX suffices for low-risk stage III","refs":["capox"]},{"year":2018,"title":"Why microsatellite-stable disease is cold","note":"Mice with all four main colorectal mutations reproduce human microsatellite-stable disease and answer checkpoint blockade only once TGF-beta is inhibited; across 1,211 tumours, WNT activation tracks the absence of T cells and MSI-high tumours have often deleted B2M and HLA.","refs":["paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018","paper-grasso-immune-evasion-colorectal-cancer-discov-2018","b2m"]},{"year":2018,"title":"The International Watch and Wait Database reports on 880 rectal cancers","note":"Among people with a complete clinical response after chemoradiotherapy who kept their rectum, local regrowth reached 25.2 percent at two years, almost all in the bowel wall and nearly all within two years; five-year overall survival was 85 percent.","refs":["watch-and-wait-rectal-cancer","clinical-complete-response"]},{"year":2019,"title":"The bowel lining is already mutated","note":"About 1% of morphologically normal colorectal crypts in middle age carry a probable driver mutation, so adenomas and cancers are the rare outcomes of a process happening everywhere.","refs":["paper-lee-six-somatic-mutation-normal-colorectal-crypts-nature-2019"]},{"year":2019,"title":"BEACON CRC gives BRAF V600E disease a targeted option","note":"665 patients; encorafenib with cetuximab and binimetinib 9.0 versus 5.4 months, the doublet 8.4 months.","refs":["paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019","beacon-crc"]},{"year":2019,"title":"England replaces the guaiac test with the faecal immunochemical test","note":"From June 2019 every screening invitation in England carries a faecal immunochemical test kit, read at a threshold of 120 micrograms of haemoglobin per gram of faeces; the programme now invites everyone aged 50 to 74 every two years.","refs":["fit-test","bowel-cancer-screening-uk"]},{"year":2020,"title":"KEYNOTE-177: chemotherapy-free first line for dMMR; BEACON: encorafenib + cetuximab for BRAF","refs":["keynote-177","encorafenib"]},{"year":2020,"title":"NICE NG151 and the UK surveillance guidelines","note":"One guideline for colorectal cancer from Lynch syndrome prevention to follow-up, alongside the BSG, ACPGBI and Public Health England rules that decide who gets a surveillance colonoscopy and when.","refs":["colonoscopy-surveillance-intervals","circumferential-resection-margin","obstructing-colorectal-cancer"]},{"year":2021,"title":"Total neoadjuvant therapy arrives in rectal cancer","note":"RAPIDO cuts three-year treatment failure from 30.4 to 23.7 percent; PRODIGE 23 raises three-year disease-free survival from 69 to 76 percent.","refs":["paper-bahadoer-rapido-short-course-radiotherapy-lancet-oncol-2021","paper-conroy-prodige-23-neoadjuvant-folfirinox-rectal-lancet-oncol-2021","paper-quenet-prodige-7-hipec-peritoneal-colorectal-lancet-oncol-2021"]},{"year":2021,"title":"PRODIGE 7 and the fall of hyperthermic intraperitoneal chemotherapy","note":"Adding oxaliplatin hyperthermic intraperitoneal chemotherapy to complete cytoreductive surgery changed nothing (median overall survival 41.7 against 41.2 months in 265 patients) and caused more late complications; in the same year the US task force lowered the screening start age to 45.","refs":["colorectal-peritoneal-metastases","hipec","colorectal-screening"]},{"year":2022,"title":"Dostarlimab: complete responses in every dMMR rectal cancer treated; PARADIGM","note":"Organ preservation without surgery in the first Memorial Sloan Kettering cohort (Cercek, NEJM); panitumumab beat bevacizumab in left-sided RAS wild-type disease.","refs":["dostarlimab","paradigm"]},{"year":2022,"title":"A blood test changes treatment","note":"DYNAMIC cut adjuvant chemotherapy use in resected stage II colon cancer from 28% to 15% with non-inferior two-year recurrence-free survival, the first randomised de-escalation on a ctDNA result in any solid tumour.","refs":["paper-dynamic-nejm-2022","paper-henriksen-ctdna-stage-iii-colorectal-improve-it-ccr-2022"]},{"year":2022,"title":"NordICC: the first randomised trial of screening colonoscopy","note":"84,585 people in Poland, Norway and Sweden; a single invitation cut the 10-year risk of colorectal cancer from 1.20 to 0.98 percent, with 455 invitations needed to prevent one cancer, in a trial where only 42 percent of those invited attended.","refs":["colorectal-screening","colonoscopy"]},{"year":2023,"title":"SUNLIGHT and FRESCO-2 expand late-line options; tucatinib + trastuzumab first HER2 regimen; NICHE-2 pCR 68%","refs":["sunlight","fresco-2","mountaineer","niche-2"]},{"year":2023,"title":"FOxTROT: chemotherapy before surgery for locally advanced colon cancer","note":"Six weeks of oxaliplatin and fluoropyrimidine before surgery, then 18 weeks after, left fewer patients with residual or recurrent disease at two years than 24 weeks after surgery alone; NICE NG151 now says to consider preoperative therapy for cT4 colon cancer.","refs":["folfox","capox"]},{"year":2024,"title":"Shield blood test approved for screening; BREAKWATER accelerated approval; CheckMate 8HW","refs":["shield","breakwater","checkmate-8hw"]},{"year":2024,"title":"The first real signal in microsatellite-stable disease","note":"An Fc-enhanced CTLA-4 antibody with a PD-1 antibody gave 17% responses and 61% disease control in 101 evaluable heavily pre-treated microsatellite-stable patients.","refs":["paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024"]},{"year":2025,"title":"ATOMIC: adjuvant atezolizumab for dMMR stage III; sotorasib + panitumumab approved; CHALLENGE exercise trial","refs":["atomic","codebreak-300","exercise-oncology"]},{"year":2026,"title":"BREAKWATER FOLFIRI cohort and full approval; AZUR-1 priority review; T-DXd and RAS(ON) inhibitors advance","refs":["breakwater","azur-1","daraxonrasib"]},{"year":2026,"title":"Incidence falls in the old and rises in the young","note":"The American Cancer Society reports colorectal cancer incidence rising 3 percent a year in adults aged 20 to 49 and 0.4 percent a year at 50 to 64, while falling 2.5 percent a year in the over-65s; rectal cancer is now 32 percent of cases, up from 27 percent in the mid-2000s.","refs":["early-onset-colorectal"]},{"year":2032,"title":"The ctDNA strategy trials complete","note":"CIRCULATE-US (NRG-GI008, 1,912 estimated participants) has a primary completion date of 10 March 2029 and the French CIRCULATE (1,980 estimated) of March 2032; NordICC's study completion, and the 15-year screening mortality answer, is listed for July 2036.","refs":["idea-crc-ctdna-de-escalation-beyond-stage-ii","nordicc","mrd-testing"]}],"pipeline":["daraxonrasib","autogene-cevumeran","signatera","pf-08634404","shr-8068","pm8002","telisotuzumab-adizutecan","oleclumab","calderasib","ak117","yl202","jdq443","ql1706","gotistobart","sitneprotafib","grt-c901","grt-r902","hr070803","sgm-101","precemtabart-tocentecan","inca33890","ibi363","vs-7375","mcla-129","ak119","xnw27011","tqb2922","abt-301","botensilimab","jk08","hdm2017","jyp0015","eik1005","onvansertib","ct3001","sotevtamab","jmt203","tst003","vb15010","azur-1","mountaineer","circulate-japan","zoldonrasib","checkmate-8hw","idea-ctdna-guided-adjuvant-crc","idea-immunotherapy-mss-crc","neoadjuvant-io-dmmr","colorectal-screening","trastuzumab-deruxtecan","divarasib","olomorasib","eli-002-7p","shield","idea-crc-early-onset-cause-hunt","idea-crc-screening-uptake-and-age-extension","idea-crc-ctdna-de-escalation-beyond-stage-ii","idea-crc-organ-preservation-randomised-in-pmmr-rectal","idea-crc-mss-immunotherapy-by-biomarker-not-by-line","idea-crc-peritoneal-disease-found-early-and-treated-in-networks","idea-crc-exercise-as-a-funded-treatment","idea-crc-uk-colonoscopy-capacity-and-fit-threshold","idea-crc-uk-young-patient-referral-and-diagnostic-interval","mountaineer-03","nct05855200","nct06252649","nct04793958","circulate-us","tracc","nct05608044","chronos","cave"],"openProblems":["Outcomes differ sharply by race, income and geography, and the gap survives adjustment for stage: five-year bowel cancer survival in England is 55 percent in the most deprived group against 62.9 percent in the least (Cancer Research UK), and emergency presentation, which carries the worst outlook, is concentrated in the same places.","Microsatellite-stable disease, 95% of metastatic colorectal cancer, has no working immunotherapy: the phase 3 test of atezolizumab with or without a MEK inhibitor matched regorafenib, and the best signal so far, botensilimab plus balstilimab, comes from single-arm cohorts (17% of 101 response-evaluable patients in the phase 1, Bullock 2024; 21% of 123 patients selected for the absence of liver metastases in the 2026 report). No randomised trial has yet selected patients by immune biology rather than by line of therapy.","The consensus molecular subtypes were predictive of which biological drug works in the one randomised analysis of them, yet the mesenchymal class is largely a measurement of stroma rather than of cancer cells, no assay is approved, and no prospective subtype-directed trial has been run.","KRAS G12D, the commonest colorectal KRAS allele at about 29% of KRAS mutations, and G13D at about 18%, have no approved inhibitor; the only targeted allele, G12C, is about 3% of cases and needs an EGFR antibody alongside it.","POLE-ultramutated tumours, 1% of cases and the most mutated in the disease, are invisible to the mismatch repair immunohistochemistry and MSI tests that every patient gets, so they are found only where sequencing is done.","Extended RAS testing is required before an EGFR antibody, yet an assay that reads only KRAS codons 12 and 13 still misses about one in six KRAS mutations and nearly all NRAS mutations, and the FDA companion diagnostic list still carries the old codon 12 and 13 definition for cetuximab beside the extended one for panitumumab, so two tumours called wild-type by two laboratories are not making the same claim.","Screening delivers the effect of its uptake, not of its test: 40.4 percent of the Nottingham screening group never returned a kit, and endoscopy capacity and the endoscopist's adenoma detection rate then decide what a positive test is worth.","Incidence in adults under 50 is rising by 1.6 to 7.9 percent a year across Europe and the United States, the stage shift screening bought is reversing (60 percent of United States cases advanced in 2019 against 52 percent in the mid-2000s), and the only mechanistic lead is a bacterial toxin signature enriched 3.3-fold in cancers diagnosed before 40.","Organ preservation for mismatch repair-proficient rectal cancer has never been randomised against surgery, and the bowel, urinary and sexual function that justifies it has never been a primary endpoint.","Circulating tumour DNA identifies who will relapse but has still not been shown to tell anyone what to do about it outside stage II colon cancer: DYNAMIC-III could not prove de-escalation non-inferior in stage III, its escalation arm gave no benefit, and ALTAIR's post-adjuvant trifluridine/tipiracil missed its endpoint while causing grade 3 or higher haematological toxicity in 73 percent. The negative result is not a safe one either: about one in ten circulating tumour DNA-negative stage II patients still recurs.","Peritoneal metastases have no systemic or regional treatment that adds to complete cytoreductive surgery: oxaliplatin HIPEC failed in PRODIGE 7 as treatment, in COLOPEC as prophylaxis and in PROPHYLOCHIP as second-look surgery, and no other intraperitoneal agent has randomised evidence.","Why adding cetuximab around resection of colorectal liver metastases shortened median survival from 81.0 to 55.4 months in New EPOC has never been explained, and until it is, the safety of any targeted drug in a curative pathway rests on assumption rather than mechanism.","The HER2 and KRAS G12C combinations approved in the United States on response rate alone have no confirmatory phase 3 result yet (MOUNTAINEER-03 completes December 2027, KRYSTAL-10 is closed but unreported, CodeBreaK 301 completes September 2028) and none is funded in England, so a patient's access to a biomarker-matched treatment now depends more on country than on biology.","Palliative care in colorectal cancer, stents against stomas, medical management of inoperable obstruction, liver capsule pain, rests largely on small series and consensus rather than randomised evidence, even though obstruction is how a fifth of these cancers present.","The screening threshold is a rationing decision. England calls a screened person for colonoscopy at 120 micrograms of haemoglobin per gram of faeces and refers a symptomatic person at 10; the gap is set by colonoscopy capacity, not by biology, and modelling of the English pilot shows how many cancers and adenomas a lower threshold would find (Br J Cancer 2022).","Screening uptake carries the inequality. NordICC found only 42 percent of invited people attended, and the English programme's own standards set an acceptable uptake of 62 percent at ages 60 to 74 with no level yet agreed for the newly invited 50 to 59 group.","Serrated lesions are the ones that get missed. They cause about 30 percent of colorectal cancers, bleed rarely so faecal tests find few of them, and are flat and pale enough to be missed at colonoscopy; interval cancers concentrate here.","Quality of surgery and pathology still varies. The circumferential resection margin and the completeness of the mesorectal envelope are the strongest things a rectal cancer team controls, and both depend on reporting standards that are not applied everywhere."],"basics":{"symptoms":["Changes in your poo: looser or harder than usual, or going more or less often than usual, lasting more than a few weeks (NHS)","Blood in your poo, which may look red or black, or bleeding from your bottom; a persistent feeling of needing to poo even just after going (NHS)","Tummy pain, a lump in the tummy, bloating, losing weight without trying, and tiredness or breathlessness from the anaemia a slow bleed causes (NHS)","See a GP for any of these; ask for an urgent GP appointment or use NHS 111 for black or dark red poo or bloody diarrhoea; call 999 or go to A&E for non-stop bleeding from the bottom or large blood clots (NHS)","GP referral rules (NICE NG12 1.3.1 to 1.3.5): a quantitative faecal immunochemical test for an abdominal mass, a change in bowel habit or iron-deficiency anaemia, for weight loss with abdominal pain at 40 and over, for rectal bleeding with pain or weight loss under 50, for unexplained rectal bleeding, abdominal pain or weight loss at 50 and over, and for anaemia at 60 and over; 10 micrograms of haemoglobin per gram of faeces or more refers on the suspected cancer pathway; a rectal mass is referred without the test","A negative screening test does not exempt a symptomatic person from being tested again (NICE NG12 1.3.1)","In England in 2019, 38 percent of bowel cancers came through an urgent suspected cancer referral, 22 percent after an emergency presentation and 12 percent through screening (Cancer Research UK)"],"diagnosis":["Colonoscopy with biopsy makes the diagnosis and removes precursor polyps at the same visit; computed tomography colonography is the alternative when colonoscopy is not possible (Cancer Research UK)","Staging: computed tomography of the chest, abdomen and pelvis for everyone, plus high-resolution magnetic resonance imaging of the pelvis for every rectal cancer to read the circumferential resection margin and extramural venous invasion (MERCURY 2006)","Test every metastatic tumour for RAS and BRAF V600E mutations before systemic anticancer therapy (NICE NG151 1.4.1); mismatch repair or microsatellite instability testing at diagnosis identifies both immunotherapy candidates and Lynch syndrome","Sidedness is recorded because right-sided and left-sided tumours differ in biology and in their response to EGFR antibodies","Carcinoembryonic antigen is not a diagnostic test; NG151 1.6.1 puts it in follow-up, alongside computed tomography of the chest, abdomen and pelvis for the first three years"],"staging":["TNM 8th edition, tumour: Tis in the bowel lining only; T1 into the inner layer; T2 into the muscle layer; T3 through the muscle into surrounding tissue; T4a through the outer lining into the peritoneum; T4b into a nearby organ (Cancer Research UK)","Nodes: N1a one node, N1b two or three nodes, N1c tumour deposits in nearby tissue with clear nodes; N2a four to six nodes, N2b seven or more (Cancer Research UK)","Metastasis: M1a one distant site, M1b two or more, M1c spread to the peritoneum with or without other sites (Cancer Research UK)","The number stages 1 to 4 are built from those categories; the older Dukes system is rarely used now (Cancer Research UK)","In the United States 34 percent of cases are localised at diagnosis, 37 percent regional, 23 percent distant and 6 percent unstaged (SEER); in England 47 percent of staged cases in 2022 were stage I or II (Cancer Research UK)"],"sources":[{"label":"NHS: symptoms of bowel cancer (when to get urgent help)","url":"https://www.nhs.uk/conditions/bowel-cancer/symptoms/"},{"label":"NICE NG12: suspected cancer, recommendations by site (lower gastrointestinal tract 1.3.1 to 1.3.5)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"},{"label":"NICE NG151: colorectal cancer, recommendations (Lynch 1.1, local disease 1.3, biomarkers 1.4, metastatic disease 1.5, ongoing care and support including follow-up 1.6)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"},{"label":"CRUK: TNM staging for bowel cancer","url":"https://www.cancerresearchuk.org/about-cancer/bowel-cancer/stages-types-and-grades/TNM-staging"},{"label":"CRUK: grades and types of bowel cancer","url":"https://www.cancerresearchuk.org/about-cancer/bowel-cancer/stages-types-and-grades/grades-and-types"},{"label":"SEER Cancer Stat Facts: colorectal cancer (rates, stage distribution, survival by stage, age and race)","url":"https://seer.cancer.gov/statfacts/html/colorect.html"},{"label":"CRUK: bowel cancer statistics (incidence, mortality, survival, early diagnosis, treatment)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer"},{"label":"MERCURY Study Group, BMJ 2006: diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer (408 patients)","url":"https://doi.org/10.1136/bmj.38937.646400.55"}]},"prognosis":{"text":"Population averages, not a personal prognosis. In the United States, 65.4 percent of people diagnosed with colorectal cancer in 2016 to 2022 were alive five years later relative to people of the same age without the disease (SEER). Stage at diagnosis is the biggest lever: five-year relative survival is 91.3 percent for the 34 percent found while confined to the bowel, 75.2 percent for regional disease (37 percent of cases) and 16.9 percent for distant disease (23 percent). England's figures, for people diagnosed in 2016 to 2020, are around 90 percent at five years for stage 1, around 85 percent for stage 2, 65 percent for stage 3 and around 10 percent for stage 4; across all stages around 80 percent survive a year, almost 60 percent five years and almost 55 percent ten years (Cancer Research UK). UK ten-year survival is predicted at 54.3 percent for colon cancer and 53.9 percent for rectal cancer among people diagnosed in 2018, against 22.4 and 24.6 percent in the 1970s. Age and deprivation move the figures: ten-year colon cancer survival is 64.3 percent for women and 60.5 percent for men diagnosed at 15 to 44, against 48.0 and 48.5 percent at 75 to 99; five-year bowel cancer survival in England is 55 percent in the most deprived group and 62.9 percent in the least. Survival is conditional on what has already happened: of people diagnosed in England in 2015 to 2019, almost 57 percent survived five years, but among those who had already survived one year it was 74.5 percent. Liver metastases are not automatically the end of the story: in an English study of people whose liver metastases could be operated on, around 45 percent survived five years or more after the operation (Morris 2010, quoted by Cancer Research UK).","sources":[{"label":"SEER Cancer Stat Facts: colorectal cancer (rates, stage distribution, survival by stage, age and race)","url":"https://seer.cancer.gov/statfacts/html/colorect.html"},{"label":"CRUK: bowel cancer survival statistics (professional)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer/survival"},{"label":"CRUK: survival for bowel cancer (by stage, England 2016 to 2020)","url":"https://www.cancerresearchuk.org/about-cancer/bowel-cancer/survival"},{"label":"Morris, Br J Surg 2010: surgical management and outcomes of colorectal cancer liver metastases (England)","url":"https://doi.org/10.1002/bjs.7032"}]}},{"id":"conjunctival-melanoma","kind":"cancer","name":"Conjunctival melanoma","aka":["Melanoma of the conjunctiva","Ocular surface melanoma","Conjunctival malignant melanoma"],"tldr":"Conjunctival melanoma is a rare melanoma of the clear membrane over the white of the eye, usually growing out of a flat brown patch called primary acquired melanosis. It is removed with a margin and the edges frozen or treated with chemotherapy drops; about one in five spread within five years, and advanced disease is treated like skin melanoma with targeted or immune drugs.","summary":"Conjunctival melanoma is a mucosal-surface melanoma of the eye, distinct from uveal melanoma in origin, genetics and behaviour and classified with the conjunctival tumours in the WHO eye classification. In 382 consecutive patients, the melanoma arose from primary acquired melanosis in 74 percent, from a pre-existing naevus in 7 percent and de novo in 19 percent; melanoma-related metastasis at five (ten) years occurred in 19 (25) percent of tumours arising from primary acquired melanosis, 10 (26) percent from naevus and 35 (49) percent de novo, and de novo origin and palpebral location predicted metastasis (Shields 2011). In Denmark the incidence was 0.5 per million a year and rising, with BRAF mutations in 39 of 111 tumours (35 percent) (Acta Ophthalmologica 2016).\n\nHow it differs from its parent: it behaves and mutates like cutaneous rather than uveal melanoma (BRAF, NRAS, NF1 rather than GNAQ and GNA11), it spreads to regional lymph nodes first, and its local treatment is ophthalmic surgery with adjuvant cryotherapy or topical chemotherapy rather than wide skin excision.\n\nHow common: about 0.5 per million a year (Acta Ophthalmologica 2016).\n\nTreatment: excision without touching the tumour, with cryotherapy to the margins and topical mitomycin or interferon for the associated melanosis, as in the ophthalmic series; sentinel node biopsy in selected cases; metastatic disease treated as on the melanoma page with BRAF and MEK inhibitors when mutated and checkpoint inhibitors otherwise (Shields 2011 for the surgical series).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Conjunctival_melanoma","links":[{"label":"NCI PDQ: intraocular (uveal) melanoma treatment","url":"https://www.cancer.gov/types/eye/patient/intraocular-melanoma-treatment-pdq"},{"label":"Shields 2011, Ophthalmology: conjunctival melanoma outcomes by tumour origin in 382 consecutive cases","url":"https://doi.org/10.1016/j.ophtha.2010.06.021"},{"label":"Acta Ophthalmologica 2016: BRAF mutations, incidence and prognosis of conjunctival melanoma in Denmark","url":"https://doi.org/10.1111/aos.13007"}],"tags":["subtype-page","wave4","rare"],"related":["melanoma","uveal-melanoma","mucosal-melanoma","acral-melanoma"],"cancers":[],"sections":[],"technologies":[],"targets":["braf"],"drugs":["mitomycin","dabrafenib","trametinib","nivolumab","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"skin","burden":"About 0.5 cases per million a year in Denmark, rising over 1960 to 2012 (Acta Ophthalmologica 2016); the largest clinical series holds 382 consecutive patients (Shields 2011). It is separate from uveal melanoma, which GLOBOCAN also does not count apart.","subtypes":["Conjunctival melanoma arising from primary acquired melanosis with atypia (74 percent)","Conjunctival melanoma arising from a naevus (7 percent)","De novo conjunctival melanoma (19 percent; highest metastatic risk)","Palpebral, forniceal or caruncular conjunctival melanoma (non-bulbar; worse outlook); distinct from uveal melanoma"],"biomarkers":["BRAF V600E (about 35 percent), NRAS and NF1 mutations","Tumour origin and location (bulbar versus non-bulbar)","Tumour thickness and ulceration","Sentinel node status in selected cases"],"standardOfCare":[{"setting":"Localised","approach":"No-touch excision with cryotherapy to the margins and topical mitomycin or interferon for associated melanosis; sentinel node biopsy in selected cases.","refs":["melanoma","mitomycin"]},{"setting":"Metastatic","approach":"Treated as on the melanoma page: BRAF and MEK inhibitors when mutated, checkpoint inhibitors otherwise.","refs":["melanoma","dabrafenib","trametinib","nivolumab","pembrolizumab"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"melanoma"},{"id":"corticotroph-pitnet","kind":"cancer","name":"Corticotroph pituitary neuroendocrine tumour (Cushing disease and silent corticotroph tumour)","aka":["Corticotroph tumour","Corticotroph tumour (Cushing disease, silent corticotroph)","ACTH-secreting pituitary adenoma","Cushing disease","Silent corticotroph adenoma","Crooke cell tumour"],"tldr":"A corticotroph tumour is a pituitary tumour of the cells that make ACTH. When it secretes it floods the body with cortisol, causing Cushing disease (weight gain, diabetes, high blood pressure, thin skin); the silent form is found as a large non-functioning mass. Surgery through the nose is the main treatment; cortisol-lowering drugs, repeat surgery or radiotherapy follow for those not cured.","summary":"The 2022 WHO classification places the corticotroph tumour in the TPIT lineage with densely granulated, sparsely granulated and Crooke cell subtypes, functioning (Cushing disease) or silent (Asa 2022). Silent corticotroph tumours were graded as high-risk adenomas in the 2017 classification; a meta-analysis of 14 studies with 297 patients found a recurrence rate of 5.96 per 100 person-years and recurrence in 31 percent at five or more years, without proof of a higher risk than other non-functioning adenomas (JCEM 2018). In 100 silent corticotroph against 841 other non-functioning adenomas at one institution, the silent corticotroph group presented more often with cranial neuropathy (13 against 5.7 percent) and the series defined recurrence patterns and treatment strategies (J Neurosurg 2021).\n\nHow it differs from its parent: the functioning tumour is usually a microadenoma diagnosed by the endocrine syndrome and cured by selective surgery in most, whereas the silent tumour is a macroadenoma diagnosed by mass effects; both recur more than other pituitary tumours and the Crooke cell subtype is aggressive.\n\nHow common: no separate incidence figure in the sources read.\n\nTreatment: transsphenoidal selective adenomectomy first; for persistent or recurrent Cushing disease, repeat surgery, radiotherapy (including radiosurgery), and cortisol-directed drugs (osilodrostat, ketoconazole, metyrapone), pasireotide or cabergoline directed at the tumour, or bilateral adrenalectomy; silent tumours by surgery and radiotherapy for regrowth, with temozolomide for aggressive tumours, as on the parent page.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Cushing%27s_disease","links":[{"label":"NCI PDQ: pituitary tumours treatment","url":"https://www.cancer.gov/types/pituitary/treatment"},{"label":"Asa 2022, Endocrine Pathology: overview of the 2022 WHO classification of pituitary tumours","url":"https://doi.org/10.1007/s12022-022-09703-7"},{"label":"JCEM 2018: recurrence in silent corticotroph adenomas after primary treatment, meta-analysis of 297 patients","url":"https://doi.org/10.1210/jc.2018-01956"},{"label":"J Neurosurg 2021: silent corticotroph adenomas, 100 patients against 841 other non-functioning adenomas","url":"https://doi.org/10.3171/2020.10.jns203236"}],"tags":["subtype-page","wave4","rare"],"related":["pituitary-tumours","lactotroph-pitnet","somatotroph-pitnet","gonadotroph-pitnet","adrenocortical"],"cancers":[],"sections":[],"technologies":["radiosurgery-srs"],"targets":[],"drugs":["osilodrostat","pasireotide","cabergoline","mifepristone","temozolomide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"The tumour behind Cushing disease and about a tenth of non-functioning pituitary tumours in its silent form; one centre operated on 100 silent corticotroph and 841 other non-functioning adenomas over 2000 to 2019 (J Neurosurg 2021). GLOBOCAN does not count pituitary tumours.","subtypes":["Densely granulated corticotroph tumour (typical Cushing disease microadenoma)","Sparsely granulated corticotroph tumour","Crooke cell tumour (aggressive)","Silent corticotroph tumour (ACTH-immunopositive, non-functioning macroadenoma; 31 percent recur)"],"biomarkers":["Late-night salivary cortisol, urinary free cortisol, dexamethasone suppression, plasma ACTH","TPIT lineage and ACTH immunostaining; Crooke hyaline change","Inferior petrosal sinus sampling when MRI is negative","Ki-67 and USP8 mutation (functioning microadenomas)"],"standardOfCare":[{"setting":"Cushing disease, first line","approach":"Transsphenoidal selective adenomectomy.","refs":["pituitary-tumours"]},{"setting":"Persistent or recurrent","approach":"Repeat surgery, radiotherapy, osilodrostat or other cortisol-directed drugs, pasireotide or cabergoline, or bilateral adrenalectomy; temozolomide for aggressive tumours.","refs":["osilodrostat","pasireotide","cabergoline","radiosurgery-srs","temozolomide","mifepristone"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"pituitary-tumours"},{"id":"craniopharyngioma","kind":"cancer","name":"Craniopharyngioma","aka":["Adamantinomatous craniopharyngioma","Papillary craniopharyngioma","Childhood craniopharyngioma"],"tldr":"Craniopharyngioma is a benign but destructive brain tumour growing from embryonic remnants beside the pituitary gland and hypothalamus. Surgery, or limited surgery plus radiotherapy, cures most people, but the price can be lifelong hormone deficiency and severe obesity. The adult (papillary) form carries a BRAF mutation and shrinks markedly with BRAF and MEK inhibitors, its first drug treatment.","summary":"Craniopharyngioma is a WHO grade 1 epithelial tumour of the sellar and suprasellar region with two distinct types. Adamantinomatous craniopharyngioma (ACP), the childhood form, carries activating CTNNB1 (beta-catenin) mutations, forms cysts filled with motor-oil fluid, and invades the hypothalamus; papillary craniopharyngioma (PCP), almost exclusively adult, carries BRAF V600E in nearly every case. Neither metastasises, but both damage vision, pituitary function and the hypothalamic centres that control appetite, sleep and temperature.\n\nManagement has shifted from radical resection at any cost to preserving the hypothalamus. Gross total resection cures if achieved, but attempts to strip tumour from the hypothalamus cause hypothalamic obesity, which is refractory to diet and exercise and is the dominant determinant of quality of life in survivors. Hypothalamus-sparing subtotal resection followed by conformal or proton radiotherapy gives equivalent tumour control with fewer severe late effects, and is now the favoured approach for tumours with hypothalamic involvement (KRANIOPHARYNGEOM 2007 and St Jude data). Cysts can be managed with catheter drainage, intracystic interferon or bleomycin, or stereotactic radiosurgery. Lifelong endocrine replacement is the norm.\n\nThe molecular findings created two therapeutic openings. In papillary tumours, BRAF plus MEK inhibition (vemurafenib-cobimetinib in the Alliance A071601 phase 2, Lancet Oncology 2024) produced marked shrinkage in almost all treated patients, allowing surgery and radiotherapy to be reduced; dabrafenib-trametinib case series show the same. In adamantinomatous tumours, the inflammatory cyst fluid is rich in IL-6, and the IL-6 receptor antibody tocilizumab has shrunk cysts in children in case series and an early trial. Treatments for hypothalamic obesity itself (GLP-1 agonists, setmelanotide, oxytocin) are being studied.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Craniopharyngioma","links":[{"label":"NCI PDQ: childhood craniopharyngioma","url":"https://www.cancer.gov/types/brain/hp/child-cranio-treatment-pdq"},{"label":"Alliance A071601: BRAF/MEK inhibition in papillary craniopharyngioma (Lancet Oncology 2024)","url":"https://doi.org/10.1016/S1470-2045(23)00492-9"},{"label":"Brastianos 2014: exome sequencing of craniopharyngioma (Nature Genetics)","url":"https://doi.org/10.1038/ng.2868"}],"tags":["nci-coverage","paediatric","cns"],"related":["pituitary-tumours","paediatric-low-grade-glioma","cns-germ-cell-tumours","meningioma"],"cancers":[],"sections":[],"technologies":["proton-therapy","imrt-igrt","mri","survivorship-care-plan"],"targets":["braf"],"drugs":["dabrafenib-trametinib","vemurafenib","cobimetinib","interferon-alfa","bleomycin","setmelanotide"],"companies":["childrens-oncology-group","alliance-oncology"],"institutions":["st-jude"],"pathways":["wnt","ras-mapk","inflammation-nfkb"],"terms":["late-effects"],"trials":[],"people":[],"bottlenecks":["b-survivorship","b-rare-cancers"],"keyPapers":["paper-brastianos-nat-genet"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Rare: a few percent of childhood brain tumours, with a second peak in adults in their fifties and sixties (NCI PDQ).","subtypes":["Adamantinomatous (CTNNB1-mutant; children and adults)","Papillary (BRAF V600E; adults)"],"biomarkers":["CTNNB1 exon 3 mutation and nuclear beta-catenin (adamantinomatous)","BRAF V600E (papillary)","Hypothalamic involvement grade on MRI (Puget or Muller grading)","Pituitary hormone panel and visual fields at baseline","Body-mass-index trajectory after treatment"],"standardOfCare":[{"setting":"Newly diagnosed, no or limited hypothalamic involvement","approach":"Gross total resection (transsphenoidal or craniotomy) with endocrine replacement; observation with serial MRI.","refs":["mri"],"guideline":{"version":"NCI PDQ: childhood craniopharyngioma","url":"https://www.cancer.gov/types/brain/hp/child-cranio-treatment-pdq"}},{"setting":"Hypothalamic involvement","approach":"Hypothalamus-sparing subtotal resection or cyst drainage followed by conformal or proton radiotherapy; intracystic therapy for predominantly cystic tumours.","refs":["proton-therapy","imrt-igrt"],"guideline":{"version":"KRANIOPHARYNGEOM 2007; NCI PDQ","url":"https://www.cancer.gov/types/brain/hp/child-cranio-treatment-pdq"}},{"setting":"Papillary craniopharyngioma, BRAF V600E","approach":"BRAF plus MEK inhibition (vemurafenib-cobimetinib per Alliance A071601, or dabrafenib-trametinib) before or instead of extensive surgery; radiotherapy after response.","refs":["dabrafenib-trametinib","vemurafenib","cobimetinib"],"guideline":{"version":"Alliance A071601 (Lancet Oncology 2024)","url":"https://doi.org/10.1016/S1470-2045(23)00492-9"}},{"setting":"Survivorship","approach":"Lifelong endocrinology follow-up, management of hypothalamic obesity, sleep and behavioural sequelae; structured survivorship care.","refs":["survivorship-care-plan"]}],"stateOfArt":["The goal has shifted from radical removal to hypothalamus preservation: limited surgery plus radiotherapy controls the tumour with far less obesity and neuropsychological harm.","Papillary craniopharyngioma is the first benign brain tumour treated by targeted therapy: BRAF/MEK inhibition shrinks nearly all tumours in the Alliance A071601 trial.","IL-6 blockade with tocilizumab is an emerging cyst-directed therapy for adamantinomatous tumours in children.","Proton therapy reduces dose to the temporal lobes and hypothalamus in children who need irradiation."],"history":[{"year":1932,"title":"Cushing names craniopharyngioma","refs":[]},{"year":2005,"title":"Nuclear beta-catenin and CTNNB1 mutations define adamantinomatous tumours","refs":[]},{"year":2014,"title":"BRAF V600E found in papillary craniopharyngioma","note":"Brastianos and colleagues (Nature Genetics) show near-universal BRAF V600E in PCP and CTNNB1 in ACP.","refs":["braf"]},{"year":2015,"title":"First dramatic response to BRAF/MEK inhibition in papillary craniopharyngioma","note":"Case report (JNCI) leads to the Alliance A071601 trial.","refs":["dabrafenib-trametinib"]},{"year":2016,"title":"Hypothalamus-sparing surgery recommended","note":"KRANIOPHARYNGEOM 2007 shows radical resection with hypothalamic injury worsens quality of life without improving control.","refs":[]},{"year":2024,"title":"Alliance A071601 published","note":"Vemurafenib plus cobimetinib produces responses in nearly all BRAF V600E papillary craniopharyngiomas (Lancet Oncology).","refs":["vemurafenib","cobimetinib"]}],"pipeline":["dabrafenib-trametinib","proton-therapy","glp1-agonists-cancer-risk"],"openProblems":["Hypothalamic obesity in survivors has no reliable treatment; GLP-1 agonists, setmelanotide and oxytocin are in trials.","No systemic therapy is established for adamantinomatous tumours; IL-6 blockade and MEK inhibition (downstream of the beta-catenin-driven inflammatory programme) are being tested.","How long BRAF/MEK inhibition should continue in papillary tumours and whether radiotherapy can be omitted after response.","Recurrence after subtotal resection in children too young for radiotherapy."],"parent":"brain-tumours"},{"id":"cutaneous-scc","kind":"cancer","name":"Cutaneous squamous cell carcinoma","aka":["cSCC","Squamous Cell Carcinoma of the Skin","Squamous cell skin cancer","Squamous cell carcinoma of the skin","SCC of the skin","Keratinocyte carcinoma, squamous type","Cutaneous SCC","Epidermoid carcinoma of skin"],"tldr":"Cutaneous squamous cell carcinoma is a sun-related skin cancer with over a million US cases a year, almost all cured by removing them. The 2 to 5% that grow deep or spread respond to PD-1 immunotherapy (cemiplimab, pembrolizumab), which is now also given after surgery in high-risk cases; transplant recipients cannot safely receive it.","summary":"Cutaneous squamous cell carcinoma (cSCC) arises from UV-damaged keratinocytes and has one of the highest mutational burdens of any cancer (TP53, NOTCH1/2, CDKN2A). Immunosuppression (transplant recipients have 65-100-fold higher risk) and chronic wounds are other causes. Most tumours are cured by excision or Mohs surgery; risk of recurrence and metastasis is stratified by BWH/AJCC-8 staging (depth, perineural invasion, differentiation, immunosuppression), with radiotherapy for high-risk or inoperable disease.\n\nCemiplimab (EMPOWER-CSCC-1, 2018) was the first systemic therapy approved for advanced cSCC, with ~45-50% response and durable disease control; pembrolizumab (KEYNOTE-629, 2020) and cosibelimab (anti-PD-L1, December 2024) followed. Neoadjuvant cemiplimab produced pathological complete response in 51% of stage II-IV disease (Gross, NEJM 2022), and the C-POST trial (2025) showed adjuvant cemiplimab after surgery and radiotherapy cut recurrence in high-risk patients, leading to an adjuvant approval. EGFR antibodies (cetuximab) and chemotherapy are reserved for immunotherapy-ineligible patients such as organ-transplant recipients.\n\nOpen: managing transplant recipients (checkpoint inhibitors cause graft rejection), chemoprevention (nicotinamide, acitretin), and the burden of field cancerisation.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Squamous-cell_carcinoma_of_the_skin","links":[{"label":"NCCN Guidelines: Squamous Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1465"},{"label":"C-POST (NEJM 2025)","url":"https://doi.org/10.1056/NEJMoa2502449"},{"label":"NCI PDQ: skin cancer","url":"https://www.cancer.gov/types/skin/patient/skin-treatment-pdq"},{"label":"Brantsch et al., analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: prospective study of 615 patients (Lancet Oncology 2008)","url":"https://doi.org/10.1016/S1470-2045(08)70178-5"},{"label":"Schmults et al., factors predictive of recurrence and death from cutaneous squamous cell carcinoma: 10-year, single-institution cohort study of 985 patients (JAMA Dermatology 2013)","url":"https://doi.org/10.1001/jamadermatol.2013.2139"},{"label":"Lansbury et al., interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies (BMJ 2013)","url":"https://doi.org/10.1136/bmj.f6153"},{"label":"Marcil and Stern, risk of developing a subsequent non-melanoma skin cancer in patients with a history of non-melanoma skin cancer: review and meta-analysis (Arch Dermatol 2000)","url":"https://doi.org/10.1001/archderm.136.12.1524"},{"label":"Morecroft et al., immunotherapy and radiation for clinical perineural invasion in cutaneous squamous cell carcinoma (Cancers 2025)","url":"https://doi.org/10.3390/cancers17243921"},{"label":"British Association of Dermatologists: squamous cell carcinomas, patient information leaflet (updated April 2022; the leaflet gives its own next review date as April 2025 and no newer version exists at this address or at bad.org.uk)","url":"https://www.skinhealthinfo.org.uk/condition/squamous-cell-carcinomas/"},{"label":"British Association of Dermatologists and BSSCII: skin cancer advice for organ transplant recipients, patient information leaflet (June 2024)","url":"https://www.skinhealthinfo.org.uk/condition/skin-cancer-in-organ-transplant-recipients/"},{"label":"Cancer Research UK: follow-up after non-melanoma skin cancer treatment","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/treatment/follow-up-appointments"},{"label":"Cancer Research UK: types of surgery for non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/treatment/surgery/treatment-surgery-types"},{"label":"Krynitz et al., risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008, Swedish population-based study of 10,476 recipients (Int J Cancer 2013)","url":"https://doi.org/10.1002/ijc.27765"},{"label":"Garrett et al., incidence of and risk factors for skin cancer in organ transplant recipients in the United States, 10,649 recipients (JAMA Dermatology 2017)","url":"https://doi.org/10.1001/jamadermatol.2016.4920"},{"label":"Royal College of Pathologists G124: dataset for histopathological reporting of primary invasive cutaneous squamous cell carcinoma and regional lymph nodes, version 4, February 2019 (Slater and Barrett)","url":"https://www.rcpath.org/resourceLibrary/g124datasetsquamous-pdf.html"},{"label":"Cancer Research UK: squamous cell carcinoma of the skin","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/types/squamous-cell-carcinoma"},{"label":"Keohane et al., British Journal of Dermatology 2021;184(3):401 to 414: British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma 2020","url":"https://doi.org/10.1111/bjd.19621"},{"label":"Royal College of Pathologists appendix A: UICC TNM 9 pathological staging of primary cutaneous carcinoma (squamous cell)","url":"https://www.rcpath.org/resourceLibrary/squamous-cell-tnm9.html"},{"label":"Jambusaria-Pahlajani et al., JAMA Dermatology 2013;149:402 to 410: evaluation of AJCC tumour staging for cutaneous squamous cell carcinoma and a proposed alternative tumour staging system (256 primary high-risk tumours; the derivation of the Brigham and Women's Hospital system)","url":"https://doi.org/10.1001/jamadermatol.2013.2456"},{"label":"Karia et al., Journal of Clinical Oncology 2014;32:327 to 334: evaluation of AJCC, UICC and Brigham and Women's Hospital tumour staging for cutaneous squamous cell carcinoma (1,818 primary tumours, 2000 to 2009)","url":"https://doi.org/10.1200/jco.2012.48.5326"},{"label":"Ruiz, Karia, Besaw and Schmults, JAMA Dermatology 2019;155:819 to 825: performance of the AJCC staging manual 8th edition versus the Brigham and Women's Hospital tumour classification system for cutaneous squamous cell carcinoma","url":"https://doi.org/10.1001/jamadermatol.2019.0032"},{"label":"Karia et al., JAMA Dermatology 2018;154:175 to 181: comparison of tumour classifications for cutaneous squamous cell carcinoma of the head and neck in the 7th versus the 8th edition of the AJCC staging manual (680 tumours in 459 patients)","url":"https://doi.org/10.1001/jamadermatol.2017.3960"},{"label":"Cancer Research UK: survival for non-melanoma skin cancer (net survival for skin squamous cell carcinoma, England, first tumours diagnosed 2014 to 2016, from the NDRS Get Data Out programme)","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/survival"},{"label":"van Bodegraven et al., British Journal of Dermatology 2023;188(6):777 to 784: 'Get Data Out' Skin, national cancer registry incidence and survival rates for all registered skin tumour groups for 2013 to 2019 in England","url":"https://doi.org/10.1093/bjd/ljad033"},{"label":"Mistry, Levell, Karponis, Wakkee, Whiteman, Proby and Venables, British Journal of Dermatology 2026: trends in keratinocyte cancers in England 2013 to 2022, basal cell carcinoma incidence, cutaneous squamous cell carcinoma incidence and non-melanoma skin cancer mortality","url":"https://doi.org/10.1093/bjd/ljag315"},{"label":"Kwiatkowska et al., Skin Health and Disease 2021;1(4):e61: an updated report on the incidence and epidemiological trends of keratinocyte cancers in the United Kingdom 2013 to 2018","url":"https://doi.org/10.1002/ski2.61"},{"label":"NHS: non-melanoma skin cancer, symptoms","url":"https://www.nhs.uk/conditions/non-melanoma-skin-cancer/symptoms/"}],"tags":["gap-fill","skin"],"related":["basal-cell-carcinoma","melanoma","merkel-cell-carcinoma","bowens-disease"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","imrt-igrt","monoclonal-antibody","chemoprevention","dermoscopy-ai","oncolytic-virus","black-salve-escharotics","survivorship-care-plan","multidisciplinary-tumour-board","psycho-oncology"],"targets":["pd1","pdl1","egfr","tp53"],"drugs":["cemiplimab","pembrolizumab","cosibelimab","cetuximab","carboplatin","vusolimogene-oderparepvec","imiquimod","aminolevulinic-acid","acitretin","nicotinamide"],"companies":["regeneron","sanofi","merck","summit-therapeutics","replimune","rakuten-medical"],"institutions":[],"pathways":["pd1-checkpoint","p53-cell-cycle"],"terms":["tmb","pcr","irae","perineural-invasion","second-primary-skin-cancer","sun-protection-after-skin-cancer","skin-cancer-after-organ-transplant","curettage-and-cautery","facial-scar-after-skin-cancer","skin-graft-and-flap-reconstruction","field-cancerisation","keratinocyte-cancer","actinic-keratosis","cscc-subtype-and-grade","bwh-staging-cscc","tnm-skin-carcinoma","skin-cancer-high-risk-features","keratinocyte-cancer-counting","keratoacanthoma","inherited-skin-cancer-syndromes","carcinoma-in-situ","mohs-surgery","resection-margins","radiotherapy-for-skin-cancer","surgical-margins-keratinocyte-cancer"],"trials":["nct06585410","empower-cscc-1","c-post","neoadjuvant-cemiplimab-cscc","trog-05-01","tumorapa","cemiplimab-kidney-transplant-cscc","mohs-versus-excision-facial-bcc"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Cutaneous squamous cell carcinoma, the dangerous minority and the follow-up: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the number they gave you come first, and no figure on this page is a prediction about you. The thickness thresholds come from a prospective study of 615 patients with a median follow-up of 43 months and the outcome rates from a cohort of 985 patients at one Boston hospital followed for a median of 50 months. They describe those cohorts. Nothing here is a prognosis for a reader.","The disagreement between the British Association of Dermatologists (regular follow-up for one to two years for higher-risk disease) and Cancer Research UK (every four to six months for at least five years) is left visible rather than averaged away, because a reader who has been told one of those two is better served by knowing the other exists.","What this page does not carry: cemiplimab, pembrolizumab, cosibelimab and the management of locally advanced and metastatic disease, which belong to the advanced cutaneous squamous cell carcinoma record; and the face, Mohs as a day, the sun, the mind and immunosuppression, which are written once on the skin cancer family page.","Every number on this page rests on a counting rule. UK registration long recorded only the first squamous cell carcinoma in a person's lifetime; counting one per person per year instead found 42 percent more over 2013 to 2022 in England, and still misses about 2 tumours per 100 patients. Scotland is the exception and registers every squamous cell carcinoma manually, which is why its figures and England's are not directly comparable. The whole group is excluded from the UK's headline cancer total (see `keratinocyte-cancer-counting`).","How common it is. About 25 in every 100 skin cancers, which is how Cancer Research UK words it; its basal cell figure of 75 in every 100 is worded against non-melanoma skin cancers, so the two sentences do not share a denominator. In England the registered rate in 2019 was 85.24 per 100,000 person-years; on the annual counting method it was 102 per 100,000 in 2022. Across the UK the annual-method estimate is 50,582 a year for 2016 to 2018. Rates are about 13 to 14 times higher in the White ethnic group than in the Asian or Black groups in England (Ahmed 2026).","Where this cancer comes from, and why people get more than one. It arises from keratinocytes that have accumulated ultraviolet damage, usually in skin that has had decades of it, and it is often surrounded by a field of the same damage that is visible as actinic keratoses. That field is why a person who has one is likely to have another, and why treatment is sometimes aimed at an area rather than a lesion. The other routes to it are the same damage from a different source: chronic wounds and old burns and scars, human papillomavirus at some sites, and, most powerfully, long-term immunosuppression.","Why the report gives both a subtype and a grade, and what each is for. The subtype says what shape the tumour grows in and is mostly a yes-or-no question about four named high-risk patterns; if none is present the report says no special type. The grade says how much the cells still look like skin, on three levels, and is taken from the worst area found. Either one alone can put a tumour into the high-risk group, which is the point: they are describing different ways of being dangerous.","What the word spreading actually means here, and how likely it is. Cancer Research UK states that these cancers do not often spread, and that when they do it is usually to the deeper layers of the skin, then to nearby lymph nodes, and only rarely beyond. That is why nodal assessment and treatment after surgery are reserved for the small high-risk group, and why so much of the argument about staging is really an argument about how to find that group without treating everybody.","The word keratoacanthoma on a report. WHO terminology treats keratoacanthoma as synonymous with invasive squamous cell carcinoma of keratoacanthomatous type, and the UK dataset records that no single criterion reliably distinguishes the two, so the diagnosis rests on the whole clinical and pathological picture. The dataset also advises avoiding the term in immunosuppressed people, in large lesions and in subungual sites, because those behave more aggressively. Anyone whose report carries the word is on the right page here."],"group":"skin","burden":"Second most common skin cancer; over one million cases per year in the US, almost all cured by removal; about 2-5% metastasise, which still amounts to several thousand deaths a year and is where PD-1 immunotherapy now helps.","subtypes":["Low-risk cSCC (small, well-differentiated, no perineural invasion)","High-risk cSCC (BWH T2b-T3; deep invasion, perineural invasion, poorly differentiated)","Locally advanced unresectable cSCC","Metastatic cSCC","cSCC in organ-transplant recipients / immunosuppressed","Keratoacanthoma and in situ (Bowen) disease","No special type, also called classic, which is the default when none of the high-risk subtype features is present (RCPath G124)","High-risk subtypes named by UK national guidelines and NICE: acantholytic, desmoplastic (more than 30 percent desmoplastic stroma) and spindle cell or sarcomatoid","Adenosquamous carcinoma, high risk to WHO; basaloid squamous cell carcinoma, poorly differentiated by definition and distinguished from basal cell carcinoma by BerEP4 and EMA staining","Squamous cell carcinoma with adjacent Bowen's disease, usually counted as a high-risk variant","By grade rather than type: well, moderately and poorly differentiated, graded from the most poorly differentiated region present","By origin: from surface epidermis or from follicular epithelium, either of which can be in situ or invasive","Bowen's disease, squamous cell carcinoma in situ, which has its own page; keratoacanthoma, which the WHO treats as a keratoacanthomatous type of this cancer and which is a glossary term here"],"biomarkers":["BWH and AJCC-8 T stage","Perineural invasion, depth beyond fat, differentiation","Immunosuppression status","Gene-expression prognostic test (40-GEP, DecisionDx-SCC)","PD-L1 (not required)","TMB (very high)","Grade: well, moderately or poorly differentiated, assigned from the most poorly differentiated region irrespective of percentage (RCPath G124)","Subtype: acantholytic, desmoplastic, spindle cell or adenosquamous, each a high-risk feature on its own","Thickness over 4 mm, and level of invasion reaching or passing the subcutaneous fat","Perineural invasion and lymphovascular invasion","Margins: involved at 0 mm, or clear but under 1 mm","Immunosuppression, which is not on the slide and is added by the clinician or the multidisciplinary team","UICC pathological T category, and separately the Brigham and Women's Hospital factor count where a clinician uses it"],"standardOfCare":[{"setting":"Localised low- and high-risk","approach":"Excision with margin control or Mohs micrographic surgery; adjuvant radiotherapy for high-risk features (perineural invasion, positive margins); nodal evaluation for very high risk.","refs":["imrt-igrt","sentinel-node"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Squamous Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1465"}},{"setting":"High-risk after surgery and radiotherapy","approach":"Adjuvant cemiplimab (C-POST, 2025: reduced locoregional and distant recurrence).","refs":["cemiplimab"],"guideline":{"version":"C-POST (NEJM 2025)","url":"https://doi.org/10.1056/NEJMoa2502449"}},{"setting":"Locally advanced or metastatic","approach":"Cemiplimab, pembrolizumab or cosibelimab; neoadjuvant cemiplimab for resectable stage II-IV to shrink surgery (51% pCR).","refs":["cemiplimab","pembrolizumab","cosibelimab"],"guideline":{"nccn":"Category 2A (preferred: cemiplimab, pembrolizumab)","version":"NCCN Guidelines: Squamous Cell Skin Cancer"}},{"setting":"Immunotherapy-ineligible or refractory","approach":"Cetuximab ± radiotherapy, platinum-based chemotherapy, capecitabine; trials of intratumoural agents (RP1) and EGFR ADCs.","refs":["cetuximab","carboplatin","vusolimogene-oderparepvec"]},{"setting":"Which squamous cell carcinomas are the dangerous ones","approach":"Most of these are cured by removing them, and the British Association of Dermatologists says exactly that: most squamous cell carcinomas are low-risk skin cancers and can be cured, and a small number recur locally or spread to the lymph nodes or elsewhere. The useful thing is to know which is which, and two cohorts did the work. In a prospective study of 615 patients followed for a median of 43 months, no tumour 2.0 mm thick or less metastasised at all; metastases occurred in 12 of 318 tumours between 2.1 and 6.0 mm thick (4 percent) and in 14 of 90 thicker than 6.0 mm (16 percent). On multivariate analysis the factors that mattered were increasing thickness (hazard ratio 4.79), immunosuppression (4.32), a location on the ear (3.61) and increasing width (2.22); local recurrence was driven by thickness and by desmoplastic growth (16.11). In a ten-year cohort of 985 patients with 1,832 tumours, local recurrence occurred in 4.6 percent, nodal metastasis in 3.7 percent and death from the cancer in 2.1 percent, and the independent predictors of nodal spread and of death were a diameter of at least 2 cm, poor differentiation, invasion beyond the fat, and an ear or temple location, with perineural invasion also associated with death from the cancer. Those are the words to look for on your pathology report, and they are the ones that decide whether radiotherapy after surgery, imaging or a specialist team referral are discussed. Perineural invasion comes in two forms and the distinction changes the outlook: found only on the slide with no symptoms, or clinically evident through pain, altered sensation or weakness, which is the worse kind and the reason those symptoms are on the red cards. Treatment is surgical: the BAD says removal with a margin of normal skin under local anaesthetic, closed with stitches or sometimes a graft, with curettage and cautery for some lesions and Mohs in some circumstances, and radiotherapy as an alternative. It is the BAD's transplant leaflet rather than its squamous cell one that says when radiotherapy is chosen: for skin cancers that are difficult to remove with surgery or have a high risk of returning after it. A pooled analysis of observational studies put local recurrence at 3.0 percent after Mohs, 5.4 percent after standard excision and 6.4 percent after radiotherapy, while warning that the tumours sent to each were not comparable and that photodynamic therapy, at 26.4 percent, is not a treatment for an invasive squamous cell carcinoma.","refs":["perineural-invasion","wide-local-excision","mohs-surgery","curettage-and-cautery","imrt-igrt","skin-cancer-after-organ-transplant","multidisciplinary-tumour-board","curative-intent"],"guideline":{"version":"Brantsch et al., prospective study of 615 patients (Lancet Oncology 2008) and Schmults et al., cohort of 985 patients (JAMA Dermatology 2013), with British Association of Dermatologists patient information on squamous cell carcinoma (updated April 2022)","url":"https://doi.org/10.1016/S1470-2045(08)70178-5"}},{"setting":"Follow-up, the lymph nodes, and the chance of a second one","approach":"Follow-up after a squamous cell carcinoma is where the UK sources openly disagree, and it is better to know that than to be surprised by it. The BAD patient leaflet says current guidelines are that people at low risk of a second one do not need a specialist following them up, and that higher-risk cancers should be followed up regularly for one to two years by the specialist or their team. Cancer Research UK says a high-risk squamous cell carcinoma might mean appointments every four to six months for at least five years, and that a low-risk one might mean a single appointment and then none. Ask which your team is doing and why, because the answer tells you how they have classified your cancer. What is checked is your skin, all of it, and the lymph nodes nearest the original cancer; Cancer Research UK says tests may include a skin biopsy, an ultrasound or a CT scan, and that surgery to remove lymph nodes is uncommon for these cancers but is done if a squamous cell carcinoma has spread to them, which for a scalp or face primary means the nodes on the same side of the neck. Then the second question, which is more likely than recurrence. In the meta-analysis of 17 studies the three-year cumulative risk of a further squamous cell carcinoma after a first was 18 percent, at least ten times the general population rate, and the risk of also developing a basal cell carcinoma was about the same as for someone whose first cancer was a basal cell carcinoma. The BAD's leaflet puts it higher over five years: about 40 percent after a low-risk squamous cell carcinoma and possibly as high as 80 percent after a higher-risk one. This is why a dermatologist may treat skin that does not look like cancer to you: the BAD says treating areas of scaly sun damage, meaning actinic keratosis and Bowen disease, may reduce the risk of a squamous cell carcinoma, and describes large areas of such damage as field change. Three symptoms are worth a phone call rather than a wait: a new scaly or crusted lump that is growing, especially a painful one; a lump in the lymph nodes of the neck, armpit or groin on the side of a previous squamous cell carcinoma; and new numbness, tingling, burning pain or weakness in the face near where one was treated.","refs":["second-primary-skin-cancer","perineural-invasion","sun-protection-after-skin-cancer","skin-cancer-after-organ-transplant","chemoprevention","survivorship-care-plan","field-cancerisation","sentinel-node"],"guideline":{"version":"British Association of Dermatologists patient information: squamous cell carcinomas (updated April 2022, review due April 2025 and not yet revised), with Cancer Research UK on follow-up (reviewed July 2026), which differ on the interval and are both quoted","url":"https://www.skinhealthinfo.org.uk/condition/squamous-cell-carcinomas/"}},{"setting":"Radiotherapy after surgery, and what not to add to it","approach":"For high-risk disease, surgery followed by postoperative radiotherapy of 60 to 66 Gy. The habit of adding chemotherapy, carried over from head and neck oncology, was tested in TROG 05.01: 321 patients randomised to postoperative radiotherapy with or without weekly carboplatin, with freedom from locoregional relapse at five years of 87 against 83 per cent, hazard ratio 0.84 (0.46 to 1.55, p=0.58), and no difference in disease-free or overall survival. Carboplatin should not be added. The control arm is the number to carry forward: surgery and radiotherapy alone controlled 83 per cent of these tumours locoregionally at five years, and only 7 per cent failed first at a distant site.","refs":["trog-05-01","radiotherapy-for-skin-cancer","carboplatin","perineural-invasion"],"guideline":{"version":"TROG 05.01 (Journal of Clinical Oncology 2018)","url":"https://doi.org/10.1200/jco.2017.77.0941"}},{"setting":"Before surgery, when the operation would be disfiguring","approach":"Up to four doses of cemiplimab before an operation planned with curative intent. In 79 patients with resectable stage II to IV disease, a pathological complete response, meaning no viable tumour cells anywhere in the specimen on central review, was found in 40 (51 per cent, 39 to 62) and a pathological major response in a further 10 (13 per cent). Imaging understated it, at 68 per cent objective response. Grade 3 or higher adverse events occurred in 18 per cent. What the trial does not answer is whether the surgery can then be reduced or omitted, because everyone was resected; that is the next question and it is the same one being asked in rectal and bladder cancer.","refs":["neoadjuvant-cemiplimab-cscc","cemiplimab","pcr","surgical-margins-keratinocyte-cancer"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Squamous Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1465"}},{"setting":"The transplant recipient and the immunosuppressed patient","approach":"A group with 65 to 100 times the ordinary risk, tumours that are multiple and far more likely to spread, and almost no evidence, because every registration trial excluded them. Three levers. Switching immunosuppression: TUMORAPA randomised 120 kidney transplant recipients who had already had one of these cancers and found new squamous cell carcinomas in 22 per cent after a switch to sirolimus against 39 per cent continuing a calcineurin inhibitor (relative risk 0.56, 0.32 to 0.98), at the price of 60 serious adverse events against 14 and 23 per cent stopping the drug. Chemoprevention: acitretin and nicotinamide, with the nicotinamide effect not reproduced in transplant recipients. Immunotherapy, long refused because of the risk to the graft: a twelve-patient phase 1 study that cross-tapered to a mammalian target of rapamycin inhibitor and pulsed prednisone around each cycle reported no rejection and no graft loss, with responses in 5 of 11 evaluable patients. That is the whole prospective evidence base.","refs":["skin-cancer-after-organ-transplant","tumorapa","cemiplimab-kidney-transplant-cscc","acitretin","nicotinamide","cemiplimab"],"guideline":{"version":"TUMORAPA (New England Journal of Medicine 2012) and the Dana-Farber phase 1 (Journal of Clinical Oncology 2024)","url":"https://doi.org/10.1200/jco.23.01498"}},{"setting":"What is available in England","approach":"NICE technology appraisal TA802 recommendation 1.1 recommends cemiplimab for metastatic or locally advanced cutaneous squamous cell carcinoma in adults when curative surgery or curative radiotherapy is not suitable, only if it is stopped at 24 months or earlier on progression and the company supplies it under the commercial arrangement. It replaced TA592, which had recommended it within the Cancer Drugs Fund. That single appraisal is the extent of NICE's appraisal guidance for this disease, though not of its guidance: pembrolizumab and cosibelimab have not been appraised for it, and the adjuvant indication that C-POST supports has no appraisal either, while HTG333 on electrochemotherapy, HTG99 on photodynamic therapy, NG12 recommendation 1.7.4 and QS130 all cover it.","refs":["cemiplimab","pembrolizumab","cosibelimab","c-post"],"guideline":{"version":"NICE TA802 recommendation 1.1 (cemiplimab recommended, stopped at 24 months)","url":"https://www.nice.org.uk/guidance/ta802"}}],"stateOfArt":["PD-1 blockade produces durable responses in about half of advanced cSCC, one of the best response rates of any solid tumour, explained by extreme UV mutational burden.","Neoadjuvant cemiplimab (51% pCR) is redefining surgery for large tumours; adjuvant cemiplimab (C-POST) is the first to reduce recurrence after surgery and radiation.","Cosibelimab adds an anti-PD-L1 option with a different toxicity profile.","Transplant recipients remain the hardest group: immunotherapy risks graft loss; mTOR-inhibitor switching and acitretin are the preventive levers."],"history":[{"year":1775,"title":"Percivall Pott links chimney-sweep soot to scrotal SCC","note":"First occupational carcinogen described.","refs":[]},{"year":1938,"title":"Mohs micrographic surgery introduced","refs":[]},{"year":2011,"title":"Cetuximab activity in unresectable cSCC (phase 2)","refs":["cetuximab"]},{"year":2012,"title":"TUMORAPA: changing the anti-rejection drug halves the next skin cancer","note":"120 kidney transplant recipients randomised; new squamous cell carcinomas in 22 per cent after a switch to sirolimus against 39 per cent continuing a calcineurin inhibitor, with 23 per cent stopping the new drug.","refs":["tumorapa"]},{"year":2018,"title":"Cemiplimab: first systemic approval for cSCC","note":"EMPOWER-CSCC-1 (NEJM 2018).","refs":["cemiplimab"]},{"year":2018,"title":"TROG 05.01: chemotherapy adds nothing to postoperative radiotherapy","note":"321 patients randomised; freedom from locoregional relapse at five years 87 against 83 per cent with weekly carboplatin added, hazard ratio 0.84.","refs":["trog-05-01"]},{"year":2020,"title":"Pembrolizumab approved (KEYNOTE-629)","refs":["pembrolizumab"]},{"year":2022,"title":"Neoadjuvant cemiplimab: 51% pathological complete response (NEJM)","refs":["cemiplimab"]},{"year":2024,"title":"Cosibelimab approved (December)","refs":["cosibelimab"]},{"year":2024,"title":"The first prospective immunotherapy evidence in transplant recipients","note":"Twelve kidney transplant recipients given cemiplimab after cross-taper to a mammalian target of rapamycin inhibitor with pulsed steroids: no rejection, no graft loss, responses in 5 of 11 evaluable patients.","refs":["cemiplimab-kidney-transplant-cscc"]},{"year":2025,"title":"C-POST: adjuvant cemiplimab reduces recurrence","refs":["cemiplimab"]},{"year":2025,"title":"C-POST establishes adjuvant immunotherapy","note":"415 patients randomised after surgery and radiotherapy; 24-month disease-free survival 87.1 against 64.1 per cent, hazard ratio 0.32.","refs":["c-post"]}],"pipeline":["cemiplimab","cosibelimab","vusolimogene-oderparepvec","hmbd-001"],"openProblems":["Organ-transplant recipients: high incidence, no safe immunotherapy.","Who needs adjuvant therapy: gene-expression tests vs clinicopathologic staging.","Field cancerisation and multiple primaries in the elderly.","Access to Mohs surgery and dermatology capacity.","The two staging systems disagree about who is high risk and neither side has conceded. The anatomical systems place most tumours and most poor outcomes in the same low categories; the alternative built to fix that has been validated only in single-centre cohorts and the Royal College of Pathologists has published its objection to the risk bands derived from it. The decision this is supposed to inform, who needs nodal assessment or treatment after surgery, is being made in its absence.","Incidence is still rising while basal cell carcinoma has levelled off. Age-standardised rates in England rose 6.1 percent a year from 2013 to 2015 and 2.3 percent a year from 2015 to 2019 on the annual counting method, and continued to rise in people under 60 and over 80 after plateauing in the middle age groups. Non-melanoma skin cancer mortality rose about 4 percent a year over the same period.","The people at highest risk are the ones with the fewest options. Immunosuppression is a high-risk feature that no pathologist can see and that transplant recipients cannot simply stop, and it is added to the risk assessment clinically rather than measured.","The grading rule is strict and its reproducibility is untested at scale. A tumour is graded by its most poorly differentiated focus however small, which is defensible on safety grounds and means the grade depends on how much of the tumour was examined.","The counting problem applies here too, in a smaller but still large form: the annual counting method finds 42 percent more squamous cell carcinomas than the lifetime-first rule and still misses about 2 per 100 patients, and Scotland, which registers every tumour, is the only part of the UK whose figures are not affected.","Solid organ transplant recipients have 65 to 100 times the risk of this cancer and their whole prospective evidence base is one randomised trial of 120 patients and one phase 1 study of twelve. The gap is a consequence of an eligibility criterion rather than of biology.","Neoadjuvant cemiplimab leaves no viable tumour in half of the specimens, but every patient in the trial was operated on anyway, so nobody knows whether the surgery can be reduced or omitted after a complete response.","There is no NICE appraisal of adjuvant cemiplimab, of pembrolizumab or of cosibelimab in this disease, so the only routinely funded systemic option in England is cemiplimab for advanced disease under TA802, stopped at 24 months."],"basics":{"symptoms":["A squamous cell carcinoma can be a pink or red scaly small bump or patch; on brown or black skin it may look crusty or scaly or appear as a dark nodule. It may be sore or painless and may ulcerate in the middle (Cancer Research UK)","Most develop on areas of skin exposed to the sun: parts of the head, the neck, and the backs of the hands and forearms; they can also develop in scars or on skin that was previously burned (Cancer Research UK)","They can grow slowly, or quickly and then spread. They do not often spread; if they do it is usually to the deeper layers of the skin, and they can reach nearby lymph nodes and other parts of the body, but this is unusual (Cancer Research UK)","A lesion that has grown noticeably over weeks rather than years, that is tender, or that bleeds and will not heal, is the pattern that most often turns out to be this rather than a basal cell carcinoma","See a GP if you have a growth on your skin that is getting bigger or has changed colour or texture, or a growth or area of skin that hurts, itches, bleeds, crusts or scabs for more than 4 weeks (NHS)"],"diagnosis":["The diagnosis is histological, and the report carries a subtype and a grade as two separate things (RCPath G124)","The grade is taken from the most poorly differentiated region present, irrespective of what percentage of the tumour that region occupies, because AJCC gives no guidance on a proportion; recording the percentages of each component is optional","Basaloid tumours must be told from basal cell carcinoma with immunohistochemistry, BerEP4 and EMA, because the treatment and the outlook differ","Where the word keratoacanthoma appears, it should be read as a way this cancer can look rather than a different disease, and the UK dataset advises against using the word at all in immunosuppressed people, in large lesions and under a nail","The report also gives thickness, level of invasion, perineural and lymphovascular invasion and margins, all of which are high-risk features in their own right"],"staging":["This is the skin cancer most likely to be staged, because it is the keratinocyte cancer that can spread, although that is still uncommon (Cancer Research UK)","UK reports stage against UICC TNM, ninth edition since the appendix dated 6 November 2025, with separate chapters for head and neck and for trunk and limbs; the boundary is the acromioclavicular joint in front and the upper shoulder blade behind (RCPath G124 and appendix A)","pT1 is 20 mm or less, pT2 over 20 up to 40 mm, pT3 over 40 mm or minor bone erosion or perineural invasion or deep invasion; pT4a gross cortical or marrow invasion, pT4b axial skeleton invasion. Deep invasion is beyond the subcutaneous fat or more than 6 mm from the granular layer","The AJCC 8 system, which American sources use, covers the head and neck only and has no system for squamous cell carcinoma on the rest of the body","There is a competing system. The Brigham and Women's Hospital classification counts four risk factors, poor differentiation, perineural invasion, diameter 2 cm or more, and invasion beyond fat: none is T1, one is T2a, two or three is T2b, four or bone invasion is T3. It identifies the dangerous tumours in a much smaller group, and it is not what UK reports use (see `bwh-staging-cscc`)","The Royal College of Pathologists sets out numerical risk bands of its own: an adverse consequence rate under 5 percent is low risk, 5 to 20 percent high risk, over 20 percent very high risk; and a tumour under 20 mm across or under 2 mm thick with no other factors is of negligible risk. It explicitly rejects the alternative bands derived from the Brigham system as leaving serious intermediate cases under-rated","Its final position is that risk stratification belongs to the treating clinician and the skin cancer multidisciplinary team rather than to the pathology report, because the pathologist cannot see the site, the immune state, the growth rate or whether the tumour is a recurrence"],"sources":[{"label":"Cancer Research UK: squamous cell carcinoma of the skin","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/types/squamous-cell-carcinoma"},{"label":"NHS: non-melanoma skin cancer, symptoms","url":"https://www.nhs.uk/conditions/non-melanoma-skin-cancer/symptoms/"},{"label":"Royal College of Pathologists G124: dataset for histopathological reporting of primary invasive cutaneous squamous cell carcinoma and regional lymph nodes, version 4, February 2019 (Slater and Barrett)","url":"https://www.rcpath.org/resourceLibrary/g124datasetsquamous-pdf.html"},{"label":"Royal College of Pathologists appendix A: UICC TNM 9 pathological staging of primary cutaneous carcinoma (squamous cell)","url":"https://www.rcpath.org/resourceLibrary/squamous-cell-tnm9.html"},{"label":"Keohane et al., British Journal of Dermatology 2021;184(3):401 to 414: British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma 2020","url":"https://doi.org/10.1111/bjd.19621"}]},"prognosis":{"text":"Most people with a cutaneous squamous cell carcinoma are cured. There are no UK-wide survival statistics; for England, among people diagnosed with their first squamous cell carcinoma between 2014 and 2016, excluding tumours starting in the genitals, 90 out of 100 survived their cancer for 5 years or more. The English registry study of 2013 to 2019 reported five-year net survival of 89.8 percent, which it noted was comparable to net survival for all melanomas. What separates the people for whom this is a minor operation from the few for whom it is not is a short list: how thick the tumour is, whether it has passed the subcutaneous fat, whether it is poorly differentiated, whether nerves are involved, where on the body it is, whether it has recurred before, and above all whether the person's immune system is suppressed. In single-centre cohorts selected for difficulty, tumours with none or one of the four Brigham factors had ten-year rates of local recurrence, nodal metastasis and death from the cancer of 1.4, 0.6 and 0.2 percent, while tumours with two or more had 24, 24 and 16 percent; those percentages come from a referral population and are higher than an unselected one would show, but the ranking holds. These are averages over populations counted on a rule that records only the first tumour per person, and they are not a personal prognosis.","sources":[{"label":"Cancer Research UK: survival for non-melanoma skin cancer (net survival for skin squamous cell carcinoma, England, first tumours diagnosed 2014 to 2016, from the NDRS Get Data Out programme)","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/survival"},{"label":"van Bodegraven et al., British Journal of Dermatology 2023;188(6):777 to 784: 'Get Data Out' Skin, national cancer registry incidence and survival rates for all registered skin tumour groups for 2013 to 2019 in England","url":"https://doi.org/10.1093/bjd/ljad033"},{"label":"Karia et al., Journal of Clinical Oncology 2014;32:327 to 334: evaluation of AJCC, UICC and Brigham and Women's Hospital tumour staging for cutaneous squamous cell carcinoma (1,818 primary tumours, 2000 to 2009)","url":"https://doi.org/10.1200/jco.2012.48.5326"}]},"parent":"skin-cancer"},{"id":"cutaneous-t-cell-lymphoma","kind":"cancer","name":"Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome)","aka":["CTCL","Mycosis fungoides","Sezary syndrome"],"tldr":"Cutaneous T-cell lymphoma is a family of nine lymphomas that start in the skin and mostly stay there, of which mycosis fungoides is by far the commonest. Most of them are long-term skin conditions managed over decades rather than cancers that are cured or not cured, and two of the nine are genuinely aggressive.","summary":"What the family is. Primary cutaneous T-cell lymphomas are lymphomas that start in the skin and, for most of their course, stay there. WHO-HAEM5 gives them a family of their own inside the chapter on mature T-cell and NK-cell neoplasms, and lists nine entities in it. The word primary is load-bearing: a systemic lymphoma that has spread to the skin is not a cutaneous lymphoma, is staged differently and is treated differently, so the first job after the biopsy is to show that there is no disease anywhere else.\n\nThe nine entities. Mycosis fungoides, which is the commonest by a wide margin and has its own page. The two primary cutaneous CD30-positive lymphoproliferative disorders, lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma, which are two ends of one spectrum and both have pages. Primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, which usually presents as a single nodule on the head or neck and behaves benignly. Primary cutaneous acral CD8-positive lymphoproliferative disorder, which WHO-HAEM5 renamed from lymphoma to lymphoproliferative disorder because of how it behaves. Subcutaneous panniculitis-like T-cell lymphoma, which grows in the fat under the skin and can be mistaken for an inflammatory panniculitis. Primary cutaneous gamma/delta T-cell lymphoma and primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, the two genuinely aggressive members. And primary cutaneous peripheral T-cell lymphoma not otherwise specified, a name coined in 2022 for the rare cases that fit none of the others.\n\nWhat changed in 2022. Four of those entities, the gamma/delta lymphoma, the CD8-positive aggressive epidermotropic lymphoma, the acral CD8-positive disorder and the CD4-positive small or medium disorder, had been grouped in the previous classification under a single heading, cutaneous peripheral T-cell lymphoma, rare subtypes. WHO-HAEM5 separated them because their clinical behaviour, their appearance and their genetics differ, and the behaviour differs enormously: two of the four are indolent and two are aggressive, so a single heading hid the only fact a patient needed.\n\nWhy the dermatologist is part of the diagnosis. These conditions overlap under the microscope, and WHO-HAEM5 says so directly: because the appearances and the surface markers overlap across the primary cutaneous T-cell lymphomas, correlation with the clinical history, the signs and the symptoms is a key element of the work-up, and dermatological examination and clinical photographic documentation are indispensable. A biopsy of lymphomatoid papulosis read without the history is reported as an aggressive lymphoma; a biopsy of early mycosis fungoides read without the history is reported as eczema. Dated photographs and a record of how lesions have behaved over months are therefore part of the diagnostic material, not a courtesy.\n\nWhat is not in this family. Sezary syndrome, although it is a disease of the skin and the blood and is managed by the same teams, is classified by WHO-HAEM5 among the mature T-cell and NK-cell leukaemias rather than among the primary cutaneous lymphomas, because it is leukaemic from the start; it has its own page here and is kept beside mycosis fungoides because that is how it is treated. The primary cutaneous B-cell lymphomas, primary cutaneous marginal zone lymphoma, primary cutaneous follicle centre lymphoma and primary cutaneous diffuse large B-cell lymphoma of the leg type, arise in the skin from B cells and belong to the B-cell side of the classification; the first two are indolent and the third is not. Primary cutaneous anaplastic large cell lymphoma is in this family, while the systemic anaplastic large cell lymphomas are not, which is the distinction that most often goes wrong because the cells look the same.\n\nHow common they are, and how they behave. The skin lymphomas are rare. In the United Kingdom population series that reports lymphoma by subtype, mycosis fungoides accounted for 39 of 5,796 lymphomas and the CD30-positive lymphoproliferative disorders for 37, European age-standardised rates of 0.12 and 0.13 per 100,000 a year, with five-year relative survival of 86.6 and 88.3 per cent. Those two figures carry the character of the family: most of these conditions are long-term skin diseases that are managed for decades rather than cancers that are cured or not cured, and the usual harm is over-treatment rather than under-treatment. The aggressive members, the gamma/delta lymphoma and the CD8-positive aggressive epidermotropic lymphoma, are the exceptions and are treated as systemic disease from the start.\n\nHow they are staged. Mycosis fungoides and Sezary syndrome are staged by the ISCL and EORTC system revised in 2007, which classifies the skin, the lymph nodes, the viscera and the blood separately; that system is on the mycosis fungoides page. The other cutaneous lymphomas use a separate ISCL and EORTC system that records the number, size and distribution of skin lesions and whether lymph nodes or other organs are involved. Neither is the Lugano classification used for nodal lymphoma, because counting lymph node regions does not describe a disease that lives in the skin.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Mycosis_fungoides","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Mycosis_fungoides"},{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"},{"label":"Lymphoma Action: types of lymphoma (UK patient charity)","url":"https://lymphoma-action.org.uk/types-lymphoma"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"}],"tags":["subtype-page"],"related":["peripheral-t-cell-lymphoma","marginal-zone-lymphoma","ig-tcr-clonality","mycosis-fungoides","sezary-syndrome","lymphomatoid-papulosis","primary-cutaneous-anaplastic-large-cell-lymphoma","primary-cutaneous-marginal-zone-lymphoma"],"cancers":[],"sections":[],"technologies":["clonality-testing","flow-cytometry-mrd","histopathology-ihc"],"targets":["ccr4","cd52","cd30","stat3","stat5","jak3"],"drugs":["hypericin-sgx301"],"companies":[],"institutions":[],"pathways":["jak-stat","tumor-microenvironment"],"terms":["lymphoma-bio-lineage-antigen-cost","lymphoma-classification-2022","lymphoma-b-versus-t-cell","lymphoma-indolent-versus-aggressive","lymphoma-nodal-versus-extranodal","lymphoma-tx-skin-directed-therapy"],"trials":["alcanza","mavoric"],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2022-lymphoid-alaggio-leukemia-2022","paper-mavoric-mogamulizumab-lancet-oncol-2018","paper-alcanza-brentuximab-vedotin-lancet-2017","paper-olsen-mycosis-fungoides-staging-blood-2007"],"journals":[],"dependsOn":[],"notes":["Taxonomy. WHO-HAEM5 gives the primary cutaneous T-cell lymphomas a family of their own with nine entities, and separated four of them from a single previous heading, cutaneous peripheral T-cell lymphoma, rare subtypes, because two of the four are indolent and two are aggressive. Sezary syndrome is classified among the mature T-cell and NK-cell leukaemias rather than in this family, and is kept beside mycosis fungoides here because that is how it is treated. The primary cutaneous B-cell lymphomas arise in the skin and belong to the B-cell side of the classification."],"group":"haematologic","burden":"Rare. In the United Kingdom population series that reports lymphoma by subtype, mycosis fungoides accounted for 39 of 5,796 lymphomas and the primary cutaneous CD30-positive lymphoproliferative disorders for 37, European age-standardised rates of 0.12 and 0.13 per 100,000 a year, with five-year relative survival of 86.6 and 88.3 per cent respectively. The remaining entities in the family are individually rarer than either.","subtypes":["Mycosis fungoides, early stage (patches and plaques)","Mycosis fungoides, tumour stage and large-cell transformation","Folliculotropic mycosis fungoides","Sezary syndrome (erythroderma with blood involvement)","Primary cutaneous CD30-positive lymphoproliferative disorders (related)","Mycosis fungoides, the commonest, with its variants including the folliculotropic form","Primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma","Primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder","Primary cutaneous acral CD8-positive lymphoproliferative disorder, renamed from lymphoma in 2022","Subcutaneous panniculitis-like T-cell lymphoma, which grows in the fat beneath the skin","Primary cutaneous gamma/delta T-cell lymphoma, one of the two aggressive members","Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, the other","Primary cutaneous peripheral T-cell lymphoma, not otherwise specified, a name coined in 2022","Sezary syndrome, which is managed with this family but is classified among the mature T-cell leukaemias"],"biomarkers":["Stage (skin, node, blood, viscera)","CD30 expression (brentuximab vedotin)","CCR4 expression and blood involvement (mogamulizumab)","Large-cell transformation on biopsy","T-cell receptor clonality in skin and blood","Staging that shows no lymphoma outside the skin, which is what makes a cutaneous lymphoma primary","The clinical history and dated photographs, which WHO-HAEM5 calls indispensable because the appearances overlap","CD30, which separates the two CD30-positive lymphoproliferative disorders and decides whether brentuximab vedotin is an option","CD4 against CD8, and alpha-beta against gamma-delta T-cell receptor, which separate the indolent entities from the aggressive ones","A clonal T-cell receptor rearrangement in the skin and, where relevant, in the blood","Blood involvement, which moves the disease from a skin problem to a systemic one"],"standardOfCare":[{"setting":"Early stage (patches and plaques)","approach":"Topical steroids, nitrogen mustard or bexarotene gel; narrowband UVB or PUVA phototherapy; local radiotherapy; total skin electron beam therapy for widespread disease.","refs":["total-skin-electron-therapy","superficial-radiotherapy","bexarotene"]},{"setting":"Advanced skin or blood disease","approach":"Extracorporeal photopheresis, interferon, oral bexarotene, low-dose methotrexate; mogamulizumab for blood involvement (MAVORIC); brentuximab vedotin for CD30-positive disease (ALCANZA); vorinostat or romidepsin.","refs":["methoxsalen-ecp","bexarotene","methotrexate","mogamulizumab","brentuximab-vedotin","vorinostat","romidepsin"]},{"setting":"Refractory or transformed","approach":"Gemcitabine or liposomal doxorubicin chemotherapy; allogeneic stem cell transplant in fit younger patients.","refs":["gemcitabine","allogeneic-hsct"]}],"stateOfArt":["Mogamulizumab and brentuximab vedotin were the first targeted antibodies to beat standard care in randomised trials of this disease.","Skin-directed therapy, including total skin electron beam, keeps most patients well for years without systemic drugs.","Hypericin ointment activated by visible light (HyBryte) completed phase 3 and is under review.","CCR4 is the antigen that defines treatment here. More than 80% of mycosis fungoides and Sezary syndrome carry it, and mogamulizumab, a defucosylated antibody that works mainly through natural killer cells, was tested against vorinostat in 372 previously treated patients.","The cost is specific. CCR4 is also on regulatory T cells, so depleting it causes rash and raises the risk of autoimmune complications, and giving it shortly before an allogeneic transplant has been associated with severe graft-versus-host disease because the cells that would restrain it are gone.","Clonality testing is used more here than in most lymphomas, because the differential against inflammatory skin disease cannot be settled on appearance, and because a clonal T-cell population can be found in reactive skin conditions too, so the result is evidence rather than a diagnosis."],"history":[{"year":1806,"title":"Alibert describes mycosis fungoides","refs":[]},{"year":1987,"title":"Extracorporeal photopheresis approved for cutaneous T-cell lymphoma","refs":["methoxsalen-ecp"]},{"year":1999,"title":"Bexarotene approved","refs":["bexarotene"]},{"year":2006,"title":"Vorinostat: first HDAC inhibitor approved for any cancer","refs":["vorinostat"]},{"year":2017,"title":"ALCANZA: brentuximab vedotin beats standard therapy in CD30-positive disease","refs":["brentuximab-vedotin"]},{"year":2018,"title":"MAVORIC: mogamulizumab approved","refs":["mogamulizumab"]}],"pipeline":["soligenix","mogamulizumab"],"openProblems":["Diagnosis takes years because early disease mimics eczema.","No cure without transplant.","Quality of life with itch and visible disease is under-measured in trials.","The diagnosis depends on a correlation between the biopsy and the clinical course, and that correlation is only as good as the access to a dermatologist who sees these conditions often. Most people with early mycosis fungoides are managed for years before anybody makes it.","Over-treatment is the commonest harm in this family. Combination chemotherapy produces short remissions and real damage in conditions that are otherwise controlled for decades.","The two aggressive entities in the family are individually so rare that their treatment rests on case series, and they are easy to mistake for the indolent ones at first."],"basics":{"symptoms":["Flat scaly patches that have been treated as eczema or psoriasis for years, which is the usual start of mycosis fungoides.","Crops of small red bumps that ulcerate, crust and heal on their own over weeks, leaving small scars, which is lymphomatoid papulosis.","One or a few firm red or violet nodules, often ulcerated, which is primary cutaneous anaplastic large cell lymphoma.","Deep tender lumps in the fat of the limbs or trunk, sometimes with fevers, which is subcutaneous panniculitis-like T-cell lymphoma.","Redness over most of the body with intense itch, which is erythroderma and raises the question of Sezary syndrome.","Rapidly growing, ulcerating tumours over weeks rather than years, which point to one of the two aggressive entities and are treated urgently."],"diagnosis":["A skin biopsy, read by a dermatopathologist alongside the clinical history and photographs. Several biopsies over months or years are normal in early disease and are not a failure.","Immunohistochemistry for the T-cell markers, CD30, CD4 and CD8, and for the type of T-cell receptor the cells carry.","A test for a clonal T-cell receptor rearrangement in the skin, which supports the diagnosis and does not make it on its own: clones are found in inflammatory skin disease too.","Blood tests including a film and flow cytometry for circulating lymphoma cells where the skin is red all over or the disease is advanced.","Imaging and, where indicated, a lymph node biopsy to confirm there is no lymphoma outside the skin, which is what makes it a primary cutaneous lymphoma."],"staging":["Mycosis fungoides and Sezary syndrome use the ISCL and EORTC system revised in 2007, which classifies skin, nodes, viscera and blood separately.","The other cutaneous lymphomas use a separate ISCL and EORTC system that records the number, size and distribution of lesions and whether nodes or organs are involved.","The Lugano classification used for nodal lymphoma is not used here, because counting lymph node regions does not describe a disease that lives in the skin.","Stage decides the treatment more directly than in most lymphomas: skin-directed treatment for skin-limited disease, systemic treatment once the nodes, organs or blood are involved."],"sources":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"},{"label":"Lymphoma Action: types of lymphoma (UK patient charity)","url":"https://lymphoma-action.org.uk/types-lymphoma"}]},"parent":"peripheral-t-cell-lymphoma"},{"id":"cystic-duct-carcinoma","kind":"cancer","name":"Cystic duct carcinoma","aka":["Cystic duct cancer","Carcinoma of the cystic duct","Remnant cystic duct carcinoma"],"tldr":"Cystic duct carcinoma is a bile duct cancer arising in the short tube that joins the gallbladder to the main bile duct. It is staged as a gallbladder cancer under the AJCC system, and behaves better when it stays inside the duct than when it grows beyond it. It is so rare that its treatment borrows from gallbladder and bile duct cancer.","summary":"The cystic duct runs from the gallbladder neck to the common hepatic duct. Cancers arising here have been classified sometimes with the extrahepatic bile ducts and sometimes with the gallbladder; the AJCC staging manual has placed the cystic duct in the gallbladder chapter since its 7th edition (2010) (Prasoon 2019), and the WHO classification covers the gallbladder and extrahepatic bile ducts in one chapter. A 2025 Korean study compared 38 cystic duct cancers with 345 gallbladder and 349 distal bile duct cancers: overall survival did not differ between the three, the gallbladder T categories separated survival in cystic duct cancer better than the bile duct categories did, and tumours confined within the duct (Nakata type 1) did significantly better than those extending beyond it, leading the authors to propose a two-tier T category (T1 confined to the duct, T2 beyond it) (Kim 2025). Cancers can also arise in the cystic duct remnant years after cholecystectomy; jaundice, haemobilia and positive bile cytology led to the diagnosis in one reported case, staged pT1b N0 after bile duct resection (Prasoon 2019).\n\nWhat differs in treatment: the tumour sits at the junction with the common duct, so resection usually means excision of the extrahepatic bile duct with hepaticojejunostomy and regional lymphadenectomy, often with the gallbladder and liver bed as in a radical cholecystectomy, and the cystic duct margin of any gallbladder specimen is where such a tumour is first suspected. Systemic treatment follows the biliary tract cancer trials. No trial has studied cystic duct cancer on its own.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Cystic_duct","links":[{"label":"Kim, Cancer Res Treat 2025: stage evaluation of cystic duct cancer","url":"https://doi.org/10.4143/crt.2024.660"},{"label":"Prasoon, BMC Surg 2019: remnant cystic duct adenocarcinoma, with the AJCC history of cystic duct staging","url":"https://doi.org/10.1186/s12893-019-0647-9"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"}],"tags":["gallbladder","biliary","subtype-page"],"related":["gallbladder","cholangiocarcinoma","extrahepatic-cholangiocarcinoma","incidental-gallbladder-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["cystic-duct-margin","obstructive-jaundice","biliary-anatomy-subtypes"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Very rare: 38 cases against 345 gallbladder and 349 distal bile duct cancers in the Korean series that defined its staging (Kim 2025); only a handful of cancers arising in the remnant cystic duct after cholecystectomy have ever been reported (Prasoon 2019).","subtypes":["Cystic duct carcinoma confined within the cystic duct (Nakata type 1; better survival)","Cystic duct carcinoma extending to the gallbladder neck or common bile duct (Nakata types 2 to 4)","Carcinoma arising in the remnant cystic duct after cholecystectomy"],"biomarkers":["Extent: confined to the duct or beyond it","T category by the gallbladder scheme","Bile duct margin status","Bile cytology in remnant duct cancer"],"standardOfCare":[{"setting":"Resectable disease","approach":"Extrahepatic bile duct resection with regional lymphadenectomy, with cholecystectomy and liver bed resection as for radical cholecystectomy when the gallbladder is still present.","refs":["radical-cholecystectomy","lymphadenectomy","cystic-duct-margin","biliary-stenting-drainage"]},{"setting":"Advanced disease","approach":"As for biliary tract cancer.","refs":["gemcitabine-cisplatin","durvalumab","pembrolizumab"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"gallbladder"},{"id":"dedifferentiated-chordoma","kind":"cancer","name":"Dedifferentiated chordoma","aka":["Chordoma with sarcomatous transformation","Dedifferentiated chordoma (high-grade sarcoma in a chordoma)"],"tldr":"Dedifferentiated chordoma is a rare form of chordoma in which part of the tumour has turned into a high-grade sarcoma, usually after recurrence or radiotherapy but sometimes from the start. The sarcoma part decides the outcome and made up 3 to 95 percent of the tumour in the defining series, smaller areas doing better, so it is treated with surgery and sarcoma chemotherapy.","summary":"The WHO bone classification lists dedifferentiated chordoma as a chordoma subtype defined by a high-grade sarcoma juxtaposed to conventional chordoma (Am J Surg Pathol 2020). In the ten-case series the tumours measured 2.8 to 24.5 cm (median 5.8), arose de novo or at recurrence including after radiotherapy in the sacrum (5), skull base (2), lumbar spine, mediastinum and as a lung metastasis, the dedifferentiated component made up 3 to 95 percent (median 60) and was pleomorphic to fibrosarcomatous, and by immunohistochemistry the conventional or chondroid component kept cytokeratin and brachyury while the dedifferentiated component lost both (Am J Surg Pathol 2020). The dedifferentiated component dictates survival, smaller areas carrying a better prognosis; it is more often diagnosed in recurrences and after radiotherapy but arises de novo in a few (JBJS British 2008).\n\nHow it differs from its parent: loss of brachyury in the sarcomatous part, rapid growth and early metastasis against the slow course of conventional chordoma, and a treatment plan that borrows from high-grade soft tissue sarcoma.\n\nHow common: about 1 percent of chordomas (Am J Surg Pathol 2020).\n\nTreatment: en bloc resection where possible, radiotherapy (proton or carbon ion as on the parent page) and anthracycline-based chemotherapy for the sarcomatous component, borrowed from the sarcoma page; there is no trial in the subtype itself, so treatment is planned at a chordoma or sarcoma centre and chordoma trials are checked.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Chordoma","links":[{"label":"Am J Surg Pathol 2020: dedifferentiated chordoma, clinicopathologic and molecular characteristics","url":"https://doi.org/10.1097/pas.0000000000001501"},{"label":"JBJS British 2008: dedifferentiated chordoma, four cases arising de novo","url":"https://doi.org/10.1302/0301-620x.90b5.20365"}],"tags":["subtype-page","wave4","rare"],"related":["chordoma","poorly-differentiated-chordoma","sarcoma","undifferentiated-pleomorphic-sarcoma"],"cancers":[],"sections":[],"technologies":["proton-therapy"],"targets":["tbxt"],"drugs":["doxorubicin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"Under 1 percent of chordomas: 10 cases among more than 1,000 chordomas surveyed at one centre, seven men and three women aged 15 to 80 (median 54) (Am J Surg Pathol 2020).","subtypes":["Dedifferentiated chordoma arising in recurrent or irradiated conventional chordoma","Dedifferentiated chordoma arising de novo","Dedifferentiated chordoma with chondroid conventional component","Conventional and chondroid chordoma (the parent page)"],"biomarkers":["Brachyury (TBXT) and cytokeratin lost in the dedifferentiated component","Proportion of dedifferentiated component (prognostic)","High-grade sarcoma morphology (pleomorphic, fibrosarcomatous, rarely osteosarcoma or rhabdomyosarcoma)"],"standardOfCare":[{"setting":"All cases","approach":"En bloc resection, radiotherapy as on the chordoma page, and anthracycline-based chemotherapy for the sarcomatous component; no trial in the subtype.","refs":["chordoma","sarcoma","proton-therapy","doxorubicin"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"chordoma"},{"id":"dermatofibrosarcoma-protuberans","kind":"cancer","name":"Dermatofibrosarcoma protuberans","aka":["DFSP","Bednar tumour (pigmented dermatofibrosarcoma protuberans)","Fibrosarcomatous dermatofibrosarcoma protuberans"],"tldr":"Dermatofibrosarcoma protuberans is a rare, slow-growing cancer of the deeper skin that usually appears as a firm plaque or lump on the trunk and is often mistaken for a scar or cyst for years. Surgery with wide margins cures most people; for the few whose tumour cannot be removed or has spread, the pill imatinib works because almost every one is driven by a single gene fusion it blocks.","summary":"Dermatofibrosarcoma protuberans is a low-grade sarcoma of the dermis and subcutis driven in more than nine in ten cases by a translocation fusing COL1A1 to PDGFB, which places the platelet-derived growth factor B gene under a collagen promoter and creates an autocrine loop through the PDGFRB receptor. It presents as a slowly enlarging, indurated plaque or nodule, most often on the trunk or proximal limbs, that infiltrates far beyond its visible edge along fibrous septa. About one in ten tumours contains a fibrosarcomatous component, which raises the recurrence and metastatic risk; metastasis, mostly to lung, otherwise occurs in fewer than one in twenty patients. The pigmented Bednar variant and the giant cell fibroblastoma of children are related tumours with the same fusion.\n\nSurgery is the treatment: wide excision with 2 to 3 centimetre margins to fascia, or Mohs micrographic surgery or its slow variant with paraffin sections, which lets the surgeon trace the finger-like extensions and gives the lowest recurrence rates. Recurrence is a function of margin status, so re-excision of involved margins is standard, and radiotherapy is added when clear margins cannot be achieved at sites such as the head and neck. Fibrosarcomatous tumours are followed with imaging for lung metastases.\n\nImatinib, which inhibits PDGFRB, produced responses in about half of the 24 patients with unresectable or metastatic disease in the pooled EORTC 62027 and SWOG S0345 phase 2 trials, and was approved for unresectable, recurrent or metastatic dermatofibrosarcoma protuberans in October 2006, one of the first uses of a targeted drug chosen by a fusion. It is also given before surgery to shrink large or awkwardly placed tumours and reduce the defect. Fusion-negative tumours do not respond, so confirming the COL1A1-PDGFB fusion by FISH or sequencing is required before treatment; sunitinib and pazopanib have activity after imatinib failure, and fibrosarcomatous or metastatic disease may need sarcoma-type chemotherapy.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Dermatofibrosarcoma_protuberans","links":[{"label":"Imatinib in DFSP, pooled EORTC and SWOG trials (JCO 2010)","url":"https://ascopubs.org/doi/10.1200/JCO.2009.25.9899"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Dermatofibrosarcoma_protuberans"}],"tags":["subtype-page"],"related":["sarcoma","kaposi-sarcoma","desmoid-tumour","tenosynovial-giant-cell-tumour","gist","inflammatory-myofibroblastic-tumour"],"cancers":[],"sections":[],"technologies":["mohs-surgery","kinase-inhibitors","imrt-igrt"],"targets":["pdgfrb","pdgfra"],"drugs":["imatinib","sunitinib","pazopanib"],"companies":[],"institutions":[],"pathways":[],"terms":["wide-local-excision","rare-cancers"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-imatinib-dfsp-eortc-swog-rutkowski-jco-2010","paper-simon-col1a1-pdgfb-dfsp-nat-genet-1997"],"journals":[],"dependsOn":[],"notes":[],"group":"skin","burden":"Dermatofibrosarcoma protuberans is a rare sarcoma of the skin, about four cases per million people a year, commonest in adults aged 20 to 50 and roughly twice as common in Black people; it is slow-growing and rarely spreads, but it recurs locally if not excised with wide margins.","subtypes":["Classic dermatofibrosarcoma protuberans (DFSP; low grade, dermal and subcutaneous)","Fibrosarcomatous DFSP (higher grade, higher recurrence and metastatic risk)","Bednar tumour (pigmented DFSP)","Giant cell fibroblastoma (childhood variant with the same fusion)","Unresectable, recurrent or metastatic DFSP (imatinib candidates)","Fusion-negative DFSP (does not respond to imatinib)"],"biomarkers":["COL1A1-PDGFB fusion by fluorescence in situ hybridisation or sequencing (required before imatinib)","CD34 positivity and factor XIIIa negativity on immunohistochemistry","Fibrosarcomatous component on histology","Margin status after excision","Rare alternative PDGFD fusions in fusion-negative cases"],"standardOfCare":[{"setting":"Localised disease","approach":"Wide local excision with 2 to 3 cm margins to fascia, or Mohs micrographic surgery with complete circumferential margin assessment; re-excision for involved margins.","refs":["mohs-surgery","wide-local-excision"],"guideline":{"version":"NCCN Guidelines: Dermatofibrosarcoma Protuberans"}},{"setting":"Positive margins not amenable to further surgery","approach":"Adjuvant radiotherapy to the tumour bed.","refs":["imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Dermatofibrosarcoma Protuberans"}},{"setting":"Unresectable, recurrent or metastatic disease","approach":"Imatinib after confirming the COL1A1-PDGFB fusion (EORTC 62027 and SWOG S0345); surgery after response where feasible.","refs":["imatinib","pdgfrb"],"guideline":{"version":"NCCN Guidelines: Dermatofibrosarcoma Protuberans"}},{"setting":"Neoadjuvant","approach":"Imatinib for several months to shrink large or facial tumours before excision.","refs":["imatinib"],"guideline":{"version":"NCCN Guidelines: Dermatofibrosarcoma Protuberans"}},{"setting":"After imatinib failure or fibrosarcomatous metastatic disease","approach":"Sunitinib or pazopanib; sarcoma-type chemotherapy with doxorubicin for metastatic fibrosarcomatous disease.","refs":["sunitinib","pazopanib","doxorubicin"],"guideline":{"version":"NCCN Guidelines: Dermatofibrosarcoma Protuberans"}}],"stateOfArt":["Wide excision or Mohs surgery cures the great majority, and margin-controlled surgery has cut recurrence rates sharply.","Imatinib, chosen by the COL1A1-PDGFB fusion, gives responses in about half of unresectable or metastatic tumours and can make surgery possible.","Fusion testing separates responders from the rare fusion-negative tumours that need other treatment."],"history":[{"year":1924,"title":"Darier and Ferrand describe the tumour; Hoffmann names it dermatofibrosarcoma protuberans in 1925","refs":[]},{"year":1997,"title":"COL1A1-PDGFB fusion identified as the driver (Simon and colleagues, Nature Genetics)","refs":["pdgfrb"]},{"year":2002,"title":"First reports of imatinib responses in metastatic dermatofibrosarcoma protuberans","refs":["imatinib"]},{"year":2006,"title":"Imatinib approved for unresectable, recurrent or metastatic disease","refs":["imatinib"]},{"year":2010,"title":"Pooled EORTC 62027 and SWOG S0345: imatinib responses in about half of patients (JCO)","refs":["imatinib"]}],"pipeline":["imatinib","sunitinib","pazopanib"],"openProblems":["Diagnosis is delayed for years because the tumour looks like a scar, keloid or cyst.","Responses to imatinib are not permanent and the drugs after it have only small series behind them.","Fibrosarcomatous transformation is the cause of most deaths and has no specific therapy."],"parent":"sarcoma"},{"id":"desmoid-tumour","kind":"cancer","name":"Desmoid tumour","aka":["Aggressive fibromatosis","Desmoid-type fibromatosis"],"tldr":"Desmoid tumours are locally aggressive growths of fibroblast-like cells, classed with soft-tissue sarcomas, driven by WNT mutations, that never spread to distant organs but can invade nerves, bowel and muscle. Many stop growing or shrink on their own, so watching first is standard; if they progress, the gamma-secretase inhibitor nirogacestat, approved in 2023, shrinks tumours and relieves pain.","summary":"Desmoid tumours are monoclonal fibroblastic proliferations driven by WNT pathway activation: about 85 percent carry somatic CTNNB1 (beta-catenin) mutations (T41A, S45F, S45P) and most of the rest arise in familial adenomatous polyposis through germline APC loss. They do not metastasise but infiltrate locally in the abdominal wall, mesentery, limbs and trunk, and their course is unpredictable: a substantial fraction stabilise or regress spontaneously, which is why the Desmoid Tumor Working Group consensus (2020) recommends active surveillance as the initial approach for most patients, with treatment reserved for progression or symptoms.\n\nWhen treatment is needed the order has inverted over two decades: surgery, once first line, is now used selectively because recurrence after resection is common (S45F mutations and extra-abdominal sites recur most). Medical options are sorafenib (Alliance A091105, NEJM 2018: longer progression-free survival than placebo), nirogacestat (DeFi, NEJM 2023: fewer progressions than placebo with improvements in pain, symptom burden and physical function; FDA approval November 2023, the first drug approved for desmoid tumours), low-dose methotrexate-vinblastine or vinorelbine, and anthracycline chemotherapy for rapidly progressive disease. Cryoablation and high-intensity focused ultrasound offer local control for extra-abdominal tumours.\n\nGamma-secretase inhibitors block NOTCH cleavage, and their class toxicity is ovarian dysfunction in women of reproductive age, often reversible; a second agent, AL102, has completed the RINGSIDE phase 3. Open questions are how long to treat, whether intermittent dosing preserves benefit, and how to sequence surveillance, ablation and drugs.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Aggressive_fibromatosis","links":[{"label":"NCI PDQ: soft tissue sarcoma","url":"https://www.cancer.gov/types/soft-tissue-sarcoma"},{"label":"Desmoid Tumor Working Group consensus (Eur J Cancer 2020)","url":"https://doi.org/10.1016/j.ejca.2020.06.022"},{"label":"DeFi trial (NEJM 2023)","url":"https://doi.org/10.1056/NEJMoa2210140"},{"label":"FDA approval of nirogacestat","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nirogacestat-desmoid-tumors"}],"tags":["nci-coverage","rare","sarcoma"],"related":["tenosynovial-giant-cell-tumour","dermatofibrosarcoma-protuberans","inflammatory-myofibroblastic-tumour","gist"],"cancers":[],"sections":[],"technologies":["active-surveillance","mri","cytotoxic-chemotherapy","kinase-inhibitors"],"targets":[],"drugs":["nirogacestat","sorafenib","methotrexate","doxorubicin"],"companies":["springworks","bayer","elpiscience-suzhou-biopharma"],"institutions":[],"pathways":["wnt","notch"],"terms":["rare-cancers"],"trials":["defi","nct04871282"],"people":[],"bottlenecks":["b-rare-cancers","b-toxicity-qol"],"keyPapers":["paper-timbergen-eur-j-cancer","paper-gounder-n-engl-j-med"],"journals":["european-journal-of-cancer"],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"Roughly 2 to 5 new cases per million people per year, most often in young adults; more common in women and in people with familial adenomatous polyposis.","subtypes":["Sporadic (CTNNB1-mutant) desmoid","FAP-associated (APC-mutant) desmoid, often intra-abdominal","Abdominal wall desmoid (often post-partum)","Extra-abdominal desmoid (limb, trunk, head and neck)"],"biomarkers":["CTNNB1 mutation type (S45F associated with higher recurrence)","Germline APC testing when intra-abdominal or multifocal","Nuclear beta-catenin immunostaining","MRI T2 signal (hypointense tumours are more likely to be stable or regressing)","Symptom and pain scores (treatment triggers)"],"standardOfCare":[{"setting":"Newly diagnosed, asymptomatic or minimally symptomatic","approach":"Active surveillance with MRI at 1 to 2 months, then every 3 to 6 months; treat only on progression or symptoms.","refs":["active-surveillance","mri"],"guideline":{"nccn":"Category 2A (observation)","version":"Desmoid Tumor Working Group consensus (Eur J Cancer 2020); NCCN Soft Tissue Sarcoma","url":"https://doi.org/10.1016/j.ejca.2020.06.022"}},{"setting":"Progressive or symptomatic disease","approach":"Nirogacestat (DeFi) or sorafenib (Alliance A091105); alternatives include methotrexate-vinblastine, vinorelbine, anthracycline-based chemotherapy for rapidly progressive disease, and cryoablation for accessible extra-abdominal tumours.","refs":["nirogacestat","sorafenib","defi","methotrexate"],"guideline":{"nccn":"Category 1 (nirogacestat), Category 2A (sorafenib)","version":"NCCN Soft Tissue Sarcoma"}},{"setting":"Surgery","approach":"Reserved for selected abdominal wall tumours or complications (bowel obstruction, fistula); margins do not reliably predict recurrence.","refs":["limb-salvage-surgery"]}],"stateOfArt":["Watching first is now the standard: prospective surveillance cohorts showed spontaneous stabilisation or regression in a large minority, avoiding surgical morbidity for many.","Nirogacestat is the first drug approved specifically for desmoid tumours and the first gamma-secretase inhibitor approved for any cancer, converting a WNT-driven disease into a NOTCH-targeted indication.","Sorafenib gave the first randomised evidence that a systemic drug controls the disease, and remains an option where nirogacestat is unavailable.","Local ablation (cryoablation, HIFU) offers organ-sparing control for extra-abdominal tumours and is being compared with drugs in trials."],"history":[{"year":1832,"title":"MacFarlane describes abdominal wall tumours later called desmoid","note":"Named from the Greek for band-like.","refs":[]},{"year":1997,"title":"CTNNB1 and APC mutations link desmoid to the WNT pathway","note":"Tejpar and colleagues.","refs":[]},{"year":2011,"title":"Prospective observation cohorts published","note":"French Sarcoma Group and others show frequent spontaneous stabilisation, seeding the surveillance-first approach.","refs":[]},{"year":2018,"title":"Sorafenib beats placebo (Alliance A091105)","note":"Gounder and colleagues, NEJM.","refs":["sorafenib"]},{"year":2020,"title":"Desmoid Tumor Working Group consensus","note":"Active surveillance as initial management for most patients (Eur J Cancer).","refs":["active-surveillance"]},{"year":2023,"title":"Nirogacestat approved","note":"DeFi phase 3 (NEJM 2023); FDA approval 27 November 2023, the first for desmoid tumours.","refs":["nirogacestat","defi"]}],"pipeline":["nirogacestat","idea-desmoid-intermittent-dosing","defi","varegacestat"],"openProblems":["Ovarian toxicity of gamma-secretase inhibitors in young women: dose interruption and intermittent schedules are being explored.","Optimal treatment duration and whether responses persist after stopping nirogacestat.","Predicting which tumours will regress spontaneously (MRI signal and mutation type are candidate markers).","Head-to-head comparison of cryoablation versus systemic therapy for extra-abdominal disease."],"parent":"sarcoma"},{"id":"desmoplastic-small-round-cell-tumour","kind":"cancer","name":"Desmoplastic small round cell tumour","aka":["DSRCT","Desmoplastic small round cell tumor","Intra-abdominal desmoplastic small round cell tumour","EWSR1-WT1 sarcoma"],"tldr":"Desmoplastic small round cell tumour is a very rare sarcoma of adolescents and young men that grows across the lining of the abdomen as many nodules, driven by an EWSR1-WT1 fusion. Treatment is intensive chemotherapy, surgery to remove every nodule, sometimes heated abdominal chemotherapy, and radiotherapy. Most still relapse within three years, so it is treated at a sarcoma centre running trials.","summary":"Desmoplastic small round cell tumour is a small round cell sarcoma of the WHO soft tissue classification defined by the EWSR1-WT1 fusion, which up-regulates PDGFR-alpha, VEGF and other proliferation and vascular genes; it affects adolescents and young adults with a male predominance and arises from the serosal surface of the abdominal cavity (Cancers 2021). In 192 SEER cases the peak incidence was at 20 to 24 years, incidence was higher in black than white Americans, survival did not differ by sex or ethnicity, and radiotherapy after surgery was associated with a survival advantage in the adjusted analysis (Journal of Cancer Epidemiology 2014). Current management combines chemotherapy, radiotherapy and aggressive cytoreductive surgery with hyperthermic intraperitoneal chemotherapy, but most patients recur and die within three years; pazopanib, sunitinib and mTOR inhibitors have been evaluated in small trials (Cancers 2021).\n\nHow it differs from its parent: a fusion-defined sarcoma of the peritoneum rather than a limb or retroperitoneal mass, spreading as peritoneal carcinomatosis with liver metastases, treated on Ewing-type chemotherapy backbones because of its EWSR1 fusion, and with a surgical strategy borrowed from peritoneal surface oncology.\n\nHow common: 0.2 to 0.5 per million a year (Journal of Cancer Epidemiology 2014).\n\nTreatment: multi-agent Ewing-type chemotherapy (vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide), complete cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy, whole-abdominal radiotherapy in some centres, and pazopanib, sunitinib or mTOR inhibitors for relapsed disease; trials are the recommended route given the outcomes (Cancers 2021).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Desmoplastic_small-round-cell_tumor","links":[{"label":"NCI PDQ: childhood soft tissue sarcoma treatment","url":"https://www.cancer.gov/types/soft-tissue-sarcoma/patient/child-soft-tissue-treatment-pdq"},{"label":"Journal of Cancer Epidemiology 2014: incidence and outcomes of desmoplastic small round cell tumour, SEER","url":"https://doi.org/10.1155/2014/680126"},{"label":"Cancers 2021: desmoplastic small round cell tumour, molecular abnormalities and emerging therapy (review)","url":"https://doi.org/10.3390/cancers13030498"}],"tags":["subtype-page","wave4","rare"],"related":["sarcoma","ewing-sarcoma","rhabdomyosarcoma","peritoneal-mesothelioma","childhood-cancers","adamantinoma"],"cancers":[],"sections":[],"technologies":["hipec"],"targets":["wt1","pdgfra"],"drugs":["vincristine","doxorubicin","cyclophosphamide","ifosfamide","etoposide","pazopanib","sunitinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"Very rare: 192 cases in the US SEER registry, with peak incidence at ages 20 to 24 and age-adjusted rates of 0.5 per million in black and 0.2 per million in white Americans (Journal of Cancer Epidemiology 2014).","subtypes":["Intra-abdominal desmoplastic small round cell tumour (peritoneal; the usual form)","Extra-abdominal desmoplastic small round cell tumour (thoracic, paratesticular; rare)","Desmoplastic small round cell tumour with liver metastases at diagnosis"],"biomarkers":["EWSR1-WT1 fusion (FISH or RT-PCR); WT1 C-terminus immunohistochemistry","Polyphenotypic staining (cytokeratin, desmin, neural markers)","Peritoneal cancer index and completeness of cytoreduction","PDGFR-alpha and VEGF expression (targets)"],"standardOfCare":[{"setting":"All cases","approach":"Ewing-type multi-agent chemotherapy, complete cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy, radiotherapy in some centres; pazopanib, sunitinib or mTOR inhibitors on relapse; trials recommended.","refs":["sarcoma","vincristine","doxorubicin","cyclophosphamide","ifosfamide","etoposide","hipec","pazopanib","sunitinib"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"sarcoma"},{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","aka":[],"tldr":"Diffuse large B-cell lymphoma (DLBCL) is an aggressive but curable lymphoma. CAR-T cures about 40% of relapsed patients, and off-the-shelf bispecifics are now approved.","summary":"Diffuse large B-cell lymphoma is the most common aggressive lymphoma, about 30% of all non-Hodgkin lymphoma, with a median age around 65. It is curable: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) cures roughly 60% of patients, more with low IPI and fewer with high-risk features (IPI 3-5, double-hit MYC/BCL2 rearrangement, activated B-cell origin, TP53 loss). Staging uses PET-CT and the Lugano classification; biology is read from cell of origin and FISH for MYC, BCL2 and BCL6, with genetic classifiers (LymphGen) and ctDNA emerging.\n\nFrontline therapy stood still for twenty years until POLARIX (2022) showed that replacing vincristine with the CD79b ADC polatuzumab vedotin improves progression-free survival (5-year 64.9% vs 59.1%), and frontMIND (Lancet 2026) showed tafasitamab plus lenalidomide added to R-CHOP improves PFS in IPI 3-5 disease (HR 0.75); epcoritamab plus R-CHOP (EPCORE DLBCL-2) and golcadomide plus R-CHOP (GOLSEEK-1) follow. For the 30-40% who relapse, the sequence has been rebuilt around T-cell redirection: CD19 CAR-T (axi-cel, liso-cel) beats salvage chemotherapy and transplant for relapse within a year (ZUMA-7 with an overall survival benefit; TRANSFORM), while transplant remains for later chemosensitive relapse. Off-the-shelf CD20×CD3 bispecifics (glofitamab, epcoritamab, mosunetuzumab, odronextamab) give complete remissions in about 40% of heavily pretreated patients, and chemotherapy-free doublets such as mosunetuzumab-polatuzumab (SUNMO) beat salvage chemotherapy. CD19 ADC (loncastuximab), tafasitamab-lenalidomide, and the ROR1 ADC zilovertamab vedotin fill later lines.\n\nThe open questions are regulatory as much as scientific. EPCORE DLBCL-1 (2026) improved PFS but not overall survival against chemotherapy; STARGLO's survival benefit was rejected by the FDA because the trial was mostly enrolled in Asia. Nobody has compared bispecifics with CAR-T head to head. ctDNA (PhasED-seq) predicts cure better than PET and is the obvious tool for response-adapted frontline therapy. Primary refractory disease, CNS relapse, older and frail patients, and access to CAR-T outside major centres remain the hard problems.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Diffuse_large_B-cell_lymphoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Diffuse_large_B-cell_lymphoma"},{"label":"Lymphoma Action: helpline services","url":"https://lymphoma-action.org.uk/information-and-support/support-you/helpline-services"},{"label":"Lymphoma Action: questions to ask your medical team about lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/questions-ask-your-medical-team-about-lymphoma"},{"label":"Lymphoma Action: follow-up after lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/follow-after-lymphoma-treatment"},{"label":"Lymphoma Action: infections, risk and prevention","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/infections-risk-and-prevention"},{"label":"Lymphoma Action: neutropenia (low neutrophils)","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/neutropenia-low-neutrophils"},{"label":"Lymphoma Action: cancer-related fatigue","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/cancer-related-fatigue"},{"label":"Lymphoma Action: lymphoma, work and you","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/day-day-living/lymphoma-work-and-you"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Lymphoma Action: diffuse large B-cell lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/types-lymphoma/non-hodgkin-lymphoma/diffuse-large-b-cell-lymphoma"},{"label":"Lymphoma Action: CAR-T cell therapy","url":"https://lymphoma-action.org.uk/information-and-support/lymphoma-treatment/car-t-cell-therapy"},{"label":"Lymphoma Action: autologous (your own) stem cell transplant","url":"https://lymphoma-action.org.uk/information-and-support/lymphoma-treatment/stem-cell-transplants/self-autologous-stem-cell"},{"label":"Lymphoma Action: when lymphoma comes back, or does not respond","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/lymphoma-comes-back-relapses-or-doesnt-respond"},{"label":"Lymphoma Action: CT and PET/CT scans","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/ct-and-petct-scan"},{"label":"Thompson et al., utility of routine post-therapy surveillance imaging in diffuse large B-cell lymphoma, Journal of Clinical Oncology 2014","url":"https://doi.org/10.1200/JCO.2014.55.7561"},{"label":"NHS: non-Hodgkin lymphoma, treatment","url":"https://www.nhs.uk/conditions/non-hodgkin-lymphoma/treatment/"},{"label":"Macmillan: non-Hodgkin lymphoma","url":"https://www.macmillan.org.uk/cancer-information-and-support/lymphoma/non-hodgkin-lymphoma"}],"tags":["heme","spike"],"related":["car-t-before-transplant-lbcl","bispecific-plus-adc-lymphoma","lymphoma-research-foundation","follicular-lymphoma","primary-mediastinal-b-cell-lymphoma","burkitt-lymphoma","mantle-cell-lymphoma","primary-cns-lymphoma","peripheral-t-cell-lymphoma","double-hit-rearrangement","myc-bcl2-double-expressor","bcl2-rearrangement","myd88-l265p","cd79b-itam-mutation","ezh2-y646-mutation","ig-tcr-clonality","lymphoma-roadmap","lymphoma-ev-genetic-subtype-directed-first-line","lymphoma-ev-ctdna-instead-of-the-interim-scan","lymphoma-ev-manufacturing-time-as-a-trial-endpoint"],"cancers":[],"sections":[],"technologies":["car-t","t-cell-engager","adc","monoclonal-antibody","ctdna-lymphoma-monitoring","autologous-stem-cell-transplant","protac-degrader","fdg-pet","bispecific-antibody","allogeneic-hsct","pet-ct","imrt-igrt","g-csf-growth-factors","palliative-radiotherapy","palliative-care","fertility-preservation","psycho-oncology","peer-support-groups","survivorship-care-plan","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","multidisciplinary-tumour-board","oncology-nutrition","prehabilitation","histopathology-ihc","cytogenetics-fish","cgp","clonality-testing"],"targets":["cd19","cd20","cd3","ror1","bcl2","ezh2","cd47","cd79b","cd22","myd88","card11","bcl6","myc-gene","crebbp","ep300","kmt2d","tp53","cdkn2a","b2m","btk"],"drugs":["clonoseq","carmustine","prednisone","palifermin","rasburicase","polatuzumab-vedotin","tafasitamab","lenalidomide","glofitamab","epcoritamab","mosunetuzumab","zynlonta","selinexor","zilovertamab-vedotin","tocilizumab","human-normal-immunoglobulin","obinutuzumab","gemcitabine","oxaliplatin","melphalan","thiotepa"],"companies":["marker-therapeutics","ranok-therapeutics-hangzhou","roche-genentech","genmab","abbvie","gilead","bms","incyte","regeneron","adc-therapeutics","merck","novartis","foresight-diagnostics"],"institutions":["mskcc","md-anderson","dana-farber","mayo-clinic","gustave-roussy","the-christie"],"pathways":["apoptosis-bcl2","germinal-centre-reaction","bcr-signalling","inflammation-nfkb","myc","epigenetic-reprogramming"],"terms":["ipi-score","cell-of-origin","double-hit-lymphoma","lugano-classification","mrd","crs","icans","lymphoma-tx-regimen-alphabet","lymphoma-tx-cns-prophylaxis","lymphoma-tx-maintenance","lymphoma-tx-car-t-pathway","lymphoma-tx-bispecific-step-up","lymphoma-tx-transplant-role","lymphoma-tx-radiotherapy","lymphoma-tx-tumour-lysis","lymphoma-tx-hepatitis-b-reactivation","lymphoma-tx-pjp-and-infection-prophylaxis","lymphoma-tx-immunoglobulin-replacement","lymphoma-tx-crs-icans","lymphoma-tx-fertility-preservation","lymphoma-tx-uk-versus-us","lymphoma-tx-uk-access","lymphoma-tx-failed-and-negative","cancer-related-fatigue","late-effects","febrile-neutropenia","neutropenia","financial-toxicity","central-venous-access","hypogammaglobulinaemia","performance-status","quality-of-life","lymphoma-decision-transplant-or-car-t","lymphoma-decision-fertility-timing","lymphoma-decision-trial","lymphoma-decision-local-or-car-t-centre","lymphoma-living-fatigue","lymphoma-living-infection-years-after","lymphoma-living-vaccinations","lymphoma-living-scanxiety-and-surveillance","lymphoma-living-returning-to-work","tumor-lysis-syndrome","deauville","lymphoma-bio-cell-of-origin-in-practice","lymphoma-bio-lymphgen","lymphoma-bio-germinal-centre","lymphoma-bio-antigen-escape","lymphoma-bio-lineage-antigen-cost"],"trials":["nct07011056","nct07570823","nct06929624","nct07409428","nct07188558","nct07215585","nct06792253","nct04442022","nct04529772","nct04094311","nct06717347","nct07226752","nct04384484","nct05429268","nct06508658","nct01804686","nct06091865","nct04404283","l-mind","zuma-1","polarix","frontmind","zuma-7","transform","belinda","starglo","sunmo","epcore-dlbcl-1","epcore-dlbcl-2","lotis-2","waveline-003","golseek-1","flyer","calgb-50303","goya","remarc","polargo","juliet","transcend-nhl-001","polar-bear","arched"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["blood-cancer-discovery","blood-cancer-journal","clinical-lymphoma-myeloma-and-leukemia","current-hematologic-malignancy-reports","haematologica","hematological-oncology","leukemia-and-lymphoma"],"dependsOn":[],"notes":["Living with diffuse large B-cell lymphoma, the decisions and the people who make them: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the 24-hour number they gave you come first, and no figure here is a prediction about you. The decision records, the question sets, the first 60 days checklist and the red cards on this page were written from the NHS, Lymphoma Action, Macmillan and Cancer Research UK patient pages, from NICE NG52, NG47, CG151 and NG234, from the NHS Breast Screening Programme protocols and the Green Book, and from the trial reports named beside each figure, all read on 1 October 2026.","On the second-line decision. The figures in the decision record come from the trials' own publications: ZUMA-7 randomised 359 people and reported 24-month event-free survival of 41 per cent against 16 per cent, and four-year overall survival of 54.6 against 46.0 per cent at a median follow-up of 47.2 months; BELINDA randomised 322 people to a different cell product and found median event-free survival of 3.0 months in both arms. They describe those trial populations, not any one person, and the people in them were selected for early relapse."],"group":"haematologic","burden":"~150,000 new cases a year worldwide; ~25,000 in the US; median age 65; about 60% cured with first-line therapy.","subtypes":["Germinal-centre B-cell-like (GCB) vs activated B-cell-like (ABC / non-GCB)","High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double hit)","LymphGen genetic subtypes: MCD, BN2, N1, EZB, ST2, A53","Primary mediastinal B-cell lymphoma (distinct; PD-1 responsive)","Primary CNS lymphoma (distinct; methotrexate-based)","Transformed indolent lymphoma (Richter, transformed follicular)","EBV-positive DLBCL of the elderly","Primary refractory vs early relapse (<12 months) vs late relapse"],"biomarkers":["Cell of origin (GCB/ABC)","Double-hit (MYC/BCL2)","CD19/CD20","ctDNA MRD","IPI / NCCN-IPI","Cell of origin (Hans IHC, Lymph2Cx)","MYC, BCL2, BCL6 FISH","TP53 mutation","CD19 and CD20 expression (loss after CAR-T or bispecific)","Interim and end-of-treatment PET (Deauville)","ctDNA (PhasED-seq, clonoSEQ)","LDH","CNS-IPI for CNS prophylaxis decisions"],"standardOfCare":[{"setting":"Limited stage (I-II, non-bulky)","approach":"R-CHOP × 4 with PET-guided omission of radiation (FLYER, S1001): 4 cycles if interim PET negative; involved-site radiotherapy if PET positive.","refs":["doxorubicin","fdg-pet","imrt-igrt","lugano-classification"],"guideline":{"nccn":"Category 1 (R-CHOP × 4 PET-adapted for stage I-II)","version":"NCCN B-Cell Lymphomas 2026","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1480"}},{"setting":"Advanced stage, IPI 0-1","approach":"R-CHOP × 6 (or Pola-R-CHP); consider 4 cycles plus 2 rituximab in young low-risk patients (FLYER).","refs":["doxorubicin","polatuzumab-vedotin","ipi-score"],"guideline":{"nccn":"Category 1","version":"NCCN 2026"}},{"setting":"Advanced stage, IPI 2-5","approach":"Pola-R-CHP × 6 (POLARIX) or R-CHOP × 6; tafasitamab + lenalidomide + R-CHOP (frontMIND) pending approval for IPI 3-5; DA-EPOCH-R for double-hit lymphoma; CNS prophylaxis for high CNS-IPI (contested).","refs":["polarix","polatuzumab-vedotin","frontmind","tafasitamab","double-hit-lymphoma"],"guideline":{"nccn":"Pola-R-CHP category 1 for IPI 2-5","version":"NCCN 2026"}},{"setting":"Frail or elderly","approach":"R-mini-CHOP; epcoritamab-based regimens in trials for the elderly (EPCORE NHL-2 cohorts); tafasitamab-lenalidomide where transplant is never an option.","refs":["epcoritamab","tafasitamab","lenalidomide"]},{"setting":"Primary refractory or relapse within 12 months","approach":"CD19 CAR-T (axi-cel or liso-cel) preferred over salvage chemotherapy and transplant (ZUMA-7, TRANSFORM); bridging therapy while manufacturing; bispecific ± chemotherapy if CAR-T unavailable.","refs":["axicabtagene-ciloleucel","zuma-7","transform","car-t"],"guideline":{"nccn":"Category 1 (axi-cel, liso-cel)","version":"NCCN 2026"}},{"setting":"Late relapse (>12 months), transplant-eligible","approach":"Salvage chemotherapy (R-ICE, R-DHAP, R-GemOx) → high-dose therapy and autologous transplant if chemosensitive; CAR-T if not.","refs":["autologous-stem-cell-transplant","car-t"]},{"setting":"Relapse, transplant-ineligible","approach":"CD20×CD3 bispecific (glofitamab, epcoritamab) or mosunetuzumab-polatuzumab (SUNMO); pola-BR; tafasitamab-lenalidomide; loncastuximab tesirine.","refs":["glofitamab","epcoritamab","mosunetuzumab","polatuzumab-vedotin","tafasitamab","zynlonta","sunmo"]},{"setting":"Third line and beyond","approach":"CAR-T if not yet given; bispecific after CAR-T (active in CD19-negative relapse if CD20 retained); loncastuximab; zilovertamab vedotin (trial); allogeneic transplant in selected fit patients; clinical trials.","refs":["axicabtagene-ciloleucel","glofitamab","epcoritamab","zynlonta","zilovertamab-vedotin","waveline-003"]},{"setting":"Before the first dose: the tests that change the plan","approach":"An excision or core biopsy reported to the current WHO classification, with immunohistochemistry for CD20, CD10, BCL6, MUM1, BCL2, MYC, Ki-67 and, where MYC is expressed, fluorescence in situ hybridisation for MYC, BCL2 and BCL6 rearrangements, because a high-grade B-cell lymphoma with MYC and BCL2 rearrangements is treated differently from diffuse large B-cell lymphoma. Staging is by FDG-PET-CT reported by the Lugano classification, with a bone marrow biopsy only where PET leaves a question. Bloods include LDH, which is an IPI factor, and hepatitis B surface antigen and core antibody, hepatitis C and HIV, because all three change treatment. Cardiac function is assessed before doxorubicin. Fertility preservation is offered before the first cycle, not after it. The IPI (age over 60, stage III or IV, more than one extranodal site, performance status 2 or worse, raised LDH) sets the risk group, and the CNS-IPI adds kidney or adrenal involvement to estimate the risk of relapse in the brain.","refs":["lugano-classification","ipi-score","fdg-pet","double-hit-lymphoma","lymphoma-tx-cns-prophylaxis","lymphoma-tx-hepatitis-b-reactivation","lymphoma-tx-fertility-preservation"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; BSH; NCI PDQ adult non-Hodgkin lymphoma","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Limited stage (I to II), non-bulky, low risk: four cycles, and often no radiotherapy","approach":"Four cycles of R-CHOP with two extra doses of rituximab, rather than six cycles, for patients aged 18 to 60 with stage I or II disease, normal LDH, performance status 0 to 1 and no mass of 7.5 cm or more. FLYER randomised 588 such patients and found three-year progression-free survival of 96 per cent with the four-cycle arm, non-inferior to six cycles, and with fewer adverse events recorded in the four-cycle group (294 haematological and 1,036 non-haematological events against 426 and 1,280). Radiotherapy is not given routinely; an involved-site 30 to 40 Gy field is added where the end-of-treatment PET is positive, or for a bulky or skeletal site. The practical point is that a young person with truly limited, low-risk disease is now finished in about three months.","refs":["r-chop","rituximab","cyclophosphamide","doxorubicin","vincristine","prednisone","fdg-pet","imrt-igrt","lymphoma-tx-radiotherapy"],"guideline":{"nccn":"Category 1 (R-CHOP x 4 with rituximab x 2 in this group)","version":"NCCN B-Cell Lymphomas; ESMO; FLYER","url":"https://doi.org/10.1016/S0140-6736(19)33008-9"}},{"setting":"Advanced stage, IPI 0 to 1: R-CHOP for six cycles","approach":"Six cycles of R-CHOP every 21 days. This has been the reference regimen since rituximab was added to CHOP in 2002, and every attempt to improve on it in this risk group has failed: DA-EPOCH-R was no better and more toxic in Alliance/CALGB 50303 (491 patients, progression-free survival hazard ratio 0.93, febrile neutropenia 35.0 against 17.7 per cent), and obinutuzumab in place of rituximab was no better in GOYA (1,418 patients, hazard ratio 0.92). POLARIX, which established polatuzumab vedotin in place of vincristine, enrolled only patients with IPI 2 to 5, so there is no randomised evidence for pola-R-CHP in IPI 0 to 1 disease. Cure is the aim and is achieved in the large majority.","refs":["r-chop","rituximab","doxorubicin","cyclophosphamide","vincristine","prednisone","ipi-score","lymphoma-tx-failed-and-negative","lymphoma-tx-regimen-alphabet"],"guideline":{"nccn":"Category 1","version":"NCCN B-Cell Lymphomas; ESMO; BSH","url":"https://doi.org/10.1200/JCO.18.01994"}},{"setting":"Advanced stage, IPI 2 to 5: pola-R-CHP or R-CHOP, and where polatuzumab did and did not win","approach":"Six cycles of polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin and prednisone (pola-R-CHP), or six cycles of R-CHOP. POLARIX randomised 879 previously untreated patients aged 18 to 80 with IPI 2 to 5: two-year progression-free survival 76.7 against 70.2 per cent (hazard ratio 0.73) and five-year progression-free survival 64.9 against 59.1 per cent (hazard ratio 0.77). Overall survival has not separated: the five-year figures are 82.3 against 79.5 per cent, hazard ratio 0.85, not significant. So polatuzumab prevents some relapses without yet being shown to prevent deaths, and the prespecified subgroup analyses suggested the benefit sat with activated B-cell subtype and with IPI 3 to 5 rather than with germinal centre or IPI 2 disease. That is the whole argument, and it is a reasonable one to have out loud with the patient: an extra drug, more peripheral neuropathy, fewer relapses, no proven survival gain.\n\nThe newer option is tafasitamab and lenalidomide added to R-CHOP for IPI 3 to 5. frontMIND randomised 899 such patients and reported two-year progression-free survival 71.1 against 62.9 per cent (hazard ratio 0.75). DA-EPOCH-R is used instead where the disease is a high-grade B-cell lymphoma with MYC and BCL2 rearrangements, or is primary mediastinal, testicular, or leukaemic.","refs":["polarix","polatuzumab-vedotin","r-chop","rituximab","frontmind","tafasitamab","lenalidomide","ipi-score","double-hit-lymphoma","lymphoma-tx-regimen-alphabet"],"guideline":{"nccn":"Category 1 (pola-R-CHP, IPI 2 or above)","version":"NCCN B-Cell Lymphomas; ESMO; POLARIX","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit), and MYC with BCL6","approach":"Dose-adjusted EPOCH-R rather than R-CHOP, with central nervous system-directed treatment, on the basis of consistent retrospective series rather than a randomised trial; there has never been one, because the entity is uncommon and was only separated out in 2016. The diagnosis requires fluorescence in situ hybridisation, so it is missed wherever FISH is not done, which is the argument for testing every case that expresses MYC by immunohistochemistry. Dual expression of MYC and BCL2 protein without a rearrangement (double-expressor) carries a worse outlook but is not itself a reason to leave R-CHOP. MYC with BCL6 rearrangement is now classified separately and behaves less badly than MYC with BCL2. Relapsed disease follows the large B-cell lymphoma pathway: CD19 CAR-T, then bispecific antibodies.","refs":["double-hit-lymphoma","lymphoma-tx-regimen-alphabet","etoposide","doxorubicin","cyclophosphamide","vincristine","prednisone","rituximab","methotrexate","axicabtagene-ciloleucel","glofitamab","lymphoma-tx-cns-prophylaxis"],"guideline":{"version":"NCCN B-Cell Lymphomas; WHO fifth edition; no randomised evidence","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Older or frail patients: R-mini-CHOP and the comprehensive geriatric assessment","approach":"Attenuated R-CHOP (R-mini-CHOP), typically at 50 per cent of the cyclophosphamide, doxorubicin and vincristine doses, is standard for patients over about 80 and for frail patients of any age, and is given with the intention to cure rather than to palliate. A comprehensive geriatric assessment before treatment predicts who can take full-dose therapy better than age does. A pre-phase of prednisolone with or without one dose of vincristine for a week before cycle 1 improves performance status and reduces early deaths. G-CSF is given from the first cycle. Where an anthracycline cannot be given at all, options include substituting etoposide or liposomal doxorubicin, or an anthracycline-free regimen; all are less effective and should be a considered choice rather than a default. Trials of mosunetuzumab consolidation after pola-R-mini-CHP in older patients with detectable circulating tumour DNA are open.","refs":["r-chop","performance-status","rituximab","prednisone","pegylated-liposomal-doxorubicin","etoposide","g-csf-growth-factors","lymphoma-tx-pjp-and-infection-prophylaxis","mosunetuzumab"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; BSH","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Central nervous system prophylaxis: who is offered it, and the evidence against it","approach":"Relapse in the brain or spinal fluid occurs in roughly 2 to 5 per cent of patients overall and in about 10 per cent of those with a high CNS-IPI. The traditional response, intrathecal methotrexate with each cycle or two to four doses of systemic high-dose methotrexate, has not been shown to reduce it. In 1,162 adults across 21 United States academic centres who all received single-route prophylaxis, central nervous system relapse occurred in 5.7 per cent, with no difference between intrathecal (5.4 per cent) and systemic high-dose methotrexate (6.8 per cent), and the observed rate matched the rate predicted from CNS-IPI alone. There has never been a randomised trial. Practice has changed accordingly: intrathecal prophylaxis is largely abandoned in the United Kingdom, and systemic high-dose methotrexate is offered selectively, to testicular involvement, to high CNS-IPI and to high-grade B-cell lymphoma, and is increasingly framed as a choice. The interventions that do change outcome are an adequate systemic regimen and prompt investigation of any new neurological symptom.","refs":["lymphoma-tx-cns-prophylaxis","methotrexate","intrathecal-therapy","ipi-score","cns-penetration"],"guideline":{"version":"No randomised evidence; NCCN lists prophylaxis as an option for high CNS-IPI","url":"https://doi.org/10.1182/blood.2021012888"}},{"setting":"Primary refractory disease or relapse within twelve months: CAR-T, not transplant","approach":"CD19 CAR-T is the second-line standard. ZUMA-7 randomised 359 patients with large B-cell lymphoma refractory to, or relapsing within twelve months of, first-line therapy to axicabtagene ciloleucel or to salvage chemotherapy with autologous transplant in responders: median event-free survival 8.3 against 2.0 months (hazard ratio 0.40) and four-year overall survival 54.6 against 46.0 per cent (hazard ratio 0.73). TRANSFORM randomised 184 transplant-eligible patients to lisocabtagene maraleucel or the same standard of care: complete response 74 against 43 per cent, progression-free survival hazard ratio 0.400, with grade 3 cytokine release syndrome in 1 per cent and grade 3 neurological events in 4 per cent. BELINDA, with tisagenlecleucel and a longer manufacturing interval, was negative (event-free survival hazard ratio 1.07), which is why product and pathway speed are treated as part of the treatment rather than a detail of it.\n\nIn practice: refer at the first suspicion of relapse, confirm with biopsy, collect cells early, and bridge with steroids, radiotherapy, polatuzumab-based chemotherapy or a bispecific antibody while the product is made. Where CAR-T is not available or the patient is not fit for it, salvage chemoimmunotherapy with autologous transplant, or a bispecific antibody, are the alternatives.","refs":["zuma-7","transform","belinda","axicabtagene-ciloleucel","lisocabtagene-maraleucel","tisagenlecleucel","car-t","lymphoma-tx-car-t-pathway","lymphoma-tx-crs-icans","autologous-stem-cell-transplant"],"guideline":{"nccn":"Category 1 (axi-cel and liso-cel, second line, early relapse)","version":"NCCN B-Cell Lymphomas; ESMO; ZUMA-7, TRANSFORM","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Late relapse (after twelve months), transplant-eligible: salvage chemotherapy then autologous transplant","approach":"Two to three cycles of platinum-based salvage immunochemotherapy (R-ICE, R-DHAP or R-GDP), then, if the disease responds, high-dose therapy with BEAM conditioning and an autologous stem cell transplant. The randomised comparisons between the salvage regimens found no difference in response or survival, so the choice is made on toxicity: R-DHAP is harder on the kidneys and hearing, R-ICE on the marrow, R-GDP is the gentlest and can be given as an outpatient. Patients whose disease does not respond to salvage should be moved to CAR-T rather than given a second salvage regimen. Stem cells must be collected before the marrow is exhausted, which is a reason to avoid bendamustine in anyone who may need a transplant.","refs":["lymphoma-tx-regimen-alphabet","lymphoma-tx-transplant-role","autologous-stem-cell-transplant","rituximab","ifosfamide","carboplatin","etoposide","cytarabine","cisplatin","gemcitabine","dexamethasone","carmustine","melphalan","car-t"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; BSH","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Relapsed and not fit for transplant or CAR-T: bispecific antibodies and antibody-drug conjugates","approach":"Several options, none of them curative on current evidence, and the choice turns on what the person wants from treatment.\n\nFixed-duration bispecific antibodies. Glofitamab for twelve cycles then stop, after a dose of obinutuzumab to blunt cytokine release. With gemcitabine and oxaliplatin, STARGLO reported median overall survival 25.5 against 12.9 months for rituximab-GemOx (hazard ratio 0.62). This is one of the places where England is ahead of the United States: NICE TA1113 allows glofitamab with gemcitabine and oxaliplatin for relapsed or refractory diffuse large B-cell lymphoma not otherwise specified after one line of treatment in adults who are not eligible for an autologous transplant, while glofitamab's only American indication remains the accelerated approval of 15 June 2023 for disease after two or more lines.\n\nContinuous bispecific antibodies. Epcoritamab, given subcutaneously; EPCORE DLBCL-1 randomised 552 transplant-ineligible patients against investigator's choice of R-GemOx or bendamustine-rituximab and improved progression-free survival (hazard ratio 0.74) without improving overall survival (hazard ratio 0.96).\n\nCombinations. Mosunetuzumab with polatuzumab vedotin in SUNMO gave progression-free survival 11.5 against 3.8 months for R-GemOx (hazard ratio 0.41), overall response 70 against 40 per cent and complete response 51 against 24 per cent. Polatuzumab with rituximab, gemcitabine and oxaliplatin in POLARGO improved overall survival, 19.5 against 12.5 months (hazard ratio 0.6), in 255 transplant-ineligible patients.\n\nAntibody-drug conjugates and immunomodulatory pairs. Loncastuximab tesirine alone (LOTIS-2: response 48 per cent, complete response 24 per cent). Tafasitamab with lenalidomide (L-MIND: response 60 per cent, complete response 43 per cent), which suits someone who wants an outpatient oral-and-infusion regimen. Polatuzumab with bendamustine and rituximab, which should be avoided in anyone who may still go to CAR-T because bendamustine damages the T cells. Brentuximab vedotin with lenalidomide and a rituximab product, approved in the United States on 11 February 2025 on the ECHELON-3 trial, for people after two or more lines who are not eligible for an autologous transplant or for CAR-T.","refs":["starglo","epcore-dlbcl-1","sunmo","l-mind","lotis-2","glofitamab","epcoritamab","mosunetuzumab","polatuzumab-vedotin","zynlonta","tafasitamab","lenalidomide","obinutuzumab","bendamustine","gemcitabine","oxaliplatin","lymphoma-tx-bispecific-step-up"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; STARGLO, EPCORE DLBCL-1, SUNMO, POLARGO","url":"https://doi.org/10.1200/JCO-25-02849"}},{"setting":"Third line and beyond, including relapse after CAR-T","approach":"If CAR-T has not been given and the patient is fit, it is given now: ZUMA-1 reported an objective response of 82 per cent and complete response 54 per cent in refractory large B-cell lymphoma, with 42 per cent still in response at a median 15.4 months. After CAR-T, a CD20 bispecific antibody is the usual next step and retains activity where CD19 has been lost, provided CD20 is still expressed; a repeat biopsy is therefore worth doing rather than assuming. Other options are loncastuximab tesirine, selinexor, zilovertamab vedotin in a trial, an allogeneic transplant in a small number of fit younger patients with chemosensitive disease, and re-treatment with a drug that previously worked after a long interval. A clinical trial is a reasonable first choice at this point rather than a last resort. Where the aim changes from control to comfort, palliative radiotherapy to a symptomatic site works quickly and early palliative care alongside oncology is recommended.","refs":["zuma-1","axicabtagene-ciloleucel","glofitamab","epcoritamab","zynlonta","selinexor","zilovertamab-vedotin","waveline-003","allogeneic-hsct","palliative-radiotherapy","palliative-care","lymphoma-tx-bispecific-step-up"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Response assessment, follow-up and what a scan is for","approach":"Interim PET is not used to change treatment in diffuse large B-cell lymphoma outside a trial, because no randomised trial has shown that switching on an interim scan helps. End-of-treatment PET-CT, reported on the five-point Deauville scale, decides whether treatment is complete: scores 1 to 3 are a complete metabolic response, 4 to 5 need biopsy of the residual site before any further treatment, because inflammation and brown fat both light up. Afterwards, follow-up is clinical: history, examination and bloods every three months for two years, then less often. Routine surveillance CT in a person without symptoms detects few relapses that the patient would not have brought forward, and both ESMO and NCCN advise against it. Most relapses occur in the first two years and most are announced by a symptom. Late effects of doxorubicin and of any radiotherapy are watched for over decades.","refs":["fdg-pet","deauville","deauville-score","lugano-classification","pet-ct","cardiotoxicity","late-effects","lymphoma-tx-hodgkin-late-effects"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; Lugano classification","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":["CAR-T second line.","Bispecifics as off-the-shelf T-cell therapy.","Frontline has moved: Pola-R-CHP (POLARIX) is standard for IPI 2-5, and frontMIND (tafasitamab-lenalidomide-R-CHOP) is the first phase 3 to beat R-CHOP in IPI 3-5 disease since rituximab.","CD19 CAR-T is second-line standard for early relapse, with an overall survival benefit in ZUMA-7 (4-year OS 54.6% vs 46.0%).","Four CD20×CD3 bispecifics approved or conditionally approved worldwide give ~40% complete remissions off the shelf; chemotherapy-free doublets (mosun-pola) beat salvage chemotherapy.","ctDNA by phased-variant sequencing detects residual lymphoma below PET sensitivity and is entering response-adapted trials.","Regulators now scrutinise generalisability (STARGLO CRL) and demand overall survival for confirmatory bispecific trials (EPCORE DLBCL-1 missed OS).","Molecular classification. Cell of origin splits this disease into germinal-centre-like and activated B-cell-like forms with different survival, and in most laboratories it is called by three stains rather than by the expression profiling that defined it, which is why a report usually says non-germinal-centre rather than activated. The genetic subtypes, MCD for MYD88 L265P with CD79B mutation, BN2 for BCL6 fusions with NOTCH2 mutations, N1 for NOTCH1 mutations and EZB for EZH2 mutations with BCL2 translocations, explain far more and currently change nothing outside a trial.","The lesions that do change treatment. A MYC rearrangement with BCL2, with or without BCL6, is a separate WHO entity and usually moves a patient off R-CHOP; rates in 442 unselected cases were 8.8% for MYC, 13.5% for BCL2 and 28.7% for BCL6. Co-expression of MYC and BCL2 protein without rearrangement, about 21% of cases, is prognostic and is not the same thing.","What the medicines are aimed at. CD20 on essentially every case, CD19 on the same cells and retained when CD20 is lost, CD79b on more than 95% and chosen because it internalises and can carry a payload, and CD3 as the handle for the bispecific antibodies. None of the four is tested before treatment, and the one worth retesting at relapse is CD20."],"history":[{"year":1976,"title":"CHOP regimen introduced","note":"Cyclophosphamide, doxorubicin, vincristine, prednisone becomes the backbone for aggressive lymphoma.","refs":["doxorubicin","cytotoxic-chemotherapy"]},{"year":1993,"title":"CHOP proves equal to more intensive regimens; IPI published","refs":["ipi-score"]},{"year":1997,"title":"Rituximab: first antibody for cancer","refs":[]},{"year":1997,"title":"Rituximab: first monoclonal antibody approved for cancer","refs":["cd20","monoclonal-antibody"]},{"year":2000,"title":"Gene-expression profiling defines GCB and ABC subtypes","refs":["cell-of-origin"]},{"year":2002,"title":"GELA LNH-98.5: R-CHOP improves survival over CHOP","note":"Rituximab added to CHOP raises cure rates by ~15 points; the standard for the next twenty years.","refs":[]},{"year":2014,"title":"Lugano classification unifies PET-based staging and response","refs":["lugano-classification","fdg-pet"]},{"year":2017,"title":"Axi-cel CAR-T approved","refs":["axicabtagene-ciloleucel"]},{"year":2017,"title":"Axi-cel: first CAR-T approved for large B-cell lymphoma (ZUMA-1)","refs":["axicabtagene-ciloleucel","car-t"]},{"year":2019,"title":"Polatuzumab vedotin approved with BR for relapsed disease","refs":["polatuzumab-vedotin"]},{"year":2020,"title":"Tafasitamab-lenalidomide (L-MIND) approved for transplant-ineligible relapse","refs":["tafasitamab","l-mind"]},{"year":2021,"title":"Loncastuximab tesirine approved; BELINDA fails while ZUMA-7 and TRANSFORM succeed","refs":["zynlonta","lotis-2","belinda","zuma-7","transform"]},{"year":2022,"title":"ZUMA-7: CAR-T beats transplant","refs":[]},{"year":2022,"title":"POLARIX: first frontline improvement on R-CHOP in twenty years; CAR-T approved second line","refs":["polarix","polatuzumab-vedotin","axicabtagene-ciloleucel"]},{"year":2023,"title":"Glofitamab, epcoritamab approved","refs":["glofitamab"]},{"year":2023,"title":"Glofitamab and epcoritamab approved: off-the-shelf T-cell redirection","refs":["glofitamab","epcoritamab","epcore-nhl-1"]},{"year":2024,"title":"STARGLO shows OS benefit for glofitamab-GemOx; odronextamab approved in EU","refs":["starglo","odronextamab"]},{"year":2025,"title":"SUNMO positive (mosun-pola); FDA rejects STARGLO indication over applicability; POLARIX 5-year data","refs":["sunmo","starglo","polarix"]},{"year":2026,"title":"frontMIND published in Lancet; EPCORE DLBCL-1 misses OS; frontline bispecific data (EPCORE DLBCL-2) at EHA","refs":["frontmind","epcore-dlbcl-1","epcore-dlbcl-2"]}],"pipeline":["zilovertamab-vedotin","abexinostat","dzd8586","rocbrutinib","mk-1045","purinostat","sctb35","shr-a1912","hmpl-760","rondecabtagene-autoleucel","azd0486","ifupinostat","tqb2825","krt-232","zamtocabtagene-autoleucel","tc011","crc01","jnj-90014496","ctx112","allo-647","frontmind","tafasitamab","epcore-dlbcl-2","epcoritamab","golcadomide","golseek-1","mosunetuzumab","sunmo","odronextamab","waveline-003","ctdna-lymphoma-monitoring","idea-ctdna-guided-dlbcl-frontline","idea-bispecific-vs-car-t-second-line"],"openProblems":["Primary refractory disease.","CAR-T access and cost.","Primary refractory disease (~10-15%) still has poor outcomes even with CAR-T; CD19-negative and CD20-negative escape after targeted therapy.","No head-to-head comparison of bispecifics and CAR-T; sequencing is by access rather than evidence.","Overall survival is hard to demonstrate for bispecifics against chemotherapy with crossover and effective later lines (EPCORE DLBCL-1).","Trial generalisability: STARGLO's rejection shows regional enrolment can decide approvals.","CNS relapse: prophylaxis with high-dose methotrexate is of uncertain benefit and CNS-penetrant options are few.","Older and frail patients are underrepresented; R-mini-CHOP cure rates lag and cellular therapies carry toxicity.","Cost and access: CAR-T requires certified centres; bispecific CRS management needs infrastructure; lenalidomide-based triplets add expense.","Response-adapted therapy: interim PET is unreliable and ctDNA is not yet a regulatory endpoint.","Polatuzumab vedotin prevents relapses in first-line diffuse large B-cell lymphoma without a proven survival gain: POLARIX gave five-year progression-free survival of 64.9 against 59.1 per cent but overall survival of 82.3 against 79.5 per cent, hazard ratio 0.85, not significant. Nobody can yet tell an individual patient whether the extra drug will add years or only delay a relapse that is salvaged anyway.","Central nervous system prophylaxis has been given to tens of thousands of people for decades without a randomised trial, and the largest study of patients who received it found the relapse rate identical to the rate predicted without it. Whether any prophylaxis works, and for whom, is unanswered, and the trial that would answer it has never been run.","No treatment for relapsed large B-cell lymphoma after CAR-T has shown a survival benefit in a randomised trial. Bispecific antibodies produce durable remissions in a minority, and which minority cannot be predicted before treatment.","The trials that established CAR-T in second line disagreed with each other (ZUMA-7 and TRANSFORM positive, BELINDA negative) for reasons that are believed to be manufacturing time and permitted bridging rather than biology, which means a treatment's effect depends on a logistics chain that is not measured in the trial report.","Older and frail patients are systematically under-represented: POLARIX capped enrolment at 80 and required performance status 0 to 2, so the evidence for the commonest presentation of this lymphoma, a person in their late seventies or eighties, rests on single-arm and retrospective work."],"parent":"non-hodgkin-lymphoma"},{"id":"dipg-dmg","kind":"cancer","name":"Diffuse midline glioma, H3 K27-altered (including DIPG)","aka":["DIPG","Diffuse intrinsic pontine glioma","DMG","H3 K27M glioma","Paediatric high-grade glioma"],"tldr":"Diffuse midline glioma grows through the brainstem and cannot be removed surgically. A single change in a histone protein (H3 K27M) rewires how the tumour reads its DNA. Radiotherapy was long the only help; in 2025 the first drug aimed at this tumour, dordaviprone (ONC201), was approved after durable shrinkage in some patients, and GD2 CAR-T cells have produced striking early responses.","summary":"Diffuse midline glioma (DMG), H3 K27-altered, is the WHO 2021 name for the tumour long called diffuse intrinsic pontine glioma when it arises in the pons; it also occurs in the thalamus and spinal cord. Most carry a lysine-to-methionine substitution at position 27 of histone H3 (H3.3 K27M or H3.1 K27M), or an equivalent EZHIP overexpression, which inhibits the PRC2 complex, causes global loss of H3K27 trimethylation and locks cells in a stem-like state. Co-alterations in TP53, ACVR1 (H3.1 tumours), PDGFRA and PIK3CA define subgroups. The tumour infiltrates rather than displaces, so it cannot be resected; stereotactic biopsy is now standard because the molecular diagnosis guides trials and prognosis.\n\nFocal radiotherapy remains the only treatment with a proven effect, temporarily restoring function; re-irradiation at progression is now supported by prospective data. More than 200 chemotherapy and targeted agents were tested from 1990 onward and none added benefit over radiotherapy alone, which is why biopsy and molecular diagnosis became standard. The first change came from an unexpected direction: dordaviprone (ONC201), an imipridone that antagonises the dopamine receptor D2 and activates the mitochondrial protease ClpP, produced durable objective responses in a minority of recurrent H3 K27M tumours in pooled phase 2 data (JCO 2024) and received FDA accelerated approval on 6 August 2025 for progressive H3 K27M-mutant DMG in patients aged one year and older, the first systemic therapy approved for this disease. The phase 3 ACTION trial (NCT05580562) tests it after radiotherapy in newly diagnosed patients. In parallel, GD2-directed CAR-T cells delivered intravenously and into the ventricles (Stanford; Nature 2022 and 2024) have produced radiographic and clinical improvement, including a sustained complete response, alongside a manageable but serious inflammatory swelling syndrome. Convection-enhanced delivery, focused-ultrasound opening of the blood-brain barrier, and combination epigenetic strategies (PRC2 and HDAC axis) are in early trials.\n\nOpen problems are the ones that define brain-tumour drug development: getting drugs across the blood-brain barrier into an infiltrating tumour, measuring response in a region where swelling is dangerous, and building trials fast enough for a disease that progresses within months. Groups such as the Pacific Pediatric Neuro-Oncology Consortium, CONNECT and SIOPE HGG, with tissue donation programmes, have turned DIPG from the least studied to one of the best characterised childhood cancers.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Diffuse_intrinsic_pontine_glioma","links":[{"label":"NCI PDQ: childhood astrocytomas and other gliomas (includes diffuse midline glioma)","url":"https://www.cancer.gov/types/brain/hp/child-astrocytoma-treament-pdq"},{"label":"FDA: dordaviprone accelerated approval (6 August 2025)","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dordaviprone-diffuse-midline-glioma"},{"label":"ACTION phase 3 (NCT05580562)","url":"https://clinicaltrials.gov/study/NCT05580562"},{"label":"GD2 CAR-T in H3 K27M diffuse midline glioma (Nature 2022)","url":"https://doi.org/10.1038/s41586-022-04489-4"}],"tags":["nci-coverage","paediatric","cns"],"related":["paediatric-low-grade-glioma","glioblastoma","race-for-children-act","accelerate-platform","idh-mutant-astrocytoma","oligodendroglioma","paediatric-high-grade-glioma"],"cancers":[],"sections":[],"technologies":["imrt-igrt","glioma-car-t","bbb-focused-ultrasound","car-t","methylation-profiling","palliative-care"],"targets":["gd2","ezh2"],"drugs":["dordaviprone","temozolomide"],"companies":["childrens-oncology-group"],"institutions":["siop-europe","stanford","dkfz"],"pathways":["epigenetic-reprogramming","p53-cell-cycle"],"terms":["h3k27m","blood-brain-barrier","late-effects"],"trials":["action-dmg","pediatric-match"],"people":[],"bottlenecks":["b-brain-delivery","b-rare-cancers"],"keyPapers":["paper-majzner-nature"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"A few hundred children a year in the United States, mostly aged 5 to 10; the leading cause of brain-tumour death in children (NCI PDQ).","subtypes":["H3.3 K27M (most common; pons, thalamus, spine)","H3.1 K27M (younger children, ACVR1 mutations, longer natural history)","H3-wild-type with EZHIP overexpression","EGFR-mutant diffuse midline glioma (bithalamic)","Adult H3 K27M diffuse midline glioma (thalamic and spinal)"],"biomarkers":["H3 K27M by immunohistochemistry or sequencing","Loss of H3K27me3","TP53, ACVR1, PDGFRA, PIK3CA co-alterations","EGFR alteration (bithalamic subtype)","Cerebrospinal-fluid cell-free tumour DNA for H3 K27M (in development for monitoring)","MRI with diffusion and perfusion for response assessment"],"standardOfCare":[{"setting":"Newly diagnosed","approach":"Stereotactic biopsy for molecular diagnosis and trial eligibility, then focal radiotherapy (about six weeks; hypofractionated schedules are non-inferior); steroids for symptoms. Enrolment in a trial such as ACTION (dordaviprone after radiotherapy) is recommended.","refs":["imrt-igrt","action-dmg","dordaviprone"],"guideline":{"version":"NCI PDQ: childhood diffuse midline glioma; SIOPE HGG working group","url":"https://www.cancer.gov/types/brain/hp/child-astrocytoma-treament-pdq"}},{"setting":"Progressive after radiotherapy, H3 K27M-mutant","approach":"Dordaviprone (ONC201), FDA accelerated approval August 2025 for patients aged one year and older with progressive disease; re-irradiation is an alternative or addition.","refs":["dordaviprone"],"guideline":{"version":"FDA accelerated approval, 6 August 2025"}},{"setting":"Recurrent, trial-eligible","approach":"GD2 CAR-T (phase 1, Stanford and others), convection-enhanced delivery, epigenetic and combination trials through consortium networks.","refs":["glioma-car-t","gd2","bbb-focused-ultrasound"]},{"setting":"All stages","approach":"Early palliative care, steroid-sparing strategies, and support for the family; tissue donation at autopsy has been central to research progress.","refs":["palliative-care"]}],"stateOfArt":["H3 K27M defines the disease molecularly; biopsy is safe and standard, and cerebrospinal-fluid tumour DNA is emerging as a way to track it.","Dordaviprone (ONC201) is the first drug approved for DMG (FDA accelerated approval 2025), a mitochondrial-stress and DRD2 mechanism found by screening rather than design; ACTION tests it in newly diagnosed disease.","GD2 CAR-T cells given into the blood and the ventricles have produced meaningful neurological improvement and at least one durable complete response in early trials, showing the tumour is immunologically reachable.","Radiotherapy remains the backbone; re-irradiation extends benefit at progression."],"history":[{"year":1990,"title":"Two decades of negative chemotherapy trials begin","note":"Radiation-only remains standard as more than 200 agents fail to add benefit.","refs":[]},{"year":2012,"title":"H3 K27M mutation discovered","note":"Schwartzentruber and Wu (Nature Genetics) find recurrent histone H3 mutations in DIPG and paediatric glioblastoma.","refs":["h3k27m"]},{"year":2016,"title":"WHO recognises diffuse midline glioma, H3 K27M-mutant","note":"First histone-defined tumour entity.","refs":[]},{"year":2018,"title":"GD2 identified as a target on H3 K27M gliomas","note":"Mount and Monje (Nature Medicine) show GD2 CAR-T clears tumours in mouse models.","refs":["gd2","glioma-car-t"]},{"year":2022,"title":"First GD2 CAR-T responses in patients","note":"Majzner and colleagues (Nature) report clinical and radiographic improvement with intravenous then intracerebroventricular dosing.","refs":["glioma-car-t"]},{"year":2024,"title":"Pooled ONC201 phase 2 data","note":"Durable objective responses in recurrent H3 K27M DMG reported in JCO; ACTION phase 3 open.","refs":["dordaviprone","action-dmg"]},{"year":2025,"title":"Dordaviprone approved","note":"FDA accelerated approval on 6 August 2025 for progressive H3 K27M-mutant diffuse midline glioma, the first systemic therapy for the disease.","refs":["dordaviprone"]}],"pipeline":["dordaviprone","action-dmg","glioma-car-t","bbb-focused-ultrasound","pediatric-match"],"openProblems":["Most tumours still progress; dordaviprone helps a minority and the phase 3 ACTION trial will show whether earlier use extends survival.","Drug delivery across the blood-brain barrier into infiltrating tumour: convection-enhanced delivery, focused ultrasound and intraventricular cell therapy are being tested.","Response assessment: swelling and pseudo-progression confound MRI in the brainstem; cerebrospinal-fluid tumour DNA is being validated as a marker.","Trial speed: a disease measured in months needs platform trials and regulatory paths built for rarity, which the RACE for Children Act and paediatric consortia are meant to provide."],"parent":"glioblastoma"},{"id":"prostate-ductal-adenocarcinoma","kind":"cancer","name":"Ductal adenocarcinoma of the prostate","aka":["Prostatic ductal adenocarcinoma","Ductal adenocarcinoma","Ductal prostate cancer","Adenocarcinoma with ductal features","Mixed acinar-ductal adenocarcinoma","Endometrioid carcinoma of the prostate","DAC"],"tldr":"Ductal adenocarcinoma is a rare type of prostate cancer, roughly one case in six hundred, that grows from the larger ducts of the gland rather than from its small acini. It tends to make less PSA than ordinary prostate cancer, so it is found later and more often after it has spread, and it is treated as high-risk disease from the day it is named.","summary":"What it is. Ductal adenocarcinoma of the prostate is a carcinoma of the larger, more central prostatic ducts. Under the microscope it is built of tall columnar cells with stratified nuclei arranged in papillary, cribriform, glandular or solid patterns, in contrast to the cuboidal cells in small round acini that make up ordinary, acinar prostate cancer. The fifth edition of the WHO Classification of Tumours reserves the term ductal adenocarcinoma for radical prostatectomy specimens with more than 50 percent ductal morphology, and asks for the phrase 'adenocarcinoma with ductal features' on a needle biopsy whether the biopsy is pure ductal or mixed, because a needle sees too little of the gland to know the proportion.\n\nHow it differs from its parent. The fifth edition considered making ductal adenocarcinoma a subtype of acinar adenocarcinoma and decided against it, keeping it a separate type because of how differently it behaves (Kench 2022). It makes less PSA for the same amount of cancer: in a series of 371 ductal cases, ductal histology was associated with a 30 percent lower geometric mean PSA and more than twice the chance of a PSA under 4 ng/mL, independent of everything else. It presents more locally advanced (22.2 percent T3 against 8.9 percent for acinar on meta-analysis, relative risk 1.71 for T3 and 7.56 for T4) and with a 4.62 times higher relative risk of metastatic disease at diagnosis. It goes to places prostate cancer usually does not: lung, liver, brain, skin, penis, peritoneum and testis, which is why an unusual secondary tumour in a man with prostate cancer is a reason to look again at the histology.\n\nHow common it is. About 0.17 percent of prostate cancer by meta-analysis, so of the order of 100 cases a year in the UK if the same proportion holds, which has not been measured directly here. Most are mixed with acinar cancer rather than pure. It is under-diagnosed by systematic biopsy: in one series using MRI-targeted biopsy, 19 of 23 ductal cases (83 percent) had been missed entirely by a prior 12-core systematic biopsy, and expert uropathologists agreed on the diagnosis in only 52 percent of cases in a 20-reader study, so the reported incidence is a floor and the range between series is wide.\n\nHow it is treated. As high-risk prostate cancer, with no guideline written specifically for it and no randomised trial of its own. Radical prostatectomy or radical radiotherapy are used for localised disease and hormonal therapy with or without chemotherapy for metastatic disease; the few studies comparing surgery and radiotherapy are small and disagree, with cancer-specific survival looking worse after prostatectomy in the pooled picture. On meta-analysis five-year cancer-specific and overall survival were both worse than for acinar cancer (relative risks 0.85 and 0.83). DNA-repair alterations are commoner in ductal disease, reported in 49 percent of one series of 51 cases, and both the NCCN and the Philadelphia Prostate Cancer Consensus Conference recommend germline genetic testing for anyone whose prostate cancer shows ductal, intraductal or cribriform morphology, which is the one management change the diagnosis reliably triggers.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Prostate_cancer","links":[{"label":"Ranasinha et al., BJUI Compass 2021: ductal adenocarcinoma of the prostate, a systematic review and meta-analysis of incidence, presentation, prognosis and management","url":"https://doi.org/10.1002/bco2.60"},{"label":"Kench et al., Histopathology 2022: WHO Classification of Tumours fifth edition, evolving issues in the classification, diagnosis and prognostication of prostate cancer","url":"https://doi.org/10.1111/his.14711"},{"label":"WHO Classification of Tumours, 5th edition: tumours of the prostate (IARC, 2022)","url":"https://tumourclassification.iarc.who.int/chapters/36"},{"label":"Royal College of Pathologists G084: dataset for histopathology reports for prostatic carcinoma, version 4, October 2024","url":"https://www.rcpath.org/static/8cc88604-2c8d-4df4-a99542df41c102af/G084-dataset-for-histopathology-reports-for-prostatic-carcinoma.pdf"},{"label":"Netto et al., European Urology 2022: the 2022 WHO classification of tumours of the urinary system and male genital organs, part B (prostate and urinary tract)","url":"https://pubmed.ncbi.nlm.nih.gov/35965208/"}],"tags":["gu","subtype-page"],"related":["prostate","prostate-nepc","prostate-high-risk","prostate-mhspc"],"cancers":[],"sections":[],"technologies":["mp-mri","germline-testing","histopathology-ihc"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["gleason-grade-group","intraductal-carcinoma-prostate","cribriform-prostate-cancer","psa","prostate-acinar-adenocarcinoma","tnm-prostate-cancer","cambridge-prognostic-group"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Ductal is not intraductal. They sound alike, they are often found in the same gland, and they mean different things. Ductal adenocarcinoma is an invasive cancer whose cells look like duct lining; intraductal carcinoma of the prostate is cancer growing inside ducts and acini that still have their own basal cell layer, a pattern reported beside an invasive cancer rather than a tumour type of its own. Both are reasons for germline testing and both mean a worse outlook, which is probably why the two words get run together.","Why a needle biopsy report says 'adenocarcinoma with ductal features' instead. The WHO fifth edition reserves the term ductal adenocarcinoma for prostatectomy specimens where more than half the tumour is ductal, and asks for 'adenocarcinoma with ductal features' on needle biopsies whether the sample is pure or mixed, because a needle cannot measure the proportion in the whole gland. A report using the longer phrase is following the classification, not hedging.","Why the incidence figures disagree so much. The meta-analysed range across case series is 0.084 to 13.4 percent, a spread of more than a hundredfold, and the reason is diagnostic rather than biological: there is no single agreed histological definition, twenty expert uropathologists agreed on a positive ductal diagnosis in 52 percent of cases, and systematic biopsy misses the ductal component in most cases that MRI-targeted biopsy finds. Any single number quoted for how common ductal prostate cancer is should be read as an estimate of how often it is recognised."],"group":"genitourinary","burden":"About 0.17 percent of prostate cancer: a systematic review of 114 studies covering 2,907,170 prostate cancers found 5,911 ductal cases, and meta-analysis of the 21 case series that counted both types consecutively gave 0.17 percent, with a range across series of 0.084 to 13.4 percent, the spread reflecting how differently the diagnosis is made rather than how differently the disease occurs. Pure ductal disease is rarer still: in 1,051 radical prostatectomy specimens from the Karolinska University Hospital, 2 (0.2 percent) were pure ductal and 84 (8 percent) mixed acinar-ductal (BJUI Compass 2021).","subtypes":[],"biomarkers":["Ductal morphology on the report: more than 50 percent ductal at prostatectomy, or 'adenocarcinoma with ductal features' on a needle biopsy","PSA, read with caution because ductal disease makes less of it for the same tumour burden","Germline and somatic homologous recombination and mismatch repair genes, tested because ductal morphology is one of the triggers"],"standardOfCare":[{"setting":"Localised","approach":"Treated as high-risk prostate cancer: radical prostatectomy or radical radiotherapy with androgen deprivation. No guideline and no randomised trial is specific to ductal histology, and the retrospective comparisons of surgery against radiotherapy are small and inconsistent.","refs":["robotic-surgery","imrt-igrt","androgen-deprivation","prostatectomy"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Any stage, at diagnosis","approach":"Germline genetic testing, which the NCCN and the Philadelphia consensus conference recommend for ductal, intraductal or cribriform morphology whatever the stage.","refs":["germline-testing","intraductal-carcinoma-prostate","cribriform-prostate-cancer"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Metastatic","approach":"Treated as metastatic acinar prostate cancer, with androgen deprivation and an androgen receptor pathway inhibitor. In the one study that asked the question, 35 ductal cases among 634 men with de novo metastatic prostate cancer had no worse overall or cancer-specific survival than acinar cases, so the histology's disadvantage appears to be in getting to metastasis sooner rather than in behaving worse once there.","refs":["androgen-deprivation","psma-pet"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"prostate"},{"id":"ductal-carcinoma-in-situ","kind":"cancer","name":"Ductal carcinoma in situ (DCIS)","aka":["DCIS","Stage 0 breast cancer","Pre-invasive breast cancer","Intraductal carcinoma","stage 0 breast cancer","Tis (DCIS)","non-invasive breast cancer","in situ breast cancer","pre-invasive breast cancer","intraductal carcinoma of the breast"],"tldr":"DCIS is abnormal cells confined to the milk ducts of the breast; it is not yet invasive cancer and cannot spread, but some would become invasive if left. Lumpectomy with radiotherapy, or mastectomy, halves local recurrence, so the live question is which low-risk DCIS can safely be watched: the COMET trial (2024) found active monitoring no worse at two years.","summary":"Ductal carcinoma in situ is a non-obligate precursor of invasive breast cancer: neoplastic epithelial cells fill the ducts without breaching the basement membrane. It is almost always detected as microcalcifications on screening mammography, is graded low, intermediate or high by nuclear grade and necrosis, and is characterised by ER, PR and HER2 status. Natural-history data from misdiagnosed or untreated cases and from autopsy series show that a substantial share of low-grade DCIS never progresses, which makes overdiagnosis and overtreatment the central problem of the disease.\n\nStandard treatment is breast-conserving surgery with clear margins (2 mm) followed by whole-breast radiotherapy, which halves local recurrence (about half of recurrences being invasive) without affecting survival, or mastectomy for extensive disease; sentinel node biopsy is done only with mastectomy or suspicion of invasion. Adjuvant endocrine therapy (tamoxifen, or an aromatase inhibitor in postmenopausal women per NSABP B-35 and IBIS-II DCIS) reduces ipsilateral and contralateral events in ER-positive DCIS. Genomic assays (Oncotype DX DCIS Score, DCISionRT) and clinicopathological tools help identify women who can omit radiotherapy. Three randomised trials test active monitoring against surgery for low-risk DCIS: COMET (US; JAMA, December 2024) reported that active monitoring was non-inferior for the two-year rate of ipsilateral invasive cancer, LORIS (UK) and LORD (Netherlands, now including a patient-preference cohort) continue to follow patients. Longer follow-up is needed before monitoring becomes routine, but the results have already changed how DCIS is discussed with patients.\n\nThe frontier is a risk-stratified approach in which high-grade or HER2-positive DCIS is treated fully while low-risk lesions are watched, informed by molecular classifiers and, potentially, by preventive vaccines against HER2 or other DCIS antigens.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Ductal_carcinoma_in_situ","links":[{"label":"NCI: ductal carcinoma in situ","url":"https://www.cancer.gov/types/breast/breast-cancer-types/dcis"},{"label":"COMET trial (JAMA 2024)","url":"https://doi.org/10.1001/jama.2024.26698"},{"label":"SSO-ASTRO-ASCO margin guideline for DCIS (JCO 2016)","url":"https://doi.org/10.1200/JCO.2016.68.3573"},{"label":"LORD trial (NCT02492607)","url":"https://clinicaltrials.gov/study/NCT02492607"},{"label":"Royal College of Pathologists G148: dataset for histopathological reporting of breast disease in surgical excision specimens of breast cancer, version 3, November 2024 (full review due November 2026)","url":"https://www.rcpath.org/resourceLibrary/g148-dataset-for-histopathological-reporting-of-breast-disease-in-surgical-excision-specimens-of-breast-cancer.html"},{"label":"Brierley et al., International Journal of Cancer 2026: the 9th edition of the UICC TNM classification of malignant tumours, updates and rationale for change (breast: the classification remains unchanged, the yp classification is clarified)","url":"https://doi.org/10.1002/ijc.70561"}],"tags":["nci-coverage","breast","overdiagnosis"],"related":["breast-hr-positive","breast-her2-positive","tnbc","male-breast-cancer","paget-disease-of-the-nipple","phyllodes-tumour"],"cancers":[],"sections":[],"technologies":["mammography","imrt-igrt","endocrine-therapy","active-surveillance","radiology-ai-screening","mri"],"targets":["estrogen-receptor","her2"],"drugs":["tamoxifen","oncotype-dx","mammaprint","anastrozole"],"companies":[],"institutions":[],"pathways":["er-signaling"],"terms":["dcis","carcinoma-in-situ","lumpectomy","mastectomy","in-situ","tnm-breast-cancer-editions","terminal-duct-lobular-unit","er-pr-scoring-breast","nottingham-grade"],"trials":["nsabp-b39","comet-dcis","tam-01"],"people":[],"bottlenecks":["b-overdiagnosis","b-toxicity-qol"],"keyPapers":["paper-morrow-j-clin-oncol"],"journals":[],"dependsOn":[],"notes":["Why this page and not one of the receptor pages. Ductal carcinoma in situ is staged Tis (DCIS), which is stage 0, and it has not crossed the basement membrane, so it cannot have spread. That is why the receptor subtype pages, which are about systemic treatment of invasive cancer, are not where a reader with in-situ disease should start. DCIS is graded by nuclear grade and necrosis rather than by the Nottingham system used for invasive cancer, and assessing its oestrogen receptor status is not a mandatory item of the UK dataset; it is measured when endocrine treatment is being considered, using the same cut-off as for invasive cancer for want of a separate consensus."],"group":"breast","burden":"About one in five to one in four breast cancers detected by mammographic screening is DCIS; it was rare before screening and is now diagnosed in tens of thousands of women a year in the US alone (SEER; NCI).","subtypes":["Low-grade DCIS (often ER-positive)","Intermediate-grade DCIS","High-grade DCIS with comedo necrosis (often HER2-positive)","DCIS with microinvasion (staged as T1mi)","Paget disease of the nipple (DCIS extending to nipple skin)"],"biomarkers":["Nuclear grade and necrosis","ER and PR status","HER2 status (not used to select therapy outside trials)","Margin width (2 mm standard after breast conservation)","Oncotype DX DCIS Score or DCISionRT (radiotherapy omission decisions)","Extent on mammography and MRI"],"standardOfCare":[{"setting":"Localised DCIS, breast conservation","approach":"Lumpectomy to 2 mm margins followed by whole-breast radiotherapy (hypofractionated), with radiotherapy omission considered for low-risk lesions (RTOG 9804 criteria or genomic assay).","refs":["lumpectomy","imrt-igrt","oncotype-dx"],"guideline":{"nccn":"Category 1 (radiotherapy after lumpectomy)","version":"NCCN Guidelines: Breast Cancer; SSO-ASTRO-ASCO margin guideline 2016","url":"https://doi.org/10.1200/JCO.2016.68.3573"}},{"setting":"Extensive or multicentric DCIS","approach":"Mastectomy with sentinel node biopsy and optional reconstruction; radiotherapy not needed after mastectomy with clear margins.","refs":["mastectomy","sentinel-node"],"guideline":{"version":"NCCN Guidelines: Breast Cancer"}},{"setting":"ER-positive DCIS after breast conservation","approach":"Tamoxifen (or anastrozole in postmenopausal women) for five years to reduce ipsilateral and contralateral breast events; low-dose tamoxifen is an option (TAM-01).","refs":["tamoxifen","endocrine-therapy"],"guideline":{"nccn":"Category 1 (tamoxifen); Category 2A (aromatase inhibitor)","version":"NSABP B-24, B-35; IBIS-II DCIS; TAM-01","url":"https://doi.org/10.1016/S0140-6736(15)01168-X"}},{"setting":"Low-risk DCIS","approach":"Active monitoring with mammography every six months and optional endocrine therapy, in trials (COMET, LORIS, LORD) or after shared decision-making where guidelines allow.","refs":["active-surveillance","mammography","dcis","b-overdiagnosis"],"guideline":{"version":"COMET (JAMA 2024)","url":"https://doi.org/10.1001/jama.2024.26698"}}],"stateOfArt":["COMET is the first randomised evidence that low-risk DCIS can be monitored rather than operated on, at least in the short term; LORIS and LORD will add longer follow-up.","Genomic assays and validated clinicopathological criteria let many women omit radiotherapy after lumpectomy.","Hypofractionated and partial-breast radiotherapy shorten treatment for those who need it; low-dose tamoxifen cuts side effects.","DCIS is the clearest example of the overdiagnosis problem in oncology and the test bed for risk-stratified de-escalation."],"history":[{"year":1932,"title":"Broders defines carcinoma in situ","note":"The concept of non-invasive cancer confined by the basement membrane.","refs":[]},{"year":1985,"title":"Screening mammography makes DCIS common","note":"Incidence rises several-fold in screened populations.","refs":[]},{"year":1993,"title":"NSABP B-17: radiotherapy after lumpectomy for DCIS","note":"Halves local recurrence; no survival difference.","refs":["lumpectomy"]},{"year":1999,"title":"NSABP B-24: tamoxifen after lumpectomy plus radiotherapy","refs":["tamoxifen"]},{"year":2015,"title":"Anastrozole versus tamoxifen for DCIS (NSABP B-35, IBIS-II DCIS)","note":"Aromatase inhibitor an alternative in postmenopausal women.","refs":["tamoxifen"]},{"year":2016,"title":"2 mm margin standard (SSO-ASTRO-ASCO)","refs":["lumpectomy"]},{"year":2024,"title":"COMET: active monitoring non-inferior at two years","note":"Hwang and colleagues (JAMA, December 2024); first randomised evidence for monitoring low-risk DCIS.","refs":["active-surveillance"]}],"pipeline":["active-surveillance","oncotype-dx","tamoxifen"],"openProblems":["Distinguishing DCIS that would progress from DCIS that would not; molecular classifiers, mammographic AI and the monitoring trials are the route.","Long-term safety of active monitoring beyond two years; LORIS and LORD follow-up and the COMET ten-year endpoint will tell.","Overtreatment by mastectomy remains common; shared decision aids and radiotherapy omission tools are the response.","Preventing progression pharmacologically or with vaccines (HER2-directed DCIS vaccine trials) rather than surgically."],"parent":"breast-cancer"},{"id":"early-cervical-cancer","kind":"cancer","name":"Early cervical cancer and fertility-sparing surgery","aka":["Stage IA to IB2 cervical cancer","Early-stage cervical cancer","Fertility-sparing cervical cancer surgery","Radical trachelectomy candidates"],"tldr":"Early cervical cancer is confined to the cervix and is usually cured by surgery. Recent trials have shown that open surgery is safer than keyhole surgery for radical hysterectomy, that a simple hysterectomy is enough for the smallest tumours, and that young women with small tumours can keep their uterus with a trachelectomy.","summary":"FIGO 2018 defines stage IA as microscopic invasion up to five millimetres and stage IB as a visible or deeper tumour confined to the cervix, split into IB1 (up to two centimetres), IB2 (two to four centimetres) and IB3 (over four centimetres, treated as locally advanced). Squamous carcinoma and HPV-associated adenocarcinoma behave similarly at this stage, while HPV-independent gastric-type adenocarcinoma is more aggressive. Diagnosis comes from colposcopic biopsy or an excisional cone after abnormal screening, and MRI and PET-CT stage the tumour and nodes. Stage IA1 without lymphovascular invasion is treated by cone biopsy or simple hysterectomy alone; IA2 to IB2 has traditionally required radical hysterectomy with pelvic lymphadenectomy, followed by chemoradiation when nodes, margins or parametria are involved.\n\nTwo trials have reshaped the surgery. LACC randomised women with stage IA1 with lymphovascular invasion to IB1 disease between minimally invasive and open radical hysterectomy and stopped early when disease-free survival at four and a half years was 86.0 percent with keyhole surgery against 96.5 percent with open surgery, and deaths were more frequent; open surgery became the standard again and guidelines reversed a decade of practice. SHAPE then asked the opposite question for the lowest-risk tumours: in stage IA2 to IB1 disease up to two centimetres with limited stromal invasion, simple hysterectomy was non-inferior to radical hysterectomy for pelvic recurrence and caused far fewer urinary and sexual complications, so simple hysterectomy is now an accepted option for these women. Sentinel node biopsy, validated for detection in SENTICOL I and II, is being tested against full lymphadenectomy in SENTICOL III.\n\nFertility-sparing surgery follows the same logic. Cone biopsy or simple trachelectomy suffices for IA1 and selected IA2 tumours, and radical vaginal or abdominal trachelectomy with node assessment preserves the uterus in IB1 tumours up to two centimetres, with recurrence rates comparable to hysterectomy and live births in a majority of women who try to conceive, though preterm delivery is common. Neoadjuvant chemotherapy to shrink tumours of two to four centimetres before trachelectomy is investigational. HPV vaccination and HPV-based screening are shrinking this whole group of patients, which is the ultimate aim.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Cervical_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Cervical_cancer"}],"tags":["subtype-page"],"related":["locally-advanced-cervical-cancer","recurrent-metastatic-cervical-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["shape"],"people":[],"bottlenecks":[],"keyPapers":["paper-lacc-nejm-2018","paper-shape-nejm-2024"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"In screened populations about half of cervical cancers are found at stage I, often in women in their thirties and forties who have not completed their families; cure rates exceed ninety percent, so the questions are how little surgery is safe and how to preserve fertility.","subtypes":["Stage IA1 (cone biopsy or simple hysterectomy)","Stage IA2 to IB1 up to 2 cm, low risk (simple hysterectomy after SHAPE, or radical trachelectomy for fertility)","Stage IB1 to IB2 (open radical hysterectomy after LACC)","Squamous cell carcinoma of the cervix","HPV-associated adenocarcinoma","HPV-independent gastric-type adenocarcinoma (higher risk)","FIGO 2018 stage IB with intermediate risk factors (Sedlis criteria, adjuvant radiotherapy)"],"biomarkers":["FIGO 2018 stage from clinical examination, MRI and PET-CT","Tumour size and depth of stromal invasion","Lymphovascular space invasion","Sentinel or pelvic node status","HPV type and p16 (HPV-associated versus independent)","Margin and parametrial status after surgery"],"standardOfCare":[{"setting":"Stage IA1 without lymphovascular invasion","approach":"Cone biopsy with clear margins or simple hysterectomy; no node assessment needed.","refs":["colposcopy-excision","hysterectomy"]},{"setting":"Stage IA2 to IB1 up to 2 cm, low risk","approach":"Simple hysterectomy with node assessment (SHAPE) or open radical hysterectomy; sentinel node biopsy where a trial or protocol supports it.","refs":["hysterectomy","sentinel-node","senticol-iii","mri"]},{"setting":"Stage IB1 to IB2, standard","approach":"Open radical hysterectomy with pelvic lymphadenectomy; minimally invasive radical hysterectomy avoided after LACC.","refs":["lacc","caution-mis-radical-hysterectomy","robotic-surgery","minimally-invasive-surgery"]},{"setting":"Fertility preservation","approach":"Cone or simple trachelectomy for IA disease; radical trachelectomy with node assessment for IB1 tumours up to 2 cm.","refs":["colposcopy-excision","sentinel-node","mri"]},{"setting":"Adjuvant after surgery","approach":"Pelvic radiotherapy for intermediate-risk features; cisplatin chemoradiation for positive nodes, margins or parametria.","refs":["imrt-igrt","cisplatin","brachytherapy","chemoradiation"]},{"setting":"Prevention and detection","approach":"HPV vaccination and HPV-based screening with colposcopy for positives.","refs":["hpv-vaccine","hpv-testing","colposcopy-excision","hpv-status"]}],"stateOfArt":["LACC reversed the move to keyhole radical hysterectomy, a rare example of a surgical trial changing practice against the trend.","SHAPE showed that less surgery is safe for the smallest tumours.","Radical trachelectomy lets young women keep their fertility with equivalent cure."],"history":[{"year":1898,"title":"Wertheim performs the first radical abdominal hysterectomy for cervical cancer","refs":[]},{"year":1994,"title":"Dargent describes radical vaginal trachelectomy for fertility preservation","refs":[]},{"year":1999,"title":"Sedlis criteria define intermediate-risk features that warrant adjuvant radiotherapy","refs":[]},{"year":2018,"title":"LACC: minimally invasive radical hysterectomy inferior to open surgery","refs":["lacc"]},{"year":2018,"title":"FIGO 2018 staging splits IB by tumour size and adds imaging and nodal status","refs":[]},{"year":2024,"title":"SHAPE: simple hysterectomy non-inferior to radical hysterectomy in low-risk early disease","refs":[]}],"pipeline":["senticol-iii","hpv-testing","hpv-vaccine","idea-hpv-ctdna-cervical","mrd-testing"],"openProblems":["Whether sentinel node biopsy alone can replace lymphadenectomy (SENTICOL III).","Safe fertility-sparing options for tumours of two to four centimetres.","Why minimally invasive surgery did harm, and whether protective techniques can restore it."],"parent":"cervical"},{"id":"early-gastric-cancer","kind":"cancer","name":"Early gastric cancer","aka":["T1 gastric cancer","Intramucosal gastric cancer","Submucosal gastric cancer","Screen-detected gastric cancer"],"tldr":"Early gastric cancer has not grown beyond the submucosa, whatever the lymph nodes show. In Japan and Korea, where screening endoscopy finds most stomach cancers at this stage, many are removed through the endoscope without an operation, and the rest are cured by gastrectomy.","summary":"Early gastric cancer is defined by depth: a tumour limited to the mucosa (T1a) or submucosa (T1b), regardless of nodal spread. Its detection depends on endoscopy in people without symptoms. Korea has offered biennial endoscopic screening to everyone from age 40 in its national programme since 1999, and Japan recommended endoscopy over barium radiography in 2016; as a result more than half of gastric cancers in both countries are early, against about one in five in Europe and North America. Helicobacter pylori causes most of these cancers, and eradication after endoscopic resection roughly halves the risk of a second primary tumour in the remaining stomach.\n\nEndoscopic submucosal dissection removes the lesion in one piece with its margins. The Japanese Gastric Cancer Association criteria cover differentiated intramucosal tumours without ulceration of any size, differentiated ulcerated tumours up to 3 cm, and, after the JCOG1009/1010 trial, undifferentiated intramucosal tumours up to 2 cm without ulceration; when pathology shows deeper invasion, lymphovascular invasion or an involved margin (a high eCura risk), gastrectomy with lymph node dissection follows because the risk of nodal disease rises. Curative dissection preserves the stomach and its function with recurrence rates comparable to surgery in matched series.\n\nFor tumours outside those criteria, gastrectomy with D1+ node dissection is standard; laparoscopic distal gastrectomy proved non-inferior to open surgery for stage I disease in the Korean KLASS-01 and Japanese JCOG0912 trials and is now routine, with robotic surgery an alternative. Adjuvant chemotherapy is not given for stage I disease. Surveillance after endoscopic resection is annual endoscopy for metachronous lesions, and the whole model is being tested in Western trials of risk-based screening and in the gastric cancer arm of Lynch syndrome programmes.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Stomach_cancer","links":[{"label":"Japanese gastric cancer treatment guidelines 2021 (6th edition)","url":"https://pubmed.ncbi.nlm.nih.gov/36342574/"},{"label":"JCOG1009/1010 (Gastric Cancer 2020)","url":"https://pubmed.ncbi.nlm.nih.gov/32895785/"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Stomach_cancer"}],"tags":["subtype-page"],"related":["gastric-cldn18-2-positive","gastric-her2-positive","gastric-msi-high","gastric-pdl1-high"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["klass-01"],"people":[],"bottlenecks":[],"keyPapers":["paper-gotoda-endoscopic-resection-criteria-gastric-cancer-2000","paper-klass-01-kim-jama-oncol-2019","paper-jcog0912-katai-lancet-gastroenterol-hepatol-2020","paper-japanese-gastric-cancer-treatment-guidelines-2021-gastric-cancer-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"More than half of gastric cancers diagnosed in Japan and Korea, where endoscopic screening finds them, but a small minority in Western countries; five-year survival above 90 percent when the tumour is confined to the mucosa or submucosa.","subtypes":["Intramucosal (T1a) differentiated early gastric cancer (endoscopic resection)","Undifferentiated intramucosal cancer up to 2 cm (endoscopic resection after JCOG1009/1010)","Submucosal (T1b) early gastric cancer (gastrectomy)","Distal (antral) early gastric cancer, intestinal type","Screen-detected early gastric cancer (Japan and Korea)","Metachronous early gastric cancer after resection"],"biomarkers":["Depth of invasion, ulceration and size (endoscopic resection criteria)","Differentiated versus undifferentiated histology","Lymphovascular invasion and margin status on the resected specimen (eCura risk)","Helicobacter pylori status","Intestinal metaplasia and atrophy extent (Kimura-Takemoto, OLGA) for surveillance intervals"],"standardOfCare":[{"setting":"Within endoscopic criteria","approach":"Endoscopic submucosal dissection with en bloc resection and pathological assessment of depth, margins and lymphovascular invasion.","refs":["endoscopic-resection","endoscopy"]},{"setting":"Non-curative resection or outside criteria","approach":"Gastrectomy with D1+ lymph node dissection, laparoscopic or robotic (KLASS-01, JCOG0912).","refs":["gastrectomy","lymphadenectomy","robotic-surgery","jcog"]},{"setting":"After resection","approach":"Helicobacter pylori eradication and annual endoscopic surveillance for metachronous cancer; no adjuvant chemotherapy for stage I.","refs":["endoscopy","chemoprevention"]},{"setting":"Screening","approach":"Biennial endoscopy from age 40 in Korea and from 50 in Japan; risk-based screening for people of East Asian origin and with atrophic gastritis elsewhere.","refs":["screening","endoscopy"]}],"stateOfArt":["Endoscopic submucosal dissection, developed in Japan, cures the majority of early gastric cancers without removing the stomach.","Population endoscopic screening has made early-stage diagnosis the norm in Korea and Japan and is the reason their survival figures lead the world.","Helicobacter pylori eradication after resection is proven to prevent second cancers."],"history":[{"year":1962,"title":"Japanese Society of Gastroenterological Endoscopy defines early gastric cancer","refs":[]},{"year":1999,"title":"Korea launches national gastric cancer screening","refs":[]},{"year":2000,"title":"Endoscopic submucosal dissection developed in Japan","refs":["endoscopic-resection"]},{"year":2008,"title":"Fukase trial: Helicobacter pylori eradication reduces metachronous cancer after endoscopic resection","refs":[]},{"year":2016,"title":"Japan recommends endoscopic over radiographic screening; KLASS-01 supports laparoscopic gastrectomy","refs":[]},{"year":2020,"title":"JCOG1009/1010: endoscopic dissection extended to small undifferentiated tumours","refs":["jcog","endoscopic-resection"]}],"pipeline":["endoscopic-resection","robotic-surgery","liquid-biopsy","mrd-testing"],"openProblems":["Western countries have no screening and diagnose most gastric cancers late.","Predicting nodal spread in submucosal tumours to spare more patients surgery.","Artificial intelligence detection of subtle lesions is promising but not yet proven to change outcomes."],"parent":"gastric"},{"id":"hcc-early","kind":"cancer","name":"Early hepatocellular carcinoma (BCLC 0 and A)","aka":["Very early HCC (BCLC 0)","Early-stage HCC (BCLC A)","Resectable hepatocellular carcinoma","HCC within Milan criteria"],"tldr":"Early hepatocellular carcinoma means a single tumour, or up to three small ones, in a liver that still works, without spread or vein invasion. It is treated to cure: cutting out the tumour, destroying it with heat through a needle, or replacing the liver by transplant, chosen by tumour size, liver function and portal pressure.","summary":"The Barcelona Clinic Liver Cancer system, first published in 1999 and updated in 2022, defines very early disease (BCLC 0) as a single tumour under 2 cm and early disease (BCLC A) as a single tumour of any size or up to three tumours each under 3 cm, with preserved liver function and performance status and no vascular invasion or spread. Most such tumours are found by six-monthly ultrasound surveillance of people with cirrhosis or chronic hepatitis B, and diagnosis rests on contrast imaging with the LI-RADS criteria rather than biopsy in a cirrhotic liver.\n\nResection is the first choice for a single tumour when liver function is preserved and portal hypertension absent, and is increasingly done laparoscopically or by robot; thermal ablation with radiofrequency or microwave is the alternative for tumours up to 3 cm, with survival equivalent to resection in randomised trials of small tumours and fewer complications, and stereotactic radiotherapy where ablation is impossible. Liver transplantation, for patients within the Milan criteria of a single tumour up to 5 cm or up to three tumours each up to 3 cm, treats both the cancer and the cirrhosis and gives the best long-term results, with bridging ablation or chemoembolisation while waiting and downstaging protocols for those just beyond the criteria.\n\nRecurrence after resection or ablation is the main problem, reaching about 70 percent at five years because the cirrhotic liver keeps producing new tumours. No adjuvant therapy has been established: sorafenib failed in STORM, and IMbrave050, in which atezolizumab and bevacizumab improved recurrence-free survival at the first analysis, lost that benefit with longer follow-up. Antiviral therapy for hepatitis B or C, alcohol abstinence and continued surveillance are the measures that do reduce recurrence and second tumours.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Hepatocellular_carcinoma","links":[{"label":"BCLC 2022 update (J Hepatol)","url":"https://pubmed.ncbi.nlm.nih.gov/34801630/"},{"label":"Milan criteria (NEJM 1996)","url":"https://www.nejm.org/doi/full/10.1056/NEJM199603143341104"},{"label":"IMbrave050 (Lancet 2023)","url":"https://pubmed.ncbi.nlm.nih.gov/37871608/"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Hepatocellular_carcinoma"}],"tags":["subtype-page"],"related":["hcc-advanced","hcc-intermediate"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["li-rads","depth-of-invasion"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-mazzaferro-milan-criteria-nejm-1996","paper-bclc-2022-reig-j-hepatol-2022","paper-imbrave050-lancet-2023","paper-storm-adjuvant-sorafenib-bruix-lancet-oncol-2015"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"The stage at which liver cancer can be cured, reached by a minority of patients worldwide but by most of those found by surveillance in cirrhosis; the BCLC system expects five-year survival above 70 percent with resection, ablation or transplantation.","subtypes":["Very early HCC (BCLC 0): single tumour under 2 cm in a cirrhotic liver","Early HCC (BCLC A): single tumour or up to three under 3 cm","HCC within Milan criteria (transplant candidates)","HCC in a non-cirrhotic liver (resectable at larger sizes)","Recurrent HCC after resection or ablation"],"biomarkers":["BCLC stage, Child-Pugh and ALBI liver function","Portal hypertension (platelets, varices, hepatic venous pressure gradient) before resection","Alpha-fetoprotein (prognosis and transplant selection)","LI-RADS imaging category on contrast CT or MRI","Microvascular invasion and satellite nodules on the resected specimen"],"standardOfCare":[{"setting":"Single tumour, preserved liver function","approach":"Hepatectomy, increasingly laparoscopic or robotic; ablation as an alternative for tumours up to 3 cm.","refs":["hepatectomy","thermal-ablation","radiofrequency-ablation","microwave-ablation","robotic-surgery","bclc-staging"]},{"setting":"Within Milan criteria with cirrhosis or portal hypertension","approach":"Liver transplantation, with bridging ablation or chemoembolisation on the waiting list and downstaging for patients just outside the criteria.","refs":["liver-transplant-oncology","bridging-therapy","tace","thermal-ablation"]},{"setting":"Not suitable for surgery or ablation","approach":"Stereotactic body radiotherapy or radioembolisation.","refs":["sbrt","radioembolisation-tare"]},{"setting":"After curative treatment","approach":"No proven adjuvant therapy (STORM and IMbrave050 negative in the end); antiviral therapy, alcohol abstinence and continued imaging surveillance.","refs":["imbrave050","atezolizumab","bevacizumab","hcc-surveillance","hbv-hcv"]},{"setting":"Detection","approach":"Six-monthly ultrasound with alpha-fetoprotein in cirrhosis and chronic hepatitis B.","refs":["hcc-surveillance","ultrasound","afp","mri"]}],"stateOfArt":["Resection, ablation and transplantation each cure a large share of early tumours, and the choice between them is guided by liver function and portal pressure as much as by the tumour.","Surveillance in cirrhosis is what moves patients into this curable stage.","Adjuvant immunotherapy has not yet delivered a durable benefit, leaving recurrence the unsolved problem."],"history":[{"year":1996,"title":"Mazzaferro defines the Milan criteria for liver transplantation in HCC","refs":["liver-transplant-oncology"]},{"year":1999,"title":"Barcelona Clinic Liver Cancer staging published (Llovet)","refs":["bclc-staging"]},{"year":2006,"title":"Randomised trial shows radiofrequency ablation equals resection for small tumours (Chen)","refs":["radiofrequency-ablation"]},{"year":2015,"title":"STORM: adjuvant sorafenib fails after resection or ablation","refs":["sorafenib"]},{"year":2023,"title":"IMbrave050: adjuvant atezolizumab-bevacizumab improves recurrence-free survival at interim analysis","refs":["imbrave050"]},{"year":2025,"title":"IMbrave050 update: the recurrence-free survival benefit is not sustained","refs":["imbrave050"]}],"pipeline":["imbrave050","liver-transplant-oncology","idea-hcc-io-before-transplant","idea-hcc-blood-surveillance","hcc-surveillance","hifu-histotripsy","mrd-testing"],"openProblems":["Recurrence in the remaining cirrhotic liver after resection or ablation.","No adjuvant therapy has held up in a phase 3 trial.","Donor shortage limits transplantation, and access to surveillance is poor in the highest-incidence countries."],"parent":"hcc"},{"id":"her2-positive-early-breast-cancer","kind":"cancer","name":"Early HER2-positive breast cancer","aka":["Stage I to III HER2-positive breast cancer","Operable HER2-positive breast cancer","HER2-positive breast cancer treated with curative intent"],"tldr":"HER2-positive breast cancer caught early is usually cured. Chemotherapy with the antibodies trastuzumab and pertuzumab comes before surgery; if the tumour has gone by then, antibodies alone finish the year, and if cancer remains, trastuzumab emtansine or trastuzumab deruxtecan take over. Small tumours get a gentler regimen, and trials now ask how much treatment can be left out.","summary":"A year of trastuzumab is the foundation. HERA, NSABP B-31 and NCCTG N9831, reported together in 2005, showed that adding trastuzumab to adjuvant chemotherapy cut deaths by about a third, with ten-year overall survival of 84 percent against 75.2 percent in the joint American analysis. PERSEPHONE found six months almost as good as twelve (four-year disease-free survival 89.4 against 89.8 percent) with half the cardiac toxicity, but twelve months remains the standard. For tumours of 3 cm or less without node involvement, the single-arm APT study of twelve weeks of paclitaxel with a year of trastuzumab gave 93 percent seven-year disease-free survival and became the standard for stage I disease without a randomised trial.\n\nFor stage II and III disease treatment moved before surgery, where pathological complete response predicts cure and guides what follows. NeoSphere showed that pertuzumab added to trastuzumab and docetaxel raises the complete response rate, and TRAIN-2 (438 patients) showed that carboplatin and paclitaxel with both antibodies matched an anthracycline regimen (complete response 67 against 68 percent) with less cardiac damage, so anthracycline-free regimens became usual. KRISTINE (444 patients) tested replacing chemotherapy with trastuzumab emtansine plus pertuzumab and found fewer complete responses (44.4 against 55.7 percent) and more progression before surgery, a warning against de-escalating on antibody-drug conjugates alone. KATHERINE (1,486 women with residual invasive disease) showed that fourteen cycles of trastuzumab emtansine instead of trastuzumab halved recurrence (three-year invasive disease-free survival 88.3 against 77.0 percent) and improved seven-year overall survival (89.1 against 84.4 percent), and APHINITY (4,805 women) showed adjuvant pertuzumab adds a few points of invasive disease-free survival in node-positive disease and nothing in node-negative disease.\n\nTrastuzumab deruxtecan is now reshaping both ends. DESTINY-Breast05 (1,635 women with residual disease) showed it beats trastuzumab emtansine, with three-year invasive disease-free survival of 92.4 against 83.7 percent (hazard ratio 0.47), and DESTINY-Breast11 (927 women) showed trastuzumab deruxtecan followed by taxane, trastuzumab and pertuzumab before surgery gives more complete responses than dose-dense anthracycline chemotherapy (67.3 against 56.3 percent); the FDA approved both indications in 2026. In the other direction, PHERGain used an early PET scan to identify women who could be cured with antibodies and no chemotherapy at all, with 95.4 percent three-year invasive disease-free survival in the adapted arm and about a third spared chemotherapy. Who can safely skip chemotherapy, whether interstitial lung disease is acceptable in a curative setting, and how hormone receptor-positive HER2-positive tumours should be treated differently are the open questions.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/HER2-positive_breast_cancer","links":[{"label":"KATHERINE (NEJM 2019)","url":"https://doi.org/10.1056/NEJMoa1814017"},{"label":"APHINITY (NEJM 2017)","url":"https://doi.org/10.1056/NEJMoa1703643"},{"label":"TRAIN-2 (Lancet Oncology 2018)","url":"https://doi.org/10.1016/S1470-2045(18)30570-9"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/HER2-positive_breast_cancer"}],"tags":["subtype-page"],"related":["her2-positive-breast-brain-metastases"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["atempt","neosphere"],"people":[],"bottlenecks":[],"keyPapers":["paper-katherine-nejm-2019","paper-aphinity-nejm-2017","paper-apt-tolaney-nejm-2015","paper-train-2-lancet-oncol-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Around 15 to 20 percent of breast cancers overexpress HER2 and most are diagnosed at an operable stage; once the subtype with the worst outlook, it now has some of the highest cure rates after a year of HER2-directed therapy.","subtypes":["Stage I, node-negative HER2-positive tumours of 3 cm or less (paclitaxel and trastuzumab, APT)","Stage II to III hormone receptor-negative HER2-positive disease (highest pathological complete response rates)","Stage II to III hormone receptor-positive HER2-positive disease (lower response, endocrine therapy added)","Residual invasive HER2-positive disease after neoadjuvant therapy (KATHERINE and DESTINY-Breast05 population)","Pathological complete response after neoadjuvant therapy (antibodies alone to complete a year)"],"biomarkers":["HER2 immunohistochemistry 3+ or in situ hybridisation amplification","Hormone receptor status (co-positive tumours respond less to HER2 therapy alone)","Pathological complete response and residual cancer burden at surgery","Left ventricular ejection fraction before and during trastuzumab","Early FDG PET response (PHERGain, investigational)","PIK3CA mutation (lower complete response rates, research use)"],"standardOfCare":[{"setting":"Stage I, small node-negative tumours","approach":"Surgery first, then twelve weeks of paclitaxel with a year of trastuzumab (APT).","refs":["paclitaxel","trastuzumab","apt-trial"]},{"setting":"Stage II to III, before surgery","approach":"Carboplatin, a taxane, trastuzumab and pertuzumab for six cycles without an anthracycline (TRAIN-2), or trastuzumab deruxtecan followed by taxane, trastuzumab and pertuzumab (DESTINY-Breast11).","refs":["carboplatin","docetaxel","paclitaxel","trastuzumab","pertuzumab","train-2","trastuzumab-deruxtecan","destiny-breast11"]},{"setting":"Pathological complete response at surgery","approach":"Trastuzumab, with pertuzumab in node-positive disease, to complete one year (APHINITY, HERA); endocrine therapy if hormone receptor-positive.","refs":["trastuzumab","pertuzumab","aphinity","hera-b31-n9831","pcr"]},{"setting":"Residual invasive disease at surgery","approach":"Trastuzumab deruxtecan (DESTINY-Breast05) or trastuzumab emtansine for fourteen cycles (KATHERINE).","refs":["trastuzumab-deruxtecan","destiny-breast05","trastuzumab-emtansine","katherine","rcb"]},{"setting":"Local therapy and the heart","approach":"Breast conservation or mastectomy with sentinel node biopsy, radiotherapy by stage, and echocardiography every three months during trastuzumab.","refs":["lumpectomy","mastectomy","sentinel-node","hypofractionated-radiotherapy","trastuzumab-cardiotoxicity"]}],"stateOfArt":["Response-adapted treatment: what happens after surgery depends on whether the tumour has gone.","Trastuzumab deruxtecan approved in 2026 for both neoadjuvant and post-neoadjuvant use.","PET-guided and pathology-guided de-escalation trials are sparing a growing minority of women chemotherapy.","Anthracyclines have largely left HER2-positive treatment."],"history":[{"year":1987,"title":"Slamon: HER2 amplification marks aggressive disease","refs":[]},{"year":1998,"title":"Trastuzumab approved for metastatic disease","refs":["trastuzumab"]},{"year":2005,"title":"HERA, NSABP B-31 and N9831: a year of adjuvant trastuzumab","refs":["hera-b31-n9831","trastuzumab"]},{"year":2012,"title":"NeoSphere: pertuzumab raises pathological complete response","refs":["pertuzumab"]},{"year":2013,"title":"Pertuzumab: first approval granted on a pathological complete response endpoint","refs":["pertuzumab"]},{"year":2017,"title":"APHINITY: adjuvant pertuzumab helps node-positive disease","refs":["aphinity","pertuzumab"]},{"year":2018,"title":"KATHERINE, TRAIN-2 and KRISTINE","refs":["katherine","trastuzumab-emtansine","train-2","kristine"]},{"year":2019,"title":"PERSEPHONE: six months of trastuzumab nearly as good as twelve","refs":["persephone"]},{"year":2024,"title":"PHERGain: PET-guided omission of chemotherapy","refs":["phergain"]},{"year":2025,"title":"DESTINY-Breast05 and DESTINY-Breast11","refs":["destiny-breast05","destiny-breast11","trastuzumab-deruxtecan"]}],"pipeline":["destiny-breast05","destiny-breast11","phergain","trastuzumab-deruxtecan","her2-pet","zanidatamab","trastuzumab-rezetecan","mrd-testing"],"openProblems":["Which women can skip chemotherapy entirely without losing cure.","Interstitial lung disease from trastuzumab deruxtecan in women who would otherwise have been cured.","Hormone receptor-positive HER2-positive tumours respond less and the right endocrine and HER2 maintenance is unsettled.","Cardiac safety of longer and stronger HER2 regimens over decades of survivorship."],"parent":"breast-her2-positive"},{"id":"tnbc-early","kind":"cancer","name":"Early triple-negative breast cancer","aka":["Stage I to III triple-negative breast cancer","Operable triple-negative breast cancer","Curable TNBC"],"tldr":"Early triple-negative breast cancer is treated to cure. For tumours over 2 cm or with node involvement, chemotherapy plus the immunotherapy pembrolizumab before and after surgery has raised cure rates; BRCA carriers with cancer left at surgery add a year of olaparib, and others with residual cancer are offered capecitabine. Whether the tumour has vanished by surgery guides what comes next.","summary":"Early triple-negative disease is basal-like in most cases, almost always TP53-mutant, carries a germline BRCA1 or BRCA2 mutation in roughly one in five patients and is the breast cancer with the most immune infiltration. Because there is no receptor to block, chemotherapy has carried the curative burden, and it is given before surgery whenever the tumour is over 2 cm or the nodes are involved, both to shrink it and because the response at surgery, measured as pathological complete response or residual cancer burden, is the strongest predictor of relapse. Platinum added to a taxane and anthracycline raised complete response rates in GeparSixto, CALGB 40603 and BrighTNess, and tumours under 1 cm without node involvement often need no chemotherapy at all, with high tumour-infiltrating lymphocytes marking a group whose outcome is excellent regardless.\n\nKEYNOTE-522 rewrote the standard. It randomised 1,174 patients with stage II or III disease to pembrolizumab or placebo with carboplatin and paclitaxel then an anthracycline and cyclophosphamide before surgery, followed by pembrolizumab or placebo for nine cycles after. Pathological complete response rose from 51.2 to 64.8 percent, event-free survival improved (hazard ratio 0.63) and, unusually for a neoadjuvant trial, overall survival did too, with the seven-year update showing 85.1 against 77.2 percent alive; the FDA approved the regimen in July 2021 and it is given whatever the PD-L1 score. IMpassion031 showed atezolizumab raises complete response in the same setting (58 against 41 percent) but never became a standard.\n\nWhat follows surgery depends on what the pathologist finds. Women with a complete response finish their year of pembrolizumab and whether they need it at all is being tested in OptimICE-pCR. Women with residual disease and a germline BRCA mutation take olaparib for a year: OlympiA randomised 1,836 such patients with HER2-negative disease, about four in five triple-negative, and improved invasive disease-free survival (hazard ratio 0.58) and overall survival (hazard ratio 0.72). Others are offered six to eight cycles of capecitabine on the strength of CREATE-X, a Japanese trial of 910 women with residual HER2-negative disease in which five-year disease-free survival rose from 67.6 to 74.1 percent with the largest survival gain in the triple-negative group. None of these post-surgery trials included pembrolizumab, so how the pieces combine is unknown, and ASCENT-05 is testing sacituzumab govitecan with pembrolizumab in residual disease while SCARLET asks whether the anthracycline can be dropped and circulating tumour DNA is being studied to find the women who still harbour disease.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Triple-negative_breast_cancer","links":[{"label":"KEYNOTE-522 (NEJM 2020)","url":"https://doi.org/10.1056/NEJMoa1910549"},{"label":"KEYNOTE-522 overall survival (NEJM 2024)","url":"https://doi.org/10.1056/NEJMoa2409932"},{"label":"OlympiA (NEJM 2021)","url":"https://doi.org/10.1056/NEJMoa2105215"},{"label":"CREATE-X (NEJM 2017)","url":"https://doi.org/10.1056/NEJMoa1612645"}],"tags":["subtype-page"],"related":["tnbc-metastatic"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["geparsixto","brightness"],"people":[],"bottlenecks":["b-trial-diversity"],"keyPapers":["paper-olympia-nejm-2021","paper-create-x-adjuvant-capecitabine-nejm-2017"],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Most of the roughly 200,000 triple-negative breast cancers diagnosed each year are found before they have spread; relapses cluster in the first three years, so what happens around surgery decides most outcomes.","subtypes":["Stage I, node-negative basal-like tumours of 2 cm or less (chemotherapy without immunotherapy, or none for the smallest)","Stage II to III triple-negative disease (KEYNOTE-522 population)","Germline BRCA1 or BRCA2-mutant early triple-negative disease (OlympiA)","Residual invasive disease after neoadjuvant therapy (capecitabine, olaparib, trials)","Pathological complete response after neoadjuvant chemo-immunotherapy","Immunomodulatory triple-negative disease with high tumour-infiltrating lymphocytes"],"biomarkers":["Oestrogen and progesterone receptor under 1 percent and HER2 0 to 1+, or 2+ without amplification","Germline BRCA1, BRCA2 and PALB2 (olaparib eligibility, surgical choices)","Tumour-infiltrating lymphocytes (prognostic, de-escalation trials)","Pathological complete response and residual cancer burden at surgery","PD-L1 (not required for pembrolizumab in early disease)","Circulating tumour DNA after surgery (investigational)"],"standardOfCare":[{"setting":"Stage I, tumours 2 cm or less without node involvement","approach":"Surgery with sentinel node biopsy and radiotherapy; chemotherapy for tumours over 1 cm, often omitted below that, with tumour-infiltrating lymphocytes guiding de-escalation trials.","refs":["lumpectomy","sentinel-node","hypofractionated-radiotherapy","tils"]},{"setting":"Stage II to III, before surgery","approach":"Pembrolizumab with carboplatin and paclitaxel, then with doxorubicin or epirubicin and cyclophosphamide, followed by surgery (KEYNOTE-522).","refs":["pembrolizumab","carboplatin","paclitaxel","doxorubicin","epirubicin","cyclophosphamide","keynote-522","checkpoint-inhibitor"]},{"setting":"After surgery, pathological complete response","approach":"Pembrolizumab to complete a year and radiotherapy by stage; omission of adjuvant pembrolizumab is under test (OptimICE-pCR).","refs":["pembrolizumab","pcr","optimice-pcr"]},{"setting":"After surgery, residual disease","approach":"Pembrolizumab to complete a year; olaparib for one year in germline BRCA carriers (OlympiA); capecitabine for six to eight cycles otherwise (CREATE-X); sacituzumab govitecan with pembrolizumab under study (ASCENT-05).","refs":["pembrolizumab","olaparib","olympia","capecitabine","rcb","ascent-05","germline-testing"]},{"setting":"Local therapy","approach":"Breast conservation with whole-breast radiotherapy or mastectomy, sentinel node biopsy after neoadjuvant therapy, and post-mastectomy radiotherapy for node-positive disease.","refs":["lumpectomy","mastectomy","sentinel-node","imrt-igrt"]}],"stateOfArt":["Chemo-immunotherapy before and after surgery improves survival, the first curative gain in triple-negative disease in a generation.","Adjuvant olaparib for BRCA carriers makes germline testing part of every treatment plan.","Response-adapted treatment after surgery, with capecitabine or olaparib for residual disease.","De-escalation for small, lymphocyte-rich tumours is moving from cohorts into trials."],"history":[{"year":2007,"title":"Triple-negative defined as a clinical entity","refs":[]},{"year":2014,"title":"GeparSixto and CALGB 40603: carboplatin raises pathological complete response","refs":["carboplatin"]},{"year":2017,"title":"CREATE-X: capecitabine for residual disease after neoadjuvant chemotherapy","refs":["capecitabine"]},{"year":2020,"title":"KEYNOTE-522 and IMpassion031: immunotherapy raises pathological complete response","refs":["keynote-522","impassion031","pembrolizumab","atezolizumab"]},{"year":2021,"title":"Pembrolizumab approved for early disease; OlympiA adjuvant olaparib","refs":["pembrolizumab","olympia","olaparib"]},{"year":2024,"title":"KEYNOTE-522 overall survival benefit published","refs":["keynote-522"]}],"pipeline":["ascent-05","optimice-pcr","scarlet-s2212","mrd-testing","sacituzumab-govitecan","neoantigen-mrna-vaccine","tils"],"openProblems":["No trial has tested capecitabine or olaparib on top of adjuvant pembrolizumab for residual disease.","About a third of patients do not reach a complete response and most relapses come from them.","Immune-related endocrine side effects are permanent in a few percent of women who would have been cured anyway.","Black women have twice the incidence and worse outcomes, and trial enrolment does not reflect this."],"parent":"tnbc"},{"id":"early-onset-colorectal","kind":"cancer","name":"Early-onset colorectal cancer (under 50)","aka":["Young-onset colorectal cancer","Colorectal cancer in adults under 50","Early-age-onset colorectal cancer","Bowel cancer in young adults","Early-onset colorectal cancer","EOCRC"],"tldr":"Bowel cancer is rising in people under 50, for reasons that are still not understood, and it is usually found late because neither patients nor doctors expect it. Treatment is the same as in older adults and works as well stage for stage; the changes are earlier screening, genetic testing for everyone diagnosed young, and attention to fertility, work and family.","summary":"Early-onset colorectal cancer is defined by age under 50 at diagnosis. Birth-cohort analyses (Siegel and colleagues, 2017) showed that people born around 1990 have double the colon cancer risk and four times the rectal cancer risk of those born around 1950 at the same age, a rise seen across high-income countries and attributed to diet, obesity, antibiotics, the microbiome and other early-life exposures without any one cause proven; a colibactin mutational signature from pks-positive Escherichia coli acquired in childhood is enriched in early-onset tumours (Nature 2025). About one in six patients diagnosed under 50 carries a germline cancer-predisposition variant, half of them Lynch syndrome, so multigene germline testing is recommended for everyone in this group.\n\nMost early-onset tumours are left-sided or rectal, microsatellite-stable and diagnosed at stage III or IV after months of rectal bleeding, iron deficiency or change in bowel habit that was attributed to haemorrhoids or irritable bowel. Stage for stage, outcomes are similar to older adults, and treatment follows the same pathways: surgery and stage-based adjuvant chemotherapy, total neoadjuvant therapy or organ preservation for rectal tumours, and genotype-directed therapy for metastatic disease. Young patients receive more intensive chemotherapy without evidence that it helps them more.\n\nThe policy response has been earlier screening: the American Cancer Society lowered the starting age for average-risk adults from 50 to 45 in 2018 and the US Preventive Services Task Force followed in 2021; European programmes are debating the same step, and polygenic risk scores may set individual starting ages. For patients, the distinct needs are fertility preservation before pelvic radiotherapy and oxaliplatin, sexual and stoma counselling, financial and employment support, and enrolment in the cohort studies trying to explain the rise.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Colorectal_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Colorectal_cancer"},{"label":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"},{"label":"Colorectal cancer statistics, 2026 (American Cancer Society, CA: a Cancer Journal for Clinicians)","url":"https://doi.org/10.3322/caac.70067"},{"label":"Siegel, Gut 2019: global patterns and trends in colorectal cancer incidence in young adults (36 countries)","url":"https://doi.org/10.1136/gutjnl-2019-319511"},{"label":"Nature 2025: geographic and age variations in mutational processes in colorectal cancer (981 genomes from 11 countries)","url":"https://doi.org/10.1038/s41586-025-09025-8"}],"tags":["subtype-page"],"related":["braf-v600e-colorectal","her2-amplified-colorectal","kras-g12c-colorectal","msi-high-colorectal","rectal-cancer"],"cancers":[],"sections":[],"technologies":["colorectal-screening","germline-testing","exercise-oncology","ai-endoscopy-detection"],"targets":["kras","braf","her2","pd1"],"drugs":["shield","cologuard","folfox","capox"],"companies":[],"institutions":[],"pathways":["colorectal-cancer-signalling"],"terms":["lynch-syndrome","msi","fit-test","colonoscopy","sidedness","colibactin","screening-uptake","bowel-cancer-screening-uk"],"trials":["challenge","nordicc","eclipse-shield"],"people":["chadwick-boseman","michael-bretthauer"],"bottlenecks":[],"keyPapers":["paper-cms-guinney-nat-med-2015","paper-sinicrope-early-onset-crc-nejm-2022","paper-uspstf-crc-screening-45-jama-2021","paper-siegel-colorectal-incidence-birth-cohort-jnci-2017"],"journals":[],"dependsOn":[],"notes":["The numbers as they stood in September 2026. The American Cancer Society's 2026 report gives incidence rising 3 percent a year in adults aged 20 to 49 over 2013 to 2022 and 0.4 percent a year at 50 to 64, against a fall of 2.5 percent a year in the over-65s, with mortality under 50 rising 1 percent a year since 2004; rectal cancer is now 32 percent of colorectal cancers, up from 27 percent in the mid-2000s. Registry data from 36 countries showed incidence in adults under 50 rising in 19 of them and, in nine spanning three continents, rising in the young while stable or falling in older adults (Siegel 2019).","The leading mechanistic lead. In 981 colorectal cancer genomes from 11 countries, the colibactin mutational signatures SBS88 and ID18 were 3.3 times commoner in people diagnosed before 40 than after 70, were imprinted early in tumour development, and accounted for about a quarter of APC driver insertions and deletions in colibactin-positive cases, which points at an exposure to colibactin-producing gut bacteria in early life (Nature 2025)."],"group":"gastrointestinal","burden":"Roughly one in ten colorectal cancers in high-income countries is now diagnosed before 50, and incidence in this age group has risen by about 2 percent a year in the United States since the mid-1990s while falling in older adults; most are left-sided or rectal and diagnosed at a later stage.","subtypes":["Sporadic early-onset colorectal cancer (the large majority; mostly left colon and rectum, microsatellite-stable)","Hereditary early-onset colorectal cancer (Lynch syndrome, familial adenomatous polyposis and other germline variants, about one in six)","Early-onset rectal cancer (fertility, sexual function and stoma questions loom larger)","Mismatch-repair deficient early-onset tumours (immunotherapy as in other dMMR disease)"],"biomarkers":["Multigene germline panel for every patient diagnosed under 50","Mismatch repair / microsatellite status","RAS, BRAF V600E and HER2 as for all colorectal cancer","Colibactin (pks+ E. coli) mutational signature (research)","Iron deficiency and rectal bleeding as presenting signs at any age"],"standardOfCare":[{"setting":"Screening and early diagnosis","approach":"Average-risk screening from age 45 (colonoscopy, faecal immunochemical test, stool DNA or blood test); earlier and more frequent colonoscopy for family history or a known syndrome; investigate rectal bleeding and iron deficiency promptly at any age.","refs":["colorectal-screening","fit-test","colonoscopy","shield","cologuard"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Diagnosis and staging","approach":"Germline multigene testing for every patient; mismatch repair, RAS, BRAF and HER2 testing; fertility counselling before treatment.","refs":["germline-testing","lynch-syndrome","msi","histopathology-ihc"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Localised disease","approach":"As for colorectal and rectal cancer by stage: surgery, adjuvant FOLFOX or CAPOX for stage III, total neoadjuvant therapy or organ preservation for rectal tumours; no escalation on the basis of age alone.","refs":["folfox","capox","total-neoadjuvant-therapy","organ-preservation","rapido"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Metastatic disease","approach":"Genotype-directed therapy as for all metastatic colorectal cancer: checkpoint blockade if mismatch-repair deficient, encorafenib-cetuximab for BRAF V600E, HER2 or KRAS G12C combinations, otherwise chemotherapy with bevacizumab or an anti-EGFR antibody by sidedness.","refs":["pembrolizumab","encorafenib","tucatinib","sotorasib","bevacizumab","cetuximab"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Survivorship","approach":"Structured exercise (CHALLENGE), long-term neuropathy and bowel function care, fertility and sexual health follow-up, financial and employment support.","refs":["exercise-oncology","challenge"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}}],"stateOfArt":["Screening now starts at 45 in the United States, the first policy response to the rise.","Universal germline testing in patients under 50 finds a hereditary syndrome in about one in six.","Mutational signatures are beginning to point at childhood exposures, including colibactin-producing bacteria."],"history":[{"year":2017,"title":"Siegel and colleagues show a birth-cohort rise in colon and rectal cancer in young adults","refs":["colorectal-screening"]},{"year":2017,"title":"Pearlman: about one in six patients under 50 carries a germline predisposition variant","refs":["germline-testing","lynch-syndrome"]},{"year":2018,"title":"American Cancer Society lowers the screening start age to 45","refs":["colorectal-screening"]},{"year":2021,"title":"US Preventive Services Task Force recommends screening from 45","refs":["colorectal-screening","fit-test"]},{"year":2025,"title":"Colibactin mutational signature found enriched in early-onset tumours (Nature)","refs":["colorectal-screening"]}],"pipeline":["idea-prev-prs-screening-start-age","idea-prev-reflex-germline-testing","shield","colorectal-screening","idea-prev-blood-crc-test-for-non-responders"],"openProblems":["The cause of the rise is unknown; no exposure has been proven.","Diagnostic delay in young adults with rectal bleeding remains long.","Whether screening should start at 45, 40 or by individual risk is unsettled outside the United States.","Fertility, sexual function and financial toxicity are poorly measured in trials."],"parent":"colorectal"},{"id":"early-stage-classical-hodgkin-lymphoma","kind":"cancer","name":"Early-stage classical Hodgkin lymphoma (stage I to II)","aka":["Limited-stage Hodgkin lymphoma","Stage I to II classical Hodgkin lymphoma","Early favourable and early unfavourable Hodgkin lymphoma","Localised Hodgkin lymphoma"],"tldr":"Early-stage classical Hodgkin lymphoma is Hodgkin lymphoma confined to one or two lymph node regions on one side of the diaphragm, one of the most curable cancers, with most patients cured by a short course of ABVD chemotherapy with or without radiotherapy to the involved nodes. Because patients are young, trials now use PET scans after two cycles to give as little treatment as safely possible.","summary":"Classical Hodgkin lymphoma is a B-cell lymphoma in which the malignant Hodgkin and Reed-Sternberg cells, CD30 and CD15 positive and usually CD20 negative, are outnumbered by a reactive inflammatory background; nodular sclerosis is the commonest subtype in young adults, and PD-L1 amplification at 9p24.1 is near universal. Stage I and II disease is divided into favourable and unfavourable groups by the presence of bulky disease, raised erythrocyte sedimentation rate, B symptoms, three or more nodal sites or extranodal extension, definitions that differ slightly between the German Hodgkin Study Group (GHSG) and the EORTC. Radiotherapy alone cured most patients with early disease from the 1960s, but the second cancers and heart disease it caused decades later drove the shift to combined chemotherapy with smaller radiation fields and lower doses.\n\nGHSG HD10 (New England Journal of Medicine 2010) showed that two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with 20 Gy of involved-field radiotherapy was enough for favourable disease, and HD11 and HD14 defined four cycles of chemotherapy (or two escalated BEACOPP plus two ABVD) with 30 Gy for unfavourable disease. Interim PET then became the tool for de-escalation: the RAPID trial (New England Journal of Medicine 2015) and EORTC H10 showed that omitting radiotherapy in patients who were PET-negative after two or three ABVD cycles costs a few percentage points of progression-free survival without a survival difference, and HD16 and HD17 refined which PET-negative patients can safely skip radiotherapy, so today many patients receive chemotherapy alone and the rest involved-site radiotherapy with modern conformal or proton techniques that spare the heart and breasts. Brentuximab vedotin and PD-1 antibodies, established in advanced disease, are moving into early-stage trials: the Children's Oncology Group AHOD2131 trial compares brentuximab vedotin with nivolumab against standard chemotherapy in early-stage high-risk disease in patients from age 5 to 60, and the GHSG HD21 and NIVAHL programmes test PD-1 antibodies with reduced chemotherapy. Fertility preservation, cardiac protection and lifelong survivorship care, including breast screening for women irradiated young, are part of standard management.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Hodgkin_lymphoma","links":[{"label":"GHSG HD10 (NEJM 2010)","url":"https://doi.org/10.1056/NEJMoa1000067"},{"label":"RAPID (NEJM 2015)","url":"https://doi.org/10.1056/NEJMoa1408648"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Hodgkin_lymphoma"},{"label":"Lymphoma Action: helpline services","url":"https://lymphoma-action.org.uk/information-and-support/support-you/helpline-services"},{"label":"Lymphoma Action: questions to ask your medical team about lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/questions-ask-your-medical-team-about-lymphoma"},{"label":"Lymphoma Action: follow-up after lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/follow-after-lymphoma-treatment"},{"label":"Lymphoma Action: infections, risk and prevention","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/infections-risk-and-prevention"},{"label":"Lymphoma Action: neutropenia (low neutrophils)","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/neutropenia-low-neutrophils"},{"label":"Lymphoma Action: cancer-related fatigue","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/cancer-related-fatigue"},{"label":"Lymphoma Action: lymphoma, work and you","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/day-day-living/lymphoma-work-and-you"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Lymphoma Action: classical Hodgkin lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/types-lymphoma/hodgkin-lymphoma/classical-hodgkin-lymphoma"},{"label":"Lymphoma Action: late effects of lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/late-effects-lymphoma-treatment"},{"label":"GOV.UK: protocols for surveillance of women at higher risk of developing breast cancer, NHS Breast Screening Programme","url":"https://www.gov.uk/government/publications/breast-screening-higher-risk-women-surveillance-protocols/protocols-for-surveillance-of-women-at-higher-risk-of-developing-breast-cancer"},{"label":"Lymphoma Action: annual breast screening missed following radiotherapy for Hodgkin lymphoma","url":"https://lymphoma-action.org.uk/news/annual-breast-screening-missed-following-radiotherapy-hodgkin-lymphoma"},{"label":"Schaapveld et al., second cancer risk up to 40 years after treatment for Hodgkin's lymphoma, New England Journal of Medicine 2015 (3,905 Dutch survivors)","url":"https://doi.org/10.1056/NEJMoa1505949"}],"tags":["subtype-page","haematologic"],"related":["advanced-stage-classical-hodgkin-lymphoma","relapsed-refractory-hodgkin-lymphoma","nodular-lymphocyte-predominant-hodgkin-lymphoma","hodgkin-lymphoma","primary-mediastinal-b-cell-lymphoma","lymphoma-roadmap","lymphoma-ev-radiotherapy-free-early-hodgkin"],"cancers":[],"sections":[],"technologies":["fdg-pet","pet-adapted-therapy","imrt-igrt","proton-therapy","cardio-oncology","fertility-preservation","ctdna-lymphoma-monitoring","mammography","palliative-care","psycho-oncology","peer-support-groups","survivorship-care-plan","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","multidisciplinary-tumour-board","oncology-nutrition","prehabilitation"],"targets":["cd30","pd1"],"drugs":["doxorubicin","vinblastine","dacarbazine","brentuximab-vedotin","nivolumab","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["deauville-score","reed-sternberg-cell","lugano-classification","abvd-beacopp","late-effects","lymphoma-tx-radiotherapy","lymphoma-tx-hodgkin-late-effects","lymphoma-tx-fertility-preservation","lymphoma-tx-transplant-role","lymphoma-tx-uk-versus-us","lymphoma-tx-uk-access","lymphoma-tx-regimen-alphabet","cancer-related-fatigue","febrile-neutropenia","neutropenia","financial-toxicity","central-venous-access","hypogammaglobulinaemia","performance-status","quality-of-life","lymphoma-decision-fertility-timing","lymphoma-decision-trial","lymphoma-living-hodgkin-survivorship-screening","lymphoma-living-fatigue","secondary-malignancy","cardiotoxicity"],"trials":["ahod2131","nct03407144","hd10","hd16","eortc-h10","radar-hodgkin"],"people":[],"bottlenecks":[],"keyPapers":["paper-echelon-1-brentuximab-avd-nejm-2018","paper-ghsg-hd10-reduced-intensity-early-hodgkin-nejm-2010","paper-rapid-pet-directed-therapy-early-hodgkin-nejm-2015"],"journals":[],"dependsOn":[],"notes":["Early-stage Hodgkin lymphoma, and the screening that follows a cure: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the 24-hour number they gave you come first, and no figure here is a prediction about you. The decision records, the question sets, the first 60 days checklist and the red cards on this page were written from the NHS, Lymphoma Action, Macmillan and Cancer Research UK patient pages, from NICE NG52, NG47, CG151 and NG234, from the NHS Breast Screening Programme protocols and the Green Book, and from the trial reports named beside each figure, all read on 1 October 2026."],"group":"haematologic","burden":"About half of classical Hodgkin lymphoma, typically in young adults with painless neck or mediastinal nodes; cure rates exceed nine in ten, so the modern problem is avoiding late harm from treatment.","subtypes":["Early favourable classical Hodgkin lymphoma (stage I to II without risk factors; two ABVD and 20 Gy or PET-guided chemotherapy alone)","Early unfavourable classical Hodgkin lymphoma (bulk, raised ESR, three or more sites or extranodal extension)","Nodular sclerosis classical Hodgkin lymphoma (commonest in young adults, mediastinal)","Mixed cellularity classical Hodgkin lymphoma (EBV-positive, children and older adults)","Lymphocyte-rich classical Hodgkin lymphoma","Paediatric and adolescent early-stage classical Hodgkin lymphoma (Children's Oncology Group risk groups)"],"biomarkers":["Interim FDG-PET after two cycles (Deauville score; guides omission of radiotherapy)","CD30 and CD15 on Hodgkin and Reed-Sternberg cells; CD20 usually negative","Bulky disease, erythrocyte sedimentation rate, B symptoms and number of sites (GHSG and EORTC risk factors)","EBV status (EBER) in mixed cellularity disease","Baseline metabolic tumour volume (prognostic, research)","Circulating tumour DNA (research; PhasED-seq)"],"standardOfCare":[{"setting":"Staging","approach":"FDG-PET/CT with Lugano staging; bone marrow biopsy no longer needed when PET is used; fertility counselling and cardiac baseline.","refs":["fdg-pet","lugano-classification","fertility-preservation","cardio-oncology"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Early favourable disease","approach":"Two cycles of ABVD with 20 Gy involved-site radiotherapy (HD10); or PET-adapted chemotherapy alone (three ABVD if PET-negative after two, RAPID and H10) accepting a small increase in relapse.","refs":["doxorubicin","vinblastine","dacarbazine","abvd-beacopp","imrt-igrt","pet-adapted-therapy","deauville-score"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Early unfavourable disease","approach":"Four cycles of ABVD (or two escalated BEACOPP plus two ABVD) with 30 Gy involved-site radiotherapy; radiotherapy omitted in PET-negative patients after HD17.","refs":["doxorubicin","vinblastine","dacarbazine","abvd-beacopp","imrt-igrt","pet-adapted-therapy"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Children and adolescents","approach":"Response-adapted Children's Oncology Group regimens with radiotherapy for slow responders; AHOD2131 tests brentuximab vedotin with nivolumab.","refs":["ahod2131","brentuximab-vedotin","nivolumab","childrens-oncology-group"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Survivorship","approach":"Cardiac surveillance, breast screening from eight years after chest radiotherapy in women, thyroid checks and second-cancer awareness for life.","refs":["cardio-oncology","mammography","late-effects"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Early favourable Hodgkin lymphoma: two cycles of ABVD and 20 Gy, and the argument about leaving the radiotherapy out","approach":"GHSG HD10 established the smallest combined-modality treatment that works: two cycles of ABVD followed by 20 Gy involved-field radiotherapy gave five-year freedom from treatment failure of about 93 per cent and overall survival of about 97 per cent, with no advantage from four cycles or from 30 Gy, and fewer acute adverse events at the lower intensity. Four visits of chemotherapy and a fortnight of radiotherapy cure the great majority.\n\nWhether the radiotherapy can be dropped in patients whose PET is negative has been asked twice, and both answers were the same. HD16 randomised 1,150 patients: among 628 who were PET-negative after two cycles, five-year progression-free survival was 93.4 per cent with combined-modality treatment against 86.1 per cent with ABVD alone (difference 7.3 percentage points, hazard ratio 1.78), with five-year overall survival of 98.1 and 98.4 per cent. RAPID randomised patients whose PET was negative after three cycles and found three-year progression-free survival of 94.6 per cent with radiotherapy against 90.8 per cent without, with no difference in overall survival and non-inferiority not formally shown.\n\nSo omitting radiotherapy costs a few percentage points of disease control and costs nothing in survival, while avoiding a field over the heart, breasts, thyroid and lungs in a person who will live another fifty years. It is a genuine choice and it is made differently by different patients and different countries. A Deauville score of 4 on the interim PET predicts a much higher risk of failure than a score of 3, and those patients keep the radiotherapy.","refs":["paper-ghsg-hd10-reduced-intensity-early-hodgkin-nejm-2010","paper-rapid-pet-directed-therapy-early-hodgkin-nejm-2015","abvd-beacopp","doxorubicin","bleomycin","vinblastine","dacarbazine","imrt-igrt","deauville","fdg-pet","lymphoma-tx-radiotherapy","lymphoma-tx-hodgkin-late-effects"],"guideline":{"nccn":"Category 1","version":"NCCN Hodgkin Lymphoma; ESMO; HD10, HD16, RAPID","url":"https://doi.org/10.1200/JCO.19.00964"}},{"setting":"Early unfavourable Hodgkin lymphoma: more chemotherapy, and PET-guided intensification","approach":"Early-stage disease with risk factors (a large mediastinal mass, extranodal involvement, a raised erythrocyte sedimentation rate, three or four or more nodal areas, or age 50 or over depending on the criteria used) is treated with four cycles of chemotherapy and involved-site radiotherapy at 30 Gy, or with more intensive chemotherapy in place of some of it.\n\nEORTC/LYSA/FIL H10 randomised 1,950 patients and settled the PET-adapted question in both directions. In the 18.8 per cent whose PET after two cycles of ABVD was positive, switching to two cycles of escalated BEACOPP with involved-node radiotherapy raised five-year progression-free survival from 77.4 to 90.6 per cent (hazard ratio 0.42). In PET-negative patients, non-inferiority of ABVD alone could not be demonstrated in either the favourable group (99.0 against 87.1 per cent for combined-modality treatment) or the unfavourable group (92.1 against 89.6 per cent), so omitting radiotherapy again costs disease control.\n\nBrentuximab vedotin with AVD is an option for unfavourable early-stage disease in some guidelines, and AHOD2131, an international trial in patients aged 5 to 60 with stage I to II disease, is testing response-adapted brentuximab vedotin with nivolumab against standard therapy with or without radiation. That trial is the one most likely to change this row next.","refs":["ahod2131","abvd-beacopp","brentuximab-vedotin","nivolumab","doxorubicin","bleomycin","vinblastine","dacarbazine","etoposide","cyclophosphamide","procarbazine","imrt-igrt","fdg-pet","deauville","lymphoma-tx-radiotherapy"],"guideline":{"nccn":"Category 1","version":"NCCN Hodgkin Lymphoma; ESMO; EORTC H10","url":"https://doi.org/10.1200/JCO.2016.68.6394"}},{"setting":"Children, adolescents and young adults with early-stage Hodgkin lymphoma","approach":"Paediatric protocols differ from adult ones in two ways that matter: they use response-adapted designs to remove radiotherapy from as many children as possible, and they avoid or limit the agents with the worst late effects in a growing body, particularly alkylating agents and chest radiotherapy.\n\nChildren's Oncology Group and EuroNet protocols give a short course of multi-agent chemotherapy, assess response with PET after two cycles, and give involved-site radiotherapy only to sites that have not responded adequately. The aim is to cure more than 95 per cent of children with the smallest cumulative dose of anthracycline, alkylator and radiation they can be cured with.\n\nAHOD1331 showed the direction of travel in high-risk paediatric disease: replacing bleomycin with brentuximab vedotin gave three-year event-free survival of 92.1 per cent against 82.5 per cent (hazard ratio 0.41), with three-year overall survival of 99.3 against 98.5 per cent, similar toxicity and a similar proportion receiving radiotherapy (53.4 against 56.8 per cent). AHOD2131 is now testing brentuximab vedotin with nivolumab against standard therapy in early-stage disease across the ages of 5 to 60, which is unusual and deliberate: adolescents and young adults have historically fallen between paediatric and adult trials and done worse for it.\n\nGrowth, fertility, thyroid function, cardiac function and psychological support are part of the treatment plan from the first appointment, not the end of it.","refs":["paper-ahod1331-brentuximab-vedotin-paediatric-hodgkin-castellino-nejm-2022","ahod2131","brentuximab-vedotin","nivolumab","bleomycin","doxorubicin","imrt-igrt","fdg-pet","lymphoma-tx-fertility-preservation","lymphoma-tx-hodgkin-late-effects"],"guideline":{"version":"NCI PDQ childhood Hodgkin lymphoma; COG and EuroNet protocols; AHOD1331","url":"https://www.cancer.gov/types/lymphoma/hp/child-hodgkin-treatment-pdq"}}],"stateOfArt":["Cure rates above 90 percent make treatment reduction, not intensification, the aim.","Interim PET lets many patients avoid radiotherapy altogether.","Brentuximab vedotin and PD-1 antibodies are entering early-stage trials to replace parts of chemotherapy."],"history":[{"year":1832,"title":"Thomas Hodgkin describes the disease","refs":["reed-sternberg-cell"]},{"year":1962,"title":"Kaplan's extended-field radiotherapy cures early-stage disease at Stanford","refs":["imrt-igrt"]},{"year":1975,"title":"Bonadonna introduces ABVD in Milan","refs":["abvd-beacopp","doxorubicin"]},{"year":2010,"title":"GHSG HD10: two ABVD and 20 Gy suffice for early favourable disease","refs":["abvd-beacopp","imrt-igrt"]},{"year":2015,"title":"RAPID: PET-negative patients can omit radiotherapy at a small cost in relapse","refs":["pet-adapted-therapy","deauville-score"]},{"year":2021,"title":"HD17: radiotherapy omitted in PET-negative early unfavourable disease","refs":["pet-adapted-therapy"]},{"year":2022,"title":"AHOD2131 opens: brentuximab vedotin and nivolumab in early-stage high-risk disease from age 5","refs":["ahod2131","brentuximab-vedotin","nivolumab"]}],"pipeline":["ahod2131","nct03407144","pet-adapted-therapy","brentuximab-vedotin","nivolumab","ctdna-lymphoma-monitoring"],"openProblems":["Radiotherapy omission trades a few percent more relapses against late harms that take decades to appear.","Bleomycin lung toxicity and doxorubicin cardiotoxicity persist even in short regimens.","Whether PD-1 antibodies can replace chemotherapy in early disease is untested.","Older patients with early disease tolerate ABVD poorly and have no dedicated standard."],"parent":"hodgkin-lymphoma"},{"id":"ebv-positive-dlbcl","kind":"cancer","name":"EBV-positive diffuse large B-cell lymphoma","aka":["EBV-positive DLBCL","EBV-positive diffuse large B-cell lymphoma, NOS","EBV-positive diffuse large B-cell lymphoma of the elderly","Epstein-Barr virus-positive diffuse large B-cell lymphoma","EBV+ DLBCL"],"tldr":"A diffuse large B-cell lymphoma in which Epstein-Barr virus, the virus of glandular fever, is present in the tumour cells. It is diagnosed by a stain on the biopsy, it is commoner in east Asia and Latin America than in Europe, and it is treated in the same way as diffuse large B-cell lymphoma without the virus.","summary":"What it is. Epstein-Barr virus infects almost everybody by adulthood and then lives quietly inside B cells for life. In a small proportion of diffuse large B-cell lymphomas the virus is present in the tumour cells themselves, detectable by a stain called EBER in situ hybridisation. WHO-HAEM5 recognises that group as an entity in its own right and, in 2022, dropped the qualifier that had restricted it to older people.\n\nHow it differs from its family. Not much, in the clinic. It behaves as a diffuse large B-cell lymphoma and is treated as one. What differs is how it is recognised and how it is counted. The European study that found 3.1 per cent noted that no appearance and no immunohistochemical marker reliably identified the positive cases, and that only in situ hybridisation for the viral RNA found them; necrosis was present in two-thirds of positive cases and CD30 in half, but neither was specific. The practical recommendation that came out of that work was to run the stain on every new diffuse large B-cell lymphoma in a person over 50.\n\nWhy it is the hardest entity in the classification to place. WHO-HAEM5 reorganised the lymphomas of immune deficiency and dysregulation in 2022 around a three-part description: the histological diagnosis, the virus, and the immune setting. That created an unresolved boundary, which the classification states as a question rather than hiding: should an older person with a diffuse large B-cell lymphoma carrying Epstein-Barr virus be diagnosed with this entity, or with diffuse large B-cell lymphoma arising in immune deficiency, on the assumption that their immune system has aged? The classification says the answer awaits further data and that some of the terminology is arbitrary. A reader should take from that that a label of EBV-positive diffuse large B-cell lymphoma is a description of a finding, not a different disease requiring different treatment.\n\nThe boundary the other way. Lymphomatoid granulomatosis is a separate Epstein-Barr virus-driven B-cell disease that, by definition, involves the lung; a similar lesion confined to the brain or gut in somebody with an immune deficiency is classified as EBV-positive diffuse large B-cell lymphoma rather than as lymphomatoid granulomatosis. The International Consensus Classification also keeps nearly all EBV-positive diffuse large B-cell lymphomas out of the mediastinal grey zone category even when they contain Hodgkin-like cells, because the genomes differ.\n\nHow it is treated. As diffuse large B-cell lymphoma, with the same immunochemotherapy. The European series found no relationship between the virus and outcome except in the subgroup with the broadest pattern of viral gene expression. The regimens are on the diffuse large B-cell lymphoma page.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Diffuse_large_B-cell_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"Epstein-Barr virus-positive diffuse large B-cell lymphoma in elderly patients is rare in Western populations (Human Pathology 2010)","url":"https://doi.org/10.1016/j.humpath.2009.07.024"},{"label":"Geographic variation in the prevalence of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly, a comparison of a Mexican and a German population (Modern Pathology 2011)","url":"https://doi.org/10.1038/modpathol.2011.62"}],"tags":["heme","lymphoma","subtype-page"],"related":["dlbcl","post-transplant-lymphoproliferative-disorder","lymphomatoid-granulomatosis","hiv-associated-lymphoma","non-hodgkin-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","fdg-pet"],"targets":["cd30"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["ebv-term","lymphoma-classification-2022","oncogenic-viruses","lymphoma-b-versus-t-cell"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"How common it is depends on where the series was collected, which is the most useful thing to know about it. In a European tissue microarray study, 8 of 258 diffuse large B-cell lymphomas met the criteria, about 3.1 per cent. In a direct comparison of two populations, 9 of 136 Mexican cases (7 per cent) were positive against 4 of 169 German cases (2 per cent), with a median age of 66 years in Mexico and 77 in Germany. Series from east Asia, where the entity was first described, report higher proportions.","subtypes":["Polymorphic type, which contains a mixture of cell sizes","Monomorphic type, which looks like ordinary diffuse large B-cell lymphoma"],"biomarkers":["Epstein-Barr virus in the tumour cells by EBER in situ hybridisation, which is the only reliable way to find it","A non-germinal-centre phenotype in most cases: CD10 negative, MUM1 positive","LMP1, the viral membrane protein, expressed in most positive cases","CD30, expressed in about half of cases and not specific","The immune setting: transplant, HIV, immunosuppressive therapy or none identified, which decides whether the diagnosis is this entity or a lymphoma of immune deficiency"],"standardOfCare":[{"setting":"Finding it","approach":"In situ hybridisation for Epstein-Barr-encoded RNA on the biopsy. The European series that put the frequency at 3.1 per cent found that no morphological or immunohistochemical feature reliably identified the positive cases, and recommended running the stain on every new diffuse large B-cell lymphoma in a person over 50. Necrosis and CD30 expression are common in positive cases but neither is specific enough to select who to test.","refs":["ebv-term","histopathology-ihc","cd30"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Treatment","approach":"The same immunochemotherapy as diffuse large B-cell lymphoma without the virus; the presence of Epstein-Barr virus does not currently change the regimen. Where there is an identifiable cause of immune suppression, reducing it is part of the treatment, as it is for the post-transplant lymphoproliferative disorders. The regimens are on the diffuse large B-cell lymphoma page and in the treatment layer of this family.","refs":["dlbcl","rituximab","r-chop","post-transplant-lymphoproliferative-disorder","lymphoma-tx-regimen-alphabet"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":2008,"title":"Introduced as a provisional entity of the elderly","note":"The fourth edition of the WHO classification added EBV-positive diffuse large B-cell lymphoma of the elderly, largely on the strength of east Asian series.","refs":[]},{"year":2011,"title":"Shown to vary by population","note":"A direct comparison found the virus in 7 per cent of 136 Mexican diffuse large B-cell lymphomas against 2 per cent of 169 German ones, with the Mexican patients a decade younger at diagnosis.","refs":[]},{"year":2022,"title":"The age qualifier dropped, and the boundary left open","note":"WHO-HAEM5 renamed the entity EBV-positive diffuse large B-cell lymphoma and stated that where it ends and lymphoma of immune deficiency and dysregulation begins is not yet settled.","refs":["lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["The classification itself says the boundary between this entity and a lymphoma arising from an ageing immune system is arbitrary, and nobody has defined immune senescence in a way that could settle it.","The virus is present in the tumour and no treatment aims at it. Virus-specific T cells and other approaches used after transplant have not been tested here.","Almost all of the original evidence came from east Asia, and the frequency in European and North American populations is several times lower, so the entity's natural history outside Asia rests on small series."],"parent":"non-hodgkin-lymphoma"},{"id":"egfr-mutant-nsclc","kind":"cancer","name":"EGFR-mutated non-small-cell lung cancer","aka":["EGFR-mutant lung cancer","EGFR-positive NSCLC","EGFR exon 19 deletion lung cancer","EGFR L858R lung cancer","EGFR exon 20 insertion lung cancer"],"tldr":"EGFR-mutated lung cancer is driven by a single faulty growth receptor and is treated first with a pill rather than chemotherapy. Osimertinib keeps the disease under control for about a year and a half on average, adding chemotherapy or the antibody amivantamab extends that further, and three years of osimertinib after surgery roughly halves the risk of death in early-stage disease.","summary":"EGFR mutations were discovered in 2004 when three Boston groups worked out why a minority of lung cancers, mostly in never-smoking women and East Asian patients, melted away on gefitinib. The IPASS trial (2009) then showed that in mutation carriers gefitinib beat chemotherapy and in non-carriers it was worse, which made EGFR testing mandatory before first-line treatment and established the model of a driver mutation matched to a pill. Exon 19 deletions and L858R are the classical sensitising mutations; exon 20 insertions are resistant to the classical inhibitors; and uncommon mutations (G719X, L861Q, S768I) respond best to afatinib or osimertinib.\n\nOsimertinib, designed against the T790M resistance mutation, beat gefitinib and erlotinib first line in FLAURA (2018): median progression-free survival 18.9 versus 10.2 months and overall survival 38.6 versus 31.8 months, with far less brain progression. Two trials then built on it: FLAURA2 (2023) added platinum-pemetrexed to osimertinib (progression-free survival 25.5 versus 16.7 months, hazard ratio 0.62, with the 2025 survival analysis also in favour), and MARIPOSA (2024) combined the EGFR-MET bispecific antibody amivantamab with lazertinib (23.7 versus 16.6 months, hazard ratio 0.70, and longer overall survival), at the cost of rash, nail changes and venous thrombosis. For exon 20 insertions, PAPILLON (2023) showed amivantamab plus chemotherapy beat chemotherapy (11.4 versus 6.7 months, hazard ratio 0.40) and sunvozertinib was approved in 2025 after platinum chemotherapy. After osimertinib the escape routes are MET amplification (osimertinib plus savolitinib), C797S, small-cell transformation and, most often, no identifiable mechanism, where amivantamab plus chemotherapy (MARIPOSA-2) and the TROP2 antibody-drug conjugate datopotamab deruxtecan are the options.\n\nIn early disease ADAURA (2020) showed that three years of adjuvant osimertinib after resection cut recurrence by 83 percent in stage II to IIIA (hazard ratio 0.17) and improved five-year overall survival from 78 to 88 percent, and LAURA (2024) showed that osimertinib after chemoradiation for unresectable stage III disease extended progression-free survival from 5.6 to 39.1 months. Checkpoint inhibitors work poorly in EGFR-mutated disease and are held back until targeted options are exhausted. Open questions are how to choose between the three first-line strategies, whether circulating tumour DNA clearance can guide escalation, and how to prevent rather than treat resistance.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":["alk-positive-nsclc","kras-g12c-nsclc","ros1-positive-nsclc","her2-mutant-nsclc","met-altered-nsclc","pdl1-high-nsclc"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","bispecific-antibody","adc","liquid-biopsy","cgp","radiosurgery-srs"],"targets":["egfr","met","her3","trop2"],"drugs":["osimertinib","amivantamab","lazertinib","sunvozertinib","gefitinib","erlotinib","afatinib","savolitinib","datopotamab-deruxtecan","furmonertinib","mobocertinib","zipalertinib","patritumab-deruxtecan"],"companies":["astrazeneca","johnson-johnson","yuhan","dizal","daiichi-sankyo"],"institutions":[],"pathways":["nsclc-signalling","rtk-activation","pi3k-akt-mtor","ras-mapk"],"terms":["egfr-exon19-l858r","egfr-exon20-insertion","egfr-mutation-subtypes","c797s","met-amplification","histologic-transformation","oncogene-addiction","driver-mutation","resistance","tki-term","brain-metastases","leptomeningeal-disease"],"trials":["flaura","flaura2","mariposa","nct04988295","nct04538664","nct03974022","adaura","laura","tropion-lung05","herthena-lung02","nct03778229","gefitinib-chemo-tmh","chrysalis"],"people":["thomas-lynch","daniel-haber","tony-mok","jean-charles-soria","suresh-ramalingam","pasi-janne","wu-yi-long","roy-herbst","cho-byoung-chul","lecia-sequist","david-planchard"],"bottlenecks":[],"keyPapers":["paper-flaura-nejm-2018","paper-mariposa-nejm-2024","paper-adaura-nejm-2020","paper-adaura-8-year-os-jto-2026"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"About 15 percent of lung adenocarcinomas in Europe and North America and 40 to 50 percent in East Asia carry an activating EGFR mutation; it is the commonest driver in never-smokers and in women. Exon 19 deletions and L858R make up about 85 percent of cases, exon 20 insertions about 10 percent.","subtypes":["EGFR exon 19 deletion adenocarcinoma (about 45 percent)","EGFR L858R adenocarcinoma (about 40 percent)","EGFR exon 20 insertion (about 10 percent; amivantamab, sunvozertinib)","Uncommon EGFR mutations (G719X, L861Q, S768I; afatinib or osimertinib)","T790M or C797S after EGFR inhibitor therapy","EGFR-mutated disease transformed to small-cell lung cancer"],"biomarkers":["EGFR mutation by tissue or plasma sequencing before first-line therapy (exon 19 deletion, L858R, exon 20 insertion, uncommon)","T790M and C797S at progression","MET amplification at progression (fluorescence in situ hybridisation or sequencing)","Circulating tumour DNA clearance during treatment (under study)","Repeat biopsy at progression for small-cell transformation","PD-L1 (of limited use; checkpoint inhibitors work poorly)"],"standardOfCare":[{"setting":"Advanced, first line (exon 19 deletion or L858R)","approach":"Osimertinib alone (FLAURA), osimertinib plus platinum-pemetrexed (FLAURA2) for patients with high burden or brain metastases who can take chemotherapy, or amivantamab plus lazertinib (MARIPOSA) with prophylaxis against rash and clots.","refs":["osimertinib","flaura","flaura2","amivantamab","lazertinib","amivantamab-plus-lazertinib","mariposa","egfr-exon19-l858r"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, exon 20 insertion","approach":"Amivantamab plus carboplatin-pemetrexed first line (PAPILLON); sunvozertinib after platinum chemotherapy.","refs":["amivantamab","nct04538664","sunvozertinib","nct03974022","egfr-exon20-insertion","carboplatin","pemetrexed"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, after osimertinib","approach":"Biopsy or plasma test for the mechanism: osimertinib plus savolitinib for MET amplification; otherwise amivantamab plus platinum chemotherapy (MARIPOSA-2), platinum-pemetrexed, or datopotamab deruxtecan after chemotherapy; platinum-etoposide for small-cell transformation.","refs":["amivantamab","nct04988295","savolitinib","nct03778229","datopotamab-deruxtecan","tropion-lung05","met-amplification","c797s","histologic-transformation","platinum-etoposide"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Resected stage IB to IIIA","approach":"Surgery, adjuvant platinum chemotherapy where indicated, then three years of osimertinib (ADAURA).","refs":["osimertinib","adaura","lobectomy","neoadjuvant-adjuvant"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Unresectable stage III","approach":"Concurrent platinum chemoradiation followed by osimertinib until progression (LAURA) rather than durvalumab.","refs":["osimertinib","laura","chemoradiation","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Brain and leptomeningeal metastases","approach":"Osimertinib has high brain penetration and is preferred; stereotactic radiosurgery for symptomatic or large lesions; high-dose osimertinib for leptomeningeal disease.","refs":["osimertinib","radiosurgery-srs","brain-metastases","leptomeningeal-disease"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Three first-line strategies with osimertinib as the anchor: alone, with chemotherapy (FLAURA2) or replaced by amivantamab plus lazertinib (MARIPOSA), with overall survival gains for the combinations.","Amivantamab plus chemotherapy (PAPILLON) and sunvozertinib for exon 20 insertions, a group that had no effective targeted drug until 2021.","Adjuvant osimertinib (ADAURA) and post-chemoradiation osimertinib (LAURA) extend targeted therapy into curative-intent disease.","Datopotamab deruxtecan approved in 2025 for disease that has progressed on an EGFR inhibitor and chemotherapy."],"history":[{"year":2004,"title":"EGFR mutations found to explain gefitinib responses in Boston (Lynch, Paez, Pao)","refs":["gefitinib","thomas-lynch","daniel-haber","egfr"]},{"year":2009,"title":"IPASS: gefitinib beats chemotherapy in EGFR-mutant patients, worse in others; testing becomes mandatory","refs":["gefitinib","tony-mok"]},{"year":2015,"title":"Osimertinib approved for T790M resistance after first-generation inhibitors","refs":["osimertinib"]},{"year":2018,"title":"FLAURA: first-line osimertinib beats gefitinib and erlotinib","refs":["flaura","osimertinib","jean-charles-soria","suresh-ramalingam"]},{"year":2020,"title":"ADAURA: three years of adjuvant osimertinib cuts recurrence by 83 percent","refs":["adaura","osimertinib","wu-yi-long","roy-herbst"]},{"year":2021,"title":"Amivantamab approved for exon 20 insertions after chemotherapy (CHRYSALIS)","refs":["amivantamab","egfr-exon20-insertion"]},{"year":2023,"title":"FLAURA2 and PAPILLON: chemotherapy added to osimertinib; amivantamab plus chemotherapy for exon 20","refs":["flaura2","nct04538664","amivantamab"]},{"year":2024,"title":"MARIPOSA: amivantamab plus lazertinib approved first line; LAURA: osimertinib after chemoradiation in stage III","refs":["mariposa","amivantamab-plus-lazertinib","laura","cho-byoung-chul"]},{"year":2025,"title":"Sunvozertinib approved for exon 20 insertions; datopotamab deruxtecan approved after EGFR inhibitor and chemotherapy","refs":["sunvozertinib","datopotamab-deruxtecan","tropion-lung05"]}],"pipeline":["savolitinib","nct03778229","patritumab-deruxtecan","herthena-lung02","zipalertinib","nct05973773","furmonertinib","befotertinib","silevertinib","izalontamab-brengitecan","idea-bio1-ctdna-adaptive-tki","mrd-testing"],"openProblems":["No head-to-head trial compares the three first-line strategies, and the added toxicity of the combinations falls on every patient for a benefit concentrated in some.","Most resistance to osimertinib has no identifiable mechanism and no targeted option.","Whether adjuvant osimertinib cures more patients or delays recurrence beyond the three years of treatment is still being followed.","Checkpoint inhibitors add little and increase pneumonitis when combined with EGFR inhibitors."],"parent":"nsclc"},{"id":"embryonal-carcinoma-testis","kind":"cancer","name":"Embryonal carcinoma of the testis","aka":["Embryonal carcinoma","Testicular embryonal carcinoma","Pure embryonal carcinoma","Embryonal carcinoma-predominant mixed germ cell tumour"],"tldr":"Embryonal carcinoma is the most aggressive and most common building block of non-seminoma testicular cancer, made of primitive cells that resemble an early embryo and can turn into the other tumour types. On its own or as the main component it spreads early to lymph nodes and lungs, but it is highly sensitive to cisplatin chemotherapy and most men are cured.","summary":"Embryonal carcinoma is a germ cell tumour of totipotent cells growing in solid, papillary and glandular patterns with marked atypia, arising from germ cell neoplasia in situ and forming part of most mixed non-seminomatous tumours (Moch 2016). OCT4 (POU5F1), the pluripotency transcription factor, stains embryonal carcinoma and seminoma in every case among 91 testicular neoplasms tested and no other tumour type, and CD30 and SOX2 separate embryonal carcinoma from seminoma (Am J Surg Pathol 2004). Its share of a mixed tumour and the presence of lymphovascular invasion are the two histological risk factors used to decide adjuvant treatment of stage I non-seminoma.\n\nHow it differs from its parent: the non-seminoma page covers the group; embryonal carcinoma is its most proliferative component, does not raise alpha-fetoprotein on its own (a raised value implies yolk sac elements) and raises beta-hCG only modestly, and its predominance marks a higher relapse risk after orchidectomy.\n\nHow common: no separate incidence figure; it is present in most non-seminomas (Am J Surg Pathol 2004).\n\nTreatment: as non-seminoma by stage and International Germ Cell Cancer Collaborative Group risk group: orchidectomy, then surveillance or one cycle of BEP for stage I depending on lymphovascular invasion and embryonal carcinoma predominance, and three or four cycles of BEP for metastatic disease with resection of residual masses (NCI PDQ testicular summary and the parent page).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Embryonal_carcinoma","links":[{"label":"NCI PDQ: testicular cancer treatment","url":"https://www.cancer.gov/types/testicular/treatment"},{"label":"Moch 2016, European Urology: the 2016 WHO classification of urinary and male genital tumours, part A","url":"https://doi.org/10.1016/j.eururo.2016.02.029"},{"label":"Am J Surg Pathol 2004: OCT4 staining in testicular tumours, a marker for seminoma and embryonal carcinoma","url":"https://doi.org/10.1097/00000478-200407000-00014"}],"tags":["subtype-page","wave4","testicular","rare"],"related":["non-seminoma","testicular","yolk-sac-tumour-postpubertal","testicular-choriocarcinoma","germ-cell-neoplasia-in-situ","seminoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["bleomycin","etoposide","cisplatin"],"companies":[],"institutions":[],"pathways":[],"terms":["afp","tumour-markers"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"The commonest component of non-seminomatous germ cell tumours: 54 of 64 mixed germ cell tumours in a marker study contained embryonal carcinoma, more than seminoma (51), yolk sac tumour (38) or teratoma (Am J Surg Pathol 2004). Pure embryonal carcinoma is a minority of testicular cancers; no registry figure was found in the sources read.","subtypes":["Pure embryonal carcinoma","Mixed germ cell tumour with embryonal carcinoma predominance (over 50 percent; higher relapse risk in stage I)","Embryonal carcinoma with lymphovascular invasion (risk factor for adjuvant therapy)","Intratubular embryonal carcinoma (GCNIS-related precursor stage)"],"biomarkers":["OCT4, CD30 and SOX2 positive","Beta-hCG (modestly raised); alpha-fetoprotein normal unless yolk sac elements","Lymphovascular invasion and embryonal carcinoma percentage (stage I risk factors)","Isochromosome 12p"],"standardOfCare":[{"setting":"All stages","approach":"Treated as non-seminoma by stage and risk group: orchidectomy, surveillance or one cycle of BEP for stage I by risk factors, three or four cycles of BEP for metastatic disease with resection of residual masses.","refs":["non-seminoma","testicular","bleomycin","etoposide","cisplatin"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"non-seminoma"},{"id":"endometrial","kind":"cancer","name":"Endometrial cancer","aka":["UCEC","TCGA-UCEC","uterine corpus endometrial carcinoma (TCGA and CPTAC UCEC cohorts)"],"tldr":"The gynaecological cancer where immunotherapy has had the biggest impact, guided by molecular classification.","summary":"Endometrial cancer is the most common gynaecologic cancer in high-income countries (~420,000 cases a year worldwide) and one of the few cancers whose incidence and mortality are rising, driven by obesity, diabetes, and an ageing population. Most cases are low-grade endometrioid tumours found at stage I because of postmenopausal bleeding, and are cured by hysterectomy; a minority (serous, clear-cell, carcinosarcoma, and other p53-abnormal tumours) behave like high-grade ovarian cancer and account for most deaths. Since 2013, four molecular classes (POLE-mutated, mismatch-repair deficient, p53-abnormal, no specific molecular profile) have replaced histology as the primary prognostic and predictive framework.\n\nThe standard of care for early disease is minimally invasive hysterectomy with sentinel lymph node mapping, and adjuvant therapy scaled to risk: observation or vaginal brachytherapy for low and intermediate risk, pelvic radiotherapy or chemoradiation plus chemotherapy for high risk (PORTEC-3), with molecular class increasingly steering choices and fertility-sparing progestin therapy available for young women with the earliest tumours. Advanced and recurrent disease changed in 2023: three phase 3 trials (RUBY, NRG-GY018, DUO-E) established chemotherapy plus a PD-1/PD-L1 antibody as first-line standard, with dramatic benefit in dMMR tumours and a survival gain in the whole population (RUBY, OS 44.6 vs 28.2 months). Lenvatinib plus pembrolizumab (KEYNOTE-775) remains the second-line option for mismatch-repair-proficient disease, and trastuzumab deruxtecan is approved for HER2 IHC 3+ tumours.\n\nNext: molecular-class-directed adjuvant therapy (RAINBO, PORTEC-4a), folate-receptor and TROP2 ADCs (rinatabart sesutecan with Breakthrough designation, sacituzumab tirumotecan), CDK4/6 plus endocrine therapy for low-grade ER-positive disease, and HER2 ADCs moved earlier in serous cancer. The 2026 failure of selinexor maintenance (XPORT-EC-042) is a caution about subgroup-derived hypotheses. Prevention through weight management and progestin-releasing IUDs, and equitable outcomes for Black women, whose mortality is nearly double, are the population-level problems.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Endometrial_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Endometrial_cancer"}],"tags":["gyn","spike"],"related":["chemo-io-first-line-endometrial","lenvatinib-plus-pembrolizumab","io-plus-vegf"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","adc","antiangiogenic","fertility-sparing-endometrial","sentinel-node","brachytherapy","mri","germline-testing","robotic-surgery"],"targets":["pd1","her2","trop2","pik3ca","estrogen-receptor","folr1","wee1","tp53","vegf","pdl1","kras"],"drugs":["megestrol"],"companies":["shenzhen-ionova-life-sciences","gsk","merck","astrazeneca","eisai","karyopharm","genmab","daiichi-sankyo","nrg-oncology"],"institutions":[],"pathways":["pi3k-akt-mtor","pd1-checkpoint","endometrial-cancer-signalling"],"terms":["endometrial-molecular-classes","tumour-agnostic"],"trials":["nct07044336","nct06340568","nct06584032","nct06989112","nct06486441","nct07166094","nct06952504","nct05797831","nct06132958","nct06746116","nct07022483","nct07286331","nct05862272","nct05173987","nct04634877"],"people":[],"bottlenecks":[],"keyPapers":["paper-capp2-aspirin-lynch-lancet-2020","paper-lynch-frameshift-vaccine-ccr-2020"],"journals":["international-journal-of-gynecological-cancer","journal-of-gynecologic-oncology"],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"Endometrial cancer accounts for ~420,000 cases per year worldwide and is the most common gynaecologic cancer in the US and Europe; most are found at stage I because of postmenopausal bleeding and cured by hysterectomy. Incidence and mortality are rising ~1-2% per year with obesity; ~97,000 deaths per year.","subtypes":["Endometrioid (~80%; grade 1-3; usually ER/PR-positive)","Serous (~10%; p53-abnormal; HER2 amplified in ~25-30%)","Clear-cell (~3%)","Carcinosarcoma (~5%; biphasic; p53-abnormal)","Undifferentiated/dedifferentiated (often MMRd, SWI/SNF loss)","Molecular classes: POLE-ultramutated (~7%), MMRd (~25-30%), p53-abnormal (~15%), NSMP (~50%)"],"biomarkers":["MMR/MSI","POLE","p53","HER2 (serous)","ER/PR","TROP2","MMR IHC / MSI (dMMR ~25-30%; Lynch syndrome in ~3% of all cases)","POLE exonuclease-domain mutation","p53 IHC","HER2 IHC/ISH (serous, p53abn)","L1CAM (NSMP risk)","CTNNB1 (NSMP low-grade recurrence risk)","PD-L1 (limited utility)","FRα and TROP2 (ADC trials)","ARID1A, PIK3CA, PTEN (targetable in trials)"],"standardOfCare":[{"setting":"Early","approach":"Hysterectomy; adjuvant therapy by molecular class.","refs":[],"guideline":{"version":"NCCN Guidelines: Uterine Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1473"}},{"setting":"Advanced/recurrent","approach":"Chemotherapy + dostarlimab or pembrolizumab; lenvatinib-pembrolizumab; T-DXd if HER2+.","refs":["dostarlimab","pembrolizumab","trastuzumab-deruxtecan"],"guideline":{"version":"NCCN Guidelines: Uterine Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1473"}},{"setting":"Prevention and hereditary risk","approach":"Universal MMR testing of tumours to identify Lynch syndrome; risk-reducing hysterectomy and salpingo-oophorectomy for Lynch carriers after childbearing; levonorgestrel IUD and weight management reduce risk; no screening for average-risk women.","refs":["germline-testing","msi","megestrol-progestins"],"guideline":{"nccn":"2A"}},{"setting":"Diagnosis and staging","approach":"Endometrial biopsy for postmenopausal bleeding; MRI for myometrial and cervical invasion; molecular classification (p53, MMR IHC, POLE sequencing) on the diagnostic specimen.","refs":["mri","histopathology-ihc","endometrial-molecular-classes"],"guideline":{"nccn":"2A","url":"https://www.esgo.org/guidelines/"}},{"setting":"Early stage surgery","approach":"Minimally invasive total hysterectomy and bilateral salpingo-oophorectomy with sentinel lymph node mapping (FIRES, SENTOR); omentectomy for serous histology.","refs":["robotic-surgery","sentinel-node","fires-sentor"],"guideline":{"nccn":"1"}},{"setting":"Fertility-sparing (grade 1, stage IA, no invasion)","approach":"Progestin (oral or IUD) with re-biopsy every 3-6 months; hysterectomy after childbearing.","refs":["fertility-sparing-endometrial","megestrol-progestins"],"guideline":{"nccn":"2B"}},{"setting":"Adjuvant, low and intermediate risk","approach":"Observation (low risk, POLEmut) or vaginal brachytherapy (intermediate risk; PORTEC-2); molecular class may de-escalate (PORTEC-4a).","refs":["brachytherapy","endometrial-molecular-classes"],"guideline":{"nccn":"1 (brachytherapy)"}},{"setting":"Adjuvant, high risk (stage III, serous, p53abn, deep invasion grade 3)","approach":"Chemoradiation plus carboplatin-paclitaxel (PORTEC-3) or chemotherapy alone (GOG-258); pembrolizumab or dostarlimab added for stage III-IV per RUBY/GY018 eligibility.","refs":["portec-3","carboplatin","paclitaxel","imrt-igrt","pembrolizumab","dostarlimab"],"guideline":{"nccn":"1"}},{"setting":"Advanced or recurrent, first line (any MMR status)","approach":"Carboplatin-paclitaxel plus dostarlimab (RUBY), pembrolizumab (NRG-GY018/KEYNOTE-868), or durvalumab (DUO-E; dMMR in the US), continued as maintenance up to 2-3 years.","refs":["ruby","nrg-gy018-keynote-868","duo-e","dostarlimab","pembrolizumab","durvalumab","chemo-io-first-line-endometrial"],"guideline":{"nccn":"1","esmoMcbs":"4 (dMMR)"}},{"setting":"Recurrent, pMMR, after platinum","approach":"Lenvatinib + pembrolizumab (KEYNOTE-775) if not previously given immunotherapy; T-DXd if HER2 IHC 3+; chemotherapy (doxorubicin, weekly paclitaxel); hormonal therapy for low-grade ER-positive disease.","refs":["lenvatinib","pembrolizumab","keynote-775","trastuzumab-deruxtecan","destiny-pantumor02","letrozole","megestrol-progestins"],"guideline":{"nccn":"1 (lenvatinib-pembrolizumab)"}},{"setting":"Recurrent, dMMR, after chemotherapy","approach":"Single-agent PD-1 blockade (dostarlimab GARNET, pembrolizumab) if immunotherapy-naive; otherwise chemotherapy or trials.","refs":["dostarlimab","pembrolizumab","msi"],"guideline":{"nccn":"1"}},{"setting":"HER2-positive serous","approach":"Trastuzumab with carboplatin-paclitaxel (randomised phase 2) or T-DXd for IHC 3+ after prior therapy.","refs":["trastuzumab","trastuzumab-deruxtecan","her2","destiny-pantumor02"],"guideline":{"nccn":"2A"}}],"stateOfArt":["IO-chemotherapy first line with OS benefit in dMMR and beyond.","Chemotherapy plus PD-1/PD-L1 blockade is first-line standard for advanced disease, with a 16-month overall survival gain in RUBY and a 72% reduction in progression risk in dMMR tumours.","Molecular classification (POLE, MMR, p53) is part of routine diagnosis and is beginning to direct adjuvant therapy.","Sentinel lymph node mapping has replaced full lymphadenectomy, cutting lymphoedema without missing metastases.","Lenvatinib plus pembrolizumab gives an 18-month median survival in pMMR disease after platinum, where PD-1 alone barely worked.","HER2 IHC 3+ disease has an approved ADC (T-DXd) with an 85% response rate.","Fertility-sparing hormonal therapy is an evidence-based option for the earliest tumours in young women."],"history":[{"year":1971,"title":"Progestins approved for advanced endometrial cancer","refs":["megestrol-progestins"]},{"year":1983,"title":"Bokhman's type I / type II model","note":"Oestrogen-driven low-grade versus non-hormonal high-grade tumours; superseded by molecular classes.","refs":[]},{"year":2009,"title":"LAP2: laparoscopic hysterectomy equivalent to open surgery","refs":["robotic-surgery"]},{"year":2010,"title":"PORTEC-2: vaginal brachytherapy replaces pelvic radiation for intermediate risk","refs":["brachytherapy"]},{"year":2013,"title":"TCGA molecular classification","refs":[]},{"year":2013,"title":"TCGA defines four molecular classes","note":"POLE-ultramutated, MSI-hypermutated, copy-number low, copy-number high (p53-abnormal).","refs":["endometrial-molecular-classes"]},{"year":2017,"title":"FIRES: sentinel node mapping validated; pembrolizumab approved for MSI-H tumours","refs":["fires-sentor","pembrolizumab","msi"]},{"year":2018,"title":"PORTEC-3: chemoradiation plus chemotherapy for high-risk disease","refs":["portec-3"]},{"year":2019,"title":"Lenvatinib + pembrolizumab accelerated approval (KEYNOTE-146)","refs":["lenvatinib"]},{"year":2021,"title":"KEYNOTE-775: lenvatinib + pembrolizumab OS benefit; dostarlimab approved for dMMR recurrence (GARNET); molecular classification enters ESGO guidelines","refs":["keynote-775","dostarlimab","endometrial-molecular-classes"]},{"year":2023,"title":"RUBY/NRG-GY018: IO first line","refs":["dostarlimab"]},{"year":2023,"title":"RUBY, NRG-GY018, DUO-E: chemo-immunotherapy first line","note":"Three trials in one year; dostarlimab approved for dMMR (July 2023).","refs":["ruby","nrg-gy018-keynote-868","duo-e"]},{"year":2024,"title":"All-comers approvals: pembrolizumab (June), dostarlimab (August), durvalumab dMMR (June); T-DXd tumour-agnostic HER2 approval; RUBY overall survival benefit","refs":["pembrolizumab","dostarlimab","durvalumab","trastuzumab-deruxtecan","destiny-pantumor02"]},{"year":2025,"title":"Rina-S Breakthrough designation in endometrial cancer","refs":["rinatabart-sesutecan","rainfol-01"]},{"year":2026,"title":"Selinexor maintenance fails (XPORT-EC-042)","note":"Post-hoc TP53-wild-type subgroup hypothesis not confirmed.","refs":["xport-ec-042","selinexor"]}],"pipeline":["sacituzumab-tirumotecan","puxitatug-samrotecan","saruparib","hs-20089","avzo-021","serabelisib","sapanisertib","palacaparib","lorigerlimab","eik1005","vudalimab","np137","rinatabart-sesutecan","rainfol-01","luveltamab-tazevibulin","trastuzumab-deruxtecan","idea-molecular-class-adjuvant-endometrial","idea-her2-adc-serous-endometrial","letrozole","abemaciclib","wee1","mrd-testing"],"openProblems":["p53-abnormal disease behaves like serous ovarian.","Obesity-driven incidence rising.","Equity: more p53-abnormal tumours and later diagnosis mean Black women in the US have nearly twice the mortality of white women; incidence and mortality are rising overall with obesity.","p53-abnormal and carcinosarcoma histologies still relapse frequently despite chemoradiation; no subtype-specific therapy is approved beyond HER2.","Immunotherapy benefit in pMMR disease is modest and biomarkers to select pMMR responders are lacking.","Optimal adjuvant strategy by molecular class is unproven prospectively until RAINBO and PORTEC-4a report.","Whether radiation adds to chemotherapy in stage III disease remains unresolved (PORTEC-3 vs GOG-258).","Fertility-sparing therapy has a 30% relapse rate and no reliable predictor of response.","Lenvatinib-pembrolizumab toxicity forces dose reductions in two-thirds of patients."],"prognosis":{"text":"In the United States, 80.9% of women diagnosed with cancer of the uterus in 2016-2022 were alive five years later, relative to women of the same age without the disease. Most cases are caught early because bleeding after the menopause is investigated: 67% are found while confined to the uterus, with five-year relative survival of 94.9%; it is 70.1% for regional disease (18% of cases) and 19.9% for distant disease (11% of cases). SEER reports all uterine corpus cancers together, so aggressive subtypes such as serous carcinoma and carcinosarcoma sit below these averages.","sources":[{"label":"SEER Cancer Stat Facts: Uterine Cancer","url":"https://seer.cancer.gov/statfacts/html/corp.html"}]}},{"id":"endometrial-nsmp","kind":"cancer","name":"Endometrial cancer with no specific molecular profile","aka":["NSMP endometrial cancer","p53-wild-type, MMR-proficient, POLE-wild-type endometrial cancer","Copy-number-low endometrial cancer"],"tldr":"Endometrial cancer with no specific molecular profile is the default class: no POLE mutation, intact mismatch repair and normal p53. Most are low-grade, oestrogen-driven tumours cured by hysterectomy, and hormone-blocking drugs are their most natural treatment when they do recur.","summary":"The class is defined by exclusion: POLE wild-type, mismatch-repair proficient and p53 wild-type. It corresponds to the copy-number-low class of the TCGA and holds about half of endometrial cancers, dominated by grade 1 and 2 endometrioid carcinoma with PTEN, PIK3CA, ARID1A and CTNNB1 mutations and strong oestrogen and progesterone receptor expression. Outcome depends on the classical factors, grade, depth of invasion, lymphovascular space invasion and stage, and two markers refine risk within the class: L1CAM expression and loss of oestrogen receptor mark a worse group, and CTNNB1 mutation raises recurrence risk in otherwise low-risk tumours. The WHO 2020 classification and the ESGO/ESTRO/ESP guideline place low-grade, receptor-positive disease in the favourable group and high-grade or receptor-negative disease closer to p53-abnormal risk.\n\nTreatment follows stage and risk. Stage IA grade 1 to 2 disease without lymphovascular invasion is cured by hysterectomy alone; intermediate risk receives vaginal brachytherapy after PORTEC-2 showed it equivalent to pelvic radiotherapy for vaginal control; high-intermediate risk receives pelvic radiotherapy. PORTEC-3 found no meaningful benefit from adding chemotherapy in this class, and RAINBO's NSMP-ORANGE trial is testing whether adjuvant progestin therapy can replace chemotherapy for receptor-positive stage II to III disease. Young women with grade 1 tumours confined to the endometrium can be treated with a levonorgestrel intrauterine device or oral progestins to preserve fertility, with hysterectomy once childbearing is complete.\n\nRecurrent and advanced disease is treated as mismatch-repair-proficient endometrial cancer: carboplatin-paclitaxel with pembrolizumab or dostarlimab in the first line, where the immunotherapy gain is smaller than in deficient tumours, then lenvatinib with pembrolizumab, which extended median survival from 11.4 to 18.3 months in KEYNOTE-775. Endocrine therapy with letrozole, megestrol or fulvestrant gives durable control in low-grade receptor-positive disease with little toxicity, and adding a CDK4/6 inhibitor to letrozole improved progression-free survival in the randomised phase 2 PALEO trial. The XPORT-EC-042 trial of maintenance selinexor in TP53-wild-type disease, which is mostly this class, missed its primary endpoint in 2026.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Endometrial_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Endometrial_cancer"}],"tags":["subtype-page"],"related":["advanced-recurrent-endometrial-cancer","endometrial-mmr-deficient","endometrial-p53-abnormal","endometrial-pole-ultramutated","uterine-carcinosarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["nsmp","pten-loss","depth-of-invasion","mlh1-promoter-methylation"],"trials":["portec-2"],"people":[],"bottlenecks":[],"keyPapers":["paper-nrg-gy018-nejm-2023","paper-promise-talhouk-cancer-2017","paper-portec-2-lancet-2010","paper-esgo-estro-esp-endometrial-concin-ijgc-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"About half of all endometrial cancers, mostly low-grade endometrioid tumours in postmenopausal women with obesity or oestrogen excess; the great majority are cured by surgery alone, and the challenge is finding the minority that will recur.","subtypes":["Low-grade endometrioid, oestrogen receptor-positive NSMP (favourable)","CTNNB1-mutant low-grade NSMP (higher recurrence risk)","L1CAM-positive or oestrogen receptor-negative NSMP (unfavourable)","High-grade endometrioid NSMP","Stage II to III receptor-positive NSMP (RAINBO NSMP-ORANGE, progestin versus chemotherapy)","Grade 1 stage IA NSMP in young women (fertility-sparing progestin therapy)"],"biomarkers":["Negative POLE, MMR and p53 results (diagnosis by exclusion)","Oestrogen and progesterone receptor expression","L1CAM expression","CTNNB1 exon 3 mutation","Grade, depth of invasion and lymphovascular space invasion","PTEN, PIK3CA and ARID1A mutations"],"standardOfCare":[{"setting":"Low risk (stage IA grade 1 to 2, no substantial LVSI)","approach":"Hysterectomy with bilateral salpingo-oophorectomy and sentinel node mapping; no adjuvant treatment.","refs":["hysterectomy","sentinel-node","fires-sentor","robotic-surgery","endometrial-molecular-classes"]},{"setting":"Intermediate and high-intermediate risk","approach":"Vaginal brachytherapy (PORTEC-2) or pelvic radiotherapy; chemotherapy adds little in this class.","refs":["brachytherapy","imrt-igrt","portec-3"]},{"setting":"Fertility-sparing (grade 1, stage IA, no invasion)","approach":"Levonorgestrel intrauterine device or oral progestin with hysteroscopic sampling every three to six months; hysterectomy after childbearing.","refs":["fertility-sparing-endometrial","megestrol-progestins"]},{"setting":"Advanced or recurrent, first line","approach":"Carboplatin-paclitaxel with pembrolizumab or dostarlimab (smaller benefit than in dMMR); endocrine therapy for low-grade receptor-positive disease.","refs":["carboplatin","paclitaxel","pembrolizumab","dostarlimab","nrg-gy018-keynote-868","ruby","letrozole","megestrol-progestins","mss-pmmr"]},{"setting":"After platinum","approach":"Lenvatinib with pembrolizumab (KEYNOTE-775); aromatase inhibitor with or without a CDK4/6 inhibitor in receptor-positive disease.","refs":["lenvatinib","pembrolizumab","keynote-775","letrozole","abemaciclib"]}],"stateOfArt":["Molecular classification identifies NSMP as the class where classical pathology still decides treatment.","RAINBO NSMP-ORANGE is the first trial to test hormone therapy instead of chemotherapy after surgery.","CDK4/6 inhibitors with letrozole are extending the endocrine option from breast to endometrial cancer."],"history":[{"year":1983,"title":"Bokhman's type I oestrogen-driven endometrial cancer, the ancestor of this class","refs":[]},{"year":2010,"title":"PORTEC-2: vaginal brachytherapy replaces pelvic radiotherapy for high-intermediate risk","refs":["brachytherapy"]},{"year":2013,"title":"TCGA defines the copy-number-low class","refs":["endometrial-molecular-classes"]},{"year":2021,"title":"KEYNOTE-775: lenvatinib-pembrolizumab beats chemotherapy after platinum in pMMR disease","refs":["keynote-775"]},{"year":2022,"title":"RAINBO NSMP-ORANGE opens: progestin versus chemotherapy after surgery","refs":[]},{"year":2026,"title":"XPORT-EC-042: maintenance selinexor fails in TP53-wild-type disease","refs":["xport-ec-042","selinexor"]}],"pipeline":["abemaciclib","letrozole","idea-molecular-class-adjuvant-endometrial","xport-ec-042","sacituzumab-tirumotecan"],"openProblems":["Splitting the class into truly low-risk and higher-risk tumours with L1CAM, CTNNB1 and receptor status.","Whether progestins can replace chemotherapy after surgery.","Small immunotherapy benefit in proficient tumours."],"parent":"endometrial"},{"id":"enteropathy-associated-t-cell-lymphoma","kind":"cancer","name":"Enteropathy-associated T-cell lymphoma","aka":["EATL","Enteropathy-type T-cell lymphoma","Enteropathy-associated and hepatosplenic T-cell lymphoma","Coeliac-associated T-cell lymphoma","Type I EATL"],"tldr":"An aggressive T-cell lymphoma of the small bowel that arises out of coeliac disease, usually in somebody whose coeliac disease was diagnosed late or has not responded to a gluten-free diet. It often announces itself as a perforation or obstruction of the bowel in a person who is already underweight, which is why treatment has to deal with nutrition at the same time as the lymphoma.","summary":"What it is. A lymphoma of the T cells that live between the cells lining the small bowel. It arises in people with coeliac disease, the immune reaction to gluten, and particularly in those whose disease was diagnosed in adulthood or whose symptoms have not settled on a gluten-free diet. It is the reason coeliac disease that stops responding to the diet is investigated rather than managed.\n\nHow it presents, and why that shapes the treatment. WHO-HAEM5 tabulates the presentation: abdominal symptoms, with perforation or obstruction of the bowel common, deep involvement of the bowel wall, and a tumour made of pleomorphic large or medium cells against a prominent inflammatory background. A substantial proportion of patients come to attention as a surgical emergency. They are usually malnourished before the lymphoma starts, because the coeliac disease has been damaging the bowel, and chemotherapy in a malnourished person with a bowel at risk of perforating is a different proposition from chemotherapy in a well person. Nutritional support, often intravenous, and surgical involvement are part of the treatment and not an afterthought.\n\nHow it differs from the lymphoma it is most often confused with. Monomorphic epitheliotropic intestinal T-cell lymphoma arises in the same part of the gut and presents in the same way, and it is not associated with coeliac disease. Under the microscope it is monotonous where this one is pleomorphic, its cells are usually CD8-positive where these are usually negative for both CD4 and CD8, and it carries SETD2 mutations which this does not. It was called type II enteropathy-associated T-cell lymphoma until 2016 and has had its own name and its own page since.\n\nWhat treatment achieves. The Newcastle group reported both halves of the picture from one population. Treated with conventional anthracycline-based chemotherapy, with or without surgery, median progression-free survival was 3.4 months and median overall survival 7.1 months. From 1998 the same group gave patients fit enough for it a regimen of ifosfamide, etoposide and epirubicin alternating with methotrexate, followed by an autologous stem cell transplant; in 26 patients treated that way, five-year progression-free survival was 52 per cent and overall survival 60 per cent, significantly better than the historical comparison. That is a before-and-after comparison within one region rather than a randomised trial, and it is the best evidence this disease has.\n\nWhat should also happen. A strict gluten-free diet is continued, both for the bowel and because the rest of the family may need testing for coeliac disease. Refractory coeliac disease of the type with an abnormal clone of lymphocytes is the precursor state, and the International Consensus Classification lists it as a provisional entity of its own, which WHO-HAEM5 does not.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Enteropathy-associated_T-cell_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"Evaluation of enteropathy-associated T-cell lymphoma comparing standard therapies with a novel regimen including autologous stem cell transplantation (Sieniawski, Blood 2010)","url":"https://doi.org/10.1182/blood-2009-07-231324"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["monomorphic-epitheliotropic-intestinal-t-cell-lymphoma","peripheral-t-cell-lymphoma","hepatosplenic-t-cell-lymphoma","small-bowel","non-hodgkin-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","fdg-pet","autologous-stem-cell-transplant"],"targets":[],"drugs":["ifosfamide","etoposide","methotrexate"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-nodal-versus-extranodal","lymphoma-classification-2022","lymphoma-pit-score","lymphoma-tx-transplant-role","lymphoma-lugano-gastrointestinal"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare. In the population-based series from the Scotland and Newcastle Lymphoma Group, the overall incidence was 0.14 cases per 100,000 people a year, and 54 patients were identified over a five-year period. In the United Kingdom population series that reports lymphoma by subtype, 24 of 5,796 lymphomas were of the enteropathy type, a European age-standardised rate of 0.08 per 100,000 a year, a median age at diagnosis of 62.7 years and five-year relative survival of 28.0 per cent.","subtypes":[],"biomarkers":["Coeliac disease, established or newly discovered at the time of the lymphoma, which is part of the definition","A T-cell phenotype that is most often negative for both CD4 and CD8, with CD30 often positive","Pleomorphic large or medium-sized cells against a prominent inflammatory background, which separates it from the monomorphic intestinal lymphoma","Gains of 9q34 and loss of 16q12, with mutations of the JAK-STAT pathway, commonly JAK1 and STAT3","Absence of Epstein-Barr virus","Nutritional state, which determines what treatment is possible"],"standardOfCare":[{"setting":"Diagnosis, and the coeliac disease behind it","approach":"The diagnosis is often made on bowel resected as an emergency for perforation or obstruction. Where there is time, it is made at endoscopy with biopsies of the small bowel. Coeliac disease is confirmed or newly diagnosed at the same time, and the rest of the family is offered testing. Staging uses the gastrointestinal system that counts depth and node involvement, and imaging of the whole abdomen matters because disease is often multifocal.","refs":["endoscopy","histopathology-ihc","lymphoma-lugano-gastrointestinal","fdg-pet"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Nutrition and the surgical risk, which come first","approach":"Most patients are malnourished before the lymphoma starts, because the coeliac disease has been damaging the bowel, and the bowel is at risk of perforating during treatment. Nutritional assessment and support, often intravenous, and early involvement of a surgeon are part of the treatment rather than an afterthought, and they determine what chemotherapy is possible. A strict gluten-free diet is continued throughout.","refs":["lymphoma-tx-regimen-alphabet","peripheral-t-cell-lymphoma"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Systemic treatment","approach":"In the population-based series from northern England and Scotland, conventional anthracycline-based chemotherapy with or without surgery gave a median progression-free survival of 3.4 months and overall survival of 7.1 months in 54 patients. From 1998 the same group gave patients fit enough for it ifosfamide, etoposide and epirubicin alternating with methotrexate, followed by an autologous stem cell transplant; in 26 patients treated that way, five-year progression-free survival was 52 per cent and overall survival 60 per cent. That is a comparison against a historical group from the same region rather than a randomised trial, and it is the best evidence this disease has. A clinical trial is a reasonable first choice.","refs":["ifosfamide","etoposide","methotrexate","autologous-stem-cell-transplant","lymphoma-tx-transplant-role","lymphoma-tx-regimen-alphabet"],"guideline":{"version":"Scotland and Newcastle Lymphoma Group, Blood 2010; NCCN T-Cell Lymphomas; NCI PDQ","url":"https://doi.org/10.1182/blood-2009-07-231324"}}],"stateOfArt":[],"history":[{"year":2010,"title":"A population picture and a regimen that improved it","note":"Among 54 patients identified in northern England and Scotland, incidence was 0.14 per 100,000 a year and conventional chemotherapy gave a median progression-free survival of 3.4 months and overall survival of 7.1 months; 26 patients given ifosfamide, etoposide and epirubicin with methotrexate followed by autologous transplant had five-year progression-free survival of 52 per cent and overall survival of 60 per cent.","refs":["autologous-stem-cell-transplant","ifosfamide","etoposide","methotrexate"]},{"year":2016,"title":"Split in two","note":"The revised fourth edition of the WHO classification separated the type that is not associated with coeliac disease and gave it its own name, monomorphic epitheliotropic intestinal T-cell lymphoma.","refs":[]},{"year":2022,"title":"The precursor state recognised by one classification","note":"The International Consensus Classification lists type II refractory coeliac disease as a provisional entity; WHO-HAEM5 does not list it separately.","refs":["lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["No randomised trial has been run in this disease. The regimen with the best results was compared against a historical group from the same region.","Many patients present as a surgical emergency in a malnourished state, so a substantial proportion are never well enough to receive the treatment that works best.","Whether earlier diagnosis of coeliac disease and better adherence to a gluten-free diet prevent this lymphoma has not been shown, although it is the usual assumption."],"parent":"peripheral-t-cell-lymphoma"},{"id":"eosinophilic-solid-cystic-renal-cell-carcinoma","kind":"cancer","name":"Eosinophilic solid and cystic renal cell carcinoma","aka":["ESC RCC","Eosinophilic, solid and cystic renal cell carcinoma","TSC-associated eosinophilic renal cell carcinoma (syndromic form)"],"tldr":"Eosinophilic solid and cystic renal cell carcinoma is a recently named kidney cancer, almost always in women, made of pink cells in solid areas and cysts. It was first seen in people with tuberous sclerosis and then found on its own, it is nearly always confined to the kidney, and surgery cures it in almost every reported case.","summary":"The 2022 WHO classification introduced eosinophilic solid and cystic renal cell carcinoma as a new morphologically defined type (Moch 2022). It was first described in patients with tuberous sclerosis complex; a search for a sporadic counterpart found 16 morphologically identical tumours, all in women without clinical tuberous sclerosis, median age 57, with solid and macrocystic growth, voluminous eosinophilic cytoplasm with granular stippling, hobnail cyst lining, nuclear PAX8, a CK20-positive and CK7-negative phenotype and no CD117; 13 of 16 were stage pT1 (Am J Surg Pathol 2016). In 19 further cases, all women, median age 55 and median size 31 mm, CK20 was positive in 74 percent, 89 percent were pT1, and 15 of 16 with follow-up were alive without disease (Am J Surg Pathol 2017). Sporadic cases carry somatic TSC1 or TSC2 mutations, the same pathway as the syndromic form.\n\nHow it differs from its parent: a female-only series, tuberous sclerosis biology (mTOR pathway), CK20 positivity and an indolent course with rare metastasis; it is distinguished from oncocytoma and chromophobe carcinoma by the cysts, the stippled cytoplasm and CK20.\n\nHow common: no registry share.\n\nTreatment: partial nephrectomy; the mTOR inhibitor everolimus, approved for tuberous sclerosis-associated tumours, is the rational choice for the rare metastatic case, without trial evidence in this type.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Renal_cell_carcinoma","links":[{"label":"Moch 2022, European Urology: the 2022 WHO classification of urinary and male genital tumours, part A (renal, penile, testicular)","url":"https://doi.org/10.1016/j.eururo.2022.06.016"},{"label":"Am J Surg Pathol 2016: eosinophilic, solid and cystic renal cell carcinoma, 16 sporadic cases in women","url":"https://doi.org/10.1097/pas.0000000000000508"},{"label":"Am J Surg Pathol 2017: eosinophilic solid and cystic RCC, further characterisation of 19 cases","url":"https://doi.org/10.1097/pas.0000000000000838"}],"tags":["subtype-page","wave4","kidney","rare"],"related":["rcc","chromophobe-rcc","sdh-deficient-renal-cell-carcinoma","mucinous-tubular-spindle-cell-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["everolimus"],"companies":[],"institutions":[],"pathways":[],"terms":["nephrectomy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Rare: 16 sporadic cases, all in women, median age 57 (Am J Surg Pathol 2016), and 19 further cases, all women, median age 55 (Am J Surg Pathol 2017). No registry share exists for a type named in 2022.","subtypes":[],"biomarkers":["CK20 positive, CK7 negative, CD117 negative","Somatic or germline TSC1 or TSC2 mutation","Solid and cystic architecture with stippled eosinophilic cytoplasm","Stage (nearly always pT1)"],"standardOfCare":[{"setting":"All stages","approach":"Partial nephrectomy; everolimus is the rational choice for rare metastatic disease on the tuberous sclerosis biology, without trial evidence.","refs":["rcc","nephrectomy","everolimus"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"rcc"},{"id":"ependymoma","kind":"cancer","name":"Ependymoma","aka":["Childhood ependymoma","Posterior fossa ependymoma","Supratentorial ZFTA fusion ependymoma","Myxopapillary ependymoma"],"tldr":"Ependymomas grow from the cells lining the fluid spaces of the brain and spinal cord, mostly in children under five. Removing the whole tumour followed by focused radiotherapy controls most cases; molecular groups defined in 2021 behave differently, with posterior fossa group A relapsing often, and there is no approved drug.","summary":"Ependymoma is a glial tumour arising along the ventricular system and spinal canal. The WHO 2021 classification replaced grade-based labels with molecular groups that carry prognostic weight: posterior fossa group A (PF-A, infants and young children, CpG hypermethylation with EZHIP overexpression and loss of H3K27me3, chromosome 1q gain marks high risk), posterior fossa group B (PF-B, older children and adults, favourable), supratentorial ZFTA (formerly RELA) fusion-positive (NF-kB driven), supratentorial YAP1 fusion-positive (young children, favourable), and spinal groups including myxopapillary ependymoma and MYCN-amplified spinal ependymoma. Few recurrent point mutations exist; the disease is largely driven by structural and epigenetic changes.\n\nTreatment is surgical: gross total resection is the strongest modifiable prognostic factor, and second-look surgery for residual disease is standard practice. Post-operative conformal radiotherapy to the tumour bed, including in children as young as one year, was established by the St Jude RT1 and COG ACNS0121 studies and controls disease without the whole-brain exposure of earlier eras; proton therapy is increasingly used to spare cochlea, hypothalamus and healthy brain. Chemotherapy has a limited role: it is used to bridge infants to radiotherapy or to enable second surgery, and the COG trial ACNS0831 tested maintenance chemotherapy after radiotherapy without establishing it as a universal standard. There is no approved targeted drug.\n\nThe active fronts are molecular risk stratification (SIOP Ependymoma II, ACNS0831 successors), reducing radiotherapy in favourable groups such as PF-B and ST-YAP1, and finding therapies for PF-A and ZFTA tumours, where relapse is common and repeated surgery and re-irradiation are the mainstay. Epigenetic dependencies (EZHIP and PRC2 biology in PF-A, NF-kB signalling in ZFTA), CDK4/6 inhibition and immunotherapy against fusion neoantigens are in preclinical and early clinical work.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Ependymoma","links":[{"label":"NCI PDQ: childhood ependymoma","url":"https://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq"},{"label":"Pajtler 2015: molecular classification of ependymal tumours (Cancer Cell)","url":"https://doi.org/10.1016/j.ccell.2015.04.002"},{"label":"ACNS0121: conformal radiotherapy in childhood ependymoma (JCO 2019)","url":"https://doi.org/10.1200/JCO.18.01765"}],"tags":["nci-coverage","paediatric","cns"],"related":["medulloblastoma","paediatric-low-grade-glioma","atrt","glioblastoma","spinal-cord-tumours"],"cancers":[],"sections":[],"technologies":["imrt-igrt","proton-therapy","methylation-profiling","mri","survivorship-care-plan"],"targets":["cdk4-6"],"drugs":["vincristine","carboplatin","cyclophosphamide","etoposide"],"companies":["childrens-oncology-group"],"institutions":["siop-europe","st-jude","dkfz"],"pathways":["epigenetic-reprogramming","inflammation-nfkb","hippo-yap"],"terms":["late-effects","ependymoma-molecular-groups"],"trials":["pediatric-match"],"people":[],"bottlenecks":["b-rare-cancers","b-survivorship"],"keyPapers":["paper-pajtler-cancer-cell"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Roughly one in ten childhood brain tumours, most under five years of age; also occurs in adults, mainly in the spine (NCI PDQ).","subtypes":["Posterior fossa group A (PF-A; EZHIP, H3K27me3 loss; 1q gain high risk)","Posterior fossa group B (PF-B; favourable)","Supratentorial, ZFTA fusion-positive","Supratentorial, YAP1 fusion-positive","Spinal ependymoma (including MYCN-amplified)","Myxopapillary ependymoma","Subependymoma"],"biomarkers":["Methylation-based molecular group","H3K27me3 loss and EZHIP expression (PF-A)","ZFTA or YAP1 fusion by FISH or sequencing","Chromosome 1q gain and 6q loss (PF-A risk)","MYCN amplification (spinal)","Extent of resection on post-operative MRI","Cerebrospinal-fluid cytology and spinal MRI for dissemination"],"standardOfCare":[{"setting":"Newly diagnosed intracranial ependymoma, age one year and over","approach":"Maximal safe resection, second-look surgery for residual disease, then conformal or proton radiotherapy to the tumour bed (ACNS0121 approach); craniospinal irradiation only for disseminated disease.","refs":["imrt-igrt","proton-therapy","mri","acns0121"],"guideline":{"version":"COG ACNS0121 (JCO 2019); NCI PDQ","url":"https://doi.org/10.1200/JCO.18.01765"}},{"setting":"Infants under one year or unresectable residual","approach":"Chemotherapy (vincristine, carboplatin, cyclophosphamide, etoposide-based) to delay radiotherapy or facilitate second surgery, per SIOP Ependymoma II and COG protocols.","refs":["vincristine","carboplatin","cyclophosphamide","etoposide"],"guideline":{"version":"SIOP Ependymoma II; NCI PDQ","url":"https://www.cancer.gov/types/brain/hp/child-ependymoma-treatment-pdq"}},{"setting":"Recurrent","approach":"Repeat resection and re-irradiation (focal or craniospinal) where feasible; no standard systemic therapy, so trial enrolment (including Pediatric MATCH-style molecular assignment) is recommended.","refs":["pediatric-match","proton-therapy"]}],"stateOfArt":["Molecular groups (PF-A, PF-B, ZFTA, YAP1, spinal) replaced grade as the basis of prognosis in WHO 2021 and are being used to de-escalate treatment for favourable groups.","Conformal and proton radiotherapy immediately after surgery, even in very young children, gives durable control with far less neurocognitive harm than older whole-brain approaches.","Gross total resection remains the single most important treatment step; second-look surgery is standard when residual disease is seen.","No drug has yet changed outcomes; epigenetic and fusion-directed strategies are the pipeline."],"history":[{"year":2009,"title":"Conformal radiotherapy safe and effective in young children","note":"St Jude RT1 (Merchant, Lancet Oncology) shows tumour-bed irradiation controls disease with preserved cognition.","refs":["imrt-igrt"]},{"year":2011,"title":"Two posterior fossa groups discovered","note":"Witt and colleagues (Cancer Cell) separate PF-A and PF-B by expression.","refs":[]},{"year":2014,"title":"C11orf95-RELA (ZFTA) fusion identified in supratentorial ependymoma","note":"Parker and colleagues (Nature) link the fusion to NF-kB activation.","refs":[]},{"year":2015,"title":"Nine molecular groups across the neuraxis","note":"Pajtler and colleagues (Cancer Cell) define the methylation-based classification later adopted by WHO.","refs":["methylation-profiling"]},{"year":2019,"title":"ACNS0121 confirms post-operative conformal radiotherapy","note":"COG phase 2 (JCO 2019) reports outcomes by extent of resection and molecular group.","refs":[]},{"year":2021,"title":"WHO 2021 adopts molecular groups for ependymoma","refs":[]}],"pipeline":["methylation-profiling","proton-therapy","pediatric-match"],"openProblems":["PF-A and ZFTA tumours relapse often and have no effective drug; EZHIP/PRC2 and NF-kB dependencies are being tested preclinically and in early trials.","Whether radiotherapy can be omitted or reduced in PF-B, YAP1 and completely resected favourable tumours; SIOP Ependymoma II and COG successors are stratifying by group.","Late effects of radiotherapy in very young children; proton therapy is expected to reduce them and is being tracked in registries.","Adult spinal and intracranial ependymoma lack dedicated trials and borrow from paediatric evidence."],"parent":"brain-tumours"},{"id":"epithelioid-haemangioendothelioma","kind":"cancer","name":"Epithelioid haemangioendothelioma","aka":["EHE","WWTR1-CAMTA1 sarcoma","YAP1-TFE3 haemangioendothelioma"],"tldr":"Epithelioid haemangioendothelioma is a rare vascular cancer driven by a fusion gene, usually WWTR1-CAMTA1, that behaves unpredictably: some tumours sit unchanged for years while others spread quickly. Stable disease is watched, localised tumours are removed, liver-only disease can be transplanted, and mTOR blockers such as sirolimus are the most used drugs when treatment is needed.","summary":"Epithelioid haemangioendothelioma is a malignant vascular tumour of intermediate to high grade defined by the WWTR1-CAMTA1 fusion in about nine in ten cases and the YAP1-TFE3 fusion in most of the rest; both fusions hijack the Hippo pathway effectors TAZ and YAP. It presents as single or multifocal nodules in the liver, lungs, bone or soft tissue, often with pleural or peritoneal involvement, and is frequently found incidentally. Effusions, pain and weight loss mark the aggressive phenotype, while multifocal liver and lung disease is often indolent.\n\nBecause the natural history is so variable, the first decision is whether to treat at all: asymptomatic, stable, multifocal disease is placed under active surveillance with serial imaging. Localised tumours are resected, and hepatic epithelioid haemangioendothelioma is one of the few metastatic-appearing cancers for which liver transplantation is accepted, with good long-term survival in registry series. Radiotherapy palliates bone and painful lesions.\n\nSystemic therapy is used for progressive or symptomatic disease. Sirolimus produced disease stabilisation and some responses in an Italian Sarcoma Group series and prospective study, and mTOR inhibition is the most widely used first option; anti-angiogenic kinase inhibitors such as pazopanib and the MEK inhibitor trametinib (SARC033) have modest activity, and anthracycline-based chemotherapy is reserved for rapidly progressive disease. Patient groups such as the EHE Foundation have funded fusion-directed drug discovery, including TAZ-CAMTA1 degraders.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Epithelioid_hemangioendothelioma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Epithelioid_hemangioendothelioma"}],"tags":["subtype-page"],"related":["vascular-tumours","angiosarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-errani-wwtr1-camta1-ehe-gcc-2011","paper-ehe-consensus-stacchiotti-esmo-open-2021","paper-sirolimus-ehe-stacchiotti-cancer-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"Roughly one case per million people a year, in adults of any age, arising in the liver, lungs, bone and soft tissue and often multifocal at diagnosis; its course ranges from years of stability to rapid progression, and no drug is approved.","subtypes":["WWTR1-CAMTA1 epithelioid haemangioendothelioma (about 90 percent)","YAP1-TFE3 epithelioid haemangioendothelioma (younger, more vasoformative)","Hepatic epithelioid haemangioendothelioma (transplant candidate)","Pulmonary and pleural epithelioid haemangioendothelioma (effusions, poorer outlook)","Bone and soft tissue epithelioid haemangioendothelioma"],"biomarkers":["WWTR1-CAMTA1 fusion (CAMTA1 immunohistochemistry)","YAP1-TFE3 fusion (TFE3 immunohistochemistry)","Pleural effusion, serosal involvement and pain (aggressive phenotype)","Mitotic count and size (risk stratification)"],"standardOfCare":[{"setting":"Asymptomatic, stable, multifocal","approach":"Active surveillance with imaging every three to six months; treat only on progression or symptoms.","refs":["active-surveillance","ct","mri"]},{"setting":"Localised","approach":"Complete resection; liver transplantation for unresectable liver-limited disease; radiotherapy for bone lesions.","refs":["limb-salvage-surgery","liver-transplant-oncology","imrt-igrt"]},{"setting":"Progressive or symptomatic","approach":"Sirolimus or another mTOR inhibitor first; pazopanib or other anti-angiogenic kinase inhibitors; anthracycline chemotherapy for rapidly progressive disease.","refs":["mtor","everolimus","sirolimus-albumin-bound","pazopanib","doxorubicin","paclitaxel"]}],"stateOfArt":["Active surveillance is standard for stable disease because many tumours do not progress for years.","Liver transplantation offers long survival in hepatic disease despite multifocality.","Sirolimus is the most used drug, and TAZ-CAMTA1-directed agents are in preclinical development."],"history":[{"year":1982,"title":"Weiss and Enzinger describe epithelioid haemangioendothelioma","refs":[]},{"year":2011,"title":"WWTR1-CAMTA1 fusion identified as the defining alteration","refs":[]},{"year":2013,"title":"YAP1-TFE3 fusion found in a second subset","refs":[]},{"year":2016,"title":"Sirolimus activity reported in progressive epithelioid haemangioendothelioma","refs":["mtor"]},{"year":2021,"title":"SARC033: trametinib shows modest activity","refs":["mek"]}],"pipeline":["mtor","pazopanib"],"openProblems":["No approved drug and no randomised trial.","Predicting which tumours will progress is unreliable.","The fusion oncoprotein is a transcription factor with no direct inhibitor yet."],"parent":"vascular-tumours"},{"id":"epithelioid-sarcoma","kind":"cancer","name":"Epithelioid sarcoma","aka":[],"tldr":"Epithelioid sarcoma is a rare soft tissue cancer that has lost a gene brake called SMARCB1, leaving it dependent on the enzyme EZH2. Surgery cures localised tumours. The EZH2 inhibitor tazemetostat was approved in 2020 and withdrawn worldwide in March 2026 after secondary blood cancers in a lymphoma trial; the dependency it proved is still a target in development, and chemotherapy remains in use.","summary":"Epithelioid sarcoma is defined by loss of SMARCB1 (INI1), a core subunit of the SWI/SNF chromatin-remodelling complex, in over 90 percent of cases. SWI/SNF loss makes cells dependent on the antagonistic polycomb repressive complex 2 and its catalytic subunit EZH2, a synthetic-lethal relationship demonstrated in preclinical models and confirmed in patients. The distal (classic) type presents as slow-growing nodules on the hands and forearms of young adults and is often misdiagnosed as a benign lesion; the proximal type, in the pelvis, perineum and trunk, is larger and more aggressive, with rhabdoid features. Both spread to lymph nodes, which is unusual for sarcomas, and to lung.\n\nLocalised disease is treated with wide resection and radiotherapy according to soft tissue sarcoma principles; sentinel node evaluation is considered because of nodal spread. Conventional chemotherapy (anthracycline, ifosfamide, gemcitabine-docetaxel) has modest activity. Tazemetostat received FDA accelerated approval in January 2020 for metastatic or locally advanced epithelioid sarcoma not eligible for complete resection, on the basis of the single-arm EZH-202 cohort (objective responses in a minority, but durable, with a benign safety profile). The confirmatory randomised trial EZH-301 adds tazemetostat to doxorubicin in the first line; it was meant to decide whether the accelerated approval would be converted, but Ipsen withdrew the drug in all indications on 9 March 2026 after the SYMPHONY-1 follicular lymphoma trial's data monitoring committee flagged secondary haematologic malignancies (18 of 318 patients, 5.7%, per the FDA safety communication).\n\nBeyond EZH2, checkpoint inhibitors have produced occasional responses (SWI/SNF-deficient tumours are immunogenic in some settings), and combinations of tazemetostat with doxorubicin or immunotherapy are the main directions.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Epithelioid_sarcoma","links":[{"label":"NCI PDQ: soft tissue sarcoma","url":"https://www.cancer.gov/types/soft-tissue-sarcoma"},{"label":"EZH-202 (Lancet Oncol 2020)","url":"https://doi.org/10.1016/S1470-2045(20)30451-4"},{"label":"EZH-301 on ClinicalTrials.gov","url":"https://clinicaltrials.gov/study/NCT04204941"},{"label":"Ipsen withdrawal notice (9 March 2026)","url":"https://www.globenewswire.com/news-release/2026/03/09/3252192/0/en/update-ipsen-voluntarily-withdraws-tazverik-tazemetostat-in-follicular-lymphoma-and-epithelioid-sarcoma.html"},{"label":"FDA safety communication on the Tazverik withdrawal (11 May 2026)","url":"https://www.fda.gov/drugs/drug-alerts-and-statements/fda-alerts-health-care-providers-and-patients-about-increased-risk-new-blood-cancers-tazverik"},{"label":"T-VEC plus pembrolizumab in sarcoma (JAMA Oncol 2020)","url":"https://doi.org/10.1001/jamaoncol.2019.6152"},{"label":"AcSe pembrolizumab in rare sarcomas (Lancet Oncol 2023)","url":"https://doi.org/10.1016/S1470-2045(23)00282-6"}],"tags":["nci-coverage","rare","sarcoma"],"related":["atrt","alveolar-soft-part-sarcoma","synovial-sarcoma","pecoma","malignant-peripheral-nerve-sheath-tumour"],"cancers":[],"sections":[],"technologies":["epigenetic-drugs","limb-salvage-surgery","imrt-igrt","sentinel-node","cytotoxic-chemotherapy"],"targets":["ezh2"],"drugs":["tazemetostat","doxorubicin","ifosfamide"],"companies":["ipsen"],"institutions":[],"pathways":["swi-snf-chromatin","epigenetic-reprogramming"],"terms":["accelerated-approval","rare-cancers"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers"],"keyPapers":["paper-gounder-lancet-oncol","paper-kelly-jama-oncol","paper-blay-lancet-oncol"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"Under one case per million people per year; the distal type peaks in young adults aged 20 to 40, the proximal type in older adults.","subtypes":["Distal (classic) type","Proximal type (large cell, rhabdoid features)"],"biomarkers":["SMARCB1/INI1 loss by immunohistochemistry (diagnostic)","CD34 and cytokeratin co-expression","Regional lymph node status","Tumour size and depth (proximal vs distal)"],"standardOfCare":[{"setting":"Localised","approach":"Wide resection with negative margins plus radiotherapy for large, deep or close-margin tumours; lymph node assessment considered because of nodal spread.","refs":["limb-salvage-surgery","imrt-igrt","sentinel-node"],"guideline":{"nccn":"Category 2A","version":"NCCN Soft Tissue Sarcoma; ESMO-EURACAN-GENTURIS sarcoma guideline","url":"https://doi.org/10.1016/j.annonc.2021.07.006"}},{"setting":"Advanced or metastatic","approach":"Anthracycline-based chemotherapy; tazemetostat (accelerated approval 2020, EZH-202) was withdrawn from all markets in March 2026 after SYMPHONY-1 showed excess secondary blood cancers, so the EZH2 option is gone; clinical trial enrolment encouraged.","refs":["tazemetostat","doxorubicin","ifosfamide"],"guideline":{"nccn":"Category 2A","version":"NCCN Soft Tissue Sarcoma"}}],"stateOfArt":["Tazemetostat was the first EZH2 inhibitor and the first epigenetic drug approved for a solid tumour, and epithelioid sarcoma is the disease that made the SWI/SNF-EZH2 synthetic lethality a clinical reality; its withdrawal in March 2026 for secondary haematologic malignancies leaves the target validated and the disease without a drug.","The 2020 approval rested on a single-arm cohort; the randomised EZH-301 confirmatory trial with doxorubicin never got to answer whether the benefit held in first line.","Nodal spread and frequent misdiagnosis of distal lesions mean that expert pathology review and sarcoma-centre referral change outcomes.","SMARCB1 loss links this tumour to ATRT, poorly differentiated chordoma and renal medullary carcinoma, allowing shared trials across rare SWI/SNF-deficient cancers."],"history":[{"year":1970,"title":"Enzinger describes epithelioid sarcoma","note":"Named for its resemblance to carcinoma and granuloma.","refs":[]},{"year":2005,"title":"SMARCB1/INI1 loss recognised","note":"Modena and colleagues link the tumour to SWI/SNF deficiency.","refs":[]},{"year":2013,"title":"EZH2 dependency of SMARCB1-deficient cells","note":"Knutson and colleagues, PNAS: EZH2 inhibition kills INI1-negative cells.","refs":[]},{"year":2020,"title":"Tazemetostat accelerated approval","note":"FDA, 23 January 2020, based on EZH-202 (Gounder and colleagues, Lancet Oncol 2020).","refs":["tazemetostat"]},{"year":2020,"title":"EZH-301 confirmatory trial opens","note":"Doxorubicin with or without tazemetostat, first line (NCT04204941).","refs":["tazemetostat","doxorubicin"]},{"year":2026,"title":"Tazemetostat withdrawn worldwide","note":"Ipsen withdraws tazemetostat in all indications on 9 March 2026 after the SYMPHONY-1 data monitoring committee flagged secondary haematologic malignancies (18/318 patients, 5.7%, per the FDA safety communication).","refs":["tazemetostat"]}],"pipeline":["tazemetostat-doxorubicin-es","tazemetostat","ezh2","epigenetic-drugs"],"openProblems":["No approved targeted therapy since the March 2026 withdrawal: next-generation PRC2 inhibitors such as rinzimetostat (EED) are being tested in other cancers, and whether one can be brought to epithelioid sarcoma is open.","The EZH-301 doxorubicin combination and immunotherapy combinations were still recruiting when tazemetostat was withdrawn; their read-outs would show whether the EZH2 axis is worth revisiting.","Checkpoint inhibition has a signal but no approval: talimogene laherparepvec with pembrolizumab gave a 35% objective response rate across 20 patients with advanced sarcoma of mixed histology (Kelly and colleagues, JAMA Oncol 2020), and the AcSe rare-sarcoma basket gave 6.2% at week 12 across 97 patients (Blay and colleagues, Lancet Oncol 2023).","Late diagnosis of distal lesions mistaken for warts or granulomas.","Proximal-type disease remains chemoresistant and rapidly progressive."],"parent":"sarcoma"},{"id":"erdheim-chester-disease","kind":"cancer","name":"Erdheim-Chester disease","aka":["ECD","Polyostotic sclerosing histiocytosis","L-group histiocytosis (adult)","BRAF-mutant histiocytosis"],"tldr":"Erdheim-Chester disease is a rare histiocytosis, a cancer-like overgrowth of immune cells called histiocytes that scar the long bones, the tissue around the kidneys and heart, the brain and the skin. Most cases carry the BRAF V600E mutation or another fault in the same growth pathway, and the melanoma drugs vemurafenib and cobimetinib now control the disease in most patients.","summary":"Erdheim-Chester disease is a clonal neoplasm of foamy CD68-positive, CD1a-negative histiocytes that infiltrate and fibrose tissues in a characteristic distribution: symmetrical sclerosis of the long bones (seen on bone scan and PET in almost every patient), a rind of tissue around the kidneys and aorta ('hairy kidney' and 'coated aorta'), infiltration of the heart and pericardium, the pituitary (diabetes insipidus), the cerebellum and brainstem, the orbits and the skin (xanthelasma-like plaques). It was reclassified in 2016 with Langerhans cell histiocytosis in the L group of histiocytoses because the two share MAPK pathway mutations and often occur together, and the WHO now lists it among myeloid neoplasms; in some patients the histiocytes derive from a clone that also produces a myeloid neoplasm such as chronic myelomonocytic leukaemia. BRAF V600E is found in more than half of patients, and most of the rest have mutations in MAP2K1, ARAF, NRAS, KRAS or PIK3CA or kinase fusions, so the disease is almost always driven by one activating lesion in the RAS-MAPK pathway.\n\nInterferon alfa, the standard from the 1990s to the 2010s, slowed the disease but rarely reversed it. The discovery of BRAF V600E in 2012 led to treatment with vemurafenib, which in the VE-BASKET trial produced responses in most patients and in 2017 became the first drug approved for Erdheim-Chester disease, and to the MEK inhibitor cobimetinib, which produced responses in most patients with or without a BRAF mutation in a phase 2 trial (Nature Medicine 2019) and was approved in the United States in 2022 for histiocytic neoplasms including Erdheim-Chester disease, Langerhans cell histiocytosis and Rosai-Dorfman disease. Dabrafenib with trametinib is used as an alternative BRAF-directed regimen. The 2020 consensus recommendations (Blood) advise targeted therapy for all patients with symptomatic or organ-threatening disease, with interferon alfa, anakinra, cladribine or methotrexate as second-choice options, and observation for the minority with asymptomatic disease confined to bone. Kinase inhibitors are usually continued indefinitely because relapse follows withdrawal, at doses lowered to limit skin, joint and cardiac toxicity, and plasma BRAF V600E cell-free DNA is used to follow response. Survival has improved from a median of a few years to a normal life expectancy for most patients treated early.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Erdheim%E2%80%93Chester_disease","links":[{"label":"ECD consensus recommendations (Blood 2020)","url":"https://doi.org/10.1182/blood.2019003507"},{"label":"Cobimetinib in histiocytosis (Nature 2019)","url":"https://doi.org/10.1038/s41586-019-1012-y"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Erdheim%E2%80%93Chester_disease"}],"tags":["subtype-page","haematologic"],"related":["rosai-dorfman-disease","histiocytoses","lch-multisystem","braf-v600-melanoma"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","fdg-pet","liquid-biopsy","cgp","mri","active-surveillance"],"targets":["braf","pik3ca"],"drugs":["vemurafenib","cobimetinib","dabrafenib-trametinib","interferon-alfa","cladribine","methotrexate"],"companies":[],"institutions":[],"pathways":[],"terms":["braf-v600-mutation","driver-mutation","ctdna","retroperitoneum"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2022-myeloid-khoury-leukemia-2022","paper-ve-basket-vemurafenib-erdheim-chester-lch-jama-oncol-2018","paper-erdheim-chester-disease-consensus-recommendations-blood-2020","paper-emile-revised-classification-of-histiocytoses-blood-2016","paper-diamond-nature"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"A rare disease of adults in their fifties and sixties, with a few hundred cases described before 2010 and many more since BRAF testing and PET became routine; men are affected more often than women.","subtypes":["BRAF V600E-mutant Erdheim-Chester disease (vemurafenib, dabrafenib-trametinib, cobimetinib)","BRAF wild-type Erdheim-Chester disease with MAP2K1, ARAF, RAS or PIK3CA mutations (cobimetinib)","Erdheim-Chester disease with cardiac or central nervous system involvement (urgent targeted therapy)","Bone-limited asymptomatic Erdheim-Chester disease (observation)","Mixed Erdheim-Chester and Langerhans cell histiocytosis","Erdheim-Chester disease with an associated myeloid neoplasm"],"biomarkers":["BRAF V600E in tissue and plasma cell-free DNA (diagnosis and monitoring)","MAP2K1, ARAF, NRAS, KRAS, PIK3CA and kinase fusions on sequencing","CD68 and CD163 positive, CD1a and langerin negative histiocytes with Touton giant cells","FDG-PET/CT for extent and response (long bone uptake)","Cardiac MRI, brain MRI and pituitary function","Blood count and myeloid mutation panel for an associated clonal myeloid neoplasm"],"standardOfCare":[{"setting":"Diagnosis","approach":"Biopsy of an accessible lesion with BRAF V600E testing and broader sequencing; FDG-PET/CT, cardiac and brain MRI, endocrine assessment.","refs":["braf-v600-mutation","cgp","fdg-pet","mri","liquid-biopsy"],"guideline":{"version":"Consensus recommendations for Erdheim-Chester disease (Blood 2020)","url":"https://doi.org/10.1182/blood.2019003507"}},{"setting":"BRAF V600E-mutant symptomatic disease","approach":"Vemurafenib (approved 2017) or dabrafenib with trametinib; cobimetinib as an alternative; dose reduction to limit toxicity, treatment continued long term.","refs":["vemurafenib","dabrafenib-trametinib","cobimetinib","braf","kinase-inhibitors"],"guideline":{"version":"Consensus recommendations for Erdheim-Chester disease (Blood 2020)","url":"https://doi.org/10.1182/blood.2019003507"}},{"setting":"BRAF wild-type symptomatic disease","approach":"Cobimetinib (approved 2022 for histiocytic neoplasms); trametinib as an alternative MEK inhibitor.","refs":["cobimetinib","ras-mapk","kinase-inhibitors"],"guideline":{"version":"Consensus recommendations for Erdheim-Chester disease (Blood 2020)","url":"https://doi.org/10.1182/blood.2019003507"}},{"setting":"Second-choice or intolerant","approach":"Interferon alfa or pegylated interferon, anakinra, cladribine, methotrexate.","refs":["interferon-alfa","cladribine","methotrexate"],"guideline":{"version":"Consensus recommendations for Erdheim-Chester disease (Blood 2020)","url":"https://doi.org/10.1182/blood.2019003507"}},{"setting":"Asymptomatic bone-limited disease","approach":"Observation with periodic PET and organ screening.","refs":["fdg-pet","active-surveillance"],"guideline":{"version":"Consensus recommendations for Erdheim-Chester disease (Blood 2020)","url":"https://doi.org/10.1182/blood.2019003507"}}],"stateOfArt":["Targeted BRAF and MEK inhibition controls the disease in most patients and has normalised life expectancy for many.","Erdheim-Chester disease is the first histiocytosis with an approved targeted drug.","Plasma BRAF V600E DNA gives a blood test for disease burden."],"history":[{"year":1930,"title":"Jakob Erdheim and William Chester describe lipoid granulomatosis","refs":[]},{"year":2005,"title":"Interferon alfa shown to prolong survival in a retrospective series","refs":["interferon-alfa"]},{"year":2012,"title":"BRAF V600E found in more than half of patients","refs":["braf","braf-v600-mutation"]},{"year":2016,"title":"Revised histiocytosis classification places Erdheim-Chester and Langerhans cell histiocytosis together in the L group","refs":[]},{"year":2017,"title":"Vemurafenib approved for BRAF V600E-mutant Erdheim-Chester disease (VE-BASKET)","refs":["vemurafenib"]},{"year":2019,"title":"Cobimetinib phase 2 shows responses in most patients regardless of mutation","refs":["cobimetinib"]},{"year":2022,"title":"Cobimetinib approved for histiocytic neoplasms in the United States","refs":["cobimetinib"]}],"pipeline":["cobimetinib","vemurafenib","dabrafenib-trametinib"],"openProblems":["Kinase inhibitors are usually needed for life and relapse follows their withdrawal.","Long-term cardiac, skin and secondary-cancer effects of indefinite BRAF and MEK inhibition are unknown.","Established fibrosis and neurological damage do not reverse.","Diagnosis is still delayed by years because the disease is unfamiliar."],"parent":"histiocytoses"},{"id":"histiocytoses","kind":"cancer","name":"Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms","aka":["ECD","Erdheim-Chester disease","Rosai-Dorfman disease","RDD","Rosai-Dorfman-Destombes disease","Histiocytic sarcoma","Juvenile xanthogranuloma","Mixed ECD-LCH","L-group and R-group histiocytoses"],"tldr":"Histiocytoses are diseases in which immune scavenger cells build up in bone, heart, brain, kidneys and skin. They used to be treated as inflammatory conditions with steroids and interferon. The discovery that most carry mutations in the same growth pathway as melanoma turned them into targetable cancers: BRAF and MEK inhibitor pills now produce responses in nearly every treated patient.","summary":"The histiocytic neoplasms are clonal disorders of macrophage or dendritic cell lineage. The 2016 revised Histiocyte Society classification groups them into L (Langerhans: LCH, ECD, mixed ECD-LCH), C (cutaneous non-LCH, including juvenile xanthogranuloma), R (Rosai-Dorfman disease), M (malignant histiocytoses such as histiocytic sarcoma) and H (haemophagocytic lymphohistiocytosis, a hyperinflammatory syndrome rather than a neoplasm). Erdheim-Chester disease (ECD) infiltrates long bones, the retroperitoneum ('hairy kidney'), the heart and aorta, the orbits and the brain; BRAF V600E is present in around half of patients, with most of the rest carrying other MAPK-pathway alterations (MAP2K1, ARAF, NRAS, KRAS, RAF1 fusions) or PIK3CA mutations. Rosai-Dorfman disease shows emperipolesis in S100-positive, CD1a-negative histiocytes and carries KRAS or MAP2K1 mutations in a large minority. The same mutations in the same lineage in adults and children unify these diseases with Langerhans cell histiocytosis, which has its own page.\n\nTreatment was transformed by targeted therapy. Interferon alfa was the previous first line for ECD. Vemurafenib produced responses in essentially every BRAF-mutant ECD patient in the VE-BASKET trial, leading to FDA approval in November 2017, the first approval for any histiocytosis. Cobimetinib, a MEK inhibitor, gave responses regardless of mutation status in a phase 2 trial (Diamond and colleagues, Nature Medicine 2019) and was FDA-approved in October 2022 for adult histiocytic neoplasms including ECD, RDD and LCH. Responses are deep and durable but relapse follows discontinuation in most patients, so therapy is often prolonged at reduced doses. Rosai-Dorfman disease is observed if asymptomatic, and treated with surgery, steroids, sirolimus, cladribine or MEK inhibitors when it causes harm. Histiocytic sarcoma is treated with lymphoma-type chemotherapy, radiotherapy and, increasingly, MAPK-pathway inhibitors. Mixed ECD-LCH and the neurodegenerative complications of both are the hardest problems.\n\nInternational consensus recommendations for ECD (Blood 2020) and the Histiocyte Society trials network coordinate care and research.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Erdheim%E2%80%93Chester_disease","links":[{"label":"NCI PDQ: Langerhans cell histiocytosis (histiocytic disorders)","url":"https://www.cancer.gov/types/langerhans"},{"label":"Consensus recommendations for ECD (Blood 2020)","url":"https://doi.org/10.1182/blood.2019003507"},{"label":"Cobimetinib in histiocytic neoplasms (Nature Medicine 2019)","url":"https://doi.org/10.1038/s41591-019-0653-6"},{"label":"NCCN: Histiocytic Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1518"}],"tags":["nci-coverage","rare","haematologic","histiocytosis"],"related":["langerhans-cell-histiocytosis","melanoma","cmml"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","fdg-pet","liquid-biopsy","cgp","mri"],"targets":["braf","alk","pik3ca"],"drugs":["vemurafenib","cobimetinib","dabrafenib-trametinib","interferon-alfa","cladribine"],"companies":["roche-genentech"],"institutions":["histiocyte-society"],"pathways":["ras-mapk","pi3k-akt-mtor","clonal-haematopoiesis"],"terms":["braf-v600-mutation","driver-mutation","ctdna","retroperitoneum"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers","b-generic-repurposing"],"keyPapers":["paper-durham-nat-med"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Erdheim-Chester disease has been described in only a few thousand patients worldwide, mostly adults in their fifties and sixties; Rosai-Dorfman disease and histiocytic sarcoma are similarly rare (Histiocyte Society registries).","subtypes":["Erdheim-Chester disease (BRAF V600E-mutant or wild-type)","Mixed ECD-LCH","Rosai-Dorfman-Destombes disease (nodal, extranodal, cutaneous, familial)","Juvenile xanthogranuloma and other C-group cutaneous histiocytoses","Histiocytic sarcoma and other malignant histiocytoses","ALK-positive histiocytosis (rare; responds to ALK inhibitors)"],"biomarkers":["BRAF V600E (tissue; plasma ctDNA for monitoring)","MAP2K1, ARAF, NRAS, KRAS, PIK3CA, RAF1 and ALK fusions on NGS","Immunophenotype: CD68, CD163, factor XIIIa positive; CD1a and langerin negative (ECD, RDD); S100 with emperipolesis (RDD)","FDG-PET/CT for extent and response","Cardiac MRI and brain MRI for organ involvement","Clonal haematopoiesis (mutations shared with myeloid clones in some patients)"],"standardOfCare":[{"setting":"ECD, BRAF V600E-mutant, needing treatment","approach":"Vemurafenib (FDA approval 2017) or dabrafenib, often with a MEK inhibitor to reduce toxicity; long-term treatment at the lowest effective dose.","refs":["vemurafenib","dabrafenib-trametinib","braf"],"guideline":{"version":"Consensus recommendations for ECD (Blood 2020)","url":"https://doi.org/10.1182/blood.2019003507"}},{"setting":"ECD or RDD, BRAF wild-type or intolerant of BRAF inhibitors","approach":"Cobimetinib (FDA approval October 2022 for histiocytic neoplasms) or another MEK inhibitor; interferon alfa or pegylated interferon as an alternative.","refs":["cobimetinib","interferon-alfa"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Histiocytic Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1518"}},{"setting":"Rosai-Dorfman disease","approach":"Observation for asymptomatic nodal disease; surgery for isolated masses; steroids, sirolimus, cladribine or MEK inhibitors for symptomatic or multifocal disease.","refs":["cladribine","cobimetinib"],"guideline":{"version":"Consensus recommendations for RDD (Blood 2018)","url":"https://doi.org/10.1182/blood-2018-03-839753"}},{"setting":"Histiocytic sarcoma","approach":"Lymphoma-type chemotherapy (CHOP, ICE, or similar), radiotherapy for localised disease, MAPK-pathway inhibitors where mutations are found; clinical trials.","refs":["cyclophosphamide","doxorubicin","etoposide","cobimetinib"]}],"stateOfArt":["The MAPK pathway discovery (BRAF V600E in ECD, 2012) converted histiocytoses from mysterious inflammatory diseases into targetable neoplasms.","Vemurafenib (2017) and cobimetinib (2022) are the first drugs ever approved for a histiocytosis, with responses in nearly every treated patient.","Plasma BRAF V600E ctDNA and FDG-PET allow response monitoring and dose reduction without repeat biopsy.","The remaining challenges are stopping therapy without relapse, neurodegeneration, and histiocytic sarcoma."],"history":[{"year":1930,"title":"Erdheim and Chester describe 'lipoid granulomatosis'","refs":[]},{"year":1969,"title":"Rosai and Dorfman describe sinus histiocytosis with massive lymphadenopathy","note":"Destombes had reported cases in 1965.","refs":[]},{"year":2012,"title":"BRAF V600E found in ECD and LCH","note":"Haroche and colleagues (Blood 2012) after Badalian-Very's LCH discovery (2010).","refs":["braf"]},{"year":2016,"title":"Revised Histiocyte Society classification","note":"L, C, R, M and H groups (Emile et al., Blood 2016).","refs":[]},{"year":2017,"title":"Vemurafenib approved for ECD","note":"First approval for any histiocytosis (VE-BASKET); November 2017.","refs":["vemurafenib"]},{"year":2019,"title":"Cobimetinib effective regardless of genotype","note":"Diamond and colleagues, Nature Medicine 2019.","refs":["cobimetinib"]},{"year":2022,"title":"Cobimetinib approved for histiocytic neoplasms","note":"FDA approval October 2022 for adults with ECD, RDD and LCH.","refs":["cobimetinib"]}],"pipeline":["cobimetinib","vemurafenib","dabrafenib-trametinib"],"openProblems":["Most patients relapse when BRAF or MEK inhibitors stop; intermittent dosing and ctDNA-guided discontinuation are being tested.","Neurodegenerative ECD and LCH do not reverse with targeted therapy; earlier treatment and neuroprotective trials are the response.","Histiocytic sarcoma remains aggressive; MAPK inhibitors and immunotherapy are being tried.","Rarity: the Histiocyte Society, the ECD Global Alliance registry and NCCN's 2021 guideline coordinate what evidence exists."]},{"id":"essential-thrombocythaemia","kind":"cancer","name":"Essential thrombocythaemia (ET)","aka":["Essential thrombocythemia","ET","Primary thrombocythaemia","Essential thrombocytosis"],"tldr":"Essential thrombocythaemia is a slow blood cancer in which the marrow makes too many platelets. Most people need only aspirin and monitoring; those at higher risk of clots take a drug to lower the platelet count, usually hydroxyurea or interferon, with anagrelide in reserve.","summary":"Essential thrombocythaemia is a classical myeloproliferative neoplasm defined by a sustained platelet count above 450 x 10^9/L with a marrow full of large, mature megakaryocytes and no other explanation. About 60 percent carry JAK2 V617F, 20 to 25 percent a CALR mutation and 3 to 5 percent an MPL mutation; the rest are triple negative. Many people have no symptoms and are found on a routine blood count; others have headaches, visual disturbance, burning red hands and feet (erythromelalgia) or, at high platelet counts, paradoxical bleeding. Treatment is set by the IPSET-thrombosis score, which weighs age, prior clot, JAK2 status and cardiovascular risk: very low-risk patients may need nothing, low-risk patients take low-dose aspirin, and high-risk patients add cytoreduction with hydroxyurea or interferon, with anagrelide second line. The PT-1 trial showed hydroxyurea plus aspirin beats anagrelide plus aspirin on arterial clots and bleeding. Progression to myelofibrosis happens in a minority over decades and to acute leukaemia in a few percent. Bomedemstat, an LSD1 inhibitor, is in a phase 3 trial against hydroxyurea, and antibodies against mutant CALR are the first treatments aimed at the clone itself.","asOf":"2026-09-16","wikipedia":"https://en.wikipedia.org/wiki/Essential_thrombocythemia","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Essential_thrombocythemia"},{"label":"MPN Research Foundation","url":"https://www.mpnresearchfoundation.org/essential-thrombocythemia/"}],"tags":["essential-thrombocythaemia","mpn"],"related":["polycythaemia-vera","primary-myelofibrosis"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["ipset-thrombosis","mpn-driver-mutations"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Around one to two new cases per 100,000 people a year, with a second peak in women in their thirties; life expectancy is close to normal for most, and the risks are clots, bleeding and slow progression to myelofibrosis.","subtypes":["JAK2 V617F-mutated (about 60 percent; higher thrombosis risk)","CALR-mutated (20 to 25 percent; higher platelets, lower thrombosis risk)","MPL-mutated (3 to 5 percent)","Triple negative (10 to 15 percent)","Prefibrotic primary myelofibrosis (a look-alike separated by marrow histology since WHO 2016)"],"biomarkers":["Platelet count above 450 x 10^9/L","JAK2 V617F, CALR exon 9 and MPL W515 mutations","IPSET-thrombosis score (age over 60, prior thrombosis, JAK2 V617F, cardiovascular risk factors)","Marrow histology to exclude prefibrotic myelofibrosis","Acquired von Willebrand deficiency at platelet counts above 1,000 x 10^9/L (bleeding risk with aspirin)"],"standardOfCare":[{"setting":"Diagnosis","approach":"Full blood count, JAK2, CALR and MPL testing, bone marrow biopsy to confirm ET and exclude prefibrotic myelofibrosis, and exclusion of reactive causes (iron deficiency, inflammation, infection, splenectomy).","refs":["jak2","jak2-v617f","myeloproliferative-neoplasms"]},{"setting":"Very low and low risk","approach":"Observation alone in very low risk (under 60, no clot, JAK2-negative); low-dose aspirin for low risk and for anyone with microvascular symptoms, once acquired von Willebrand deficiency is excluded at very high platelet counts.","refs":["aspirin","erythromelalgia"]},{"setting":"High risk (over 60 with JAK2 or prior clot)","approach":"Cytoreduction to a platelet count under 400 x 10^9/L: hydroxyurea first line (PT-1), pegylated or ropeginterferon alfa-2b preferred under 60 and in pregnancy, anagrelide second line.","refs":["hydroxyurea","pt-1","ropeginterferon-alfa-2b","anagrelide"]},{"setting":"Hydroxyurea resistance or intolerance","approach":"Switch to interferon or anagrelide; ruxolitinib did not beat best available therapy in MAJIC-ET but relieves symptoms.","refs":["anagrelide","ruxolitinib","majic-et"]},{"setting":"Progression to myelofibrosis","approach":"Managed as myelofibrosis: JAK inhibitors for spleen and symptoms, transplant for fit higher-risk patients.","refs":["myeloproliferative-neoplasms","post-pv-myelofibrosis","ruxolitinib"]}],"stateOfArt":["Most people with ET live a near-normal lifespan; the treatment question is who needs more than aspirin, and IPSET-thrombosis answers it better than platelet count alone.","Hydroxyurea remains first line for high-risk disease because PT-1 showed fewer arterial clots and less bleeding than anagrelide.","Interferons give molecular responses in JAK2- and CALR-mutated ET and are the choice in younger patients and pregnancy.","Bomedemstat is the first new cytoreductive drug in a phase 3 trial against hydroxyurea in two decades.","Mutant-CALR antibodies (INCA033989 and others) are the first treatments that target the ET clone itself, in early trials."],"history":[{"year":1934,"title":"Epstein and Goedel describe haemorrhagic thrombocythaemia","note":"The first account of a primary platelet disorder with bleeding and clotting.","refs":[]},{"year":1951,"title":"Dameshek groups the myeloproliferative disorders","refs":["myeloproliferative-neoplasms"]},{"year":2005,"title":"JAK2 V617F found in half of ET","refs":["jak2-v617f"]},{"year":2005,"title":"PT-1: hydroxyurea beats anagrelide","note":"In 809 high-risk patients hydroxyurea plus aspirin gave fewer arterial clots, less bleeding and less progression to myelofibrosis than anagrelide plus aspirin.","refs":["pt-1","hydroxyurea","anagrelide"]},{"year":2013,"title":"CALR mutations discovered","note":"Klampfl and Nangalia find CALR exon 9 mutations in most JAK2-negative ET and myelofibrosis.","refs":[]},{"year":2016,"title":"WHO separates prefibrotic myelofibrosis from ET","note":"Marrow histology now distinguishes true ET from early myelofibrosis, which carries a worse outlook.","refs":[]},{"year":2017,"title":"MAJIC-ET: ruxolitinib not superior","note":"Ruxolitinib matched but did not beat best available therapy after hydroxyurea failure, though it eased symptoms.","refs":["majic-et","ruxolitinib"]},{"year":2023,"title":"Bomedemstat enters phase 3","note":"Merck starts the Shorespan-007 trial against hydroxyurea in high-risk ET.","refs":["bomedemstat"]}],"pipeline":["bomedemstat","ropeginterferon-alfa-2b"],"openProblems":["No treatment has been shown to prevent progression to myelofibrosis or leukaemia.","Very low-risk patients receive nothing and low-risk patients aspirin, but the evidence for aspirin in CALR-mutated low-risk disease is thin and bleeding may outweigh benefit.","Prefibrotic myelofibrosis is still often misdiagnosed as ET, and the two need different counselling.","Pregnancy management rests on small series; interferon is preferred but randomised data are lacking."],"parent":"myeloproliferative-neoplasms"},{"id":"esthesioneuroblastoma","kind":"cancer","name":"Esthesioneuroblastoma (olfactory neuroblastoma)","aka":["Olfactory neuroblastoma","ONB","Esthesioneuroepithelioma","Neuroblastoma of the olfactory epithelium"],"tldr":"Esthesioneuroblastoma is a rare cancer of the nasal cavity and sinuses that arises from the smell-sensing olfactory nerve lining at the roof of the nose, next to the brain. It is treated with surgery through the nose or skull base followed by radiotherapy, with chemotherapy added for high-grade or widespread tumours, and because it can return a decade or more later patients are followed for life.","summary":"Esthesioneuroblastoma arises from the olfactory neuroepithelium of the upper nasal vault and cribriform plate, and its position against the anterior skull base means it grows into the orbit and the frontal lobes as readily as into the sinuses. It presents with nasal obstruction, bleeding and loss of smell, and is staged by the Kadish system (A: nasal cavity; B: paranasal sinuses; C: beyond, including orbit and skull base; D: nodal or distant metastases, added later) and graded by Hyams (I to IV) on the degree of differentiation, rosettes, necrosis and mitotic activity; Hyams grade is the strongest predictor of survival, with low-grade tumours behaving indolently and high-grade tumours recurring early and spreading to neck nodes and distant sites. Immunohistochemistry (synaptophysin, chromogranin, S100 sustentacular cells) separates it from sinonasal undifferentiated carcinoma, NUT carcinoma, melanoma and lymphoma, which share the site. Most tumours express somatostatin receptor 2, which allows DOTATATE PET imaging and, in relapse, radioligand therapy; IDH2 mutations, typical of sinonasal undifferentiated carcinoma, occur in a subset of high-grade esthesioneuroblastomas.\n\nTreatment is multimodal. Craniofacial resection through a combined transfacial and transcranial approach was the standard from the 1970s, and expanded endonasal endoscopic resection with skull base reconstruction now achieves equivalent margins with less morbidity in experienced hands; postoperative radiotherapy is recommended for almost all patients because it improves local control, and intensity-modulated or proton therapy spares the optic pathways and brain. Chemotherapy, usually cisplatin with etoposide, is given as induction for Kadish C and D or Hyams III to IV tumours, sometimes with radiotherapy for unresectable disease, and elective neck irradiation is considered for high-grade tumours because late nodal recurrence is common. Recurrence occurs in up to a third of patients, often years or decades later, so surveillance MRI continues indefinitely; relapses are treated with repeat surgery, re-irradiation or radioligand therapy with lutetium-177 dotatate where the tumour takes up the tracer, and platinum-etoposide or temozolomide for metastatic disease. Because of the tumour's rarity, care belongs in a skull base team, and prospective data are limited to registry series.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Esthesioneuroblastoma","links":[{"label":"NCCN Head and Neck Cancers (ethmoid sinus)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Esthesioneuroblastoma"}],"tags":["subtype-page","head-and-neck"],"related":["sinonasal-undifferentiated-carcinoma","sinonasal","neuroblastoma","nut-carcinoma"],"cancers":[],"sections":[],"technologies":["robotic-surgery","imrt-igrt","proton-therapy","sstr-pet","prrt","radioligand-therapy","mri","ct","histopathology-ihc"],"targets":["sstr2"],"drugs":["cisplatin","etoposide","platinum-etoposide","temozolomide","lutathera"],"companies":[],"institutions":[],"pathways":[],"terms":["head-neck-subsites","rare-cancers","re-irradiation","staging-systems","chemoradiation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-dulguerov-esthesioneuroblastoma-meta-analysis-lancet-oncol-2001","paper-kadish-olfactory-neuroblastoma-staging-cancer-1976"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"A rare tumour, a few percent of sinonasal cancers, affecting all ages with peaks in young adults and the middle-aged; slow-growing in its low-grade form, aggressive in its high-grade form, and prone to relapse many years after treatment.","subtypes":["Low-grade esthesioneuroblastoma (Hyams I to II; indolent)","High-grade esthesioneuroblastoma (Hyams III to IV; aggressive, chemotherapy)","Kadish A to B esthesioneuroblastoma (nasal cavity and sinuses; surgery and radiotherapy)","Kadish C esthesioneuroblastoma (orbit or skull base; multimodal)","Kadish D esthesioneuroblastoma (nodal or distant metastases)","Recurrent esthesioneuroblastoma (late; somatostatin-receptor-directed therapy considered)"],"biomarkers":["Hyams grade (I to IV; strongest prognostic factor)","Kadish or modified Kadish stage (A to D)","Synaptophysin, chromogranin and S100 sustentacular cell pattern (diagnosis)","Somatostatin receptor expression and DOTATATE PET uptake (imaging, radioligand eligibility)","IDH2 mutation (subset of high-grade tumours)","Neck node status on MRI or PET-CT"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Endoscopic biopsy with immunohistochemistry, MRI and CT of the sinuses and skull base, neck imaging, DOTATATE PET where available.","refs":["histopathology-ihc","mri","ct","sstr-pet","pet-ct"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers (ethmoid and maxillary sinus tumours)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Resectable disease","approach":"Endoscopic endonasal or craniofacial resection with skull base reconstruction by a skull base team, followed by postoperative radiotherapy (intensity-modulated or proton) for nearly all patients.","refs":["robotic-surgery","imrt-igrt","proton-therapy"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers (ethmoid and maxillary sinus tumours)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"High-grade or advanced disease (Hyams III to IV, Kadish C to D)","approach":"Induction cisplatin and etoposide, then surgery and radiotherapy or definitive chemoradiotherapy; elective neck irradiation considered.","refs":["cisplatin","etoposide","platinum-etoposide","imrt-igrt","chemoradiation"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers (ethmoid and maxillary sinus tumours)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Recurrent or metastatic disease","approach":"Repeat surgery or re-irradiation for local relapse; lutetium-177 dotatate for somatostatin-receptor-positive disease; platinum-etoposide or temozolomide; trials.","refs":["re-irradiation","lutathera","prrt","platinum-etoposide","temozolomide"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers (ethmoid and maxillary sinus tumours)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Follow-up","approach":"MRI surveillance indefinitely because of late relapse; management of anosmia, cerebrospinal fluid leak and visual effects.","refs":["mri"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers (ethmoid and maxillary sinus tumours)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}}],"stateOfArt":["Endoscopic skull base surgery has replaced open craniofacial resection for most tumours with less morbidity.","Hyams grade guides who needs chemotherapy.","Somatostatin receptor imaging and radioligand therapy offer a targeted option in relapse."],"history":[{"year":1924,"title":"Berger and Luc describe esthesioneuroepitheliome olfactif","refs":[]},{"year":1976,"title":"Kadish staging system published","refs":["staging-systems"]},{"year":1988,"title":"Hyams grading system introduced","refs":[]},{"year":1992,"title":"Dulguerov and Calcaterra propose a TNM-based staging","refs":["staging-systems"]},{"year":2010,"title":"Endoscopic endonasal resection shown equivalent to craniofacial resection in series","refs":[]},{"year":2020,"title":"Lutetium-177 dotatate reported in relapsed somatostatin-receptor-positive esthesioneuroblastoma","refs":["lutathera"]}],"pipeline":["proton-therapy","lutathera","prrt"],"openProblems":["No prospective trial has ever been conducted; every recommendation rests on series.","Late relapse after ten or more years makes cure hard to define.","The role and timing of chemotherapy in intermediate-grade tumours is unclear.","Elective neck treatment is debated."],"parent":"sinonasal"},{"id":"ewing-sarcoma","kind":"cancer","name":"Ewing sarcoma","aka":[],"tldr":"Ewing sarcoma is a bone and soft-tissue cancer of teenagers driven by a single fusion gene, EWSR1-FLI1. Intensive chemotherapy with surgery or radiation cures most localised cases; disease that has spread at diagnosis, and relapse, remain hard to treat, and no drug against the fusion protein itself has yet succeeded.","summary":"Ewing sarcoma is defined by FET-ETS fusions, EWSR1-FLI1 in ~85% and EWSR1-ERG in ~10%, which act as aberrant transcription factors at GGAA microsatellites; the genome is otherwise quiet (STAG2, CDKN2A, TP53 alterations carry shorter survival). It arises in bone (pelvis, femur, chest wall) or soft tissue in adolescents and young adults.\n\nTreatment is multimodal: interval-compressed VDC/IE (vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide) every 2 weeks (AEWS0031), which Euro Ewing 2012 showed superior to VIDE; local control by surgery, radiotherapy or both; and metastatic disease treated with the same backbone plus whole-lung irradiation, with high-dose busulfan-melphalan benefiting selected high-risk patients (Euro-EWING 99 R2). Relapse is treated with irinotecan-temozolomide, high-dose ifosfamide or topotecan-cyclophosphamide, ranked by the rEECur adaptive trial (high-dose ifosfamide best). Targeted attempts (IGF-1R antibodies, TK216 against EWS-FLI1, PARP inhibitors) have not succeeded; lurbinectedin and combinations are in trials.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Ewing_sarcoma","links":[{"label":"NCCN Guidelines: Bone Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1418"},{"label":"NCI PDQ: Ewing sarcoma","url":"https://www.cancer.gov/types/bone/patient/ewing-treatment-pdq"}],"tags":["gap-fill","paediatric","sarcoma","aya"],"related":["osteosarcoma","rhabdomyosarcoma","chondrosarcoma","synovial-sarcoma"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","imrt-igrt","limb-salvage-surgery","proton-therapy","autologous-stem-cell-transplant","protac-degrader","car-t"],"targets":["ewsr1-fli1","tp53","parp"],"drugs":["vincristine","doxorubicin","cyclophosphamide","ifosfamide","etoposide","irinotecan","temozolomide","topotecan","lurbinectedin","docetaxel","tk216"],"companies":["pharmamar","jazz","childrens-oncology-group"],"institutions":[],"pathways":["p53-cell-cycle"],"terms":["gene-fusion","histological-response-induction"],"trials":["ccss","cabone","regobone","sarc028"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["journal-of-adolescent-and-young-adult-oncology"],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Ewing sarcoma is the second most common bone cancer in children and young adults; ~200-250 cases per year in the US, rare in people of African or East Asian ancestry; survival ~75% localised, ~30% metastatic.","subtypes":["Skeletal Ewing sarcoma","Extraosseous Ewing sarcoma","EWSR1-FLI1 vs EWSR1-ERG fusion","Round cell sarcomas with EWSR1-non-ETS, CIC or BCOR fusions (separate WHO entities)"],"biomarkers":["EWSR1-FLI1 / EWSR1-ERG fusion (FISH, RT-PCR, RNA-seq)","CD99 membranous staining, NKX2-2","Metastatic status (lung vs bone/marrow)","Histologic response to induction","STAG2 loss, TP53 mutation, CDKN2A deletion (shorter survival)","ctDNA fusion detection (emerging)"],"standardOfCare":[{"setting":"Localised","approach":"Interval-compressed VDC/IE ×14 cycles (AEWS0031 / Euro Ewing 2012) with surgery ± radiotherapy (or definitive RT 55.8 Gy) after 6 induction cycles.","refs":["vincristine","doxorubicin","cyclophosphamide","ifosfamide","etoposide","imrt-igrt","limb-salvage-surgery","aews0031"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Bone Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1418"}},{"setting":"Metastatic (lung only)","approach":"Same chemotherapy plus whole-lung irradiation; busulfan-melphalan high-dose therapy in selected patients (Euro-EWING 99 R2pulm equivocal).","refs":["vincristine","doxorubicin","cyclophosphamide","ifosfamide","etoposide","autologous-stem-cell-transplant"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Bone Cancer"}},{"setting":"Metastatic (bone/marrow)","approach":"Chemotherapy with palliative-intent local therapy; survival <20%; trials strongly preferred.","refs":["vincristine","doxorubicin","cyclophosphamide"]},{"setting":"Relapsed","approach":"High-dose ifosfamide (rEECur), irinotecan-temozolomide, topotecan-cyclophosphamide, gemcitabine-docetaxel; local therapy; trials.","refs":["ifosfamide","irinotecan","temozolomide","topotecan","cyclophosphamide"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Bone Cancer"}}],"stateOfArt":["Interval compression (chemotherapy every 2 rather than 3 weeks) improved survival without new drugs (AEWS0031, Euro Ewing 2012).","rEECur is the first randomised trial in relapsed Ewing sarcoma and ranked four regimens with high-dose ifosfamide on top.","EWSR1-FLI1 is an 'undruggable' transcription factor; degraders, LSD1 inhibitors and menin/EWS-FLI1 interactome drugs are the research directions.","International cooperation (COG, Euro Ewing) is the only way trials complete."],"history":[{"year":1921,"title":"James Ewing describes 'diffuse endothelioma of bone'","refs":[]},{"year":1974,"title":"IESS-I: adjuvant VAC + doxorubicin raises survival from ~10% to ~60%","refs":["vincristine","doxorubicin","cyclophosphamide"]},{"year":1992,"title":"EWSR1-FLI1 fusion cloned (Delattre, Nature)","refs":[]},{"year":2003,"title":"INT-0091: adding ifosfamide-etoposide improves survival (Grier, NEJM)","refs":["ifosfamide","etoposide"]},{"year":2012,"title":"AEWS0031: interval compression improves EFS (Womer, JCO)","refs":[]},{"year":2018,"title":"Euro-EWING 99 R2: busulfan-melphalan benefit in high-risk localised disease","refs":["autologous-stem-cell-transplant"]},{"year":2022,"title":"Euro Ewing 2012: VDC/IE superior to VIDE (Lancet)","refs":[]},{"year":2022,"title":"rEECur: high-dose ifosfamide best of four relapse regimens","refs":["ifosfamide"]}],"pipeline":["lurbinectedin","ifosfamide","car-t","kc1036"],"openProblems":["Metastatic-to-bone and relapsed disease: survival under 20-30%.","EWSR1-FLI1 remains undrugged after 30 years.","Late effects: cardiotoxicity, infertility, secondary leukaemia (etoposide, alkylators), radiation-induced sarcoma.","Ancestry-linked incidence differences (GGAA microsatellite polymorphism) unexplained."],"parent":"sarcoma"},{"id":"extensive-stage-sclc","kind":"cancer","name":"Extensive-stage small-cell lung cancer","aka":["ES-SCLC","Extensive-disease small-cell lung cancer","Metastatic small-cell lung cancer","Stage IV small-cell lung cancer"],"tldr":"Small-cell lung cancer that has spread responds fast to chemotherapy but almost always returns within a year. Adding an immunotherapy antibody to first-line chemotherapy helps a minority live for years, and the T-cell engager tarlatamab, which points immune cells at the DLL3 protein on the cancer, has for the first time lengthened life after relapse.","summary":"Extensive-stage small-cell lung cancer has been treated with platinum plus etoposide since the 1980s, with response rates of 60 to 70 percent but relapse within months, and thirty years of trials of added drugs, maintenance and dose intensity failed. IMpower133 (2018) was the first success: adding atezolizumab to carboplatin-etoposide lengthened median overall survival from 10.3 to 12.3 months (hazard ratio 0.70), and CASPIAN (2019) did the same with durvalumab (13.0 versus 10.3 months, hazard ratio 0.73); both were approved in 2019 and 2020 and a long tail of about 15 percent of patients alive at three years appeared. Chinese trials followed with serplulimab (ASTRUM-005, 15.4 versus 10.9 months, hazard ratio 0.63), adebrelimab and benmelstobart. IMforte (2025) then showed that adding lurbinectedin to atezolizumab maintenance after induction extended survival from 10.6 to 13.2 months (hazard ratio 0.73), approved in October 2025.\n\nSecond-line treatment was topotecan, with response rates around 20 percent, until lurbinectedin received accelerated approval in 2020 on a 35 percent response rate. Tarlatamab, a bispecific T-cell engager that binds DLL3 on small-cell cells and CD3 on T cells, produced a 40 percent response rate in DeLLphi-301 (2023) with cytokine release syndrome in about half, mostly mild, and received accelerated approval in May 2024; DeLLphi-304 (2025) then showed it lengthened median overall survival to 13.6 months against 8.3 months with chemotherapy (hazard ratio 0.60), the first randomised survival gain after relapse in this disease, and it is now the standard second-line treatment. The B7-H3 antibody-drug conjugate ifinatamab deruxtecan (IDeate-Lung02) and further DLL3 engagers are in phase 3.\n\nRadiotherapy still has roles: prophylactic cranial irradiation improved survival when brain imaging was not routine (Slotman 2007) but not in the Japanese trial with MRI surveillance (Takahashi 2017), so MRI surveillance is increasingly preferred, and thoracic consolidation radiotherapy helps patients with residual chest disease. Open questions are why only a minority benefit durably from immunotherapy, whether the transcription factor subtypes (ASCL1, NEUROD1, POU2F3, inflamed) can direct treatment, and how to move tarlatamab and other DLL3 agents into first line.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Small-cell_carcinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Small-cell_carcinoma"},{"label":"NCCN Guidelines: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}],"tags":["subtype-page","lung"],"related":["limited-stage-sclc"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","t-cell-engager","adc","cytotoxic-chemotherapy","platinum","topoisomerase-inhibitors","prophylactic-cranial-irradiation","imrt-igrt","mri","pet-ct","targeted-alpha-therapy"],"targets":["dll3","pdl1","pd1","b7h3","tp53"],"drugs":["platinum-etoposide","carboplatin","cisplatin","etoposide","atezolizumab","durvalumab","serplulimab","adebrelimab","benmelstobart","lurbinectedin","tarlatamab","topotecan","ifinatamab-deruxtecan","ryz101"],"companies":["roche-genentech","astrazeneca","amgen","jazz","pharmamar","henlius","daiichi-sankyo","merck"],"institutions":["mskcc","md-anderson"],"pathways":["sclc-signalling","p53-cell-cycle","pd1-checkpoint","apoptosis-bcl2"],"terms":["limited-extensive-stage","maintenance-therapy","consolidation-therapy","crs","icans","step-up-dosing","pci-term","brain-metastases","platinum-sensitivity","sclc-molecular-subtypes"],"trials":["impower133","caspian","astrum-005","imforte","dellphi-304","dellphi-305","ideate-lung02","slotman-pci-es-sclc","takahashi-pci","dllevate","nct05060016"],"people":["luis-paz-ares","charles-rudin","martin-reck","cheng-ying"],"bottlenecks":[],"keyPapers":["paper-dellphi-301-nejm-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"About 70 percent of small-cell lung cancers are extensive stage at diagnosis, spread beyond one side of the chest, most often to liver, bone, brain and adrenal glands; median survival was about 10 months with chemotherapy alone and is now 12 to 15 months with chemoimmunotherapy, with about one in eight patients alive at three years.","subtypes":["Extensive-stage small-cell lung cancer, first line (platinum-etoposide plus atezolizumab or durvalumab)","Extensive-stage small-cell disease with brain metastases at diagnosis","Relapsed small-cell lung cancer, platinum-sensitive (relapse more than 90 days after chemotherapy)","Relapsed small-cell lung cancer, platinum-resistant or refractory","Small-cell lung cancer transformed from EGFR-mutated adenocarcinoma","Neuroendocrine subtypes SCLC-A, SCLC-N, SCLC-P and SCLC-I (research)"],"biomarkers":["Stage by PET-CT and brain MRI","Platinum-free interval at relapse (sensitive versus resistant)","DLL3 expression (nearly universal; not required for tarlatamab)","B7-H3 (ifinatamab deruxtecan trials)","Transcription factor subtype and SLFN11 (research)","PD-L1 and tumour mutational burden (not predictive in small-cell disease)"],"standardOfCare":[{"setting":"First line","approach":"Four cycles of carboplatin or cisplatin plus etoposide with atezolizumab (IMpower133) or durvalumab (CASPIAN), then maintenance immunotherapy until progression; lurbinectedin added to atezolizumab maintenance (IMforte); serplulimab, adebrelimab or benmelstobart in China.","refs":["platinum-etoposide","carboplatin","cisplatin","etoposide","atezolizumab","impower133","durvalumab","caspian","lurbinectedin","imforte","serplulimab","astrum-005","adebrelimab","benmelstobart","maintenance-therapy"],"guideline":{"version":"NCCN Guidelines: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}},{"setting":"Second line","approach":"Tarlatamab (DeLLphi-304) with inpatient monitoring for cytokine release syndrome during the first doses; lurbinectedin or topotecan as alternatives; platinum-etoposide rechallenge if relapse is more than six months after first line.","refs":["tarlatamab","dellphi-304","t-cell-engager","crs","icans","step-up-dosing","lurbinectedin","topotecan","platinum-etoposide"],"guideline":{"version":"NCCN Guidelines: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}},{"setting":"Brain","approach":"MRI surveillance every three months or prophylactic cranial irradiation after response to first-line treatment; whole-brain or stereotactic radiotherapy for metastases.","refs":["prophylactic-cranial-irradiation","pci-term","slotman-pci-es-sclc","takahashi-pci","mri","wbrt","radiosurgery-srs"],"guideline":{"version":"NCCN Guidelines: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}},{"setting":"Thoracic consolidation","approach":"Consolidative thoracic radiotherapy (30 Gy in 10 fractions) for patients with residual chest disease after chemotherapy.","refs":["imrt-igrt","hypofractionated-radiotherapy","consolidation-therapy"],"guideline":{"version":"NCCN Guidelines: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}}],"stateOfArt":["Chemoimmunotherapy first line (IMpower133, CASPIAN) with a tail of about 15 percent alive at three years.","Tarlatamab second line: median survival 13.6 versus 8.3 months against chemotherapy in DeLLphi-304, the first randomised gain after relapse.","Lurbinectedin plus atezolizumab maintenance (IMforte) approved in 2025.","B7-H3 antibody-drug conjugates and further DLL3 engagers in phase 3; subtype-directed therapy in research."],"history":[{"year":1985,"title":"Cisplatin plus etoposide becomes the standard chemotherapy","refs":["platinum-etoposide","cisplatin","etoposide"]},{"year":1996,"title":"Topotecan approved for relapsed small-cell lung cancer","refs":["topotecan"]},{"year":2007,"title":"Slotman: prophylactic cranial irradiation improves survival in extensive stage when brain imaging is not routine","refs":["slotman-pci-es-sclc","prophylactic-cranial-irradiation"]},{"year":2017,"title":"Takahashi: no survival benefit from prophylactic cranial irradiation with MRI surveillance","refs":["takahashi-pci","mri"]},{"year":2018,"title":"IMpower133: atezolizumab plus chemotherapy, the first survival gain in decades","refs":["impower133","atezolizumab","luis-paz-ares"]},{"year":2019,"title":"CASPIAN: durvalumab plus chemotherapy","refs":["caspian","durvalumab","luis-paz-ares"]},{"year":2020,"title":"Lurbinectedin approved second line on a 35 percent response rate","refs":["lurbinectedin","jazz","pharmamar"]},{"year":2022,"title":"ASTRUM-005: serplulimab plus chemotherapy in China","refs":["astrum-005","serplulimab","cheng-ying","henlius"]},{"year":2024,"title":"Tarlatamab accelerated approval after DeLLphi-301","refs":["tarlatamab","paper-dellphi-301-nejm-2023","amgen"]},{"year":2025,"title":"DeLLphi-304: tarlatamab lengthens survival after relapse; IMforte: lurbinectedin maintenance approved","refs":["dellphi-304","tarlatamab","imforte","lurbinectedin"]}],"pipeline":["ifinatamab-deruxtecan","ideate-lung02","dellphi-305","ryz101","zl-1310","dllevate","idea-sclc-subtype-directed","tarlatamab-vs-idxd-sequence","chemo-io-then-maintenance-sclc","idea-mri-surveillance-replaces-pci"],"openProblems":["No biomarker identifies the minority who gain long-term benefit from immunotherapy; PD-L1 and mutational burden do not work in small-cell disease.","Tarlatamab needs inpatient monitoring for cytokine release syndrome, which limits access outside specialist centres.","Whether the transcription factor subtypes can direct treatment is unproven.","Brain metastases remain common and prophylactic irradiation trades cognition for a benefit that is uncertain with MRI surveillance."],"parent":"sclc"},{"id":"extragonadal-germ-cell-tumour","kind":"cancer","name":"Extragonadal germ cell tumour","aka":["Extragonadal Germ Cell Tumor","Extragonadal germ cell tumor","Mediastinal germ cell tumour","Retroperitoneal germ cell tumour","Primary mediastinal nonseminomatous germ cell tumour"],"tldr":"Extragonadal germ cell tumours are the same cancers as testicular germ cell tumours but arising in the midline of the body, most often the chest or the back of the abdomen. Seminomas are highly curable with chemotherapy; non-seminomas of the chest are the hardest germ cell tumours to cure and are treated with intensive chemotherapy followed by surgery.","summary":"Germ cell tumours occasionally arise from germ cells left along the midline during development, in the mediastinum, retroperitoneum, or the pineal and suprasellar regions of the brain, without a testicular primary. They are diagnosed by biopsy or by the tumour markers alpha-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase, and treated on the same principles as testicular cancer: cisplatin-based chemotherapy, usually BEP (bleomycin, etoposide, cisplatin) for three or four cycles, followed by surgery to remove residual masses. Retroperitoneal and mediastinal seminomas do as well as their testicular counterparts, but primary mediastinal non-seminomatous tumours are classed as poor risk by the IGCCCG system, carry associations with Klinefelter syndrome and with haematological cancers, and are the main setting where high-dose chemotherapy with stem cell rescue is considered at relapse.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Germ_cell_tumor","links":[{"label":"NCI: Extragonadal germ cell tumors","url":"https://www.cancer.gov/types/extragonadal-germ-cell"}],"tags":["rare"],"related":["testicular","paediatric-germ-cell-tumours"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["bleomycin","etoposide","cisplatin","ifosfamide","vinblastine"],"companies":[],"institutions":[],"pathways":[],"terms":["afp","tumour-markers","autologous-transplant"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Rare: only a few percent of germ cell tumours arise outside the testis or ovary, most in the chest (mediastinum) or the back of the abdomen (retroperitoneum) in young men; no separate GLOBOCAN count.","subtypes":["Mediastinal seminoma","Primary mediastinal non-seminomatous germ cell tumour","Retroperitoneal germ cell tumour","Intracranial germ cell tumours (pineal, suprasellar)","Sacrococcygeal teratoma (infants)"],"biomarkers":["Alpha-fetoprotein (AFP)","Human chorionic gonadotropin (hCG)","Lactate dehydrogenase (LDH)","IGCCCG risk group (mediastinal non-seminoma is poor risk)","Isochromosome 12p"],"standardOfCare":[{"setting":"Seminoma (mediastinal or retroperitoneal)","approach":"BEP for three cycles or EP for four; radiotherapy only for small retroperitoneal disease; PET to assess residual masses.","refs":["bleomycin","etoposide","cisplatin"]},{"setting":"Non-seminoma, retroperitoneal","approach":"BEP for three or four cycles by IGCCCG risk group, then resection of residual masses over one centimetre.","refs":["bleomycin","etoposide","cisplatin"]},{"setting":"Non-seminoma, mediastinal (poor risk)","approach":"Four cycles of BEP or VIP, then surgery of residual disease; consider high-dose chemotherapy with autologous stem cell rescue at relapse; treat in a specialist centre.","refs":["etoposide","ifosfamide","cisplatin"]}],"stateOfArt":["Extragonadal seminoma is cured as often as testicular seminoma: the 2002 international pooled analysis of 635 patients reported 88 percent overall survival whether the primary was mediastinal or retroperitoneal.","Non-seminoma depends on where it starts: about 63 percent of patients with retroperitoneal primaries and 49 percent with mediastinal primaries were alive in the same analysis, which is why primary mediastinal non-seminoma sits in the IGCCCG poor-risk group by definition.","Adverse factors for non-seminoma are liver, lung or brain metastases, a mediastinal primary and a raised beta-hCG; these guide the choice of four cycles and early referral to a high-volume centre.","Salvage is the open question: the randomised TIGER trial comparing conventional-dose TIP with high-dose chemotherapy and stem cell rescue has finished recruiting and its result will set the standard for relapse."],"history":[{"year":2002,"title":"International pooled analysis of extragonadal germ cell tumours","note":"Bokemeyer and colleagues pool 635 patients from eleven centres: seminomas do as well as testicular disease, mediastinal non-seminomas do worst, and prognostic factors are defined.","refs":["cisplatin","etoposide"]},{"year":2015,"title":"TIGER trial opens","note":"The Alliance and European groups randomise first-relapse germ cell tumours between conventional-dose TIP and high-dose TI-CE with stem cell rescue, the first randomised test of high-dose salvage since the 1990s.","refs":["tiger-trial"]},{"year":1977,"title":"Cisplatin combinations cure disseminated germ cell tumours","note":"Einhorn's PVB regimen (cisplatin, vinblastine, bleomycin) turned a usually fatal cancer into a curable one.","refs":["cisplatin","vinblastine","bleomycin"]},{"year":1987,"title":"BEP replaces PVB","note":"Etoposide in place of vinblastine gave equal cure with less neurotoxicity in the Indiana and SECSG trials.","refs":["etoposide"]},{"year":1997,"title":"IGCCCG classification","note":"The International Germ Cell Cancer Collaborative Group defined good, intermediate and poor risk; a mediastinal non-seminomatous primary alone places a patient in the poor-risk group.","refs":[]}],"pipeline":["tiger-trial","autologous-stem-cell-transplant"],"openProblems":["Cure rates for mediastinal non-seminoma remain well below those of testicular primaries.","The role of high-dose chemotherapy in first-line poor-risk disease is still being tested (TIGER trial)."]},{"id":"extrahepatic-cholangiocarcinoma","kind":"cancer","name":"Extrahepatic cholangiocarcinoma (perihilar and distal)","aka":["Perihilar cholangiocarcinoma","Klatskin tumour","Hilar cholangiocarcinoma","Distal cholangiocarcinoma","Common bile duct cancer","eCCA"],"tldr":"Extrahepatic cholangiocarcinoma blocks the main bile ducts outside the liver and shows itself as jaundice. Perihilar tumours need part of the liver removed with the duct and distal tumours a Whipple operation; where surgery is impossible, stenting relieves the jaundice and chemotherapy with immunotherapy follows, with HER2-directed antibodies for the one in six tumours that carry that target.","summary":"Extrahepatic cholangiocarcinoma is divided at the cystic duct into perihilar tumours, described by Klatskin in 1965 and classified by Bismuth and Corlette according to how far they extend into the right and left hepatic ducts, and distal tumours of the common bile duct. Both present with painless jaundice, pale stools, dark urine and itching, often with cholangitis, and CA 19-9 is raised but unreliable in the presence of obstruction. Primary sclerosing cholangitis, choledochal cysts and liver flukes are risk factors. The genome differs from intrahepatic disease: KRAS and TP53 mutations dominate, HER2 amplification occurs in about one in six, and FGFR2 fusions and IDH1 mutations are rare.\n\nSurgery is the only cure and is among the most demanding in abdominal oncology: perihilar tumours require resection of the bile duct with the ipsilateral hemiliver and caudate lobe, often after portal vein embolisation to grow the remnant and biliary drainage to reverse jaundice, while distal tumours are removed by pancreaticoduodenectomy. Clear margins are achieved in perhaps half of cases. Adjuvant capecitabine for six months follows BILCAP. For unresectable perihilar tumours in primary sclerosing cholangitis or under 3 cm, the Mayo protocol of chemoradiation followed by liver transplantation achieves long-term survival in selected patients and is offered in a few centres.\n\nUnresectable disease is treated with gemcitabine and cisplatin plus durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966), the biliary standards since 2022; FOLFOX is the second line after ABC-06, and liposomal irinotecan failed in NALIRICC. HER2-positive tumours respond to zanidatamab, which had a response rate of 41 percent in HERIZON-BTC-01 and gained accelerated FDA approval in 2024, and to trastuzumab deruxtecan; the phase 3 HERIZON-BTC-302 tests zanidatamab in the first line. Biliary stenting, endoscopic or percutaneous, and treatment of cholangitis are as important to survival as the anticancer drugs, since obstruction and infection are what usually end treatment.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Klatskin_tumor","links":[{"label":"TOPAZ-1 (NEJM Evidence 2022)","url":"https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200015"},{"label":"HERIZON-BTC-01 (Lancet Oncology 2023)","url":"https://pubmed.ncbi.nlm.nih.gov/37276871/"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Klatskin_tumor"}],"tags":["subtype-page"],"related":["intrahepatic-cholangiocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["abc-06"],"people":[],"bottlenecks":[],"keyPapers":["paper-bilcap-lancet-oncol-2019","paper-abc-02-gemcitabine-cisplatin-nejm-2010","paper-topaz-1-nejm-evidence-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Cancers of the bile ducts outside the liver, from the hilum where the ducts join to the lower duct near the pancreas; perihilar tumours are the commonest cholangiocarcinoma overall, and they present with jaundice, which brings both early symptoms and the risks of biliary obstruction.","subtypes":["Perihilar (Klatskin) cholangiocarcinoma, Bismuth-Corlette types I to IV","Distal (common bile duct) cholangiocarcinoma","HER2-positive extrahepatic cholangiocarcinoma (zanidatamab)","Extrahepatic cholangiocarcinoma in primary sclerosing cholangitis (transplant protocols)","Periductal-infiltrating versus papillary growth"],"biomarkers":["Bismuth-Corlette type and vascular involvement on MRI and CT (resectability)","CA 19-9 after biliary decompression","HER2 amplification and overexpression (about one in six)","KRAS and TP53 (prognostic)","Microsatellite instability and BRAF V600E (rare, actionable)","Bilirubin and future liver remnant volume before surgery"],"standardOfCare":[{"setting":"Diagnosis and jaundice","approach":"MRI with cholangiography and CT for staging, endoscopic brushing or biopsy, and biliary drainage by stent or percutaneous route with antibiotics for cholangitis.","refs":["mri","ct","endoscopy","biliary-stenting-drainage","ca19-9"]},{"setting":"Resectable perihilar","approach":"Bile duct resection with hemihepatectomy and caudate lobectomy after portal vein embolisation and drainage where needed, then six months of capecitabine (BILCAP).","refs":["hepatectomy","lymphadenectomy","bilcap","capecitabine"]},{"setting":"Resectable distal","approach":"Pancreaticoduodenectomy (Whipple) with lymphadenectomy, then adjuvant capecitabine.","refs":["whipple","lymphadenectomy","bilcap","capecitabine"]},{"setting":"Unresectable perihilar, selected","approach":"Neoadjuvant chemoradiation followed by liver transplantation under the Mayo protocol in specialist centres.","refs":["liver-transplant-oncology"]},{"setting":"Advanced, first line","approach":"Gemcitabine and cisplatin with durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966).","refs":["topaz-1","keynote-966","abc-02","gemcitabine-cisplatin","durvalumab","pembrolizumab","gemcis-plus-io-btc"]},{"setting":"Advanced, HER2-positive after chemotherapy","approach":"Zanidatamab (HERIZON-BTC-01) or trastuzumab deruxtecan; zanidatamab first line in HERIZON-BTC-302.","refs":["zanidatamab","trastuzumab-deruxtecan","her2","herizon-btc-302"]},{"setting":"Second line without a target","approach":"FOLFOX (ABC-06); pembrolizumab for microsatellite-unstable tumours, dabrafenib-trametinib for BRAF V600E.","refs":["folfox","pembrolizumab","msi","dabrafenib-trametinib"]}],"stateOfArt":["Surgery for perihilar tumours has become safer with portal vein embolisation and staged drainage, but remains the domain of a few high-volume centres.","Immunotherapy with gemcitabine-cisplatin is the first-line standard, and HER2 has become the actionable target of extrahepatic disease as FGFR2 and IDH1 are of intrahepatic.","Liver transplantation after chemoradiation offers cure to a small, carefully selected group with unresectable perihilar tumours."],"history":[{"year":1965,"title":"Klatskin describes adenocarcinoma at the hepatic duct bifurcation","refs":[]},{"year":1975,"title":"Bismuth and Corlette classify perihilar tumours by ductal extension","refs":[]},{"year":2010,"title":"ABC-02: gemcitabine plus cisplatin standard for advanced biliary cancer","refs":["abc-02","gemcitabine-cisplatin"]},{"year":2019,"title":"BILCAP: adjuvant capecitabine after resection","refs":["bilcap","capecitabine"]},{"year":2021,"title":"ABC-06: FOLFOX as second line","refs":["folfox"]},{"year":2022,"title":"TOPAZ-1: durvalumab added to gemcitabine-cisplatin","refs":["topaz-1","durvalumab"]},{"year":2024,"title":"Zanidatamab receives accelerated approval for HER2-positive biliary tract cancer","refs":["zanidatamab","her2"]}],"pipeline":["zanidatamab","herizon-btc-302","trastuzumab-deruxtecan","biliary-stenting-drainage","liver-transplant-oncology"],"openProblems":["Most perihilar tumours are unresectable at presentation, and half of resections leave microscopic disease.","Biliary obstruction and cholangitis, not the cancer's growth, often end treatment.","No targeted therapy exists for the KRAS-mutant majority."],"parent":"cholangiocarcinoma"},{"id":"malt-lymphoma","kind":"cancer","name":"Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)","aka":["MALT lymphoma","Mucosa-associated lymphoid tissue lymphoma","Extranodal marginal zone lymphoma","Extranodal marginal zone lymphoma of MALT","Gastric MALT lymphoma","Ocular adnexal MALT lymphoma","Orbital lymphoma (mostly MALT type)","Extranodal marginal zone lymphoma of MALT (gastric, ocular adnexal, salivary, thyroid, lung, skin)"],"tldr":"MALT lymphoma is a slow-growing lymphoma that starts in lymphoid tissue lining an organ, most often the stomach, where it is usually caused by long-standing Helicobacter pylori infection and can be cured with antibiotics alone. Other sites include the eye socket, salivary glands, thyroid, lung and skin; localised disease is treated with low-dose radiotherapy and widespread disease with rituximab.","summary":"WHO-HAEM5 keeps extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue as the extranodal member of the marginal zone lymphoma family, arising in tissue chronically inflamed by infection or autoimmunity: Helicobacter pylori in the stomach, Sjogren syndrome in the salivary glands, Hashimoto thyroiditis in the thyroid, and Chlamydia psittaci in some ocular adnexal cases (Alaggio 2022; Zucca 2020). The ESMO guideline recommends H. pylori eradication as first treatment for gastric MALT lymphoma whatever the stage, with the t(11;18) translocation predicting failure of antibiotics; even H. pylori-negative gastric disease can respond, with 12 of 13 patients alive and several in remission after antibiotics alone in one centre's series with a median follow-up of 95 months (Annals of Hematology 2015). Whether FDG-PET is useful for staging remains unsettled, with conflicting avidity across 32 studies (Clin Lymphoma Myeloma Leuk 2020).\n\nHow it differs from its parent: the parent page covers the three marginal zone lymphomas together; the extranodal type is the one with an infectious cause to remove, the one treated with involved-site radiotherapy at 24 Gy or less when localised, and the one with organ-specific presentations (gastritis, a salivary mass, an orbital swelling, lung nodules).\n\nHow common: the ESMO guideline gives marginal zone lymphomas as about 5 to 15 percent of non-Hodgkin lymphomas depending on region, with the extranodal type the largest share; no UK figure for the type alone is in the sources read.\n\nTreatment: H. pylori eradication for gastric disease; involved-site radiotherapy for localised disease at other sites; rituximab alone or with chlorambucil or bendamustine for disseminated or relapsed disease; BTK inhibitors (zanubrutinib) and lenalidomide-rituximab as later lines, as on the parent page (Zucca 2020).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/MALT_lymphoma","links":[{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq"},{"label":"Cancer Research UK: types and grades of non-Hodgkin lymphoma","url":"https://www.cancerresearchuk.org/about-cancer/non-hodgkin-lymphoma/types"},{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"Zucca 2020, Annals of Oncology: marginal zone lymphomas, ESMO clinical practice guidelines","url":"https://doi.org/10.1016/j.annonc.2019.10.010"},{"label":"Annals of Hematology 2015: antibiotics as sole management of H. pylori-negative gastric MALT lymphoma","url":"https://doi.org/10.1007/s00277-014-2298-3"},{"label":"Clin Lymphoma Myeloma Leuk 2020: FDG PET in MALT lymphoma, critical review of 32 studies","url":"https://doi.org/10.1016/j.clml.2019.10.006"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["marginal-zone-lymphoma","splenic-marginal-zone-lymphoma","nodal-marginal-zone-lymphoma","primary-cutaneous-marginal-zone-lymphoma","gastric","dlbcl","myeloid-leukaemia-of-down-syndrome","myd88-l265p","ig-tcr-clonality"],"cancers":[],"sections":[],"technologies":["cytogenetics-fish","clonality-testing","histopathology-ihc"],"targets":["malt1","bcl10","birc3","tnfaip3","myd88","cd20"],"drugs":["rituximab","chlorambucil","bendamustine","zanubrutinib","lenalidomide","orelabrutinib","umbralisib"],"companies":[],"institutions":[],"pathways":["inflammation-nfkb","microbiome-tumour"],"terms":["lymphoma-tx-h-pylori-eradication","lymphoma-tx-radiotherapy","lymphoma-tx-watch-and-wait","lymphoma-bio-germinal-centre"],"trials":["fort","augment","zuma-5","nct05100862","nct06082102"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"The commonest marginal zone lymphoma; marginal zone lymphomas together are the third most common non-Hodgkin lymphoma group in the ESMO guideline, and the stomach is the most common MALT site (Zucca 2020; Clin Lymphoma Myeloma Leuk 2020). Cancer Research UK lists marginal zone lymphomas among the low-grade types.","subtypes":["Gastric MALT lymphoma (H. pylori-associated; t(11;18) predicts antibiotic failure)","Ocular adnexal (orbital and conjunctival) MALT lymphoma","Salivary gland MALT lymphoma (Sjogren syndrome)","Thyroid MALT lymphoma (Hashimoto thyroiditis)","Pulmonary MALT lymphoma","Extranodal MALT lymphoma with transformation to diffuse large B-cell lymphoma"],"biomarkers":["Helicobacter pylori status (gastric)","t(11;18) API2-MALT1 translocation","Immunophenotype: CD20 positive, CD5 and CD10 negative","FDG avidity (variable)"],"standardOfCare":[{"setting":"Gastric, H. pylori-positive","approach":"H. pylori eradication first, with endoscopic follow-up; radiotherapy if the lymphoma persists.","refs":["marginal-zone-lymphoma"]},{"setting":"Localised at other sites","approach":"Involved-site radiotherapy (the FoRT trial tested the dose in follicular and marginal zone lymphoma).","refs":["fort","marginal-zone-lymphoma"]},{"setting":"Disseminated or relapsed","approach":"Rituximab alone or with chlorambucil or bendamustine; zanubrutinib or lenalidomide-rituximab later (AUGMENT; MAHOGANY).","refs":["rituximab","chlorambucil","bendamustine","zanubrutinib","lenalidomide","augment","nct05100862"]},{"setting":"Gastric MALT lymphoma: a cancer cured by antibiotics","approach":"Helicobacter pylori eradication is the first treatment for every Helicobacter-positive gastric MALT lymphoma, whatever the stage, and it is a cure in most of them. The observation that made this possible was published in 1993, when eradication produced regression of the lymphoma in five of six patients, and it remains one of the very few instances in oncology in which a course of antibiotics is the definitive treatment of a malignancy.\n\nWhat is given: a standard triple or quadruple eradication regimen chosen by local resistance patterns, typically a proton pump inhibitor with two antibiotics for 10 to 14 days. Eradication is then confirmed, by urea breath test or stool antigen at least four weeks after antibiotics and two weeks off the proton pump inhibitor, because failure of eradication is the commonest reason for failure of the lymphoma to respond.\n\nWhat happens next: endoscopic and histological follow-up every three to six months. Regression is slow and can take twelve to eighteen months, so persistent histological disease in a patient whose Helicobacter has been eradicated and who has no symptoms is watched, not treated. The t(11;18) translocation predicts failure to respond to eradication and is worth testing where it is available. Helicobacter-negative gastric MALT lymphoma is still given eradication therapy in many centres, because some respond, but it is not relied on.","refs":["paper-wotherspoon-h-pylori-malt-lancet-1993","lymphoma-tx-h-pylori-eradication","lymphoma-tx-watch-and-wait","endoscopy","paper-esmo-marginal-zone-lymphoma-zucca-ann-oncol-2020"],"guideline":{"nccn":"Category 1 (Helicobacter eradication, Helicobacter-positive gastric MALT)","version":"ESMO marginal zone lymphomas; NCCN B-Cell Lymphomas","url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-haematological-malignancies"}},{"setting":"Gastric MALT lymphoma that does not respond to eradication, and MALT at other sites","approach":"Where the Helicobacter has been eradicated and the lymphoma persists and is causing symptoms or progressing, radiotherapy is the next treatment: about 24 Gy in 12 fractions to the stomach, which controls the disease in the great majority. Systemic treatment, usually rituximab alone or rituximab with chlorambucil or bendamustine, is used for disseminated disease or where radiotherapy is not possible. Surgery has no routine role.\n\nMALT lymphoma at other sites, salivary gland, thyroid, lung, skin, orbit, breast, is treated on the same principle: a localised, symptomatic site gets 24 Gy, an asymptomatic one can be watched, and disseminated disease gets rituximab-based systemic treatment. Ocular adnexal MALT is sometimes given doxycycline first for Chlamydia psittaci, with response rates that vary widely by region. Salivary gland MALT in Sjogren syndrome and thyroid MALT in Hashimoto thyroiditis are managed jointly with the specialty that treats the underlying autoimmune disease.\n\nThe IELSG-19 trial is the randomised evidence for systemic treatment: five-year event-free survival was 68 per cent with chlorambucil and rituximab, 51 per cent with chlorambucil alone and 50 per cent with rituximab alone, with five-year overall survival of about 90 per cent in each arm.","refs":["lymphoma-tx-radiotherapy","rituximab","chlorambucil","bendamustine","imrt-igrt","paper-esmo-marginal-zone-lymphoma-zucca-ann-oncol-2020"],"guideline":{"version":"ESMO marginal zone lymphomas; NCCN B-Cell Lymphomas; IELSG-19","url":"https://doi.org/10.1200/JCO.2016.70.6994"}}],"stateOfArt":["Gastric MALT lymphoma begins as a lymphoma that still needs its antigen. Removing Helicobacter pylori removes the stimulus and most localised cases regress, which makes it the clearest example in oncology of curing a cancer with antibiotics.","The t(11;18) translocation is what breaks that dependence. It fuses API2 to MALT1 and makes a protein that activates NF-kB on its own, so the lymphoma no longer needs the bacterium. Among 111 patients treated with eradication, 47 of the 48 who regressed completely were negative for the API2-MALT1 transcript, which is why a positive result means eradication alone is not enough whatever the stage.","The related translocations do the same job by other routes, through BCL10 and MALT1, and inactivation of TNFAIP3 removes the brake on the same pathway. MYD88 L265P appears in 9% of MALT lymphomas, feeding NF-kB from the toll-like receptor side."],"history":[],"pipeline":[],"openProblems":[],"parent":"marginal-zone-lymphoma"},{"id":"extranodal-nk-t-cell-lymphoma","kind":"cancer","name":"Extranodal NK/T-cell lymphoma","aka":["Extranodal NK/T-cell lymphoma, nasal type","ENKTL","ENKTCL","Nasal type NK/T-cell lymphoma","NK/T-cell lymphoma","Lethal midline granuloma","Angiocentric lymphoma","Extranodal NK/T-cell lymphoma (EBV)"],"tldr":"An aggressive lymphoma of natural killer cells, always driven by Epstein-Barr virus, that destroys the tissues in the middle of the face: the nose, the palate and the sinuses. It is common in east Asia and Latin America and uncommon in Europe, and it is the one lymphoma in which ordinary anthracycline chemotherapy does not work at all.","summary":"What it is. A lymphoma of natural killer cells, and in a minority of cases of cytotoxic T cells, in which every tumour cell carries Epstein-Barr virus. The virus is part of the definition: a tumour with this appearance that does not carry it is a different disease. The cells grow around and into blood vessels, which cuts off the blood supply to the tissue they sit in, and that is why the disease destroys what it grows in rather than simply displacing it.\n\nWhere it starts and what it does. Most often in the nose and the structures around it: the nasal cavity, the sinuses, the hard palate, the back of the throat. It presents as blockage, bleeding, crusting or a hole in the palate, and it is often treated as sinusitis for months before anybody biopsies it. Extranasal sites include the skin, the gut, the testis and the soft tissues, and disease starting outside the nose behaves worse. WHO-HAEM5 dropped the qualifier nasal type from the name in 2022 for exactly that reason, because the disease is recognised at several extranodal sites; the International Consensus Classification kept it, so a report in 2026 may carry either name.\n\nHow it differs from the rest of the T-cell family, and this is the most important thing on the page. The tumour expresses P-glycoprotein, a pump that throws anthracyclines back out of the cell. Chemotherapy built around doxorubicin, which is the backbone of almost every other lymphoma regimen, therefore does not work here and must not be used. What does work is asparaginase, an enzyme that strips the amino acid asparagine out of the blood; the tumour cannot make its own and dies. WHO-HAEM5 records the consequence plainly: introducing asparaginase-based chemotherapy with radiotherapy markedly improved outcomes in this disease.\n\nTwo near neighbours it is separated from. Intravascular NK/T-cell lymphoma was counted as a form of this disease in the previous classification; in 2022 it was moved to be described alongside aggressive NK-cell leukaemia, because it does not form masses, favours the skin and the central nervous system, is not invariably positive for the virus, and its place is not yet clear. In the other direction, an indolent NK-cell lymphoproliferative disorder of the gut has almost the same surface markers and regresses on its own; what separates them is the virus, which that condition does not carry. WHO-HAEM5 says it is most important not to mistake one for the other.\n\nHow the outlook is estimated. The index in current use is PINK, built from 527 patients treated at 38 hospitals in 11 countries with regimens that contained no anthracycline. Four features predicted survival: age over 60, stage III or IV, involvement of distant lymph nodes, and disease starting outside the nose. Three-year overall survival was 81 per cent with none of them, 62 per cent with one, and 25 per cent with two or more. Adding the level of Epstein-Barr virus DNA in the blood, which is also an independent predictor, gives a second version of the index.\n\nThe treatment is on this page, moved here from the peripheral T-cell lymphoma page once this record existed. Radiotherapy matters more in early disease than in almost any other lymphoma, and delaying it worsens the outcome.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Extranodal_NK/T-cell_lymphoma,_nasal_type","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment, 527 patients from 38 hospitals in 11 countries (Kim, Lancet Oncology 2016)","url":"https://doi.org/10.1016/S1470-2045(15)00533-1"},{"label":"Extranodal NK/T cell lymphoma, nasal type: an update on epidemiology, clinical presentation and natural history in North American and European cases (Current Hematologic Malignancy Reports 2016)","url":"https://doi.org/10.1007/s11899-016-0355-9"},{"label":"Trends in the incidence of the Epstein-Barr virus-associated malignancies extranodal NK/T-cell lymphoma and nasopharyngeal carcinoma in Taiwan (PLoS One 2024)","url":"https://doi.org/10.1371/journal.pone.0315380"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["peripheral-t-cell-lymphoma","adult-t-cell-leukaemia-lymphoma","nasopharyngeal","non-hodgkin-lymphoma","hepatosplenic-t-cell-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","fdg-pet","imrt-igrt","allogeneic-hsct"],"targets":[],"drugs":["asparaginase","pembrolizumab","nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":["ebv-term","plasma-ebv-dna","lymphoma-classification-2022","lymphoma-nodal-versus-extranodal","lymphoma-pit-score","lymphoma-tx-radiotherapy","lymphoma-b-versus-t-cell","lymphoma-tx-regimen-alphabet"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Uncommon everywhere outside east Asia and Latin America. In Taiwan, 872 new diagnoses were recorded between 2008 and 2021 and the age-adjusted incidence fell over that period, with an average annual change of minus 2.47 per cent; the age-specific rate in people aged 45 to 64 fell from 0.46 to 0.32 per 100,000 person-years. In the United States it is commoner among Asian and Pacific Islander and Hispanic people than among non-Hispanic white people, and the published North American and European data are described by the specialists who collected them as very limited. The United Kingdom population series that reports lymphoma by subtype does not list it separately.","subtypes":["Nasal, arising in the nasal cavity, sinuses or palate, which is an extranodal site","Extranasal, arising in the skin, gut, testis or soft tissue, which carries a worse outlook and is a risk factor in the PINK index"],"biomarkers":["Epstein-Barr virus in every tumour cell by EBER in situ hybridisation, which is part of the definition","An NK-cell phenotype: CD56 positive, surface CD3 negative with cytoplasmic CD3-epsilon positive, and cytotoxic granule proteins present","P-glycoprotein expression, which is why anthracycline chemotherapy does not work","Plasma Epstein-Barr virus DNA, which tracks the disease and is an independent predictor of survival","The PINK index: age over 60, stage III or IV, distant lymph node involvement and non-nasal disease","Deletion of 6q21-25, and mutations of the JAK-STAT pathway, epigenetic regulators, TP53, MGA and DDX3X"],"standardOfCare":[{"setting":"Making the diagnosis, and why it is usually late","approach":"The presentation looks like sinusitis: blockage, bleeding, crusting and pain in the nose, often treated with antibiotics and steroids for months. A biopsy taken through the nose is often necrotic and non-diagnostic, so repeat biopsies are common and are not a failure. The diagnosis needs in situ hybridisation for Epstein-Barr-encoded RNA, which is positive in every tumour cell by definition, together with an NK-cell phenotype: CD56 positive, surface CD3 negative with cytoplasmic CD3-epsilon positive, and cytotoxic granule proteins present. A gut lesion with the same markers but no virus is the indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, which regresses on its own; WHO-HAEM5 says it is most important not to mistake one for the other.","refs":["histopathology-ihc","ebv-term","endoscopy","lymphoma-classification-2022"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Staging and the risk score","approach":"PET-CT of the whole body, magnetic resonance imaging of the face and sinuses to map local destruction, examination of the nose and throat, and a measurement of Epstein-Barr virus DNA in the blood, which tracks the disease and is an independent predictor of survival. The index in use is PINK, built from 527 patients treated without anthracyclines at 38 hospitals in 11 countries, which counts age over 60, stage III or IV, involvement of distant lymph nodes, and disease starting outside the nose: three-year overall survival was 81 per cent with none of those, 62 per cent with one and 25 per cent with two or more. Adding the viral DNA level gives a second version, PINK-E.","refs":["fdg-pet","plasma-ebv-dna","lugano-classification","ebv-term"],"guideline":{"version":"PINK (Lancet Oncology 2016); NCCN T-Cell Lymphomas; NCI PDQ","url":"https://doi.org/10.1016/S1470-2045(15)00533-1"}},{"setting":"Extranodal NK/T-cell lymphoma, nasal type: asparaginase, and why anthracyclines do not work","approach":"An Epstein-Barr virus-driven lymphoma that destroys the midline structures of the face, common in east Asia and Latin America and uncommon in Europe. It expresses P-glycoprotein, which pumps anthracyclines out of the cell, so CHOP is ineffective and must not be used. Every effective regimen contains asparaginase, which the tumour cannot resist because it lacks asparagine synthetase.\n\nEarly-stage disease (stage I and II, confined to the upper aerodigestive tract) is treated with radiotherapy at a relatively high dose of about 50 Gy, given concurrently with or sandwiched between asparaginase-containing chemotherapy. Radiotherapy is the single most important component in early disease and delaying it worsens outcome.\n\nAdvanced and relapsed disease is treated with an asparaginase-containing regimen. SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) was tested in 38 patients with newly diagnosed stage IV, relapsed or refractory disease: the overall response rate after two cycles was 79 per cent, complete response 45 per cent, and one-year overall survival 55 per cent, with grade 4 neutropenia in 92 per cent and grade 3 or 4 infection in 61 per cent. Nineteen of the 28 who completed treatment went on to a stem cell transplant. Gentler asparaginase-based regimens such as P-GEMOX and DDGP are widely used in China. Pegylated asparaginase has largely replaced native L-asparaginase. Plasma Epstein-Barr virus DNA is used to monitor response.\n\nPD-1 blockade has substantial activity in relapsed disease and is used where available.","refs":["asparaginase","methotrexate","ifosfamide","etoposide","dexamethasone","gemcitabine","oxaliplatin","imrt-igrt","lymphoma-tx-radiotherapy","pembrolizumab","nivolumab","ebv-term","plasma-ebv-dna","allogeneic-hsct"],"guideline":{"version":"NCCN T-Cell Lymphomas; ESMO; SMILE (JCO 2011)","url":"https://doi.org/10.1200/JCO.2011.35.6287"}}],"stateOfArt":[],"history":[{"year":2011,"title":"An asparaginase regimen tested in advanced and relapsed disease","note":"The SMILE regimen, built around asparaginase and deliberately free of anthracyclines, was tested in newly diagnosed stage IV, relapsed and refractory disease and established asparaginase as the backbone of treatment.","refs":["asparaginase"]},{"year":2016,"title":"The PINK index","note":"Built from 527 patients treated without anthracyclines at 38 hospitals in 11 countries: age over 60, stage III or IV, distant lymph node involvement and non-nasal disease gave three-year overall survival of 81, 62 and 25 per cent across the three risk groups.","refs":["plasma-ebv-dna"]},{"year":2022,"title":"Nasal type dropped from the name","note":"WHO-HAEM5 renamed the entity extranodal NK/T-cell lymphoma, recognising its presentation at several extranodal sites; the International Consensus Classification kept the nasal type qualifier.","refs":["lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["The disease is common in east Asia and Latin America and rare in the countries that run most randomised trials, so the regimens that work best were developed where most of the patients are and are least familiar where the rest of them are treated.","There is no randomised comparison between the asparaginase-containing regimens in use, and they differ substantially in toxicity.","PD-1 blockade produces responses in relapsed disease and has never been tested against anything in a randomised trial in this disease.","The commonest clinical failure is delay: the presentation looks like sinusitis, and the biopsy is often taken months after the symptoms began."],"parent":"peripheral-t-cell-lymphoma"},{"id":"extrapulmonary-nec","kind":"cancer","name":"Extrapulmonary neuroendocrine carcinoma","aka":["Extrapulmonary NEC","Gastroenteropancreatic neuroendocrine carcinoma","GEP-NEC","Extrapulmonary small-cell carcinoma","Large-cell neuroendocrine carcinoma of the gut","Poorly differentiated neuroendocrine carcinoma"],"tldr":"Extrapulmonary neuroendocrine carcinoma is the fast-growing, poorly differentiated form of neuroendocrine cancer arising outside the lung, most often in the bowel, oesophagus, stomach or pancreas. It behaves like small-cell lung cancer and is treated the same way, with platinum and etoposide chemotherapy, and drugs against the DLL3 protein are now in phase 3 trials.","summary":"Neuroendocrine carcinoma is a different disease from the well-differentiated tumours it shares a name with. The WHO classification defines it by poorly differentiated small-cell or large-cell morphology with a Ki-67 above 20 percent and usually far higher, and its genetics follow small-cell lung cancer, with loss of TP53 and RB1 rather than the MEN1, DAXX and ATRX mutations of neuroendocrine tumours; a subset of colorectal carcinomas carry BRAF V600E and a few are microsatellite unstable. Somatostatin receptor expression is usually weak, so FDG PET stages the disease where somatostatin receptor PET stages tumours, and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) combine a carcinoma component with adenocarcinoma or squamous carcinoma. Merkel cell carcinoma of the skin and neuroendocrine prostate cancer are covered on their own pages.\n\nTreatment is borrowed wholesale from small-cell lung cancer. Moertel showed in 1991 that cisplatin with etoposide produced responses in most anaplastic neuroendocrine carcinomas, and platinum-etoposide has been first-line therapy since; the NORDIC NEC series (Annals of Oncology 2013) of 305 patients confirmed that most respond but relapse quickly, and found that carcinomas with a Ki-67 below 55 percent responded less often to platinum yet lived longer, an observation that helped separate grade 3 well-differentiated tumours from true carcinoma. Randomised evidence is scarce: the ECOG-ACRIN EA2142 trial compared capecitabine-temozolomide with platinum-etoposide in high-grade gastroenteropancreatic neoplasms and did not show the oral regimen superior, and the Italian SENECA trial found both CAPTEM and FOLFIRI active in the second line. Localised disease is resected or given chemoradiotherapy with perioperative platinum-etoposide, as in limited-stage small-cell lung cancer.\n\nImmunotherapy and DLL3 are the two openings. The DART basket trial (SWOG S1609) reported responses to nivolumab with ipilimumab in high-grade neuroendocrine carcinoma but not in low-grade tumours, and PD-1 or PD-L1 antibodies are added to first-line chemotherapy by extrapolation from IMpower133 and CASPIAN while dedicated phase 2 trials such as NICE-NEC test the combination directly. DLL3, the surface protein behind tarlatamab's approval in small-cell lung cancer, is expressed by most neuroendocrine carcinomas: the T-cell engagers obrixtamig (DAREON-5, and the phase 3 DAREON-NEC-1 with carboplatin-etoposide in DLL3-positive extrapulmonary carcinoma), peluntamig and ZG006 are in trials that enrol these tumours alongside small-cell lung cancer.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor","links":[{"label":"NORDIC NEC (Annals of Oncology 2013)","url":"https://doi.org/10.1093/annonc/mds276"},{"label":"DART neuroendocrine cohort (Clinical Cancer Research 2020)","url":"https://doi.org/10.1158/1078-0432.CCR-19-3356"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor"}],"tags":["subtype-page","endocrine"],"related":["grade-3-net","lung-net","pancreatic-net","small-intestinal-net"],"cancers":[],"sections":[],"technologies":["pet","ct","t-cell-engager"],"targets":["dll3","tp53"],"drugs":["platinum-etoposide","etoposide","cisplatin","carboplatin","capecitabine-temozolomide","folfiri","folfox","topotecan","nivolumab","ipilimumab","tarlatamab","peluntamig","zg006","obrixtamig"],"companies":[],"institutions":[],"pathways":["lineage-plasticity-neuroendocrine"],"terms":["net-grade-ki67","tumour-differentiation","histologic-transformation"],"trials":["dart-s1609","nct07544654","nct05882058","nct05652686"],"people":[],"bottlenecks":[],"keyPapers":["paper-nordic-nec-sorbye-ann-oncol-2013","paper-rindi-common-classification-framework-mod-pathol-2018","paper-dart-nivolumab-ipilimumab-nec-patel-ccr-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"A minority of neuroendocrine neoplasms but the one with the shortest survival; the gastrointestinal tract (colon and rectum, oesophagus, stomach, pancreas) and unknown primary are the commonest sites, most patients present with metastases, and survival is measured in months rather than years.","subtypes":["Small-cell neuroendocrine carcinoma (NEC) of the gastrointestinal tract","Large-cell neuroendocrine carcinoma (NEC) of the gastrointestinal tract","Colorectal NEC (the commonest gut site, BRAF V600E in a subset)","Oesophageal and gastric NEC","Pancreatic NEC (distinguish from grade 3 well-differentiated pancreatic NET)","Neuroendocrine carcinoma of unknown primary","Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN)","Small-cell carcinoma of the cervix, bladder and other extrapulmonary sites"],"biomarkers":["Ki-67 above 20 percent, usually far higher, with poorly differentiated morphology","Synaptophysin, chromogranin and INSM1 by immunohistochemistry (chromogranin may be weak)","p53 and Rb by immunohistochemistry (abnormal in carcinoma, retained in grade 3 tumour)","FDG PET (somatostatin receptor PET usually negative)","DLL3 expression (trial eligibility)","BRAF V600E and microsatellite instability in colorectal NEC","Ki-67 above or below 55 percent (platinum sensitivity, NORDIC NEC)"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Biopsy with Ki-67, morphology and p53 or Rb immunohistochemistry to separate carcinoma from grade 3 tumour; FDG PET and CT; somatostatin receptor PET only if radioligand therapy is contemplated.","refs":["net-grade-ki67","tumour-differentiation","pet","ct","sstr-pet","tp53"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Localised disease","approach":"Resection or definitive chemoradiotherapy with perioperative platinum-etoposide, following the limited-stage small-cell lung cancer model.","refs":["platinum-etoposide","etoposide","cisplatin","carboplatin","radiotherapy"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Metastatic, first line","approach":"Platinum with etoposide (cisplatin or carboplatin), with a PD-1 or PD-L1 antibody added by extrapolation from small-cell lung cancer or within a trial.","refs":["platinum-etoposide","etoposide","carboplatin","cisplatin","atezolizumab","durvalumab"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Second line","approach":"FOLFIRI, FOLFOX, capecitabine-temozolomide or topotecan; nivolumab with ipilimumab in selected patients (DART); DLL3-directed T-cell engagers in trials.","refs":["folfiri","folfox","capecitabine-temozolomide","topotecan","nivolumab","ipilimumab","dart-s1609","nct07544654","nct05882058","dll3"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Ki-67 near 20 to 55 percent with well-differentiated features","approach":"Reclassify as grade 3 neuroendocrine tumour and treat accordingly.","refs":["net-grade-ki67","capecitabine-temozolomide","lutathera"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}}],"stateOfArt":["Platinum-etoposide remains the backbone after more than three decades, with immunotherapy added by extrapolation from small-cell lung cancer.","The 2019 WHO split of grade 3 tumour from carcinoma has stopped many slower tumours receiving platinum they would not respond to.","DLL3-directed T-cell engagers have reached a phase 3 trial specific to extrapulmonary carcinoma."],"history":[{"year":1991,"title":"Moertel: cisplatin with etoposide produces responses in anaplastic neuroendocrine carcinoma","refs":["platinum-etoposide"]},{"year":2010,"title":"WHO classification separates poorly differentiated neuroendocrine carcinoma from neuroendocrine tumours","refs":["net-grade-ki67"]},{"year":2013,"title":"NORDIC NEC: Ki-67 below 55 percent predicts less platinum response but longer survival","refs":[]},{"year":2019,"title":"WHO digestive system classification: grade 3 tumour and carcinoma become distinct entities","refs":["net-grade-ki67"]},{"year":2020,"title":"DART (SWOG S1609): nivolumab with ipilimumab active in high-grade neuroendocrine carcinoma","refs":["dart-s1609","nivolumab","ipilimumab"]},{"year":2024,"title":"Tarlatamab approved for small-cell lung cancer, opening DLL3 as a target for extrapulmonary carcinoma","refs":["tarlatamab","dll3"]},{"year":2026,"title":"DAREON-NEC-1 phase 3 of obrixtamig with carboplatin-etoposide opens in DLL3-positive extrapulmonary carcinoma","refs":["nct07544654"]}],"pipeline":["nct07544654","nct05882058","nct05652686","peluntamig","zg006","tarlatamab","dll3","dart-s1609","lineage-plasticity-neuroendocrine"],"openProblems":["No randomised trial has improved on platinum-etoposide in first line.","Whether adding a PD-1 or PD-L1 antibody helps, as it does in small-cell lung cancer, is untested in a phase 3.","Second-line therapy has no standard.","The disease is too rare and too heterogeneous by site for site-specific trials, so basket designs dominate."],"parent":"neuroendocrine"},{"id":"fap-associated-colorectal-cancer","kind":"cancer","name":"Familial adenomatous polyposis-associated colorectal cancer","aka":["Familial adenomatous polyposis-associated colorectal cancer (inherited APC variant; fewer than 1 percent of bowel cancers)","FAP colorectal cancer","Polyposis coli","Adenomatous polyposis coli bowel cancer","Attenuated familial adenomatous polyposis"],"tldr":"In familial adenomatous polyposis a person inherits a fault in the APC gene and grows hundreds or thousands of polyps in the large bowel from their teens. Left alone, almost all of them become cancer by about 40, so the bowel is watched from childhood and usually removed before that happens; the cancers that do occur are treated like ordinary bowel cancer.","summary":"What it is. Familial adenomatous polyposis is an inherited condition caused by a germline variant in APC, the gatekeeper of the Wnt pathway whose loss also opens the sporadic adenoma-carcinoma sequence. Carriers develop hundreds to thousands of colorectal adenomas from adolescence; an attenuated form produces fewer polyps later in life. The World Health Organization lists it among the genetic tumour syndromes of the digestive system. It is not only a bowel condition: duodenal and gastric polyposis occurs in almost all patients, desmoid tumours are a leading cause of death after colectomy, and thyroid cancer, hepatoblastoma and medulloblastoma occur (Nagtegaal 2020; Gastrointest Endosc Clin N Am 2022).\n\nHow it differs from its parent. The cancer that arises in polyposis is an ordinary colorectal adenocarcinoma; what differs is everything before and after it. Cancer Research UK records that almost all untreated patients develop bowel cancer by age 40, against a median age at diagnosis of 66 in the United States for colorectal cancer generally. The tumours are the endpoint of a field of hundreds of adenomas rather than of one, which is why segmental resection is rarely enough and why surveillance of the retained rectum or ileal pouch continues for life after surgery (Best Pract Res Clin Gastroenterol 2022).\n\nHow common it is. Fewer than 1 percent of bowel cancers (Cancer Research UK). Because carriers are identified and operated on before cancer develops, the share of cancers is much smaller than the share of the polyp burden.\n\nHow it is treated. Colonoscopy is recommended from about age 10 to 12 at intervals of one to two years, and prophylactic colectomy is the intervention that prevents the cancer; after colectomy, endoscopic surveillance of the retained rectum or the ileal pouch continues, as does upper gastrointestinal surveillance with visualisation of the ampulla, because duodenal and ampullary cancer becomes the leading gastrointestinal risk once the colon is gone (Gastrointest Endosc Clin N Am 2022; Best Pract Res Clin Gastroenterol 2022). The type and timing of colectomy are not settled by consensus. A cancer that does occur is staged and treated as colorectal adenocarcinoma, with the systemic rows of the parent page. UK surveillance and surgical practice follow the British Society of Gastroenterology, ACPGBI and UK Cancer Genetics Group guidelines (Monahan 2020).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Familial_adenomatous_polyposis","links":[{"label":"CRUK: bowel cancer risk factors (professional)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer/risk-factors"},{"label":"Gastrointest Endosc Clin N Am 2022: endoscopic management and surgical considerations for familial adenomatous polyposis","url":"https://doi.org/10.1016/j.giec.2021.08.007"},{"label":"Best Pract Res Clin Gastroenterol 2022: management of familial adenomatous polyposis and MUTYH-associated polyposis, new insights","url":"https://doi.org/10.1016/j.bpg.2022.101793"},{"label":"Monahan, Gut 2020: BSG, ACPGBI and UKCGG guidelines for the management of hereditary colorectal cancer","url":"https://doi.org/10.1136/gutjnl-2019-319915"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"NICE NG151: colorectal cancer, recommendations (Lynch 1.1, local disease 1.3, biomarkers 1.4, metastatic disease 1.5, ongoing care and support including follow-up 1.6)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"}],"tags":["gi","colorectal","subtype-page"],"related":["colorectal","lynch-associated-colorectal-cancer","colon-cancer","rectal-cancer","early-onset-colorectal","colorectal-adenoma-like-adenocarcinoma"],"cancers":[],"sections":[],"technologies":["colonoscopy","endoscopy","germline-testing","histopathology-ihc"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["wnt"],"terms":["adenoma-carcinoma-sequence","colorectal-polyp-types","colonoscopy-surveillance-intervals","germline-vs-somatic","colectomy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Familial adenomatous polyposis accounts for fewer than 1 percent of bowel cancers, and almost all untreated patients develop bowel cancer by age 40 (Cancer Research UK).","subtypes":["Classic familial adenomatous polyposis (hundreds to thousands of colorectal adenomas from adolescence)","Attenuated familial adenomatous polyposis (fewer adenomas, later onset, more proximal)","Familial adenomatous polyposis with duodenal or ampullary neoplasia (the leading gastrointestinal risk after colectomy)","Familial adenomatous polyposis with desmoid disease (a leading cause of death after colectomy)"],"biomarkers":["Germline APC variant, and MUTYH testing when polyposis is present without an APC variant","Polyp count and distribution at colonoscopy, which set the timing of surgery","Spigelman stage of duodenal polyposis and the state of the ampulla, which set upper gastrointestinal surveillance"],"standardOfCare":[{"setting":"Surveillance and prophylactic surgery in carriers","approach":"Colonoscopy from about age 10 to 12 at one to two-yearly intervals; prophylactic colectomy before cancer develops, with the type and timing decided case by case; lifelong endoscopic surveillance of the retained rectum or ileal pouch afterwards; upper gastrointestinal endoscopy with ampullary visualisation at intervals set by duodenal and gastric findings.","refs":["colonoscopy","colectomy","endoscopy","germline-testing","colonoscopy-surveillance-intervals"],"guideline":{"version":"NICE NG151: colorectal cancer (published January 2020, last updated December 2021, last reviewed April 2026)","url":"https://www.nice.org.uk/guidance/ng151"}},{"setting":"Cancer arising in polyposis","approach":"Staged and treated as colorectal adenocarcinoma of the same stage, with the extent of resection decided by the field of polyps rather than by the single tumour; the parent record carries the systemic therapy rows.","refs":["colectomy","capox","folfox"],"guideline":{"version":"NICE NG151: colorectal cancer (published January 2020, last updated December 2021, last reviewed April 2026)","url":"https://www.nice.org.uk/guidance/ng151"}}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"colorectal"},{"id":"aml-flt3","kind":"cancer","name":"FLT3-mutated acute myeloid leukaemia","aka":["FLT3-ITD AML","FLT3-TKD AML","FLT3-positive AML"],"tldr":"FLT3-mutated acute myeloid leukaemia carries a mutation in a growth-signal receptor that makes the leukaemia relapse quickly. Adding a FLT3 blocker to chemotherapy, midostaurin or quizartinib, lengthens life, and gilteritinib is the standard when the disease comes back.","summary":"FLT3 is a receptor tyrosine kinase on blood stem cells. An internal tandem duplication (ITD) in about a quarter of adult AML, or a point mutation in the tyrosine kinase domain (TKD) in under a tenth, keeps it switched on. FLT3-ITD leukaemias present with high white counts and relapse early, and the ELN 2022 classification places them in the intermediate-risk group whatever the allelic ratio, so an allogeneic transplant in first remission is usually recommended. Testing for FLT3 must return within days because the inhibitor is started with the first chemotherapy cycle.\n\nRATIFY, reported in 2017, randomised 717 patients aged 18 to 59 to midostaurin or placebo added to 7+3 induction, consolidation and a year of maintenance: median overall survival rose from 25.6 to 74.7 months (hazard ratio 0.78), and midostaurin became the first targeted drug approved in AML that year. QuANTUM-First extended the approach to FLT3-ITD patients up to 75 with the more selective quizartinib: median survival 31.9 versus 15.1 months (hazard ratio 0.776), approved in 2023. For relapsed or refractory FLT3-mutated disease, ADMIRAL showed single-agent gilteritinib beat salvage chemotherapy, median survival 9.3 versus 5.6 months (hazard ratio 0.64), and it was approved in 2018.\n\nThe open questions are which inhibitor to pair with intensive chemotherapy, whether FLT3 inhibitor maintenance after transplant should be universal or MRD-guided (MORPHO found the gilteritinib benefit concentrated in patients with detectable FLT3-ITD before or after transplant), how to combine FLT3 inhibitors with venetoclax and azacitidine in unfit patients, and how to treat the resistance mutations and clonal switches that follow each drug.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/CD135","links":[{"label":"Wikipedia: FLT3","url":"https://en.wikipedia.org/wiki/CD135"},{"label":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}],"tags":["subtype-page"],"related":["aml-idh","aml-npm1-kmt2a","aml-older-unfit","aml-secondary","aml-paediatric"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","ngs-mrd-clonoseq"],"targets":["flt3"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["flt3-itd-allelic-ratio","eln-risk","seven-plus-three"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-admiral-gilteritinib-flt3-nejm-2019","paper-quantum-first-quizartinib-lancet-2023","paper-eln-2022-aml-dohner-blood-2022","paper-ratify-midostaurin-nejm-2017"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About three in ten adults with acute myeloid leukaemia carry a FLT3 mutation, most often the internal tandem duplication, which used to mark one of the worst outlooks in the disease.","subtypes":["FLT3-ITD AML (internal tandem duplication)","FLT3-TKD AML (D835 and other kinase domain point mutations)","FLT3-mutated AML with co-mutated NPM1"],"biomarkers":["FLT3-ITD and allelic ratio","FLT3-TKD (D835, I836)","NPM1 co-mutation","ELN 2022 risk group","FLT3-ITD MRD by NGS before and after transplant","Karyotype"],"standardOfCare":[{"setting":"Newly diagnosed, fit for intensive chemotherapy","approach":"7+3 induction with midostaurin (RATIFY) or, for FLT3-ITD, quizartinib (QuANTUM-First), then consolidation and maintenance with the same inhibitor; allogeneic transplant in first remission for most FLT3-ITD patients.","refs":["midostaurin","quizartinib","cytarabine-7-3","ratify","quantum-first","allogeneic-hsct","flt3i-plus-7-3"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Newly diagnosed, unfit for intensive chemotherapy","approach":"Venetoclax plus azacitidine, with a FLT3 inhibitor added in trials or where labelled; gilteritinib with azacitidine is an option.","refs":["venetoclax","azacitidine","gilteritinib","viale-a"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Relapsed or refractory","approach":"Gilteritinib alone (ADMIRAL) as a bridge to allogeneic transplant; quizartinib where approved for relapse; FLT3 inhibitor maintenance after transplant.","refs":["gilteritinib","admiral","quizartinib","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}}],"stateOfArt":["A FLT3 inhibitor with 7+3 is standard for every newly diagnosed FLT3-mutated patient fit for chemotherapy; RATIFY roughly tripled median survival.","Gilteritinib turned relapsed FLT3-mutated AML from a chemotherapy-only setting into a targeted one.","Post-transplant FLT3 inhibitor maintenance is moving towards MRD-guided use."],"history":[{"year":1996,"title":"FLT3 internal tandem duplications described in AML","refs":["flt3"]},{"year":2017,"title":"RATIFY: midostaurin with 7+3 lengthens life; first targeted AML drug approved","refs":["ratify","midostaurin"]},{"year":2018,"title":"Gilteritinib approved for relapsed FLT3-mutated AML after ADMIRAL","refs":["admiral","gilteritinib"]},{"year":2022,"title":"ELN 2022 places all FLT3-ITD AML in intermediate risk","refs":["eln-risk"]},{"year":2023,"title":"QuANTUM-First: quizartinib approved for FLT3-ITD AML up to age 75","refs":["quantum-first","quizartinib"]}],"pipeline":["gilteritinib","quizartinib","venetoclax","myelomatch","ngs-mrd-clonoseq"],"openProblems":["Which FLT3 inhibitor to pair with intensive chemotherapy, and whether one inhibitor suits both ITD and TKD disease.","Whether post-transplant maintenance should be given to everyone or only to patients with detectable FLT3-ITD.","Resistance through FLT3 gatekeeper mutations and through loss of FLT3 dependence."],"parent":"aml"},{"id":"follicular-lymphoma","kind":"cancer","name":"Follicular lymphoma","aka":[],"tldr":"Follicular lymphoma is the most common slow-growing lymphoma, defined in about 85% of cases by a BCL2 translocation. Most people live with it for decades, treated only when it causes problems; it can be controlled repeatedly with anti-CD20 antibodies, chemotherapy, bispecifics or CAR-T but rarely cured, and a small share transform into an aggressive lymphoma each year.","summary":"Follicular lymphoma (FL) is an indolent germinal-centre B-cell lymphoma defined by t(14;18) BCL2 overexpression in ~85% and frequent CREBBP, KMT2D and EZH2 mutations. Median survival now exceeds 15-20 years, so the questions are when to treat, how to avoid over-treatment, and how to manage the ~20% who progress within 24 months (POD24) and the 2-3% per year who transform to DLBCL.\n\nAsymptomatic low-burden disease is watched or given rituximab monotherapy; symptomatic or high-burden disease receives anti-CD20 (rituximab or obinutuzumab) with bendamustine, CHOP or CVP, or with lenalidomide (R², RELEVANCE), usually followed by anti-CD20 maintenance (PRIMA). Relapsed disease has the richest menu in lymphoma: lenalidomide-rituximab (AUGMENT), CD20×CD3 bispecifics (mosunetuzumab 2022, epcoritamab 2024, odronextamab EU), CD19 CAR-T (axicabtagene 2021, tisagenlecleucel 2022, lisocabtagene 2024), zanubrutinib-obinutuzumab (ROSEWOOD, 2024) and radioimmunotherapy historically. Tazemetostat (EZH2) was withdrawn worldwide in March 2026.\n\nOpen questions: whether bispecifics or CAR-T should move to second line or even first line (EPCORE FL-1, MorningSun), PET/ctDNA-guided de-escalation, and biology-based prediction of POD24 and transformation.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Follicular_lymphoma","links":[{"label":"NCCN Guidelines: B-Cell Lymphomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1480"},{"label":"NCI PDQ: adult NHL","url":"https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq"},{"label":"Lymphoma Research Foundation: FL","url":"https://lymphoma.org/understanding-lymphoma/aboutlymphoma/nhl/fl/"},{"label":"Lymphoma Action: helpline services","url":"https://lymphoma-action.org.uk/information-and-support/support-you/helpline-services"},{"label":"Lymphoma Action: questions to ask your medical team about lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/questions-ask-your-medical-team-about-lymphoma"},{"label":"Lymphoma Action: follow-up after lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/follow-after-lymphoma-treatment"},{"label":"Lymphoma Action: infections, risk and prevention","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/infections-risk-and-prevention"},{"label":"Lymphoma Action: neutropenia (low neutrophils)","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/neutropenia-low-neutrophils"},{"label":"Lymphoma Action: cancer-related fatigue","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/cancer-related-fatigue"},{"label":"Lymphoma Action: lymphoma, work and you","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/day-day-living/lymphoma-work-and-you"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Lymphoma Action: follicular lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/types-lymphoma/non-hodgkin-lymphoma/follicular-lymphoma"},{"label":"Lymphoma Action: active monitoring (watch and wait)","url":"https://lymphoma-action.org.uk/information-and-support/lymphoma-treatment/active-monitoring-watch-and-wait"},{"label":"Lymphoma Action: transformation of lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/types-lymphoma/transformation-lymphoma"},{"label":"Lymphoma Action: the emotional impact of living with lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/emotional-impact-living-lymphoma"},{"label":"Ardeshna et al., rituximab versus a watch and wait approach in asymptomatic advanced follicular lymphoma, Lancet Oncology 2014 (379 patients)","url":"https://doi.org/10.1016/S1470-2045(14)70027-0"},{"label":"Macmillan: non-Hodgkin lymphoma","url":"https://www.macmillan.org.uk/cancer-information-and-support/lymphoma/non-hodgkin-lymphoma"}],"tags":["gap-fill","haematologic"],"related":["lymphoma-research-foundation","marginal-zone-lymphoma","waldenstrom","mantle-cell-lymphoma","dlbcl","bcl2-rearrangement","ezh2-y646-mutation","double-hit-rearrangement","ig-tcr-clonality","lymphoma-roadmap","lymphoma-ev-fixed-duration-chemotherapy-free-first-line","lymphoma-ev-ctdna-instead-of-the-interim-scan"],"cancers":[],"sections":[],"technologies":["monoclonal-antibody","t-cell-engager","car-t","pet-ct","radioimmunotherapy","palliative-care","psycho-oncology","peer-support-groups","survivorship-care-plan","fertility-preservation","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","multidisciplinary-tumour-board","oncology-nutrition","prehabilitation","bispecific-antibody","cytogenetics-fish","histopathology-ihc","cgp"],"targets":["cd20","cd19","cd3","bcl2","ezh2","btk","crebbp","ep300","kmt2d","cd79b","myc-gene","tp53"],"drugs":["rituximab","obinutuzumab","bendamustine","lenalidomide","mosunetuzumab","epcoritamab","odronextamab","axicabtagene-ciloleucel","tisagenlecleucel","lisocabtagene-maraleucel","zanubrutinib","tazemetostat","chlorambucil","ibritumomab-tiuxetan","tafasitamab"],"companies":["roche-genentech","genmab","abbvie","gilead","beone","regeneron","haihe-biopharma"],"institutions":[],"pathways":["apoptosis-bcl2","germinal-centre-reaction","epigenetic-reprogramming"],"terms":["lugano-classification","histologic-transformation","deauville-score","flipi","lymphoma-tx-pod24","lymphoma-tx-watch-and-wait","lymphoma-tx-maintenance","lymphoma-tx-radiotherapy","lymphoma-tx-bispecific-step-up","lymphoma-tx-car-t-pathway","lymphoma-tx-uk-access","cancer-related-fatigue","late-effects","febrile-neutropenia","neutropenia","financial-toxicity","central-venous-access","hypogammaglobulinaemia","performance-status","quality-of-life","lymphoma-decision-watch-and-wait","lymphoma-decision-trial","lymphoma-decision-fertility-timing","lymphoma-living-indolent-lymphoma","lymphoma-living-scanxiety-and-surveillance","lymphoma-living-fatigue","lymphoma-living-infection-years-after","lymphoma-living-vaccinations","lymphoma-living-returning-to-work","watchful-waiting","deauville","lymphoma-bio-germinal-centre","lymphoma-bio-transformation","lymphoma-bio-antigen-escape"],"trials":["nct07634471","nct07562022","nct06097364","nct04712097","nct06549595","nct06149286","nct06191744","nct06911502","nct04224493","nct01804686","nct04680052","nct06091254","nct05100862","nct05888493","nct05409066","nct05371093","augment","zuma-5","gallium","relevance","prima-follicular","trog-99-03","elara","rosewood","fortplus","mosun-lbt-fl"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["hematological-oncology"],"dependsOn":[],"notes":["Living with follicular lymphoma, the decisions and the people who make them: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the 24-hour number they gave you come first, and no figure here is a prediction about you. The decision records, the question sets, the first 60 days checklist and the red cards on this page were written from the NHS, Lymphoma Action, Macmillan and Cancer Research UK patient pages, from NICE NG52, NG47, CG151 and NG234, from the NHS Breast Screening Programme protocols and the Green Book, and from the trial reports named beside each figure, all read on 1 October 2026.","On being told nobody will treat it. Lymphoma Action's page on active monitoring is the best patient-facing account of this in English and is quoted at length in the decision record, including a person on monitoring describing it as counter-intuitive and a psychological rather than a physical challenge. The randomised evidence behind the approach is a British-led trial of 379 people with asymptomatic, non-bulky, advanced follicular lymphoma, in which early rituximab delayed the need for chemotherapy or radiotherapy without a difference in overall survival."],"group":"haematologic","burden":"Follicular lymphoma is the second most common non-Hodgkin lymphoma in the West (~20% of NHL; about 3-4 per 100,000 per year), median age ~65.","subtypes":["Classic FL (grades 1-3A)","Follicular large B-cell lymphoma (formerly 3B)","FL with unusual cytological features","Duodenal-type FL","Paediatric-type FL","Transformed FL"],"biomarkers":["t(14;18)/BCL2","FLIPI / FLIPI2 / m7-FLIPI","PET-CT (Lugano) staging and end-of-induction response","POD24 (progression within 24 months)","EZH2 mutation","ctDNA (investigational MRD)"],"standardOfCare":[{"setting":"Limited stage (I-II)","approach":"Involved-site radiotherapy 24 Gy (FoRT); rituximab alone or observation in selected cases.","refs":["rituximab","imrt-igrt","fort"],"guideline":{"nccn":"Category 1 (ISRT)","version":"NCCN Guidelines: B-Cell Lymphomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1480"}},{"setting":"Advanced, low burden, asymptomatic","approach":"Watch and wait (no survival penalty), or rituximab monotherapy to delay chemotherapy.","refs":["rituximab","active-surveillance"]},{"setting":"Advanced, high burden (GELF criteria)","approach":"Bendamustine-rituximab or bendamustine-obinutuzumab (GALLIUM), R-CHOP, or lenalidomide-rituximab (RELEVANCE); anti-CD20 maintenance 2 years (PRIMA).","refs":["rituximab","obinutuzumab","bendamustine","lenalidomide","gallium","relevance"],"guideline":{"nccn":"Category 1","esmoMcbs":"3 (GALLIUM)","version":"NCCN Guidelines: B-Cell Lymphomas"}},{"setting":"Relapsed (≥2 lines)","approach":"Lenalidomide-rituximab (AUGMENT); CD20×CD3 bispecific (mosunetuzumab, epcoritamab); CD19 CAR-T (axi-cel, tisa-cel, liso-cel); zanubrutinib + obinutuzumab; clinical trials.","refs":["mosunetuzumab","epcoritamab","axicabtagene-ciloleucel","tisagenlecleucel","lisocabtagene-maraleucel","zanubrutinib","odronextamab"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: B-Cell Lymphomas"}},{"setting":"Stage I and contiguous stage II follicular lymphoma: radiotherapy with curative intent","approach":"Truly localised follicular lymphoma, which means stage I or contiguous stage II confirmed on PET-CT and marrow assessment, is treated with 24 Gy in 12 fractions to an involved-site field and a substantial minority never relapse. PET staging matters: a quarter or more of patients thought to have stage I on CT are upstaged, and those are the ones who relapse outside the field.\n\nAdding systemic treatment lengthens remission without proven survival gain. TROG 99.03 randomised 150 patients after 30 Gy involved-field radiotherapy to observation or six cycles of CVP, with rituximab added from 2006: ten-year progression-free survival was 59 per cent with systemic therapy against 41 per cent with radiotherapy alone (hazard ratio 0.57), overall survival was not significantly different (95 against 87 per cent), and the effect was largest in the rituximab-containing subgroup. Four gray in two fractions is not an alternative for cure: FoRT found it clearly inferior to 24 Gy for local control.\n\nObservation is a defensible option in an older patient with a small, asymptomatic node, and so is rituximab alone. Doing nothing is not the same as doing nothing wrong.","refs":["paper-fort-4gy-vs-24gy-indolent-lymphoma-hoskin-lancet-oncol-2014","lymphoma-tx-radiotherapy","imrt-igrt","fdg-pet","rituximab","cyclophosphamide","vincristine","prednisone","lymphoma-tx-watch-and-wait","flipi"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; TROG 99.03, FoRT","url":"https://doi.org/10.1200/JCO.2018.77.9892"}},{"setting":"Advanced follicular lymphoma with no symptoms: watch and wait, or rituximab alone","approach":"Starting chemotherapy early does not lengthen life in asymptomatic, low-burden disease, and a third of people never need treatment in the first few years. The British-led trial that settled this randomised 379 patients with asymptomatic, non-bulky, advanced disease: at three years, 46 per cent of those watched had not needed treatment against 88 per cent of those given four weekly doses of rituximab and two years of maintenance (hazard ratio 0.21), with no overall survival difference. So rituximab delays the next treatment; it does not extend life, and it costs two years of visits.\n\nThe GELF criteria are the usual trigger to treat: a mass of 7 cm or more, three or more nodal sites each 3 cm or more, B symptoms, splenomegaly, effusion, cytopenias or a leukaemic phase. Monitoring is clinic review and bloods every three to six months; routine scanning of a well person finds little.","refs":["lymphoma-tx-watch-and-wait","watchful-waiting","rituximab","flipi","lymphoma-tx-maintenance"],"guideline":{"nccn":"Category 1 (observation for low tumour burden)","version":"NCCN B-Cell Lymphomas; ESMO; Ardeshna 2014","url":"https://doi.org/10.1016/S1470-2045(14)70027-0"}},{"setting":"Advanced follicular lymphoma needing treatment: which induction, and whether to add maintenance","approach":"Chemoimmunotherapy is the usual first treatment, and the choice of chemotherapy backbone is made on toxicity. Bendamustine with rituximab gave median progression-free survival of 69.5 against 31.2 months for R-CHOP in the StiL NHL1 trial of indolent and mantle cell lymphoma (hazard ratio 0.58), with no alopecia, less haematological toxicity, fewer infections and far less neuropathy, and is the commonest first choice; it does deplete T cells for a long time, which matters for anyone who may need CAR-T later. R-CHOP is preferred where transformation is suspected. R-CVP is the gentlest.\n\nObinutuzumab instead of rituximab improves progression-free survival: GALLIUM randomised 1,401 patients and gave three-year progression-free survival of 80.0 against 73.3 per cent (hazard ratio 0.66), at the cost of more grade 3 to 5 adverse events (74.6 against 67.8 per cent) and more infusion reactions.\n\nChemotherapy-free induction is a real alternative. RELEVANCE randomised 1,030 patients to rituximab with lenalidomide or rituximab with the investigator's chemotherapy: complete response at 120 weeks was 48 against 53 per cent and median progression-free survival 120.2 against 123.8 months (hazard ratio 0.92), so R-squared is not superior but is equivalent, with less neutropenia (32 against 50 per cent) and more rash.\n\nMaintenance rituximab for two years afterwards lengthens remission substantially and does not lengthen life: in PRIMA median progression-free survival was 10.5 against 4.1 years but ten-year overall survival was about 80 per cent in both arms. It is a choice, not a requirement.","refs":["gallium","relevance","obinutuzumab","rituximab","bendamustine","lenalidomide","r-chop","cyclophosphamide","vincristine","prednisone","lymphoma-tx-maintenance","paper-rummel-lancet","paper-gallium-obinutuzumab-first-line-follicular-lymphoma-marcus-nejm-2017","paper-relevance-rituximab-lenalidomide-follicular-lymphoma-morschhauser-nejm-2018"],"guideline":{"nccn":"Category 1","version":"NCCN B-Cell Lymphomas; ESMO; GALLIUM, RELEVANCE, StiL NHL1, PRIMA","url":"https://doi.org/10.1200/JCO.19.01073"}},{"setting":"Progression within two years of first chemotherapy (POD24): biopsy first, then a different class of treatment","approach":"About one in five people treated with first-line chemoimmunotherapy progress within two years, and their five-year overall survival in the National LymphoCare Study was 50 per cent against 90 per cent for everyone else, a difference that held after adjusting for FLIPI.\n\nThe first step is a repeat biopsy, because transformation to diffuse large B-cell lymphoma is the commonest explanation and is treated as aggressive lymphoma. If it is still follicular, the plan changes class rather than repeating it: CD19 CAR-T (ZUMA-5 reported an overall response of 92 per cent and complete response 74 per cent; ELARA with tisagenlecleucel reported complete response 69.1 per cent and overall response 86.2 per cent), a CD20 bispecific antibody, or lenalidomide with rituximab. A clinical trial is a reasonable first choice at this point. Autologous transplant still has a role in younger patients with chemosensitive early relapse and is used less than it was.","refs":["lymphoma-tx-pod24","zuma-5","axicabtagene-ciloleucel","tisagenlecleucel","mosunetuzumab","odronextamab","epcoritamab","lenalidomide","rituximab","car-t","lymphoma-tx-car-t-pathway","autologous-stem-cell-transplant","flipi"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; ZUMA-5, ELARA","url":"https://doi.org/10.1038/s41591-021-01622-0"}},{"setting":"Relapsed follicular lymphoma after two or more lines: bispecific antibodies, CAR-T and R-squared","approach":"Nothing here is curative and all of it can produce long remissions, so the choice is about duration of treatment, side effects and how far a person is willing to travel.\n\nFixed-duration bispecific antibodies. Mosunetuzumab, given intravenously in 21-day cycles with step-up dosing and stopped after eight cycles in complete responders, produced a complete response in 60.0 per cent of 90 patients after two or more lines. Odronextamab in ELM-2 gave an objective response of 80.0 per cent, complete response 73.4 per cent and median progression-free survival 20.7 months in 128 patients, with grade 3 or worse cytokine release syndrome of 1.7 per cent using the split step-up. Epcoritamab is approved in combination with rituximab and lenalidomide.\n\nCAR-T. Axicabtagene ciloleucel (ZUMA-5) and tisagenlecleucel (ELARA) both produce high complete response rates with remissions that are lasting in a substantial minority; the trade is a single intensive episode against repeated outpatient treatment.\n\nRituximab with lenalidomide. AUGMENT randomised 358 patients with relapsed follicular or marginal zone lymphoma to lenalidomide with rituximab or rituximab with placebo: median progression-free survival 39.4 against 14.1 months (hazard ratio 0.46), with grade 3 to 4 neutropenia in 50 against 13 per cent.\n\nAntibody and inhibitor combinations approved since 2024. Tafasitamab with lenalidomide and rituximab received traditional United States approval on 18 June 2025 on the inMIND trial, with a label note that it is not indicated in relapsed or refractory marginal zone lymphoma outside a trial. Zanubrutinib with obinutuzumab was given accelerated approval on 7 March 2024 on ROSEWOOD. Lisocabtagene maraleucel's follicular approval of 15 May 2024 converted to traditional approval on 20 February 2026, and a separate marginal zone lymphoma approval followed on 4 December 2025.\n\nOther options: a different chemoimmunotherapy backbone from the one used before, obinutuzumab with bendamustine in rituximab-refractory disease, tazemetostat for EZH2-mutant disease or where nothing else is suitable, radiotherapy to a single symptomatic site, and radioimmunotherapy where it is still available. The PI3K inhibitors (idelalisib, duvelisib, copanlisib) have largely been withdrawn from this indication on the basis of toxicity and unconfirmed benefit.","refs":["augment","zuma-5","mosunetuzumab","odronextamab","epcoritamab","lenalidomide","rituximab","obinutuzumab","bendamustine","tazemetostat","axicabtagene-ciloleucel","tisagenlecleucel","lisocabtagene-maraleucel","tafasitamab","zanubrutinib","radioimmunotherapy","lymphoma-tx-bispecific-step-up","lymphoma-tx-radiotherapy","paper-augment-lenalidomide-rituximab-leonard-jco-2019"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; AUGMENT, ELM-2, mosunetuzumab phase 2","url":"https://doi.org/10.1016/j.annonc.2024.08.2239"}},{"setting":"Transformation of follicular lymphoma to diffuse large B-cell lymphoma","approach":"Suspected when a single site grows quickly, LDH rises, B symptoms appear or the PET shows one site far brighter than the rest; confirmed by biopsy of that site, which is why a repeat biopsy rather than a scan is the right first step. It occurs in roughly 2 to 3 per cent of patients a year.\n\nTreatment follows the aggressive lymphoma pathway, not the follicular one. In a patient who has had little or no previous chemotherapy, R-CHOP or pola-R-CHP with the intent to cure, often followed by consideration of autologous transplant consolidation. In a patient who has already had several lines, CD19 CAR-T; transformed disease was included in the pivotal CAR-T populations. Bispecific antibodies are active. The outlook is better than it was when transformation was treated with more of the same.","refs":["r-chop","polarix","polatuzumab-vedotin","rituximab","axicabtagene-ciloleucel","lisocabtagene-maraleucel","glofitamab","epcoritamab","autologous-stem-cell-transplant","fdg-pet","lymphoma-tx-car-t-pathway","lymphoma-tx-pod24"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":["Chemotherapy-free options now exist at every line: R² first line, bispecifics and BTK-anti-CD20 combinations at relapse.","CAR-T gives durable remissions in heavily pretreated FL (ZUMA-5 ~50% progression-free at 4 years) and is being tested against bispecifics.","POD24 identifies the high-risk fifth; how to treat them differently up front is still unknown.","Trials of bispecific plus lenalidomide first line (EPCORE FL-2, CELESTIMO) will decide whether chemotherapy leaves front-line FL.","The founding lesion is a mistake made years earlier. The t(14;18) translocation puts BCL2 under an immunoglobulin enhancer, and the breakpoint sequences show it was made by the VDJ recombinase at the pre-B-cell stage. A cell carrying it can be found in the blood of healthy people, so the translocation is the beginning of the story rather than the disease.","What makes it a lymphoma is chromatin. KMT2D was mutated in 89% of follicular lymphomas in the discovery series, CREBBP or EP300 in about 41%, and EZH2 at Tyr646 in 7.2%. The EZH2 mutations are gain-of-function, which is why tazemetostat works and why it is the only genotype-selected tablet in B-cell lymphoma. The seven genes of the m7-FLIPI score are largely this machinery.","Transformation is the event that changes everything. An indolent follicular lymphoma that acquires a MYC rearrangement, TP53 loss or CDKN2A deletion behaves as an aggressive lymphoma and is treated as one. The sign is usually one site growing much faster than the rest, and the answer is a biopsy of that site."],"history":[{"year":1984,"title":"t(14;18) links BCL2 to follicular lymphoma","note":"Tsujimoto and Croce clone the breakpoint; BCL2 becomes the first anti-apoptotic oncogene.","refs":["bcl2"]},{"year":1997,"title":"Rituximab approved","note":"First monoclonal antibody for cancer, in relapsed indolent lymphoma.","refs":["rituximab"]},{"year":2004,"title":"FLIPI prognostic index","refs":[]},{"year":2011,"title":"PRIMA: rituximab maintenance","note":"Two years of maintenance doubles PFS after chemo-immunotherapy.","refs":["rituximab"]},{"year":2017,"title":"Obinutuzumab first line (GALLIUM)","refs":["obinutuzumab"]},{"year":2018,"title":"RELEVANCE: chemo-free R²","note":"Lenalidomide-rituximab matches chemo-immunotherapy first line.","refs":["lenalidomide"]},{"year":2021,"title":"CAR-T enters FL","note":"Axicabtagene (ZUMA-5) approved; tisagenlecleucel (ELARA) 2022; lisocabtagene 2024.","refs":["axicabtagene-ciloleucel","tisagenlecleucel","lisocabtagene-maraleucel"]},{"year":2022,"title":"First bispecific: mosunetuzumab","note":"Off-the-shelf CD20×CD3 with ~60% CR in third line.","refs":["mosunetuzumab"]},{"year":2024,"title":"Epcoritamab and zanubrutinib-obinutuzumab approved for relapsed FL","refs":["epcoritamab","zanubrutinib"]},{"year":2026,"title":"Tazemetostat withdrawn worldwide","note":"Secondary haematologic malignancies; EZH2 leaves the FL armamentarium.","refs":["tazemetostat"]}],"pipeline":["epcoritamab","mosunetuzumab","odronextamab","golcadomide","lisocabtagene-maraleucel","abexinostat","mk-1045","sctb35","xnw5004","tc011","crc01","ctx112"],"openProblems":["Transformation to DLBCL cannot be predicted or prevented.","Sequencing bispecifics vs CAR-T.","Whether earlier intensive therapy for POD24 patients improves survival.","Late toxicities of decades of therapy (secondary cancers, infections, immunoglobulin loss)."],"parent":"non-hodgkin-lymphoma"},{"id":"follicular-thyroid-cancer","kind":"cancer","name":"Follicular thyroid cancer","aka":["Follicular thyroid carcinoma","FTC","Oncocytic (Hurthle cell) carcinoma"],"tldr":"Follicular thyroid cancer looks like a benign nodule on a needle biopsy, so the diagnosis is usually made only after surgery. It spreads through the bloodstream rather than to neck nodes, is treated like papillary cancer with surgery and radioactive iodine, and has a good outlook when caught early.","summary":"Follicular thyroid cancer is separated from a benign follicular adenoma only by invasion of the capsule or blood vessels, which a fine-needle biopsy cannot show; a follicular result on biopsy therefore leads to diagnostic lobectomy, and molecular tests on the aspirate now help decide who needs it. RAS mutations and the PAX8-PPARG fusion are common, and TERT promoter mutations mark aggressive disease. Minimally invasive tumours are cured by lobectomy; widely invasive tumours receive total thyroidectomy and radioactive iodine, which also treats the lung and bone metastases the disease favours. Oncocytic (Hurthle cell) carcinoma, once a follicular variant, is a separate entity in the 2022 WHO classification and takes up iodine poorly. Iodine-refractory disease is treated as in papillary cancer with lenvatinib or sorafenib.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Follicular_thyroid_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Follicular_thyroid_cancer"}],"tags":["subtype-page"],"related":["anaplastic-thyroid-cancer","medullary-thyroid-cancer","papillary-thyroid-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-ata-2015-thyroid-nodules-dtc-haugen-thyroid-2016","paper-select-lenvatinib-nejm-2015","paper-decision-sorafenib-lancet-2014"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"About one in ten thyroid cancers, commoner where iodine is scarce; it spreads through the blood to bone and lung rather than to neck nodes, and survival is somewhat lower than for papillary cancer but still high.","subtypes":["Minimally invasive (capsular invasion only)","Encapsulated angioinvasive","Widely invasive","Oncocytic (Hurthle cell) carcinoma (separate entity since WHO 2022)"],"biomarkers":["RAS mutations","PAX8-PPARG fusion","TERT promoter mutation","Molecular tests on indeterminate aspirates (Afirma, ThyroSeq)","Thyroglobulin"],"standardOfCare":[{"setting":"Indeterminate follicular nodule","approach":"Molecular testing of the aspirate; diagnostic lobectomy when suspicious.","refs":["thyroid"]},{"setting":"Minimally invasive","approach":"Lobectomy alone in most cases; completion surgery and iodine only for high-risk features.","refs":["thyroid"]},{"setting":"Widely invasive or metastatic","approach":"Total thyroidectomy, radioactive iodine, TSH suppression; bone metastases may need surgery or radiotherapy.","refs":["radioiodine-therapy","palliative-radiotherapy"]},{"setting":"Iodine-refractory","approach":"Lenvatinib or sorafenib; clinical trials of redifferentiation.","refs":["lenvatinib","sorafenib","rai-refractory"]}],"stateOfArt":["Molecular testing of indeterminate nodules spares many patients a diagnostic operation.","Most follicular cancers are cured by surgery alone; the widely invasive minority drives the deaths.","Oncocytic carcinoma's separation as its own entity reflects its distinct genetics and poor iodine avidity."],"history":[{"year":1946,"title":"Radioactive iodine treats metastatic follicular cancer","refs":["radioiodine-therapy"]},{"year":2000,"title":"PAX8-PPARG fusion discovered","refs":[]},{"year":2022,"title":"WHO separates oncocytic carcinoma from follicular cancer","refs":[]}],"pipeline":["dabrafenib","lenvatinib"],"openProblems":["Telling adenoma from carcinoma without surgery.","Bone metastases respond poorly to iodine.","Few trials specific to follicular histology."],"parent":"thyroid"},{"id":"fh-deficient-renal-cell-carcinoma","kind":"cancer","name":"Fumarate hydratase-deficient renal cell carcinoma (HLRCC-associated)","aka":["FH-deficient renal cell carcinoma","Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma","HLRCC-associated RCC","Fumarate hydratase-deficient renal cell carcinoma (HLRCC syndrome)","Papillary renal cell carcinoma type 2 (former label for many cases)"],"tldr":"Fumarate hydratase-deficient renal cell carcinoma is a rare, aggressive kidney cancer in which the FH gene is lost, most often because the person was born with a faulty copy as part of the HLRCC syndrome, which also causes skin and womb fibroids. It strikes younger adults, is found by a stain for the missing enzyme, and needs family testing; advanced disease gets the usual kidney cancer drugs.","summary":"The 2016 WHO classification introduced hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma, and the 2022 edition names it fumarate hydratase-deficient renal cell carcinoma because sporadic cases with somatic FH loss occur (Moch 2016; Moch 2022). Immunohistochemistry for FH loss with 2-succinocysteine positivity identified 24 FH-deficient tumours among 124 cases previously diagnosed as unclassified high-grade or papillary type 2 carcinoma; FH mutations were found in 19 of 21 FH-deficient tumours, germline in all nine tested, and the median age was 44 (Am J Surg Pathol 2016). A tubulocystic carcinoma with poorly differentiated foci is a frequent pattern: of 29 such tumours (median age 46, median size 9 cm), 79 percent showed perinephric extension, 41 percent nodal involvement and 86 percent metastasis, and 55 percent had FH loss, with HLRCC identifiable in the family only retrospectively in 12 percent (Am J Surg Pathol 2016). A low-grade oncocytic form resembling SDH-deficient carcinoma also exists (Histopathology 2017).\n\nHow it differs from its parent: it is a metabolic (Krebs cycle) cancer, hereditary in most cases, aggressive even when small, and it needs germline FH testing and surveillance of relatives; the corpus's papillary page lists it as a former type 2 papillary carcinoma.\n\nHow common: about 0.5 percent of renal cell carcinomas on an unselected microarray (Am J Surg Pathol 2016).\n\nTreatment: early and complete surgery, with no role for active surveillance of small tumours because of their aggression; advanced disease has no approved therapy of its own and is treated on the renal cell carcinoma page's VEGF and checkpoint pathways; germline testing is offered to every patient and their relatives.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Hereditary_leiomyomatosis_and_renal_cell_cancer_syndrome","links":[{"label":"NCI PDQ: renal cell cancer treatment","url":"https://www.cancer.gov/types/kidney/patient/kidney-treatment-pdq"},{"label":"Moch 2016, European Urology: the 2016 WHO classification of urinary and male genital tumours, part A","url":"https://doi.org/10.1016/j.eururo.2016.02.029"},{"label":"Moch 2022, European Urology: the 2022 WHO classification of urinary and male genital tumours, part A (renal, penile, testicular)","url":"https://doi.org/10.1016/j.eururo.2022.06.016"},{"label":"Am J Surg Pathol 2016: fumarate hydratase-deficient RCC is strongly correlated with FH mutation and HLRCC","url":"https://doi.org/10.1097/pas.0000000000000617"},{"label":"Am J Surg Pathol 2016: tubulocystic carcinoma with poorly differentiated foci, a pattern of FH-deficient RCC","url":"https://doi.org/10.1097/pas.0000000000000719"},{"label":"Histopathology 2017: a low-grade oncocytic FH-deficient RCC resembling SDH-deficient RCC","url":"https://doi.org/10.1111/his.13183"}],"tags":["subtype-page","wave4","kidney","rare"],"related":["rcc","papillary-rcc","sdh-deficient-renal-cell-carcinoma","collecting-duct-carcinoma","hereditary-ppgl"],"cancers":[],"sections":[],"technologies":["germline-testing"],"targets":["fh"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["nephrectomy","hereditary-cancer-syndromes"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Rare: 24 of 124 tumours (19 percent) previously labelled unclassified high-grade or papillary type 2 were fumarate hydratase-deficient, but only 2 of 776 (0.5 percent) unselected renal cell carcinomas on a tissue microarray; patients had a median age of 44 (Am J Surg Pathol 2016).","subtypes":["FH-deficient renal cell carcinoma in HLRCC (germline FH mutation; papillary or tubulocystic with poorly differentiated foci)","Sporadic FH-deficient renal cell carcinoma (somatic FH loss)","Low-grade oncocytic FH-deficient renal cell carcinoma (rare)"],"biomarkers":["FH loss and 2-succinocysteine positivity on immunohistochemistry","Germline FH mutation (HLRCC)","Cutaneous and uterine leiomyomas in the patient or family","High nuclear grade with prominent eosinophilic nucleoli"],"standardOfCare":[{"setting":"All stages","approach":"Early complete surgery; germline FH testing for the patient and relatives; advanced disease on the renal cell carcinoma page's pathways without a dedicated standard.","refs":["rcc","papillary-rcc","germline-testing","nephrectomy"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"rcc"},{"id":"gallbladder-adenocarcinoma","kind":"cancer","name":"Gallbladder adenocarcinoma","aka":["Adenocarcinoma of the gallbladder","Non-papillary adenocarcinoma of the gallbladder","Pancreatobiliary-type gallbladder adenocarcinoma"],"tldr":"Adenocarcinoma is the usual form of gallbladder cancer, about nine in ten cases, starting in the mucus-making gland cells of the lining. Everything on the main gallbladder cancer page (causes, staging, surgery, chemotherapy with immunotherapy) is written about this type unless it says otherwise.","summary":"Adenocarcinoma of the gallbladder arises from the glandular epithelium of the mucosa, usually on a background of chronic cholecystitis and gallstones, and in the WHO classification (5th edition, 2019) is subdivided by pattern: the common biliary (pancreatobiliary) type, intestinal type, gastric foveolar, mucinous, signet-ring, clear cell, hepatoid and other rare patterns (Nagtegaal 2020; Roa 2022). Cancer Research UK uses a simpler split into non-papillary, papillary and mucinous adenocarcinoma. In the largest pathology series conventional pancreatobiliary-type adenocarcinomas had a female to male ratio of 3.9 and a mean size of 2.9 cm (Dursun 2012, in which they were the comparator for mucinous carcinoma). Grade (1 well, 2 moderate, 3 poorly differentiated), depth of invasion (T category), the T2a or T2b side, lymphovascular and perineural invasion, node number and the cystic duct margin are the pathological findings that drive treatment (CRUK stages and grades; Shindoh 2015; Aloia 2015).\n\nBecause adenocarcinoma is the type every guideline and trial assumes, its management is the main page's: simple cholecystectomy suffices for Tis and T1a, radical cholecystectomy from T1b, adjuvant capecitabine after resection (BILCAP), and gemcitabine and cisplatin with durvalumab or pembrolizumab for advanced disease (TOPAZ-1, KEYNOTE-966), with HER2-directed therapy for the HER2-positive subset. The mucinous, papillary, adenosquamous and neuroendocrine pages describe how the rarer types differ.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Gallbladder_cancer","links":[{"label":"CRUK: types of gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/types"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"Roa, Nature Reviews Disease Primers 2022: gallbladder cancer","url":"https://doi.org/10.1038/s41572-022-00398-y"},{"label":"Dursun, Arch Pathol Lab Med 2012: mucinous carcinomas of the gallbladder, 15 of 606 carcinomas","url":"https://doi.org/10.5858/arpa.2011-0447-oa"},{"label":"Louis, Cancer Causes Control 2025: gallbladder adenocarcinoma and neuroendocrine carcinoma in the National Cancer Database","url":"https://doi.org/10.1007/s10552-025-01967-8"},{"label":"CRUK: stages and grades of gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/stages-and-grades"}],"tags":["gallbladder","biliary","subtype-page"],"related":["gallbladder","gallbladder-papillary-carcinoma","gallbladder-mucinous-carcinoma","gallbladder-adenosquamous-squamous-carcinoma","cholangiocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":["her2"],"drugs":["gemcitabine-cisplatin","durvalumab","pembrolizumab","capecitabine","zanidatamab"],"companies":[],"institutions":[],"pathways":[],"terms":["tumour-grade","t2a-versus-t2b","cystic-duct-margin","radical-cholecystectomy"],"trials":["bilcap","topaz-1","keynote-966"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 90 percent of gallbladder cancers (Cancer Research UK); 96.7 percent of gallbladder neoplasms recorded in the US National Cancer Database in 2011 to 2020 were adenocarcinomas when compared with neuroendocrine carcinomas (Louis 2025).","subtypes":["Biliary (pancreatobiliary) type gallbladder adenocarcinoma, the commonest","Intestinal-type gallbladder adenocarcinoma","Mucinous gallbladder adenocarcinoma (own page)","Papillary gallbladder carcinoma (own page)","Signet-ring, clear cell and hepatoid variants (rare)"],"biomarkers":["Grade 1 to 3","T category and T2a or T2b side","Node number (N1 one to three, N2 four or more)","Cystic duct margin","HER2, mismatch repair, BRAF V600E and NTRK (frequencies on the main gallbladder cancer page)"],"standardOfCare":[{"setting":"Resectable disease","approach":"Simple cholecystectomy for Tis and T1a; radical cholecystectomy with liver bed and portal lymphadenectomy from T1b; adjuvant capecitabine (BILCAP).","refs":["simple-cholecystectomy","radical-cholecystectomy","capecitabine","bilcap"]},{"setting":"Advanced disease","approach":"Gemcitabine and cisplatin with durvalumab or pembrolizumab; zanidatamab for HER2-positive disease after chemotherapy.","refs":["gemcitabine-cisplatin","durvalumab","pembrolizumab","zanidatamab"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"gallbladder"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","aka":["Gallbladder cancer","Gallbladder carcinoma","Carcinoma of the gallbladder","Gall bladder cancer","Biliary tract cancer of the gallbladder","GBC","ICD-10 C23"],"tldr":"Gallbladder cancer starts in the small bile-storing sac under the liver and is one of the biliary tract cancers. Most cases are found late, or by chance when a gallbladder is removed for gallstones. It is rare in the UK, with about 1,300 cases a year, and much commoner in Chile, Bolivia and northern India. Found early, an operation can cure it.","summary":"The gallbladder is a pear-shaped pouch about 8 cm long under the right lobe of the liver that concentrates and stores bile; it is not essential and people digest normally without it (CRUK, what is gallbladder cancer). Cancer here is grouped with cholangiocarcinoma as biliary tract cancer, and most systemic-therapy evidence comes from mixed biliary trials, but gallbladder cancer differs in its causes (gallstones and chronic inflammation rather than liver fluke or primary sclerosing cholangitis), its geography, the way it is found (often incidentally in a cholecystectomy specimen), its staging (a separate AJCC chapter with the T2a and T2b split) and its molecular profile (HER2 alterations more often than FGFR2 fusions or IDH1 mutations). Hundal and Shaffer describe it as the commonest biliary tract cancer, 80 to 95 percent of biliary tract cancers in their review, and Roa and colleagues note that most cases are discovered incidentally after cholecystectomy for symptomatic stones.\n\nWorld: the IARC gallbladder fact sheet, served today with the GLOBOCAN 2024 estimates, gives 126,384 new cases (22nd commonest cancer, age-standardised rate 1.2 per 100,000) and 92,029 deaths (20th, 0.82 per 100,000) a year, with 72.4 percent of cases in Asia, 10.0 percent in Europe, 8.8 percent in Latin America and the Caribbean and 4.3 percent in Northern America. The highest national age-standardised incidence on the sheet is Bolivia (6.7 per 100,000, both sexes; 6.0 in men) and Chile (7.6 per 100,000 in women); the highest regions are South Central Asia, South America and Eastern Asia. Earlier GLOBOCAN rounds gave lower counts, so the version matters when figures are compared. Randi and colleagues (2006) recorded the highest registry rates in women in Delhi (21.5 per 100,000), South Karachi (13.8) and Quito (12.9), high rates in Korea, Japan and parts of central and eastern Europe, and a female to male ratio of about 3. In the United States about 3,700 people a year were diagnosed in 2007 to 2011 (1.13 per 100,000) and 2,000 died (0.62 per 100,000), two thirds of them women, with rates three times higher in American Indian and Alaska Native people (Henley 2015); a 2026 meta-analysis found 3 to 3.5-fold higher incidence in Native American people nationally and 6 to 8.5-fold in the Southwest and Alaska (Kosuru 2026). SEER incidence fell by 1.65 percent a year from 1973 but has been flat since 2002 (Low 2022). In India a Tata Memorial registry of 1,950 patients (2019 to 2022) found 84.6 percent came from, or had migrated from, the Gangetic belt, and 60 percent had metastatic disease at presentation (Patkar 2025); in Pakistan a prospective series of 233 cases was 77 percent women with a mean age of 55 (Malik 2003).\n\nUnited Kingdom (Cancer Research UK, drawing on the national registries): 1,288 new cases a year (2019 and 2021 to 2022 average, ICD-10 C23), around 900 in females and 380 in males, under 1 percent of all cancers; 54 percent are diagnosed at 75 or over and rates peak at ages 85 to 89, which account for 13 percent of cases. Incidence rates have risen by 79 percent since the early 1990s and by 33 percent in the last decade, and are projected to rise a further 43 percent by 2038 to 2040 to about 3,100 cases a year. Rates are higher in the Asian and Black ethnic groups than the White group in England (2013 to 2017). There are about 810 deaths a year (2022 to 2024), 60 percent at 75 or over; it is the 23rd commonest cause of cancer death (20th in women). Mortality rates are 28 percent lower than in the early 1970s but 29 percent higher than a decade ago. Lifetime risk is about 1 in 210 for females and 1 in 670 for males born in 1961. A UK primary-care cohort found biliary tract cancer incidence rising 4 percent a year in 2000 to 2010 and higher in the most deprived quintile (Keane 2014). Half of cases in England (2019) were diagnosed after an emergency presentation and 17 percent through an urgent suspected cancer referral; in Northern Ireland 24 percent of staged cases were stage I or II (2015 to 2019); in England in 2022, 21 percent of patients had surgery, 22 percent systemic therapy and 2 percent radiotherapy as part of primary treatment (CRUK main statistics page). National Disease Registration Service tables could not be read directly for this record (the site blocks automated readers); the CRUK figures above are derived from registry data.\n\nRisk factors, with the evidence: gallstones are the strongest (pooled relative risk 4.9 for a history of benign gallbladder disease, Randi 2006; odds ratio 7.26 for gallbladder cancer in a 2021 meta-analysis of 30 studies, Huang; hazard ratio 7.35 for gallbladder cancer death in 396,720 Koreans followed by ultrasound, Ryu 2016), and larger stones carry more risk (odds ratio 2.4 for stones 2.0 to 2.9 cm and 10.1 for 3 cm or larger versus under 1 cm, Diehl 1983). Yet gallstones are very common and this cancer very rare, so most people with stones never develop it (CRUK). Porcelain gallbladder: about eight times the risk (CRUK, citing Schnelldorfer), but the 2013 systematic review found cancer in only 6 percent of calcified gallbladders in studies without selection bias against 1 percent in matched controls, and a 2018 cohort observed 90 patients for a mean 3.2 years without a cancer (DesJardins). Gallbladder polyps: about 8 percent of polyps of 10 mm or more are malignant and about 4 percent of polyps reach that size (CRUK, citing Elmasry 2016, whose review found 0.57 percent of 5,482 ultrasound-detected polyps were malignant). Primary sclerosing cholangitis: 37 percent of explanted gallbladders showed dysplasia and 14 percent adenocarcinoma in one transplant series (Lewis 2007); polyps were seen in 16 percent of 453 patients and the cancer rate among those with a polyp was 8.8 per 1,000 person-years (van Erp 2020). Chronic Salmonella Typhi carriage: summary relative risk 4.6 for anti-Vi antibodies and 5.0 for bile or stool culture across more than 1,000 cases (Koshiol 2016; pooled 4.8 in Randi 2006). Anomalous pancreaticobiliary junction: about seven times the risk in a meta-analysis of case-control studies (CRUK, citing Deng 2011); in a 2025 MRCP series the anomaly was present in 0.44 percent of benign cholecystectomies but 16 percent of gallbladder cancers, an estimated 38-fold higher incidence (Shirai 2025). Obesity: 20 percent of UK cases are attributed to overweight and obesity; risk is 22 to 29 percent higher in overweight women and 68 to 78 percent higher in obese women, and 43 to 54 percent higher in obese men (CRUK risk page; relative risk 1.69 for obesity across 14 cohorts, Liu 2016). Sex and age: 71 percent of UK patients are women and risk climbs steeply after 75 (CRUK). Aflatoxin: exposure markers were found in 32 percent of Shanghai gallbladder cancer patients against 15 percent of gallstone controls, odds ratio 7.61 for the top exposure quartile and a population attributable fraction of 20 percent (Koshiol 2017), with a parallel signal in Chile (Nogueira 2015). Genetics: a family history raises risk about five-fold (CRUK); the Indian genome-wide association study found risk variants at 7q21.12 spanning the bile phospholipid transporter genes ABCB1 and ABCB4 (per-allele odds ratios 1.47 to 1.61) and estimated a sibling relative risk of 3.15 from common variation (Mhatre 2017); in Chile each 1 percent rise in Mapuche ancestry raised risk by about 0.8 percent in a Mendelian randomisation analysis, partly through gallstones (Zollner 2023; Lorenzo Bermejo 2017). Also on the CRUK list: type 2 diabetes (44 to 49 percent higher), smoking (19 percent higher in current smokers), heavy alcohol (about three times at 50 g or more a day), choledochal cysts and ionising radiation. About 20 percent of UK cases are judged preventable.\n\nPresentation takes two forms. A large share is found by the pathologist after a cholecystectomy for presumed gallstone disease: 0.25 to 0.89 percent of all cholecystectomy specimens in the series reviewed by Soreide (2019), 0.29 percent of 9,698 in a Danish department (0.08 percent under 60, 0.67 percent over 60; Lerche-Jorgensen 2025). The rest present with symptoms that are vague until late: pain or a dragging feeling in the right upper abdomen, feeling or being sick, loss of appetite and weight, fever, a lump in the abdomen, a swollen abdomen, and jaundice with itching, dark urine and pale stools (NHS). In the Pakistani series pain was the presenting symptom in 89 percent, weight loss in 42 percent, jaundice in 33 percent and a palpable mass in a quarter (Malik 2003). Jaundice usually means the tumour has reached the bile duct or hilar nodes: even among patients without distant spread who were operated on, five-year survival was 21.9 percent with jaundice against 68.3 percent without (Chaudhary 2021, Langenbecks Arch Surg, doi 10.1007/s00423-020-02075-8). The NHS asks people to seek urgent help for jaundice or for vomiting lasting more than two days, and NICE NG12 (1.2.10) tells GPs to consider an urgent direct-access ultrasound for an upper abdominal mass consistent with an enlarged gallbladder.\n\nDiagnosis: ultrasound is the first test for a gallbladder mass, wall thickening or polyp, and the joint European polyp guideline keeps it as the primary investigation, with contrast-enhanced or endoscopic ultrasound reserved for expert centres in difficult cases (Foley 2022). Contrast CT of chest, abdomen and pelvis stages the tumour and judges resectability (pooled sensitivity 99 percent, specificity 76 percent for resectability; Li 2013); MRI with MRCP maps the bile ducts and liver invasion. Both are weak at finding involved lymph nodes: CT sensitivity ranged from 25 to 93 percent across studies and MRI pooled sensitivity was 75 percent (de Savornin Lohman 2019). FDG PET-CT is accurate for the primary (sensitivity 96 percent) and for distant metastases (95 percent) but less so for nodes (75 percent), and changes management in a meaningful share of patients (Parida 2021); gallbladder cancers are PET-avid, and PET can spare a futile re-resection (Soreide 2019). Blood tests include liver function and the tumour markers CA 19-9 and CEA, which are raised more often in cancer than in benign disease but cannot make or exclude the diagnosis and did not predict survival in a 200-patient Indian series (Sinha 2022); 58 percent of the Pakistani series had a raised CEA (Malik 2003). The AHPBA consensus sets the minimum staging as contrast cross-sectional imaging plus diagnostic laparoscopy (Aloia 2015). When imaging shows a resectable mass, UK hepatobiliary teams generally do not biopsy through the tumour beforehand: the Liverpool MDT relied on the surgeon's intraoperative assessment with frozen section, which matched final histology in every case but doubled operating time (Chan 2022), and an Imperial College unit runs a single-stage operation in which frozen section decides whether to extend a cholecystectomy to a radical resection (Banh 2024). Biopsy is used when the disease is clearly unresectable and systemic treatment is planned, or to confirm metastases (NHS tests page lists biopsy, laparoscopy and ERCP among the possible tests).\n\nPathology: about 90 percent are adenocarcinomas, which Cancer Research UK divides into non-papillary, papillary and mucinous; squamous cell carcinoma makes up about 5 percent, and adenosquamous carcinoma, small cell (neuroendocrine) carcinoma, sarcoma, neuroendocrine tumours and lymphoma are rare (CRUK types page). The WHO Classification of Tumours of the Digestive System, 5th edition (2019; summarised by Nagtegaal 2020), is the reference classification for the gallbladder and extrahepatic bile ducts; it also names the precursor lesions, flat biliary intraepithelial neoplasia and the polypoid intracholecystic papillary neoplasm (Adsay 2012; Akita 2019). Mucinous carcinoma is defined by extracellular mucin in more than half of the tumour and was 2.5 percent of 606 carcinomas (Dursun 2012); adenosquamous carcinoma needs a squamous component above 25 percent and was 5 percent of adenocarcinoma-plus-adenosquamous cases in the National Cancer Database (Murimwa 2021; Gasparello 2026); neuroendocrine carcinoma was 31 of 636 cancers, under 5 percent, in a pathology cohort and 1.6 percent of gallbladder carcinomas in SEER (Reid 2026; Cai 2022). Grade runs from 1 (well differentiated) to 3 (poorly differentiated) (CRUK stages and grades). Early cancers are often invisible to the naked eye: 60 percent of 190 Tis, T1a and T1b tumours were not apparent on gross examination, which is why the AHPBA asks for at least three sections and the cystic duct margin from every routine specimen in high-incidence areas (Roa 2013; Aloia 2015). Each subtype has its own page below.\n\nStaging follows the AJCC and UICC TNM 8th edition (2017), described in plain words by Cancer Research UK. Tis: cancer cells confined to the lining. T1a: into the connective tissue under the lining; T1b: into the muscle layer. T2: through the muscle into the connective tissue beyond it, still within the gallbladder, split into T2a on the peritoneal side (the free side facing the abdominal cavity) and T2b on the hepatic side (the side against the liver). T3: through the outer wall, or into the liver or one adjacent organ. T4: into the main portal vein or hepatic artery, or into two or more organs outside the liver. N1: one to three regional nodes; N2: four or more (the count replaced the 7th edition's anatomical grouping after series such as Shirai 2012 showed 0, 1 to 3 and 4 or more nodes stratified survival). M1: distant spread. Stage groups: I is T1 N0, II is T2 N0, IIIA is T3 N0, IIIB is T1 to T3 with N1, IVA is T4 with N0 or N1, and IVB is any N2 or any M1. What each means for surgery: Tis and T1a are cured by the cholecystectomy already done in almost all cases (five-year survival up to 100 percent after cholecystectomy alone, Soreide 2019); from T1b upwards guidelines recommend radical (extended) cholecystectomy with resection of the liver bed and portal lymphadenectomy, though the T1b benefit is contested (meta-analysis of 26 cohorts: better overall survival with extended surgery, hazard ratio 0.48, but no difference in disease-specific survival, Cho 2026; no survival difference in 950 National Cancer Database patients, Rhodin 2024); T2b tumours carry more vascular invasion (51 versus 19 percent), perineural invasion (33 versus 8 percent) and nodal spread (40 versus 17 percent) than T2a and roughly twice the hazard of death (Shindoh 2015; Alrawashdeh 2022 meta-analysis of 2,531 patients), so liver resection matters most on the hepatic side; T3 disease is resectable when one adjacent organ can be taken en bloc; T4 disease and N2 nodes, or para-aortic node involvement, rarely benefit from resection and are directed to systemic treatment (Aloia 2015). The 8th edition N split did not improve prognostic performance over the 7th in a 7,743-patient validation (Giannis 2021), and a Korean series found the N category discriminated only when six or more nodes had been examined (Sung 2020), the count the AHPBA asks surgeons to aim for.\n\nScreening and prevention: there is no screening programme for gallbladder cancer in the UK because no test picks it up reliably at an early stage (CRUK screening page), and none exists anywhere at population level, even in Chile or northern India (open problem). Prevention rests on managing the precursors. Polyps: the 2022 ESGAR, EAES, EFISDS and ESGE guideline recommends cholecystectomy for polyps of 10 mm or more; for 6 to 9 mm polyps with a risk factor (age over 60, primary sclerosing cholangitis, Asian ethnicity, or a sessile polyp including focal wall thickening over 4 mm); ultrasound at 6 months, 1 year and 2 years for 6 to 9 mm polyps without risk factors or 5 mm or smaller polyps with one, stopping after 2 years if there is no growth; no follow-up for polyps of 5 mm or less with no risk factors; cholecystectomy if a polyp reaches 10 mm, and discussion if it grows 2 mm or more (Foley 2022). Cancer Research UK lists anomalous pancreaticobiliary junction and choledochal cysts among the congenital risk factors, and the 38-fold incidence estimated with the maljunction (Shirai 2025) is the argument for removing the gallbladder once it is found. Prophylactic cholecystectomy has traditionally been advised for porcelain gallbladder (the CRUK patient page says a doctor may suggest it); that advice is now debated because the cancer risk in unselected calcified gallbladders is far lower than once thought and observation caused no cancers in a 90-patient cohort (Schnelldorfer 2013; DesJardins 2018). Weight, alcohol and smoking are the modifiable factors the NHS names.\n\nIncidental cancer is the commonest route to cure. About half of incidental tumours are pT2 and a third pT1 (Soreide 2019). For T1b or deeper disease the patient should be referred to a hepatobiliary centre for re-resection, ideally 4 to 8 weeks after the first operation (median survival 40.4 months, against 17.4 months for under 4 weeks and 22.4 months for over 8 weeks in 207 US patients, Ethun 2017), with cross-sectional imaging and often PET-CT in the interval. Port-site metastases fell from 18.6 percent before 2000 to 10.3 percent since (Berger-Richardson 2017), and routine excision of port sites has no effect on survival (Soreide 2019). A Dutch study found only 53.9 percent of patients eligible for re-resection were referred to a tertiary centre (van Dooren 2024), a gap the UK pathway pages take up.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Gallbladder_cancer","links":[{"label":"CRUK: what is gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer"},{"label":"CRUK: types of gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/types"},{"label":"CRUK: stages and grades of gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/stages-and-grades"},{"label":"CRUK: risks and causes of gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/risks-causes"},{"label":"CRUK: survival for gallbladder cancer (England and SEER by stage)","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/survival"},{"label":"CRUK: screening for gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/getting-diagnosed/screening"},{"label":"CRUK: gallbladder cancer statistics (diagnosis routes, stage, treatment)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/gallbladder-cancer"},{"label":"CRUK: gallbladder cancer incidence statistics","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/gallbladder-cancer/incidence"},{"label":"CRUK: gallbladder cancer mortality statistics","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/gallbladder-cancer/mortality"},{"label":"CRUK: gallbladder cancer survival statistics","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/gallbladder-cancer/survival"},{"label":"CRUK: gallbladder cancer risk factors (professional)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/gallbladder-cancer/risk-factors"},{"label":"NHS: gallbladder cancer","url":"https://www.nhs.uk/conditions/gallbladder-cancer/"},{"label":"NHS: symptoms of gallbladder cancer","url":"https://www.nhs.uk/conditions/gallbladder-cancer/symptoms/"},{"label":"NHS: causes of gallbladder cancer","url":"https://www.nhs.uk/conditions/gallbladder-cancer/causes/"},{"label":"NHS: tests and next steps for gallbladder cancer","url":"https://www.nhs.uk/conditions/gallbladder-cancer/tests-and-next-steps/"},{"label":"GLOBOCAN gallbladder fact sheet (IARC Global Cancer Observatory)","url":"https://gco.iarc.who.int/media/globocan/factsheets/cancers/12-gallbladder-fact-sheet.pdf"},{"label":"NICE NG12: suspected cancer, recommendations by site (gall bladder cancer 1.2.10)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"},{"label":"NCI PDQ: gallbladder cancer","url":"https://www.cancer.gov/types/gallbladder"},{"label":"Roa, Nature Reviews Disease Primers 2022: gallbladder cancer","url":"https://doi.org/10.1038/s41572-022-00398-y"},{"label":"Hundal and Shaffer, Clin Epidemiol 2014: gallbladder cancer epidemiology and outcome","url":"https://doi.org/10.2147/clep.s37357"},{"label":"Randi, Int J Cancer 2006: gallbladder cancer worldwide, geographical distribution and risk factors","url":"https://doi.org/10.1002/ijc.21683"},{"label":"Henley, Cancer Epidemiol Biomarkers Prev 2015: gallbladder cancer incidence and mortality, United States 1999 to 2011","url":"https://doi.org/10.1158/1055-9965.epi-15-0199"},{"label":"Kosuru, J Racial Ethn Health Disparities 2026: gallbladder cancer incidence in Native American people, 1962 to 2021","url":"https://doi.org/10.1007/s40615-026-02959-3"},{"label":"Low, Am J Clin Oncol 2022: SEER trends in gallbladder cancer incidence 1973 to 2015","url":"https://doi.org/10.1097/coc.0000000000000918"},{"label":"Patkar, Cancer Epidemiol 2025: hospital-based gallbladder cancer registry, Tata Memorial, India","url":"https://doi.org/10.1016/j.canep.2025.102958"},{"label":"Malik, J Gastroenterol Hepatol 2003: 233 gallbladder cancers in Pakistan","url":"https://doi.org/10.1046/j.1440-1746.2003.03066.x"},{"label":"Keane, PLoS One 2014: incidence of pancreatic and biliary tract cancer in UK primary care 2000 to 2010","url":"https://doi.org/10.1371/journal.pone.0108498"},{"label":"Diehl, JAMA 1983: gallstone size and the risk of gallbladder cancer","url":"https://doi.org/10.1001/jama.1983.03340170049027"},{"label":"Huang, Epidemiol Health 2021: gallstones and biliary tract cancer risk, meta-analysis","url":"https://doi.org/10.4178/epih.e2021011"},{"label":"Ryu, Am J Gastroenterol 2016: gallstones and gallbladder cancer mortality in 396,720 Koreans","url":"https://doi.org/10.1038/ajg.2016.345"},{"label":"Schnelldorfer, J Gastrointest Surg 2013: porcelain gallbladder, benign process or concern for malignancy","url":"https://doi.org/10.1007/s11605-013-2170-0"},{"label":"DesJardins, J Am Coll Surg 2018: is observation of porcelain gallbladder safe","url":"https://doi.org/10.1016/j.jamcollsurg.2017.11.026"},{"label":"Elmasry, Int J Surg 2016: risk of malignancy in ultrasound-detected gallbladder polyps","url":"https://doi.org/10.1016/j.ijsu.2016.07.061"},{"label":"ESGAR, EAES, EFISDS and ESGE joint guideline on gallbladder polyps (Foley, Eur Radiol 2022)","url":"https://doi.org/10.1007/s00330-021-08384-w"},{"label":"Lewis, Am J Surg Pathol 2007: gallbladder neoplasia in primary sclerosing cholangitis explants","url":"https://doi.org/10.1097/01.pas.0000213435.99492.8a"},{"label":"van Erp, Liver Int 2020: gallbladder polyps and cancer risk in primary sclerosing cholangitis","url":"https://doi.org/10.1111/liv.14326"},{"label":"Koshiol, Cancer Med 2016: Salmonella Typhi and gallbladder cancer, case-control and meta-analysis","url":"https://doi.org/10.1002/cam4.915"},{"label":"Shirai, J Hepatobiliary Pancreat Sci 2025: prevalence of pancreaticobiliary maljunction and gallbladder cancer incidence","url":"https://doi.org/10.1002/jhbp.12187"},{"label":"Liu, Med Sci Monit Basic Res 2016: body mass index and gallbladder cancer, meta-analysis of 14 cohorts","url":"https://doi.org/10.12659/msmbr.901651"},{"label":"Koshiol, Gastroenterology 2017: aflatoxin and gallbladder cancer (Shanghai case-control)","url":"https://doi.org/10.1053/j.gastro.2017.04.005"},{"label":"Nogueira, JAMA 2015: aflatoxin and gallbladder cancer in Chile","url":"https://doi.org/10.1001/jama.2015.4559"},{"label":"Mhatre, Lancet Oncol 2017: genome-wide association study of gallbladder cancer in India (ABCB1 and ABCB4)","url":"https://doi.org/10.1016/s1470-2045(17)30167-5"},{"label":"Lorenzo Bermejo, PLoS Genet 2017: Mapuche ancestry and gallbladder cancer risk in Chile","url":"https://doi.org/10.1371/journal.pgen.1006756"},{"label":"Zollner, Cancers 2023: Mapuche ancestry and gallbladder cancer, Mendelian randomisation","url":"https://doi.org/10.3390/cancers15164033"},{"label":"AHPBA expert consensus statement on gallbladder cancer (Aloia, HPB 2015)","url":"https://doi.org/10.1111/hpb.12444"},{"label":"Soreide, Br J Surg 2019: systematic review of incidental gallbladder cancer after cholecystectomy","url":"https://doi.org/10.1002/bjs.11035"},{"label":"Ethun, JAMA Surg 2017: timing of re-resection for incidental gallbladder cancer","url":"https://doi.org/10.1001/jamasurg.2016.3642"},{"label":"Berger-Richardson, Surgery 2017: trends in port-site metastasis after laparoscopic resection of incidental gallbladder cancer","url":"https://doi.org/10.1016/j.surg.2016.08.007"},{"label":"van Dooren, BJS Open 2024: referral of incidental gallbladder cancer from 27 Dutch secondary centres","url":"https://doi.org/10.1093/bjsopen/zrae013"},{"label":"Lerche-Jorgensen, Dan Med J 2025: incidental gallbladder cancer in 9,698 cholecystectomies","url":"https://doi.org/10.61409/a11240787"},{"label":"Shindoh, Ann Surg 2015: tumour location in T2 gallbladder cancer (hepatic versus peritoneal side)","url":"https://doi.org/10.1097/sla.0000000000000728"},{"label":"Alrawashdeh, HPB 2022: meta-analysis of T2a and T2b gallbladder cancer","url":"https://doi.org/10.1016/j.hpb.2021.12.019"},{"label":"Sung, Cancer Res Treat 2020: validation of the AJCC 8th edition for gallbladder cancer","url":"https://doi.org/10.4143/crt.2019.271"},{"label":"Giannis, Cancers 2021: AJCC 8th edition validation in the National Cancer Database","url":"https://doi.org/10.3390/cancers13030547"},{"label":"Shirai, World J Surg Oncol 2012: number of positive nodes (0, 1 to 3, 4 or more) in gallbladder cancer","url":"https://doi.org/10.1186/1477-7819-10-87"},{"label":"Cho, Ann Hepatobiliary Pancreat Surg 2026: extended versus simple cholecystectomy for T1b, meta-analysis","url":"https://doi.org/10.14701/ahbps.26-091"},{"label":"Rhodin, HPB 2024: simple versus radical cholecystectomy for T1b in the National Cancer Database","url":"https://doi.org/10.1016/j.hpb.2024.01.012"},{"label":"Chen, Front Oncol 2023: wedge resection versus segment IVb and V resection for T2, meta-analysis","url":"https://doi.org/10.3389/fonc.2023.1186378"},{"label":"Parida, Nucl Med Commun 2021: FDG PET-CT in staging gallbladder cancer, meta-analysis","url":"https://doi.org/10.1097/mnm.0000000000001405"},{"label":"Li, Clin Imaging 2013: CT for assessing resectability of gallbladder carcinoma, meta-analysis","url":"https://doi.org/10.1016/j.clinimag.2012.05.009"},{"label":"de Savornin Lohman, Eur J Radiol 2019: CT and MRI for lymph node metastases in gallbladder cancer","url":"https://doi.org/10.1016/j.ejrad.2018.11.034"},{"label":"Sinha, World J Gastrointest Surg 2022: CA 19-9, CEA, CA 125 and CA 242 in gallbladder cancer","url":"https://doi.org/10.4240/wjgs.v14.i11.1272"},{"label":"Chan, J Surg Oncol 2022: intraoperative frozen section for suspected gallbladder cancer (Liverpool)","url":"https://doi.org/10.1002/jso.26726"},{"label":"Banh, Int J Surg 2024: single-stage management of suspected gallbladder cancer with frozen section (London)","url":"https://doi.org/10.1097/js9.0000000000001456"},{"label":"Roa, Virchows Arch 2013: early gallbladder carcinoma and Rokitansky-Aschoff sinus involvement","url":"https://doi.org/10.1007/s00428-013-1478-1"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"Zhu, Medicine 2020: survival of 2,433 SEER gallbladder cancer patients 2010 to 2015","url":"https://doi.org/10.1097/md.0000000000022292"},{"label":"Chaudhary, Langenbecks Arch Surg 2021: resection in gallbladder cancer with jaundice","url":"https://doi.org/10.1007/s00423-020-02075-8"},{"label":"TOPAZ-1 (NEJM Evidence 2022)","url":"https://doi.org/10.1056/EVIDoa2200015"},{"label":"KEYNOTE-966 (Lancet 2023)","url":"https://doi.org/10.1016/S0140-6736(23)00727-4"},{"label":"HERIZON-BTC-01 (Lancet Oncol 2023)","url":"https://doi.org/10.1016/S1470-2045(23)00242-5"},{"label":"NCCN: Biliary Tract Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1517"},{"label":"NHS: gallbladder cancer, treatment","url":"https://www.nhs.uk/conditions/gallbladder-cancer/treatment/"},{"label":"NHS: gallbladder cancer, help and support","url":"https://www.nhs.uk/conditions/gallbladder-cancer/help-and-support/"},{"label":"Macmillan: gallbladder cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/gallbladder-cancer"},{"label":"Cancer Research UK: gallbladder cancer treatment decisions","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/treatment/treatment-decisions"},{"label":"Cancer Research UK: follow up after gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/treatment/follow-up"},{"label":"AMMF, the UK cholangiocarcinoma charity","url":"https://ammf.org.uk/"},{"label":"AMMF: UK centres with hepatobiliary expertise","url":"https://ammf.org.uk/second-opinions-and-liver-disease-centres/"},{"label":"ESMO: biliary tract cancer, a guide for patients","url":"https://www.esmo.org/for-patients/patient-guides/biliary-tract-cancer-a-guide-for-patients"},{"label":"NICE TA944: durvalumab with gemcitabine and cisplatin for unresectable or advanced biliary tract cancer","url":"https://www.nice.org.uk/guidance/ta944"},{"label":"Cancer Research UK: prehabilitation","url":"https://www.cancerresearchuk.org/about-cancer/treatment/prehabilitation"},{"label":"BILCAP: adjuvant capecitabine (Lancet Oncology 2019)","url":"https://doi.org/10.1016/S1470-2045(18)30915-X"},{"label":"Cancer Research UK: chemotherapy for gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/treatment/chemotherapy"},{"label":"Cancer Research UK: immunotherapy for gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/treatment/immunotherapy"},{"label":"Cancer Research UK: surgery for gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/treatment/surgery"},{"label":"cBioPortal study gbc_mskcc_2022 (Gallbladder Cancer, MSK 2022; 244 samples from 233 patients)","url":"https://www.cbioportal.org/study/summary?id=gbc_mskcc_2022"},{"label":"cBioPortal study gbc_msk_2018 (Gallbladder Cancer, MSK, Cancer 2018; 103 samples)","url":"https://www.cbioportal.org/study/summary?id=gbc_msk_2018"},{"label":"cBioPortal study gbc_shanghai_2014 (Gallbladder Carcinoma, Shanghai, Nat Genet 2014; 32 exomes)","url":"https://www.cbioportal.org/study/summary?id=gbc_shanghai_2014"},{"label":"Giraldo et al., Clin Cancer Res 2022: MSK-IMPACT profiling of 244 gallbladder carcinoma samples","url":"https://doi.org/10.1158/1078-0432.ccr-22-1954"},{"label":"Suryavanshi et al., JCO Glob Oncol 2025: genomic profiling of 376 Indian gallbladder carcinomas","url":"https://doi.org/10.1200/go-25-00332"},{"label":"Mondaca et al., JCO Glob Oncol 2024: ERBB2-altered gallbladder cancer in an American and a Chilean cohort","url":"https://doi.org/10.1200/go.24.00090"},{"label":"NICE: guidance on biliary tract cancers","url":"https://www.nice.org.uk/guidance/conditions-and-diseases/cancer/biliary-tract-cancers/products"},{"label":"IARC Cancer Today: GLOBOCAN 2022 (gallbladder, C23) by country and sex","url":"https://gco.iarc.who.int/today"},{"label":"ICMR-NCDIR: National Cancer Registry Programme report 2020, gall bladder (C23-C24) by registry","url":"https://ncdirindia.org/All_Reports/Report_2020/resources/Chapter5ComparisonofcancerincidenceandpatternsofallPopulationBasedCancerRegistries.pdf"},{"label":"Superintendencia de Salud (Chile): GES problem 26, preventive cholecystectomy at 35 to 49","url":"https://www.supersalud.gob.cl/difusion/665/w3-propertyvalue-1962.html"},{"label":"National Cancer Center Japan: gallbladder and bile duct cancer statistics","url":"https://ganjoho.jp/reg_stat/statistics/stat/cancer/9_gallbladder.html"},{"label":"ESMO Clinical Practice Guideline: biliary tract cancer (Ann Oncol 2023)","url":"https://doi.org/10.1016/j.annonc.2022.10.506"},{"label":"CAPBIL: incidental gallbladder cancer in the UK (Br J Surg 2026)","url":"https://doi.org/10.1093/bjs/znag050"}],"tags":["gallbladder","biliary","nci-coverage","rare"],"related":["cholangiocarcinoma","ampullary","biliary-tract-cancer","gallbladder-adenocarcinoma","incidental-gallbladder-cancer","globocan","seer","her2-ihc-3-plus","her2-ihc-2-plus","her2-ish-amplified","her2-mutation","msi-high","dmmr-ihc","tmb-high","ntrk-fusion","pd-l1-tps","pd-l1-cps","braf-v600e","gallbladder-cancer-roadmap"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","checkpoint-inhibitor","monoclonal-antibody","cgp","robotic-surgery","biliary-stenting-drainage","palliative-care","pain-management","oncology-nutrition","multidisciplinary-tumour-board","enteral-parenteral-nutrition","cbt-fatigue-distress","exercise-during-chemotherapy","liquid-biopsy","gallbladder-cancer-surgery","sbrt"],"targets":["her2","pd1","pdl1","braf","ntrk","tp53","kras","her3","pik3ca","cdkn2a","cdkn2b","arid1a","smad4","ctnnb1","egfr","mdm2","idh","fgfr2","mmr","brca","atm","palb2","elf3","stk11","ccne1"],"drugs":["gemcitabine-cisplatin","durvalumab","pembrolizumab","zanidatamab","folfox","capecitabine","dabrafenib-trametinib","larotrectinib","entrectinib","trastuzumab-deruxtecan","her2-testing-assays","foundationone-cdx","guardant360-cdx","ventana-mmr-rxdx","trastuzumab","pertuzumab","zanidatamab-zovodotin","liposomal-irinotecan","nab-paclitaxel","varlitinib","tegafur-gimeracil-oteracil","ivonescimab"],"companies":["astrazeneca","merck","jazz"],"institutions":["cruk","nice","ammf","kings-college-hospital-london","liverpool-hpb-centre","royal-free-hospital","birmingham-cancer-centre","leeds-cancer-centre","newcastle-cancer-centre","southampton-cancer"],"pathways":["inflammation-nfkb","rtk-activation","ras-mapk","pi3k-akt-mtor","p53-cell-cycle","p53-mdm2-axis","cell-cycle-engine-cdks","wnt","homologous-recombination-repair","mismatch-repair-msi"],"terms":["porcelain-gallbladder","gallbladder-polyp","simple-cholecystectomy","radical-cholecystectomy","segment-ivb-v-resection","port-site-metastasis","t2a-versus-t2b","rokitansky-aschoff-sinus","anomalous-pancreaticobiliary-junction","cystic-duct-margin","ca19-9","biliary-anatomy-subtypes","obstructive-jaundice","hepatectomy","lymphadenectomy","tnm-staging","staging-laparoscopy","carcinoma-in-situ","dysplasia","tumour-grade","peritoneal-metastasis","incidental-gallbladder-cancer","stent-or-bypass-for-jaundice","genomic-testing-biliary-uk","trial-or-standard-treatment-biliary","jaundice-and-itch-biliary","biliary-stent-problems","acute-cholangitis","pain-with-biliary-cancer","weight-loss-and-fat-digestion-biliary","cancer-related-fatigue","eating-after-gallbladder-removal","urgent-help-gallbladder-cancer","emotional-support-cancer-uk","carers-gallbladder-cancer-uk","biliary-stent","cachexia","performance-status","metaplasia-dysplasia-carcinoma-sequence","intracholecystic-papillary-tubular-neoplasm","salmonella-typhi-gallbladder-cancer","her2-testing-in-biliary-cancer","ihc","fish","msi","tmb","ctdna","ngs","gene-amplification","her2-positive","tumour-agnostic","tils","mutational-signature","hrd","lynch-syndrome","gallbladder-cancer-in-biliary-trials","biliary-drainage-routes","duodenal-stenting-gastric-outlet","gallbladder-cancer-symptom-control","prophylactic-cholecystectomy"],"trials":["bilcap","topaz-1","keynote-966","abc-02","herizon-btc-302","abc-06","mypathway","destiny-pantumor02","acticca-1","ascot-jcog1202","swog-s0809","opt-in","gain-igbc","polcagb","neogb","rugb","debate","swog-s1815","gap-phase2-mdacc","nifty","nife","treetopp","eortc-1607-pembro-cisgem","sevilla","safir-abc10","determine-arm04","abc-07","abc-12","ea2197-ivonescimab","combomatch-binimetinib-folfox","trap-btc","tesla-rct","herizon-btc-01","roar","keynote-158","nct05482516","nct07062263","nct07745296","nct06037980","nct06355427","nct06662877","nct07437287","nct07598318","nct02151084","nct02632305","nct03364530","nct03482102","nct03801083","nct03937830","nct04005339","nct04042831","nct04183712","nct04238637","nct04634058","nct04910386","nct04941287","nct04969887","nct05170438","nct05222971","nct05422690","nct05451043","nct05451290","nct05640791","nct05705492","nct05724563","nct05733000","nct05757336","nct05985707","nct06001658","nct06037655","nct06048133","nct06135896","nct06230471","nct06274879","nct06280508","nct06389500","nct06423170","nct06438822","nct06490107","nct06502080","nct06530823","nct06531291","nct06591650","nct06620848","nct06638931","nct06654947","nct06708858","nct06717464","nct06728410","nct06789848","nct06852287","nct06892925","nct06901622","nct06903273","nct06919848","nct06963060","nct06993025","nct07003815","nct07025174","nct07036380","nct07062536","nct07099794","nct07105852","nct07109167","nct07129018","nct07135544","nct07146646","nct07151872","nct07159204","nct07159217","nct07160283","nct07263360","nct07267078","nct07282262","nct07282912","nct07296666","nct07310069","nct07351591","nct07433673","nct07471165","nct07472933","nct07478523","nct07506057","nct07514533","nct07530445","nct07561775","nct07569679","nct07570849","nct07599995","nct07623642","nct07631884","nct07635290","nct07636824","nct07638501","nct07649980","nct07654530","nct07668453","nct07670273","nct07679399","nct07701122","nct07704177","nct07723534","nct07726446","nct07729033","nct07729917","nct07733115","nct07767994","nct07780838","nct07786766","nct07793253","nct07797816","nct07829874","nct07831993","nct04068194","nct04645160","nct04781192","nct05000294","nct05749900","nct05849480","nct05994001","nct06548412","nct07269158","nct07392541","nct07594626","nct07632235","nct07636798","nct06109779"],"people":[],"bottlenecks":["b-rare-cancers","b-early-detection"],"keyPapers":["paper-li-gallbladder-exome-erbb-nat-genet-2014","paper-nakamura-biliary-genomic-spectra-nat-genet-2015","paper-javle-biliary-ngs-cancer-2016","paper-wardell-biliary-drivers-germline-j-hepatol-2018","paper-narayan-gallbladder-regional-mutations-cancer-2019","paper-weinberg-biliary-profiling-jgo-2019","paper-pandey-gallbladder-elf3-nat-commun-2020","paper-nepal-gallbladder-microenvironment-subtypes-j-hepatol-2021","paper-giraldo-gallbladder-msk-impact-ccr-2022","paper-mondaca-erbb2-gallbladder-us-chile-jco-go-2024","paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025","paper-erices-chilean-gallbladder-landscape-front-oncol-2025","paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026","paper-goeppert-cholangiocarcinoma-mmr-deficiency-bjc-2019","paper-hiraoka-her2-status-biliary-hum-pathol-2020","paper-roa-her2-overexpression-gallbladder-gcr-2014","paper-angerilli-her2-ihc-cish-biliary-hum-pathol-2026","paper-neyaz-pdl1-gallbladder-histopathology-2018","paper-albrecht-pdl1-western-gallbladder-cancers-2021","paper-patil-gallbladder-immune-microenvironment-aimm-2021","paper-scanu-salmonella-gallbladder-transformation-cell-host-microbe-2015","paper-roa-gallbladder-preneoplastic-lesions-jso-2006","paper-roa-dysplasia-to-carcinoma-interval-gastroenterology-1996","paper-adsay-icpn-gallbladder-ajsp-2012","paper-lin-gallbladder-neoplasia-carcinoma-evolution-nat-commun-2021","paper-mody-biliary-ctdna-profiling-jco-po-2019","paper-ettrich-cholangiocarcinoma-ctdna-genotyping-sci-rep-2019","paper-javle-mypathway-her2-biliary-lancet-oncol-2021","paper-ohba-herb-trastuzumab-deruxtecan-biliary-jco-2024","paper-oh-destiny-pantumor02-biliary-pancreatic-esmo-open-2026","paper-harding-lancet-oncol"],"journals":[],"dependsOn":[],"notes":["Patients and carers ask: my gallbladder was removed for stones and the report says cancer, what now? It depends on how deep the tumour went. Tis and T1a tumours confined to the lining and the layer beneath are treated by the operation already done. T1b or deeper tumours are referred to a liver and bile duct (hepatobiliary) centre for a second operation, ideally 4 to 8 weeks after the first, after new scans (Soreide 2019; Ethun 2017).","Is gallbladder cancer the same as bile duct cancer? They are grouped together as biliary tract cancers and share the same chemotherapy trials, but the gallbladder is a separate organ with its own staging, its own causes (gallstones rather than liver disease) and a different mix of gene changes (CRUK, what is gallbladder cancer; Roa 2022).","I have gallstones, will I get it? Gallstones raise the risk about five-fold, but gallbladder cancer is very rare and the great majority of people with stones never develop it (CRUK risks and causes).","Should my polyp be removed? The European guideline says yes at 10 mm or more, yes at 6 to 9 mm with a risk factor (age over 60, primary sclerosing cholangitis, Asian ethnicity, a sessile polyp or wall thickening over 4 mm), and otherwise ultrasound checks at 6, 12 and 24 months; polyps of 5 mm or less with no risk factor need no follow-up (Foley 2022).","I have a porcelain gallbladder, must it come out? The link with cancer is weaker than older textbooks said: about 6 percent in unbiased studies versus 1 percent in controls, and one cohort observed 90 people for three years without a cancer. Many surgeons still offer removal to fit patients; the decision is individual (Schnelldorfer 2013; DesJardins 2018; CRUK).","Is there a screening test? No. There is no UK screening programme because no test finds it reliably early (CRUK screening page).","Why was it found so late, or at A and E? Symptoms are vague until the tumour blocks the bile duct or forms a mass, and half of English cases are diagnosed after an emergency presentation (NHS; CRUK).","Does it run in families? A family history raises risk about five-fold, and common inherited variants near the bile transporter genes ABCB1 and ABCB4 were found in India, but no single gene test is used and the absolute risk stays small (CRUK; Mhatre 2017).","Which symptoms need urgent attention? Yellow eyes or skin, or being sick for more than two days: ask for an urgent GP appointment or call 111 the same day (NHS symptoms page).","What do T2a and T2b mean on my report? Both mean the tumour has grown through the muscle layer but is still inside the gallbladder. T2a is on the free (peritoneal) side; T2b is on the side against the liver, which spreads more often, so the surgeon removes more liver tissue (CRUK stages page; Shindoh 2015).","Frequencies marked cBioPortal were computed from the public API on the named study id on 24 September 2026 as sample-level counts (mutation, high-level amplification or deep deletion) over the study's sequenced or copy-number sample list; they are not the paper's own per-patient percentages, which are quoted alongside where the abstract gives them."],"group":"gastrointestinal","burden":"Around 1,300 people a year in the UK, seven in ten of them women and more than half aged 75 or over; rare here, but common where gallstones are common, above all Bolivia, Chile, northern India and Pakistan (Cancer Research UK; GLOBOCAN).","subtypes":["Gallbladder adenocarcinoma (about 90 percent; biliary, intestinal, mucinous and other patterns)","Papillary carcinoma of the gallbladder, and its precursor the intracholecystic papillary neoplasm","Mucinous carcinoma of the gallbladder (about 2.5 percent)","Adenosquamous and squamous carcinoma of the gallbladder (about 5 percent)","Neuroendocrine carcinoma of the gallbladder (small cell and large cell; under 5 percent)","Incidental gallbladder cancer found in the cholecystectomy specimen","Carcinoma in situ and dysplasia of the gallbladder (biliary intraepithelial neoplasia; stage 0)","Cystic duct carcinoma (staged with gallbladder cancer)"],"biomarkers":["T category on the cholecystectomy specimen (T1a versus T1b or deeper decides whether a second operation is offered)","T2a versus T2b (peritoneal versus hepatic side), the strongest pathological predictor within T2","Cystic duct margin status (positive margin adds a bile duct resection)","Lymph node count and number involved (N1 one to three, N2 four or more; six or more nodes examined for a reliable N stage)","Grade 1 to 3 and histological type (adenosquamous and neuroendocrine carcinomas behave worse)","Lymphovascular and perineural invasion; Rokitansky-Aschoff sinus involvement in early cancers","HER2 amplification or over-expression (more frequent than in cholangiocarcinoma; the molecular rows below carry the figures by cohort)","Mismatch repair deficiency, BRAF V600E, NTRK fusions (tumour-agnostic treatments)","CA 19-9 and CEA (often raised, neither diagnostic nor reliably prognostic)","TP53 mutation: 63% (63% of 244 MSK-IMPACT samples (Giraldo 2022)","KRAS mutation (amplification rarer): 11% (11% of 244 samples (Giraldo 2022)","ERBB2 (HER2) amplification: 8-10% (8% amplification alone plus 1.5% amplification with a mutation among 260 patients (Mondaca 2024))","ERBB2 (HER2) activating mutation (s310f/y hotspot): 4-8% (4% mutation alone, 1.5% with amplification and 0.4% fusion among 260 patients (Mondaca 2024))","ERBB2 (HER2) protein overexpression (ihc): 9-31% (31.3% HER2-positive among 80 resected Japanese gallbladder carcinomas scored by the gastro-oesophageal guideline (Hiraoka 2020))","ERBB3 (HER3) mutation (amplification rarer): 7-12% (11.8% of 57 (Li 2014, a significantly mutated gene))","PIK3CA mutation: 11% (Mutation in 26 of 244 samples, 10.7%, in cBioPortal gbc_mskcc_2022 and 11 of 103, 10.7%, in gbc_msk_2018)","CDKN2A / CDKN2B deletion or mutation: 21% (CDKN2A 21% (Giraldo 2022))","CDKN2B deep deletion (with cdkn2a): 14% (Deep deletion in 34 of 244 samples, 13.9%, in cBioPortal gbc_mskcc_2022 and 12 of 103, 11.7%, in gbc_msk_2018)","ARID1A mutation (loss of function): 13-25% (13% of 85 (Javle 2016))","SMAD4 mutation or deletion: 21-38% (38% in Chile, 36% in Japan and 27% in the United States among 81 patients, with worse survival (10 versus 25 months)","CTNNB1 mutation (wnt activation): 6% (Mutation in 15 of 244 samples, 6.1%, in cBioPortal gbc_mskcc_2022 and 6 of 103, 5.8%, in gbc_msk_2018)","EGFR amplification or mutation: 1-3% (Amplification in 8 of 244 samples, 3.3%, and mutation in 3 of 244, 1.2%, in cBioPortal gbc_mskcc_2022)","MDM2 amplification: 12% (Amplification in 29 of 244 samples, 11.9%, in cBioPortal gbc_mskcc_2022 and 12 of 103, 11.7%, in gbc_msk_2018)","BRAF mutation: 3% (Mutation in 7 of 244 samples, 2.9%, in cBioPortal gbc_mskcc_2022 and 5 of 103, 4.9%, in gbc_msk_2018)","IDH1 / IDH2 mutation: 0.4% (IDH1 mutation in 1 of 244 samples, 0.4%, and no IDH2 mutation in cBioPortal gbc_mskcc_2022)","FGFR2 fusion, mutation or amplification: 1% (No FGFR2 fusion among the structural variants deposited for cBioPortal gbc_mskcc_2022)","NTRK1 / NTRK2 / NTRK3 gene fusion: 0.4% (One LMNA::NTRK1 fusion patient (four samples) among 233 patients in cBioPortal gbc_mskcc_2022, about 0.4%)","MLH1 / MSH2 / MSH6 / PMS2 microsatellite instability (msi-high): 0.6-2.5% (6 of 244 samples, 2.5%, called unstable by MSIsensor in cBioPortal gbc_mskcc_2022)","Tumour mutational burden tmb (mutations per megabase): 1-12% (Median 4.1 non-synonymous mutations per megabase, with 28 of 244 samples, 11.5%, at 10 or more on the MSK-IMPACT panel (cBioPortal gbc_mskcc_2022))","BRCA1 / BRCA2 mutation (somatic or germline): 1-5% (BRCA2 mutation in 13 of 244 samples, 5.3%, and BRCA1 in 3 of 244, 1.2%, in cBioPortal gbc_mskcc_2022)","ATM mutation: 7-16% (Mutation in 16 of 244 samples, 6.6%, in cBioPortal gbc_mskcc_2022 and 16 of 103, 15.5%, in gbc_msk_2018)","PALB2 mutation: 1.6% (Mutation in 4 of 244 samples, 1.6%, in cBioPortal gbc_mskcc_2022)","ELF3 frameshift and truncating mutation: 9% (Mutation in 21 of 244 samples, 8.6%, in cBioPortal gbc_mskcc_2022)","STK11 mutation: 9% (Mutation in 22 of 244 samples, 9.0%, in cBioPortal gbc_mskcc_2022)","CCNE1 amplification: 9% (Amplification in 22 of 244 samples, 9.0%, in cBioPortal gbc_mskcc_2022)","CD274 (PD-L1) protein expression (ihc): 15-23% (Tumour cells positive at 1% or more in 23.0% of 174 Indian cases (SP263)"],"standardOfCare":[{"setting":"Suspected cancer in primary care","approach":"Urgent direct-access ultrasound for an upper abdominal mass consistent with an enlarged gallbladder (NICE NG12 1.2.10); urgent referral for jaundice; the UK pathway page carries the detail.","refs":["ultrasound","obstructive-jaundice"],"guideline":{"version":"NICE NG12 (2015, updated)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"}},{"setting":"Diagnosis and staging","approach":"Ultrasound, contrast CT, MRI with MRCP, FDG PET-CT before radical surgery, staging laparoscopy; frozen section rather than needle biopsy when the mass is resectable.","refs":["ultrasound","ct","mri","pet-ct","staging-laparoscopy","tnm-staging"]},{"setting":"Tis or T1a found in the cholecystectomy specimen","approach":"No further surgery when the cystic duct margin is clear; the simple cholecystectomy is curative in almost all cases.","refs":["simple-cholecystectomy","cystic-duct-margin","gallbladder-carcinoma-in-situ-and-dysplasia"]},{"setting":"T1b, T2 or T3 (incidental or suspected before surgery)","approach":"Radical (extended) cholecystectomy: resection of the liver bed (wedge or segments IVb and V) with portal lymphadenectomy, bile duct resection only when the cystic duct margin is positive; re-resection 4 to 8 weeks after an incidental diagnosis; port sites not routinely excised.","refs":["radical-cholecystectomy","segment-ivb-v-resection","hepatectomy","lymphadenectomy","cystic-duct-margin","port-site-metastasis","incidental-gallbladder-cancer"],"guideline":{"version":"AHPBA consensus statement (HPB 2015)","url":"https://doi.org/10.1111/hpb.12444"}},{"setting":"After resection","approach":"Adjuvant capecitabine for six months (BILCAP, a UK trial in a mixed biliary population that required muscle-invasive gallbladder cancer for entry); the BILCAP record carries the figures, and the UK CAPBIL cohort saw no matched benefit, so ACTICCA-1 is awaited.","refs":["capecitabine","bilcap","acticca-1"],"guideline":{"version":"BILCAP (Lancet Oncol 2019)","url":"https://doi.org/10.1016/S1470-2045(18)30915-X"}},{"setting":"Unresectable or metastatic disease, first line","approach":"Gemcitabine and cisplatin with durvalumab (TOPAZ-1, in which 25 percent of patients had gallbladder cancer; NICE TA944) or with pembrolizumab (KEYNOTE-966; not appraised by NICE), with molecular profiling including HER2 at diagnosis and biliary drainage first if jaundiced. Second-line, HER2-directed and other targeted options follow in the rows below.","refs":["gemcitabine-cisplatin","durvalumab","pembrolizumab","topaz-1","keynote-966","her2"],"guideline":{"version":"NICE TA944 (2024)","url":"https://www.nice.org.uk/guidance/ta944"}},{"setting":"Polyps and precursors (prevention)","approach":"Cholecystectomy for polyps of 10 mm or more, or 6 to 9 mm with a risk factor; ultrasound surveillance at 6, 12 and 24 months otherwise; no follow-up for polyps of 5 mm or less without risk factors (ESGAR, EAES, EFISDS and ESGE 2022).","refs":["gallbladder-polyp","porcelain-gallbladder","anomalous-pancreaticobiliary-junction","simple-cholecystectomy"],"guideline":{"version":"Joint European polyp guideline (Eur Radiol 2022)","url":"https://doi.org/10.1007/s00330-021-08384-w"}},{"setting":"Jaundice from a blocked bile duct: stent or bypass","approach":"A stent placed by ERCP, or through the skin (PTC), is the usual way to relieve jaundice; metal stents stay open longer than plastic and are used when surgery to remove the cancer is not planned; a surgical bypass (joining the bile duct above the blockage to the small bowel) is reserved for people already having an operation or when a stent cannot be placed. Jaundice must be relieved before chemotherapy can be given safely.","refs":["biliary-stenting-drainage","stent-or-bypass-for-jaundice","biliary-stent","obstructive-jaundice"],"guideline":{"version":"Almadi 2017 meta-analyses (metal versus plastic stents); Cancer Research UK advanced gallbladder cancer","url":"https://doi.org/10.1038/ajg.2016.512"}},{"setting":"Newly diagnosed advanced disease: HER2 and genomic testing","approach":"HER2 testing (immunohistochemistry and in situ hybridisation) and a tumour gene panel at diagnosis of advanced disease: about one in ten gallbladder cancers is HER2-positive on staining and about one in seven carries a HER2 gene change, and zanidatamab is licensed (MHRA, February 2026) and NICE-recommended (TA1153, May 2026) for HER2-positive biliary cancer after chemotherapy; mismatch repair, BRAF V600E and NTRK results open tumour-agnostic options. On the NHS the hospital team requests the test through the Genomic Medicine Service on tissue already taken.","refs":["her2-testing-assays","cgp","zanidatamab","her2","genomic-testing-biliary-uk","genomic-profiling"],"guideline":{"nccn":"Molecular testing recommended for all advanced biliary tract cancers","version":"NCCN Guidelines: Biliary Tract Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1517"}},{"setting":"A clinical trial or standard treatment","approach":"At every stage a trial can be a reasonable choice beside standard treatment: ask what the comparison arm is, whether a placebo is used (in KEYNOTE-966 the control arm had chemotherapy plus placebo, never placebo alone), what extra visits are involved, and that you can leave at any time. AMMF lists biliary trials open in the UK; HERIZON-BTC-302 is the first-line HER2 trial.","refs":["trial-or-standard-treatment-biliary","clinical-trial","informed-consent","placebo","keynote-966","herizon-btc-302"],"guideline":{"version":"NHS: clinical trials; ESMO patient guide to biliary tract cancer","url":"https://www.esmo.org/for-patients/patient-guides/biliary-tract-cancer-a-guide-for-patients"}},{"setting":"Locally advanced, unresectable, non-metastatic","approach":"Gemcitabine and cisplatin with durvalumab as for metastatic disease; consider chemoradiotherapy or stereotactic radiotherapy within a trial (UK ABC-07; India POLCAGB, RUGB) and reassess for conversion surgery.","refs":["topaz-1","abc-07","polcagb","rugb","sbrt"],"guideline":{"nccn":"Category 2A (systemic therapy); radiotherapy 2B","version":"NCCN Biliary Tract Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1517"}},{"setting":"HER2-positive (IHC 3+ or amplified), after first-line therapy","approach":"Zanidatamab (HERIZON-BTC-01: 41 percent response, 53 percent gallbladder cancer; FDA 2024, EU 2025, MHRA February 2026, NICE TA1153 May 2026) or trastuzumab deruxtecan for IHC 3+ (DESTINY-PanTumor02 biliary cohort 45 percent response; FDA tumour-agnostic 2024, not NICE-appraised); trastuzumab with pertuzumab through the UK DETERMINE platform; first-line zanidatamab within HERIZON-BTC-302 and SAFIR-ABC10.","refs":["zanidatamab","herizon-btc-01","trastuzumab-deruxtecan","destiny-pantumor02","determine-arm04","herizon-btc-302","safir-abc10","her2"],"guideline":{"nccn":"Category 2A","version":"NICE TA1153 (7 May 2026)","url":"https://www.nice.org.uk/guidance/ta1153"}},{"setting":"Other actionable alterations (rare in gallbladder cancer)","approach":"BRAF V600E: dabrafenib with trametinib (ROAR biliary cohort 51 percent response; FDA tumour-agnostic 2022). Mismatch-repair deficiency or high tumour mutational burden: pembrolizumab (KEYNOTE-158). NTRK fusion: larotrectinib or entrectinib. KRAS G12C: sotorasib or adagrasib off-label or in trials. FGFR2 fusions (pemigatinib, futibatinib) and IDH1 mutations (ivosidenib) are intrahepatic features; the licences and NICE appraisals (TA722, TA1005, TA948) cover cholangiocarcinoma and the trials enrolled almost no gallbladder cancer.","refs":["dabrafenib-trametinib","roar","pembrolizumab","keynote-158","larotrectinib","entrectinib","sotorasib","adagrasib","pemigatinib","futibatinib","ivosidenib","cgp"],"guideline":{"nccn":"Category 2A (tumour-agnostic)","version":"NCCN Biliary Tract Cancers; NICE TA722, TA948, TA1005","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1517"}},{"setting":"Second line, no actionable target","approach":"FOLFOX with active symptom control (ABC-06, UK: overall survival 6.2 versus 5.3 months; gallbladder cancer eligible); liposomal irinotecan with fluorouracil is an NCCN option on NIFTY but was negative in NALIRICC and is not commissioned in the UK; trials preferred (SEVILLA ivonescimab versus FOLFOX at UCL; ComboMATCH for MAPK-mutant disease).","refs":["folfox","abc-06","liposomal-irinotecan","nifty","naliricc","sevilla"],"guideline":{"nccn":"Category 1 (FOLFOX)","version":"ABC-06 (Lancet Oncology 2021); NCCN Biliary Tract Cancers","url":"https://doi.org/10.1016/S1470-2045(21)00027-9"}},{"setting":"Palliation of obstruction and symptoms","approach":"Biliary drainage by ERCP metal stent, percutaneous transhepatic drainage for hilar block or failed ERCP, or EUS-guided drainage (non-inferior to ERCP with fewer complications in a 125-patient randomised trial); duodenal stent or gastrojejunostomy for gastric outlet obstruction by expected survival (SUSTENT); opioids with coeliac plexus block for visceral pain; paracentesis or tunnelled catheter for ascites; early integrated palliative care.","refs":["biliary-drainage-routes","biliary-stenting-drainage","duodenal-stenting-gastric-outlet","gallbladder-cancer-symptom-control","palliative-care"],"guideline":{"nccn":"Category 2A","version":"NCCN Biliary Tract Cancers; ESMO 2023","url":"https://doi.org/10.1016/j.annonc.2022.10.506"}}],"stateOfArt":["Where it is found matters more than any drug: the same tumour has a five-year survival near 100 percent as a T1a incidental finding and under 5 percent once it has spread (Soreide 2019; CRUK quoting SEER).","The 8th edition split of T2 into peritoneal-side T2a and hepatic-side T2b, built on the 437-patient international series of Shindoh and colleagues, is the main staging advance of the decade and steers how much liver is removed.","Incidental cancers are rising with the volume of cholecystectomies; the evidence now favours re-resection 4 to 8 weeks after the first operation, PET-CT beforehand, and no routine port-site excision.","The joint European polyp guideline (2022) gives ultrasound-based rules by polyp size and risk factor, replacing ad hoc surveillance.","Immunotherapy added to gemcitabine and cisplatin is the first-line standard for advanced disease and HER2 is the most useful gallbladder-specific target; the standard-of-care rows and the trial records linked from this page carry the evidence.","The disease is under-studied on its own: most trial evidence comes from mixed biliary populations and UK statistics do not report it by stage.","Genomic landscape. TP53 (47 to 63%), CDKN2A/B loss (14 to 21%), ERBB2 (14 to 16%, split roughly 8% amplification and 4% mutation), KRAS (7 to 11%), PIK3CA (about 11%), ARID1A (13 to 25%), SMAD4 (21 to 38%, prognostic), CTNNB1 (about 6%), ELF3 (about 9%), STK11 (about 9%, prognostic), MDM2 amplification (about 12%) and CCNE1 amplification (about 9%) define the disease; IDH1 (0.4%), FGFR2 fusions (none deposited) and NTRK fusions (about 0.4%) are rare, the mirror image of intrahepatic cholangiocarcinoma. About a third of patients carry something actionable (Giraldo 2022) and 22% a top-tier alteration (Cowzer 2026). Every figure and cohort is in the molecular table.","Regional biology. Indian patients present a decade earlier with less ARID1A, SMAD4 and CDKN2A but the same 15% ERBB2 (Suryavanshi 2025); Chilean tumours show lower TP53 and high TSC2 and NOTCH1 on a small panel series (Erices 2025) and a comparable ERBB2 rate to the United States (Mondaca 2024); Japanese tumours are older, better differentiated, less stone-related and lack ARID1A and PIK3CA mutations (Narayan 2019); Chinese exomes put the ErbB pathway in 36.8% (Li 2014).","Premalignant sequence. Most cancers arise through flat metaplasia, dysplasia and carcinoma in situ over 10 to 15 years (Roa 1996, 2006); a minority through adenomas and intracholecystic papillary-tubular neoplasms, which carry invasive cancer in 55% but a better outlook (Adsay 2012). CTNNB1 sits at the start of the raised route and some carcinomas diverge early from the visible precursor (Lin 2021). Chronic Salmonella Typhi carriage raises risk four to five fold and the bacterium transforms predisposed cells through MAPK and AKT signalling (Koshiol 2016, Scanu 2015).","Immune microenvironment. PD-L1 on tumour cells at a 1% cut-off is 14.7% in Western and 23% in Indian series, and higher PD-L1 marks poorly differentiated tumours with shorter survival (Albrecht 2021, Neyaz 2018); poor-survival transcriptomic subtypes are defined by myeloid suppressor cells, desmoplasia, hypoxia and T-cell dysfunction (Nepal 2021). MSI-high (0.6 to 2.5%) and TMB-high are rare, and the first-line immunotherapy approvals were unselected.","Testing. HER2 is scored by the gastric rules; IHC 3+ is enough for zanidatamab and IHC 2+ needs ISH; staining is heterogeneous in most positive tumours, so larger samples are preferred (Hiraoka 2020, Angerilli 2026). A comprehensive panel at diagnosis captures ERBB2 copy number and mutations, MSI, TMB, BRAF, NTRK and repair genes in one run, and plasma panels found a therapeutically relevant alteration in 55% of advanced biliary patients (Mody 2019). Germline testing is warranted because 11% of biliary patients carried a predisposing repair-gene variant (Wardell 2018)."],"history":[{"year":1777,"title":"First description","note":"Maximilian de Stoll describes gallbladder carcinoma at autopsy in Vienna.","refs":[]},{"year":1882,"title":"Carl Langenbuch performs the first cholecystectomy","note":"Lazarus Hospital, Berlin, July 1882 (Hardy 1993; Traverso 1976). The operation for gallstones through which most gallbladder cancers are still discovered.","refs":["radical-cholecystectomy","incidental-gallbladder-cancer"]},{"year":1954,"title":"Radical cholecystectomy proposed","note":"Glenn and Hays describe en bloc liver-bed resection with lymphadenectomy.","refs":["radical-cholecystectomy"]},{"year":1976,"title":"Nevin stages gallbladder cancer by depth of invasion","note":"Sixty-six cases and 399 from the literature; essentially all found incidentally at gallstone surgery.","refs":["paper-nevin-gallbladder-carcinoma-staging-cancer-1976","tnm-staging"]},{"year":1983,"title":"Large gallstones linked to cancer","note":"Diehl's case-control study finds an odds ratio of 10.1 for stones of 3 cm or more.","refs":[]},{"year":2006,"title":"Chile guarantees preventive cholecystectomy for gallstones at ages 35 to 49","note":"The GES programme, the world's only national prophylactic cholecystectomy policy against gallbladder cancer; 284,139 notifications by 2024.","refs":["prophylactic-cholecystectomy","paper-samaniego-chile-ges-programme-evaluation-rev-med-chile-2024"]},{"year":2007,"title":"Residual disease found in 46 percent of re-resections for incidental cancer","note":"Pawlik and colleagues, six centres, 115 patients: the observational basis for re-resecting T1b or deeper tumours.","refs":["paper-pawlik-incidental-gallbladder-cancer-residual-disease-jgs-2007","radical-cholecystectomy"]},{"year":2010,"title":"Gemcitabine and cisplatin become the biliary standard","note":"ABC-02 (NEJM 2010) in a mixed biliary population including gallbladder cancer.","refs":["abc-02","gemcitabine-cisplatin"]},{"year":2010,"title":"Cystic duct cancer joins gallbladder staging","note":"The AJCC 7th edition stages carcinoma of the cystic duct with gallbladder cancer.","refs":["cystic-duct-carcinoma"]},{"year":2014,"title":"First exome landscape of gallbladder cancer","note":"57 Chinese tumours: TP53 47%, ERBB3 12%, ErbB pathway in 37% with worse survival (Li et al., Nature Genetics).","refs":["paper-li-gallbladder-exome-erbb-nat-genet-2014","her3","tp53"]},{"year":2015,"title":"Hepatic-side T2 tumours shown to behave worse","note":"Shindoh and colleagues' international series (437 patients) separates peritoneal-side from hepatic-side T2 disease: five-year survival 42.6 versus 64.7 percent.","refs":["t2a-versus-t2b","paper-shindoh-t2-gallbladder-cancer-tumour-location-ann-surg-2015"]},{"year":2015,"title":"Biliary subtypes separated molecularly","note":"260 Japanese biliary cancers: FGFR2 fusions intrahepatic, APOBEC signature and ELF3 in gallbladder and extrahepatic tumours (Nakamura et al., Nature Genetics).","refs":["paper-nakamura-biliary-genomic-spectra-nat-genet-2015","elf3"]},{"year":2015,"title":"SWOG S0809: the only prospective adjuvant chemoradiation trial","note":"79 patients, two-year survival 65 percent; no randomised trial has followed.","refs":["swog-s0809","paper-swog-s0809-adjuvant-chemoradiation-jco-2015"]},{"year":2017,"title":"AJCC and UICC 8th edition","note":"T2 is split into T2a and T2b and N stage is defined by the number of involved nodes (N1 one to three, N2 four or more).","refs":["tnm-staging","t2a-versus-t2b","paper-chun-ajcc-8th-edition-hepatobiliary-aso-2018"]},{"year":2017,"title":"First genome-wide risk variants","note":"The Indian genome-wide association study finds common variants at ABCB1 and ABCB4 that raise gallbladder cancer risk.","refs":[]},{"year":2017,"title":"Re-resection at four to eight weeks associated with longest survival","note":"Ethun and colleagues, ten US centres, 207 patients; a 2026 individual patient data meta-analysis found no difference by timing.","refs":["paper-ethun-re-resection-timing-incidental-gallbladder-cancer-jama-surg-2017","paper-selvakumar-revision-surgery-timing-ipd-meta-analysis-hpb-2026"]},{"year":2019,"title":"BILCAP: adjuvant capecitabine","note":"Six months of capecitabine after resection of biliary tract cancer becomes the adjuvant standard.","refs":["bilcap"]},{"year":2019,"title":"WHO classification, 5th edition","note":"The digestive system volume standardises the nomenclature of gallbladder carcinoma and its precursors (biliary intraepithelial neoplasia, intracholecystic papillary neoplasm).","refs":["gallbladder-carcinoma-in-situ-and-dysplasia"]},{"year":2020,"title":"Three-continent gallbladder genomics","note":"167 tumours from Korea, India and Chile: ELF3 frameshift neoantigens, CTNNB1, STK11 and Wnt alterations (Pandey et al., Nature Communications).","refs":["paper-pandey-gallbladder-elf3-nat-commun-2020","ctnnb1"]},{"year":2021,"title":"ABC-06 published: second-line FOLFOX","note":"Median overall survival 6.2 vs 5.3 months; one-year survival 25.9 vs 11.4 percent. NIFTY (liposomal irinotecan) published the same year.","refs":["abc-06","paper-abc-06-folfox-second-line-lancet-oncol-2021","nifty"]},{"year":2022,"title":"Joint European polyp guideline updated","note":"ESGAR, EAES, EFISDS and ESGE set size and risk-factor rules for cholecystectomy and ultrasound follow-up.","refs":["gallbladder-polyp","paper-gallbladder-polyp-joint-guideline-eur-radiol-2022"]},{"year":2022,"title":"TOPAZ-1: durvalumab added to chemotherapy","note":"First immunotherapy survival benefit in biliary tract cancer; FDA approval September 2022.","refs":["topaz-1","durvalumab"]},{"year":2022,"title":"MSK-IMPACT reference cohort","note":"244 samples: TP53 63%, CDKN2A 21%, ERBB2 15%, KRAS 11%, actionable alterations in 35% of patients (Giraldo et al., Clinical Cancer Research).","refs":["paper-giraldo-gallbladder-msk-impact-ccr-2022"]},{"year":2023,"title":"KEYNOTE-966: pembrolizumab confirms the class effect","refs":["keynote-966","pembrolizumab"]},{"year":2023,"title":"HERIZON-BTC-01 published; ESMO biliary tract cancer guideline","note":"Zanidatamab response rate 41.3 percent in HER2-positive disease after chemotherapy.","refs":["herizon-btc-01","paper-harding-lancet-oncol","paper-esmo-biliary-tract-cancer-guideline-ann-oncol-2023"]},{"year":2024,"title":"Zanidatamab for HER2-positive biliary cancer","note":"FDA accelerated approval (November 2024) on HERIZON-BTC-01, in which gallbladder cancer was the largest subgroup.","refs":["zanidatamab","her2"]},{"year":2025,"title":"Indian and Chilean landscapes published","note":"376 Indian patients (Suryavanshi et al.) and 56 Chilean tumours (Erices et al.) give the high-incidence regions their own frequencies.","refs":["paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025","paper-erices-chilean-gallbladder-landscape-front-oncol-2025"]},{"year":2025,"title":"TOPAZ-1 three-year update; ctDNA residual disease shown prognostic after biliary resection","note":"36-month survival 14.6 vs 6.9 percent with durvalumab. Residual disease hazard ratios of 26 (2025) and 15.86 (2026) in two cohorts.","refs":["paper-topaz-1-three-year-survival-j-hepatol-2025","paper-yu-ctdna-early-recurrence-biliary-tract-cancer-jco-po-2025","paper-malla-ctdna-resected-biliary-tract-cancer-esmo-gi-onc-2026"]},{"year":2026,"title":"CAPBIL: first UK nationwide gallbladder cancer cohorts","note":"285 incidental cancers and 516 operated patients across 24 centres, 2014 to 2022; 67.7 percent of incidental cancers had liver resection.","refs":["paper-mcclements-capbil-incidental-gallbladder-cancer-bjs-2026","paper-mcclements-capbil-surgical-outcomes-gallbladder-cancer-hpb-2026"]}],"pipeline":["zanidatamab","herizon-btc-302","trastuzumab-deruxtecan","gemcis-plus-io-btc","safir-abc10","sevilla","opt-in","acticca-1","abc-07","ea2197-ivonescimab","gain-igbc","polcagb","nct06109779","idea-gbc-report-gallbladder-separately-in-biliary-trials","idea-gbc-national-incidental-cancer-pathway","idea-gbc-t1b-simple-cholecystectomy-prospective-study","idea-gbc-t2a-spare-liver-resection-trial","idea-gbc-reflex-her2-testing-advanced-biliary","idea-gbc-risk-targeted-ultrasound-in-high-incidence-regions","idea-gbc-prophylactic-cholecystectomy-targeted-and-evaluated","idea-gbc-typhoid-carrier-cholecystectomy-or-surveillance","idea-gbc-ctdna-residual-disease-guided-adjuvant-trial","idea-gbc-neoadjuvant-for-high-risk-incidental-cancer","idea-gbc-randomised-adjuvant-chemoradiation-r1-node-positive","idea-gbc-burden-to-funding-audit-and-dedicated-call"],"openProblems":["No screening test and no surveillance programme even in the highest-incidence regions; ultrasound-based surveillance and cholecystectomy policies are unproven.","Whether T1b tumours need radical re-resection: no randomised trial exists, meta-analyses of retrospective cohorts disagree on disease-specific benefit, and the largest international series found five-year disease-specific survival of 93.7 versus 95.5 percent after simple versus extended cholecystectomy in 237 patients (Kim 2018); bile duct excision and port-site policy rest on the same kind of series.","How much liver to remove for T2 disease: a 2023 meta-analysis found better one-year disease-free survival but worse three-year overall survival and more complications with anatomical segment IVb and V resection than with a wedge, and two meta-analyses suggest peritoneal-side (T2a) tumours may not need the liver resection at all.","Only about half of patients eligible for re-resection reached a specialist centre in the Dutch study that measured it, and two thirds had liver resection in the UK CAPBIL cohort; why the rest did not is not recorded.","UK survival and stage at diagnosis are not reported for gallbladder cancer outside Northern Ireland.","Why incidence is rising in the UK while falling in the United States is not explained.","The highest-incidence populations are the least sequenced: 23 Chilean patients in the largest comparative HER2 series and 56 Chilean tumours in the first landscape paper, against 244 samples from New York.","HER2 heterogeneity and loss at progression (Cowzer 2026) mean a positive biopsy does not guarantee benefit and a single diagnostic test may not describe the relapsed tumour.","No immunotherapy biomarker works in gallbladder cancer: PD-L1 rates swing six-fold with the assay, MSI-high and TMB-high are rare, and the transcriptomic microenvironment subtypes have not been tested prospectively.","MDM2 and CCNE1 amplification, SMAD4 and STK11 loss, and ELF3 frameshift neoantigens are recurrent but untargeted in this disease.","Neoadjuvant chemotherapy for incidental gallbladder cancer is untested: GAIN closed after 68 of 333 planned patients and OPT-IN will not report before 2028.","Gallbladder cancer is a quarter or less of the landmark first-line trials and their gallbladder hazard ratios are unpublished or exploratory; S1815 hinted at a gallbladder-specific taxane effect that no trial is designed to confirm.","HER2 positivity in gallbladder cancer ranges from 9 percent (Italian resected series scored by the HERIZON-BTC-01 rule, Angerilli 2026) through 13 percent (Chile, breast scoring, Roa 2014) to 31 percent (Japan, gastric scoring, Hiraoka 2020) depending on cohort and scoring rule, so the size of the zanidatamab-eligible population in the UK is uncertain.","Second-line evidence is thin: FOLFOX adds a month, liposomal irinotecan has one positive and one negative trial, and the UK's randomised second-line option is a single phase 2 (SEVILLA) at one site.","Why the map looks as it does: gallstones explain much of the excess in the Andes, the Gangetic belt and Pakistan but not the sex ratio of Korea and Japan, nor why India's south is spared; ancestry (Mapuche, Aymara, Native American), typhoid carriage, aflatoxin, mustard oil and water contamination are each supported by case-control studies and none by a prevention trial.","Adjuvant capecitabine's benefit is borrowed from BILCAP's mixed population; the UK CAPBIL cohort saw none in matched analysis. ACTICCA-1 and ARTEMIDE-Biliary01 are the tests.","Residual disease blood tests are strongly prognostic after biliary resection but no trial acts on them.","Prevention in high-incidence regions: Chile's prophylactic cholecystectomy programme has run since 2006 without an evaluable design; typhoid carriers have never been offered a trial."],"basics":{"symptoms":["Often none until late; many cancers are found by the pathologist after a gallbladder is removed for stones (NHS; Soreide 2019)","Aching or dragging pain in the right upper tummy, sometimes sharp; feeling or being sick; loss of appetite or unexplained weight loss (NHS)","Yellow whites of the eyes or skin (jaundice), which may be harder to see on brown or black skin, with itchy skin, dark urine and pale stools: seek urgent help the same day (NHS)","A high temperature, a lump in the tummy, or a swollen tummy not related to eating (NHS)","Half of English cases are diagnosed after an emergency presentation, so new or worsening symptoms should not wait for a routine check (CRUK)"],"diagnosis":["GP examination and blood tests (liver function, sometimes CA 19-9 and CEA); NICE NG12 asks for an urgent direct-access ultrasound if there is an upper abdominal mass consistent with an enlarged gallbladder","Ultrasound first for a mass, wall thickening or polyp; endoscopic or contrast-enhanced ultrasound in expert centres for difficult cases (Foley 2022)","Contrast CT of chest, abdomen and pelvis to stage and judge resectability; MRI with MRCP for the bile ducts and liver; both miss small involved nodes (Li 2013; de Savornin Lohman 2019)","FDG PET-CT before any radical or re-resection, accurate for the primary and for distant spread, less so for nodes (Parida 2021)","Staging laparoscopy before radical surgery is part of the minimum work-up in the AHPBA consensus (Aloia 2015)","A needle biopsy is usually avoided when the mass looks resectable; surgeons rely on imaging and intraoperative frozen section, and biopsy when the disease is unresectable and drug treatment is planned (Chan 2022; Banh 2024; NHS)"],"staging":["TNM 8th edition. Tis: confined to the lining. T1a: into the connective tissue under the lining. T1b: into the muscle layer (CRUK)","T2a: through the muscle on the peritoneal (free) side; T2b: on the hepatic (liver) side, which spreads to nodes and vessels more often and roughly doubles the risk of death (Shindoh 2015; Alrawashdeh 2022)","T3: through the outer wall, or into the liver or one other nearby organ. T4: into the main portal vein or hepatic artery, or two or more organs outside the liver (CRUK)","N1: one to three regional nodes; N2: four or more. M1: distant spread (CRUK)","Stage I is T1 N0, stage II is T2 N0, IIIA is T3 N0, IIIB is T1 to T3 with N1, IVA is T4 with N0 or N1, IVB is any N2 or any M1 (CRUK)","For surgery: Tis and T1a are treated by the cholecystectomy already performed; T1b and above are referred for radical cholecystectomy; N2 or para-aortic nodes, T4 or metastases generally rule out resection (Soreide 2019; Aloia 2015)"],"sources":[{"label":"NHS: symptoms of gallbladder cancer","url":"https://www.nhs.uk/conditions/gallbladder-cancer/symptoms/"},{"label":"NHS: tests and next steps for gallbladder cancer","url":"https://www.nhs.uk/conditions/gallbladder-cancer/tests-and-next-steps/"},{"label":"NICE NG12: suspected cancer, recommendations by site (gall bladder cancer 1.2.10)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"},{"label":"CRUK: stages and grades of gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/stages-and-grades"},{"label":"ESGAR, EAES, EFISDS and ESGE joint guideline on gallbladder polyps (Foley, Eur Radiol 2022)","url":"https://doi.org/10.1007/s00330-021-08384-w"},{"label":"AHPBA expert consensus statement on gallbladder cancer (Aloia, HPB 2015)","url":"https://doi.org/10.1111/hpb.12444"},{"label":"Soreide, Br J Surg 2019: systematic review of incidental gallbladder cancer after cholecystectomy","url":"https://doi.org/10.1002/bjs.11035"},{"label":"Shindoh, Ann Surg 2015: tumour location in T2 gallbladder cancer (hepatic versus peritoneal side)","url":"https://doi.org/10.1097/sla.0000000000000728"},{"label":"Alrawashdeh, HPB 2022: meta-analysis of T2a and T2b gallbladder cancer","url":"https://doi.org/10.1016/j.hpb.2021.12.019"},{"label":"Parida, Nucl Med Commun 2021: FDG PET-CT in staging gallbladder cancer, meta-analysis","url":"https://doi.org/10.1097/mnm.0000000000001405"},{"label":"Li, Clin Imaging 2013: CT for assessing resectability of gallbladder carcinoma, meta-analysis","url":"https://doi.org/10.1016/j.clinimag.2012.05.009"},{"label":"de Savornin Lohman, Eur J Radiol 2019: CT and MRI for lymph node metastases in gallbladder cancer","url":"https://doi.org/10.1016/j.ejrad.2018.11.034"},{"label":"Chan, J Surg Oncol 2022: intraoperative frozen section for suspected gallbladder cancer (Liverpool)","url":"https://doi.org/10.1002/jso.26726"},{"label":"Banh, Int J Surg 2024: single-stage management of suspected gallbladder cancer with frozen section (London)","url":"https://doi.org/10.1097/js9.0000000000001456"}]},"prognosis":{"text":"England, people diagnosed 2016 to 2020: around 30 percent survive one year and 11.8 percent survive five years (net survival), similar in men and women and similar to the European average; 18.2 percent at ages 15 to 54 against 6.7 percent at 75 to 99. An older cohort (2009 to 2013) gave 15 percent ten-year survival. There are no UK-wide figures by stage. Cancer Research UK quotes the US SEER programme for people diagnosed 2013 to 2019 instead: more than 65 percent five-year relative survival for localised disease, almost 30 percent for regional disease, and almost 5 percent for distant disease, with the caution that US health care and data collection differ from the UK. Two further figures qualify the averages: cancers confined to the mucosa (T1a or less) had five-year survival of up to 100 percent after cholecystectomy alone in the series reviewed by Soreide, and 190 early (Tis, T1a, T1b) carcinomas from a high-incidence region had 92.3 percent five-year and 90.4 percent ten-year survival (Roa 2013). In a SEER cohort of 2,433 patients diagnosed 2010 to 2015, 82 percent of whom had surgery, median survival was 19 months and five-year survival 28.8 percent (Zhu 2020). Stage at diagnosis, whether a complete resection is possible, jaundice at presentation, histological type and general fitness are the factors these sources name.","sources":[{"label":"CRUK: gallbladder cancer survival statistics","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/gallbladder-cancer/survival"},{"label":"CRUK: survival for gallbladder cancer (England and SEER by stage)","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/survival"},{"label":"Soreide, Br J Surg 2019: systematic review of incidental gallbladder cancer after cholecystectomy","url":"https://doi.org/10.1002/bjs.11035"},{"label":"Roa, Virchows Arch 2013: early gallbladder carcinoma and Rokitansky-Aschoff sinus involvement","url":"https://doi.org/10.1007/s00428-013-1478-1"},{"label":"Zhu, Medicine 2020: survival of 2,433 SEER gallbladder cancer patients 2010 to 2015","url":"https://doi.org/10.1097/md.0000000000022292"}]},"parent":"biliary-tract-cancer"},{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","aka":["STAD","TCGA-STAD","stomach adenocarcinoma (TCGA STAD cohort)"],"tldr":"A cancer with three new targets in five years: Claudin 18.2, FGFR2b, and HER2 with new ADCs, plus immunotherapy in first line.","summary":"Gastric and gastro-oesophageal junction adenocarcinoma is curable when found early: Japan and Korea screen endoscopically and cure most cases. It causes about one million new cases a year, concentrated in East Asia, Eastern Europe, and Latin America, where Helicobacter pylori infection, salt, and smoking drive incidence; elsewhere two-thirds present with advanced disease, which is why it accounts for 660,000 deaths a year and five-year survival outside screened populations is under 30%. Biology splits by the Lauren classification (intestinal vs diffuse) and the TCGA classes (EBV-positive, MSI, genomically stable, chromosomally unstable), and clinically by three actionable biomarkers: HER2 (~15-20%), PD-L1 (CPS ≥5 in ~60%), and Claudin 18.2 (~38% at the approval threshold), with FGFR2b, MSI, and EBV as further strata.\n\nLocalised disease is treated with gastrectomy and D2 lymphadenectomy plus perioperative chemotherapy: FLOT in the West, adjuvant S-1 or CAPOX in Asia. MATTERHORN (2025) added durvalumab to FLOT, the first perioperative immunotherapy with an overall survival benefit (3-year OS 68.6%). Advanced disease is stratified at diagnosis: HER2-positive tumours get trastuzumab + chemotherapy + pembrolizumab (KEYNOTE-811) or, after HERIZON-GEA-01, zanidatamab + chemotherapy ± tislelizumab; HER2-negative, PD-L1 CPS ≥5 tumours get nivolumab or pembrolizumab with chemotherapy (CheckMate 649 5-year OS 16% vs 6%); CLDN18.2-positive tumours get zolbetuximab + chemotherapy (SPOTLIGHT/GLOW). Second line: T-DXd for HER2-positive disease (DESTINY-Gastric04, OS 14.7 vs 11.4 months), ramucirumab + paclitaxel otherwise, and from 2026 the CLDN18.2 ADC sonesitatug vedotin (CLARITY-Gastric 01). Third line: trifluridine/tipiracil.\n\nThe frontier is Claudin 18.2 (ADCs, CAR-T satri-cel approved in China, bispecifics), biomarker overlap and combination quadruplets, peritoneal-directed therapy for the commonest site of relapse, FGFR2b after the mixed FORTITUDE-101 result, and ctDNA-guided perioperative strategies. Diffuse-type and genomically stable tumours remain the least treatable subgroup.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Stomach_cancer","links":[{"label":"NCCN Gastric Cancer guideline","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434"},{"label":"ESMO gastric cancer guideline","url":"https://www.esmo.org/guidelines/guidelines-by-topic/esmo-clinical-practice-guidelines-gastrointestinal-cancers/"},{"label":"NCI PDQ gastric cancer treatment","url":"https://www.cancer.gov/types/stomach/hp/stomach-treatment-pdq"}],"tags":["gi","spike"],"related":[],"cancers":[],"sections":[],"technologies":["adc","car-t","checkpoint-inhibitor","hipec","fapi-pet","gastric-endoscopic-screening","monoclonal-antibody","bispecific-antibody","antiangiogenic","companion-diagnostic","endoscopic-resection"],"targets":["her2","cldn18-2","fgfr2","pd1","fap","vegf","pdl1"],"drugs":["her2-testing-assays","epirubicin","catumaxomab","tegafur-gimeracil-oteracil"],"companies":["neonc-technologies","askgene-pharma","astellas","bms","merck","astrazeneca","daiichi-sankyo","jazz","beone","amgen","eli-lilly","carsgen","remegen","keymed"],"institutions":["ncc-japan","snuh","samsung-medical-center","asan-medical-center","jfcr","sysucc"],"pathways":["pi3k-akt-mtor","gastric-cancer-signalling","ras-mapk","vegf-angiogenesis","pd1-checkpoint"],"terms":["cps","siewert-classification","lauren-classification","peritoneal-metastasis","msi","neoadjuvant-adjuvant","adcc","ild","flot-term"],"trials":["symbiotic-gi-16","nct07362186","nct07385703","aspen-06","nct06532006","nct07673887","nct06177041","nct06504732","nct07103668","int-0116","nct05427383","nct05980481","nct06731478","nct06901531","nct06764875","nct07518147","nct06221748","nct07221149","nct07217704","nct05144854","nct07431281","nct07023315","nct07315750","spotlight-glow","nct07522151","nct06123494","nct06296706","nct04342910"],"people":["mitsuru-sasako"],"bottlenecks":[],"keyPapers":["paper-spotlight-lancet-2023"],"journals":["gastric-cancer","journal-of-gastric-cancer","journal-of-gastrointestinal-cancer"],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"~1 million cases per year, the fifth most common cancer; where endoscopic screening finds it early (Korea, Japan) most cases are cured. 5-year survival exceeds 60% there, versus under 30% in most of the West, where it is found late; ~660,000 deaths per year, fifth among cancers.","subtypes":["Intestinal type (Lauren; H. pylori-associated, HER2-enriched)","Diffuse / signet-ring type (CDH1, spreads to the peritoneum, fewer drug targets)","TCGA: EBV-positive (~9%, PD-L1 high, IO-responsive)","TCGA: MSI-high (~20% localised, ~5% advanced)","TCGA: genomically stable (diffuse, RHOA/CLDN18-ARHGAP fusions)","TCGA: chromosomal instability (HER2, EGFR, MET amplification)","HER2-positive (~15-20%)","CLDN18.2-positive ≥75% (~38%)","FGFR2b-overexpressing (~30% any; ~16% at ≥10% 2+/3+)","Hereditary diffuse gastric cancer (germline CDH1)","GEJ tumours by Siewert type"],"biomarkers":["HER2","PD-L1 CPS","CLDN18.2","MSI","FGFR2b","EBV","HER2 IHC/ISH (all advanced cases)","PD-L1 CPS (22C3 or 28-8)","CLDN18.2 IHC (VENTANA 43-14A; ≥75% 2+/3+)","MSI/dMMR","EBV (EBER in situ hybridisation)","FGFR2b IHC (trials)","Germline CDH1 in diffuse type or family history","Staging laparoscopy with peritoneal cytology","ctDNA (trials)"],"standardOfCare":[{"setting":"Localised","approach":"Perioperative FLOT ± durvalumab; D2 gastrectomy.","refs":["durvalumab","robotic-surgery"],"guideline":{"version":"NCCN Guidelines: Gastric Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434"}},{"setting":"Advanced first line","approach":"Chemotherapy + PD-1 ± trastuzumab ± zolbetuximab by biomarker.","refs":["nivolumab","pembrolizumab","trastuzumab"],"guideline":{"version":"NCCN Guidelines: Gastric Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434"}},{"setting":"Later lines","approach":"T-DXd (HER2+), zanidatamab, CLDN18.2 CAR-T/ADC in trials.","refs":["trastuzumab-deruxtecan","zanidatamab","satricabtagene-autoleucel","cmg901"],"guideline":{"esmoMcbs":"2 (DESTINY-Gastric01 trastuzumab deruxtecan)","version":"NCCN Guidelines: Gastric Cancer","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11163648/"}},{"setting":"Prevention and screening","approach":"H. pylori eradication reduces incidence; endoscopic screening programmes in Japan and Korea (biennial from age 40-50) detect most cancers at a curable stage. No population screening in the West. Prophylactic total gastrectomy for germline CDH1 carriers.","refs":["chemoprevention","germline-testing"],"guideline":{"url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434"}},{"setting":"Early (T1a) disease","approach":"Endoscopic submucosal dissection for well-differentiated mucosal tumours ≤2 cm without ulceration (expanded criteria in Japan); otherwise gastrectomy.","refs":["endoscopic-resection"],"guideline":{"url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434"}},{"setting":"Resectable stage II-III (Western)","approach":"Perioperative FLOT + durvalumab (MATTERHORN: OS HR 0.78, pCR 19%) with D2 gastrectomy; FOLFOX/CAPOX perioperatively for patients unfit for docetaxel.","refs":["matterhorn","flot","durvalumab","capox"],"guideline":{"nccn":"Category 1 (perioperative FLOT)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434"}},{"setting":"Resectable stage II-III (Asian practice)","approach":"D2 gastrectomy then adjuvant S-1 (ACTS-GC) or CAPOX (CLASSIC) for 6-12 months; neoadjuvant approaches increasingly adopted.","refs":["capox","classic"],"guideline":{"url":"https://www.esmo.org/guidelines/guidelines-by-topic/esmo-clinical-practice-guidelines-gastrointestinal-cancers/"}},{"setting":"Advanced, HER2-positive, first line","approach":"Trastuzumab + fluoropyrimidine/platinum + pembrolizumab (KEYNOTE-811, PD-L1 CPS ≥1); zanidatamab + chemotherapy ± tislelizumab after HERIZON-GEA-01 (PFS 12.4 vs 8.1 months; sBLA 2026).","refs":["toga","herizon-gea-01","trastuzumab","zanidatamab","pembrolizumab","tislelizumab","her2-gastric-sequence"],"guideline":{"nccn":"Category 1 (trastuzumab + chemo ± pembrolizumab)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434"}},{"setting":"Advanced, HER2-negative, PD-L1 CPS ≥5 (or ≥1), first line","approach":"Nivolumab (CheckMate 649) or pembrolizumab (KEYNOTE-859) or tislelizumab (RATIONALE-305) with FOLFOX or CAPOX; add zolbetuximab if CLDN18.2-positive (sequencing/combination under study).","refs":["checkmate-649","keynote-859","nivolumab","pembrolizumab","tislelizumab","folfox","capox"],"guideline":{"nccn":"Category 1 (CPS ≥5)","esmoMcbs":"3 (nivolumab, CPS ≥5)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434"}},{"setting":"Advanced, CLDN18.2-positive (≥75%), HER2-negative, first line","approach":"Zolbetuximab + mFOLFOX6 or CAPOX (SPOTLIGHT/GLOW). PD-L1 CPS ≥5 double-positives: either add-on; combination trials ongoing.","refs":["spotlight-glow","zolbetuximab","folfox","capox","idea-biomarker-quadruplet-gastric"],"guideline":{"nccn":"Category 1","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434"}},{"setting":"Advanced, HER2-negative, PD-L1 CPS <1 and CLDN18.2-negative","approach":"FOLFOX or CAPOX chemotherapy alone; MSI-high tumours get PD-1 blockade regardless of CPS.","refs":["folfox","capox","msi"],"guideline":{"url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434"}},{"setting":"Second line, HER2-positive","approach":"Trastuzumab deruxtecan 6.4 mg/kg (DESTINY-Gastric04, OS 14.7 vs 11.4 months) if HER2 persists on re-biopsy or ctDNA.","refs":["destiny-gastric04","trastuzumab-deruxtecan"],"guideline":{"nccn":"Category 1","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434"}},{"setting":"Second line, HER2-negative","approach":"Ramucirumab + paclitaxel (RAINBOW, OS 9.6 vs 7.4 months); CLDN18.2-positive: sonesitatug vedotin after CLARITY-Gastric 01 (2026) or satri-cel CAR-T (China).","refs":["rainbow","ramucirumab","paclitaxel","clarity-gastric01","cmg901","satricabtagene-autoleucel","cldn18-antibody-then-adc"],"guideline":{"nccn":"Category 1 (ramucirumab + paclitaxel)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434"}},{"setting":"Third line and beyond","approach":"Trifluridine/tipiracil (TAGS, OS 5.7 vs 3.6 months); irinotecan; clinical trials (FGFR2b, CLDN18.2 bispecifics, T-cell engagers).","refs":["trifluridine-tipiracil"],"guideline":{"url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1434"}},{"setting":"Peritoneal metastases","approach":"Systemic therapy; intraperitoneal paclitaxel, HIPEC, and PIPAC in trials; palliative gastrectomy not recommended (REGATTA).","refs":["peritoneal-metastasis","hipec","idea-peritoneal-directed-gastric"],"guideline":{"url":"https://www.esmo.org/guidelines/guidelines-by-topic/esmo-clinical-practice-guidelines-gastrointestinal-cancers/"}}],"stateOfArt":["Biomarker-stratified first line with four possible add-ons.","First solid-tumour CAR-T approval (China).","Three first-line biomarkers (HER2, PD-L1, CLDN18.2) each with a phase 3-proven add-on to chemotherapy; testing all three at diagnosis is standard.","Perioperative durvalumab + FLOT (MATTERHORN) is the first immunotherapy to improve survival in resectable gastric cancer (FDA November 2025).","Zanidatamab beat trastuzumab head-to-head first line (HERIZON-GEA-01, 2026), the first HER2 advance in first line since ToGA.","T-DXd has phase 3 proof in second-line HER2-positive disease (DESTINY-Gastric04).","Claudin 18.2 is the first target with an antibody, an ADC with OS benefit (CLARITY-Gastric 01, 2026), and an approved CAR-T (satri-cel, China).","Five-year survivors exist with chemo-immunotherapy in PD-L1-rich disease (16% vs 6%, CheckMate 649)."],"history":[{"year":1881,"title":"Billroth performs the first successful gastrectomy for cancer","refs":["robotic-surgery"]},{"year":1965,"title":"Lauren describes intestinal and diffuse types","refs":["lauren-classification"]},{"year":1983,"title":"Helicobacter pylori identified (Marshall and Warren)","note":"Later classified as a class I carcinogen (1994); eradication shown to reduce gastric cancer incidence.","refs":["chemoprevention"]},{"year":1990,"title":"Japan and Korea institute endoscopic screening programmes","note":"Shift to early-stage diagnosis and 5-year survival >60%.","refs":[]},{"year":2006,"title":"MAGIC: perioperative chemotherapy improves survival (ECF)","refs":["cytotoxic-chemotherapy"]},{"year":2010,"title":"ToGA: trastuzumab in HER2+ gastric cancer","refs":["trastuzumab"]},{"year":2010,"title":"ToGA: trastuzumab, the first targeted therapy in gastric cancer","refs":["toga","trastuzumab"]},{"year":2014,"title":"TCGA molecular classification; RAINBOW establishes ramucirumab + paclitaxel","refs":["rainbow","ramucirumab"]},{"year":2017,"title":"Nivolumab third line (ATTRACTION-2); pembrolizumab for MSI-high tumours","refs":["nivolumab","pembrolizumab","msi"]},{"year":2019,"title":"FLOT4: docetaxel quadruplet becomes perioperative standard; trifluridine/tipiracil third line (TAGS)","refs":["flot","trifluridine-tipiracil"]},{"year":2021,"title":"Nivolumab + chemotherapy first line","refs":["nivolumab"]},{"year":2021,"title":"CheckMate 649: nivolumab + chemotherapy first line; KEYNOTE-811 adds pembrolizumab to trastuzumab; T-DXd approved (DESTINY-Gastric01)","refs":["checkmate-649","trastuzumab-deruxtecan"]},{"year":2023,"title":"SPOTLIGHT and GLOW: Claudin 18.2 validated; KEYNOTE-859","refs":["spotlight-glow","keynote-859"]},{"year":2024,"title":"Zolbetuximab: first CLDN18.2 drug","refs":[]},{"year":2024,"title":"Zolbetuximab approved (Japan March, US October); zanidatamab approved in biliary cancer","refs":["zolbetuximab","zanidatamab"]},{"year":2025,"title":"Satri-cel CAR-T approved in China","refs":["satricabtagene-autoleucel"]},{"year":2025,"title":"MATTERHORN: perioperative durvalumab approved; DESTINY-Gastric04 phase 3; satri-cel CAR-T approved in China; FORTITUDE-101 mixed; CheckMate 649 five-year data","refs":["matterhorn","destiny-gastric04","satricabtagene-autoleucel","fortitude-101","checkmate-649"]},{"year":2026,"title":"HERIZON-GEA-01: zanidatamab beats trastuzumab; CLARITY-Gastric 01: first CLDN18.2 ADC with OS benefit","refs":["herizon-gea-01","clarity-gastric01"]}],"pipeline":["cmg901","satricabtagene-autoleucel","disitamab-vedotin","zanidatamab","fapi-pet","pf-08634404","shr-8068","lm-108","gotistobart","mrg002","lm-302","evorpacept","hlx22","asp2138","m108","iah0968","mcla-129","trk-950","xnw27011","cinrebafusp-alfa","azd4360","absk061","jk08","bdc-4182","azd7789","spevatamig","azd5863","herizon-gea-01","clarity-gastric01","bemarituzumab","fortitude-101","idea-biomarker-quadruplet-gastric","idea-peritoneal-directed-gastric","her2-gastric-sequence","cldn18-antibody-then-adc","mrd-testing","trastuzumab-deruxtecan"],"openProblems":["Peritoneal metastasis.","Heterogeneous CLDN18.2/HER2 expression.","Screening only in Japan/Korea.","Peritoneal metastasis is the dominant relapse pattern and is poorly imaged, poorly penetrated by drugs, and excluded from most trials.","Diffuse-type and genomically stable tumours lack targets and respond poorly to chemotherapy and immunotherapy.","Biomarker overlap (CLDN18.2 with PD-L1) has no randomised guidance on combination versus sequence.","HER2 and CLDN18.2 expression are heterogeneous and can be lost at progression; re-biopsy or ctDNA before second-line targeting is not standard.","No Western screening strategy; most patients present with advanced disease.","FGFR2b benefit is uncertain after FORTITUDE-101; the control arm lacked immunotherapy.","Perioperative immunotherapy benefit by PD-L1 or MSI status, and whether chemotherapy can be omitted in MSI-high disease, are unresolved."],"prognosis":{"text":"In the United States, 39.8% of people diagnosed with stomach cancer in 2016-2022 were alive five years later, relative to people of the same age without the disease. 32% of cases are found while confined to the stomach, with five-year relative survival of 78.1%; it is 39% for regional disease (23% of cases) and 8.1% for distant disease (35% of cases). Outcomes are better in Japan and Korea, where endoscopic screening finds most cancers early; the US figures do not yet reflect immunotherapy and claudin 18.2 antibodies in advanced disease.","sources":[{"label":"SEER Cancer Stat Facts: Stomach Cancer","url":"https://seer.cancer.gov/statfacts/html/stomach.html"}]}},{"id":"gastric-malt-lymphoma","kind":"cancer","name":"Gastric MALT lymphoma","aka":["Gastric mucosa-associated lymphoid tissue lymphoma","Gastric marginal zone lymphoma","Gastric MALToma","Extranodal marginal zone lymphoma of the stomach","Helicobacter pylori-associated gastric lymphoma","Primary gastric lymphoma"],"tldr":"A slow-growing MALT lymphoma that grows in the lining of the stomach, usually caused by a long-standing infection with the bacterium Helicobacter pylori. It is the one lymphoma that is often cured by a fortnight of antibiotics, and a single chromosome change predicts the minority in whom antibiotics will not work.","summary":"What it is. The stomach has no lymphoid tissue of its own. Chronic infection with Helicobacter pylori creates some, as part of the immune response to the bacterium, and over years a clone of B cells in that tissue can become a lymphoma. The lymphoma depends on the signals the infection provides, which is the reason for the treatment that follows.\n\nHow it differs from its parent. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue arises at many sites and the sites differ genetically: WHO-HAEM5 sets out that ocular adnexal disease commonly carries mutation or deletion of TNFAIP3, salivary gland disease carries recurrent GPR34 mutation, and thyroid disease carries deleterious mutations of CD274, TNFRSF14 or TET2. What the stomach has, and only the stomach and the lung among the common sites, is the translocation t(11;18)(q21;q21), which fuses BIRC3 to MALT1. WHO-HAEM5 states its clinical application in one sentence: that fusion identifies the cases of gastric extranodal marginal zone lymphoma that will not respond to eradication of Helicobacter pylori.\n\nHow it presents and how it is found. Indigestion, pain, nausea, anaemia from slow bleeding, or nothing at all, found when an endoscopy is done for something else. The appearance at endoscopy is often unimpressive: thickened folds, redness, erosions, rather than an obvious tumour. Multiple biopsies are taken from the abnormal area and from each part of the normal-looking stomach, because the lymphoma is patchy. The depth of the lymphoma in the stomach wall is measured by endoscopic ultrasound, and the depth is part of the decision about antibiotics.\n\nThe treatment, and the numbers behind it. Eradicating Helicobacter pylori is the first treatment, and in early disease it is often the only one. In a prospective multicentre trial that followed 120 patients with stage I disease for a median of 75 months, 80 per cent (96 of 120) achieved a complete histological remission, 80 per cent of those remained in continuous remission, 3 per cent relapsed and were referred for other treatment, and five-year survival was 90 per cent. Seventeen per cent of those in remission showed residual lymphoma histologically at some point during follow-up; they were watched rather than treated and all entered a second remission, which is the evidence for not reacting to a single abnormal biopsy. Fifteen per cent of the lymphomas carried t(11;18), and both that translocation and a persisting monoclonal band were associated with a higher risk of not responding or of relapsing, although both were also found in patients who stayed in remission.\n\nWhat follows if antibiotics do not work. Radiotherapy to the stomach at a low dose, or an anti-CD20 antibody, or both, depending on the stage and on whether the translocation is present. Surgery has essentially no role, which is the main thing that separates this disease from gastric adenocarcinoma. Follow-up is by repeated endoscopy and biopsy, and a small number of people develop a gastric carcinoma later, so the endoscopies serve two purposes. The regimens sit in the treatment layer of this family and on the MALT lymphoma page.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/MALT_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication, 120 patients with stage I disease (Fischbach, J Clin Oncol 2005)","url":"https://doi.org/10.1200/JCO.2005.02.3903"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["malt-lymphoma","marginal-zone-lymphoma","ocular-adnexal-malt-lymphoma","gastric","non-hodgkin-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","endoscopic-ultrasound-systems"],"targets":[],"drugs":["rituximab","bendamustine"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-tx-h-pylori-eradication","lymphoma-lugano-gastrointestinal","lymphoma-nodal-versus-extranodal","lymphoma-indolent-versus-aggressive","lymphoma-tx-watch-and-wait","lymphoma-transformation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-wotherspoon-h-pylori-malt-lancet-1993","paper-esmo-marginal-zone-lymphoma-zucca-ann-oncol-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"No separate incidence figure for the stomach is published in the United Kingdom population series, which counts all extranodal marginal zone lymphomas together: 211 of 5,796 lymphomas (3.6 per cent), a European age-standardised rate of 0.60 per 100,000 a year, a median age at diagnosis of 68.8 years and five-year relative survival of 87.9 per cent across all extranodal sites. The stomach is the commonest of those sites. The corpus does not quote a gastric-only incidence figure because it could not verify one.","subtypes":["Helicobacter pylori-positive, the great majority","Helicobacter pylori-negative, in which a minority still respond to eradication therapy","With t(11;18)(q21;q21) producing BIRC3::MALT1, which predicts failure of eradication therapy"],"biomarkers":["Helicobacter pylori, by histology, urea breath test, stool antigen or serology; more than one test is used because treatment with acid suppression makes the biopsy unreliable","t(11;18)(q21;q21) giving BIRC3::MALT1, found in about 15 per cent, which predicts that eradication will not work","Depth of invasion of the stomach wall on endoscopic ultrasound, which predicts response to eradication","A monoclonal immunoglobulin heavy chain rearrangement, which often persists after histological remission and does not by itself mean treatment has failed","Trisomy 3 and trisomy 18, common across all marginal zone lymphomas","Large cells on the biopsy, which mean transformation to diffuse large B-cell lymphoma and change the treatment entirely"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Endoscopy with multiple biopsies from the abnormal area and from every region of the stomach, because the lymphoma is patchy and a single biopsy can miss it. Helicobacter pylori is sought by more than one method. Endoscopic ultrasound measures how deep the lymphoma goes, which predicts whether antibiotics alone will work; in a prospective comparison against the resected stomach it judged the depth correctly in 91.5 per cent of cases. Fluorescence in situ hybridisation for t(11;18) is done where it will change the plan. Staging uses the gastrointestinal system that counts depth and node involvement rather than the ordinary node-region count.","refs":["endoscopy","endoscopic-ultrasound-systems","lymphoma-lugano-gastrointestinal","histopathology-ihc","paper-wotherspoon-h-pylori-malt-lancet-1993"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"First treatment: eradicate the bacterium","approach":"A standard eradication regimen of a proton pump inhibitor with two antibiotics, chosen by local resistance patterns, is the first treatment for Helicobacter pylori-positive disease and is also offered in negative disease, where a minority still respond. Success is confirmed by a breath or stool test after treatment, and the lymphoma is then followed by repeated endoscopy and biopsy over months, because regression is slow. In the prospective series of 120 patients with stage I disease, 80 per cent achieved complete histological remission and 80 per cent of those remained in continuous remission at a median follow-up of 75 months.","refs":["lymphoma-tx-h-pylori-eradication","endoscopy","lymphoma-tx-watch-and-wait","lymphoma-lugano-gastrointestinal"],"guideline":{"version":"Fischbach, J Clin Oncol 2005; ESMO marginal zone lymphoma guideline; NCI PDQ","url":"https://doi.org/10.1200/JCO.2005.02.3903"}},{"setting":"Residual disease on a follow-up biopsy","approach":"Residual lymphoma on a biopsy after successful eradication is common and usually does not need treatment. In the same series, 17 per cent of those who had reached complete remission later showed histological residual disease; they were watched rather than treated, and all of them entered a second remission. A persisting monoclonal band in the immunoglobulin genes is also common and is not by itself a reason to treat. What does need action is growth, new symptoms, or large cells appearing on the biopsy.","refs":["lymphoma-tx-watch-and-wait","endoscopy","histopathology-ihc"],"guideline":{"version":"Fischbach, J Clin Oncol 2005","url":"https://doi.org/10.1200/JCO.2005.02.3903"}},{"setting":"When antibiotics do not work, or cannot","approach":"Radiotherapy to the stomach at a low dose is the usual next step for disease that stays localised, and anti-CD20 antibody treatment, alone or with chemotherapy, for disease that has spread or that carries t(11;18) and is therefore unlikely to respond to eradication. Surgery has essentially no role at any stage, which is the main difference from gastric cancer. The regimens, the doses and the evidence are on the MALT lymphoma page and in the treatment layer of this family.","refs":["malt-lymphoma","rituximab","lymphoma-tx-radiotherapy","bendamustine","paper-esmo-marginal-zone-lymphoma-zucca-ann-oncol-2020"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":1993,"title":"Regression after antibiotics","note":"Wotherspoon and colleagues showed in the Lancet that eradicating Helicobacter pylori made gastric MALT lymphoma regress, the first time an antibiotic had been shown to treat a cancer.","refs":["paper-wotherspoon-h-pylori-malt-lancet-1993","lymphoma-tx-h-pylori-eradication"]},{"year":2005,"title":"Long-term follow-up confirms the remissions hold","note":"In 120 patients with stage I disease followed for a median of 75 months, 80 per cent reached complete histological remission, 80 per cent of those stayed in it, five-year survival was 90 per cent, and 15 per cent of lymphomas carried t(11;18), which predicted failure to respond.","refs":[]},{"year":2022,"title":"The translocation named as the clinical test","note":"WHO-HAEM5 sets out that BIRC3::MALT1 from t(11;18) is recurrent in gastric and pulmonary disease and rare at other sites, and that it identifies the gastric cases that will not respond to eradication.","refs":["lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["Helicobacter pylori resistance to clarithromycin is rising in many countries, and the first treatment for this lymphoma is an antibiotic regimen that is becoming less reliable.","There is no agreed definition of how long to watch residual lymphoma on biopsy before treating it, and the evidence that watching is safe comes from one prospective series.","Nobody knows why a minority of Helicobacter pylori-negative gastric MALT lymphomas respond to eradication therapy anyway."],"parent":"malt-lymphoma"},{"id":"gist","kind":"cancer","name":"Gastrointestinal stromal tumour (GIST)","aka":[],"tldr":"GIST is a sarcoma of the gut wall driven almost always by a KIT or PDGFRA mutation. It was the proof that a pill can control a solid tumour: imatinib turned a median survival of about a year into one of eight years or more, and the mutation now dictates which drug to use.","summary":"GIST arises from interstitial cells of Cajal and carries activating KIT mutations (~75%, mostly exon 11, some exon 9) or PDGFRA mutations (~10%, including the imatinib-resistant D842V); the remainder are SDH-deficient (young patients, Carney-Stratakis), NF1-associated, or BRAF/NTRK-driven. Risk after resection is estimated from size, mitotic rate and site (Miettinen/AFIP, modified NIH).\n\nSurgery is the only cure; adjuvant imatinib for three years improves survival in high-risk disease (SSGXVIII), with five years or longer under study. Advanced disease is treated with imatinib (400 mg; 800 mg for exon 9), then sunitinib (2006), regorafenib (2013) and ripretinib (INVICTUS, 2020) in sequence; avapritinib is the drug for PDGFRA D842V (2020). Resistance comes from secondary KIT mutations in the ATP-binding pocket (exon 13/14) or activation loop (exon 17/18) and is heterogeneous across lesions, which is why single next-generation inhibitors have struggled (INTRIGUE: ripretinib not superior to sunitinib overall, but better in ctDNA-defined exon 11 + 17/18 disease, now tested in INSIGHT) and why combinations (bezuclastinib + sunitinib, Peak) and ctDNA-guided selection are the current strategy. SDH-deficient GIST is TKI-insensitive and slow-growing; temozolomide has activity.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Gastrointestinal_stromal_tumor","links":[{"label":"NCCN Guidelines: GIST","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1507"},{"label":"ESMO-EURACAN GIST guideline (2022)","url":"https://doi.org/10.1016/j.annonc.2021.09.005"},{"label":"Life Raft Group (patient organisation)","url":"https://liferaftgroup.org/"}],"tags":["gap-fill","gastrointestinal","sarcoma"],"related":["leiomyosarcoma","desmoid-tumour","inflammatory-myofibroblastic-tumour","dermatofibrosarcoma-protuberans"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","liquid-biopsy","robotic-surgery","endoscopic-resection"],"targets":["kit","pdgfra","ntrk","braf"],"drugs":["imatinib","sunitinib","regorafenib","ripretinib","avapritinib","temozolomide"],"companies":["novartis","pfizer","bayer","deciphera","sanofi"],"institutions":[],"pathways":["ras-mapk","pi3k-akt-mtor"],"terms":["oncogene-addiction","resistance","ctdna","gist-risk-stratification","sdh-deficiency"],"trials":["nct07585266","nct05208047","nct07218926","nct07379047","nct03673501","grid","navigator"],"people":[],"bottlenecks":[],"keyPapers":["paper-casali-ann-oncol"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"GIST affects about 10-15 per million per year (the most common sarcoma); stomach 60%, small bowel 30%; median age ~65.","subtypes":["KIT exon 11-mutant (most common, imatinib-sensitive)","KIT exon 9-mutant (small bowel; imatinib 800 mg)","PDGFRA-mutant (D842V imatinib-resistant → avapritinib)","SDH-deficient (paediatric/young adult, Carney triad)","NF1-associated GIST","BRAF / NTRK-driven (rare)"],"biomarkers":["KIT and PDGFRA mutation status (mandatory before therapy)","Secondary KIT mutations by ctDNA at progression","SDHB immunohistochemistry","Mitotic rate, size, site (risk)","CD117 (KIT) and DOG1 IHC","NF1, BRAF, NTRK in wild-type GIST"],"standardOfCare":[{"setting":"Localised, resectable","approach":"Complete resection without lymphadenectomy; adjuvant imatinib 3 years for high-risk (SSGXVIII); neoadjuvant imatinib to downsize when organ-sparing matters.","refs":["imatinib"],"guideline":{"nccn":"Category 1 (adjuvant imatinib, high risk)","esmoMcbs":"A","version":"NCCN Guidelines: GIST","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1507"}},{"setting":"Advanced, first line","approach":"Imatinib 400 mg (800 mg for KIT exon 9); avapritinib for PDGFRA D842V; continue until progression.","refs":["imatinib","avapritinib"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: GIST"}},{"setting":"Advanced, second line","approach":"Sunitinib (or ripretinib for KIT exon 11 + 17/18 secondary mutations per ctDNA, INSIGHT).","refs":["sunitinib","ripretinib","liquid-biopsy"],"guideline":{"nccn":"Category 1 (sunitinib)","version":"NCCN Guidelines: GIST"}},{"setting":"Advanced, third/fourth line","approach":"Regorafenib, then ripretinib (INVICTUS); rechallenge or continue TKI beyond progression; clinical trials (bezuclastinib-sunitinib).","refs":["regorafenib","ripretinib"],"guideline":{"nccn":"Category 1 (regorafenib, ripretinib)","version":"NCCN Guidelines: GIST"}}],"stateOfArt":["Five approved TKIs sequenced by genotype; median survival in advanced GIST is now around 8 years.","ctDNA genotyping of secondary KIT mutations is becoming the way to pick second-line therapy (INSIGHT).","Avapritinib solved the PDGFRA D842V problem with ~90% response.","Combination inhibition (bezuclastinib + sunitinib) aims to cover both ATP-pocket and activation-loop resistance at once."],"history":[{"year":1998,"title":"KIT mutations discovered in GIST (Hirota, Science)","refs":["kit"]},{"year":2000,"title":"Imatinib: dramatic response in a single GIST patient (Joensuu, NEJM 2001)","refs":["imatinib"]},{"year":2002,"title":"Imatinib approved for advanced GIST","refs":["imatinib"]},{"year":2003,"title":"PDGFRA mutations in KIT-wild-type GIST (Heinrich, Science)","refs":["pdgfra"]},{"year":2006,"title":"Sunitinib approved after imatinib failure","refs":["sunitinib"]},{"year":2012,"title":"SSGXVIII: three years of adjuvant imatinib improves overall survival","refs":["imatinib"]},{"year":2013,"title":"Regorafenib approved (GRID)","refs":["regorafenib"]},{"year":2020,"title":"Avapritinib (PDGFRA D842V) and ripretinib (INVICTUS) approved","refs":["avapritinib","ripretinib"]},{"year":2022,"title":"INTRIGUE: ctDNA genotype predicts ripretinib vs sunitinib benefit","refs":["ripretinib","sunitinib"]}],"pipeline":["ripretinib","avapritinib","liquid-biopsy","velzatinib","bezuclastinib","idrx-42","nb003"],"openProblems":["Polyclonal resistance: different lesions carry different secondary KIT mutations.","SDH-deficient and other wild-type GIST have no effective TKI.","Optimal duration of adjuvant imatinib (3 vs 5-6 years).","Long-term imatinib toxicity and adherence."],"parent":"sarcoma"},{"id":"germ-cell-neoplasia-in-situ","kind":"cancer","name":"Germ cell neoplasia in situ (GCNIS)","aka":["GCNIS","Intratubular germ cell neoplasia, unclassified","IGCNU","Testicular intraepithelial neoplasia","TIN","Carcinoma in situ of the testis","Germ cell neoplasia in situ (precursor)"],"tldr":"Germ cell neoplasia in situ is the pre-cancer of testicular germ cell tumours: abnormal fetal-type germ cells sitting inside the seminiferous tubules, which will become seminoma or non-seminoma if left. It is found beside almost every testicular cancer and sometimes on its own in the other testis, where low-dose radiotherapy or surgery prevents a second cancer.","summary":"The pre-invasive lesion of postpubertal testicular germ cell tumours was recognised in the early 1970s and carried several names (carcinoma in situ, intratubular germ cell neoplasia unclassified, testicular intraepithelial neoplasia) until the 2016 WHO consensus classification united them as germ cell neoplasia in situ (Histopathology 2016; Moch 2016). The cells resemble seminoma cells, express OCT4, PLAP and KIT, lie along the tubular basement membrane in tubules without spermatogenesis, and are the origin of seminoma, embryonal carcinoma, yolk sac tumour, choriocarcinoma and postpubertal teratoma, but not of spermatocytic tumour or prepubertal tumours. Testicular biopsy is the only established way to diagnose it; serum microRNA-371a-3p, a marker of invasive germ cell tumours, was raised in 51.9 percent of 27 men with isolated GCNIS (J Cancer Res Clin Oncol 2017).\n\nHow it differs from its parent: it is not yet a cancer, is not staged and raises no conventional serum markers; its importance is the roughly one in two chance of progression to invasive tumour over five years quoted in the classification literature, which drives contralateral biopsy policies in some countries.\n\nHow common: present beside almost all germ cell tumours; isolated GCNIS has no population figure in the sources read.\n\nTreatment: for GCNIS in the remaining testis after orchidectomy for cancer, low-dose testicular radiotherapy (which preserves testosterone production but ends fertility), orchidectomy, or surveillance in men who wish to father children; chemotherapy for the invasive tumour eradicates GCNIS incompletely, so the contralateral testis is watched (NCI PDQ testicular summary for the invasive pathways).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Germ_cell_neoplasia_in_situ","links":[{"label":"NCI PDQ: testicular cancer treatment","url":"https://www.cancer.gov/types/testicular/treatment"},{"label":"Moch 2016, European Urology: the 2016 WHO classification of urinary and male genital tumours, part A","url":"https://doi.org/10.1016/j.eururo.2016.02.029"},{"label":"Histopathology 2016: germ cell neoplasia in situ, evolution of the nomenclature","url":"https://doi.org/10.1111/his.12958"},{"label":"J Cancer Res Clin Oncol 2017: serum microRNA-371a-3p in 27 patients with germ cell neoplasia in situ","url":"https://doi.org/10.1007/s00432-017-2490-7"}],"tags":["subtype-page","wave4","testicular","rare"],"related":["testicular","seminoma","non-seminoma","spermatocytic-tumour","embryonal-carcinoma-testis"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["carcinoma-in-situ","tumour-markers"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"The precursor of almost every postpubertal testicular germ cell tumour, found in the tissue beside the tumour; as an isolated finding it is diagnosed on biopsy in men investigated for infertility, a contralateral tumour or cryptorchidism (Histopathology 2016). No incidence figure exists for the isolated lesion in the sources read.","subtypes":["GCNIS adjacent to seminoma or embryonal carcinoma (the usual finding)","Isolated GCNIS in the contralateral testis after orchidectomy","GCNIS in cryptorchid or infertile testes","Intratubular seminoma and intratubular embryonal carcinoma (intermediate stages)"],"biomarkers":["OCT4, PLAP and KIT positive cells along the tubular basement membrane","Serum microRNA-371a-3p (research)","Absent spermatogenesis in affected tubules","Isochromosome 12p in the invasive tumour that follows"],"standardOfCare":[{"setting":"Isolated GCNIS in the remaining testis","approach":"Low-dose testicular radiotherapy, orchidectomy, or surveillance in men wanting children; the invasive tumour that follows is treated as seminoma or non-seminoma.","refs":["testicular","seminoma","non-seminoma"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"testicular"},{"id":"paediatric-germ-cell-tumours","kind":"cancer","name":"Germ cell tumours of childhood and adolescence (extracranial and CNS)","aka":["Childhood extracranial germ cell tumour","CNS germ cell tumour","Germinoma","Ovarian germ cell tumour","Sacrococcygeal teratoma","Malignant germ cell tumour (children and adolescents)"],"tldr":"Germ cell tumours arise from the cells meant to become eggs or sperm and can appear in the gonads, lower back, chest or brain. They are among the most curable childhood cancers because they respond to cisplatin chemotherapy and release blood markers that make monitoring easy. The work now is to cure with less: surgery alone for low-risk tumours, gentler platinum drugs, and protecting hearing.","summary":"Paediatric and adolescent germ cell tumours (GCTs) are a heterogeneous family (mature and immature teratoma, yolk sac tumour, germinoma or seminoma or dysgerminoma, embryonal carcinoma, choriocarcinoma and mixed tumours) arising in gonadal and extragonadal midline sites: sacrococcygeal region, retroperitoneum, mediastinum and the pineal and suprasellar regions of the brain. Infant tumours are mostly yolk sac tumours and teratomas with a distinct genome; adolescent tumours resemble adult testicular cancer, with 12p gain. Serum AFP and beta-hCG are diagnostic, prognostic and used for surveillance.\n\nMalignant extracranial GCTs are cured in most children with surgery and cisplatin-based chemotherapy (PEb: cisplatin, etoposide, bleomycin in North America; JEb with carboplatin in the United Kingdom). The Malignant Germ Cell International Consortium (MaGIC) pooled COG and CCLG data to build a shared risk classification, which underpins the current joint trial AGCT1531: low-risk tumours are managed with surgery and active surveillance, with chemotherapy only on relapse, and standard-risk patients are randomised between cisplatin and carboplatin to test whether hearing and kidney toxicity can be reduced without losing cure. Cisplatin ototoxicity, the main long-term harm, can be reduced with sodium thiosulfate given after each dose (ACCL0431 and SIOPEL 6, approved for children with localised solid tumours). Salvage for relapse uses high-dose chemotherapy with stem-cell rescue as in adults.\n\nCNS germ cell tumours are treated differently: germinomas are exquisitely radiosensitive and are cured with chemotherapy followed by reduced-dose whole-ventricular radiotherapy (SIOP CNS GCT II and ACNS1123 approaches), while non-germinomatous tumours need chemotherapy, craniospinal or focal radiotherapy and second-look surgery. Ovarian GCTs in adolescents are managed with fertility-sparing surgery and, for malignant tumours beyond stage I, the same platinum regimens. Because the adult, adolescent and paediatric worlds treat the same disease with different protocols, harmonising them is itself a research programme.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Germ_cell_tumor","links":[{"label":"NCI PDQ: childhood extracranial germ cell tumours","url":"https://www.cancer.gov/types/extracranial-germ-cell/hp/germ-cell-treatment-pdq"},{"label":"NCI PDQ: childhood CNS germ cell tumours","url":"https://www.cancer.gov/types/brain/hp/child-cns-germ-cell-treatment-pdq"},{"label":"AGCT1531 (NCT03067181)","url":"https://clinicaltrials.gov/study/NCT03067181"},{"label":"MaGIC risk classification (JCO 2015)","url":"https://doi.org/10.1200/JCO.2014.58.3369"},{"label":"SIOPEL 6: sodium thiosulfate otoprotection (NEJM 2018)","url":"https://doi.org/10.1056/NEJMoa1801109"}],"tags":["nci-coverage","paediatric","germ-cell"],"related":["testicular","ovarian","rare-childhood-cancers","neuroblastoma","hepatoblastoma"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","active-surveillance","autologous-stem-cell-transplant","imrt-igrt","proton-therapy","fertility-preservation","survivorship-care-plan"],"targets":[],"drugs":["cisplatin","carboplatin","etoposide","bleomycin","ifosfamide","sodium-thiosulfate"],"companies":["childrens-oncology-group","cclg"],"institutions":["siop-europe"],"pathways":[],"terms":["afp","late-effects","aya-oncology","bleomycin-omission-caution","retroperitoneum"],"trials":[],"people":[],"bottlenecks":["b-survivorship","b-rare-cancers"],"keyPapers":["paper-brock-n-engl-j-med","paper-frazier-j-clin-oncol"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"A few percent of childhood cancers overall, with peaks in infancy (sacrococcygeal and testicular teratomas and yolk sac tumours) and adolescence (ovarian, testicular and mediastinal tumours) (NCI PDQ).","subtypes":["Teratoma (mature, immature; sacrococcygeal in infants)","Yolk sac tumour (infants; AFP-secreting)","Germinoma / seminoma / dysgerminoma (adolescents; CNS germinoma)","Embryonal carcinoma and choriocarcinoma (hCG-secreting)","Mixed malignant germ cell tumour","CNS non-germinomatous germ cell tumour","Ovarian germ cell tumour (adolescent)"],"biomarkers":["Serum and cerebrospinal-fluid AFP","Serum and cerebrospinal-fluid beta-hCG","Lactate dehydrogenase","Isochromosome 12p (adolescent tumours)","MaGIC risk group (site, stage, age, marker level)","Audiometry before and after cisplatin","Fertility assessment and preservation"],"standardOfCare":[{"setting":"Low-risk malignant extracranial GCT (e.g. stage I testicular, stage I ovarian)","approach":"Complete resection followed by active surveillance with serial tumour markers and imaging; chemotherapy only for relapse (AGCT1531 stratum).","refs":["afp","active-surveillance","agct1531"],"guideline":{"version":"COG/CCLG AGCT1531; NCI PDQ","url":"https://www.cancer.gov/types/extracranial-germ-cell/hp/germ-cell-treatment-pdq"}},{"setting":"Standard- and high-risk malignant extracranial GCT","approach":"Cisplatin, etoposide and bleomycin (PEb) or carboplatin-based JEb, with surgery of residual masses; sodium thiosulfate for otoprotection; high-dose chemotherapy with stem-cell rescue at relapse.","refs":["cisplatin","carboplatin","etoposide","bleomycin","sodium-thiosulfate","autologous-stem-cell-transplant"],"guideline":{"version":"NCI PDQ; MaGIC risk classification","url":"https://www.cancer.gov/types/extracranial-germ-cell/hp/germ-cell-treatment-pdq"}},{"setting":"CNS germinoma","approach":"Platinum-based chemotherapy followed by reduced-dose whole-ventricular radiotherapy with tumour boost (SIOP CNS GCT II, ACNS1123).","refs":["carboplatin","etoposide","imrt-igrt","proton-therapy","acns1123"],"guideline":{"version":"NCI PDQ: childhood CNS germ cell tumours","url":"https://www.cancer.gov/types/brain/hp/child-cns-germ-cell-treatment-pdq"}},{"setting":"CNS non-germinomatous GCT","approach":"Intensive platinum-based chemotherapy, second-look surgery for residual disease, then craniospinal or whole-ventricular radiotherapy depending on response and stage.","refs":["cisplatin","ifosfamide","etoposide","proton-therapy"]}],"stateOfArt":["Most children and adolescents with malignant germ cell tumours are cured; the agenda is reducing toxicity, tested directly in the joint COG/CCLG AGCT1531 trial.","Active surveillance replaces chemotherapy for low-risk resected tumours, sparing many children platinum exposure altogether.","Sodium thiosulfate after cisplatin protects hearing without compromising cure in localised disease and is now approved for children.","CNS germinoma is cured with chemotherapy plus reduced-dose ventricular radiotherapy, sparing cognition compared with historical craniospinal irradiation."],"history":[{"year":1977,"title":"Cisplatin combinations cure disseminated germ cell tumours","note":"Einhorn's PVB regimen in testicular cancer, later adapted to children.","refs":["cisplatin"]},{"year":1990,"title":"Carboplatin-based JEb adopted in the United Kingdom","note":"UKCCSG shows carboplatin can replace cisplatin in children with less hearing and kidney toxicity.","refs":["carboplatin"]},{"year":2004,"title":"Surveillance for stage I paediatric testicular tumours","note":"POG/CCG intergroup studies show surgery alone is safe for low-stage disease.","refs":[]},{"year":2015,"title":"MaGIC pooled risk classification","note":"Frazier and colleagues (JCO) combine COG and CCLG data to define shared risk groups.","refs":[]},{"year":2018,"title":"Sodium thiosulfate protects hearing","note":"SIOPEL 6 (NEJM 2018) and ACCL0431 show reduced cisplatin ototoxicity; FDA approval 2022.","refs":["sodium-thiosulfate"]},{"year":2017,"title":"AGCT1531 opens","note":"Joint COG/CCLG trial of active surveillance and carboplatin versus cisplatin.","refs":["carboplatin","cisplatin"]}],"pipeline":["sodium-thiosulfate","active-surveillance","fertility-preservation","proton-therapy"],"openProblems":["Whether carboplatin can fully replace cisplatin without losing cures in standard-risk disease; AGCT1531 is the answer trial.","Relapsed and platinum-refractory disease, especially mediastinal and CNS non-germinomatous tumours, where high-dose chemotherapy is the only option.","Long-term hearing, kidney, fertility and cardiovascular effects; otoprotection, fertility preservation and survivorship clinics address them.","Harmonising paediatric, adolescent and adult protocols so that a 17-year-old and a 19-year-old receive the same evidence-based care."],"parent":"childhood-cancers"},{"id":"gestational-trophoblastic","kind":"cancer","name":"Gestational trophoblastic neoplasia","aka":["GTN","Choriocarcinoma","Molar pregnancy","Placental site trophoblastic tumour","Gestational Trophoblastic Disease"],"tldr":"Cancers that grow from placental tissue after a pregnancy. They make a hormone (hCG) that acts as a perfect blood test, and they were the first solid cancer ever cured by chemotherapy. Immunotherapy now rescues the few that resist drugs.","summary":"Gestational trophoblastic neoplasia (GTN) follows a molar pregnancy (complete or partial hydatidiform mole) or, less often, any pregnancy, and includes invasive mole, choriocarcinoma, placental-site and epithelioid trophoblastic tumours. Serum hCG tracks disease burden with unique precision, so diagnosis is usually made from a plateau or rise in hCG after molar evacuation without histology. The FIGO 2000 prognostic score separates low-risk (single-agent methotrexate or actinomycin D) from high-risk disease (multi-agent EMA-CO), with ultra-high-risk patients started on low-dose induction etoposide-cisplatin to prevent early death.\n\nGTN is highly immunogenic (paternal antigens, PD-L1 expression), and PD-1 blockade produced durable complete remissions in chemotherapy-resistant disease (pembrolizumab, Ghorani 2017; avelumab TROPHIMMUN 2020), now in guidelines. Placental-site and epithelioid tumours are chemo-resistant and treated by hysterectomy. Outcomes depend on centralised care with hCG registries (Charing Cross, Sheffield, Brewer).","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Gestational_trophoblastic_disease","links":[{"label":"NCCN Guidelines: GTN","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"},{"label":"NCI PDQ: GTD","url":"https://www.cancer.gov/types/gestational-trophoblastic/patient/gtd-treatment-pdq"}],"tags":["gap-fill","gynaecologic","rare"],"related":[],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","checkpoint-inhibitor","ultrasound","fertility-preservation"],"targets":["pd1","pdl1"],"drugs":["methotrexate","dactinomycin","etoposide","cyclophosphamide","vincristine","cisplatin","pembrolizumab","avelumab"],"companies":["merck","pfizer"],"institutions":[],"pathways":["pd1-checkpoint"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"Molar pregnancy in ~1 per 1,000 pregnancies (higher in Asia); GTN requiring chemotherapy in ~1 per 40,000 pregnancies; cure rates approach 100% in low-risk and >90% in high-risk disease.","subtypes":["Complete and partial hydatidiform mole (premalignant)","Invasive mole","Gestational choriocarcinoma","Placental-site trophoblastic tumour (PSTT)","Epithelioid trophoblastic tumour (ETT)"],"biomarkers":["Serum hCG (diagnosis, staging, response, surveillance)","FIGO 2000 prognostic score (low ≤6, high ≥7, ultra-high ≥13)","Hyperglycosylated hCG / hCG-free beta (PSTT)","Genotyping to confirm gestational origin","PD-L1 (expressed in nearly all GTN)"],"standardOfCare":[{"setting":"Low-risk GTN (FIGO score 0-6)","approach":"Single-agent methotrexate (8-day regimen) or pulsed actinomycin D; switch agent on resistance; consolidate 3 cycles after hCG normalisation.","refs":["methotrexate","dactinomycin"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}},{"setting":"High-risk GTN (score ≥7)","approach":"EMA-CO (etoposide, methotrexate, actinomycin D / cyclophosphamide, vincristine); induction low-dose EP for ultra-high-risk; EP-EMA or TP/TE at relapse; surgery for resistant foci.","refs":["etoposide","methotrexate","dactinomycin","cyclophosphamide","vincristine","cisplatin"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia"}},{"setting":"Chemotherapy-resistant GTN","approach":"PD-1/PD-L1 blockade (pembrolizumab, avelumab), high-dose chemotherapy with stem-cell rescue in selected cases, hysterectomy or metastasectomy.","refs":["pembrolizumab","avelumab","autologous-stem-cell-transplant"],"guideline":{"version":"NCCN 2A; EOTTD guidance"}},{"setting":"PSTT / ETT","approach":"Hysterectomy; platinum-etoposide chemotherapy if metastatic or >4 years from antecedent pregnancy.","refs":["cisplatin","etoposide"]}],"stateOfArt":["The only cancer routinely diagnosed and monitored by a hormone alone, with near-universal cure.","Immunotherapy cures a majority of drug-resistant cases; trials (TROPHAMET, TROPHIMMUN) now test it earlier to avoid chemotherapy.","Centralised registries remain the model for how rare cancers should be managed."],"history":[{"year":1956,"title":"Methotrexate cures metastatic choriocarcinoma (Li, Hertz, Spencer)","note":"The first solid tumour cured by chemotherapy.","refs":["methotrexate"]},{"year":1973,"title":"Charing Cross hCG surveillance service established","note":"Model for centralised GTD registries.","refs":[]},{"year":1979,"title":"EMA-CO introduced by Bagshawe for high-risk disease","refs":["etoposide","methotrexate","dactinomycin"]},{"year":2000,"title":"FIGO 2000 staging and prognostic score","refs":[]},{"year":2017,"title":"Pembrolizumab cures chemoresistant GTN (Ghorani, Lancet)","refs":["pembrolizumab"]},{"year":2020,"title":"TROPHIMMUN: avelumab in methotrexate-resistant low-risk GTN","refs":["avelumab"]}],"pipeline":["pembrolizumab","avelumab"],"openProblems":["Late diagnosis where hCG surveillance after molar pregnancy is absent (much of the world).","Fertility and psychological burden of a pregnancy-related cancer.","PSTT/ETT chemo-resistance.","Cumulative etoposide exposure and second cancers."]},{"id":"glioblastoma","kind":"cancer","name":"Glioma & glioblastoma","aka":[],"tldr":"Gliomas are now diagnosed by molecular class, and three classes got their first targeted drugs in 2024-25 (vorasidenib for IDH-mutant glioma, tovorafenib for BRAF-altered paediatric glioma, dordaviprone for H3 K27M). Glioblastoma is the hardest to treat: surgery, radiotherapy with temozolomide and tumour treating fields are its backbone, with CAR-T into the brain and focused ultrasound in trials.","summary":"Gliomas are classified by the WHO 2021 system on molecular grounds: IDH-wild-type glioblastoma (grade 4, ~50% of gliomas, median age 65, median survival ~15 months with maximal therapy), IDH-mutant astrocytoma (grades 2-4) and 1p/19q-codeleted oligodendroglioma (better prognosis, decades of survival possible), and paediatric-type tumours including H3 K27M-mutant diffuse midline glioma (median survival ~11 months) and BRAF-altered low-grade glioma (the commonest childhood brain tumour, rarely life-threatening but chronically disabling). The two shared barriers are the blood-brain barrier, which excludes most drugs, and diffuse infiltration, which makes complete resection impossible.\n\nGlioblastoma treatment has been static since 2005: maximal safe resection (improved by 5-ALA fluorescence, intraoperative MRI, and awake mapping; the extent of resection is itself prognostic and is now graded by the RANO resect classes), radiotherapy with concurrent and adjuvant temozolomide (Stupp), and tumour treating fields (EF-14). MGMT promoter methylation predicts temozolomide benefit; unmethylated tumours gain less, though not nothing, and how much remains debated (in the elderly trials NOA-08 and Nordic, unmethylated tumours did better with radiotherapy than with temozolomide alone). No systemic drug tested since has beaten it in phase 3: bevacizumab improved progression-free but not overall survival, and rindopepimut (ACT IV), nivolumab (CheckMate 143, 498, 548) and depatuxizumab mafodotin (INTELLANCE-1) were negative. At recurrence the options are re-resection or LITT where feasible, lomustine, re-irradiation, bevacizumab for oedema, and a clinical trial, which NCCN-aligned practice prefers; median survival after recurrence is under a year in the trial series, and half of the people in those series lived longer. DCVax-L's externally controlled phase 3 remains contested.\n\nProgress has come at the edges. Vorasidenib (INDIGO, approved 2024) is the first targeted therapy for grade 2 IDH-mutant glioma, delaying radiation and chemotherapy by years. Dabrafenib with trametinib (2023) was the first targeted therapy approved for BRAF V600E paediatric low-grade glioma; tovorafenib (2024) followed for relapsed or refractory BRAF-altered tumours, including BRAF fusions. Dordaviprone (August 2025) is the first drug approved for H3 K27M diffuse midline glioma. Methylation-based classification and intraoperative nanopore sequencing have transformed diagnosis. For glioblastoma itself the most promising directions are locoregional CAR-T (IL13Rα2, GD2, multi-target), focused-ultrasound and LITT-based barrier opening to deliver ADCs, radioconjugates, and chemotherapy, neoadjuvant immunotherapy with window designs, personalised neoantigen vaccines (NeoVax), and combinations built on the unmethylated-MGMT population, where temozolomide adds least.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Glioblastoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Glioblastoma"}],"tags":["cns","spike"],"related":["cell-therapy-roadmap","immunotherapy-roadmap","national-brain-tumor-society","meningioma","secondary-brain-tumours","ependymoma","medulloblastoma"],"cancers":[],"sections":[],"technologies":["ttfields","epigenetic-drugs","fluorescence-guided-surgery","methylation-profiling","car-t","hifu-histotripsy","mri","bnct","antineoplastons","imrt-igrt","proton-therapy","litt","bbb-focused-ultrasound","glioma-car-t","kinase-inhibitors","cytotoxic-chemotherapy","antiangiogenic","shared-antigen-vaccine","neoantigen-mrna-vaccine","hyperthermia"],"targets":["idh","egfr","tp53","braf","pd1","vegf","b7h3"],"drugs":["carmustine","procarbazine","depatuxizumab-mafodotin","neovax"],"companies":["philogen-s-p-a","neonc-technologies","aveta-biomics","hangzhou-hanx-biopharmaceuticals","servier","novocure","jazz","day-one-biopharmaceuticals","ipsen","insightec","northwest-biotherapeutics","roche-genentech","bms","curie-nki-eortc"],"institutions":["city-of-hope","stanford","mgh","penn-abramson","heidelberg-nct","dkfz"],"pathways":["glioma-signalling","ras-mapk","p53-cell-cycle","vegf-angiogenesis","pd1-checkpoint","pi3k-akt-mtor"],"terms":["mgmt","h3k27m","egfrviii","blood-brain-barrier","cold-vs-hot","accelerated-approval","re-irradiation","extent-of-resection"],"trials":["nct04250922","nct05118776","nct05303519","catnon","rtog-9402","eortc-26951","eortc-22033","nct07100730","nct06496971","nct05902169","nct05566795","nct07195591","nct06556563","intellance-1","eortc-26981","cctg-ce6","ef-14","indigo","checkmate-143","checkmate-498","checkmate-548","act-iv"],"people":[],"bottlenecks":[],"keyPapers":["paper-singh-brain-tumour-initiating-cells-nature-2004"],"journals":["brain-tumor-pathology","cns-oncology","journal-of-neuro-oncology"],"dependsOn":[],"notes":[],"group":"central nervous system","burden":"About 300,000 CNS tumours occur per year, most of them not glioblastoma; IDH-mutant and paediatric low-grade gliomas can be lived with for decades and now have targeted drugs. In the Stupp trial (EORTC 26981-NCIC, 2005) median survival with surgery, radiotherapy and temozolomide was 14.6 months against 12.1 with radiotherapy alone, and two-year survival rose from 10 to 27 percent; half of that trial's patients lived longer than the median, and a median describes a trial population rather than one person.","subtypes":["Glioblastoma, IDH-wild-type (WHO grade 4; TERT promoter, EGFR amplification, +7/−10)","Astrocytoma, IDH-mutant (grades 2-4; CDKN2A/B deletion defines grade 4)","Oligodendroglioma, IDH-mutant and 1p/19q-codeleted (grades 2-3)","Diffuse midline glioma, H3 K27M-altered (including DIPG)","Paediatric low-grade glioma (BRAF fusion or V600E, NF1)","Diffuse hemispheric glioma H3 G34-mutant; infant-type hemispheric glioma (NTRK/ALK/ROS1 fusions)"],"biomarkers":["IDH1/2","1p/19q codeletion","MGMT methylation","H3K27M","EGFR amplification","Methylation class","IDH1/2 mutation (vorasidenib eligibility)","MGMT promoter methylation (temozolomide benefit)","H3 K27M (dordaviprone eligibility)","BRAF fusion / V600E (tovorafenib, dabrafenib-trametinib)","TERT promoter, EGFR amplification, +7/−10 (molecular glioblastoma)","CDKN2A/B homozygous deletion (grade 4 astrocytoma)","DNA methylation class (Heidelberg classifier)","NTRK/ALK/ROS1 fusions (infant gliomas)","TMB / mismatch repair (rare hypermutant, IO-responsive)"],"standardOfCare":[{"setting":"Glioblastoma","approach":"Resection → RT + temozolomide → TTFields; lomustine/bevacizumab at relapse.","refs":["fluorescence-guided-surgery","imrt-igrt","optune"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"IDH-mutant grade 2","approach":"Resection → vorasidenib or observation; RT/PCV for high-risk.","refs":["vorasidenib"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Diagnosis","approach":"MRI with contrast; maximal safe resection with 5-ALA and intraoperative mapping, with early postoperative MRI to measure the extent of resection; integrated histo-molecular diagnosis with methylation classification where available.","refs":["mri","fluorescence-guided-surgery","extent-of-resection","methylation-profiling"]},{"setting":"Glioblastoma, newly diagnosed","approach":"Radiotherapy 60 Gy in 30 fractions with concurrent and 6 cycles adjuvant temozolomide; from age 65, short-course radiotherapy (40 Gy in 15 fractions) with temozolomide (CCTG CE.6); for older patients unfit for combined treatment, temozolomide alone or hypofractionated radiotherapy alone, chosen by MGMT status (Nordic, NOA-08); TTFields with maintenance temozolomide; trials for MGMT-unmethylated patients.","refs":["eortc-26981","cctg-ce6","temozolomide","ef-14","optune","imrt-igrt","mgmt","noa-08"]},{"setting":"Glioblastoma, recurrent","approach":"Re-resection or LITT if feasible; lomustine; bevacizumab for oedema/steroid sparing; re-irradiation; clinical trial (CAR-T, FUS-BBB, vaccines) strongly preferred.","refs":["lomustine","bevacizumab-glioma","litt","glioma-car-t","bbb-focused-ultrasound","sbrt"]},{"setting":"IDH-mutant grade 2 glioma","approach":"Maximal resection; vorasidenib for residual/recurrent disease (INDIGO); radiotherapy plus PCV or temozolomide for high-risk or progressive disease.","refs":["vorasidenib","indigo"]},{"setting":"Oligodendroglioma grade 3 / astrocytoma grade 3","approach":"Radiotherapy plus PCV (RTOG 9402, EORTC 26951) or temozolomide (CATNON).","refs":["temozolomide","imrt-igrt"]},{"setting":"H3 K27M diffuse midline glioma","approach":"Radiotherapy; dordaviprone at progression (2025); GD2 CAR-T and ONC201 first-line trials.","refs":["dordaviprone","glioma-car-t"]},{"setting":"Paediatric low-grade glioma","approach":"Resection where safe; chemotherapy (carboplatin/vincristine) or tovorafenib / dabrafenib-trametinib for BRAF-altered relapsed disease; avoid radiation in young children.","refs":["tovorafenib"]}],"stateOfArt":["Vorasidenib in low-grade glioma.","Methylation-based diagnosis.","TTFields.","Three first-in-class targeted approvals for glioma subtypes in 2024-25: vorasidenib (IDH-mutant), tovorafenib (BRAF paediatric), dordaviprone (H3 K27M).","Molecular classification (WHO 2021, methylation classifier, intraoperative nanopore) now defines diagnosis.","Locoregional CAR-T produces objective responses in recurrent glioblastoma and in diffuse midline glioma, including a sustained complete response; most responses so far have been short-lived, and making them last is what the phase 1 trials are testing.","Focused ultrasound opens the blood-brain barrier in humans with 4-6x higher drug delivery; efficacy trials underway."],"history":[{"year":1926,"title":"Bailey and Cushing classify gliomas","note":"Histologic classification that lasted, in essence, until 2016.","refs":[]},{"year":1978,"title":"Radiotherapy proven to extend survival (BTSG)","note":"Whole-brain then involved-field radiation becomes standard.","refs":["imrt-igrt"]},{"year":1999,"title":"Temozolomide approved (anaplastic astrocytoma)","refs":["temozolomide"]},{"year":2005,"title":"Stupp regimen: temozolomide + RT","refs":[]},{"year":2008,"title":"IDH1 mutations discovered in glioma","note":"Parsons/Vogelstein glioblastoma genome sequencing; reclassification follows.","refs":["idh"]},{"year":2009,"title":"Bevacizumab accelerated approval at recurrence","note":"Radiographic response without survival benefit.","refs":["bevacizumab-glioma"]},{"year":2014,"title":"AVAglio / RTOG 0825: bevacizumab no OS benefit; 5-ALA and methylation classifier emerge","refs":["bevacizumab-glioma","fluorescence-guided-surgery","methylation-profiling"]},{"year":2015,"title":"TTFields improves OS (EF-14)","refs":["optune"]},{"year":2016,"title":"WHO 2016 integrates molecular markers; ACT IV vaccine fails","refs":["act-iv","rindopepimut"]},{"year":2017,"title":"Short-course radiotherapy plus temozolomide extends survival from age 65 (CCTG CE.6)","refs":["cctg-ce6"]},{"year":2020,"title":"CheckMate 143: immunotherapy fails at recurrence","note":"CheckMate 548 (2022) and CheckMate 498 (2023) follow in newly diagnosed disease; all three negative.","refs":["checkmate-143","checkmate-548","checkmate-498"]},{"year":2021,"title":"WHO 2021: IDH-wild-type glioblastoma defined molecularly","refs":[]},{"year":2022,"title":"GD2 CAR-T responses in DIPG (Stanford)","refs":["glioma-car-t"]},{"year":2023,"title":"INDIGO: vorasidenib in grade 2 IDH-mutant glioma; DCVax-L contested publication","refs":["indigo","dcvax-l"]},{"year":2024,"title":"Vorasidenib approved","refs":["vorasidenib"]},{"year":2025,"title":"Dordaviprone approved for H3 K27M diffuse midline glioma","note":"6 August 2025; first systemic therapy for the disease.","refs":["dordaviprone"]},{"year":2026,"title":"ASCO 2026: NeoVax personalised vaccine immune responses; multi-target CAR-T; tovorafenib EU approval","refs":["tovorafenib","glioma-car-t","idea-neoadjuvant-io-glioblastoma"]}],"pipeline":["armored-car","bnct","hyperthermia","lam561","cobolimab","asc40","safusidenib","ino-5401","tng456","bcb-276","doc1021","glioma-car-t","bbb-focused-ultrasound","litt","dcvax-l","dordaviprone","tovorafenib","idea-neoadjuvant-io-glioblastoma","idea-fus-plus-adc-glioma","neoantigen-mrna-vaccine","in-vivo-car-t"],"openProblems":["Blood-brain barrier.","Immunologically cold, heterogeneous, infiltrative.","Glioblastoma: no systemic drug has beaten the 2005 standard; getting drugs across the blood-brain barrier is the crux.","No systemic drug has beaten the 2005 chemoradiation standard in a phase 3 trial, though tumour treating fields (EF-14, 2015) and short-course radiotherapy from age 65 (CCTG CE.6, 2017) both added survival; locoregional CAR-T, focused-ultrasound barrier opening and neoantigen vaccines are the current attempts.","MGMT-unmethylated glioblastoma (~60%) gains less from temozolomide than methylated disease, and how much less is still debated; NCCN keeps radiotherapy with temozolomide as an option for this group alongside a clinical trial, and it is the population most current trials are built on.","Blood-brain barrier and diffuse infiltration limit delivery and resection; imaging cannot distinguish progression from pseudoprogression reliably.","Immunotherapy failure: low TMB, T-cell exclusion, dexamethasone, and treatment-induced lymphopenia; neoadjuvant approaches are the only signal.","Antigen heterogeneity and loss (EGFRvIII, IL13Rα2) undermine single-target vaccines, ADCs, and CAR-T.","Diffuse midline glioma has one approved drug, dordaviprone, with a 22% response rate; making those responses last is the open question, and the phase 3 ACTION trial, GD2 CAR-T and convection-enhanced delivery are the attempts on it.","Trial design: single-arm and external-control comparisons (DCVax-L, historical vaccine data) have repeatedly misled the field."],"parent":"brain-tumours"},{"id":"glucagonoma","kind":"cancer","name":"Glucagonoma","aka":["Glucagon-secreting pancreatic neuroendocrine tumour","Glucagonoma syndrome","Alpha-cell tumour of the pancreas"],"tldr":"Glucagonoma is a very rare pancreatic neuroendocrine tumour that pours out the hormone glucagon, causing weight loss, diabetes and a distinctive migrating red rash. Because the rash is so characteristic, spotting it early can lead to diagnosis before the tumour has spread to the liver; surgery is the definitive treatment and somatostatin analogues control the symptoms.","summary":"Glucagonoma is a functioning pancreatic neuroendocrine tumour of alpha cells, classified by the WHO with the other functioning pancreatic neuroendocrine tumours by the hormone secreted, and accompanied in most cases by the glucagonoma syndrome of necrolytic migratory erythema, weight loss, diabetes mellitus, diarrhoea, weakness and thrombosis (Clinical Endocrinology 2011). In the six-patient series, weight loss and necrolytic migratory erythema each occurred in 83 percent and diabetes in 66 percent, plasma glucagon was raised in all, and somatostatin analogues with an aggressive surgical approach gave symptom relief and tumour control (Clinical Endocrinology 2011). The rash is usually the initial and specific finding, though it also occurs without a tumour (pseudoglucagonoma syndrome); metastases occur late, so recognising the rash before liver spread can be life-saving (JEADV 2016).\n\nHow it differs from its parent: the pancreatic neuroendocrine tumour page covers non-functioning tumours and the shared grading and treatment; glucagonoma is defined by its hormone and its syndrome, is usually large and in the tail of the pancreas by the time it is found, and is often metastatic at diagnosis after years of unrecognised symptoms.\n\nHow common: no registry figure in the sources read; the parent page notes that functioning tumours are a minority of pancreatic neuroendocrine tumours.\n\nTreatment: surgical resection is definitive; somatostatin analogues for the syndrome; the parent page's pathways (everolimus, sunitinib, peptide receptor radionuclide therapy, liver-directed therapy) for metastatic disease (JEADV 2016; NCI PDQ).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Glucagonoma","links":[{"label":"NCI PDQ: pancreatic neuroendocrine (islet cell) tumour treatment","url":"https://www.cancer.gov/types/pancreatic/neuroendocrine-tumors/treatment"},{"label":"Clinical Endocrinology 2011: glucagonoma and the glucagonoma syndrome, 25 years of experience","url":"https://doi.org/10.1111/j.1365-2265.2011.03967.x"},{"label":"JEADV 2016: glucagonoma syndrome, review and update on treatment","url":"https://doi.org/10.1111/jdv.13752"}],"tags":["subtype-page","wave4","rare"],"related":["pancreatic-net","vipoma","somatostatinoma","men1-syndrome","neuroendocrine"],"cancers":[],"sections":[],"technologies":["prrt"],"targets":[],"drugs":["everolimus","sunitinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"Very rare: one endocrine centre treated six patients in 25 years, median age 53.5, with a median of 39 months from first symptom to diagnosis (Clinical Endocrinology 2011). No registry figure is in the sources read.","subtypes":["Glucagonoma with the full glucagonoma syndrome (rash, weight loss, diabetes)","Glucagonoma without rash (glucagon-secreting neuroendocrine tumour)","MEN1-associated glucagonoma"],"biomarkers":["Plasma glucagon","Necrolytic migratory erythema on skin biopsy","Chromogranin A; WHO grade (Ki-67)","Somatostatin receptor imaging"],"standardOfCare":[{"setting":"All cases","approach":"Resection where possible; somatostatin analogues for the syndrome; the parent page's pathways (everolimus, sunitinib, peptide receptor radionuclide therapy) for metastatic disease.","refs":["pancreatic-net","everolimus","sunitinib","prrt"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"pancreatic-net"},{"id":"goblet-cell-adenocarcinoma","kind":"cancer","name":"Goblet cell adenocarcinoma of the appendix","aka":["Goblet cell carcinoid (obsolete)","Adenocarcinoma ex goblet cell carcinoid (obsolete)","GCA","Crypt cell carcinoma","Mixed adenoneuroendocrine carcinoma of the appendix (obsolete)"],"tldr":"Goblet cell adenocarcinoma is a rare appendix cancer whose cells mix mucus-filled goblet cells with neuroendocrine features, once called goblet cell carcinoid but now classed and treated as an adenocarcinoma. It is removed by right hemicolectomy, given bowel-cancer chemotherapy when it is high grade or has spread, and not treated with the somatostatin drugs used for true neuroendocrine tumours.","summary":"Goblet cell adenocarcinoma is an amphicrine tumour: its cells contain both mucin, like intestinal goblet cells, and neuroendocrine granules, and it grows in a concentric, infiltrative pattern through the appendiceal wall, often without a visible mass, so it is usually discovered after appendicectomy for appendicitis. Because of its neuroendocrine component it was long called goblet cell carcinoid and lumped with appendiceal neuroendocrine tumours, but it spreads like a carcinoma, to the peritoneum and, in women, to the ovaries, and does not express somatostatin receptors or respond to somatostatin analogues. The 2019 WHO classification renamed it goblet cell adenocarcinoma and grades it by the proportion of tubular or clustered goblet cell growth against poorly cohesive or signet ring growth (grades 1 to 3), replacing the earlier Tang classification; grade and stage determine survival, which is long for grade 1 tumours confined to the appendix and short for grade 3 tumours with peritoneal spread. The genetics are distinct from both appendiceal adenocarcinoma and neuroendocrine tumours, with mutations in chromatin-remodelling and Wnt pathway genes and few KRAS mutations.\n\nRight hemicolectomy with lymphadenectomy is recommended for almost all patients because nodal spread is common even with small tumours, and bilateral oophorectomy is considered in postmenopausal women. Adjuvant chemotherapy with FOLFOX or CAPOX is used for node-positive or grade 2 to 3 disease by analogy with colon cancer, and peritoneal metastases are treated with cytoreductive surgery and HIPEC in selected patients, with outcomes between those of low-grade pseudomyxoma peritonei and signet ring cell carcinoma. Metastatic disease receives colorectal chemotherapy regimens; platinum-etoposide, the treatment for neuroendocrine carcinoma, is not appropriate. Because the disease is so rare, care is best delivered in a peritoneal surface oncology centre with pathology review.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Goblet_cell_carcinoid","links":[{"label":"WHO Classification of Tumours: Digestive System (2019)","url":"https://publications.iarc.who.int/579"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Goblet_cell_carcinoid"}],"tags":["subtype-page","gastrointestinal"],"related":["appendiceal-adenocarcinoma","low-grade-appendiceal-mucinous-neoplasm","appendiceal","small-intestinal-net"],"cancers":[],"sections":[],"technologies":["hipec","histopathology-ihc","ct","cytotoxic-chemotherapy"],"targets":[],"drugs":["folfox","capox","folfiri"],"companies":[],"institutions":[],"pathways":[],"terms":["colectomy","lymphadenectomy","hipec-procedure","peritoneal-metastasis","endoscopy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2019-digestive-system-tumours-nagtegaal-histopathology-2020","paper-chicago-consensus-appendiceal-neoplasms-cancer-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"A rare tumour almost unique to the appendix, typically found in people in their fifties and sixties after appendicectomy; behaviour ranges from indolent to aggressive according to grade.","subtypes":["Grade 1 goblet cell adenocarcinoma (tubular or clustered pattern, indolent)","Grade 2 goblet cell adenocarcinoma","Grade 3 goblet cell adenocarcinoma (poorly cohesive or signet ring pattern, aggressive)","Goblet cell adenocarcinoma confined to the appendix (right hemicolectomy)","Goblet cell adenocarcinoma with peritoneal or ovarian metastases (cytoreduction and HIPEC in selected patients)"],"biomarkers":["WHO 2019 grade (proportion of low-grade tubular pattern)","TNM stage after right hemicolectomy","Synaptophysin and chromogranin (focal) with mucin stains (diagnosis)","Somatostatin receptor status (negative; not a target)","CEA, CA 19-9 and CA-125 for surveillance","Peritoneal cancer index where peritoneal disease is present"],"standardOfCare":[{"setting":"Diagnosis","approach":"Expert pathology review with WHO 2019 grading; CT of chest, abdomen and pelvis; colonoscopy; tumour markers; no somatostatin receptor imaging is needed.","refs":["histopathology-ihc","ct","endoscopy"],"guideline":{"version":"NCCN Guidelines: Colon Cancer (appendiceal section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Localised disease","approach":"Right hemicolectomy with lymphadenectomy for all grades; oophorectomy considered in postmenopausal women; adjuvant FOLFOX or CAPOX for node-positive or grade 2 to 3 disease.","refs":["colectomy","lymphadenectomy","folfox","capox"],"guideline":{"version":"NCCN Guidelines: Colon Cancer (appendiceal section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Peritoneal metastases","approach":"Cytoreductive surgery with HIPEC in fit patients with limited disease, with perioperative systemic chemotherapy.","refs":["hipec","hipec-procedure","peritoneal-metastasis","folfox"],"guideline":{"version":"NCCN Guidelines: Colon Cancer (appendiceal section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Metastatic disease","approach":"FOLFOX or CAPOX, then FOLFIRI, as for colorectal adenocarcinoma; somatostatin analogues and platinum-etoposide are not used.","refs":["folfox","capox","folfiri"],"guideline":{"version":"NCCN Guidelines: Colon Cancer (appendiceal section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}}],"stateOfArt":["The 2019 WHO reclassification ended decades of confusion with neuroendocrine tumours and aligned treatment with adenocarcinoma.","Right hemicolectomy is standard because nodal spread is common.","Grade now predicts outcome and steers adjuvant therapy."],"history":[{"year":1974,"title":"Goblet cell carcinoid of the appendix described as a distinct tumour","refs":[]},{"year":2008,"title":"Tang classification separates typical goblet cell carcinoid from adenocarcinoma ex goblet cell carcinoid","refs":[]},{"year":2019,"title":"WHO renames the tumour goblet cell adenocarcinoma with a three-tier grade","refs":[]},{"year":2021,"title":"Molecular studies show a genotype distinct from appendiceal adenocarcinoma and neuroendocrine tumours","refs":[]}],"pipeline":["folfox","hipec"],"openProblems":["No prospective trial has ever been conducted; all treatment is extrapolated.","The benefit of adjuvant chemotherapy in grade 1 node-negative disease is unknown.","Whether HIPEC helps in goblet cell adenocarcinoma specifically is defined only by small series.","Diagnosis is delayed by the absence of a mass and by old terminology."],"parent":"appendiceal"},{"id":"gonadotroph-pitnet","kind":"cancer","name":"Gonadotroph pituitary neuroendocrine tumour (non-functioning adenoma)","aka":["Gonadotroph tumour","Gonadotroph tumour (most non-functioning adenomas)","Gonadotroph adenoma","Non-functioning pituitary adenoma (most are gonadotroph)","SF1-lineage PitNET","Null cell adenoma (many reclassified as gonadotroph)"],"tldr":"A gonadotroph tumour is a pituitary tumour of the cells that normally make the fertility hormones, but it almost never secretes enough to cause symptoms, so it is found as a large non-functioning mass pressing on the optic nerves or by chance. Surgery through the nose is the treatment when it threatens vision or grows; there is no drug for it, and radiotherapy is used for regrowth.","summary":"The 2022 WHO classification places the gonadotroph tumour in the SF1 lineage, defined by SF1, GATA3 and oestrogen receptor alpha with variable FSH and LH staining, and it accounts for most tumours previously called non-functioning or null cell adenomas (Asa 2022). Gonadotroph adenomas often present as invasive macroadenomas not amenable to complete resection; radiotherapy is the only postoperative option for large invasive or recurrent lesions, no medical treatment is available, and the somatostatin analogues that target SSTR2 have little effect, which prompted the study of SSTR3 expression in 108 patients as a possible target (Endocrine-Related Cancer 2015). Gonadotroph tumours carry a heavier CD68-positive M2 macrophage infiltrate than somatotroph, lactotroph or corticotroph tumours, linked to invasion (JCEM 2020).\n\nHow it differs from its parent: it is the pituitary tumour without a hormone syndrome or a drug, managed by observation, surgery for mass effects and radiotherapy for regrowth; its risk is to vision and to the remaining pituitary function.\n\nHow common: the commonest non-functioning pituitary tumour; no separate incidence figure in the sources read.\n\nTreatment: observation with MRI and visual fields for incidental tumours away from the optic chiasm; transsphenoidal surgery for visual compromise, growth or pituitary failure; radiotherapy or radiosurgery for residual or recurrent tumour; hormone replacement for hypopituitarism; temozolomide for the rare aggressive tumour, as on the parent page.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Pituitary_adenoma","links":[{"label":"NCI PDQ: pituitary tumours treatment","url":"https://www.cancer.gov/types/pituitary/treatment"},{"label":"Asa 2022, Endocrine Pathology: overview of the 2022 WHO classification of pituitary tumours","url":"https://doi.org/10.1007/s12022-022-09703-7"},{"label":"Endocrine-Related Cancer 2015: SSTR3 as a target for the medical treatment of gonadotroph adenomas, 108 patients","url":"https://doi.org/10.1530/erc-14-0472"},{"label":"JCEM 2020: immune landscape of pituitary tumours, macrophages and gonadotroph tumour invasion","url":"https://doi.org/10.1210/clinem/dgaa520"}],"tags":["subtype-page","wave4","rare"],"related":["pituitary-tumours","lactotroph-pitnet","corticotroph-pitnet","thyrotroph-pitnet","craniopharyngioma"],"cancers":[],"sections":[],"technologies":["radiosurgery-srs"],"targets":[],"drugs":["temozolomide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"The commonest non-functioning pituitary tumour; the SSTR3 study assembled 108 patients from one pathology cohort (Endocrine-Related Cancer 2015). GLOBOCAN does not count pituitary tumours.","subtypes":["Gonadotroph pituitary tumour presenting as a non-functioning macroadenoma (the usual form)","Incidental gonadotroph microadenoma (observation)","Gonadotroph tumour with clinically apparent FSH or LH excess (rare; ovarian hyperstimulation)","Aggressive or recurrent gonadotroph tumour (radiotherapy, temozolomide)"],"biomarkers":["SF1, GATA3 and oestrogen receptor alpha lineage markers; FSH and LH immunostaining","Visual fields and optic chiasm contact on MRI","Anterior pituitary hormone panel for hypopituitarism","Ki-67 and invasion (recurrence risk)"],"standardOfCare":[{"setting":"Incidental, away from the chiasm","approach":"Observation with MRI and visual fields.","refs":["pituitary-tumours"]},{"setting":"Visual compromise, growth or recurrence","approach":"Transsphenoidal surgery; radiotherapy or radiosurgery for residual or recurrent tumour; temozolomide for aggressive tumours.","refs":["radiosurgery-srs","temozolomide","pituitary-tumours"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"pituitary-tumours"},{"id":"grade-3-net","kind":"cancer","name":"Grade 3 well-differentiated neuroendocrine tumour","aka":["NET G3","Grade 3 NET","Well-differentiated grade 3 neuroendocrine tumour","High-grade well-differentiated NET"],"tldr":"Grade 3 well-differentiated neuroendocrine tumours divide fast enough to be called grade 3 yet still look and behave like their slower relatives rather than like neuroendocrine carcinoma. Recognised as separate since 2017, they keep the somatostatin receptor, respond less well to platinum chemotherapy, and in the NETTER-2 trial were among the first treated with lutetium-177 dotatate up front.","summary":"Until 2017 every neuroendocrine neoplasm with a Ki-67 above 20 percent was called neuroendocrine carcinoma and treated like small-cell lung cancer. Pathologists noticed that some of these tumours kept the organoid architecture, uniform nuclei and somatostatin receptor expression of well-differentiated tumours, and that their patients lived far longer than those with carcinoma. Multicentre series, notably Heetfeld and colleagues (2015), showed that these tumours, usually pancreatic and usually with a Ki-67 between 20 and 55 percent, responded poorly to platinum-etoposide but survived longer, and the NORDIC NEC series (2013) had already found that a Ki-67 below 55 percent predicted the same pattern. The WHO classified pancreatic NET G3 as a distinct entity in 2017 and extended it to the whole digestive system in 2019; molecularly these tumours carry the MEN1, DAXX and ATRX changes of neuroendocrine tumours and retain p53 and Rb, whereas carcinoma loses them, which is why p53 and Rb immunohistochemistry is now used when morphology is ambiguous.\n\nTreatment evidence is thin because the entity is new and small. Capecitabine with temozolomide is the most used chemotherapy, on the basis of pancreatic tumour data from E2211 and retrospective grade 3 series, and everolimus and sunitinib are used with less evidence. Somatostatin receptor PET is usually positive, often with FDG avidity as well, and this dual pattern makes radioligand therapy plausible: NETTER-2 (Lancet 2024) was designed to include grade 3 tumours with a Ki-67 up to 55 percent alongside higher grade 2 tumours, and first-line lutetium-177 dotatate lengthened progression-free survival from 8.5 to 22.8 months across the 226 patients, the first randomised evidence in this group. COMPOSE randomises well-differentiated aggressive grade 2 and grade 3 gastroenteropancreatic tumours between 177Lu-edotreotide and CAPTEM, everolimus or FOLFOX, and is due to report in 2027.\n\nThe practical decisions are about tempo and receptor status. Tumours near the upper end of Ki-67, growing fast or losing receptor expression on PET are treated more like carcinoma with platinum-etoposide, while receptor-positive tumours with slower tempo are treated like grade 2 tumours with radioligand therapy or CAPTEM. Surgery and liver-directed therapy are used as for other well-differentiated tumours when disease is limited. Whether grade 3 tumours should be graded further, and where the Ki-67 line between tumour and carcinoma really lies, remain open.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor","links":[{"label":"NETTER-2 (Lancet 2024)","url":"https://doi.org/10.1016/S0140-6736(24)00701-3"},{"label":"Heetfeld et al. (Endocrine-Related Cancer 2015)","url":"https://doi.org/10.1530/ERC-15-0119"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor"}],"tags":["subtype-page","endocrine"],"related":["extrapulmonary-nec","lung-net","pancreatic-net","small-intestinal-net"],"cancers":[],"sections":[],"technologies":["sstr-pet","prrt","pet","radioligand-therapy"],"targets":["sstr2","tp53","menin"],"drugs":["lutathera","capecitabine-temozolomide","everolimus","sunitinib","platinum-etoposide","itm-11","octreotide-lanreotide"],"companies":[],"institutions":[],"pathways":[],"terms":["net-grade-ki67","tumour-differentiation","chromogranin-a","prrt-term"],"trials":["nct03972488","nct04919226","compete"],"people":[],"bottlenecks":[],"keyPapers":["paper-netter-2-lancet-2024","paper-rindi-common-classification-framework-mod-pathol-2018","paper-heetfeld-grade-3-net-erc-2015"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"A small fraction of neuroendocrine neoplasms, most often pancreatic; recognised as a separate entity by the WHO in 2017 for the pancreas and 2019 for the whole digestive system after series showed it outlives neuroendocrine carcinoma and responds less to platinum.","subtypes":["Grade 3 well-differentiated pancreatic NET (the commonest site)","Grade 3 well-differentiated small intestinal and other gastroenteropancreatic NET","NET G3 with Ki-67 20 to 55 percent, somatostatin receptor-positive (radioligand candidates)","NET G3 with high FDG avidity or falling receptor expression (carcinoma-like behaviour)","Grade 2 to grade 3 progression within a known neuroendocrine tumour"],"biomarkers":["Ki-67 above 20 percent (usually 20 to 55 percent) with well-differentiated morphology","Retained p53 and Rb by immunohistochemistry (abnormal in carcinoma)","Somatostatin receptor PET, usually positive, with FDG PET for dual-tracer assessment","Chromogranin A (monitoring)","MEN1, DAXX and ATRX alterations (tumour lineage, research)","MGMT status (CAPTEM response, investigational)"],"standardOfCare":[{"setting":"Diagnosis","approach":"Morphology, Ki-67 and p53 or Rb immunohistochemistry to separate grade 3 tumour from carcinoma; somatostatin receptor and FDG PET together.","refs":["net-grade-ki67","tumour-differentiation","sstr-pet","pet","tp53"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Advanced, somatostatin receptor-positive","approach":"Lutetium-177 dotatate first line for Ki-67 up to 55 percent (NETTER-2); somatostatin analogue alongside.","refs":["lutathera","nct03972488","prrt","octreotide-lanreotide"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Advanced, shrinkage needed or receptor-negative","approach":"Capecitabine with temozolomide; everolimus or sunitinib for pancreatic tumours; platinum-etoposide for carcinoma-like tempo or Ki-67 near 55 percent.","refs":["capecitabine-temozolomide","everolimus","sunitinib","platinum-etoposide"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Trials","approach":"COMPOSE: 177Lu-edotreotide against CAPTEM, everolimus or FOLFOX in aggressive grade 2 and grade 3 gastroenteropancreatic tumours.","refs":["nct04919226","itm-11"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Limited disease","approach":"Resection and liver-directed therapy as for other well-differentiated tumours.","refs":["hepatectomy","thermal-ablation","tace","liver-directed-therapy"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}}],"stateOfArt":["The 2017 and 2019 WHO classifications turned a pathology observation into a treatable category and spared these patients platinum they did not benefit from.","NETTER-2 supplied the first randomised evidence in grade 3 tumours and put radioligand therapy first line.","p53 and Rb immunohistochemistry and dual-tracer PET give practical tools for the ambiguous case."],"history":[{"year":2013,"title":"NORDIC NEC: Ki-67 below 55 percent marks a less platinum-sensitive, longer-surviving group","refs":[]},{"year":2015,"title":"Heetfeld and colleagues characterise well-differentiated grade 3 tumours as distinct from carcinoma","refs":[]},{"year":2017,"title":"WHO classification of pancreatic tumours creates NET G3","refs":["net-grade-ki67"]},{"year":2019,"title":"WHO digestive system classification extends NET G3 to the whole gut","refs":["net-grade-ki67"]},{"year":2021,"title":"COMPOSE opens: 177Lu-edotreotide against chemotherapy or everolimus in aggressive grade 2 and grade 3 tumours","refs":["nct04919226","itm-11"]},{"year":2024,"title":"NETTER-2: first-line lutetium-177 dotatate in grade 2 to 3 tumours with Ki-67 up to 55 percent","refs":["nct03972488","lutathera"]}],"pipeline":["nct04919226","itm-11","lutathera","capecitabine-temozolomide","idea-net-dosimetry-prrt"],"openProblems":["The Ki-67 boundary between grade 3 tumour and carcinoma is not sharp, and some cases can only be settled by molecular testing.","No trial has been run in grade 3 tumours alone; NETTER-2 and COMPOSE mix them with grade 2.","Whether platinum-etoposide, CAPTEM or radioligand therapy should come first in the fastest grade 3 tumours is unknown."],"parent":"neuroendocrine"},{"id":"medulloblastoma-group-3-4","kind":"cancer","name":"Group 3 and group 4 medulloblastoma (non-WNT/non-SHH)","aka":["Non-WNT/non-SHH medulloblastoma","Group 3 medulloblastoma","Group 4 medulloblastoma","MYC-amplified medulloblastoma"],"tldr":"Group 3 and group 4 medulloblastoma are the two commonest forms of this cerebellar brain tumour and the ones without a druggable driver. Group 3 strikes young children, often with extra copies of MYC and spread through the spinal fluid; group 4 affects older boys. Both get surgery, craniospinal radiotherapy and chemotherapy; trials showed the radiation dose cannot be cut for young children.","summary":"Groups 3 and 4 arise from the upper rhombic lip and unipolar brush cell lineages and share enough that WHO 2021 groups them as non-WNT/non-SHH medulloblastoma with eight methylation subgroups. Group 3 (about a quarter of medulloblastoma) occurs in infants and young children, often with large-cell/anaplastic histology, MYC amplification in about 17 percent, GFI1 enhancer hijacking, and metastases in 40 to 45 percent at diagnosis. Group 4 (about 35 to 40 percent) affects older children and adolescents, three boys to one girl, with isochromosome 17q in most, KDM6A and PRDM6 alterations and MYCN amplification in some, and metastases in about a third. Metastatic stage, MYC amplification and residual tumour define high risk in both.\n\nThe trials that set standard therapy predate the groups. SIOP PNET3 showed pre-radiotherapy chemotherapy improved event-free survival; COG A9961 in 2006 established the average-risk regimen of 23.4 Gy craniospinal radiotherapy with a boost followed by cisplatin, vincristine and cyclophosphamide or lomustine, with five-year event-free survival of 81 percent; HIT-SIOP PNET4 found hyperfractionated radiotherapy no better than standard. ACNS0331, reported in 2021, tried to lower the craniospinal dose to 18 Gy in children aged three to seven with average-risk disease and found it inferior, five-year event-free survival 71.4 percent against 82.9 percent, while confirming that boosting the tumour bed rather than the whole posterior fossa is safe. ACNS0332, for high-risk disease, showed that carboplatin given daily during craniospinal radiotherapy improved five-year event-free survival in group 3 from 53.7 to 73.2 percent with no benefit in group 4, and that isotretinoin maintenance added nothing. Infants with group 3 disease receive intensive chemotherapy with high-dose consolidation and stem cell rescue to avoid or delay radiotherapy.\n\nRelapse in groups 3 and 4 is almost always fatal, recurs in the same molecular group, and typically occurs in the leptomeninges rather than the tumour bed; temozolomide, irinotecan and bevacizumab, re-irradiation and high-dose chemotherapy buy time. The current trials assign therapy by methylation subgroup: SJMB12 and the SIOP PNET5 and HIT-MED studies reduce therapy for low-risk group 4 (chromosome 11 loss or whole chromosome 17 gain without metastases) and intensify it for MYC-amplified group 3. No targeted drug has worked: MYC and MYCN have no inhibitor, and immunotherapy trials to date have shown little in an immunologically cold tumour. The long-term price of craniospinal radiotherapy, in intellect, hearing, endocrine function, stroke and second tumours, is why proton therapy is the preferred modality where available and why the dose question keeps being asked.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Medulloblastoma","links":[{"label":"Wikipedia: Medulloblastoma","url":"https://en.wikipedia.org/wiki/Medulloblastoma"},{"label":"NCI PDQ: Childhood Medulloblastoma Treatment","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}],"tags":["subtype-page","paediatric","cns"],"related":["medulloblastoma-wnt","medulloblastoma-shh"],"cancers":[],"sections":[],"technologies":["proton-therapy","imrt-igrt","methylation-profiling","autologous-stem-cell-transplant"],"targets":[],"drugs":["isotretinoin"],"companies":["childrens-oncology-group"],"institutions":["siop-europe","st-jude"],"pathways":["myc"],"terms":["late-effects","medulloblastoma-molecular-groups"],"trials":["acns0332"],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2021-cns-louis-neuro-oncology-2021","paper-taylor-medulloblastoma-consensus-acta-neuropathol-2012","paper-cavalli-medulloblastoma-subtypes-cancer-cell-2017","paper-acns0332-leary-jama-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Groups 3 and 4 together make up about 60 to 65 percent of medulloblastoma: group 4 is the commonest single group and group 3, often MYC-amplified and metastatic in young children, the most lethal.","subtypes":["Group 3 medulloblastoma, MYC-amplified (very high risk; often metastatic)","Group 3 medulloblastoma without MYC amplification","Group 4 medulloblastoma, low risk (chromosome 11 loss or whole chromosome 17 gain, non-metastatic)","Group 4 medulloblastoma, standard and high risk (metastatic or MYCN-amplified)","Non-WNT/non-SHH medulloblastoma in infants (group 3; radiotherapy-avoiding chemotherapy)","Large-cell/anaplastic histology (mostly group 3)"],"biomarkers":["DNA methylation profiling (non-WNT/non-SHH subgroups I to VIII)","MYC and MYCN amplification","Isochromosome 17q","Chromosome 11 loss and whole chromosome 17 gain (low-risk group 4)","Metastatic staging by spinal MRI and CSF cytology (Chang M stage)","Residual tumour on postoperative MRI","Large-cell/anaplastic histology"],"standardOfCare":[{"setting":"Average risk (aged 3 or over, no metastases, residual under 1.5 square centimetres)","approach":"Maximal safe resection, 23.4 Gy craniospinal radiotherapy with tumour-bed boost (ACNS0331 showed 18 Gy is inferior), then cisplatin, vincristine and cyclophosphamide or lomustine.","refs":["proton-therapy","imrt-igrt","cisplatin","vincristine","cyclophosphamide","lomustine","acns0331"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"High risk (metastatic, residual disease or MYC amplification)","approach":"36 Gy craniospinal radiotherapy with boost, daily carboplatin during radiotherapy for group 3 (ACNS0332), then cisplatin, vincristine and cyclophosphamide.","refs":["carboplatin","imrt-igrt","proton-therapy","cisplatin","vincristine","cyclophosphamide"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"Infants under three","approach":"Intensive chemotherapy with methotrexate, then high-dose consolidation with stem cell rescue, to avoid or delay craniospinal radiotherapy.","refs":["methotrexate","cyclophosphamide","vincristine","carboplatin","thiotepa","autologous-stem-cell-transplant"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"Relapsed","approach":"Temozolomide with irinotecan, bevacizumab, re-irradiation or high-dose chemotherapy; almost never curative; early-phase trials.","refs":["temozolomide","irinotecan","bevacizumab","autologous-stem-cell-transplant","imrt-igrt"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"Survivorship","approach":"Neurocognitive, endocrine, hearing, vascular and second-tumour follow-up for life.","refs":["late-effects","survivorship-care-plan"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}}],"stateOfArt":["Craniospinal radiotherapy at 23.4 Gy plus chemotherapy cures about four in five average-risk children, and ACNS0331 showed the dose cannot be lowered to 18 Gy in young children.","Carboplatin during radiotherapy improved event-free survival in high-risk group 3 in ACNS0332.","Methylation subgroups now steer trials: less therapy for low-risk group 4, more for MYC-amplified group 3."],"history":[{"year":1925,"title":"Bailey and Cushing name medulloblastoma","refs":[]},{"year":1953,"title":"Craniospinal irradiation introduced for medulloblastoma","refs":[]},{"year":2003,"title":"SIOP PNET3: chemotherapy before radiotherapy improves event-free survival","refs":[]},{"year":2006,"title":"A9961: 23.4 Gy craniospinal radiotherapy with cisplatin-based chemotherapy gives 81 percent five-year event-free survival","refs":["cisplatin","vincristine","lomustine","cyclophosphamide"]},{"year":2012,"title":"Consensus on four molecular groups; group 3 and group 4 named","refs":[]},{"year":2021,"title":"ACNS0331: 18 Gy craniospinal radiotherapy inferior in young children; ACNS0332: carboplatin during radiotherapy helps group 3","refs":["acns0331","carboplatin"]},{"year":2021,"title":"WHO 2021 groups them as non-WNT/non-SHH medulloblastoma with eight subgroups","refs":["methylation-profiling"]}],"pipeline":["methylation-profiling","proton-therapy","temozolomide","bevacizumab","idea-fund-proton-coverage-with-evidence"],"openProblems":["MYC and MYCN have no inhibitor, and relapse is almost always fatal.","Craniospinal radiotherapy dose cannot be reduced in young children without losing cures.","Immunotherapy has shown little in an immunologically cold tumour."],"parent":"medulloblastoma"},{"id":"hairy-cell-leukemia","kind":"cancer","name":"Hairy cell leukaemia","aka":[],"tldr":"Hairy cell leukaemia is a rare, slow B-cell leukaemia with a single defining mutation (BRAF V600E) that is unusually curable: one week of a purine analogue puts most people into remission for years, and BRAF drugs rescue those who relapse.","summary":"Classic hairy cell leukaemia (HCL) is a mature B-cell neoplasm with a distinctive morphology and immunophenotype (CD11c, CD25, CD103, CD123, annexin A1) and BRAF V600E in essentially all cases (Tiacci 2011); the variant HCL-v lacks BRAF V600E, is CD25-negative, and behaves worse (often MAP2K1-mutant). Patients present with pancytopenia, splenomegaly and infections.\n\nPurine analogues (cladribine or pentostatin) give complete remission in 80-90% with a single course, and adding rituximab (concurrent or delayed) deepens responses and achieves MRD negativity in most (Chihara et al.). Relapse is treated with a second purine analogue course plus rituximab; BRAF inhibition (vemurafenib ± rituximab) gives durable remissions in multiply relapsed disease (Tiacci 2021, NEJM), and BRAF+MEK combinations are an option. Moxetumomab pasudotox (anti-CD22 immunotoxin) was approved in 2018 and withdrawn commercially in 2023. Ibrutinib has modest activity. Overall survival is now close to age-matched controls.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Hairy_cell_leukemia","links":[{"label":"NCCN Guidelines: Hairy Cell Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1481"},{"label":"Hairy Cell Leukemia Foundation","url":"https://www.hairycellleukemia.org/"},{"label":"Tiacci 2011 NEJM","url":"https://doi.org/10.1056/NEJMoa1014209"}],"tags":["gap-fill","haematologic"],"related":["cll","cml"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","monoclonal-antibody","flow-cytometry-mrd","cytotoxic-chemotherapy"],"targets":["braf","cd20","cd22","cd123","btk"],"drugs":["cladribine","rituximab","vemurafenib","dabrafenib-trametinib","moxetumomab-pasudotox","ibrutinib","interferon-alfa"],"companies":["roche-genentech","astrazeneca"],"institutions":[],"pathways":["ras-mapk"],"terms":["mrd"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-tiacci-n-engl-j-med"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Hairy cell leukaemia causes about 1,000-1,200 cases per year in the US (~2% of leukaemias); median age ~55, 4:1 male.","subtypes":["Classic HCL (BRAF V600E)","HCL variant (BRAF-wild-type, CD25-negative, MAP2K1 mutations)","IGHV4-34 HCL (poor risk)"],"biomarkers":["BRAF V600E (IHC VE1, PCR, ddPCR)","Flow cytometry: CD11c, CD25, CD103, CD123","MRD by flow or BRAF ddPCR","IGHV4-34 usage","MAP2K1 mutations (variant)"],"standardOfCare":[{"setting":"First line, symptomatic","approach":"Cladribine (5-7 days) or pentostatin, with rituximab concurrent or delayed (improves MRD-negative CR).","refs":["cladribine","rituximab"],"guideline":{"nccn":"Category 1 (cladribine ± rituximab)","version":"NCCN Guidelines: Hairy Cell Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1481"}},{"setting":"Relapse after >2 years","approach":"Repeat purine analogue + rituximab.","refs":["cladribine","rituximab"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Hairy Cell Leukemia"}},{"setting":"Early relapse or refractory","approach":"Vemurafenib + rituximab (or dabrafenib-trametinib); ibrutinib; clinical trial. Moxetumomab pasudotox produced durable remissions but was withdrawn from sale in 2023 and is no longer available.","refs":["vemurafenib","rituximab","dabrafenib-trametinib","ibrutinib","moxetumomab-pasudotox"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Hairy Cell Leukemia"}}],"stateOfArt":["One week of cladribine remains one of the most effective single treatments in oncology.","BRAF V600E is universal in classic HCL; vemurafenib-rituximab produces MRD-negative remissions in most relapsed patients without chemotherapy.","Life expectancy is near normal; the residual problems are infection during induction and the aggressive variant."],"history":[{"year":1958,"title":"Bouroncle describes 'leukemic reticuloendotheliosis'","refs":[]},{"year":1984,"title":"Interferon alfa: first effective therapy","refs":["interferon-alfa"]},{"year":1990,"title":"Cladribine: durable remissions after one course (Piro, NEJM)","refs":["cladribine"]},{"year":2011,"title":"BRAF V600E found in all classic HCL (Tiacci, NEJM)","refs":["braf"]},{"year":2015,"title":"Vemurafenib active in relapsed HCL","refs":["vemurafenib"]},{"year":2018,"title":"Moxetumomab pasudotox approved","note":"First CD22 immunotoxin; withdrawn from the US market in 2023 for commercial reasons.","refs":["moxetumomab-pasudotox"]},{"year":2021,"title":"Vemurafenib + rituximab: chemo-free durable remissions (NEJM)","refs":["vemurafenib","rituximab"]}],"pipeline":["vemurafenib","dabrafenib-trametinib"],"openProblems":["Variant HCL and IGHV4-34 disease respond poorly to purine analogues.","Infection risk during induction neutropenia.","Whether MRD eradication should be a treatment goal."],"parent":"leukaemia"},{"id":"head-and-neck","kind":"cancer","name":"Head and neck squamous cell carcinoma","aka":["HNSC","HNSCC","TCGA-HNSC","head and neck squamous cell carcinoma (TCGA HNSC cohort)"],"tldr":"Cancers of the mouth and throat, increasingly caused by HPV. Immunotherapy is first line for advanced disease and now used before surgery.","summary":"Head and neck squamous cell carcinoma arises from the lining of the mouth, throat (oropharynx, hypopharynx), voice box, and nose, and includes the distinct Epstein-Barr-virus-driven nasopharyngeal carcinoma. Two epidemics coexist: tobacco- and alcohol-related cancers, declining in rich countries but common globally, and HPV-driven oropharyngeal cancer, rising among younger non-smokers and now the most common HPV cancer in the US. HPV-positive disease is far more curable (3-year survival >80%) and has its own staging system.\n\nCurative treatment is surgery (increasingly transoral robotic surgery) and/or cisplatin-based chemoradiation with IMRT; both leave lasting effects on speech, swallowing, and salivation, which is why de-escalation for HPV-positive disease has been pursued so hard, and why its repeated failure (RTOG 1016, De-ESCALaTE, NRG-HN005) matters. Immunotherapy transformed recurrent and metastatic disease: nivolumab (CheckMate 141) and then pembrolizumab first line (KEYNOTE-048) replaced the cetuximab-chemotherapy EXTREME regimen, and in June 2025 KEYNOTE-689 delivered the first perioperative approval, doubling event-free survival by giving pembrolizumab before and after surgery. Immunotherapy given concurrently with chemoradiation, by contrast, has failed repeatedly. Nasopharyngeal carcinoma gained its first US approval with toripalimab plus chemotherapy in 2023.\n\nWhat is coming: EGFR-directed bispecifics with pembrolizumab (petosemtamab, ficerafusp alfa) posting response rates two to three times those of pembrolizumab alone in early trials, now in phase 3; photoimmunotherapy (approved in Japan) in global phase 3; ctHPV-DNA to guide response-adapted de-escalation; and B7-H3 and EGFR×HER3 ADCs. Open problems include the lack of targets beyond EGFR and PD-1, the functional toxicity of curative treatment, and the lower cure rate of HPV-negative disease.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Head_and_neck_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Head_and_neck_cancer"}],"tags":["head-neck","spike"],"related":["io-before-surgery-hnscc","egfr-bispecific-plus-pd1-hnscc","hpv-deescalation-caution","immunotherapy-roadmap"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","photoimmunotherapy","bnct","proton-therapy","hpv-vaccine","robotic-surgery","acupuncture-xerostomia","glutamine-mucositis-neuropathy","honey-radiation-mucositis","hyperbaric-oxygen-radiation-injury","tors","cthpv-dna","imrt-igrt","sentinel-node"],"targets":["pd1","egfr","pik3ca","b7h3","pdl1","lgr5"],"drugs":["toripalimab","petosemtamab","ficerafusp-alfa","cetuximab-sarotalocan","amifostine","temoporfin"],"companies":["epicentrx","neonc-technologies","rakuten-medical","ap-biosciences","aveta-biomics","qbiotics","scancell","tiumbio","vyriad","merck","bms","merus","genmab","debiopharm","intuitive-surgical","nrg-oncology"],"institutions":["sysucc","tata-memorial","dana-farber"],"pathways":[],"terms":["hpv-p16","lgr5","cps","neoadjuvant-adjuvant"],"trials":["nct06082167","nct06601335","nct04590963","nct05751512","nct06295731","nct04892173","nct04534205","nct06064877","nct06699212","nct06496178","nct03769506","nct06256588","nct07276399","nct05893888","keynote-048","keynote-689","extreme","checkmate-141","rtog-0129","nrg-hn002-hn005","javelin-hn-100","trilynx","jupiter-02","liger-hn1","fortifi-hn01"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["head-and-neck-journal","head-and-neck-pathology","oral-oncology"],"dependsOn":[],"notes":[],"group":"head and neck","burden":"~900,000 cases per year; HPV-driven oropharyngeal cancer rising, tobacco-related declining.","subtypes":["Oral cavity","Oropharynx, HPV-positive (p16+)","Oropharynx, HPV-negative","Larynx","Hypopharynx","Nasopharyngeal carcinoma (EBV-driven; endemic in southern China and Southeast Asia)","Salivary gland cancers (distinct histologies; HER2, AR, NTRK targets)","Sinonasal","Cutaneous SCC of the head and neck (cemiplimab)"],"biomarkers":["HPV/p16","PD-L1 CPS","EGFR","HPV / p16 status (staging and prognosis)","PD-L1 CPS (first-line pembrolizumab eligibility and KEYNOTE-689)","EGFR (near-universal; cetuximab, bispecifics)","EBV DNA (nasopharyngeal carcinoma surveillance)","ctHPV-DNA (response and recurrence)","TP53, CDKN2A, PIK3CA, NOTCH1 (HPV-negative genomics)","Smoking history (modifies HPV-positive prognosis)"],"standardOfCare":[{"setting":"Resectable","approach":"Neoadjuvant + adjuvant pembrolizumab with surgery; or chemoradiation.","refs":["pembrolizumab","imrt-igrt","robotic-surgery"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Recurrent/metastatic","approach":"Pembrolizumab ± platinum/5-FU; cetuximab-based; photoimmunotherapy (Japan).","refs":["pembrolizumab","photoimmunotherapy"],"guideline":{"esmoMcbs":"2 (cetuximab sarotalocan, Japan, single-arm)","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11163648/"}},{"setting":"Prevention","approach":"HPV vaccination (also prevents oropharyngeal cancer in men), tobacco and alcohol cessation; no validated screening.","refs":["hpv-vaccine"],"guideline":{"nccn":"Prevention guideline"}},{"setting":"Early stage (I-II) oral cavity and larynx","approach":"Single-modality surgery or radiation; sentinel node or elective neck dissection for oral cavity; larynx preservation with radiation for T1-T2 glottic cancer.","refs":["imrt-igrt","sentinel-node"],"guideline":{"nccn":"2A"}},{"setting":"Early HPV-positive oropharynx","approach":"TORS with pathology-guided adjuvant therapy or definitive (chemo)radiation; standard 70 Gy dose because de-escalation trials failed.","refs":["tors","nrg-hn002-hn005","hpv-deescalation-caution","rtog-0129"],"guideline":{"nccn":"2A"}},{"setting":"Locally advanced, resectable (stage III-IVA)","approach":"Neoadjuvant pembrolizumab, surgery, adjuvant pembrolizumab with (chemo)radiation for PD-L1 CPS ≥1 (KEYNOTE-689); otherwise surgery then risk-adapted (chemo)radiation.","refs":["keynote-689","pembrolizumab","io-before-surgery-hnscc"],"guideline":{"nccn":"1 (CPS ≥1)","esmoMcbs":"A"}},{"setting":"Locally advanced, unresectable or organ preservation","approach":"Cisplatin (100 mg/m² q3w or weekly) with 70 Gy IMRT; cetuximab-radiation only if cisplatin-ineligible; concurrent immunotherapy is not indicated (JAVELIN Head and Neck 100, KEYNOTE-412) and adding xevinapant to chemoradiation gave no benefit (TrilynX).","refs":["imrt-igrt","javelin-hn-100","trilynx"],"guideline":{"nccn":"1"}},{"setting":"Recurrent or metastatic, first line","approach":"Pembrolizumab alone (CPS ≥20, or ≥1) or with platinum/5-FU (any CPS); EXTREME if immunotherapy contraindicated.","refs":["keynote-048","pembrolizumab","extreme"],"guideline":{"nccn":"1","esmoMcbs":"4"}},{"setting":"Recurrent or metastatic, after platinum","approach":"Nivolumab or pembrolizumab if immunotherapy-naive; otherwise cetuximab, taxane, or methotrexate; clinical trials (bispecifics, ADCs).","refs":["checkmate-141","nivolumab","liger-hn1","fortifi-hn01"],"guideline":{"nccn":"1 (IO-naive)"}},{"setting":"Locally recurrent, unresectable (Japan)","approach":"Cetuximab sarotalocan photoimmunotherapy; re-irradiation (proton or IMRT) in selected patients elsewhere.","refs":["cetuximab-sarotalocan","photoimmunotherapy","proton-therapy","bnct"]},{"setting":"Nasopharyngeal carcinoma","approach":"Induction gemcitabine-cisplatin then chemoradiation for locoregional disease; toripalimab (or other PD-1) + gemcitabine-cisplatin for recurrent/metastatic; plasma EBV DNA for surveillance.","refs":["jupiter-02","toripalimab","imrt-igrt"],"guideline":{"nccn":"1"}},{"setting":"Survivorship","approach":"Swallowing and speech therapy, dental care after radiation, thyroid monitoring, lymphoedema management, smoking cessation; second primary surveillance.","refs":["supportive-care"]}],"stateOfArt":["Perioperative IO.","HPV vaccination reducing future incidence.","Perioperative pembrolizumab (KEYNOTE-689) is the first curative-intent advance since cetuximab-radiation in 2006, with median event-free survival roughly doubled.","Pembrolizumab-based first-line therapy for recurrent or metastatic disease produces a durable survival tail that chemotherapy never did.","HPV-positive oropharyngeal cancer is recognised as a distinct, highly curable disease, but the standard dose of chemoradiation still stands because every de-escalation trial has fallen short.","Nasopharyngeal carcinoma has immunotherapy-chemotherapy as first line in the US, EU, and China.","Transoral robotic surgery gives many patients a surgical option without splitting the jaw.","EGFR-directed bispecifics plus PD-1 blockade are showing response rates not seen before in this disease and are in phase 3."],"history":[{"year":1987,"title":"Cisplatin-5-FU induction and larynx preservation trials begin","note":"VA Larynx study establishes organ preservation with chemoradiation.","refs":[]},{"year":2000,"title":"Concurrent cisplatin chemoradiation becomes standard for locally advanced disease","note":"Meta-analysis (MACH-NC) confirms ~6.5% absolute survival gain.","refs":["imrt-igrt","platinum"]},{"year":2006,"title":"Cetuximab + RT","refs":[]},{"year":2006,"title":"Cetuximab + radiation improves survival (Bonner)","note":"First targeted agent in HNSCC.","refs":["egfr"]},{"year":2008,"title":"EXTREME defines first-line therapy for recurrent/metastatic disease","refs":["extreme"]},{"year":2009,"title":"Transoral robotic surgery FDA-cleared","refs":["tors"]},{"year":2010,"title":"RTOG 0129: HPV status is the dominant prognostic factor","refs":["rtog-0129","hpv-p16"]},{"year":2016,"title":"PD-1 approved second line","refs":[]},{"year":2016,"title":"Nivolumab (CheckMate 141) and pembrolizumab approved after platinum","refs":["checkmate-141","nivolumab","pembrolizumab"]},{"year":2018,"title":"AJCC 8th edition gives HPV-positive oropharynx cancer its own staging","refs":["hpv-p16","tnm-staging"]},{"year":2019,"title":"KEYNOTE-048: IO first line","refs":[]},{"year":2019,"title":"KEYNOTE-048: pembrolizumab first line; RTOG 1016 and De-ESCALaTE show cetuximab cannot replace cisplatin","refs":["keynote-048","hpv-deescalation-caution"]},{"year":2020,"title":"Cetuximab sarotalocan photoimmunotherapy approved in Japan; JAVELIN H&N 100 negative","refs":["cetuximab-sarotalocan","javelin-hn-100"]},{"year":2021,"title":"JUPITER-02: PD-1 plus chemotherapy in nasopharyngeal carcinoma; BNCT approved in Japan","refs":["jupiter-02","bnct"]},{"year":2023,"title":"Toripalimab first US approval for nasopharyngeal carcinoma","refs":["toripalimab"]},{"year":2024,"title":"TrilynX (xevinapant) stopped for futility; petosemtamab Breakthrough designation","refs":["trilynx","petosemtamab"]},{"year":2025,"title":"KEYNOTE-689: neoadjuvant IO","refs":[]},{"year":2025,"title":"KEYNOTE-689 perioperative pembrolizumab approved; NRG-HN005 de-escalation fails; petosemtamab and ficerafusp alfa phase 3 trials","refs":["keynote-689","nrg-hn002-hn005","liger-hn1","fortifi-hn01"]}],"pipeline":["tilatamig-samrotecan","lifileucel","shr-a2102","domvanalimab","si-b001","hs-20093","zanzalintinib","ak117","monalizumab","sys6010","mrg003","gotistobart","io102-io103","inbrx-106","jnj-90301900","bnt113","ficlatuzumab","t3011","mcla-129","hmbd-001","jk08","lvgn6051","avasopasem-manganese","petosemtamab","liger-hn1","ficerafusp-alfa","fortifi-hn01","cetuximab-sarotalocan","cthpv-dna","idea-cthpv-adapted-deescalation","idea-photoimmunotherapy-plus-pd1","egfr-bispecific-plus-pd1-hnscc","bnct","proton-therapy","b7h3"],"openProblems":["Functional toxicity of chemoradiation.","Few targets beyond EGFR/PD-1.","HPV-negative, tobacco-related disease has 5-year survival around 50% and has seen little improvement in curative outcomes beyond KEYNOTE-689.","De-escalation for HPV-positive disease has failed in every randomised trial; the field still lacks a validated way to identify who can receive less.","Only two drug targets (EGFR and PD-1) have approved agents; PIK3CA, NOTCH, and CDKN2A alterations remain undrugged.","Immunotherapy concurrent with chemoradiation has failed three times; the mechanism is not fully understood.","Curative treatment causes permanent swallowing, speech, dental, and thyroid damage; survivorship care is under-resourced.","Nasopharyngeal carcinoma outside East Asia is rare and under-studied; EBV-directed cell therapies remain experimental.","Second primary cancers and field cancerisation in smokers are not addressed by any approved chemoprevention.","Global burden falls on South Asia (oral cavity cancer from smokeless tobacco and areca nut), where access to IMRT and immunotherapy is limited."]},{"id":"hepatoblastoma","kind":"cancer","name":"Hepatoblastoma","aka":[],"tldr":"Hepatoblastoma is a childhood liver cancer, mostly of toddlers, cured in most standard-risk cases with cisplatin chemotherapy and surgery, including liver transplant when the tumour cannot be cut out. Sodium thiosulfate given after cisplatin halves the permanent hearing loss cisplatin causes, and became the first approved otoprotectant in 2022.","summary":"Hepatoblastoma is an embryonal liver tumour with CTNNB1 (β-catenin) mutations in most cases, associated with prematurity, Beckwith-Wiedemann syndrome and familial adenomatous polyposis. Alpha-fetoprotein (AFP) is elevated in >90% and tracks response; very low AFP (<100 ng/mL) marks an aggressive small-cell-undifferentiated variant. Staging uses PRETEXT (extent within the liver) plus annotation factors (vascular involvement, extrahepatic extension, metastases, rupture) under the international CHIC risk stratification.\n\nTreatment combines cisplatin-based chemotherapy with complete surgical resection; standard-risk disease is cured in ~90% with cisplatin monotherapy (SIOPEL-3), high-risk disease uses cisplatin-doxorubicin (PLADO) or dose-dense cisplatin (SIOPEL-4), and unresectable tumours confined to the liver are transplanted with excellent outcomes. The Paediatric Hepatic International Tumour Trial (PHITT) harmonises COG, SIOPEL and JPLT approaches. Sodium thiosulfate given 6 hours after cisplatin halves permanent hearing loss without compromising survival (SIOPEL-6, NEJM 2018), leading to FDA approval of the first otoprotectant (2022).","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Hepatoblastoma","links":[{"label":"NCI PDQ: childhood liver cancer","url":"https://www.cancer.gov/types/liver/patient/child-liver-treatment-pdq"},{"label":"SIOPEL-6 (NEJM 2018)","url":"https://doi.org/10.1056/NEJMoa1801109"},{"label":"PHITT trial","url":"https://clinicaltrials.gov/study/NCT03017326"}],"tags":["gap-fill","paediatric"],"related":["wilms-tumor","neuroblastoma","retinoblastoma","paediatric-germ-cell-tumours"],"cancers":[],"sections":[],"technologies":["platinum","cytotoxic-chemotherapy","liver-transplant-oncology","hcc-surveillance","ultrasound","survivorship-care-plan"],"targets":[],"drugs":["cisplatin","doxorubicin","vincristine","fluorouracil","irinotecan","sodium-thiosulfate"],"companies":["childrens-oncology-group"],"institutions":[],"pathways":["wnt"],"terms":["afp","pretext-chic"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-brock-n-engl-j-med"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Hepatoblastoma is the most common childhood liver cancer (~1-2 per million children per year, ~100-150 cases per year in the US), mostly under age 3; incidence rising with survival of very-low-birth-weight infants.","subtypes":["Epithelial: fetal (well-differentiated, favourable), embryonal, macrotrabecular","Small-cell undifferentiated (low AFP, aggressive; exclude rhabdoid/INI1 loss)","Mixed epithelial-mesenchymal (with or without teratoid features)","Hepatocellular neoplasm NOS / transitional liver cell tumour (older children)"],"biomarkers":["Serum AFP (diagnosis, response, relapse; <100 ng/mL poor)","PRETEXT / POST-TEXT group and annotation factors (V, P, E, M, R)","CHIC risk group (age, AFP, PRETEXT, metastases)","CTNNB1 mutation, NFE2L2, TERT","Germline APC (FAP) and 11p15 (Beckwith-Wiedemann)"],"standardOfCare":[{"setting":"Very low / standard risk (PRETEXT I-III, resectable, AFP >100)","approach":"Upfront resection for PRETEXT I-II (COG) or cisplatin monotherapy ×4-6 with delayed resection (SIOPEL-3); sodium thiosulfate after each cisplatin dose for otoprotection.","refs":["cisplatin","sodium-thiosulfate","siopel-3"],"guideline":{"version":"PHITT / SIOPEL-3 (Lancet Oncol 2013); SIOPEL-6 (NEJM 2018)","url":"https://doi.org/10.1056/NEJMoa1801109"}},{"setting":"High risk (metastatic, AFP <100, PRETEXT IV, vascular involvement)","approach":"Cisplatin-doxorubicin (PLADO) or dose-dense cisplatin (SIOPEL-4), resection of primary and lung metastases; consider C5VD (COG).","refs":["cisplatin","doxorubicin","vincristine","fluorouracil","siopel-4"],"guideline":{"version":"SIOPEL-4; COG AHEP0731"}},{"setting":"Unresectable after chemotherapy (POST-TEXT IV, central vascular involvement)","approach":"Orthotopic liver transplantation (5-year survival ~80%); early referral to a transplant centre.","refs":["liver-transplant-oncology"],"guideline":{"version":"SIOPEL guidance"}},{"setting":"Relapsed/refractory","approach":"Irinotecan-based salvage, surgery for isolated recurrence, transplant if liver-confined; trials.","refs":["irinotecan","liver-transplant-oncology"]}],"stateOfArt":["Overall survival ~80-90%; cisplatin alone cures most standard-risk children, and transplant rescues unresectable disease.","Sodium thiosulfate is a model of supportive-care evidence: a randomised trial in children changed a global standard and produced a drug approval.","PHITT is the first global paediatric liver tumour trial with harmonised risk groups.","Low-AFP small-cell undifferentiated tumours and metastatic disease remain the challenging minority."],"history":[{"year":1967,"title":"Ishak and Glunz define hepatoblastoma histology","refs":[]},{"year":1980,"title":"Cisplatin and doxorubicin shown active; survival rises from ~30% to ~70%","refs":["cisplatin","doxorubicin"]},{"year":1990,"title":"SIOPEL-1 introduces PRETEXT staging and pre-operative chemotherapy","refs":[]},{"year":2009,"title":"SIOPEL-3: cisplatin alone suffices for standard risk (NEJM)","refs":["cisplatin"]},{"year":2013,"title":"SIOPEL-4: dose-dense cisplatin in high-risk disease (Lancet Oncol)","refs":["cisplatin"]},{"year":2017,"title":"CHIC international risk stratification (Lancet Oncol)","refs":[]},{"year":2018,"title":"SIOPEL-6: sodium thiosulfate halves cisplatin hearing loss (NEJM)","note":"FDA approval of sodium thiosulfate (Pedmark) 2022.","refs":["sodium-thiosulfate"]}],"pipeline":["sodium-thiosulfate","liver-transplant-oncology"],"openProblems":["Metastatic and low-AFP disease.","Long-term effects of cisplatin (hearing, kidney) and doxorubicin (heart).","Rising incidence with extreme prematurity.","Transplant organ availability and lifelong immunosuppression in children."],"parent":"childhood-cancers"},{"id":"hcc","kind":"cancer","name":"Hepatocellular carcinoma","aka":["LIHC","TCGA-LIHC","liver hepatocellular carcinoma (TCGA LIHC cohort)","Liver Cancer"],"tldr":"Liver cancer almost always grows in a liver already damaged by hepatitis, alcohol or fatty liver disease. It is one of the most preventable cancers, and since 2020 immunotherapy combinations have roughly doubled how long people with advanced disease live.","summary":"Hepatocellular carcinoma is the dominant primary liver cancer (~75-85%) and one of the most preventable: HBV vaccination and HCV cure have cut incidence wherever they were deployed. Its defining feature is that it arises in a diseased organ: chronic hepatitis B, hepatitis C, alcohol-related and metabolic (MASLD) cirrhosis account for most cases, so the liver's remaining function (Child-Pugh, ALBI) matters as much as tumour stage. The BCLC system integrates both and maps each stage to a treatment: ablation, resection or transplantation for early disease; TACE or radioembolisation for intermediate disease; systemic therapy for advanced disease. Surveillance of at-risk patients with six-monthly ultrasound is recommended but poorly adopted, and most patients still present beyond curative stages, which is why it remains the third leading cause of cancer death worldwide.\n\nSystemic therapy changed completely between 2018 and 2026. Sorafenib (SHARP, 2007) was the only option for a decade. Lenvatinib matched it (REFLECT), then IMbrave150 made atezolizumab plus bevacizumab the first regimen to beat sorafenib on survival (OS 19.2 vs 13.4 months). HIMALAYA's STRIDE regimen (single-dose tremelimumab plus durvalumab) followed with a doubling of five-year survival (19.6% vs 9.4%), and CheckMate 9DW's nivolumab plus ipilimumab reached a median OS of 23.7 months (approved 2025). Camrelizumab plus rivoceranib (CARES-310, OS 23.8 vs 15.2 months) is approved in China but has received three FDA complete response letters for manufacturing reasons, most recently in July 2026. Second-line options after sorafenib (regorafenib, cabozantinib, ramucirumab for AFP ≥400) lack data after immunotherapy, the setting most patients now reach.\n\nThe frontier is combining local and systemic therapy. Three phase 3 trials (EMERALD-1, LEAP-012, EMERALD-3) show that adding immunotherapy and anti-VEGF drugs to TACE prolongs progression-free survival by about 30%, but LEAP-012's final overall-survival hazard ratio of 0.98 shows PFS is a weak surrogate here, and adjuvant atezolizumab-bevacizumab (IMbrave050) lost its early benefit with follow-up. Open questions include the right therapy after first-line immunotherapy, the role of immunotherapy before transplantation, GPC3-directed cell therapy, and above all prevention: HBV vaccination and HCV cure could avert most cases, while MASLD-driven HCC in non-cirrhotic livers is rising and escapes surveillance.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Hepatocellular_carcinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Hepatocellular_carcinoma"}],"tags":["gi","spike"],"related":["io-plus-vegf","tace-plus-systemic","io-varices-caution"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","antiangiogenic","thermal-ablation","hifu-histotripsy","car-t","hpv-vaccine","tace","radioembolisation-tare","liver-transplant-oncology","hcc-surveillance","kinase-inhibitors","sbrt"],"targets":["gpc3","vegf","pd1","ctla4","fap","pdl1","met"],"drugs":[],"companies":["nanjing-leads-biolabs","catalym","bioinvent-international","ascentawits-pharmaceuticals","shanghai-abelzeta","roche-genentech","astrazeneca","bms","eisai","merck","bayer","exelixis","eli-lilly","hengrui","elevar-therapeutics","sirtex","boston-scientific"],"institutions":["asan-medical-center","mayo-clinic","mskcc","sysucc","snuh","gustave-roussy"],"pathways":["vegf-angiogenesis","wnt","hepatocellular-carcinoma-signalling"],"terms":["afp","child-pugh-albi","bclc-staging","hbv-hcv","dosimetry","tace-term"],"trials":["nct06109272","nct05317819","nct07490262","nct06844357","nct04639180","nct05320692","nct04194775","nct03755791","nct05489289","nct06921785","nct05862337","nct05883644","nct03847428","nct05904886","nct03383458","nct05557838","nct06371157","nct04712643","nct05201404"],"people":["audre-lorde"],"bottlenecks":[],"keyPapers":["paper-alcohol-cancer-burden-lancet-oncol-2021"],"journals":["journal-of-gastrointestinal-cancer"],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Roughly 900,000 liver cancer cases a year worldwide (GLOBOCAN), ~80% in Asia and Africa, and largely preventable: HBV vaccination and HCV cure have cut incidence in Taiwan, Japan and Egypt. Deaths are ~800,000 a year, and in the United States the death rate has risen faster than for any other cancer over the past two decades, driven by hepatitis C and fatty liver disease.","subtypes":["Viral (HBV, HCV) HCC","Alcohol-related HCC","MASLD/MASH-related HCC (often non-cirrhotic)","Fibrolamellar carcinoma (young adults, DNAJB1-PRKACA fusion)","Combined hepatocellular-cholangiocarcinoma","BCLC stages 0/A, B, C, D"],"biomarkers":["AFP","GPC3 (trials)","Child-Pugh / ALBI liver function","AFP (prognosis; ≥400 ng/mL for ramucirumab)","BCLC stage and performance status","Portal vein tumour thrombus","HBV/HCV status","AFP-L3 and DCP (GALAD score)"],"standardOfCare":[{"setting":"Early","approach":"Resection, ablation, transplant.","refs":["thermal-ablation","hifu-histotripsy"],"guideline":{"version":"NCCN Guidelines: Hepatocellular Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1514"}},{"setting":"Intermediate","approach":"TACE/TARE ± systemic therapy.","refs":["radioligand-therapy"],"guideline":{"version":"NCCN Guidelines: Hepatocellular Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1514"}},{"setting":"Advanced","approach":"Atezolizumab-bevacizumab, durvalumab-tremelimumab, or nivolumab-ipilimumab.","refs":["atezolizumab","durvalumab","nivolumab","ipilimumab"],"guideline":{"version":"NCCN Guidelines: Hepatocellular Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1514"}},{"setting":"Prevention","approach":"Universal HBV vaccination; antiviral suppression of HBV; direct-acting antiviral cure of HCV; alcohol and metabolic risk reduction.","refs":["hbv-hcv","hpv-vaccine"],"guideline":{"nccn":"Hepatobiliary Cancers","version":"AASLD 2023 / EASL 2025"}},{"setting":"Surveillance","approach":"Six-monthly ultrasound ± AFP in cirrhosis and high-risk HBV carriers; abbreviated MRI where ultrasound is inadequate.","refs":["hcc-surveillance","ultrasound","afp"],"guideline":{"version":"AASLD 2023 Practice Guidance"}},{"setting":"Very early / early (BCLC 0-A)","approach":"Ablation (RFA/microwave) for ≤3 cm; resection for preserved liver function; transplantation within Milan or downstaged criteria; radiation segmentectomy as an alternative.","refs":["thermal-ablation","liver-transplant-oncology","radioembolisation-tare","bclc-staging"],"guideline":{"nccn":"Category 1 for resection/ablation/transplant"}},{"setting":"Intermediate (BCLC B)","approach":"TACE (conventional or DEB-TACE) or TARE; systemic therapy for high tumour burden or TACE-refractory disease; TACE + durvalumab-bevacizumab or STRIDE + lenvatinib prolong PFS (OS unproven).","refs":["tace","radioembolisation-tare","emerald-1","leap-012","emerald-3"],"guideline":{"nccn":"TACE category 1; combinations not yet standard"}},{"setting":"Advanced (BCLC C), first line","approach":"Atezolizumab + bevacizumab (IMbrave150), STRIDE tremelimumab + durvalumab (HIMALAYA), or nivolumab + ipilimumab (CheckMate 9DW); lenvatinib or sorafenib if immunotherapy is contraindicated (transplant, active autoimmune disease).","refs":["imbrave150","himalaya","checkmate-9dw","atezolizumab","durvalumab","tremelimumab","nivolumab","ipilimumab","lenvatinib","sorafenib"],"guideline":{"nccn":"Category 1 (preferred) for all three IO regimens","esmoMcbs":"IMbrave150 grade 5"}},{"setting":"Advanced, second line and beyond","approach":"After immunotherapy: lenvatinib, sorafenib, cabozantinib or regorafenib by extrapolation (no dedicated phase 3); ramucirumab if AFP ≥400 ng/mL; clinical trials.","refs":["cabozantinib","regorafenib","ramucirumab","lenvatinib","resorce","celestial"],"guideline":{"nccn":"Category 2A after IO"}},{"setting":"Adjuvant after resection/ablation","approach":"No approved adjuvant therapy; IMbrave050 benefit not sustained. Surveillance imaging every 3-6 months.","refs":["imbrave050"]},{"setting":"Portal vein tumour thrombosis","approach":"Systemic immunotherapy; Y-90 radioembolisation where TACE is contraindicated; radiotherapy to the thrombus in selected patients.","refs":["radioembolisation-tare","sbrt"]}],"stateOfArt":["IO doublets first line.","GPC3 CAR-T and bispecifics emerging.","Three first-line immunotherapy regimens with overall-survival benefit over sorafenib; median OS approaching two years and five-year survival of one in five with STRIDE.","Choice of regimen is driven by bleeding risk (varices), autoimmune disease and transplant candidacy rather than a predictive biomarker.","Radioembolisation and radiation segmentectomy offer curative-intent options for small tumours and for portal vein thrombosis.","TACE plus systemic therapy prolongs PFS in intermediate-stage disease in three phase 3 trials, but overall survival is unproven (LEAP-012 OS HR 0.98).","Prevention works: HBV vaccination and HCV antivirals have cut incidence in Taiwan, Japan and Egypt; MASLD is the rising cause.","Living-donor transplantation and downstaging widen the pool of curable patients, led by Asian high-volume centres."],"history":[{"year":1941,"title":"Hepatocellular carcinoma linked to cirrhosis in large autopsy series","note":"Establishes the disease-in-a-diseased-organ paradigm.","refs":[]},{"year":1964,"title":"Hepatitis B surface antigen discovered (Blumberg)","note":"Nobel Prize 1976; leads to the vaccine.","refs":["hbv-hcv"]},{"year":1984,"title":"Taiwan begins universal HBV vaccination","note":"Childhood HCC incidence later falls ~70%.","refs":["hpv-vaccine"]},{"year":1996,"title":"Milan criteria for liver transplantation","note":"Mazzaferro: ~70% five-year survival for small tumours.","refs":["liver-transplant-oncology"]},{"year":1999,"title":"BCLC staging system published","refs":["bclc-staging"]},{"year":2002,"title":"TACE proven to prolong survival (Llovet, Lo)","refs":["tace"]},{"year":2007,"title":"Sorafenib: first systemic therapy","refs":[]},{"year":2007,"title":"SHARP: sorafenib, the first systemic therapy","refs":["sharp","sorafenib"]},{"year":2014,"title":"Direct-acting antivirals cure hepatitis C","note":"HCC risk falls ~70% after cure.","refs":["hbv-hcv"]},{"year":2017,"title":"RESORCE: regorafenib, first second-line benefit; SARAH/SIRveNIB negative for Y-90 vs sorafenib","refs":["resorce","sarah-sirvenib"]},{"year":2018,"title":"REFLECT: lenvatinib non-inferior first line; CELESTIAL: cabozantinib second line","refs":["reflect","celestial"]},{"year":2020,"title":"IMbrave150: atezolizumab-bevacizumab","refs":["atezolizumab"]},{"year":2020,"title":"IMbrave150: atezolizumab + bevacizumab beats sorafenib","note":"First regimen to improve OS over sorafenib; new standard.","refs":["imbrave150","atezolizumab"]},{"year":2022,"title":"HIMALAYA: STRIDE approved; BCLC update adds systemic therapy for some BCLC-B","refs":["himalaya","tremelimumab"]},{"year":2024,"title":"EMERALD-1 and LEAP-012: TACE + systemic therapy improves PFS; HIMALAYA 5-year OS 19.6%","refs":["emerald-1","leap-012"]},{"year":2025,"title":"CheckMate 9DW approval (nivolumab + ipilimumab); second FDA CRL for camrelizumab-rivoceranib","refs":["checkmate-9dw","camrelizumab-rivoceranib"]},{"year":2026,"title":"EMERALD-3 positive for PFS; LEAP-012 final OS HR 0.98; IMbrave050 update negative; third camrelizumab-rivoceranib CRL (23 July)","refs":["emerald-3","leap-012","imbrave050","cares-310"]}],"pipeline":["fapi-pet","pf-08634404","budigalimab","livmoniplimab","cobolimab","adi-peg20","ibi310","adg126","azd9793","jk08","camrelizumab-rivoceranib","emerald-3","tace-plus-systemic","radioembolisation-tare","gpc3","car-t","idea-hcc-io-before-transplant","idea-hcc-blood-surveillance","hcc-surveillance","mced","cabozantinib","hifu-histotripsy","ivonescimab"],"openProblems":["Liver function limits therapy.","Surveillance uptake in cirrhosis is poor.","No predictive biomarker chooses among the three first-line immunotherapy regimens; PD-L1, TMB and viral aetiology are weak.","Second-line therapy after immunotherapy failure is extrapolated from the sorafenib era; no dedicated phase 3 has read out.","TACE combinations prolong PFS but not (yet) OS; sequencing local and systemic therapy is unresolved.","Adjuvant therapy after curative resection remains unproven; recurrence is ~70% at five years.","Surveillance uptake is below 25% and ultrasound misses early tumours in obese, steatotic livers; MASLD-HCC often arises without cirrhosis.","Immunotherapy in transplant candidates risks rejection; safe washout intervals are undefined.","Child-Pugh B patients are excluded from almost every trial yet make up a large share of real-world patients.","Global inequity: most cases occur in Asia and Africa, where HBV vaccination, HCV treatment and systemic therapy access are uneven."]},{"id":"hepatosplenic-t-cell-lymphoma","kind":"cancer","name":"Hepatosplenic T-cell lymphoma","aka":["HSTCL","HSTL","Hepatosplenic gamma-delta T-cell lymphoma","Enteropathy-associated and hepatosplenic T-cell lymphoma"],"tldr":"Hepatosplenic T-cell lymphoma is a rare, very aggressive lymphoma of young men in which gamma-delta T cells fill the liver, spleen and bone marrow without forming lumps in the nodes. It is linked to long-term immune suppression, above all thiopurines with or without anti-TNF drugs for inflammatory bowel disease, and is treated with intensive chemotherapy then a stem cell transplant where possible.","summary":"WHO-HAEM5 keeps hepatosplenic T-cell lymphoma as an entity of cytotoxic, usually gamma-delta T cells with sinusoidal infiltration of spleen, liver and marrow, isochromosome 7q and an aggressive course (Alaggio 2022). Whole-exome sequencing of 68 cases defined its drivers: chromatin-modifying genes (SETD2, INO80, ARID1B) mutated in 62 percent, SETD2 the most frequently silenced and shown to act as a tumour suppressor, and STAT5B (31 percent), STAT3 (9 percent) and PIK3CD (9 percent) mutations that activate targetable signalling (McKinney 2017). Of 36 patients with the lymphoma arising during treatment of inflammatory bowel disease, 20 had received infliximab with a thiopurine and 16 a thiopurine alone; 27 of 30 with known age were under 35 and only 2 of 31 were women (Clin Gastroenterol Hepatol 2011).\n\nHow it differs from its parent: no lymphadenopathy, a leukaemic and hepatosplenic pattern, a young male population, an iatrogenic immunosuppression association, and an outcome worse than most peripheral T-cell lymphomas, with median survival under two years in the older literature and CHOP alone rarely producing durable remission.\n\nHow common: no registry share in the sources read; rare.\n\nTreatment: intensive induction (ICE, IVAC or similar platinum- and cytarabine-containing regimens rather than CHOP) followed by allogeneic or autologous stem cell transplant in first remission for fit patients, as on the parent page; JAK-STAT and PI3K-delta inhibitors are the rational targets from the genetics but have no trial (McKinney 2017).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Hepatosplenic_T-cell_lymphoma","links":[{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq"},{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"McKinney 2017, Cancer Discovery: the genetic basis of hepatosplenic T-cell lymphoma, 68 cases","url":"https://doi.org/10.1158/2159-8290.cd-16-0330"},{"label":"Clin Gastroenterol Hepatol 2011: factors contributing to hepatosplenic T-cell lymphoma in inflammatory bowel disease","url":"https://doi.org/10.1016/j.cgh.2010.09.016"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["peripheral-t-cell-lymphoma","angioimmunoblastic-t-cell-lymphoma","t-large-granular-lymphocytic-leukaemia","post-transplant-lymphoproliferative-disorder"],"cancers":[],"sections":[],"technologies":[],"targets":["stat3"],"drugs":["cytarabine","cisplatin","etoposide"],"companies":[],"institutions":[],"pathways":["jak-stat"],"terms":["allogeneic-transplant"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare and usually fatal, affecting mainly men under 35 (Clin Gastroenterol Hepatol 2011); the largest genetic study holds 68 cases (McKinney 2017). No registry share is in the sources read.","subtypes":["Hepatosplenic T-cell lymphoma, gamma-delta type (the usual form)","Hepatosplenic T-cell lymphoma, alpha-beta type","Hepatosplenic T-cell lymphoma after thiopurine or anti-TNF therapy (inflammatory bowel disease, transplant)"],"biomarkers":["Sinusoidal infiltration of spleen, liver and marrow; gamma-delta T-cell receptor","Isochromosome 7q and trisomy 8","SETD2, STAT5B, STAT3 and PIK3CD mutations","History of thiopurine or anti-TNF exposure"],"standardOfCare":[{"setting":"All cases","approach":"Intensive platinum- and cytarabine-based induction rather than CHOP, then allogeneic or autologous transplant in first remission for fit patients.","refs":["peripheral-t-cell-lymphoma","cytarabine","cisplatin","allogeneic-transplant"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"peripheral-t-cell-lymphoma"},{"id":"her2-amplified-colorectal","kind":"cancer","name":"HER2-amplified colorectal cancer","aka":["HER2-positive colorectal cancer","ERBB2-amplified colorectal cancer","HER2-overexpressing bowel cancer"],"tldr":"A few bowel cancers make too much of the HER2 protein, the same target as in HER2-positive breast cancer. Two HER2 drugs together, tucatinib and trastuzumab, shrink about four in ten of these tumours after chemotherapy has failed, and the antibody-drug conjugate trastuzumab deruxtecan works even when other HER2 drugs have stopped.","summary":"HER2 (ERBB2) amplification was recognised as a cause of primary resistance to cetuximab and panitumumab in patient-derived xenografts in 2011, and the HERACLES trial (2016) showed that dual HER2 blockade with trastuzumab and lapatinib produced responses in 30 percent of heavily pre-treated, RAS wild-type patients; MyPathway (2019) did the same with trastuzumab and pertuzumab. Testing is by immunohistochemistry 3+ or 2+ with in situ hybridisation, or by ERBB2 copy number on tumour or plasma sequencing, and is now recommended for every metastatic colorectal cancer alongside RAS, BRAF and mismatch repair.\n\nMOUNTAINEER (2022) treated 84 patients with previously treated, RAS wild-type, HER2-positive metastatic colorectal cancer with tucatinib and trastuzumab: the response rate was 38 percent, median response duration 12.4 months, progression-free survival 8.2 months and overall survival 24.1 months, with little of the diarrhoea seen with other HER2 kinase inhibitors, and the FDA granted accelerated approval in January 2023, the first HER2 approval in this cancer. DESTINY-CRC02 (2023) gave trastuzumab deruxtecan at 5.4 mg/kg to 122 patients, including those with RAS mutations and prior HER2 therapy, with a response rate of 38 percent; the tumour-agnostic approval for HER2 immunohistochemistry 3+ solid tumours in April 2024 covers colorectal cancer.\n\nMOUNTAINEER-03 is testing tucatinib, trastuzumab and mFOLFOX6 against standard first-line chemotherapy; zanidatamab and other bispecific HER2 antibodies, next-generation HER2 antibody-drug conjugates and HER2 kinase inhibitors are in trials. The open questions are whether HER2 blockade should start first line, how RAS co-mutations blunt it, and how to sequence the kinase inhibitor combination and the antibody-drug conjugate.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/HER2/neu","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/HER2/neu"},{"label":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}],"tags":["subtype-page"],"related":["braf-v600e-colorectal","early-onset-colorectal","kras-g12c-colorectal","msi-high-colorectal","rectal-cancer"],"cancers":[],"sections":[],"technologies":["her2-tyrosine-kinase-inhibitors","monoclonal-antibody","adc","histopathology-ihc","bispecific-antibody"],"targets":["her2","egfr","vegf"],"drugs":["tucatinib","trastuzumab","trastuzumab-deruxtecan","pertuzumab","zanidatamab"],"companies":[],"institutions":[],"pathways":["ras-mapk","colorectal-cancer-signalling"],"terms":["sidedness","tumour-agnostic","ihc"],"trials":["mountaineer","destiny-crc02","mypathway","nct06695845","nct06589830","nct06434597","heracles"],"people":["tanios-bekaii-saab"],"bottlenecks":[],"keyPapers":["paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023","paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016","paper-siena-destiny-crc01-trastuzumab-deruxtecan-lancet-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 3 to 5 percent of colorectal cancers, and about 5 to 8 percent of RAS and BRAF wild-type tumours, have HER2 amplification; they are mostly left-sided and rectal, and respond poorly to anti-EGFR antibodies.","subtypes":["HER2-amplified, RAS and BRAF wild-type, left-sided (the classic group, responsive to dual HER2 blockade)","HER2-amplified with RAS mutation (rarer; antibody-drug conjugates rather than dual antibody or kinase blockade)","HER2 activating mutations without amplification (uncertain response)","HER2 immunohistochemistry 3+ tumours eligible for tumour-agnostic trastuzumab deruxtecan"],"biomarkers":["HER2 immunohistochemistry 3+, or 2+ with in situ hybridisation amplification","ERBB2 copy number on tumour or circulating tumour DNA sequencing","RAS and BRAF wild-type status (predicts response to dual HER2 blockade)","Left-sided or rectal primary"],"standardOfCare":[{"setting":"Metastatic, RAS wild-type, previously treated","approach":"Tucatinib plus trastuzumab (MOUNTAINEER); trastuzumab plus pertuzumab or lapatinib where tucatinib is unavailable.","refs":["mountaineer","tucatinib","trastuzumab","pertuzumab","her2-tyrosine-kinase-inhibitors"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"After HER2 antibodies, or with RAS mutation","approach":"Trastuzumab deruxtecan (DESTINY-CRC02; tumour-agnostic approval for immunohistochemistry 3+), watching for pneumonitis.","refs":["destiny-crc02","trastuzumab-deruxtecan","adc"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Metastatic, first line","approach":"Standard doublet chemotherapy with bevacizumab; anti-EGFR antibodies are less effective in HER2-amplified tumours; tucatinib-trastuzumab-FOLFOX is under test in MOUNTAINEER-03.","refs":["folfox","folfiri","bevacizumab","mountaineer"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}}],"stateOfArt":["Tucatinib plus trastuzumab is the first HER2-directed approval in colorectal cancer (2023).","Trastuzumab deruxtecan works after other HER2 drugs and in RAS-mutant tumours.","HER2 testing is now routine in metastatic disease, alongside RAS, BRAF and mismatch repair."],"history":[{"year":2011,"title":"HER2 amplification identified as a cause of anti-EGFR resistance in patient-derived xenografts","refs":["her2","egfr"]},{"year":2016,"title":"HERACLES: trastuzumab plus lapatinib produces responses in 30 percent","refs":["trastuzumab"]},{"year":2019,"title":"MyPathway: trastuzumab plus pertuzumab active in HER2-amplified colorectal cancer","refs":["mypathway","pertuzumab","trastuzumab"]},{"year":2022,"title":"MOUNTAINEER: tucatinib plus trastuzumab, response rate 38 percent, median survival 24 months","refs":["mountaineer","tucatinib","tanios-bekaii-saab"]},{"year":2023,"title":"FDA accelerated approval of tucatinib with trastuzumab, the first HER2 approval in colorectal cancer","refs":["tucatinib"]},{"year":2024,"title":"Tumour-agnostic approval of trastuzumab deruxtecan for HER2 3+ solid tumours after DESTINY-CRC02","refs":["trastuzumab-deruxtecan","destiny-crc02"]}],"pipeline":["mountaineer","zanidatamab","nct06695845","nct06589830","nct06434597","trastuzumab-deruxtecan"],"openProblems":["No randomised evidence yet for HER2 blockade in first line.","RAS co-mutation blunts dual HER2 blockade and the best option for those patients is unclear.","Optimal sequence of tucatinib-trastuzumab and trastuzumab deruxtecan is untested.","HER2 mutations without amplification have no proven therapy."],"parent":"colorectal"},{"id":"her2-low-metastatic-breast-cancer","kind":"cancer","name":"HER2-low and HER2-ultralow metastatic breast cancer","aka":["HER2 IHC 1+ or 2+ ISH-negative breast cancer","Metastatic breast cancer with low HER2 expression"],"tldr":"HER2-low is not a new kind of breast cancer but a new way of reading an old test: tumours once called HER2-negative that carry a little HER2 protein. That trace is enough for the antibody-drug conjugate trastuzumab deruxtecan to deliver its chemotherapy payload, and since 2022 it has been the standard for these patients after endocrine therapy or a first chemotherapy.","summary":"HER2 status was binary for two decades: 3+ by immunohistochemistry or amplified by in situ hybridisation meant trastuzumab, anything less meant nothing. Trastuzumab deruxtecan changed that because its payload, a topoisomerase I inhibitor carried eight to an antibody with a cleavable linker, is released inside the cell and diffuses into neighbours, so tumours with only a few receptors per cell still respond. HER2-low is defined as 1+ or 2+ without amplification, and HER2-ultralow as a score of 0 with membrane staining in 10 percent of cells or fewer; the 2023 ASCO and CAP testing update recognised the categories, and because expression varies between the primary and metastases and between blocks, retesting a metastatic biopsy is recommended before ruling a patient out.\n\nDESTINY-Breast04 randomised 557 patients with HER2-low metastatic breast cancer after one or two chemotherapy lines to trastuzumab deruxtecan or the physician's choice of chemotherapy. In the hormone receptor-positive cohort progression-free survival rose from 5.4 to 10.1 months (hazard ratio 0.51) and overall survival from 17.5 to 23.9 months (hazard ratio 0.64), with the small hormone receptor-negative cohort pointing the same way. Adjudicated interstitial lung disease occurred in about 12 percent and was fatal in under one percent, and the FDA approved the indication in August 2022, the first time a HER2-directed drug had been licensed for HER2-negative disease.\n\nDESTINY-Breast06 moved the drug earlier and wider: 866 patients with hormone receptor-positive HER2-low or ultralow disease who had progressed on endocrine therapy but never had chemotherapy for metastases were randomised to trastuzumab deruxtecan or chemotherapy, and progression-free survival rose from 8.1 to 13.2 months in HER2-low disease (hazard ratio 0.62) with a similar effect in the ultralow group; approval followed in 2025. The triple-negative share of HER2-low disease sits behind the TROP2 antibody-drug conjugates in sequence, and whether any threshold of HER2 expression matters at all, how to sequence one topoisomerase payload after another and how to prevent lung toxicity are the open questions.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Trastuzumab_deruxtecan","links":[{"label":"DESTINY-Breast04 (NEJM 2022)","url":"https://doi.org/10.1056/NEJMoa2203690"},{"label":"DESTINY-Breast06 on ClinicalTrials.gov","url":"https://clinicaltrials.gov/study/NCT04494425"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Trastuzumab_deruxtecan"}],"tags":["subtype-page"],"related":["breast-her2-positive","tnbc","breast-hr-positive"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-destiny-breast06-nejm-2024"],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"About half of all breast cancers, and around six in ten hormone receptor-positive tumours, show low HER2 expression (immunohistochemistry 1+, or 2+ without gene amplification) that was long classed as HER2-negative; ultralow adds tumours scored 0 with faint staining in a tenth of cells or fewer.","subtypes":["Hormone receptor-positive HER2-low disease (about six in ten luminal tumours)","Hormone receptor-positive HER2-ultralow disease (IHC 0 with faint staining)","Triple-negative HER2-low disease (about a third of triple-negative tumours)","HER2-low disease after chemotherapy (DESTINY-Breast04 population)","HER2-low disease after endocrine therapy, chemotherapy-naive (DESTINY-Breast06 population)"],"biomarkers":["HER2 immunohistochemistry score 0, ultralow, 1+ or 2+ with in situ hybridisation for 2+","Retesting on a metastatic biopsy because HER2-low status changes over time","Hormone receptor status","Baseline chest imaging and lung function for interstitial lung disease surveillance","PIK3CA, ESR1 and germline BRCA status to sequence against targeted options"],"standardOfCare":[{"setting":"Hormone receptor-positive, after endocrine therapy, chemotherapy-naive","approach":"Trastuzumab deruxtecan ahead of chemotherapy for HER2-low or ultralow disease (DESTINY-Breast06).","refs":["trastuzumab-deruxtecan","destiny-breast06","her2-low"]},{"setting":"After one or two lines of chemotherapy","approach":"Trastuzumab deruxtecan for HER2-low disease of either hormone receptor status (DESTINY-Breast04).","refs":["trastuzumab-deruxtecan","destiny-breast04","her2-low"]},{"setting":"Triple-negative HER2-low disease","approach":"TROP2 antibody-drug conjugates first (ASCENT, TROPION-Breast02), trastuzumab deruxtecan as a later option.","refs":["sacituzumab-govitecan","datopotamab-deruxtecan","ascent","tropion-breast02","trastuzumab-deruxtecan"]},{"setting":"Lung toxicity","approach":"Baseline and interval CT, prompt corticosteroids and permanent discontinuation for grade 2 or higher interstitial lung disease.","refs":["ct","ild"]}],"stateOfArt":["Roughly half of all metastatic breast cancers became eligible for a HER2-directed drug in 2022.","The ultralow category, defined by DESTINY-Breast06, pushes the boundary to tumours pathologists once called negative.","Interstitial lung disease monitoring protocols have cut fatal cases as experience has grown."],"history":[{"year":1998,"title":"Trastuzumab approved for HER2-overexpressing disease","refs":["trastuzumab"]},{"year":2019,"title":"Phase 1b: trastuzumab deruxtecan responses in HER2-low tumours","refs":["trastuzumab-deruxtecan"]},{"year":2020,"title":"HER2-low proposed as a clinical category","refs":[]},{"year":2022,"title":"DESTINY-Breast04 and FDA approval","refs":["destiny-breast04","trastuzumab-deruxtecan"]},{"year":2023,"title":"ASCO and CAP HER2 testing update recognises HER2-low","refs":[]},{"year":2024,"title":"DESTINY-Breast06: earlier line and HER2-ultralow","refs":["destiny-breast06"]}],"pipeline":["trastuzumab-deruxtecan","sacituzumab-tirumotecan","trastuzumab-rezetecan","disitamab-vedotin","her2-pet","datopotamab-deruxtecan"],"openProblems":["Immunohistochemistry was never designed to score low expression and pathologists disagree at the 0 to 1+ boundary.","Whether a second topoisomerase I payload works after the first.","Interstitial lung disease remains unpredictable.","The triple-negative HER2-low group has only exploratory randomised data."],"parent":"breast-cancer"},{"id":"her2-mutant-nsclc","kind":"cancer","name":"HER2-mutant non-small-cell lung cancer","aka":["ERBB2-mutant lung cancer","HER2 exon 20 insertion NSCLC","HER2-positive lung adenocarcinoma"],"tldr":"HER2-mutant lung cancer carries a mutation in the same receptor that drives HER2-positive breast cancer, but the breast cancer antibodies alone did little here. The antibody-drug conjugate trastuzumab deruxtecan shrinks about half of tumours after chemotherapy, and the pill zongertinib about seven in ten, and both are approved.","summary":"HER2 mutations in lung cancer were recognised in 2004, but for fifteen years the drugs borrowed from breast cancer disappointed: trastuzumab and the pan-HER inhibitors afatinib, neratinib and dacomitinib gave response rates below 20 percent, and poziotinib and pyrotinib were limited by EGFR-driven diarrhoea and rash. First-line treatment is still pembrolizumab plus platinum-pemetrexed as for driver-negative disease, although checkpoint inhibitors alone work poorly and the mutation is one of the few that is usually found by DNA panel rather than RNA testing.\n\nTrastuzumab deruxtecan, a HER2 antibody carrying a topoisomerase I payload, changed the picture: DESTINY-Lung01 (2022) reported a 55 percent response rate in previously treated patients, the FDA granted accelerated approval in August 2022, the first HER2-directed therapy in lung cancer, and DESTINY-Lung02 (2023) confirmed a 49 percent response rate at the 5.4 mg/kg dose with interstitial lung disease in 13 percent, half the rate of the higher dose. Zongertinib, an oral inhibitor selective for mutant HER2 over EGFR, produced a 71 percent confirmed response rate in 75 previously treated patients in Beamion LUNG-1 and 48 percent in patients who had already received a HER2 antibody-drug conjugate, with mostly low-grade diarrhoea and rash, and was approved in August 2025, the first oral HER2 drug for lung cancer. Sevabertinib, a second HER2-selective inhibitor tested in SOHO-01, followed.\n\nBeamion LUNG-2 is comparing zongertinib with chemoimmunotherapy first line, and DESTINY-Lung04 is doing the same for trastuzumab deruxtecan. Open questions are whether an oral inhibitor or an antibody-drug conjugate should come first, how to manage interstitial lung disease, and whether HER2-amplified and HER2-overexpressing tumours without a mutation benefit from the same drugs.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/HER2","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/HER2"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":["egfr-mutant-nsclc","kras-g12c-nsclc","braf-v600e-nsclc","met-altered-nsclc","alk-positive-nsclc","ntrk-fusion-nsclc"],"cancers":[],"sections":[],"technologies":["adc","her2-tyrosine-kinase-inhibitors","kinase-inhibitors","topoisomerase-inhibitors","cgp"],"targets":["her2","pd1"],"drugs":["trastuzumab-deruxtecan","zongertinib","sevabertinib","pembrolizumab","afatinib","neratinib","poziotinib"],"companies":["daiichi-sankyo","astrazeneca","boehringer-ingelheim","bayer"],"institutions":[],"pathways":["nsclc-signalling","rtk-activation","pi3k-akt-mtor"],"terms":["driver-mutation","ild","hepatotoxicity","brain-metastases","her2-positive"],"trials":["destiny-lung02","beamion-lung-1","soho-01","nct06151574","destiny-lung01","nct05048797"],"people":["john-heymach","pasi-janne"],"bottlenecks":[],"keyPapers":["paper-destiny-lung01-nejm-2022","paper-destiny-lung02-goto-jco-2023","paper-beamion-lung-1-zongertinib-nejm-2025"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"HER2 (ERBB2) activating mutations, mostly exon 20 insertions such as A775_G776insYVMA, occur in 2 to 3 percent of lung adenocarcinomas, more often in women and never-smokers; brain metastases develop in about half. HER2 amplification and protein overexpression without mutation are separate and less well defined groups.","subtypes":["HER2 exon 20 insertion adenocarcinoma (A775_G776insYVMA and others; zongertinib, trastuzumab deruxtecan)","HER2 point mutations outside exon 20 (tyrosine kinase domain and extracellular)","HER2-amplified or HER2-overexpressing adenocarcinoma without a mutation (trastuzumab deruxtecan under study)","HER2-mutant disease with brain metastases"],"biomarkers":["HER2 (ERBB2) mutation by DNA sequencing (tyrosine kinase domain, exon 20)","HER2 amplification by sequencing or fluorescence in situ hybridisation","HER2 immunohistochemistry (expression, not mutation; separate indication)","Brain MRI at diagnosis","Lung imaging and symptoms for interstitial lung disease on trastuzumab deruxtecan; liver enzymes on zongertinib"],"standardOfCare":[{"setting":"Advanced, first line","approach":"Pembrolizumab plus platinum-pemetrexed as for driver-negative disease; zongertinib or trastuzumab deruxtecan first line only in trials (Beamion LUNG-2, DESTINY-Lung04).","refs":["pembrolizumab","carboplatin","pemetrexed","keynote-024-189","nct06151574"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, after platinum chemotherapy","approach":"Zongertinib (Beamion LUNG-1) or trastuzumab deruxtecan 5.4 mg/kg (DESTINY-Lung02); the other agent at further progression.","refs":["zongertinib","beamion-lung-1","trastuzumab-deruxtecan","destiny-lung02","sevabertinib","soho-01","ild"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Brain metastases","approach":"Zongertinib and trastuzumab deruxtecan both have intracranial activity; stereotactic radiosurgery for large or symptomatic lesions.","refs":["zongertinib","trastuzumab-deruxtecan","radiosurgery-srs","brain-metastases"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Trastuzumab deruxtecan (2022) and zongertinib (2025) approved after platinum chemotherapy, the first HER2-directed therapies in lung cancer.","HER2-selective inhibitors that spare EGFR remove the diarrhoea and rash that sank earlier pan-HER drugs.","First-line phase 3 trials of both drugs against chemoimmunotherapy under way."],"history":[{"year":2004,"title":"HER2 kinase domain mutations found in lung adenocarcinoma","refs":["her2"]},{"year":2022,"title":"DESTINY-Lung01: trastuzumab deruxtecan approved, the first HER2-directed lung cancer therapy","refs":["trastuzumab-deruxtecan","daiichi-sankyo"]},{"year":2023,"title":"DESTINY-Lung02 confirms the 5.4 mg/kg dose with less lung inflammation","refs":["destiny-lung02","trastuzumab-deruxtecan"]},{"year":2025,"title":"Beamion LUNG-1: zongertinib approved, the first oral HER2 inhibitor for lung cancer","refs":["beamion-lung-1","zongertinib","john-heymach","boehringer-ingelheim"]}],"pipeline":["nct06151574","sevabertinib","soho-01","zongertinib","trastuzumab-deruxtecan"],"openProblems":["No trial yet compares an oral HER2 inhibitor with an antibody-drug conjugate or settles the sequence.","Interstitial lung disease from trastuzumab deruxtecan is unpredictable and occasionally fatal.","HER2-amplified and HER2-overexpressing lung cancers without a mutation lack a defined standard."],"parent":"nsclc"},{"id":"breast-her2-positive","kind":"cancer","name":"HER2-positive breast cancer","aka":["HER2 positive ER positive breast cancer","triple positive breast cancer","ER positive HER2 positive","HER2+ HR+","HER2-positive hormone receptor-positive","HER2 3+ breast cancer","HER2 amplified breast cancer"],"tldr":"HER2-positive breast cancer was once the most aggressive subtype and is now one of the most treatable, thanks to trastuzumab and, more recently, Enhertu.","summary":"HER2-positive breast cancer (15-20% of cases; HER2 IHC 3+ or ISH-amplified) was the most aggressive subtype until trastuzumab (1998) made it one of the most treatable. The modern curative pathway is response-adapted: neoadjuvant chemotherapy with dual HER2 blockade (or, since 2026, T-DXd followed by THP), surgery, then either antibody completion for patients with a pathologic complete response or an ADC for residual disease (T-DM1 from KATHERINE, now T-DXd from DESTINY-Breast05). Small node-negative tumours are cured with paclitaxel-trastuzumab alone; PHERGain showed that an early PET response can spare a third of patients chemotherapy altogether. Extended adjuvant neratinib and adjuvant pertuzumab add small gains in higher-risk, node-positive disease.\n\nMetastatic disease has been transformed twice: by CLEOPATRA's pertuzumab (OS 57 months) and then by trastuzumab deruxtecan, which beat T-DM1 by a wide margin in second line (DESTINY-Breast03) and beat THP in first line (DESTINY-Breast09, PFS 40.7 months; approved 2025). Brain metastases, which develop in up to half of patients, are now treatable systemically with tucatinib (HER2CLIMB) and T-DXd (DESTINY-Breast12). HER2CLIMB-05 (tucatinib maintenance) and PATINA (palbociclib maintenance in HR+/HER2+, approved 2026) intensify chemotherapy-free maintenance, and a wave of Chinese HER2 ADCs (trastuzumab rezetecan, BL-M07D1, ARX788, disitamab vedotin) is producing Enhertu-scale results.\n\nOpen problems are the sequencing of HER2 ADCs after T-DXd (payload cross-resistance), interstitial lung disease, cardiotoxicity across years of therapy, the cost and duration of antibody therapy, brain metastases prevention, and de-escalation: identifying the substantial fraction of patients who are over-treated. The pipeline is defined by T-DXd's move into every curative setting, tucatinib-based maintenance, next-generation and biparatopic HER2 ADCs (zanidatamab zovodotin), HER2 CAR-T and vaccines, and imaging- and ctDNA-adapted de-escalation trials.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/HER2-positive_breast_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/HER2-positive_breast_cancer"},{"label":"NCCN Guidelines for Patients and the NCCN breast cancer guideline summary (PMC)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13114725/"},{"label":"SEER Cancer Stat Facts: female breast cancer subtypes (share of cases and five-year relative survival by receptor subtype and stage, SEER 21)","url":"https://seer.cancer.gov/statfacts/html/breast-subtypes.html"},{"label":"Royal College of Pathologists G148: dataset for histopathological reporting of breast disease in surgical excision specimens of breast cancer, version 3, November 2024 (full review due November 2026)","url":"https://www.rcpath.org/resourceLibrary/g148-dataset-for-histopathological-reporting-of-breast-disease-in-surgical-excision-specimens-of-breast-cancer.html"},{"label":"Rakha et al., Journal of Clinical Pathology 2023;76:217 to 227: UK recommendations for HER2 assessment in breast cancer, an update","url":"https://doi.org/10.1136/jcp-2022-208632"}],"tags":["breast","spike"],"related":["adc-generations","tucatinib-triplet-brain-mets","pet-adapted-her2-deescalation","breast-hr-positive","tnbc","her2-low-metastatic-breast-cancer","inflammatory-breast-cancer"],"cancers":[],"sections":[],"technologies":["adc","monoclonal-antibody","kinase-inhibitors","her2-pet","bispecific-antibody","cdk46-inhibitor","fdg-pet","sbrt","cardio-oncology","site-specific-conjugation","mrd-testing"],"targets":["her2","cdk4-6","her3","pik3ca","egfr"],"drugs":["her2-testing-assays","epirubicin","zanidatamab-zovodotin"],"companies":["roche-genentech","daiichi-sankyo","astrazeneca","pfizer","hengrui","systimmune","johnson-johnson","jazz","zymeworks","puma-biotechnology","macrogenics","remegen"],"institutions":[],"pathways":["pi3k-akt-mtor","ras-mapk","breast-cancer-signalling","p53-cell-cycle"],"terms":["dual-her2-blockade","her2-brain-metastases","trastuzumab-cardiotoxicity","biosimilar","pcr","ild","adc-sequencing","her2-testing-uk-breast","grade-stage-receptor-breast","receptor-conversion-breast","nottingham-grade","tnm-breast-cancer-editions","who-breast-classification"],"trials":["hera-b31-n9831","cleopatra","aphinity","katherine","destiny-breast05","her2climb","her2climb-02","her2climb-05","destiny-breast12","phergain","persephone","apt-trial","horizon-breast01","ace-breast-02","destiny-breast03","destiny-breast09","destiny-breast11","tmist","nct07003074","nct07008976","nct07043725","nct05838066","nct07441460","nct06747338","nct06846437","nct07377643","nct06968585","nct05346224","nct07386938","nct07413939","nct07673029","start-b","import-low","nsabp-b39","eortc-22922","ma-20","dbcg-82bc","nct06313086","nct07518173","nct06435429","nct06830889","nct06316531","nct07196774","nct06891833","nct05802225","nct07294508","nct06057610","nct04208178","nct04873362","nct07047365","nct06126640","nct06957886","nct05950945","nct05894239","atempt","nala","patina","tuxedo-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["breast-cancer-jbcs","breast-cancer-research","breast-cancer-research-and-treatment","clinical-breast-cancer","journal-of-mammary-gland-biology-and-neoplasia","the-breast","the-breast-journal"],"dependsOn":[],"notes":["What this page is called on a report, and why it is your page even if you are also hormone receptor positive. HER2 positive means immunohistochemistry 3+, or 2+ with amplification on in situ hybridisation; the UK asks for the HER2 to chromosome 17 ratio, the HER2 copy number and the chromosome 17 copy number to be reported, and it counts one borderline group as positive that the American guideline counts as negative (ratio 2.0 or more with a copy number below 4). HER2 positivity runs at 13 to 20 percent of early breast cancer (RCPath G148), and most of it is hormone receptor positive too: of American cases with a known subtype, 9.3 percent are hormone receptor-positive and HER2-positive against 4.0 percent HER2-positive alone (SEER 21, 2019 to 2023). If that is you, this page carries the HER2 treatment that decides the backbone and the HR-positive page carries the endocrine treatment that is added to it; five-year relative survival in the two groups was 92.2 and 87.0 percent (SEER 21, 2016 to 2022)."],"group":"breast","burden":"15-20% of breast cancers (roughly 400,000 cases per year worldwide). Ten-year survival for early-stage disease treated with trastuzumab-based therapy exceeds 80%.","subtypes":["HER2-enriched (PAM50; highest pCR rates to HER2 blockade)","HR+/HER2+ ('triple-positive', ~50% of HER2+; lower pCR, endocrine therapy and CDK4/6 maintenance relevant)","HR-/HER2+ (higher pCR, more relapse in first 3 years)","HER2-mutant (activating mutations without amplification; T-DXd tumour-agnostic, HER2 TKIs; more common in lobular and HER2-low)","HER2 heterogeneous tumours (mixed amplified and non-amplified clones; lower pCR)","Small node-negative (stage I) disease cured by de-escalated therapy"],"biomarkers":["HER2 IHC 3+ or ISH-amplified","HR status","pCR after neoadjuvant therapy","HER2 IHC 3+ or IHC 2+ with ISH amplification (ASCO/CAP 2018 criteria); HER2 heterogeneity","HR status (drives triple-positive management, PATINA eligibility)","Pathologic complete response after neoadjuvant therapy (selects T-DM1/T-DXd post-neoadjuvant)","Early FDG-PET response (PHERGain de-escalation)","LVEF by echocardiography or MUGA every 3 months on anti-HER2 therapy","Brain MRI when symptomatic; surveillance MRI debated","HER2 status on re-biopsy at progression (conversion in 10-15%)","PIK3CA mutation (lower pCR; INAVO122 tests inavolisib in HER2+)","ctDNA MRD (investigational for post-neoadjuvant escalation)"],"standardOfCare":[{"setting":"Stage I (≤2-3 cm, node-negative)","approach":"Surgery then weekly paclitaxel × 12 + trastuzumab × 1 year (APT); T-DM1 × 17 cycles is an alternative (ATEMPT). Endocrine therapy if HR+.","refs":["apt-trial","paclitaxel","trastuzumab","trastuzumab-emtansine"],"guideline":{"nccn":"2A","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Stage II-III, neoadjuvant","approach":"TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab) or anthracycline-taxane + HP; from 2026, T-DXd × 4 → THP (DESTINY-Breast11, pCR 67%). PET-adapted chemotherapy omission (PHERGain) in trials.","refs":["destiny-breast11","trastuzumab-deruxtecan","pertuzumab","phergain"],"guideline":{"nccn":"1","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Post-neoadjuvant, pathologic complete response","approach":"Complete 1 year of trastuzumab (± pertuzumab if node-positive at diagnosis); endocrine therapy if HR+; radiation per stage.","refs":["trastuzumab","pertuzumab","aphinity","hera-b31-n9831"],"guideline":{"nccn":"1","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Post-neoadjuvant, residual invasive disease","approach":"T-DXd (DESTINY-Breast05, iDFS HR 0.47 vs T-DM1; approved 2026) replacing T-DM1 (KATHERINE); consider extended adjuvant neratinib for HR+ high-risk.","refs":["destiny-breast05","katherine","trastuzumab-deruxtecan","trastuzumab-emtansine","neratinib"],"guideline":{"nccn":"1 (T-DM1); T-DXd pending update","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Adjuvant (upfront surgery), node-positive","approach":"Chemotherapy + trastuzumab + pertuzumab for 1 year (APHINITY); trastuzumab alone for lower risk; 6 months acceptable where resources are limited (PERSEPHONE).","refs":["aphinity","persephone","pertuzumab","trastuzumab"],"guideline":{"nccn":"1","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Metastatic, first line","approach":"T-DXd + pertuzumab (DESTINY-Breast09, PFS 40.7 months; approved 2025) or taxane + trastuzumab + pertuzumab (CLEOPATRA) followed by maintenance: HP ± tucatinib (HER2CLIMB-05) and, if HR+, endocrine therapy + palbociclib (PATINA, approved 2026).","refs":["destiny-breast09","cleopatra","her2climb-05","trastuzumab-deruxtecan","pertuzumab","tucatinib","palbociclib"],"guideline":{"nccn":"1, preferred (T-DXd + pertuzumab)","esmoMcbs":"4 (CLEOPATRA)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Metastatic, second line","approach":"T-DXd if not used first line (DESTINY-Breast03, PFS HR 0.33 vs T-DM1); tucatinib + trastuzumab + capecitabine, especially with brain metastases (HER2CLIMB).","refs":["destiny-breast03","her2climb","trastuzumab-deruxtecan","tucatinib"],"guideline":{"nccn":"1","esmoMcbs":"4 (DESTINY-Breast03)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Metastatic, later lines","approach":"T-DM1; neratinib or lapatinib + capecitabine; margetuximab + chemotherapy; trastuzumab + chemotherapy (continued HER2 blockade); zanidatamab and Chinese ADCs (trastuzumab rezetecan, disitamab vedotin) where available; trials.","refs":["trastuzumab-emtansine","neratinib","lapatinib","margetuximab","zanidatamab","trastuzumab-rezetecan","disitamab-vedotin"],"guideline":{"nccn":"2A","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Brain metastases","approach":"Systemic: tucatinib triplet or T-DXd (DESTINY-Breast12, intracranial ORR 72%); local: stereotactic radiosurgery or surgery for symptomatic or large lesions; whole-brain RT reserved.","refs":["her2climb","destiny-breast12","tucatinib","trastuzumab-deruxtecan","sbrt"],"guideline":{"nccn":"1 (tucatinib triplet)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Cardiac monitoring and survivorship","approach":"LVEF every 3 months during anti-HER2 therapy; hold and cardioprotect for declines; anthracycline-free regimens preferred; long-term surveillance for late recurrence in HR+/HER2+.","refs":["cardio-oncology","persephone"]}],"stateOfArt":["Ten-year survival above 80% for early disease: the subtype with the poorest outlook in the 1990s is now one of the most treatable.","Response-adapted curative therapy: pCR patients de-escalate, residual disease escalates to an ADC (now T-DXd, iDFS HR 0.47 vs T-DM1).","T-DXd across the continuum: neoadjuvant (2026), post-neoadjuvant (2026), first-line metastatic with pertuzumab (2025, PFS 40.7 months), second line, and brain metastases.","Systemic control of brain metastases (tucatinib, T-DXd) allowing deferral of radiation.","Chemotherapy-free maintenance intensification: tucatinib (HER2CLIMB-05) and palbociclib for HR+/HER2+ (PATINA).","Chemotherapy omission for a third of patients using early PET response (PHERGain)."],"history":[{"year":1987,"title":"Slamon shows HER2 amplification marks aggressive disease, and a drug target","note":"Science paper identifying HER2/neu amplification in 25-30% of breast cancers.","refs":["her2"]},{"year":1998,"title":"Trastuzumab approved for metastatic disease","note":"First antibody for a solid tumour; OS benefit with chemotherapy.","refs":["trastuzumab"]},{"year":2005,"title":"Adjuvant trastuzumab halves recurrence (HERA, B-31/N9831)","refs":["hera-b31-n9831"]},{"year":2007,"title":"Lapatinib: first HER2 pill","refs":["lapatinib"]},{"year":2012,"title":"Pertuzumab and dual blockade (CLEOPATRA)","refs":["pertuzumab","cleopatra"]},{"year":2013,"title":"T-DM1: first solid-tumour ADC; pertuzumab first pCR-based approval","refs":["trastuzumab-emtansine","pertuzumab"]},{"year":2015,"title":"APT: de-escalation for small tumours","refs":["apt-trial"]},{"year":2017,"title":"First trastuzumab biosimilar; neratinib; APHINITY","refs":["trastuzumab-biosimilars","neratinib","aphinity"]},{"year":2018,"title":"KATHERINE: T-DM1 for residual disease","refs":["katherine"]},{"year":2019,"title":"T-DXd approved; HER2CLIMB proves CNS benefit","refs":["trastuzumab-deruxtecan","her2climb"]},{"year":2020,"title":"Tucatinib, margetuximab, Phesgo approved","refs":["tucatinib","margetuximab","pertuzumab"]},{"year":2021,"title":"DESTINY-Breast03: T-DXd beats T-DM1","refs":["destiny-breast03"]},{"year":2024,"title":"PHERGain chemotherapy omission; DESTINY-Breast12 brain metastases; zanidatamab approved (BTC)","refs":["phergain","destiny-breast12","zanidatamab"]},{"year":2025,"title":"DESTINY-Breast09 first-line approval; DESTINY-Breast05 and HER2CLIMB-05 positive; trastuzumab rezetecan approved (China, NSCLC)","refs":["destiny-breast09","destiny-breast05","her2climb-05","trastuzumab-rezetecan"]},{"year":2026,"title":"T-DXd approved neoadjuvant and post-neoadjuvant; palbociclib maintenance for HR+/HER2+ (PATINA)","refs":["destiny-breast11","destiny-breast05","palbociclib"]}],"pipeline":["her2-pet","zanidatamab","disitamab-vedotin","tqb2102","hb1801","jskn003","kn026","ibi354","a166","evorpacept","hlx11","rph-051","ro7771950","gq1005","trastuzumab-rezetecan","trastuzumab-brengitecan","arx788","her2climb-05","horizon-breast01","phergain","idea-tdxd-first-then-nothing","idea-cns-first-adc-strategy","idea-her2-adc-sequencing-payload","inavolisib","mrd-testing"],"openProblems":["Sequencing after T-DXd: no randomised data on which HER2 ADC or TKI works after TOP1-payload failure.","Interstitial lung disease with T-DXd in curative settings, where patients would otherwise be cured.","Over-treatment: which patients need pertuzumab, a full year of antibodies, or any chemotherapy at all (PHERGain-2, response-adapted trials).","Brain metastasis prevention and whether systemic-first strategies preserve cognition.","HR+/HER2+ ('triple-positive') disease: optimal integration of endocrine therapy, CDK4/6 inhibitors, and HER2 blockade.","Cardiotoxicity surveillance burden versus event rates in low-risk patients.","Global access: biosimilars have widened trastuzumab access but pertuzumab, T-DM1, and T-DXd remain unavailable in much of the world.","HER2 heterogeneity and HER2 conversion at relapse require re-biopsy strategies or HER2 PET."],"parent":"breast-cancer"},{"id":"her2-positive-breast-brain-metastases","kind":"cancer","name":"HER2-positive breast cancer with brain metastases","aka":["HER2-positive brain metastases","Central nervous system metastases from HER2-positive breast cancer","Intracranial HER2-positive disease"],"tldr":"The brain is the weak point of HER2-positive breast cancer: antibodies control the rest of the body but cross poorly into the brain, so up to half of patients with advanced disease develop brain metastases. Tucatinib with trastuzumab and capecitabine was the first drug proven to help, and trastuzumab deruxtecan shrinks brain lesions in most patients.","summary":"Brain metastases became the signature problem of HER2-positive disease once trastuzumab began to control it elsewhere: antibodies are too large to cross an intact blood-brain barrier, so the brain was often the first and only site of progression. Lesions present with headache, seizures or focal deficits, or are found on staging MRI; guidelines do not recommend routine screening MRI, though the landmark trials required it. Local treatment follows the number and size of lesions: stereotactic radiosurgery for a limited number, which the Alliance N0574 trial showed preserves cognition better than adding whole-brain radiotherapy, surgery for a large symptomatic lesion, and whole-brain radiotherapy held back for many lesions or leptomeningeal spread.\n\nHER2CLIMB was the first randomised trial to enrol patients with active, untreated brain metastases and prove a drug helps them. It randomised 612 women who had received trastuzumab, pertuzumab and trastuzumab emtansine, almost half with brain metastases, to tucatinib or placebo with trastuzumab and capecitabine: progression-free survival rose from 5.6 to 7.8 months (hazard ratio 0.54), overall survival from 17.4 to 21.9 months (hazard ratio 0.66), and the risk of intracranial progression fell by about two thirds, leading to approval in April 2020. Earlier, lapatinib with capecitabine had shown intracranial responses in the single-arm LANDSCAPE study, and neratinib reduced the need for brain interventions in NALA; HER2CLIMB-02 later added tucatinib to trastuzumab emtansine with a modest gain concentrated in patients with brain disease, and HER2CLIMB-05 in 2025 showed tucatinib added to first-line antibody maintenance delays progression by more than eight months.\n\nTrastuzumab deruxtecan then showed that an antibody-drug conjugate can work inside the brain. Small phase 2 studies (TUXEDO-1, DEBBRAH) reported high intracranial response rates, and DESTINY-Breast12 treated 504 patients, 263 with brain metastases, with an intracranial objective response in 71.7 percent and 61.6 percent of the brain-metastasis cohort progression-free at twelve months, including patients whose lesions had not been irradiated. Because trastuzumab deruxtecan is also the second-line standard after DESTINY-Breast03, and first line with pertuzumab after DESTINY-Breast09, many patients now receive brain-active systemic therapy before the brain is ever involved. Whether systemic therapy should replace radiotherapy first in selected asymptomatic patients, how to treat leptomeningeal disease, and the risk of radionecrosis when radiosurgery and antibody-drug conjugates are combined are the open questions.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Brain_metastasis","links":[{"label":"HER2CLIMB (NEJM 2020)","url":"https://doi.org/10.1056/NEJMoa1914609"},{"label":"HER2CLIMB brain metastasis analysis (JCO 2020)","url":"https://doi.org/10.1200/JCO.20.00775"},{"label":"DESTINY-Breast12 (Nature Medicine 2024)","url":"https://www.nature.com/articles/s41591-024-03261-7"}],"tags":["subtype-page"],"related":["secondary-brain-tumours","her2-brain-metastases","brain-metastases","tucatinib-triplet-brain-mets","leptomeningeal-disease","her2-positive-early-breast-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["nala","tuxedo-1"],"people":[],"bottlenecks":["b-brain-delivery"],"keyPapers":["paper-her2climb-nejm-2020","paper-her2climb-brain-lin-jco-2020","paper-tuxedo-1-trastuzumab-deruxtecan-brain-metastases-nat-med-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Up to half of women with metastatic HER2-positive breast cancer develop brain metastases during their illness, more than in any other breast subtype, partly because HER2 antibodies control disease elsewhere while the brain remains a sanctuary.","subtypes":["Asymptomatic HER2-positive brain metastases found on staging MRI (systemic therapy first under study)","Active or progressing HER2-positive brain metastases (HER2CLIMB population)","Stable, previously irradiated HER2-positive brain metastases","Leptomeningeal disease from HER2-positive breast cancer","Oligometastatic HER2-positive brain disease treated with stereotactic radiosurgery","HER2-positive brain metastases without extracranial progression"],"biomarkers":["HER2 status on the primary or an extracranial metastasis (brain biopsy rarely needed)","Contrast-enhanced brain MRI at baseline and every six to twelve weeks on treatment","Number, size and location of lesions (radiosurgery versus whole-brain radiotherapy)","Hormone receptor status","Cerebrospinal fluid cytology when leptomeningeal disease is suspected","Neurological performance status and corticosteroid requirement"],"standardOfCare":[{"setting":"Limited brain metastases at first presentation","approach":"Stereotactic radiosurgery to each lesion, or surgery for a large symptomatic lesion, followed by HER2-directed systemic therapy; whole-brain radiotherapy reserved for many lesions.","refs":["radiosurgery-srs","stereotactic-radiosurgery","alliance-n0574","mri","brain-metastases"]},{"setting":"Active brain metastases after trastuzumab, pertuzumab and trastuzumab emtansine","approach":"Tucatinib with trastuzumab and capecitabine (HER2CLIMB), which improved survival and delayed brain progression.","refs":["tucatinib","trastuzumab","capecitabine","her2climb","her2-brain-metastases"]},{"setting":"Brain metastases, stable or active, second line","approach":"Trastuzumab deruxtecan, with intracranial responses in most patients (DESTINY-Breast12), positioned as second-line therapy after DESTINY-Breast03.","refs":["trastuzumab-deruxtecan","destiny-breast12","destiny-breast03"]},{"setting":"First-line maintenance to delay brain progression","approach":"Tucatinib added to trastuzumab and pertuzumab maintenance after induction chemotherapy (HER2CLIMB-05).","refs":["tucatinib","trastuzumab","pertuzumab","her2climb-05"]},{"setting":"Later lines","approach":"Neratinib or lapatinib with capecitabine, trastuzumab emtansine with tucatinib (HER2CLIMB-02), repeat radiosurgery, or a clinical trial.","refs":["neratinib","lapatinib","capecitabine","trastuzumab-emtansine","her2climb-02"]}],"stateOfArt":["HER2CLIMB proved a systemic drug can extend survival in patients with active brain metastases, and it changed trial eligibility rules across oncology.","Trastuzumab deruxtecan achieves intracranial responses in most patients, including untreated lesions.","Radiosurgery has replaced whole-brain radiotherapy for limited disease, preserving cognition.","Brain-metastasis cohorts are now written into first-line HER2 trials rather than excluded."],"history":[{"year":2003,"title":"Brain as the first site of progression on trastuzumab described","refs":["trastuzumab"]},{"year":2013,"title":"LANDSCAPE: lapatinib with capecitabine shrinks untreated brain metastases","refs":["lapatinib","capecitabine"]},{"year":2016,"title":"Alliance N0574: radiosurgery alone preserves cognition better than adding whole-brain radiotherapy","refs":["alliance-n0574"]},{"year":2020,"title":"HER2CLIMB: tucatinib approved, the first drug proven in active brain metastases","refs":["her2climb","tucatinib"]},{"year":2022,"title":"TUXEDO-1 and DEBBRAH: trastuzumab deruxtecan active in the brain","refs":["trastuzumab-deruxtecan"]},{"year":2023,"title":"HER2CLIMB-02: tucatinib with trastuzumab emtansine","refs":["her2climb-02"]},{"year":2024,"title":"DESTINY-Breast12: intracranial response in most patients","refs":["destiny-breast12"]},{"year":2025,"title":"HER2CLIMB-05: tucatinib in first-line maintenance","refs":["her2climb-05"]}],"pipeline":["trastuzumab-deruxtecan","tucatinib","her2climb-05","idea-cns-first-adc-strategy","zanidatamab","trastuzumab-rezetecan","pyrotinib","her2-pet"],"openProblems":["No randomised trial has compared systemic therapy first with radiosurgery first for asymptomatic lesions.","Leptomeningeal disease still has no proven treatment.","Radionecrosis after radiosurgery may be commoner with antibody-drug conjugates.","Screening MRI might find lesions earlier but no trial shows it helps."],"parent":"breast-her2-positive"},{"id":"gastric-her2-positive","kind":"cancer","name":"HER2-positive gastric cancer","aka":["HER2-positive gastro-oesophageal adenocarcinoma","ERBB2-amplified gastric cancer","HER2+ GEA"],"tldr":"HER2-positive gastric cancer overexpresses the HER2 growth receptor and is treated with trastuzumab added to chemotherapy, now usually with pembrolizumab as well. After progression the antibody-drug conjugate trastuzumab deruxtecan gives responses that plain chemotherapy cannot.","summary":"HER2 positivity is defined in stomach cancer as immunohistochemistry 3+ or 2+ with amplification on in situ hybridisation, and every advanced gastric or junctional adenocarcinoma is tested at diagnosis. HER2-positive tumours are more often intestinal type and sit more often at the junction than in the distal stomach; staining is heterogeneous, so biopsies from several sites are recommended and a negative result on a small sample can be wrong.\n\nToGA (Lancet 2010) added trastuzumab to cisplatin and a fluoropyrimidine and extended median overall survival from 11.1 to 13.8 months, and to 16.0 months in patients with strong HER2 expression; it made trastuzumab the first targeted therapy in stomach cancer. KEYNOTE-811 then added pembrolizumab to trastuzumab and chemotherapy, raising response rates and improving survival in PD-L1-positive tumours, so the triplet is now first-line standard where PD-L1 is expressed. Zanidatamab, a bispecific HER2 antibody, is being tested against trastuzumab in the same setting in HERIZON-GEA-01.\n\nDESTINY-Gastric01 (NEJM 2020) showed that trastuzumab deruxtecan, an antibody-drug conjugate carrying a topoisomerase inhibitor payload, produced responses in 51 percent of previously treated patients against 14 percent with chemotherapy and improved median survival from 8.4 to 12.5 months, earning FDA approval in 2021. DESTINY-Gastric04 confirmed the benefit in the second line against ramucirumab and paclitaxel, with median survival of 14.7 against 11.4 months. Interstitial lung disease is the toxicity that needs watching. HER2 expression is often lost after trastuzumab, so a fresh biopsy before second-line HER2 therapy is advised.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Stomach_cancer","links":[{"label":"ToGA (Lancet 2010)","url":"https://pubmed.ncbi.nlm.nih.gov/20728210/"},{"label":"DESTINY-Gastric01 (NEJM 2020)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2004413"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Stomach_cancer"}],"tags":["subtype-page"],"related":["gastric-cldn18-2-positive","early-gastric-cancer","gastric-msi-high","gastric-pdl1-high"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["destiny-gastric01","destiny-gastric02","keynote-811","gatsby"],"people":[],"bottlenecks":[],"keyPapers":["paper-toga-trastuzumab-gastric-lancet-2010","paper-flot4-lancet-2019","paper-keynote-811-janjigian-lancet-2023","paper-destiny-gastric01-nejm-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About one in six advanced gastric and junctional adenocarcinomas, commoner in intestinal-type and junctional tumours than in diffuse-type disease; it was the first molecular subgroup of stomach cancer to get its own treatment.","subtypes":["HER2 3+ by immunohistochemistry","HER2 2+ with amplification on in situ hybridisation","HER2-positive, PD-L1 CPS 1 or above (trastuzumab, pembrolizumab and chemotherapy)","HER2-positive junctional adenocarcinoma","HER2 loss after trastuzumab"],"biomarkers":["HER2 by immunohistochemistry and in situ hybridisation (multiple biopsy sites)","PD-L1 combined positive score (decides pembrolizumab in first line)","HER2 status on repeat biopsy at progression","ERBB2 amplification on plasma ctDNA (trials)"],"standardOfCare":[{"setting":"Advanced, first line","approach":"Trastuzumab with a platinum and a fluoropyrimidine (ToGA), plus pembrolizumab when PD-L1 CPS is 1 or above (KEYNOTE-811).","refs":["toga","trastuzumab","pembrolizumab","cisplatin","oxaliplatin","capecitabine","fluorouracil","her2","her2-gastric-sequence"]},{"setting":"Second line","approach":"Trastuzumab deruxtecan (DESTINY-Gastric01 and DESTINY-Gastric04); ramucirumab with paclitaxel where the conjugate is unavailable.","refs":["trastuzumab-deruxtecan","destiny-gastric04","ramucirumab","paclitaxel"]},{"setting":"Later lines","approach":"Trifluridine-tipiracil; trials of zanidatamab and other HER2 agents.","refs":["trifluridine-tipiracil","zanidatamab","herizon-gea-01"]},{"setting":"Localised disease","approach":"Perioperative FLOT and gastrectomy as for HER2-negative disease; adding HER2 therapy before surgery is unproven.","refs":["flot","gastrectomy"]}],"stateOfArt":["ToGA made HER2 the first biomarker in stomach cancer and trastuzumab-chemotherapy the standard first line for fifteen years.","Trastuzumab deruxtecan gives a second HER2-directed line with a real survival gain, unlike lapatinib and trastuzumab emtansine before it.","Pembrolizumab added to trastuzumab and chemotherapy is now the first-line triplet in PD-L1-positive tumours."],"history":[{"year":2010,"title":"ToGA: trastuzumab plus chemotherapy extends survival in HER2-positive gastric cancer","refs":["toga","trastuzumab"]},{"year":2017,"title":"GATSBY: trastuzumab emtansine fails in the second line","refs":[]},{"year":2020,"title":"DESTINY-Gastric01: trastuzumab deruxtecan beats chemotherapy after trastuzumab","refs":["trastuzumab-deruxtecan"]},{"year":2021,"title":"FDA approves trastuzumab deruxtecan for HER2-positive gastric cancer; KEYNOTE-811 adds pembrolizumab first line","refs":["trastuzumab-deruxtecan","pembrolizumab"]},{"year":2025,"title":"DESTINY-Gastric04: trastuzumab deruxtecan beats ramucirumab-paclitaxel in the second line","refs":["destiny-gastric04"]}],"pipeline":["zanidatamab","herizon-gea-01","disitamab-vedotin","her2-gastric-sequence","trastuzumab-deruxtecan"],"openProblems":["HER2 heterogeneity and loss after treatment make a single biopsy unreliable.","No HER2-directed therapy has yet improved cure rates in resectable disease.","Interstitial lung disease with trastuzumab deruxtecan needs early recognition."],"parent":"gastric"},{"id":"hereditary-ppgl","kind":"cancer","name":"Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127)","aka":["Familial paraganglioma syndromes","SDHB-related paraganglioma","SDHD-related head and neck paraganglioma","VHL-associated pheochromocytoma","MEN2-associated pheochromocytoma","Hereditary PPGL"],"tldr":"Hereditary pheochromocytoma and paraganglioma is the inherited form of these adrenaline-producing tumours, caused by a fault in one of more than a dozen genes, most often SDHB, SDHD, VHL and RET. Knowing the gene changes care: SDHB carriers have the highest risk of spread, VHL and MEN2 patients get adrenal-sparing surgery because tumours arise on both sides, and relatives are screened.","summary":"Pheochromocytomas (adrenal) and paragangliomas (sympathetic chain, head and neck) have the strongest hereditary basis of any tumour type: germline mutations are found in 30 to 40 percent of patients, in the succinate dehydrogenase genes (SDHB, SDHD, SDHC, SDHA and SDHAF2), VHL, RET (MEN2), NF1, MAX, TMEM127, FH and others, and the Endocrine Society guideline recommends that all patients be offered testing. The genes fall into two clusters that shape the tumour: cluster 1 (SDHx, VHL, FH, EPAS1) tumours are pseudohypoxic, noradrenergic or non-secreting, often extra-adrenal and multiple, and express somatostatin receptors strongly; cluster 2 (RET, NF1, MAX, TMEM127) tumours are kinase-driven, adrenergic and usually adrenal. SDHB mutations carry the highest risk of metastasis, SDHD (paternally inherited) causes multiple head and neck paragangliomas, VHL and MEN2 cause bilateral pheochromocytomas alongside their other tumours, and SDHx carriers are also at risk of gastrointestinal stromal tumours, renal cell carcinoma and pituitary adenomas.\n\nManagement differs from sporadic disease at every step. Diagnosis rests on plasma or urinary metanephrines and, for non-secreting head and neck tumours, imaging; SDHB immunohistochemistry on the tumour flags an SDHx mutation, and 68Ga-DOTATATE PET is the preferred whole-body scan for cluster 1 disease because of its somatostatin receptor expression. Surgery follows alpha-blockade, and in VHL and MEN2 a cortical-sparing adrenalectomy is preferred to avoid lifelong steroid dependence after bilateral tumours; head and neck paragangliomas, which rarely secrete and grow slowly, are often watched or irradiated rather than resected because surgery risks the cranial nerves. Carriers enter lifelong surveillance with annual metanephrines and periodic whole-body MRI from childhood in SDHB and SDHD families, and cascade testing is offered to relatives. For carriers who develop advanced disease, the HIF-2 alpha inhibitor belzutifan, approved for VHL-associated tumours in 2021 and for advanced pheochromocytoma and paraganglioma in 2025, exploits the pseudohypoxia pathway directly, and radioligand therapy with lutetium-177 dotatate suits the somatostatin-receptor-rich cluster 1 tumours. The genetics also guide prognosis: metastatic risk, multiplicity and the chance of a second primary all follow the gene.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Paraganglioma","links":[{"label":"Endocrine Society PPGL guideline 2014","url":"https://doi.org/10.1210/jc.2014-1498"},{"label":"Belzutifan in VHL (NEJM 2021)","url":"https://doi.org/10.1056/NEJMoa2103425"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Paraganglioma"}],"tags":["subtype-page","endocrine"],"related":["metastatic-ppgl","pheochromocytoma-paraganglioma","medullary-thyroid-cancer","localised-adrenocortical-carcinoma"],"cancers":[],"sections":[],"technologies":["germline-testing","sstr-pet","radioligand-therapy","prrt","mri","ct","active-surveillance","imrt-igrt","sbrt"],"targets":["hif2a","sstr2","ret"],"drugs":["belzutifan","lutathera"],"companies":[],"institutions":[],"pathways":[],"terms":["hereditary-cancer-syndromes","adrenalectomy","sdh-deficiency","rare-cancers"],"trials":["nct04924075"],"people":[],"bottlenecks":[],"keyPapers":["paper-belzutifan-vhl-jonasch-nejm-2021","paper-neumann-germline-mutations-nonsyndromic-pheochromocytoma-nejm-2002","paper-endocrine-society-pheochromocytoma-paraganglioma-guideline-jcem-2014"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"Up to four in ten pheochromocytomas and paragangliomas are caused by a germline mutation, the highest proportion of any cancer, so every patient is offered genetic testing; carriers face lifelong surveillance for new tumours.","subtypes":["SDHB-related paraganglioma (highest metastatic risk; extra-adrenal, abdominal and thoracic)","SDHD-related head and neck paraganglioma (multiple, paternal inheritance, rarely secreting)","SDHC, SDHA and SDHAF2-related paraganglioma (rarer, lower penetrance)","VHL-associated pheochromocytoma (bilateral, noradrenergic; belzutifan eligible)","MEN2 (RET)-associated pheochromocytoma (bilateral, adrenergic; with medullary thyroid cancer)","NF1, MAX and TMEM127-associated pheochromocytoma (adrenal, later onset)","Carney triad and Carney-Stratakis dyad (paraganglioma with gastrointestinal stromal tumour)"],"biomarkers":["Germline panel testing (SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, RET, NF1, MAX, TMEM127, FH, EPAS1)","Plasma free or urinary fractionated metanephrines (noradrenergic pattern in cluster 1)","SDHB immunohistochemistry (loss indicates any SDHx mutation)","68Ga-DOTATATE PET (somatostatin receptor expression, staging and radioligand eligibility)","Tumour size, extra-adrenal site and SDHB status as metastatic risk factors","Surveillance whole-body MRI in carriers"],"standardOfCare":[{"setting":"Genetic diagnosis","approach":"Germline panel testing offered to every patient; SDHB immunohistochemistry on tumour tissue; cascade testing of relatives with genetic counselling.","refs":["germline-testing","hereditary-cancer-syndromes","sdh-deficiency"],"guideline":{"version":"Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors","url":"https://doi.org/10.1210/jc.2014-1498"}},{"setting":"Biochemical and imaging work-up","approach":"Plasma or urinary metanephrines; CT or MRI; 68Ga-DOTATATE PET as the preferred functional scan for SDHx and other cluster 1 disease.","refs":["sstr-pet","mri","ct"],"guideline":{"version":"Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors","url":"https://doi.org/10.1210/jc.2014-1498"}},{"setting":"Adrenal tumours in VHL and MEN2","approach":"Alpha-blockade then cortical-sparing (partial) adrenalectomy to preserve adrenal function given the risk of bilateral disease.","refs":["adrenalectomy","robotic-surgery"],"guideline":{"version":"Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors","url":"https://doi.org/10.1210/jc.2014-1498"}},{"setting":"Head and neck paragangliomas","approach":"Observation for small asymptomatic tumours; surgery or fractionated or stereotactic radiotherapy when growing or symptomatic, weighing cranial nerve risk.","refs":["active-surveillance","imrt-igrt","sbrt"],"guideline":{"version":"Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors","url":"https://doi.org/10.1210/jc.2014-1498"}},{"setting":"Surveillance of carriers","approach":"Annual metanephrines and clinical review from childhood, with whole-body MRI every two to three years in SDHB and SDHD carriers; screening for associated tumours (GIST, renal cell carcinoma, pituitary).","refs":["mri","germline-testing"],"guideline":{"version":"Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors","url":"https://doi.org/10.1210/jc.2014-1498"}},{"setting":"Advanced disease in carriers","approach":"Belzutifan (approved for VHL-associated tumours 2021 and for advanced pheochromocytoma and paraganglioma 2025); lutetium-177 dotatate for somatostatin-receptor-positive disease; see the metastatic record.","refs":["belzutifan","nct04924075","lutathera","prrt"],"guideline":{"version":"Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors","url":"https://doi.org/10.1210/jc.2014-1498"}}],"stateOfArt":["Universal germline testing and gene-based surveillance find tumours before they cause harm.","The cluster 1 and cluster 2 framework links gene, biochemistry, imaging and therapy.","Belzutifan is the first drug aimed at the pseudohypoxia pathway that drives cluster 1 tumours."],"history":[{"year":1993,"title":"RET mutations identified in MEN2; VHL gene cloned","refs":["ret","hereditary-cancer-syndromes"]},{"year":2000,"title":"SDHD mutations found in familial head and neck paraganglioma; SDHB follows in 2001","refs":["sdh-deficiency"]},{"year":2014,"title":"Endocrine Society guideline recommends germline testing for all patients","refs":["germline-testing"]},{"year":2017,"title":"TCGA analysis defines the pseudohypoxia and kinase clusters","refs":[]},{"year":2021,"title":"Belzutifan approved for VHL-associated tumours","refs":["belzutifan"]},{"year":2025,"title":"Belzutifan approved for advanced pheochromocytoma and paraganglioma","refs":["belzutifan","nct04924075"]}],"pipeline":["belzutifan","nct04924075","lutathera","prrt","germline-testing"],"openProblems":["Penetrance of SDHx mutations is incomplete and variable, so how intensively to screen carriers is debated.","No treatment prevents new tumours in carriers.","Whether belzutifan works in SDHx-related as well as VHL-related disease needs more data.","Head and neck paragangliomas have no effective medical therapy."],"parent":"pheochromocytoma-paraganglioma"},{"id":"high-grade-b-cell-lymphoma-myc-bcl2","kind":"cancer","name":"High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma)","aka":["Double-hit lymphoma","DHL","HGBL-MYC/BCL2","HGBCL-DH-BCL2","Diffuse large B-cell lymphoma/high grade B-cell lymphoma with MYC and BCL2 rearrangements","High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements","Double-hit B-cell lymphoma","Triple-hit lymphoma"],"tldr":"An aggressive B-cell lymphoma defined not by how it looks but by two genetic faults in the same cell: a rearrangement of MYC, which drives growth, and one of BCL2, which blocks the cell from dying. It behaves worse than ordinary diffuse large B-cell lymphoma, so finding the rearrangements changes the treatment.","summary":"What it is. Two genes have to be broken for this diagnosis. MYC is a master switch for cell growth; BCL2 is the brake on programmed cell death. A cell that is told to grow and is also prevented from dying becomes a lymphoma that behaves worse than either fault alone would predict. The rearrangements are found by fluorescence in situ hybridisation, a test done on the biopsy, and they are the diagnosis. Nothing about the way the cells look under a microscope reliably identifies them, which is why every aggressive B-cell lymphoma is now tested.\n\nHow it differs from its family. It is a separate entity from diffuse large B-cell lymphoma, although it was carved out of it. WHO-HAEM5 named it diffuse large B-cell lymphoma / high-grade B-cell lymphoma with MYC and BCL2 rearrangements, so that a tumour made of large cells and one made of smaller blastoid cells can carry the same name once the genetics are known; the two books describe it as a homogeneous group with a germinal-centre gene expression profile and a close relationship to follicular lymphoma. Its gene expression overlaps that of Burkitt lymphoma, which is the other aggressive germinal-centre disease driven by MYC.\n\nWhere the two classifications disagree, and why it matters to a reader. Until 2022, cases with MYC and BCL6 rearrangements were counted in the same category. Both books removed them, because their gene expression and mutations are varied and differ from the MYC and BCL2 group. WHO-HAEM5 sends them back to diffuse large B-cell lymphoma or to high-grade B-cell lymphoma not otherwise specified, chosen on how the cells look. The International Consensus Classification created a new provisional entity for them instead, called high-grade B-cell lymphoma with MYC and BCL6 rearrangements. So a person with MYC and BCL6 rearrangements may be told they have a double-hit lymphoma by one pathologist and diffuse large B-cell lymphoma by another, and both are following a 2022 classification.\n\nWhat the signature adds. The gene expression signature that characterises this entity can be present without the rearrangements. In the study that defined it, the signature was found in 27 per cent of germinal-centre diffuse large B-cell lymphomas, only half of which had the double rearrangement, and the people who carried the signature had worse outcomes after standard immunochemotherapy whether or not the rearrangements were there: a five-year time to progression of 57 per cent against 81 per cent. A commercial assay (the DLBCL90 NanoString panel) reproduced that result. The clinical implication is uncomfortable and honest: the test in daily use identifies some but not all of the biologically distinct group.\n\nHow it is treated. More intensively than diffuse large B-cell lymphoma, with prophylaxis against spread to the brain and spinal cord, which is more likely here. The regimens and the evidence for them, which is observational rather than randomised, are written on the diffuse large B-cell lymphoma page and in the treatment layer of this family.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Diffuse_large_B-cell_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"Double-hit gene expression signature defines a distinct subgroup of germinal centre B-cell-like diffuse large B-cell lymphoma (Ennishi and Rosenwald, J Clin Oncol 2019)","url":"https://doi.org/10.1200/JCO.18.01583"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["dlbcl","burkitt-lymphoma","follicular-lymphoma","non-hodgkin-lymphoma","primary-mediastinal-b-cell-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","fdg-pet"],"targets":["myc","bcl2"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["double-hit-lymphoma","lymphoma-classification-2022","lymphoma-indolent-versus-aggressive","ipi-score","lymphoma-tx-cns-prophylaxis"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"No United Kingdom population figure exists under the name the 2022 classifications gave this entity, and the corpus does not invent one. What can be said is how often the genetics are found when they are looked for: in the gene-expression study that defined the double-hit signature, 25 of 157 germinal-centre diffuse large B-cell lymphomas carried rearrangements of both MYC and BCL2, and 27 per cent of the whole series carried the signature even though only half of those had the rearrangements. That cohort was assembled to contain the cases, so it is not a population frequency.","subtypes":["Large-cell morphology, which looks like diffuse large B-cell lymphoma down the microscope","High-grade or blastoid morphology, made of medium-sized cells","With an additional BCL6 rearrangement, historically called triple-hit"],"biomarkers":["MYC rearrangement and BCL2 rearrangement, both by fluorescence in situ hybridisation; the diagnosis cannot be made without them","BCL6 rearrangement, reported separately because the 2022 classifications moved MYC with BCL6 out of this entity","Germinal-centre B-cell phenotype: CD10 positive, BCL6 positive, MUM1 usually negative","The double-hit gene expression signature (DHITsig or MHG), measurable on a NanoString panel, which marks a larger group than the rearrangements do","Dual expression of MYC and BCL2 protein by immunohistochemistry, which is a different and much commoner finding and is not this entity"],"standardOfCare":[{"setting":"Making the diagnosis","approach":"Every aggressive B-cell lymphoma biopsy is tested by fluorescence in situ hybridisation for MYC, and if MYC is rearranged, for BCL2 and BCL6. A lymphoma cannot be identified as double-hit by appearance, by immunohistochemistry for MYC and BCL2 protein, or by the cell-of-origin assay; dual protein expression is a separate and much commoner finding with its own, lesser, prognostic weight. Follicular lymphoma is excluded from the entity by both classifications even when it carries both rearrangements.","refs":["histopathology-ihc","myc","bcl2","double-hit-lymphoma","lymphoma-classification-2022"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Treatment, and what is known about it","approach":"Treated more intensively than diffuse large B-cell lymphoma, and with prophylaxis against disease in the brain and spinal cord, which is more frequent here. There has never been a randomised trial confined to this entity: the intensified regimens in use were adopted from retrospective comparisons after the group was shown to do less well with standard immunochemotherapy. The regimens, the doses and the evidence behind each are on the diffuse large B-cell lymphoma page and in the treatment layer of this family.","refs":["dlbcl","rituximab","lymphoma-tx-cns-prophylaxis","lymphoma-tx-regimen-alphabet","r-chop"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":2016,"title":"Carved out of diffuse large B-cell lymphoma","note":"The revised fourth edition of the WHO classification created high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements as a category of its own, which made testing for the rearrangements routine.","refs":["dlbcl"]},{"year":2019,"title":"A gene expression signature wider than the rearrangements","note":"An analysis of 157 germinal-centre diffuse large B-cell lymphomas defined a 104-gene double-hit signature present in 27 per cent of them, only half of which carried the rearrangements; those with the signature had a five-year time to progression of 57 per cent against 81 per cent.","refs":["myc","bcl2"]},{"year":2022,"title":"The two classifications split over MYC and BCL6","note":"Both removed cases with MYC and BCL6 rearrangements from the double-hit entity. WHO-HAEM5 reassigns them by appearance; the International Consensus Classification made them a provisional entity of their own.","refs":["lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["No randomised trial has ever been run in this entity. The intensified regimens used for it were adopted from retrospective comparisons, and whether they are better than standard immunochemotherapy for an individual patient is not known.","The test used to make the diagnosis identifies a narrower group than the biology does: the double-hit gene expression signature marks about twice as many patients as the rearrangements do, and those extra patients have the same outcome and are treated as ordinary diffuse large B-cell lymphoma.","The two 2022 classifications handle MYC with BCL6 differently, so the same biopsy can yield two different diagnoses and two different trial eligibilities."],"parent":"non-hodgkin-lymphoma"},{"id":"high-grade-serous-ovarian-cancer","kind":"cancer","name":"High-grade serous ovarian cancer","aka":["HGSOC","High-grade serous carcinoma of the ovary, fallopian tube and peritoneum"],"tldr":"High-grade serous cancer is the common, aggressive form of ovarian cancer, now known to start in the fallopian tube. It is treated with surgery and platinum chemotherapy, and maintenance PARP inhibitors have changed its course for the half of patients whose tumours cannot repair DNA properly.","summary":"High-grade serous carcinoma arises in the fimbria of the fallopian tube and spreads across the peritoneum before it causes symptoms. Every tumour carries a TP53 mutation; about a fifth have a germline or somatic BRCA1 or BRCA2 mutation and roughly half are homologous recombination deficient, which makes them exquisitely sensitive to platinum and to PARP inhibitors. Standard care is complete cytoreductive surgery, before or after three cycles of carboplatin-paclitaxel, with bevacizumab in higher-risk disease, then maintenance: olaparib for BRCA-mutant tumours (SOLO-1), niraparib for all comers (PRIMA) or olaparib with bevacizumab for HRD-positive tumours (PAOLA-1). Secondary surgery helps selected patients at first relapse (DESKTOP III), and platinum-resistant disease has gained mirvetuximab soravtansine for folate receptor alpha-high tumours. Germline testing of every patient and risk-reducing salpingo-oophorectomy in carriers are part of the standard.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Ovarian_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Ovarian_cancer"}],"tags":["subtype-page"],"related":["platinum-sensitive-ovarian-cancer","platinum-resistant-ovarian-cancer","low-grade-serous-ovarian-cancer","clear-cell-ovarian-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["soraya"],"people":[],"bottlenecks":[],"keyPapers":["paper-solo-1-nejm-2018","paper-paola-1-nejm-2019","paper-mirasol-nejm-2023","paper-tcga-ovarian-nature-2011"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"About seven in ten ovarian cancers and most of the deaths; three quarters present at stage III or IV, most respond to platinum chemotherapy and most relapse, but PARP inhibitor maintenance now keeps a growing share of BRCA-mutant patients disease-free for years.","subtypes":["BRCA1 or BRCA2-mutant (germline or somatic, about 20 percent)","Homologous recombination deficient without BRCA mutation","Homologous recombination proficient","Primary peritoneal and fallopian tube carcinoma (same disease)"],"biomarkers":["TP53 mutation (universal)","Germline and somatic BRCA1/2","HRD score (Myriad myChoice or equivalent)","Folate receptor alpha (mirvetuximab)","CA-125 for monitoring","Platinum-free interval"],"standardOfCare":[{"setting":"First line","approach":"Complete cytoreductive surgery, primary or after three cycles, with carboplatin-paclitaxel for six cycles; bevacizumab added in stage IV or residual disease.","refs":["carboplatin","paclitaxel","bevacizumab","hipec"]},{"setting":"Maintenance after first line","approach":"Olaparib for BRCA-mutant tumours (SOLO-1), niraparib for all comers (PRIMA), olaparib plus bevacizumab for HRD-positive tumours (PAOLA-1).","refs":["olaparib","niraparib","solo-1","prima","paola-1","hrd","brca"]},{"setting":"Platinum-sensitive relapse","approach":"Secondary cytoreduction in selected patients (DESKTOP III), platinum doublet, PARP inhibitor maintenance if not already used.","refs":["desktop-iii","rucaparib","niraparib"]},{"setting":"Platinum-resistant relapse","approach":"Single-agent chemotherapy with or without bevacizumab; mirvetuximab soravtansine for folate receptor alpha-high tumours (MIRASOL); relacorilant with nab-paclitaxel in trials and early approvals.","refs":["mirvetuximab-soravtansine","folr1","relacorilant","bevacizumab"]},{"setting":"Prevention in carriers","approach":"Risk-reducing salpingo-oophorectomy around age 35 to 45 by gene; opportunistic salpingectomy at other pelvic surgery for everyone.","refs":["brca","risk-reducing-salpingectomy"]}],"stateOfArt":["PARP inhibitor maintenance has turned a disease that nearly always relapsed into one where a large fraction of BRCA-mutant patients remain disease-free seven years on.","The fallopian tube origin has made opportunistic salpingectomy a population prevention strategy.","Antibody-drug conjugates against folate receptor alpha are the first new active drugs in platinum-resistant disease in a decade."],"history":[{"year":1996,"title":"Carboplatin-paclitaxel becomes standard (GOG 111 and successors)","refs":["carboplatin","paclitaxel"]},{"year":2007,"title":"Fallopian tube fimbria identified as the origin of serous cancer","refs":[]},{"year":2011,"title":"Bevacizumab improves progression-free survival (GOG-0218, ICON7)","refs":["bevacizumab"]},{"year":2014,"title":"Olaparib: first PARP inhibitor approved","refs":["olaparib"]},{"year":2018,"title":"SOLO-1: olaparib maintenance transforms BRCA-mutant first-line outcomes","refs":["solo-1"]},{"year":2019,"title":"PRIMA and PAOLA-1 extend PARP maintenance beyond BRCA","refs":["prima","paola-1"]},{"year":2022,"title":"Mirvetuximab soravtansine approved for platinum-resistant disease","refs":["mirvetuximab-soravtansine"]}],"pipeline":["mirvetuximab-soravtansine","relacorilant","folr1"],"openProblems":["No screening test lowers mortality.","Homologous recombination proficient tumours gain little from PARP inhibitors.","Platinum-resistant disease remains largely incurable.","Access to HRD testing and PARP inhibitors outside high-income countries."],"parent":"ovarian"},{"id":"all-paediatric-high-risk","kind":"cancer","name":"High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL)","aka":["NCI high-risk B-ALL","Very high-risk childhood ALL","Childhood T-cell ALL","T-ALL in children"],"tldr":"High-risk childhood leukaemia means a child aged ten or over, a very high white cell count, T-cell disease, spread to the brain or testes, or adverse genetics, and it is treated with longer and more intensive chemotherapy. Most children are still cured; the T-cell form gained the drug nelarabine after the AALL0434 trial, and cranial radiotherapy has been dropped for almost everyone.","summary":"High risk is set at diagnosis by age ten or over or a white count of 50 x 10^9/L or more, by T-cell immunophenotype, by central nervous system or testicular disease, and by adverse genetics: hypodiploidy, KMT2A rearrangement, iAMP21, TCF3::HLF and BCR::ABL1-like signatures. It is revised after induction by measurable residual disease, so a standard-risk child with residual disease above 0.01 percent joins this group and a high-risk child who clears it may be spared the most intensive blocks. T-ALL makes up around 15 percent of childhood ALL, presents with high counts and mediastinal masses in adolescent boys, and the early T-cell precursor subtype is treated by residual disease response rather than by immunophenotype.\n\nThe augmented Berlin-Frankfurt-Münster regimen, tested by the Children's Cancer Group in the 1990s for slow early responders, is the backbone: four-drug induction adding an anthracycline, consolidation with cyclophosphamide, cytarabine, mercaptopurine and asparaginase, and two interim maintenance and delayed intensification blocks. AALL0232 found high-dose methotrexate with leucovorin rescue superior to escalating Capizzi methotrexate for high-risk B-ALL, and dexamethasone superior to prednisone in children under ten. AALL0434, the largest T-ALL trial ever run, showed the opposite for T-ALL, Capizzi methotrexate beating high-dose methotrexate, and added nelarabine for intermediate- and high-risk T-ALL: five-year disease-free survival 88.2 percent against 82.1 percent, now standard. AALL1231 then removed prophylactic cranial irradiation for all but the highest-risk T-ALL and showed that bortezomib helped T-lymphoblastic lymphoma but not T-ALL. Allogeneic transplant in first remission is reserved for induction failure, hypodiploidy and persistent residual disease at the end of consolidation.\n\nImmunotherapy is moving from relapse into first-line high-risk therapy. E1910 in adults and AALL1731 in standard-risk children showed blinatumomab consolidation lowers relapse, AALL1732 is testing inotuzumab ozogamicin added to chemotherapy for high-risk B-ALL, and CD19 CAR T-cells are being tried as consolidation for children with persistent residual disease instead of transplant. T-ALL has no antibody target in routine use: nelarabine, venetoclax combinations and CD7-directed CAR T-cells are the candidates, and daratumumab against CD38 is being tested in relapsed T-ALL. Toxicity is the other frontier: asparaginase-related thrombosis and pancreatitis, osteonecrosis in adolescents, methotrexate neurotoxicity, and the late cardiac and cognitive costs that push every trial to remove a drug wherever residual disease allows.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia","links":[{"label":"Wikipedia: Acute lymphoblastic leukaemia","url":"https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia"},{"label":"NCI PDQ: Childhood ALL Treatment","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}],"tags":["subtype-page","paediatric"],"related":["all-paediatric-standard-risk","all-paediatric-ph-positive","all-ph-like","all-paediatric-relapsed","all-infant"],"cancers":[],"sections":[],"technologies":["flow-cytometry-mrd","allogeneic-hsct","cytotoxic-chemotherapy"],"targets":["cd19","cd22","cd38"],"drugs":[],"companies":["childrens-oncology-group"],"institutions":[],"pathways":[],"terms":["mrd","efs","b-all-cytogenetic-risk","ph-like-all"],"trials":["aall0434"],"people":[],"bottlenecks":[],"keyPapers":["paper-aall0232-larsen-jco-2016","paper-aall0434-nelarabine-t-all-dunsmore-jco-2020","paper-hunger-mullighan-all-children-nejm-2015"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About a third of children with B-cell ALL are high risk by age or white count, and T-cell ALL adds about 15 percent of childhood ALL; together they account for most of the relapses and deaths in a disease that is otherwise usually cured.","subtypes":["High-risk B-ALL by age or white count (NCI high risk: aged 10 or over, or white count 50 x 10^9/L or more)","B-ALL with adverse genetics (hypodiploidy, KMT2A rearrangement, iAMP21, TCF3::HLF)","B-ALL with end-induction or end-consolidation residual disease (very high risk)","T-cell ALL (about 15 percent of childhood ALL; nelarabine added for intermediate and high risk)","Early T-cell precursor ALL (treated by residual disease response)","ALL with CNS or testicular involvement at diagnosis"],"biomarkers":["Age and white cell count (NCI criteria)","Immunophenotype (CD19, CD22, CD7, cytoplasmic CD3)","Karyotype and FISH (hypodiploidy, KMT2A, iAMP21)","BCR::ABL1 and BCR::ABL1-like screening","Flow cytometry MRD at day 29 and end of consolidation","CNS status (CNS1 to CNS3)"],"standardOfCare":[{"setting":"Induction (four weeks)","approach":"Four-drug induction: vincristine, dexamethasone or prednisone, daunorubicin and pegylated asparaginase with intrathecal methotrexate; MRD at day 29.","refs":["vincristine","dexamethasone","prednisone","daunorubicin","asparaginase","methotrexate","flow-cytometry-mrd"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Consolidation and interim maintenance, high-risk B-ALL","approach":"Augmented BFM consolidation with cyclophosphamide, cytarabine, mercaptopurine and asparaginase; high-dose methotrexate with leucovorin rescue (AALL0232); blinatumomab or inotuzumab ozogamicin added in current trials.","refs":["cyclophosphamide","cytarabine","mercaptopurine","asparaginase","methotrexate","leucovorin","blinatumomab","inotuzumab-ozogamicin","aall0232"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"T-cell ALL","approach":"Augmented BFM with Capizzi escalating methotrexate and nelarabine courses for intermediate- and high-risk disease (AALL0434); cranial irradiation only for CNS3 or the highest risk (AALL1231).","refs":["nelarabine","methotrexate","asparaginase","prophylactic-cranial-irradiation","aall1231"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Delayed intensification and maintenance","approach":"Two delayed intensification blocks with vincristine, dexamethasone, doxorubicin, cyclophosphamide, cytarabine and thioguanine; maintenance with mercaptopurine, methotrexate and vincristine-steroid pulses.","refs":["vincristine","dexamethasone","doxorubicin","cyclophosphamide","cytarabine","thioguanine","mercaptopurine","methotrexate"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Very high risk: induction failure, hypodiploidy, persistent residual disease","approach":"Blinatumomab to clear residual disease, then allogeneic transplant in first remission; CD19 CAR T-cells as consolidation in trials.","refs":["allogeneic-hsct","blinatumomab","tisagenlecleucel","flow-cytometry-mrd","ngs-mrd-clonoseq"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}}],"stateOfArt":["Nelarabine is standard for intermediate- and high-risk T-ALL after AALL0434 raised five-year disease-free survival to 88 percent.","Prophylactic cranial irradiation has been dropped for almost all children after AALL1231, with intrathecal therapy taking its place.","Blinatumomab and inotuzumab ozogamicin are being folded into first-line high-risk B-ALL therapy, and transplant is confined to persistent residual disease."],"history":[{"year":1998,"title":"Children's Cancer Group: augmented BFM therapy improves outcome for slow early responders","refs":[]},{"year":2016,"title":"AALL0232: high-dose methotrexate beats Capizzi methotrexate in high-risk B-ALL","refs":["methotrexate","leucovorin"]},{"year":2020,"title":"AALL0434: nelarabine improves disease-free survival in T-ALL","refs":["nelarabine"]},{"year":2022,"title":"AALL1231 removes prophylactic cranial irradiation for most T-ALL; bortezomib helps T-lymphoblastic lymphoma only","refs":["prophylactic-cranial-irradiation","bortezomib"]},{"year":2024,"title":"Blinatumomab approved for consolidation of newly diagnosed CD19-positive B-ALL","refs":["blinatumomab","e1910"]}],"pipeline":["inotuzumab-ozogamicin","blinatumomab","tisagenlecleucel","venetoclax","ngs-mrd-clonoseq","allogeneic-hsct"],"openProblems":["No antibody or cell therapy target in routine use for T-ALL.","Which high-risk children still need transplant once immunotherapy clears residual disease.","Asparaginase toxicity and osteonecrosis in adolescents receiving the most intensive regimens."],"parent":"all-leukemia"},{"id":"hr-positive-early-high-risk","kind":"cancer","name":"High-risk early HR-positive breast cancer","aka":["High-risk early hormone receptor-positive, HER2-negative breast cancer","Node-positive luminal breast cancer","Stage II to III HR-positive breast cancer"],"tldr":"Most hormone-driven breast cancers are cured with surgery, radiotherapy and five to ten years of endocrine tablets. Women whose tumours are larger, higher grade or have reached the lymph nodes face a higher risk of relapse: two to three years of a CDK4/6 inhibitor added to endocrine therapy cuts recurrence, and genomic tests such as Oncotype DX and MammaPrint decide who also needs chemotherapy.","summary":"High-risk early disease is defined clinically and genomically. monarchE took node-positive tumours with four or more nodes, or one to three nodes with grade 3, a tumour of 5 cm or more or Ki-67 of 20 percent or more; NATALEE widened the net to stage II and III disease including node-negative stage IIA tumours with high-risk features. Genomic assays sort the rest: TAILORx showed that women over 50 with node-negative tumours and an Oncotype DX recurrence score of 11 to 25 gain nothing from chemotherapy (nine-year invasive disease-free survival 83.3 percent without and 84.3 percent with), RxPONDER showed the same for postmenopausal women with one to three positive nodes and a score up to 25 while premenopausal women still benefited, and MINDACT showed that clinically high-risk tumours with a low MammaPrint score reach 94.7 percent five-year distant metastasis-free survival without chemotherapy.\n\nEndocrine therapy is the backbone. Five years of tamoxifen cuts recurrence and breast cancer death for at least fifteen years, aromatase inhibitors do slightly better in postmenopausal women, and the SOFT and TEXT trials showed that premenopausal women at higher risk do best with ovarian function suppression plus exemestane, with twelve-year disease-free survival of 80.5 percent against 75.9 percent for suppression plus tamoxifen; adding suppression to tamoxifen improved overall survival in the women who had needed chemotherapy. ATLAS and aTTom showed that ten years of tamoxifen beats five, and MA.17 that letrozole after five years of tamoxifen reduces late recurrence, so extended therapy to seven to ten years is offered in node-positive disease at the price of bone loss, joint pain and adherence that falls with every year.\n\nThe CDK4/6 inhibitors changed the adjuvant standard. monarchE randomised 5,637 women to two years of abemaciclib with endocrine therapy or endocrine therapy alone and cut invasive recurrence (hazard ratio 0.68), with the gap still widening at five years; NATALEE randomised 5,101 to three years of ribociclib with an aromatase inhibitor (hazard ratio 0.75) and won approval in September 2024. Palbociclib failed twice in the same setting (PALLAS, PENELOPE-B), a reminder that the class does not behave as one drug. Adjuvant olaparib for a year adds survival for germline BRCA carriers (OlympiA), adjuvant giredestrant improved invasive disease-free survival in lidERA in 2025, camizestrant switching is being tested in CAMBRIA, and circulating tumour DNA is being studied to find the women whose late relapse is coming.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Breast_cancer","links":[{"label":"TAILORx (NEJM 2018)","url":"https://doi.org/10.1056/NEJMoa1804710"},{"label":"monarchE (JCO 2020)","url":"https://doi.org/10.1200/JCO.20.02514"},{"label":"NATALEE (NEJM 2024)","url":"https://doi.org/10.1056/NEJMoa2305488"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Breast_cancer"}],"tags":["subtype-page"],"related":["hr-positive-metastatic-post-cdk46"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["penelope-b"],"people":[],"bottlenecks":[],"keyPapers":["paper-monarche-jco-2020","paper-natalee-nejm-2024","paper-olympia-nejm-2021","paper-tailorx-nejm-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Hormone receptor-positive, HER2-negative tumours are about seven in ten breast cancers and most are cured; the high-risk minority with node involvement, large size or high grade account for most of the relapses, which in this subtype can arrive ten or twenty years after diagnosis.","subtypes":["Luminal A-like, node-positive disease (genomic assay decides chemotherapy)","Luminal B-like disease with high grade or high Ki-67 (chemotherapy and CDK4/6 inhibitor candidates)","Node-positive disease with four or more nodes (monarchE population)","Stage II node-negative disease with high-risk features (NATALEE population)","Premenopausal disease (ovarian function suppression, SOFT and TEXT)","Late recurrence risk beyond five years (extended endocrine therapy)"],"biomarkers":["Oestrogen and progesterone receptor percentage","HER2-negative status (HER2-low noted for later lines)","Tumour grade and Ki-67","Nodal stage and tumour size (monarchE and NATALEE eligibility)","Oncotype DX recurrence score (TAILORx, RxPONDER)","MammaPrint 70-gene risk (MINDACT)","Menopausal status and oestradiol during ovarian suppression","Germline BRCA1 and BRCA2 (OlympiA eligibility)"],"standardOfCare":[{"setting":"Deciding on chemotherapy","approach":"Genomic assay on node-negative and one to three node-positive tumours; chemotherapy for a high recurrence score, for premenopausal women with node-positive disease and a score up to 25, and for clinically high-risk tumours without a low genomic score.","refs":["oncotype-dx","mammaprint","tailorx","rxponder","mindact"]},{"setting":"Endocrine therapy","approach":"Aromatase inhibitor for postmenopausal women; tamoxifen, or ovarian function suppression with an aromatase inhibitor for premenopausal women at higher risk (SOFT and TEXT); five years, extended to seven to ten in node-positive disease.","refs":["letrozole","exemestane","tamoxifen","goserelin","soft-text","endocrine-therapy"]},{"setting":"Adjuvant CDK4/6 inhibitor","approach":"Abemaciclib for two years (monarchE, node-positive high-risk disease) or ribociclib for three years (NATALEE, stage II to III) alongside the aromatase inhibitor.","refs":["abemaciclib","ribociclib","monarche","natalee","cdk46-inhibitor"]},{"setting":"Germline BRCA carriers","approach":"One year of adjuvant olaparib after chemotherapy for high-risk disease (OlympiA).","refs":["olaparib","olympia","germline-testing"]},{"setting":"Local therapy","approach":"Breast-conserving surgery with hypofractionated whole-breast radiotherapy or mastectomy, sentinel node biopsy, and regional nodal irradiation when nodes are involved.","refs":["lumpectomy","mastectomy","sentinel-node","hypofractionated-radiotherapy"]},{"setting":"Bone protection","approach":"Zoledronic acid or denosumab during aromatase inhibitor therapy in postmenopausal women reduces fractures, and bisphosphonates also reduce bone recurrence.","refs":["zoledronic-acid","denosumab"]}],"stateOfArt":["Two adjuvant CDK4/6 inhibitors, abemaciclib and ribociclib, are approved for high-risk disease on the strength of trials of more than five thousand women each.","Genomic assays have moved most node-negative and many node-positive postmenopausal women off chemotherapy without loss of cure.","Ovarian suppression with an aromatase inhibitor is the standard for higher-risk premenopausal women, and the POSITIVE study showed endocrine therapy can be paused safely to attempt pregnancy.","Oral oestrogen receptor degraders are entering the adjuvant setting after lidERA."],"history":[{"year":1977,"title":"Tamoxifen approved","refs":["tamoxifen"]},{"year":1998,"title":"EBCTCG overview: five years of tamoxifen cuts recurrence and death","refs":["tamoxifen"]},{"year":2004,"title":"MA.17: letrozole after five years of tamoxifen reduces late recurrence","refs":["letrozole"]},{"year":2013,"title":"ATLAS: ten years of tamoxifen beats five","refs":["tamoxifen"]},{"year":2014,"title":"SOFT and TEXT: ovarian suppression with exemestane in premenopausal women","refs":["soft-text","exemestane","goserelin"]},{"year":2016,"title":"MINDACT: genomic low-risk women can skip chemotherapy","refs":["mindact","mammaprint"]},{"year":2018,"title":"TAILORx: no chemotherapy benefit for intermediate recurrence scores","refs":["tailorx","oncotype-dx"]},{"year":2020,"title":"monarchE: adjuvant abemaciclib; RxPONDER in node-positive disease","refs":["monarche","abemaciclib","rxponder"]},{"year":2023,"title":"NATALEE: adjuvant ribociclib in stage II to III disease","refs":["natalee","ribociclib"]},{"year":2025,"title":"lidERA: adjuvant giredestrant improves invasive disease-free survival","refs":["lidera","giredestrant"]}],"pipeline":["lidera","cambria","nct03725059","giredestrant","camizestrant","liquid-biopsy","mrd-testing","artera-ai-breast"],"openProblems":["No test yet identifies the women whose relapse will come after ten years, when endocrine therapy has stopped.","Two to three years of a CDK4/6 inhibitor is costly and its overall survival benefit is not yet proven.","Adherence to endocrine therapy falls to about half by five years because of joint pain, hot flushes and sexual side effects.","Premenopausal women with node-positive disease still gain from chemotherapy in RxPONDER, and whether ovarian suppression could replace it is unanswered."],"parent":"breast-hr-positive"},{"id":"high-risk-gtn","kind":"cancer","name":"High-risk gestational trophoblastic neoplasia (FIGO score 7 or more, including ultra-high-risk)","aka":["High-risk GTN","Metastatic gestational choriocarcinoma","Ultra-high-risk gestational trophoblastic neoplasia (score 13 or more)","Choriocarcinoma after term pregnancy"],"tldr":"High-risk gestational trophoblastic neoplasia is the aggressive form of this pregnancy-related cancer, usually choriocarcinoma that has spread to the lungs, liver or brain and produces very high hCG. It is treated with the multi-drug EMA-CO regimen, started gently in the sickest women to avoid early deaths, and most are cured; resistant disease gets platinum regimens, immunotherapy or surgery.","summary":"High-risk gestational trophoblastic neoplasia, a FIGO 2000 score of 7 or more, is usually gestational choriocarcinoma, a tumour of syncytiotrophoblast and cytotrophoblast that follows a molar, term, miscarried or ectopic pregnancy and spreads through the blood to the lungs, vagina, liver and brain; it bleeds readily and produces enormous amounts of hCG. Choriocarcinoma after a term pregnancy is often diagnosed late because nobody suspects it, and any woman of reproductive age with unexplained metastases should have an hCG measured. Multi-agent chemotherapy became standard in the 1980s when Kenneth Bagshawe's group at Charing Cross developed EMA-CO (etoposide, methotrexate and actinomycin D alternating weekly with cyclophosphamide and vincristine), which cures more than nine in ten women with high-risk disease and remains the first-line regimen in the NCCN and FIGO guidelines.\n\nThe main causes of death are early haemorrhage and organ failure in women with very high tumour burden, and late resistance. For ultra-high-risk disease (score 13 or more, or liver or brain metastases) the Charing Cross and Sheffield centres showed that starting with one or two cycles of low-dose etoposide and cisplatin before EMA-CO prevents the early deaths caused by tumour breakdown and haemorrhage, and brain metastases are treated with higher-dose intrathecal or systemic methotrexate with or without radiotherapy or surgery. Women whose hCG plateaus on EMA-CO switch to EP-EMA (etoposide and cisplatin alternating with EMA) or to TP/TE (paclitaxel with cisplatin alternating with paclitaxel and etoposide), which cure most of the remainder; hysterectomy, lung resection or excision of a resistant focus localised by PET can remove the last chemoresistant deposit, and high-dose chemotherapy with autologous stem cell rescue has cured a few. Because trophoblast expresses PD-L1, pembrolizumab produced durable remissions in women with multiply resistant disease in the first case series (Lancet 2017), and avelumab and pembrolizumab are now tested as salvage and as first-line partners. hCG follow-up runs for at least a year, often longer, before pregnancy is allowed, and late effects of etoposide, including a small excess of leukaemia, are monitored.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Choriocarcinoma","links":[{"label":"FIGO cancer report: gestational trophoblastic disease (2021)","url":"https://doi.org/10.1002/ijgo.13877"},{"label":"NCCN Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Choriocarcinoma"}],"tags":["subtype-page","gynaecologic"],"related":["low-risk-gtn","placental-site-trophoblastic-tumour","gestational-trophoblastic","non-seminoma"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","checkpoint-inhibitor","ultrasound","mri","ct","pet-ct","imrt-igrt","sbrt","autologous-stem-cell-transplant","serum-tumour-markers"],"targets":["pdl1","pd1"],"drugs":["etoposide","methotrexate","dactinomycin","cyclophosphamide","vincristine","cisplatin","paclitaxel","pembrolizumab","avelumab"],"companies":[],"institutions":[],"pathways":[],"terms":["tumour-markers","staging-systems"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bower-ema-co-high-risk-gtn-charing-cross-jco-1997","paper-figo-cancer-report-gestational-trophoblastic-disease-ijgo-2021","paper-figo-2000-staging-gestational-trophoblastic-neoplasia-ijgo-2002"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"A minority of gestational trophoblastic neoplasia, often choriocarcinoma after a non-molar pregnancy with metastases to lung, liver or brain and very high hCG; cure rates still exceed nine in ten with multi-agent chemotherapy.","subtypes":["High-risk gestational choriocarcinoma with lung metastases (FIGO score 7 to 12)","Ultra-high-risk gestational trophoblastic neoplasia (score 13 or more; induction low-dose etoposide-cisplatin)","Gestational trophoblastic neoplasia with liver metastases","Gestational trophoblastic neoplasia with brain metastases (high-dose methotrexate, radiotherapy or surgery)","Choriocarcinoma after term pregnancy or miscarriage (late diagnosis)","EMA-CO-resistant gestational trophoblastic neoplasia (EP-EMA, TP/TE, pembrolizumab, surgery)"],"biomarkers":["Serum hCG (very high; response and surveillance)","FIGO 2000 score (7 or more high risk; 13 or more ultra-high risk)","Sites of metastasis on CT, MRI of brain and pelvic ultrasound (liver and brain define ultra-high risk)","Cerebrospinal fluid to serum hCG ratio (brain involvement)","Genotyping to confirm gestational origin and identify the causative pregnancy","PD-L1 expression (universal; checkpoint inhibitor rationale)"],"standardOfCare":[{"setting":"Staging","approach":"hCG, chest CT, brain MRI, abdominal imaging, pelvic Doppler ultrasound and FIGO scoring; genotyping where the antecedent pregnancy is unclear.","refs":["ct","mri","ultrasound","tumour-markers","staging-systems"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}},{"setting":"High-risk disease, first line","approach":"EMA-CO (etoposide, methotrexate, actinomycin D alternating with cyclophosphamide and vincristine) until hCG normalises plus at least three consolidation cycles.","refs":["etoposide","methotrexate","dactinomycin","cyclophosphamide","vincristine","cytotoxic-chemotherapy"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}},{"setting":"Ultra-high-risk disease","approach":"Induction low-dose etoposide and cisplatin for one to three cycles before EMA-CO to prevent early death from haemorrhage and organ failure.","refs":["etoposide","cisplatin"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}},{"setting":"Brain metastases","approach":"High-dose systemic and intrathecal methotrexate within EMA-CO, with whole-brain or stereotactic radiotherapy or craniotomy for bleeding or single lesions.","refs":["methotrexate","imrt-igrt","sbrt"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}},{"setting":"Resistant or relapsed disease","approach":"EP-EMA or TP/TE; resection of a resistant focus (hysterectomy, lung wedge); pembrolizumab or avelumab; high-dose chemotherapy with autologous rescue in exceptional cases.","refs":["etoposide","cisplatin","paclitaxel","pembrolizumab","avelumab","autologous-stem-cell-transplant","pet-ct"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}}],"stateOfArt":["EMA-CO cures more than nine in ten women with high-risk disease.","Low-dose induction chemotherapy has largely eliminated early deaths in ultra-high-risk disease.","PD-1 and PD-L1 antibodies rescue women with multiply resistant disease."],"history":[{"year":1956,"title":"Methotrexate cures metastatic choriocarcinoma at the NCI","refs":["methotrexate"]},{"year":1976,"title":"Bagshawe develops the first prognostic scoring system at Charing Cross","refs":["staging-systems"]},{"year":1986,"title":"EMA-CO reported as a regimen for high-risk disease","refs":["etoposide","methotrexate","dactinomycin","cyclophosphamide","vincristine"]},{"year":2000,"title":"FIGO combines anatomical stage and prognostic score","refs":["staging-systems"]},{"year":2013,"title":"Low-dose induction etoposide-cisplatin shown to reduce early deaths in ultra-high-risk disease","refs":["etoposide","cisplatin"]},{"year":2017,"title":"Pembrolizumab produces durable remissions in chemoresistant gestational trophoblastic neoplasia","refs":["pembrolizumab"]}],"pipeline":["pembrolizumab","avelumab"],"openProblems":["EMA-CO has never been tested against any other regimen in a randomised trial.","Late diagnosis of choriocarcinoma after term pregnancy still costs lives.","Etoposide raises the long-term risk of leukaemia and its dose cannot easily be reduced.","Where checkpoint inhibitors belong in the sequence is being worked out from small series."],"parent":"gestational-trophoblastic"},{"id":"neuroblastoma-high-risk","kind":"cancer","name":"High-risk neuroblastoma","aka":["INRG high-risk neuroblastoma","Metastatic neuroblastoma","MYCN-amplified neuroblastoma","Stage 4 neuroblastoma"],"tldr":"High-risk neuroblastoma has spread widely in a child over 18 months old or carries extra copies of the MYCN gene. Treatment lasts about 18 months and uses every tool: chemotherapy, surgery, high-dose chemotherapy with stem cell rescue, radiotherapy, and the anti-GD2 antibody dinutuximab, which raised survival in ANBL0032; eflornithine, given afterwards, was approved in 2023 to lower relapse.","summary":"High-risk disease is stage M neuroblastoma in a child over 18 months, MYCN-amplified disease at any age and stage, and a few L2 and infant M cases with unfavourable genetics. Treatment runs in blocks. Induction with five or six cycles (cyclophosphamide and topotecan, cisplatin and etoposide, cyclophosphamide with doxorubicin and vincristine in the COG regimen; rapid COJEC in Europe) brings most children to a partial response and clears the marrow; surgery removes the primary; consolidation with myeloablative chemotherapy and autologous stem cell rescue follows; radiotherapy to the primary site and residual metastases; then post-consolidation immunotherapy with an anti-GD2 antibody and isotretinoin for six months. CCG-3891, reported in 1999, established both myeloablative therapy with autologous marrow rescue and 13-cis-retinoic acid maintenance: three-year event-free survival 34 percent against 22 percent with transplant, and 46 percent against 29 percent with retinoic acid.\n\nANBL0032 randomised 226 children after transplant to isotretinoin alone or with the chimeric anti-GD2 antibody ch14.18 (dinutuximab), GM-CSF and interleukin-2: two-year event-free survival 66 percent against 46 percent and overall survival 86 percent against 75 percent, and dinutuximab was approved in March 2015. SIOPEN HR-NBL1 showed that busulfan and melphalan beat carboplatin, etoposide and melphalan as the myeloablative regimen, three-year event-free survival 50 percent against 38 percent, and that adding interleukin-2 to dinutuximab beta brought toxicity without benefit. COG ANBL0532 showed tandem transplant with thiotepa-cyclophosphamide then carboplatin-etoposide-melphalan beat a single transplant, three-year event-free survival 61.6 percent against 48.4 percent. Eflornithine (DFMO), an ornithine decarboxylase inhibitor that lowers MYCN-driven polyamine synthesis, was approved in December 2023 as two years of maintenance after immunotherapy on the basis of the NMTRC003 and 003B single-arm studies compared with matched ANBL0032 controls, the first approval in neuroblastoma on an external control. Naxitamab, a humanised anti-GD2 antibody given with GM-CSF, was granted accelerated approval in November 2020 for relapsed or refractory disease in bone or marrow.\n\nAbout half of children still relapse, and relapsed high-risk disease is rarely cured. Irinotecan and temozolomide with dinutuximab (ANBL1221) is the standard relapse chemo-immunotherapy; iodine-131 MIBG delivers targeted radiation to the roughly 90 percent of tumours that take up the tracer and is being tested in induction in ANBL1531, which also gives lorlatinib to the roughly one in ten children whose tumours carry an ALK mutation after the NANT phase 1 showed responses in relapsed ALK-mutant disease. GD2 CAR T-cells produced remissions in relapsed children in the Bambino Gesù phase 1/2 trial reported in 2023, anti-GD2 antibody is being moved into induction alongside chemotherapy, and fluorine-18 MFBG PET may replace MIBG scans. The survivors carry the heaviest late-effect burden in childhood oncology: cisplatin hearing loss in most, infertility, growth failure, cardiac and renal damage, and second cancers.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Neuroblastoma","links":[{"label":"Wikipedia: Neuroblastoma","url":"https://en.wikipedia.org/wiki/Neuroblastoma"},{"label":"NCI PDQ: Neuroblastoma Treatment","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}],"tags":["subtype-page","paediatric"],"related":["neuroblastoma-low-risk","neuroblastoma-intermediate-risk"],"cancers":[],"sections":[],"technologies":["monoclonal-antibody","autologous-stem-cell-transplant","tandem-transplant","mibg-theranostics","car-t"],"targets":["gd2","alk"],"drugs":["isotretinoin"],"companies":["y-mabs","united-therapeutics","us-worldmeds","childrens-oncology-group"],"institutions":["siop-europe"],"pathways":[],"terms":["mycn-amplification","inrg-staging","late-effects","adcc","segmental-chromosomal-aberrations","urinary-catecholamines","curie-siopen-score"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-inrg-cohn-jco-2009","paper-yu-anti-gd2-neuroblastoma-nejm-2010","paper-hr-nbl1-busulfan-melphalan-ladenstein-lancet-oncol-2017","paper-anbl0532-tandem-transplant-park-jama-2019"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About half of children with neuroblastoma have high-risk disease, metastatic at over 18 months of age or MYCN-amplified at any age; it accounts for around one in eight childhood cancer deaths, and only about half of children are cured despite the most intensive treatment given to any child.","subtypes":["Stage M neuroblastoma over 18 months without MYCN amplification","MYCN-amplified neuroblastoma at any age or stage (about a fifth of all neuroblastoma)","ALK-mutated or ALK-amplified high-risk neuroblastoma (lorlatinib added in ANBL1531)","Ultra-high-risk neuroblastoma (poor end-of-induction response, or MYCN amplification with ALK or TERT alterations)","Relapsed or refractory high-risk neuroblastoma (MIBG-avid and MIBG-non-avid; bone and marrow versus soft tissue)","Adolescent and adult neuroblastoma (indolent, chemotherapy-resistant; ALK and ATRX alterations)"],"biomarkers":["MYCN amplification","ALK mutation or amplification","11q loss, 1p loss and 17q gain","TERT rearrangement and ATRX loss (telomere maintenance)","MIBG avidity and Curie or SIOPEN score","End-of-induction response (INRC)","Marrow minimal residual disease by GD2 synthase or PHOX2B PCR","Urinary catecholamine metabolites"],"standardOfCare":[{"setting":"Induction","approach":"Five or six cycles of cyclophosphamide-topotecan, cisplatin-etoposide and cyclophosphamide-doxorubicin-vincristine (COG) or rapid COJEC (SIOPEN); iodine-131 MIBG and, for ALK-mutant disease, lorlatinib within ANBL1531; surgery after induction.","refs":["cyclophosphamide","topotecan","cisplatin","etoposide","doxorubicin","vincristine","anbl1531","i131-mibg","lorlatinib","mibg-theranostics"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}},{"setting":"Consolidation","approach":"Busulfan-melphalan (HR-NBL1) or tandem thiotepa-cyclophosphamide then carboplatin-etoposide-melphalan (ANBL0532) with autologous stem cell rescue.","refs":["busulfan","melphalan","thiotepa","carboplatin","etoposide","autologous-stem-cell-transplant","tandem-transplant","anbl0532","hr-nbl1"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}},{"setting":"Local control","approach":"Radiotherapy to the primary site bed and residual MIBG-avid metastases after transplant.","refs":["imrt-igrt","proton-therapy"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}},{"setting":"Post-consolidation","approach":"Dinutuximab with GM-CSF and isotretinoin for five cycles (ANBL0032; interleukin-2 dropped after HR-NBL1), then two years of eflornithine maintenance.","refs":["dinutuximab","sargramostim","aldesleukin","anbl0032","il2-anti-gd2-caution","eflornithine","nmtrc003"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}},{"setting":"Relapsed or refractory","approach":"Irinotecan-temozolomide with dinutuximab (ANBL1221) or naxitamab with GM-CSF; iodine-131 MIBG for avid disease; lorlatinib for ALK-mutant disease; GD2 CAR T-cells in trials.","refs":["dinutuximab","irinotecan","temozolomide","anti-gd2-plus-chemo-relapse","naxitamab","naxitamab-201","i131-mibg","lorlatinib","gd2-cart01","anbl1221"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}},{"setting":"Survivorship","approach":"Hearing, cardiac, renal, endocrine, fertility and second-cancer follow-up for life.","refs":["cardio-oncology","late-effects","fertility-preservation"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}}],"stateOfArt":["Anti-GD2 immunotherapy after transplant raised two-year event-free survival from 46 to 66 percent in ANBL0032 and is standard worldwide.","Tandem transplant (ANBL0532) and busulfan-melphalan (HR-NBL1) each beat the older single-transplant regimens.","Eflornithine maintenance, approved in 2023 on an external-control comparison, and lorlatinib for ALK-mutant disease are the newest additions; GD2 CAR T-cells have produced remissions in relapse."],"history":[{"year":1985,"title":"Iodine-131 MIBG therapy first given for neuroblastoma","refs":["i131-mibg","mibg-theranostics"]},{"year":1999,"title":"CCG-3891: myeloablative therapy with autologous rescue and 13-cis-retinoic acid each improve event-free survival","refs":["autologous-stem-cell-transplant"]},{"year":2010,"title":"ANBL0032: anti-GD2 antibody with GM-CSF and interleukin-2 raises two-year event-free survival from 46 to 66 percent","refs":["anbl0032","dinutuximab"]},{"year":2015,"title":"Dinutuximab approved for high-risk neuroblastoma","refs":["dinutuximab"]},{"year":2017,"title":"HR-NBL1: busulfan-melphalan beats carboplatin-etoposide-melphalan","refs":["hr-nbl1","busulfan","melphalan"]},{"year":2019,"title":"ANBL0532: tandem transplant beats single transplant","refs":["anbl0532","tandem-transplant"]},{"year":2020,"title":"Naxitamab granted accelerated approval for relapsed or refractory bone or marrow disease","refs":["naxitamab","naxitamab-201"]},{"year":2023,"title":"Eflornithine approved as maintenance on an external-control comparison; GD2 CAR T-cells produce remissions in relapsed disease","refs":["eflornithine","nmtrc003","gd2-cart01"]}],"pipeline":["anbl1531","i131-mibg","lorlatinib","gd2-cart01","idea-gd2-car-t-frontline-consolidation","idea-mfbg-pet-replaces-mibg","mibg-theranostics","eflornithine","naxitamab","anti-gd2-plus-chemo-relapse","tandem-transplant"],"openProblems":["About half of children relapse and relapsed disease is rarely cured.","MYCN has no direct inhibitor; eflornithine and lorlatinib act around it.","Cisplatin hearing loss, infertility and second cancers in survivors of the most intensive regimen in paediatric oncology."],"parent":"neuroblastoma"},{"id":"mds-higher-risk","kind":"cancer","name":"Higher-risk myelodysplastic syndromes","aka":["High-risk MDS","IPSS-R high and very high MDS","MDS with increased blasts","Higher-risk myelodysplastic neoplasms"],"tldr":"Higher-risk myelodysplastic syndromes behave like a slow leukaemia and often become one. Azacitidine lengthens life and a donor stem cell transplant is the only cure; every attempt to improve on azacitidine in a large trial, including the venetoclax combination tested in VERONA, has so far failed.","summary":"Higher-risk disease is IPSS-R above 3.5 (intermediate with adverse features, high and very high) or IPSS-M moderate-high and above: excess blasts (5 to 19 percent), adverse cytogenetics including complex karyotype and chromosome 7 loss, deep cytopenias and mutations such as TP53, ASXL1, RUNX1 and EZH2. Multi-hit TP53 disease is the worst group and is now classified separately by both WHO and ICC. The goal shifts from managing cytopenias to changing the natural history, and the first question at diagnosis is whether the patient can reach an allogeneic transplant.\n\nAzacitidine is the standard for those who cannot: AZA-001 (2009) showed median survival of 24.5 months against 15 months with conventional care, the first drug to lengthen life in MDS, and decitabine and the oral decitabine-cedazuridine combination (2020) are equivalents. For fit patients up to about 75, allogeneic transplant is the only cure; the BMT CTN 1102 donor-versus-no-donor study (2021) found three-year survival of 47.9 percent with a donor against 26.6 percent without, and most centres give hypomethylating therapy to bridge and debulk before transplant. Relapse after transplant remains common in TP53-mutated disease.\n\nThe failures are as important as the standards. Adding venetoclax to azacitidine produced high response rates in phase 1b but VERONA, the phase 3, did not lengthen survival when it reported in 2024 and 2025; magrolimab (ENHANCE) stopped for futility in 2023, sabatolimab (STIMULUS-MDS2) and pevonedistat (PANTHER) were negative, and eprenetapopt failed in TP53-mutated disease. Hypomethylating agents plus a partner remain unproven, and trials now test menin inhibitors for KMT2A- or NPM1-driven disease, IDH inhibitors, post-transplant maintenance and better conditioning to reduce relapse.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Myelodysplastic_syndrome","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Myelodysplastic_syndrome"},{"label":"NCCN Guidelines: Myelodysplastic Syndromes","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}],"tags":["subtype-page"],"related":["mds-lower-risk"],"cancers":[],"sections":[],"technologies":["allogeneic-hsct","cd47-blockade","tim3-blockade"],"targets":["tp53","cd47","tim3"],"drugs":["pevonedistat"],"companies":[],"institutions":[],"pathways":[],"terms":["hma","tp53-mutated","staging-systems","allogeneic-transplant","conditioning-regimen","ipss-m-ipss-r"],"trials":["verona","aza-001"],"people":[],"bottlenecks":[],"keyPapers":["paper-aza-001-fenaux-lancet-oncol-2009","paper-ipss-m-bernard-nejm-evidence-2022","paper-who-2022-myeloid-khoury-leukemia-2022","paper-icc-2022-arber-blood-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About a third of myelodysplastic syndromes are higher risk; without treatment median survival is around a year and a half or less, and most progress to acute myeloid leukaemia.","subtypes":["MDS with increased blasts (IB1, 5 to 9 percent; IB2, 10 to 19 percent)","MDS with biallelic (multi-hit) TP53 inactivation","MDS with complex or monosomal karyotype","Therapy-related higher-risk MDS","Higher-risk MDS eligible for allogeneic transplant","Higher-risk MDS in patients unfit for transplant"],"biomarkers":["IPSS-R and IPSS-M scores","Marrow blast percentage","Karyotype: complex, monosomy 7, del(7q)","TP53 mutation and allelic state","ASXL1, RUNX1, EZH2 and spliceosome mutations","Donor availability and HCT comorbidity index","Measurable residual disease before and after transplant"],"standardOfCare":[{"setting":"Transplant candidate","approach":"Allogeneic stem cell transplant after donor search, usually with azacitidine or decitabine to bridge and reduce blasts; reduced-intensity conditioning in older patients.","refs":["allogeneic-hsct","azacitidine","decitabine","conditioning-regimen","nct07216443"],"guideline":{"version":"NCCN Guidelines: Myelodysplastic Syndromes","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}},{"setting":"Not a transplant candidate","approach":"Azacitidine (AZA-001) or decitabine, or oral decitabine-cedazuridine, continued until progression; trials of hypomethylating agent combinations.","refs":["azacitidine","decitabine","decitabine-cedazuridine","hma","nct05883956"],"guideline":{"version":"NCCN Guidelines: Myelodysplastic Syndromes","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}},{"setting":"Failure of hypomethylating therapy","approach":"Clinical trial; venetoclax combinations off-label in selected patients; genotype-directed drugs where IDH, FLT3 or KMT2A targets exist; best supportive care.","refs":["venetoclax","ivosidenib","revumenib","transfusion-support","nct05732103"],"guideline":{"version":"NCCN Guidelines: Myelodysplastic Syndromes","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}}],"stateOfArt":["Azacitidine remains the only drug shown to lengthen life without transplant, fifteen years after AZA-001.","Allogeneic transplant doubles three-year survival for patients who can reach it.","Every phase 3 add-on to azacitidine, including venetoclax in VERONA, magrolimab and sabatolimab, has failed."],"history":[{"year":2004,"title":"Azacitidine approved for MDS in the United States","refs":["azacitidine"]},{"year":2009,"title":"AZA-001: azacitidine lengthens survival in higher-risk MDS","refs":["azacitidine"]},{"year":2020,"title":"Oral decitabine-cedazuridine approved","refs":["decitabine-cedazuridine"]},{"year":2021,"title":"BMT CTN 1102: transplant improves survival in 50 to 75 year olds","refs":["allogeneic-hsct"]},{"year":2023,"title":"Magrolimab and sabatolimab combinations fail","refs":["magrolimab","sabatolimab"]},{"year":2024,"title":"VERONA: venetoclax plus azacitidine does not lengthen life","refs":["venetoclax","azacitidine"]}],"pipeline":["allogeneic-hsct","venetoclax","revumenib","tuspetinib","nct05732103","nct07216443","tregzi"],"openProblems":["Nothing has beaten azacitidine alone in a phase 3 trial.","TP53 multi-hit disease relapses after transplant and responds to no drug durably.","Post-transplant maintenance to prevent relapse is unproven."],"parent":"mds"},{"id":"hiv-associated-lymphoma","kind":"cancer","name":"HIV-associated (AIDS-related) lymphomas","aka":["AIDS-related lymphoma","ARL","Primary effusion lymphoma","Plasmablastic lymphoma","HIV-associated Hodgkin lymphoma"],"tldr":"People living with HIV have a raised risk of aggressive lymphomas, driven by immune suppression and viruses such as Epstein-Barr virus. The transformation of the last two decades is that, with antiretroviral therapy continued through treatment, these lymphomas are treated with the same full-dose chemotherapy and antibody regimens as in anyone else, with similar chances of cure.","summary":"HIV-associated lymphomas are mostly aggressive B-cell lymphomas: diffuse large B-cell lymphoma (including immunoblastic and CNS variants), Burkitt lymphoma, and two entities almost specific to immunosuppression, primary effusion lymphoma (HHV-8-driven, presenting as effusions without a mass) and plasmablastic lymphoma (EBV-associated, often oral). Primary CNS lymphoma in HIV is uniformly EBV-positive and occurs at very low CD4 counts. Classical Hodgkin lymphoma is also several-fold more common in people with HIV and, unlike NHL, its incidence has not declined with antiretroviral therapy. Pathogenesis combines loss of immune surveillance of EBV and HHV-8, chronic B-cell activation, and the same oncogenic events seen in immunocompetent patients (MYC translocations in Burkitt, BCL6 rearrangements).\n\nThe pre-1996 approach of dose-reduced chemotherapy has been replaced by full-dose, curative-intent therapy alongside antiretroviral therapy, with attention to drug interactions (ritonavir- and cobicistat-boosted regimens interfere with vinca alkaloids and other agents) and infection prophylaxis. The AIDS Malignancy Consortium (AMC) trials established that rituximab is safe and beneficial when CD4 counts exceed 50 cells per microlitre (AMC 034), that R-CHOP or dose-adjusted EPOCH-R cures HIV-associated DLBCL at rates approaching those in HIV-negative patients, and that intensive Burkitt regimens or DA-EPOCH-R are effective in HIV-associated Burkitt lymphoma. Autologous transplant for relapse is feasible (BMT CTN 0803 / AMC 071), and CAR-T therapy has been given safely to people with HIV in case series and is now permitted in most CAR-T trials, reversing decades of routine exclusion. Hodgkin lymphoma is treated with ABVD or brentuximab-based regimens as in the general population.\n\nThe open fronts are HHV-8-driven disease (primary effusion lymphoma and multicentric Castleman disease, where response to standard chemotherapy is poor and pomalidomide and anti-IL-6 approaches are studied), the plasmablastic lymphoma subset (bortezomib-containing regimens, daratumumab), CNS lymphoma at low CD4 counts, and access in sub-Saharan Africa where most HIV-associated lymphoma now occurs.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/AIDS-related_lymphoma","links":[{"label":"NCI PDQ: AIDS-related lymphoma","url":"https://www.cancer.gov/types/lymphoma/patient/aids-related-treatment-pdq"},{"label":"AMC 034: rituximab plus EPOCH in HIV-associated lymphoma (Blood 2010)","url":"https://doi.org/10.1182/blood-2009-08-231613"},{"label":"NCCN: B-Cell Lymphomas (AIDS-related)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1480"},{"label":"AIDS Malignancy Consortium","url":"https://amcoperations.com/"}],"tags":["nci-coverage","rare","haematologic","virus-associated"],"related":["dlbcl","burkitt-lymphoma","primary-cns-lymphoma","hodgkin-lymphoma","kaposi-sarcoma","post-transplant-lymphoproliferative-disorder"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","monoclonal-antibody","car-t","autologous-stem-cell-transplant","bispecific-antibody","global-oncology-access"],"targets":["cd20","cd19","cd30","cd38"],"drugs":["rituximab","cyclophosphamide","doxorubicin","vincristine","etoposide","methotrexate","bortezomib","daratumumab","pomalidomide","brentuximab-vedotin","axicabtagene-ciloleucel","glofitamab","epcoritamab"],"companies":[],"institutions":[],"pathways":["oncogenic-viruses","myc","antigen-presentation-immunoediting"],"terms":["ebv-term","double-hit-lymphoma","cell-of-origin","intrathecal-therapy","hhv8-kshv"],"trials":[],"people":[],"bottlenecks":["b-trial-diversity","b-global-access"],"keyPapers":["paper-sparano-blood"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Lymphoma is the most common AIDS-defining cancer in the antiretroviral era; incidence has fallen many-fold since 1996 but remains several times higher than in the general population, and Hodgkin lymphoma incidence in people with HIV has not fallen (NCI; CDC).","subtypes":["Diffuse large B-cell lymphoma (including immunoblastic)","Burkitt lymphoma","Primary effusion lymphoma (HHV-8)","Plasmablastic lymphoma (EBV, MYC)","Primary CNS lymphoma in HIV (EBV-positive)","Classical Hodgkin lymphoma in HIV","Polymorphic lymphoproliferative disorders resembling PTLD"],"biomarkers":["CD4 count and HIV viral load at diagnosis","EBV (EBER) and HHV-8 (LANA) in tumour tissue","CD20 expression (rituximab eligibility; absent in plasmablastic and often in PEL)","MYC, BCL2, BCL6 rearrangements (Burkitt vs double-hit)","CSF EBV DNA and cytology (CNS involvement)","Antiretroviral regimen and interaction profile"],"standardOfCare":[{"setting":"HIV-associated DLBCL","approach":"R-CHOP or dose-adjusted EPOCH-R at full dose with concurrent antiretroviral therapy (avoiding boosted protease inhibitors or cobicistat where possible), G-CSF support and opportunistic-infection prophylaxis; CNS prophylaxis by risk.","refs":["rituximab","cyclophosphamide","doxorubicin","vincristine","etoposide","g-csf-growth-factors"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: B-Cell Lymphomas (AIDS-related B-cell lymphomas); AMC 034 (Blood 2010)","url":"https://doi.org/10.1182/blood-2009-08-231613"}},{"setting":"HIV-associated Burkitt lymphoma","approach":"Intensive Burkitt regimens (CODOX-M/IVAC with rituximab) in fit patients, or DA-EPOCH-R (low-intensity variant studied in HIV); intrathecal prophylaxis.","refs":["rituximab","methotrexate","cyclophosphamide","etoposide"],"guideline":{"version":"NCCN Guidelines: B-Cell Lymphomas"}},{"setting":"Primary effusion and plasmablastic lymphoma","approach":"CHOP or EPOCH-based chemotherapy with antiretroviral therapy; bortezomib-containing regimens for plasmablastic; clinical trials (pomalidomide, daratumumab, anti-IL-6).","refs":["bortezomib","daratumumab","pomalidomide","etoposide"]},{"setting":"Relapsed or refractory","approach":"Salvage chemotherapy and autologous transplant (feasible with controlled HIV; BMT CTN 0803); CD19 CAR-T on the same criteria as HIV-negative patients; bispecific antibodies emerging.","refs":["autologous-stem-cell-transplant","axicabtagene-ciloleucel","car-t","glofitamab","epcoritamab","bmt-ctn-0803"]},{"setting":"HIV-associated Hodgkin lymphoma","approach":"ABVD or brentuximab-based regimens as for the general population, with antiretroviral therapy.","refs":["brentuximab-vedotin","doxorubicin","bleomycin"]}],"stateOfArt":["Full-dose immunochemotherapy with antiretroviral therapy gives cure rates approaching those in HIV-negative patients; the era of dose reduction is over.","Rituximab, once feared for infection risk, is standard when CD4 counts exceed 50, on the basis of AMC 034.","Autologous transplant and CAR-T are feasible in people with HIV; the NCI and FDA have pushed to end blanket exclusion of people with HIV from cancer trials.","The unsolved entities are HHV-8-driven and plasmablastic lymphomas and CNS lymphoma at very low CD4 counts; the AMC runs dedicated trials."],"history":[{"year":1982,"title":"Lymphoma recognised as an AIDS-defining illness","note":"Aggressive B-cell lymphoma in young men with AIDS reported; added to the CDC case definition in 1985.","refs":[]},{"year":1989,"title":"HHV-8 and EBV linked to AIDS lymphomas","note":"EBV in CNS lymphoma; HHV-8 (KSHV) identified in 1994 and linked to primary effusion lymphoma in 1995.","refs":["ebv-term"]},{"year":1996,"title":"Combination antiretroviral therapy","note":"Incidence of AIDS-related NHL falls sharply; survival after lymphoma improves as immune function is preserved.","refs":[]},{"year":2005,"title":"Rituximab controversy","note":"AMC 010 shows excess infection deaths with rituximab at very low CD4; later analyses restrict the risk to CD4 under 50.","refs":["rituximab"]},{"year":2010,"title":"AMC 034: rituximab with EPOCH is safe and effective","note":"Sparano and colleagues (Blood 2010) establish concurrent R-EPOCH.","refs":["rituximab","etoposide"]},{"year":2019,"title":"Autologous transplant in HIV lymphoma (BMT CTN 0803 / AMC 071)","note":"Outcomes comparable to HIV-negative controls.","refs":["autologous-stem-cell-transplant"]},{"year":2021,"title":"CAR-T therapy in people with HIV","note":"Case series and the AMC-sponsored study show safety; trial eligibility broadened.","refs":["car-t"]}],"pipeline":["car-t","glofitamab","epcoritamab","daratumumab","pomalidomide"],"openProblems":["Primary effusion lymphoma and multicentric Castleman disease respond poorly to chemotherapy; pomalidomide, anti-IL-6 and HHV-8-directed approaches are in AMC trials.","Plasmablastic lymphoma lacks CD20 and relapses early; bortezomib and daratumumab combinations are being tested.","CNS lymphoma at low CD4 counts remains hard to cure; high-dose methotrexate with antiretroviral therapy is now the approach rather than radiotherapy alone.","Most HIV-associated lymphoma now occurs in sub-Saharan Africa with limited access to rituximab, pathology and supportive care; global oncology programmes are the response."],"parent":"non-hodgkin-lymphoma"},{"id":"hodgkin-lymphoma","kind":"cancer","name":"Hodgkin lymphoma","aka":[],"tldr":"Hodgkin lymphoma is one of the most curable cancers, where the goal is now to cure with less toxicity, using brentuximab and, from 2026, first-line nivolumab.","summary":"Classical Hodgkin lymphoma is a B-cell cancer in which rare, giant Reed-Sternberg cells (about 1% of the mass) recruit an inflammatory microenvironment and hide behind amplified PD-L1. It peaks in young adults and again after 55, is staged with PET-CT and the Lugano system, and is cured in more than 85% of patients overall and in over 90% of early-stage disease. Because most patients are young and will live for decades, the field's defining problem is not cure but the cost of cure: anthracycline heart disease, bleomycin lung injury, infertility, and second cancers from alkylators and radiation.\n\nThat is why Hodgkin lymphoma pioneered response-adapted therapy. Interim PET after two cycles (Deauville score) steers de-escalation (drop bleomycin after negative PET2 in RATHL; omit radiotherapy in early stage in HD16/HD17/RAPID at a small PFS cost) or escalation to BEACOPP-type regimens. Two ADC- and immunotherapy-based regimens then replaced ABVD for advanced disease: brentuximab vedotin-AVD (ECHELON-1, overall survival benefit) and, from March 2026, nivolumab-AVD (SWOG S1826, PFS HR 0.45 versus BV-AVD, neuropathy halved, children and adults together). In Europe, GHSG HD21's PET-guided BrECADD matches escalated BEACOPP's ~94% PFS with far less toxicity. Relapse is treated with PD-1 blockade (pembrolizumab beat brentuximab in KEYNOTE-204), brentuximab, salvage chemotherapy and autologous transplant, with brentuximab consolidation for high-risk patients (AETHERA); allogeneic transplant and CD30 CAR-T are options for the few who fail everything.\n\nThe next questions are how far chemotherapy can be removed. AHOD2131 tests brentuximab-nivolumab in early-stage disease across children and adults; ctDNA may replace PET for steering; older patients, who have half the cure rate of young ones, need regimens they can tolerate (nivolumab-AVD, brentuximab-based). Survivorship care for the tens of thousands cured decades ago, and the shift from radiotherapy to systemic de-escalation, remain the field's distinctive concerns.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Hodgkin_lymphoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Hodgkin_lymphoma"},{"label":"Lymphoma Action: helpline services","url":"https://lymphoma-action.org.uk/information-and-support/support-you/helpline-services"},{"label":"Lymphoma Action: questions to ask your medical team about lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/questions-ask-your-medical-team-about-lymphoma"},{"label":"Lymphoma Action: follow-up after lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/follow-after-lymphoma-treatment"},{"label":"Lymphoma Action: infections, risk and prevention","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/infections-risk-and-prevention"},{"label":"Lymphoma Action: neutropenia (low neutrophils)","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/neutropenia-low-neutrophils"},{"label":"Lymphoma Action: cancer-related fatigue","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/cancer-related-fatigue"},{"label":"Lymphoma Action: lymphoma, work and you","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/day-day-living/lymphoma-work-and-you"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Lymphoma Action: classical Hodgkin lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/types-lymphoma/hodgkin-lymphoma/classical-hodgkin-lymphoma"},{"label":"Lymphoma Action: late effects of lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/late-effects-lymphoma-treatment"},{"label":"Lymphoma Action: annual breast screening missed following radiotherapy for Hodgkin lymphoma","url":"https://lymphoma-action.org.uk/news/annual-breast-screening-missed-following-radiotherapy-hodgkin-lymphoma"},{"label":"GOV.UK: protocols for surveillance of women at higher risk of developing breast cancer, NHS Breast Screening Programme","url":"https://www.gov.uk/government/publications/breast-screening-higher-risk-women-surveillance-protocols/protocols-for-surveillance-of-women-at-higher-risk-of-developing-breast-cancer"},{"label":"Schaapveld et al., second cancer risk up to 40 years after treatment for Hodgkin's lymphoma, New England Journal of Medicine 2015 (3,905 Dutch survivors)","url":"https://doi.org/10.1056/NEJMoa1505949"},{"label":"van Nimwegen et al., cardiovascular disease after Hodgkin lymphoma treatment, 40-year disease risk, JAMA Internal Medicine 2015 (2,524 Dutch patients)","url":"https://doi.org/10.1001/jamainternmed.2015.1180"},{"label":"NHS: Hodgkin lymphoma","url":"https://www.nhs.uk/conditions/hodgkin-lymphoma/"},{"label":"NHS: Hodgkin lymphoma, symptoms","url":"https://www.nhs.uk/conditions/hodgkin-lymphoma/symptoms/"},{"label":"NHS: Hodgkin lymphoma, treatment","url":"https://www.nhs.uk/conditions/hodgkin-lymphoma/treatment/"},{"label":"Macmillan: Hodgkin lymphoma","url":"https://www.macmillan.org.uk/cancer-information-and-support/lymphoma/hodgkin-lymphoma"},{"label":"Cancer Research UK: living with Hodgkin lymphoma","url":"https://www.cancerresearchuk.org/about-cancer/hodgkin-lymphoma/living-with"},{"label":"Macmillan: superior vena cava obstruction","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/superior-vena-cava-obstruction"},{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"}],"tags":["heme","spike"],"related":["pd1-plus-avd-hodgkin","bleomycin-omission-caution","pd-ligand-9p24-alteration","lymphoma-roadmap","lymphoma-ev-radiotherapy-free-early-hodgkin","lymphoma-ev-late-effects-of-the-treatments-given-now"],"cancers":[],"sections":[],"technologies":["adc","checkpoint-inhibitor","fdg-pet","pet-adapted-therapy","autologous-stem-cell-transplant","ctdna-lymphoma-monitoring","cardio-oncology","imrt-igrt","proton-therapy","survivorship-care-plan","fertility-preservation","palliative-care","psycho-oncology","peer-support-groups","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","multidisciplinary-tumour-board","oncology-nutrition","prehabilitation","pet-ct","mammography","histopathology-ihc","cytogenetics-fish"],"targets":["pd1","cd30","pdl1","jak2","ciita","jak1","stat3","socs1","b2m"],"drugs":["carmustine","chlorambucil","dacarbazine","mechlorethamine","procarbazine","prednisone","palifermin","brentuximab-vedotin","nivolumab","pembrolizumab","doxorubicin","bleomycin","vinblastine","etoposide"],"companies":["haihe-biopharma","bms","merck","pfizer","takeda","swog","childrens-oncology-group","gbg"],"institutions":["cruk","mskcc","dana-farber"],"pathways":["pd1-checkpoint","jak-stat","tumor-microenvironment","antigen-presentation-immunoediting","oncogenic-viruses","myeloid-suppression-axis"],"terms":["deauville-score","reed-sternberg-cell","lugano-classification","pfs","os","lymphoma-tx-radiotherapy","lymphoma-tx-hodgkin-late-effects","lymphoma-tx-fertility-preservation","lymphoma-tx-transplant-role","lymphoma-tx-uk-versus-us","lymphoma-tx-uk-access","lymphoma-tx-regimen-alphabet","cancer-related-fatigue","late-effects","febrile-neutropenia","neutropenia","financial-toxicity","central-venous-access","hypogammaglobulinaemia","performance-status","quality-of-life","lymphoma-decision-beacopp-or-abvd","lymphoma-decision-fertility-timing","lymphoma-decision-trial","lymphoma-living-hodgkin-survivorship-screening","lymphoma-living-fatigue","lymphoma-living-scanxiety-and-surveillance","lymphoma-living-returning-to-work","lymphoma-living-vaccinations","secondary-malignancy","cardiotoxicity","deauville","lymphoma-bio-hodgkin-microenvironment","lymphoma-bio-ebv-latency","lymphoma-bio-lineage-antigen-cost","plasma-ebv-dna","lymphoma-classification-2022","lymphoma-b-versus-t-cell"],"trials":["ccss","nct07188558","nct04002297","nct06230224","rathl","echelon-1","swog-s1826","hd21","aethera","keynote-204","checkmate-205","ahod2131","hd10","hd16","hd18","ahl2011","eortc-h10","radar-hodgkin"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["hematological-oncology","journal-of-adolescent-and-young-adult-oncology"],"dependsOn":[],"notes":["Living with and after Hodgkin lymphoma, the decisions and the people who make them: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the 24-hour number they gave you come first, and no figure here is a prediction about you. The decision records, the question sets, the first 60 days checklist and the red cards on this page were written from the NHS, Lymphoma Action, Macmillan and Cancer Research UK patient pages, from NICE NG52, NG47, CG151 and NG234, from the NHS Breast Screening Programme protocols and the Green Book, and from the trial reports named beside each figure, all read on 1 October 2026.","On the forty-year figures. The second-cancer and cardiovascular cumulative incidences quoted on this page come from two Dutch cohorts treated between 1965 and 2000 with the radiotherapy fields and doses of that era, which are far larger than anything given now. They describe what happened to those cohorts. What modern fields and PET-guided de-escalation are worth over forty years is not yet known, because the cohort that would measure it has not been followed for forty years. The reason to carry the figures anyway is that the screening programmes attached to them are the thing a survivor can act on, and the commonest failure is not being enrolled in one.","Taxonomy. The two classifications of 2022 disagree about the name of the non-classical form. The International Consensus Classification renamed nodular lymphocyte predominant Hodgkin lymphoma to nodular lymphocyte predominant B-cell lymphoma by consensus, because it differs biologically and clinically from classic Hodgkin lymphoma and is closely related to T-cell/histiocyte-rich large B-cell lymphoma. WHO-HAEM5 kept the old name so as not to interfere with trials in progress, while stating that the new name is acceptable in preparation for adopting it. The corpus keeps the record under the WHO-HAEM5 name and carries the other as an alias. Both books leave the four subtypes of classic Hodgkin lymphoma unchanged and both note that with modern treatment those subtypes have lost most of their prognostic meaning."],"group":"haematologic","burden":"~83,000 new cases a year worldwide, ~8,500 in the US, with age peaks at 20-30 and over 55. More than 85% are cured, so the research agenda is curing with less toxicity. Five-year survival is ~89% overall in high-income countries; ~23,000 deaths a year worldwide.","subtypes":["Classical Hodgkin lymphoma: nodular sclerosis (most common in young adults), mixed cellularity, lymphocyte-rich, lymphocyte-depleted","Nodular lymphocyte-predominant B-cell lymphoma (reclassified 2022; indolent, CD20+, rituximab-responsive)","Early stage (I-II) favourable vs unfavourable (bulk, ESR, ≥3 sites)","Advanced stage (III-IV); IPS 0-7 risk score","Paediatric / adolescent-young-adult vs older (>60) disease","EBV-positive (more common in children, older adults, and low-income settings)"],"biomarkers":["Interim PET (Deauville)","CD30","PD-L1 (9p24.1 amplification)","Interim PET (Deauville score) after cycle 2","CD30 and CD15 on Reed-Sternberg cells; CD20 in NLPBL","9p24.1 (PD-L1/PD-L2) amplification","EBV status (EBER)","International Prognostic Score (IPS)","Baseline metabolic tumour volume","ctDNA (research; PhasED-seq)","Soluble CD30 (research)"],"standardOfCare":[{"setting":"Advanced stage","approach":"Nivolumab-AVD (2026) or BV-AVD; PET-adapted.","refs":["nivolumab","brentuximab-vedotin","fdg-pet"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Early stage, favourable (I-II)","approach":"ABVD × 2 + involved-site radiotherapy 20 Gy (HD10), or PET-adapted omission of radiotherapy after 3 cycles if PET-negative (RAPID, HD16) accepting ~5% lower PFS; AHOD2131 tests BV-nivo.","refs":["doxorubicin","pet-adapted-therapy","imrt-igrt","deauville-score","ahod2131"],"guideline":{"nccn":"Category 1 (ABVD × 2 + ISRT 20 Gy or PET-adapted chemotherapy alone)","version":"NCCN Hodgkin Lymphoma 2026"}},{"setting":"Early stage, unfavourable (I-II bulky or risk factors)","approach":"ABVD × 4 + ISRT 30 Gy, or escalated BEACOPP × 2 + ABVD × 2 + RT (HD14/HD17 PET-guided); nivolumab- or BV-containing regimens in trials.","refs":["doxorubicin","pet-adapted-therapy","imrt-igrt"],"guideline":{"nccn":"Category 2A","version":"NCCN 2026"}},{"setting":"Advanced stage (III-IV), age ≤60","approach":"Nivolumab-AVD × 6 (S1826; approved March 2026, no routine radiotherapy) or BV-AVD × 6 with G-CSF (ECHELON-1); in Europe PET-guided BrECADD × 4-6 (HD21) or eBEACOPP; PET-adapted ABVD/AVD (RATHL) where novel agents unavailable.","refs":["swog-s1826","nivolumab","echelon-1","brentuximab-vedotin","hd21","rathl","pd1-plus-avd-hodgkin"],"guideline":{"nccn":"Category 1 (nivolumab-AVD preferred; BV-AVD)","esmoMcbs":"A (ECHELON-1)","version":"NCCN 2026"}},{"setting":"Advanced stage, age >60","approach":"Nivolumab-AVD (S1826 included older adults with less toxicity than BV-AVD); sequential brentuximab → AVD → brentuximab; avoid bleomycin; ABVD/AVD with dose adaptation.","refs":["swog-s1826","nivolumab","brentuximab-vedotin","bleomycin-omission-caution"]},{"setting":"First relapse, transplant-eligible","approach":"Salvage (ICE, DHAP, GVD, BV-nivolumab or pembrolizumab-GVD) → PET-negative → high-dose therapy and autologous transplant; brentuximab consolidation for high-risk (AETHERA); PD-1 maintenance in trials.","refs":["autologous-stem-cell-transplant","brentuximab-vedotin","nivolumab","pembrolizumab","aethera"],"guideline":{"nccn":"Category 1 (ASCT after chemosensitive salvage; BV consolidation for high risk)","version":"NCCN 2026"}},{"setting":"Relapse after transplant or transplant-ineligible","approach":"Pembrolizumab (KEYNOTE-204) or nivolumab; brentuximab vedotin if not yet given; BV + nivolumab; allogeneic transplant for fit patients after response; CD30 CAR-T in trials; palliative radiotherapy or bendamustine.","refs":["pembrolizumab","keynote-204","nivolumab","checkmate-205","brentuximab-vedotin","idea-cd30-car-t-hodgkin"],"guideline":{"nccn":"Category 1 (pembrolizumab, nivolumab, brentuximab)","version":"NCCN 2026"}},{"setting":"Paediatric (COG / EuroNet)","approach":"Risk-adapted OEPA/COPDAC (EuroNet-PHL-C2) or ABVE-PC with brentuximab (AHOD1331, EFS benefit) and PET-guided radiotherapy omission; S1826 and AHOD2131 now enrol from age 12 or 5.","refs":["brentuximab-vedotin","pet-adapted-therapy","childrens-oncology-group","ahod1331","euronet-phl-c2"]},{"setting":"Survivorship","approach":"Lifelong surveillance for cardiac disease (anthracycline, mediastinal RT), breast cancer screening from 8 years after chest RT in women, thyroid and lung checks, fertility counselling before therapy.","refs":["cardio-oncology","mammography"]},{"setting":"Choosing treatment in Hodgkin lymphoma: stage, risk factors and the interim PET","approach":"Three inputs. Stage by PET-CT reported with the Lugano classification. Risk factors, which differ by group: the German Hodgkin Study Group counts a large mediastinal mass, extranodal disease, a raised erythrocyte sedimentation rate and three or more nodal areas; EORTC counts a large mediastinal mass, age 50 or over, a raised sedimentation rate and four or more nodal areas. And the interim PET after two cycles, scored 1 to 5 on the Deauville scale, which is used to intensify treatment in patients who have not responded and to reduce it in those who have.\n\nThat last step, PET adaptation, is the structural idea behind modern Hodgkin treatment. RATHL showed that bleomycin can be dropped from cycles 3 to 6 in patients whose PET after two cycles is negative, with three-year progression-free survival of 85.7 per cent for continued ABVD against 84.4 per cent for AVD, which removed lung toxicity from most patients' treatment. EORTC H10 showed the reverse direction: in patients whose early PET was positive, switching from ABVD to escalated BEACOPP with involved-node radiotherapy raised five-year progression-free survival from 77.4 to 90.6 per cent (hazard ratio 0.42).\n\nBefore the first cycle: lung function tests if bleomycin is planned, echocardiography, hepatitis B, hepatitis C and HIV testing, and a fertility conversation, which in a disease of young people is not optional.","refs":["rathl","deauville","deauville-score","fdg-pet","pet-adapted-therapy","lugano-classification","abvd-beacopp","lymphoma-tx-fertility-preservation","lymphoma-tx-hepatitis-b-reactivation"],"guideline":{"version":"NCCN Hodgkin Lymphoma; ESMO; RATHL, EORTC H10","url":"https://www.cancer.gov/types/lymphoma/hp/adult-hodgkin-treatment-pdq"}},{"setting":"Survivorship after Hodgkin lymphoma: what the cure costs, and what is watched for","approach":"Most people treated for Hodgkin lymphoma are cured and then live for decades with the consequences. Anthracyclines cause cardiomyopathy. Mediastinal radiotherapy causes coronary and valve disease, and, twenty to thirty years later, breast and lung cancer inside the irradiated field; the lung cancer risk multiplies with smoking rather than adding to it. Neck radiotherapy causes hypothyroidism in a large minority. Procarbazine and other alkylators cause infertility and a small excess of myelodysplasia and leukaemia. Bleomycin causes lung fibrosis.\n\nThe long-term German Hodgkin Study Group series of 471 patients with the nodular lymphocyte-predominant subtype makes the arithmetic plain: ten-year overall survival was 92.1 per cent, second cancers occurred in 10.2 per cent, and of 43 deaths only 10 were from the lymphoma, against 20 from second cancers and 13 from conditions possibly related to treatment.\n\nFollow-up therefore includes cardiovascular risk assessment, thyroid function after neck or upper mediastinal radiotherapy, echocardiography at intervals, active smoking cessation support, and, in England, automatic referral into the NHS breast screening programme's very high risk pathway for women who had radiotherapy to breast tissue for Hodgkin or non-Hodgkin lymphoma between the ages of 10 and under 36. All of it is the reason treatment keeps being de-escalated.","refs":["lymphoma-tx-hodgkin-late-effects","late-effects","secondary-malignancy","cardiotoxicity","survivorship-care-plan","strain-echocardiography-gls","paper-eichenauer-nlphl-ghsg-hd7-hd15-long-term-jco-2020"],"guideline":{"version":"NCCN Hodgkin Lymphoma survivorship; NCI PDQ","url":"https://www.cancer.gov/types/lymphoma/hp/adult-hodgkin-treatment-pdq"}}],"stateOfArt":["Immunotherapy in first line with less toxicity.","Nivolumab-AVD is the new frontline standard for advanced disease (S1826: 2-year PFS 92%, neuropathy halved), approved March 2026 for ages 12 and up.","Two intensive but de-toxified European options: PET-guided BrECADD (HD21) achieves ~94% 5-year PFS with 40% less morbidity than eBEACOPP.","Interim PET steers therapy for nearly every patient: bleomycin omission (RATHL), radiotherapy omission (HD16/17, RAPID), cycle number (HD18, HD21).","Radiotherapy is disappearing from advanced-stage care (<1% in S1826) and being minimised in early stage.","PD-1 blockade is the most effective single agent in any lymphoma relapse (ORR ~70%), and beat brentuximab head to head (KEYNOTE-204).","Cure rates above 90% in young patients shift the research agenda to late effects and to older adults.","The cancer cell is the minority. A classical Hodgkin lymph node is mostly T cells, eosinophils, plasma cells, macrophages and fibrosis; the Hodgkin and Reed-Sternberg cells are a small fraction of it, and their clonal B-cell identity had to be proved by picking single cells off a slide with a micromanipulator. This is why an excisional biopsy is usually needed and why bulk sequencing of a Hodgkin node measures the infiltrate rather than the tumour.","Checkpoint blockade works here for a genetic reason. The 9p24.1 amplicon carries CD274, PDCD1LG2 and JAK2, so one copy-number event raises both PD-1 ligands by gene dose and by transcription; 97% of 108 cases carried concordant alterations of the two ligand loci, with amplification in 36% and copy gain in 56%. PD-1 blockade gave an objective response in 20 of 23 heavily pre-treated patients. Nothing is tested first, because almost every case has the alteration.","What predicts a complete remission on a checkpoint inhibitor is MHC class II, not class I, on the Reed-Sternberg cells, which points at a CD4 T cell as the effector and makes CIITA rearrangement, present in 15% of cases, an escape route as well as a cause.","The infiltrate carries prognosis of its own: more CD68-positive macrophages meant shorter progression-free survival, more relapse after autologous transplant and shorter disease-specific survival in an independent cohort of 166 patients, outperforming the International Prognostic Score. It is not used to choose treatment; the interim PET scan is."],"history":[{"year":1832,"title":"Thomas Hodgkin describes the disease; Reed and Sternberg characterise the cell (1898-1902)","refs":["reed-sternberg-cell"]},{"year":1950,"title":"Peters shows extended-field radiotherapy can cure early-stage disease","refs":["imrt-igrt"]},{"year":1964,"title":"MOPP: first combination chemotherapy cure","refs":[]},{"year":1964,"title":"MOPP: the first combination chemotherapy to cure an advanced cancer (DeVita, NCI)","refs":["cytotoxic-chemotherapy"]},{"year":1975,"title":"ABVD introduced (Bonadonna); becomes global standard by the 1990s","refs":["doxorubicin"]},{"year":1992,"title":"Escalated BEACOPP developed by the German Hodgkin Study Group","refs":["gbg"]},{"year":2000,"title":"Autologous transplant standard for relapse; late-effects registries reveal cardiac and second-cancer burden","refs":["autologous-stem-cell-transplant","cardio-oncology"]},{"year":2003,"title":"The dose-response curve for breast cancer after Hodgkin radiotherapy","note":"Travis: 4 Gy or more to the breast carried a 3.2-fold risk and over 40 Gy an eightfold risk, with no plateau; ovarian damage from alkylating agents or radiation lowered the risk, showing that hormonal stimulation is needed for radiation-induced breast cancer.","refs":["paper-travis-breast-cancer-after-hodgkin-radiotherapy-jama-2003"]},{"year":2010,"title":"Two cycles and 20 Gy is enough for early favourable disease","note":"HD10 randomised 1,370 patients in a two by two design: five-year freedom from treatment failure 93.0 against 91.1 per cent for four against two cycles of ABVD (p = 0.39) and no difference between 30 Gy and 20 Gy (p = 1.00).","refs":["paper-ghsg-hd10-reduced-intensity-early-hodgkin-nejm-2010","hd10"]},{"year":2011,"title":"Brentuximab vedotin approved","refs":["brentuximab-vedotin"]},{"year":2011,"title":"Brentuximab vedotin approved for relapsed disease; CD30 validated as an ADC target","refs":["brentuximab-vedotin","cd30"]},{"year":2014,"title":"Lugano classification formalises PET staging and the Deauville scale","refs":["lugano-classification","deauville-score"]},{"year":2015,"title":"AETHERA: brentuximab consolidation after transplant","refs":["aethera"]},{"year":2015,"title":"What curing Hodgkin lymphoma costs forty years later","note":"Schaapveld: 48.5 per cent of 3,905 survivors developed a second cancer within 40 years, with risk still 3.9 times the population rate after 35 years and no fall between the 1965 to 1976 and 1989 to 2000 treatment periods. Van Nimwegen: 50 per cent developed cardiovascular disease within 40 years.","refs":["paper-schaapveld-second-cancer-risk-40-years-hodgkin-nejm-2015","paper-van-nimwegen-cardiovascular-disease-after-hodgkin-jama-intern-med-2015","lymphoma-ev-late-effects-of-the-treatments-given-now"]},{"year":2016,"title":"RATHL: bleomycin dropped after negative interim PET; nivolumab approved for relapse (CheckMate 205)","refs":["rathl","checkmate-205","nivolumab"]},{"year":2017,"title":"The interim scan directs intensification better than it directs de-escalation","note":"EORTC H10 raised five-year progression-free survival in scan-positive early-stage patients from 77.4 to 90.6 per cent by switching to escalated BEACOPP, but could not demonstrate non-inferiority of dropping radiotherapy after a negative scan in either risk group. HD18 shortened escalated BEACOPP to four cycles after a negative scan with five-year progression-free survival of 92.2 against 90.8 per cent and half the severe infections.","refs":["paper-eortc-h10-pet-adapted-early-hodgkin-jco-2017","paper-ghsg-hd18-pet-guided-escalated-beacopp-lancet-2017","eortc-h10","hd18"]},{"year":2018,"title":"ECHELON-1: BV-AVD approved frontline; radiotherapy omission trials (RAPID, HD16/17) report","refs":["echelon-1","pet-adapted-therapy"]},{"year":2019,"title":"Omitting radiotherapy costs 7.3 points, and switching to ABVD costs nothing","note":"HD16: five-year progression-free survival 86.1 per cent without radiotherapy against 93.4 per cent with it after a negative scan. AHL2011: switching scan-negative patients from escalated BEACOPP to ABVD gave 85.7 against 86.2 per cent with grade 3 to 4 anaemia falling from 69 to 28 per cent.","refs":["paper-ghsg-hd16-pet-guided-early-favourable-hodgkin-jco-2019","paper-ahl2011-pet-adapted-treatment-advanced-hodgkin-lancet-oncol-2019","hd16","ahl2011"]},{"year":2020,"title":"KEYNOTE-204: pembrolizumab beats brentuximab in relapse","refs":["keynote-204","pembrolizumab"]},{"year":2022,"title":"ECHELON-1 shows overall survival benefit; WHO reclassifies nodular lymphocyte-predominant disease","refs":["echelon-1"]},{"year":2023,"title":"SWOG S1826: nivolumab-AVD beats BV-AVD (ASCO plenary)","refs":["swog-s1826"]},{"year":2024,"title":"HD21 (BrECADD) published in Lancet; S1826 in NEJM","refs":["hd21","swog-s1826"]},{"year":2026,"title":"Nivolumab-AVD approved first line","refs":["nivolumab"]},{"year":2026,"title":"Nivolumab-AVD approved by FDA (20 March) for ages 12+; HD21 5-year data confirm BrECADD","refs":["swog-s1826","nivolumab","hd21"]},{"year":2030,"title":"RADAR reports","note":"RADAR (NCT04685616, 1,042 estimated participants) replaces bleomycin with brentuximab vedotin and omits radiotherapy entirely after a Deauville score of 1 to 3; the registry lists primary completion for September 2030.","refs":["radar-hodgkin","lymphoma-ev-radiotherapy-free-early-hodgkin"]}],"pipeline":["abexinostat","mk-1045","cobolimab","rondecabtagene-autoleucel","krt-232","azd3470","englumafusp-alfa","azd4512","jnj-90014496","ctx112","at101","men1703","cd19-t-hank","ahod2131","idea-chemo-free-hodgkin","idea-cd30-car-t-hodgkin","ctdna-lymphoma-monitoring","pet-adapted-therapy","cd30","hd21"],"openProblems":["Late toxicity in survivors.","Older patients.","Late effects dominate: cardiac disease, breast and lung cancer after mediastinal radiotherapy, infertility; survivors need lifelong surveillance that most health systems do not organise.","Older patients (>60) have roughly half the cure rate and double the toxicity; the best regimen for them is unsettled.","The ~10-15% with primary refractory or early-relapsing disease still need transplant; those failing PD-1 blockade have few options beyond allogeneic transplant.","Interim PET has limited positive predictive value; ctDNA-guided designs are unproven.","Access: brentuximab and nivolumab are costly and unavailable in many countries where EBV-positive Hodgkin lymphoma is common in children.","Nodular lymphocyte-predominant disease is now a separate entity with little trial evidence of its own.","Radiotherapy omission trades a few percent of PFS for lower late toxicity; the right trade-off differs by age and sex.","Three countries now have three different standards for the same advanced-stage disease: nivolumab with AVD in the United States after SWOG S1826, PET-guided BrECADD in Germany after HD21, and PET-adapted ABVD or brentuximab-AVD in much of the United Kingdom. They have never been compared with each other, and none has overall survival data at the timescale on which this disease is measured.","The consequences of PD-1 blockade given to a 20-year-old who will live another sixty years are unknown, and the trials that made it a first-line standard have a few years of follow-up in a disease whose main late harms appear after twenty.","Omitting radiotherapy in PET-negative early-stage disease costs several percentage points of disease control in both HD16 and RAPID and costs nothing in survival, and there is no way to tell an individual patient whether they are one of the people it would have saved a relapse.","Older patients tolerate every intensive Hodgkin regimen poorly and are excluded from most trials, so the commonest treatment failure in this disease happens in the group with the least evidence.","Every attempt to omit radiotherapy from early-stage Hodgkin lymphoma on the strength of a negative interim scan has cost tumour control: 7.3 percentage points in HD16 and a failure to demonstrate non-inferiority in either risk group of EORTC H10.","The late-effect figures that justify de-escalation come from patients treated up to 2000 with mantle fields. Nobody knows the forty-year risks of involved-site radiotherapy, brentuximab vedotin, checkpoint inhibitors or CAR-T, and the field is making decisions on a harm estimate drawn from a treatment that is no longer given."]},{"id":"hpv-associated-vulvar-cancer","kind":"cancer","name":"HPV-associated vulvar squamous cell carcinoma","aka":["HPV-positive vulvar cancer","p16-positive vulvar squamous cell carcinoma","Basaloid and warty vulvar carcinoma","Vulvar cancer arising from usual-type VIN"],"tldr":"HPV-associated vulvar cancer is the type of vulvar squamous cell cancer caused by persistent HPV infection, growing out of the precancer called usual-type VIN and marked by the p16 protein. It tends to affect younger women, responds better to radiotherapy and recurs less often than the HPV-independent type, and it is preventable by HPV vaccination.","summary":"The 2020 WHO classification splits vulvar squamous cell carcinoma into HPV-associated and HPV-independent disease because the two arise by different routes and behave differently. HPV-associated tumours follow persistent high-risk HPV infection, above all type 16, through the precursor high-grade squamous intraepithelial lesion (usual-type VIN), often in women who smoke or are immunosuppressed and often alongside cervical or anal HPV disease. They are basaloid or warty under the microscope, express p16 diffusely and keep wild-type p53. Large series and the AGO-CaRE-1 cohort have shown that p16-positive tumours have fewer local recurrences and better survival than p53-mutant tumours, and that they respond more completely to radiotherapy, which is why molecular subtype is now part of the pathology report even though it does not yet change first treatment.\n\nTreatment follows stage rather than subtype. Usual-type VIN is excised or treated with imiquimod, with trials of topical agents such as artesunate under way; early cancers are removed by wide local excision with sentinel node biopsy for tumours under four centimetres with more than a millimetre of invasion (GROINSS-V I), and GROINSS-V II showed that groin radiotherapy can replace lymphadenectomy when the sentinel node metastasis is two millimetres or smaller. Locally advanced disease is treated with cisplatin chemoradiotherapy (GOG 205) to avoid exenterative surgery, and recurrent or metastatic disease with carboplatin and paclitaxel, with pembrolizumab available for PD-L1-positive tumours after chemotherapy on the strength of the KEYNOTE-158 vulvar cohort. Trials now test PD-1 antibodies with lenvatinib or with the PD-1 and CTLA-4 bispecific cadonilimab in recurrent disease, and the nonavalent HPV vaccine prevents the infections that start the disease.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Vulvar_cancer","links":[{"label":"GROINSS-V II (JCO 2021)","url":"https://doi.org/10.1200/JCO.21.00006"},{"label":"NCCN Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Vulvar_cancer"}],"tags":["subtype-page","gynaecologic"],"related":["hpv-independent-vulvar-cancer","vulvar","vaginal-squamous-cell-carcinoma"],"cancers":[],"sections":[],"technologies":["sentinel-node","imrt-igrt","checkpoint-inhibitor","hpv-vaccine","precancer-ablation"],"targets":["pd1"],"drugs":["cisplatin","carboplatin","paclitaxel","bevacizumab","pembrolizumab","gardasil-9"],"companies":[],"institutions":[],"pathways":[],"terms":["hpv-p16","cps","lymphadenectomy","chemoradiation"],"trials":["nct06075264","nct04422366","nct05903833","nct05932212"],"people":[],"bottlenecks":[],"keyPapers":["paper-groinss-v-sentinel-node-vulvar-cancer-jco-2008","paper-groinss-v-ii-radiotherapy-vulvar-micrometastases-jco-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"Roughly a third to two fifths of vulvar squamous cell carcinomas; the commoner type in younger women and the share that HPV vaccination will eventually prevent.","subtypes":["Usual-type vulvar intraepithelial neoplasia (HPV-associated precursor, p16 positive)","Basaloid HPV-associated vulvar squamous cell carcinoma","Warty HPV-associated vulvar squamous cell carcinoma","Early-stage HPV-associated vulvar cancer (wide local excision and sentinel node)","Locally advanced HPV-associated vulvar cancer (chemoradiotherapy, radiosensitive)"],"biomarkers":["p16 immunohistochemistry (block positive) and HPV DNA","p53 immunohistochemistry (wild-type pattern)","Depth of invasion (over one millimetre triggers nodal assessment)","Sentinel node status and metastasis size (two millimetres threshold, GROINSS-V II)","PD-L1 combined positive score (pembrolizumab)","Margin status"],"standardOfCare":[{"setting":"Precursor (usual-type VIN)","approach":"Excision or laser ablation of visible lesions; imiquimod as a medical alternative; trials of artesunate ointment; HPV vaccination for prevention.","refs":["precancer-ablation","hpv-vaccine","gardasil-9","nct06075264","nct04422366"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}},{"setting":"Early stage (tumour under four centimetres, clinically negative groins)","approach":"Wide local excision with sentinel node biopsy (GROINSS-V I); groin radiotherapy for sentinel node metastases of two millimetres or less and lymphadenectomy for larger ones (GROINSS-V II).","refs":["sentinel-node","imrt-igrt","lymphadenectomy"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}},{"setting":"Locally advanced disease","approach":"Cisplatin-based chemoradiotherapy (GOG 205); surgery for residual disease; p16-positive tumours respond well.","refs":["cisplatin","imrt-igrt","chemoradiation"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}},{"setting":"Recurrent or metastatic disease","approach":"Carboplatin and paclitaxel with or without bevacizumab; pembrolizumab for PD-L1-positive or mismatch-repair-deficient tumours after chemotherapy; trials of pembrolizumab with lenvatinib and of cadonilimab.","refs":["carboplatin","paclitaxel","bevacizumab","pembrolizumab","nct05903833","nct05932212"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}}],"stateOfArt":["Molecular subtyping by p16 and p53 is now routine and predicts recurrence and radiosensitivity.","Sentinel node biopsy and radiotherapy for small node metastases have removed most groin dissections in early disease.","HPV vaccination will prevent this subtype in vaccinated cohorts."],"history":[{"year":1986,"title":"ISSVD recognises vulvar intraepithelial neoplasia as the precursor lesion","refs":["hpv-p16"]},{"year":2008,"title":"GROINSS-V I: sentinel node biopsy is safe in early vulvar cancer","refs":["sentinel-node"]},{"year":2020,"title":"WHO classification divides vulvar squamous cell carcinoma into HPV-associated and HPV-independent types","refs":["hpv-p16"]},{"year":2021,"title":"GROINSS-V II: radiotherapy replaces lymphadenectomy for sentinel node metastases of two millimetres or less","refs":["sentinel-node","imrt-igrt"]},{"year":2022,"title":"Pembrolizumab responses reported in the KEYNOTE-158 vulvar cohort","refs":["pembrolizumab"]}],"pipeline":["pembrolizumab","nct05903833","nct05932212","nct06075264","hpv-vaccine"],"openProblems":["No treatment yet differs by HPV status despite the difference in behaviour.","Recurrence of usual-type VIN after treatment is common.","Checkpoint inhibitors help only a minority in recurrent disease.","Vulvar cancer is too rare for large randomised trials, so most evidence is borrowed from cervical cancer."],"parent":"vulvar"},{"id":"hpv-independent-vulvar-cancer","kind":"cancer","name":"HPV-independent vulvar squamous cell carcinoma (p53-mutant)","aka":["HPV-negative vulvar cancer","p53-abnormal vulvar squamous cell carcinoma","Keratinising vulvar carcinoma","Vulvar cancer arising from differentiated VIN and lichen sclerosus"],"tldr":"HPV-independent vulvar cancer is the commoner type of vulvar squamous cell cancer, arising in older women from the chronic skin condition lichen sclerosus rather than from HPV, and marked by faults in the p53 gene. It recurs locally far more often than the HPV type, so treatment centres on complete surgical removal, control of the surrounding skin disease and long follow-up.","summary":"Most vulvar squamous cell carcinomas have nothing to do with HPV. They arise in a background of lichen sclerosus or chronic inflammation through the precursor differentiated VIN, a subtle lesion that is easily missed on biopsy, and they carry TP53 mutations in most cases, shown by abnormal p53 immunohistochemistry (overexpression or complete loss); a smaller HPV-independent, p53 wild-type group with NOTCH1 or HRAS mutations sits between the two main types and has an intermediate prognosis. HPV-independent tumours are usually keratinising, occur in women a generation older than those with HPV-associated disease, and in the AGO-CaRE-1 cohort and other series had a markedly higher rate of local recurrence and worse disease-specific survival stage for stage, with recurrences arising years later in the diseased skin around the original tumour.\n\nSurgery is the same stage-based approach as for HPV-associated disease, wide local excision with sentinel node biopsy or lymphadenectomy, but with more attention to margins and to the surrounding field: lichen sclerosus is treated with potent topical steroids, which appears to reduce the risk of cancer, and any new lesion is biopsied. Adjuvant radiotherapy is given for close margins and node-positive disease, and locally advanced tumours receive cisplatin chemoradiotherapy, although p53-mutant tumours respond less completely than p16-positive ones. Recurrent and metastatic disease is treated with carboplatin and paclitaxel, and pembrolizumab is an option for PD-L1-positive tumours; response rates to checkpoint inhibitors are modest and trials combining PD-1 antibodies with lenvatinib or testing cadonilimab enrol both subtypes. Because these tumours share biology with cutaneous squamous cell carcinoma, cemiplimab and epidermal growth factor receptor inhibitors are also being explored.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Vulvar_cancer","links":[{"label":"NCCN Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Vulvar_cancer"}],"tags":["subtype-page","gynaecologic"],"related":["hpv-associated-vulvar-cancer","vulvar","cutaneous-scc"],"cancers":[],"sections":[],"technologies":["sentinel-node","imrt-igrt","checkpoint-inhibitor","precancer-ablation"],"targets":["tp53","pd1"],"drugs":["cisplatin","carboplatin","paclitaxel","bevacizumab","pembrolizumab","cemiplimab"],"companies":[],"institutions":[],"pathways":[],"terms":["hpv-p16","cps","lymphadenectomy","chemoradiation"],"trials":["nct05903833","nct05932212"],"people":[],"bottlenecks":[],"keyPapers":["paper-groinss-v-ii-radiotherapy-vulvar-micrometastases-jco-2021","paper-groinss-v-sentinel-node-vulvar-cancer-jco-2008"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"The majority of vulvar squamous cell carcinomas, typically in women over 70 with long-standing lichen sclerosus; the subtype with the highest local recurrence rate.","subtypes":["Differentiated vulvar intraepithelial neoplasia (dVIN, HPV-independent precursor)","HPV-independent p53-mutant vulvar squamous cell carcinoma (keratinising)","HPV-independent p53 wild-type vulvar squamous cell carcinoma (NOTCH1 or HRAS mutant, intermediate prognosis)","Verrucous carcinoma of the vulva (locally destructive, rarely metastatic)","Vulvar cancer with lichen sclerosus (field at risk of further tumours)"],"biomarkers":["p53 immunohistochemistry (mutant patterns: overexpression, null, cytoplasmic)","p16 immunohistochemistry (negative)","TP53 sequencing where immunohistochemistry is equivocal","NOTCH1 and HRAS mutations (p53 wild-type HPV-independent group)","Margin status and presence of differentiated VIN or lichen sclerosus at the margin","PD-L1 combined positive score"],"standardOfCare":[{"setting":"Precursor (differentiated VIN) and lichen sclerosus","approach":"Excision of differentiated VIN; long-term potent topical corticosteroids for lichen sclerosus; low threshold for biopsy of new lesions.","refs":["precancer-ablation"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}},{"setting":"Early stage","approach":"Wide local excision with attention to margins, sentinel node biopsy or inguinofemoral lymphadenectomy by the GROINSS-V criteria; adjuvant radiotherapy for close margins or positive nodes.","refs":["sentinel-node","lymphadenectomy","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}},{"setting":"Locally advanced disease","approach":"Cisplatin chemoradiotherapy with surgery for residual disease; responses are less complete than in p16-positive tumours.","refs":["cisplatin","imrt-igrt","chemoradiation"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}},{"setting":"Recurrent or metastatic disease","approach":"Carboplatin and paclitaxel with or without bevacizumab; pembrolizumab for PD-L1-positive tumours; trials of pembrolizumab with lenvatinib and of cadonilimab.","refs":["carboplatin","paclitaxel","bevacizumab","pembrolizumab","nct05903833","nct05932212"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}},{"setting":"Follow-up","approach":"Lifelong surveillance of the vulvar skin because new tumours arise in the lichen sclerosus field years later.","refs":["hpv-p16"],"guideline":{"version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}}],"stateOfArt":["p53 immunohistochemistry identifies the high-recurrence subtype at diagnosis.","Treating lichen sclerosus with topical steroids is the one preventive measure with supporting evidence.","Systemic options remain those borrowed from cervical and skin squamous cell carcinoma."],"history":[{"year":1961,"title":"Differentiated VIN described as a distinct precursor of keratinising vulvar carcinoma","refs":[]},{"year":2015,"title":"Treatment of lichen sclerosus with topical steroids associated with fewer vulvar cancers in a prospective cohort","refs":[]},{"year":2020,"title":"WHO classification defines HPV-independent vulvar squamous cell carcinoma; p53-mutant and wild-type groups recognised","refs":["hpv-p16"]},{"year":2021,"title":"GROINSS-V II node management applies to both subtypes","refs":["sentinel-node"]}],"pipeline":["pembrolizumab","cemiplimab","nct05903833","nct05932212"],"openProblems":["Differentiated VIN is hard to recognise and is often diagnosed only next to an invasive cancer.","Whether wider margins or adjuvant radiotherapy prevent the frequent local recurrences has not been tested prospectively.","p53-mutant tumours are relatively radioresistant and have no targeted therapy.","Older patients are under-represented in the few trials that exist."],"parent":"vulvar"},{"id":"hpv-negative-head-and-neck-cancer","kind":"cancer","name":"HPV-negative head and neck squamous cell carcinoma (including HPV-negative oropharyngeal cancer)","aka":["Tobacco-related head and neck cancer","HPV-negative oropharyngeal cancer","p16-negative head and neck cancer"],"tldr":"Head and neck cancers caused by tobacco and alcohol rather than HPV are harder to cure: surgery or cisplatin chemoradiation is the mainstay, immunotherapy given around surgery (KEYNOTE-689) or after it (NIVOPOSTOP) has begun to help, and pembrolizumab is the first treatment once the disease has spread.","summary":"HPV-negative head and neck squamous cell carcinoma is the classical, tobacco and alcohol driven disease of the oral cavity, larynx, hypopharynx and oropharynx, with areca nut and chewed tobacco the cause in South Asia. Tumours almost always carry TP53 mutation and CDKN2A loss, often EGFR overexpression, and arise from a field of damaged mucosa that produces second primaries; HPV-negative oropharyngeal cancer had three-year survival of 57.1 percent in the RTOG 0129 analysis against 82.4 percent for HPV-positive disease, and it is staged and treated with the other HPV-negative sites rather than with HPV-positive oropharyngeal cancer.\n\nCurative treatment is surgery followed by radiotherapy, with cisplatin added when there is extranodal extension or a positive margin (the Bernier and Cooper trials of 2004), or definitive cisplatin chemoradiation, which the MACH-NC meta-analysis showed adds about 6.5 percentage points to five-year survival over radiotherapy alone; cetuximab with radiotherapy (Bonner) is the option for patients who cannot have cisplatin. Adding PD-1 or PD-L1 antibodies during chemoradiation failed in JAVELIN Head and Neck 100 and KEYNOTE-412, and the radiosensitiser xevinapant made outcomes worse in TrilynX, but immunotherapy around surgery has succeeded: KEYNOTE-689 gave median event-free survival of 59.7 against 29.6 months with perioperative pembrolizumab in tumours with a PD-L1 combined positive score of 1 or more, and NIVOPOSTOP raised three-year disease-free survival from 52.5 to 63.1 percent with nivolumab added to postoperative chemoradiation.\n\nRecurrent or metastatic disease is treated as for all head and neck squamous cell carcinoma: pembrolizumab alone or with platinum and fluorouracil (KEYNOTE-048) replaced the cetuximab-based EXTREME regimen, though HPV-negative tumours respond less often to PD-1 blockade than HPV-positive ones. Trials now target this group specifically: FORTIFI-HN01 tests the EGFR and TGF-beta antibody ficerafusp alfa with pembrolizumab only in HPV-negative disease, and a phase 3 of ficlatuzumab with cetuximab is restricted to HPV-negative tumours. In India, oral metronomic methotrexate-celecoxib and low-dose nivolumab from Tata Memorial have set low-cost standards, and smoking cessation and alcohol reduction remain the interventions with the largest effect.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Head_and_neck_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Head_and_neck_cancer"}],"tags":["subtype-page","head-and-neck"],"related":["laryngeal-cancer","oral-cavity-cancer","oropharyngeal-cancer","recurrent-metastatic-hnscc"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["celecoxib","xevinapant"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-412"],"people":[],"bottlenecks":[],"keyPapers":["paper-bonner-cetuximab-radiotherapy-nejm-2006","paper-bernier-eortc-22931-nejm-2004","paper-cooper-rtog-9501-nejm-2004","paper-keynote-689-nejm-2025"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"Most of the close to 900,000 head and neck cancers diagnosed each year worldwide are HPV-negative: oral cavity, laryngeal and hypopharyngeal cancers in smokers and drinkers, and areca-nut related oral cancer in South Asia; in the RTOG 0129 analysis three-year survival for HPV-negative oropharyngeal cancer was 57 percent.","subtypes":["HPV-negative oropharyngeal cancer","Oral cavity squamous cell carcinoma (almost always HPV-negative)","Laryngeal and hypopharyngeal squamous cell carcinoma","TP53-mutant, CDKN2A-deleted tumours (the commonest genotype)","Tobacco and alcohol related, and areca-nut related, disease"],"biomarkers":["p16 negative and HPV DNA negative","PD-L1 combined positive score (perioperative and recurrent treatment)","TP53 mutation and CDKN2A loss","EGFR expression (a target, not a predictive marker)","Extranodal extension and margin status (postoperative treatment)","Smoking and alcohol exposure"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Biopsy with p16 (and HPV testing for oropharyngeal primaries), PD-L1 combined positive score, panendoscopy for second primaries, CT or MRI and PET-CT for stage III to IV.","refs":["hpv-p16","pd-l1-testing","pet-ct"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Resectable stage III to IVA","approach":"Surgery with neck dissection; perioperative pembrolizumab for tumours with a combined positive score of 1 or more (KEYNOTE-689), then radiotherapy or chemoradiation by pathology.","refs":["pembrolizumab","keynote-689","imrt-igrt"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"After surgery, high risk","approach":"Postoperative cisplatin chemoradiation for extranodal extension or positive margins; nivolumab added on the basis of NIVOPOSTOP.","refs":["cisplatin","chemoradiation","imrt-igrt","nivolumab","nivopostop"],"guideline":{"nccn":"Category 1 (chemoradiation)","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Unresectable or organ-preserving","approach":"Definitive cisplatin chemoradiation to 70 Gy; cetuximab with radiotherapy for patients who cannot have cisplatin (Bonner).","refs":["cisplatin","chemoradiation","imrt-igrt","cetuximab","bonner-cetuximab-rt"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Recurrent or metastatic","approach":"Pembrolizumab alone (combined positive score 1 or more) or with platinum-fluorouracil (KEYNOTE-048); cetuximab-based EXTREME for rapid disease or PD-1 failure.","refs":["pembrolizumab","keynote-048","cetuximab","extreme","recurrent-metastatic-hnscc"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Resource-limited settings","approach":"Oral metronomic methotrexate with celecoxib, with or without low-dose nivolumab (Tata Memorial trials).","refs":["methotrexate","metronomic-vs-cisplatin-tmh","low-dose-nivolumab-tmh"]},{"setting":"Prevention","approach":"Smoking cessation, alcohol reduction and betel quid cessation; second primaries make cessation after diagnosis worthwhile.","refs":["smoking-cessation-after-diagnosis","alcohol-reduction-labelling"]}],"stateOfArt":["Cisplatin chemoradiation and surgery with postoperative treatment remain the curative backbone, essentially unchanged since 2004 until KEYNOTE-689 and NIVOPOSTOP.","Immunotherapy helps when given around surgery, not during radiotherapy, a lesson from JAVELIN Head and Neck 100 and KEYNOTE-412.","Two decades of radiosensitisers and EGFR inhibitors added to chemoradiation have not improved on cisplatin."],"history":[{"year":2004,"title":"Bernier and Cooper trials: postoperative cisplatin chemoradiation for extranodal extension or positive margins","refs":[]},{"year":2006,"title":"Cetuximab with radiotherapy improves survival (Bonner)","refs":["bonner-cetuximab-rt"]},{"year":2008,"title":"EXTREME: cetuximab with platinum-fluorouracil first line","refs":["extreme"]},{"year":2009,"title":"MACH-NC update: concomitant chemotherapy adds about 6.5 points to five-year survival","refs":[]},{"year":2019,"title":"KEYNOTE-048: pembrolizumab first line in recurrent disease","refs":["keynote-048"]},{"year":2020,"title":"JAVELIN Head and Neck 100: PD-L1 blockade with chemoradiation fails","refs":["javelin-hn-100"]},{"year":2024,"title":"TrilynX stopped: xevinapant worsens outcomes","refs":["trilynx"]},{"year":2025,"title":"KEYNOTE-689 approval and NIVOPOSTOP: immunotherapy around surgery","refs":["keynote-689","nivopostop"]}],"pipeline":["ficerafusp-alfa","fortifi-hn01","nct06064877","nct06256588","petosemtamab","mrg003","cetuximab-sarotalocan","nivopostop"],"openProblems":["Cure rates for locally advanced HPV-negative disease have barely moved in twenty years.","No predictive biomarker beyond PD-L1, which is imperfect.","Function after laryngectomy, glossectomy and high-dose radiotherapy.","Second primaries and continued smoking after treatment.","Incidence still rising where tobacco and areca nut use are common."],"parent":"head-and-neck"},{"id":"hpv-positive-oropharyngeal-cancer","kind":"cancer","name":"HPV-positive oropharyngeal cancer","aka":["p16-positive oropharyngeal cancer","HPV-associated oropharyngeal squamous cell carcinoma","HPV-driven throat cancer"],"tldr":"Throat cancers caused by HPV are usually cured with chemoradiation or robotic surgery, so trials now ask how much treatment can be taken away: swapping cisplatin for cetuximab failed, cutting the radiation dose has worked only after surgery so far, and blood tests for HPV DNA may pick out the patients who can safely have less.","summary":"HPV-positive oropharyngeal squamous cell carcinoma arises in the tonsils and base of tongue when high-risk human papillomavirus, almost always type 16, integrates into the crypt epithelium and its E6 and E7 proteins disable p53 and Rb. Tumours are recognised by strong p16 staining, confirmed by HPV DNA or RNA testing where available, and they present with a neck node and a small primary. The RTOG 0129 analysis by Ang and colleagues in 2010 showed three-year overall survival of 82.4 percent for HPV-positive against 57.1 percent for HPV-negative disease, with smoking history worsening the outlook, and the eighth edition of the staging system gave HPV-positive disease a staging system of its own.\n\nStandard treatment is cisplatin chemoradiation to 70 Gy, or transoral robotic surgery with neck dissection followed by pathology-guided adjuvant treatment for smaller tumours. Two trials that replaced cisplatin with cetuximab to spare toxicity both failed: RTOG 1016 found five-year overall survival of 84.6 percent with cisplatin against 77.9 percent with cetuximab, and De-ESCALaTE found two-year survival of 97.5 against 89.4 percent, so cetuximab is reserved for patients who cannot have cisplatin. The Canadian ORATOR trial found swallowing scores slightly better after radiotherapy than after surgery, so neither route is superior for every patient.\n\nDe-escalation has worked only where selection was tight. NRG-HN002 found that 60 Gy with weekly cisplatin met its two-year progression-free survival threshold while 60 Gy alone did not; NRG-HN005 then closed early because the reduced-dose arms had worse progression-free survival than the 70 Gy control. After transoral surgery, however, ECOG-ACRIN E3311 reported two-year progression-free survival of about 95 percent with 50 Gy in intermediate-risk patients, and PATHOS is testing the same approach with swallowing and survival endpoints. Circulating tumour HPV DNA, shown by Chera and colleagues in 2020 to detect recurrence before scans, is now being used to adapt treatment, and HPV vaccination of boys and girls is expected to prevent most future cases.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/HPV-positive_oropharyngeal_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/HPV-positive_oropharyngeal_cancer"}],"tags":["subtype-page","head-and-neck"],"related":["oropharyngeal-cancer","hpv-negative-head-and-neck-cancer","recurrent-metastatic-hnscc"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["de-escalate","orator"],"people":[],"bottlenecks":[],"keyPapers":["paper-ang-hpv-oropharyngeal-nejm-2010","paper-rtog-1016-lancet-2019","paper-de-escalate-lancet-2019","paper-e3311-transoral-surgery-ferris-jco-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"Now the majority of oropharyngeal cancers in North America and Western Europe, typically in men in their fifties and sixties who never smoked heavily; in the RTOG 0129 analysis three-year survival was 82 percent against 57 percent for HPV-negative disease.","subtypes":["HPV-positive tonsil cancer","HPV-positive base of tongue cancer","Low-risk (small primary, limited nodes, light or never smoker) disease eligible for de-escalation trials","High-risk HPV-positive disease (heavy smokers, bulky or low neck nodes)","p16-positive but HPV DNA-negative discordant tumours (behave more like HPV-negative disease)"],"biomarkers":["p16 immunohistochemistry (strong nuclear and cytoplasmic staining in at least 70 percent of cells)","HPV DNA or E6/E7 RNA in situ hybridisation (confirms p16)","Smoking pack-years (modifies risk group)","Circulating tumour HPV DNA (surveillance and adaptive de-escalation)","PD-L1 combined positive score (recurrent disease)"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Fine-needle biopsy of the neck node with p16 staining, HPV confirmation where p16 is equivocal, examination and imaging of the tonsils and tongue base, and PET-CT; staged with the HPV-positive system.","refs":["hpv-p16","pet-ct"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Early disease (small primary, limited nodes)","approach":"Transoral robotic surgery with neck dissection and pathology-guided adjuvant radiotherapy (E3311), or radiotherapy alone; choice by expected swallowing and voice.","refs":["tors","imrt-igrt","ecog-e3311"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Locally advanced disease","approach":"Cisplatin chemoradiation to 70 Gy; cetuximab only for patients who cannot have cisplatin, since RTOG 1016 and De-ESCALaTE showed it inferior.","refs":["cisplatin","chemoradiation","imrt-igrt","cetuximab","rtog-1016","de-escalate"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"De-escalation","approach":"Reduced-dose or chemotherapy-free treatment only within a trial; NRG-HN005 showed that lowering the dose in definitive chemoradiation on HPV status alone loses control.","refs":["nrg-hn002-hn005","pathos","cthpv-dna","hpv-deescalation-caution"]},{"setting":"Surveillance","approach":"Examination and PET-CT at about three months; circulating tumour HPV DNA is emerging as a blood test for recurrence.","refs":["pet-ct","cthpv-dna"]},{"setting":"Recurrent or metastatic","approach":"Pembrolizumab alone or with platinum-fluorouracil (KEYNOTE-048); HPV-positive tumours respond at least as well as HPV-negative ones.","refs":["pembrolizumab","keynote-048","recurrent-metastatic-hnscc"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Prevention","approach":"HPV vaccination of girls and boys before exposure; catch-up vaccination of men is being argued for.","refs":["hpv-vaccine","gardasil-9","idea-prev-hpv-male-catchup-oropharynx"]}],"stateOfArt":["Cure rates above 80 percent with standard chemoradiation make toxicity, not survival, the main problem, which is why every major trial of the last decade has tried to remove treatment.","Surgery-first de-escalation (E3311, PATHOS) has held up; radiotherapy-dose de-escalation in the definitive setting (NRG-HN005) has not.","Circulating tumour HPV DNA is the most promising selector for who can have less and who is relapsing."],"history":[{"year":2000,"title":"Gillison links HPV16 to a distinct subset of oropharyngeal cancers","refs":[]},{"year":2010,"title":"RTOG 0129 analysis: HPV status is the strongest prognostic factor","refs":["rtog-0129"]},{"year":2017,"title":"Separate staging system for HPV-positive disease (AJCC 8th edition)","refs":[]},{"year":2019,"title":"RTOG 1016 and De-ESCALaTE: cetuximab inferior to cisplatin","refs":["rtog-1016","de-escalate"]},{"year":2020,"title":"Circulating tumour HPV DNA detects recurrence before imaging","refs":["cthpv-dna"]},{"year":2021,"title":"NRG-HN002: 60 Gy with cisplatin acceptable, 60 Gy alone not","refs":["nrg-hn002-hn005"]},{"year":2022,"title":"E3311: reduced-dose radiotherapy after transoral surgery","refs":["ecog-e3311"]},{"year":2025,"title":"NRG-HN005 closed: de-escalated chemoradiation arms worse","refs":["nrg-hn002-hn005"]}],"pipeline":["cthpv-dna","pathos","nrg-hn002-hn005","idea-cthpv-adapted-deescalation","bnt113","nct04534205","hpv-vaccine"],"openProblems":["Which patients can safely have less treatment, and by what test.","Long-term dry mouth, swallowing difficulty and fibrosis in people cured in their fifties.","Whether therapeutic HPV vaccines add to immunotherapy in recurrent disease.","HPV vaccination uptake in boys and in countries where the epidemic is beginning."],"parent":"oropharyngeal-cancer"},{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","aka":["ER positive HER2 negative breast cancer","ER-positive, HER2-negative","oestrogen receptor positive breast cancer","hormone-positive breast cancer","ER+ PR+ HER2-","ER positive PR positive HER2 negative","hormone sensitive breast cancer"],"tldr":"HR-positive breast cancer is the most common breast cancer, driven by oestrogen. It was treated for years with hormone-blocking pills, now joined by CDK4/6 inhibitors, PI3K-pathway drugs, degraders, and ADCs.","summary":"Hormone receptor-positive, HER2-negative breast cancer is about 70% of all breast cancers and the archetype of a hormone-driven, slow-evolving disease. Oestrogen receptor signalling drives proliferation, so endocrine therapy has been the backbone since tamoxifen (1977) and aromatase inhibitors (1990s); because recurrences can occur 10-20 years after diagnosis, therapy lasts 5-10 years and adherence is a major real-world determinant of outcome. Gene-expression assays (Oncotype DX, MammaPrint) now spare roughly 70% of node-negative and most postmenopausal node-positive patients chemotherapy, while adjuvant CDK4/6 inhibitors (abemaciclib, ribociclib) reduce recurrence in the high-risk minority.\n\nMetastatic disease is treated as a sequence of endocrine-based combinations. First line is a CDK4/6 inhibitor plus endocrine therapy, with ribociclib and abemaciclib showing overall survival gains that palbociclib did not. Progression is increasingly managed by genotype: ESR1 mutations detected in ctDNA (30-40% after aromatase inhibitors) call for oral SERDs (elacestrant, imlunestrant) or the PROTAC vepdegestrant, and since September 2026 for camizestrant switched in at molecular progression; PIK3CA/AKT1/PTEN alterations (about 50%) call for inavolisib, capivasertib, or alpelisib; gedatolisib (2026) works in PIK3CA-wild-type disease. After endocrine options are exhausted, antibody-drug conjugates precede chemotherapy: T-DXd for the ~60% with HER2-low or ultralow expression, and the TROP2 ADCs sacituzumab govitecan and datopotamab deruxtecan.\n\nOpen problems are the evolution of resistance across this long sequence (CDK4/6, then endocrine, then ADC payload resistance), the absence of a validated test for late recurrence, toxicity and adherence over years of therapy, and translating ctDNA-guided decisions into proven survival gains. The near-term pipeline is defined by oral SERDs moving into the adjuvant setting (lidERA positive; CAMBRIA and EMBER-4 pending), CDK4-selective inhibitors, new HER2-low and TROP2 ADCs, and ctDNA-triggered switching, which the FDA endorsed over a negative advisory vote in 2026.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Breast_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Breast_cancer"},{"label":"NCCN Guidelines for Patients and the NCCN breast cancer guideline summary (PMC)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13114725/"},{"label":"SEER Cancer Stat Facts: female breast cancer subtypes (share of cases and five-year relative survival by receptor subtype and stage, SEER 21)","url":"https://seer.cancer.gov/statfacts/html/breast-subtypes.html"},{"label":"Royal College of Pathologists G148: dataset for histopathological reporting of breast disease in surgical excision specimens of breast cancer, version 3, November 2024 (full review due November 2026)","url":"https://www.rcpath.org/resourceLibrary/g148-dataset-for-histopathological-reporting-of-breast-disease-in-surgical-excision-specimens-of-breast-cancer.html"},{"label":"NICE NG101: early and locally advanced breast cancer, diagnosis and management (published 18 July 2018, last updated 14 April 2025)","url":"https://www.nice.org.uk/guidance/ng101/chapter/recommendations"},{"label":"GLOBOCAN breast fact sheet (IARC Global Cancer Observatory, 2024 estimates)","url":"https://gco.iarc.who.int/media/globocan/factsheets/cancers/20-breast-fact-sheet.pdf"}],"tags":["breast","spike"],"related":["adc-generations","trop2-adc-roadmap","oral-serd-plus-cdk46-after-esr1","pi3k-pathway-plus-endocrine","genomic-assay-to-chemo-omission","cdk46-plus-endocrine","breast-her2-positive","tnbc","her2-low-metastatic-breast-cancer","male-breast-cancer","ductal-carcinoma-in-situ"],"cancers":[],"sections":[],"technologies":["endocrine-therapy","cdk46-inhibitor","protac-degrader","adc","liquid-biopsy","digital-pathology-ai","mammography","acupuncture-aromatase-inhibitor-arthralgia","acupuncture-hot-flushes","hypnosis-cancer-care","dance-movement-therapy","peer-support-groups","lymphoedema-decongestive-therapy","shark-cartilage","mrd-testing","rna-seq","kinase-inhibitors","germline-testing","exercise-oncology"],"targets":["estrogen-receptor","cdk4-6","pik3ca","akt","her2","trop2","brca","her3"],"drugs":["guardant360-cdx","therascreen-cdx","her2-testing-assays","caris-mi-cancer-seek","lunit-insight-mmg","epirubicin","ixabepilone","megestrol","thiotepa","toremifene","raloxifene","triptorelin","dexrazoxane","talc-sclerosant","samarium-153-lexidronam","ibandronic-acid","anastrozole"],"companies":["oncolytics-biotech","shenzhen-ionova-life-sciences","treadwell-therapeutics","forward-pharmaceuticals","mbrace-therapeutics","olema-pharmaceuticals","astrazeneca","eli-lilly","novartis","pfizer","roche-genentech","menarini","arvinas","celcuity","gilead","daiichi-sankyo","exact-sciences"],"institutions":[],"pathways":["er-signaling","pi3k-akt-mtor","p53-cell-cycle","breast-cancer-signalling"],"terms":["esr1-mutation","oral-serd","endocrine-resistance","ovarian-function-suppression","late-recurrence","her2-low","ctdna","er-pr-scoring-breast","grade-stage-receptor-breast","nottingham-grade","nottingham-prognostic-index","receptor-conversion-breast","tnm-breast-cancer-editions","who-breast-classification"],"trials":["monaleesa-2","monarch-3","paloma-2","solar-1","capitello-291","inavo120","emerald","ember-3","serena-6","evera","persevera","lidera","postmonarch","tailorx","rxponder","soft-text","pallas-penelope-b","tropics-02","fourlight-1","cambria","tmist","nct07003074","nct06561607","nct07008976","nct07043725","nct07354022","nct07024173","nct07349069","nct05744687","nct05860465","nct07461454","nct05780567","nct05365178","nct06079983","nct05077449","nct07062965","nct06383767","nct06998108","nct07207070","pik3ca-2","nct05232916","nct06954961","simrise","nct06982521","nct05346224","nct07386938","nct07492641","nct07413939","start-b","prime-ii","lumina","import-low","nsabp-b39","eortc-22922","ma-20","dbcg-82bc","nct03725059","nct06065748","nct05840211","nct06016738","nct02107703","nct05646862","nct07085767","nct00099437","nct04711252","nct06112379","nct05587296","nct06757634","nct05038735","nct05950945","nct06380751","nct07647328","nct06760637","nct06790693","nct07205822"],"people":["murray-brunt"],"bottlenecks":[],"keyPapers":["paper-predimed-breast-jama-im-2015","paper-brca-risk-reducing-surgery-jama-2010"],"journals":["breast-cancer-jbcs","breast-cancer-research","breast-cancer-research-and-treatment","clinical-breast-cancer","journal-of-breast-imaging","journal-of-mammary-gland-biology-and-neoplasia","the-breast","the-breast-journal"],"dependsOn":[],"notes":["What this page is called on a report. Anything that says the oestrogen receptor or the progesterone receptor is positive, at 1 percent of nuclei or more, and that HER2 is 0, 1+, or 2+ without amplification, lands here. The report may give a percentage and an intensity, an Allred score out of 8 or an H score out of 300; with modern methods the result is close to all-or-nothing, so 80 percent and 100 percent mean the same thing in practice. Two results send you elsewhere as well: an oestrogen receptor figure of 1 to 10 percent, reported as ER low positive, behaves more like triple-negative disease, and a HER2 result of positive puts the HER2 page in charge of the treatment backbone while this page still explains the endocrine half."],"group":"breast","burden":"HR-positive, HER2-negative disease is 70.1 percent of American cases with a known receptor subtype (SEER 21, 2019 to 2023), so, if the same share holds elsewhere, of the order of 1.7 million of the 2,434,087 breast cancers diagnosed worldwide each year (GLOBOCAN 2024). Most are found early, treated with surgery and endocrine therapy, and spared chemotherapy by genomic assays; five-year relative survival in this group is 95.8 percent, the best of the four receptor boxes (SEER 21, 2016 to 2022). Because it can recur late, it accounts for the majority of the 693,660 annual breast cancer deaths, which is why adjuvant therapy lasts years and tests for late recurrence are a research priority.","subtypes":["Luminal A","Luminal B","HER2-low (~60% of HR+)","ESR1-mutant (acquired)","PIK3CA-mutant (~40%)","Luminal A (low proliferation, best prognosis)","Luminal B (higher proliferation, Ki-67 high, benefits more from chemotherapy and CDK4/6)","HER2-low (IHC 1+/2+ ISH-negative, ~60% of HR+) and HER2-ultralow: eligible for T-DXd","ESR1-mutant (acquired under aromatase inhibitors, 30-40%)","PIK3CA-mutant (~40%), AKT1 or PTEN altered (~10%)","Invasive lobular carcinoma (~10-15%; CDH1 loss, often ER+, distinct metastatic pattern)","Endocrine-resistant primary (relapse within 2 years of adjuvant ET) vs secondary","Male breast cancer (>90% ER+)"],"biomarkers":["ER/PR","HER2 IHC 0/1+/2+ (low, ultralow)","Ki-67","Oncotype DX / MammaPrint / Prosigna","PIK3CA/AKT1/PTEN","ESR1 (ctDNA)","gBRCA","ER and PR by IHC (≥1%; 1-10% 'ER-low' behaves like TNBC)","HER2 IHC 0/1+/2+ with the low and ultralow categories for T-DXd eligibility","Ki-67 (≥20% defines high risk for adjuvant abemaciclib, monarchE cohort 2)","Oncotype DX recurrence score, MammaPrint, Prosigna, Breast Cancer Index (late recurrence, extended ET)","PIK3CA, AKT1, PTEN alterations (tissue or ctDNA) for PI3K/AKT-pathway drugs","ESR1 mutation by ctDNA (serial monitoring endorsed by SERENA-6)","gBRCA1/2 (olaparib, OlympiA)","Menopausal status and oestradiol (for AI eligibility, OFS adequacy)","Bone density (AI-induced loss)","CDK4/6 resistance markers under study: RB1 loss, CCNE1, FGFR1 amplification"],"standardOfCare":[{"setting":"Screening and diagnosis","approach":"Mammography ± tomosynthesis; supplemental MRI for dense breasts or high risk; core biopsy with ER/PR/HER2/Ki-67; AI-assisted reading being deployed.","refs":["mammography","radiology-ai-screening","histopathology-ihc"],"guideline":{"nccn":"Breast Cancer Screening","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Early stage, deciding on chemotherapy","approach":"Genomic assay (Oncotype DX RS ≤25 node-negative or postmenopausal 1-3 nodes; MammaPrint low risk) → endocrine therapy alone; premenopausal RS 16-25 or high clinical risk → chemotherapy or OFS-based escalation.","refs":["tailorx","rxponder","oncotype-dx","mammaprint"],"guideline":{"nccn":"1","version":"NCCN Breast v.2026","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Early stage, adjuvant endocrine therapy","approach":"Postmenopausal: aromatase inhibitor 5-10 years (or tamoxifen → AI switch). Premenopausal: tamoxifen 5-10 years; add OFS (+ AI or tamoxifen) for higher-risk or chemotherapy-treated women (SOFT/TEXT).","refs":["letrozole","tamoxifen","goserelin","soft-text"],"guideline":{"nccn":"1","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Early stage, high risk: adjuvant CDK4/6","approach":"Abemaciclib 2 years for node-positive high-risk (monarchE); ribociclib 3 years for stage II-III including node-negative high-risk (NATALEE). Palbociclib not effective (PALLAS/PENELOPE-B). Olaparib 1 year if gBRCA (OlympiA).","refs":["abemaciclib","ribociclib","monarche","natalee","pallas-penelope-b","olaparib"],"guideline":{"nccn":"1","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Early stage, extended and adjuvant SERD (emerging)","approach":"Extended AI to 10 years for higher-risk (MA.17R, NSABP B-42); adjuvant giredestrant positive in lidERA (2025, not yet approved); CAMBRIA (camizestrant) and EMBER-4 (imlunestrant) ongoing.","refs":["lidera","cambria","giredestrant"]},{"setting":"Metastatic, first line","approach":"CDK4/6 inhibitor + aromatase inhibitor (or fulvestrant): ribociclib or abemaciclib preferred where OS data are valued; palbociclib acceptable. Premenopausal: add OFS. For relapse on/within 12 months of adjuvant ET with PIK3CA mutation: inavolisib + palbociclib + fulvestrant (INAVO120).","refs":["monaleesa-2","monarch-3","paloma-2","inavo120","ribociclib","abemaciclib","palbociclib","inavolisib"],"guideline":{"nccn":"1, preferred","esmoMcbs":"4 (ribociclib, OS)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Metastatic, molecular progression on first line","approach":"Serial ctDNA; on emergent ESR1 mutation before radiographic progression, switch AI → camizestrant and continue the CDK4/6 inhibitor (SERENA-6; accelerated approval 4 Sep 2026).","refs":["serena-6","camizestrant"],"guideline":{"nccn":"Pending inclusion (approval Sep 2026)"}},{"setting":"Metastatic, second line by genotype","approach":"ESR1-mutant: elacestrant, imlunestrant (± abemaciclib), or vepdegestrant. PIK3CA/AKT1/PTEN: capivasertib + fulvestrant; alpelisib + fulvestrant. Any genotype after CDK4/6: gedatolisib + palbociclib + fulvestrant (PIK3CA-wild-type, 2026); everolimus + exemestane or giredestrant (filed); abemaciclib switch (postMONARCH, modest).","refs":["ember-3","emerald","veritac-2","capitello-291","solar-1","gedatolisib","evera","postmonarch","elacestrant","imlunestrant","vepdegestrant","capivasertib"],"guideline":{"nccn":"1 / 2A by agent","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Metastatic, endocrine-resistant: ADC before chemotherapy","approach":"HER2-low or ultralow (~60%): T-DXd (DESTINY-Breast06 chemotherapy-naive; DESTINY-Breast04 after chemotherapy). HER2-zero: sacituzumab govitecan or Dato-DXd after chemotherapy (TROPiCS-02, TROPION-Breast01).","refs":["destiny-breast06","destiny-breast04","tropics-02","tropion-breast01","trastuzumab-deruxtecan","sacituzumab-govitecan","datopotamab-deruxtecan"],"guideline":{"nccn":"1 (T-DXd HER2-low)","esmoMcbs":"4 (DESTINY-Breast04)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Metastatic, chemotherapy and later lines","approach":"Sequential single-agent chemotherapy (capecitabine, taxanes, eribulin, vinorelbine); olaparib/talazoparib if gBRCA; clinical trials; supportive and palliative care integrated early.","refs":["paclitaxel","olaparib","talazoparib"]},{"setting":"Bone-predominant disease and survivorship","approach":"Bisphosphonate or denosumab for bone metastases and AI-induced bone loss; adjuvant bisphosphonates in postmenopausal women; exercise, cardio-oncology, and adherence support.","refs":["exercise-oncology","cardio-oncology"]}],"stateOfArt":["Chemotherapy omission for ~70% of node-negative and most postmenopausal node-positive patients using genomic assays (TAILORx, RxPONDER, MINDACT).","Adjuvant CDK4/6 inhibitors (abemaciclib, ribociclib) cut recurrence in high-risk early disease; the first adjuvant oral SERD (giredestrant, lidERA) is positive and awaiting approval.","First-line CDK4/6 + endocrine therapy with median OS beyond five years (MONALEESA-2: 63.9 months).","Genotype-directed second line: ESR1-mutant → oral SERDs or the first approved PROTAC (vepdegestrant); PIK3CA/AKT/PTEN → inavolisib (OS benefit), capivasertib.","The first ctDNA-triggered treatment switch approved by the FDA (camizestrant, SERENA-6, September 2026), over a negative advisory vote.","ADCs before chemotherapy in endocrine-resistant disease: T-DXd for HER2-low and ultralow (DESTINY-Breast06), TROP2 ADCs for the rest."],"history":[{"year":1896,"title":"Beatson removes ovaries to treat advanced breast cancer","note":"First hormonal therapy for any cancer.","refs":[]},{"year":1958,"title":"Oestrogen receptor discovered (Jensen)","note":"Basis for predicting hormone responsiveness.","refs":[]},{"year":1977,"title":"Tamoxifen approved","note":"The first targeted cancer drug; later shown to reduce mortality by a third over 15 years.","refs":["tamoxifen"]},{"year":1998,"title":"Anastrozole and letrozole approved; tamoxifen for prevention","refs":["letrozole","tamoxifen"]},{"year":2002,"title":"Fulvestrant: first SERD","refs":["fulvestrant"]},{"year":2004,"title":"Oncotype DX launched","note":"Gene-expression recurrence score enters practice.","refs":["oncotype-dx"]},{"year":2012,"title":"Everolimus + exemestane (BOLERO-2)","note":"First targeted agent to overcome endocrine resistance.","refs":["everolimus"]},{"year":2014,"title":"SOFT/TEXT: ovarian suppression in premenopausal women","refs":["soft-text"]},{"year":2015,"title":"Palbociclib: first CDK4/6 inhibitor","refs":["palbociclib","paloma-2"]},{"year":2018,"title":"TAILORx: most women can skip chemotherapy","refs":["tailorx"]},{"year":2019,"title":"Alpelisib: first PI3K inhibitor in breast cancer","refs":["alpelisib","solar-1"]},{"year":2020,"title":"monarchE: adjuvant abemaciclib; PALLAS negative for palbociclib","refs":["monarche","pallas-penelope-b"]},{"year":2021,"title":"MONALEESA-2 final OS: ribociclib extends survival by a year","refs":["monaleesa-2"]},{"year":2022,"title":"HER2-low becomes a treatment category (DESTINY-Breast04)","refs":["destiny-breast04"]},{"year":2023,"title":"Elacestrant (first oral SERD), capivasertib, sacituzumab in HR+","refs":["elacestrant","emerald","capivasertib","capitello-291","tropics-02"]},{"year":2024,"title":"Adjuvant ribociclib (NATALEE); inavolisib approved","refs":["natalee","inavolisib","inavo120"]},{"year":2025,"title":"Imlunestrant approved; INAVO120 OS benefit; T-DXd in HER2-ultralow; evERA and lidERA positive","refs":["imlunestrant","ember-3","destiny-breast06","evera","lidera"]},{"year":2026,"title":"First PROTAC (vepdegestrant), gedatolisib, and the first ctDNA-triggered switch (camizestrant) approved; persevERA fails upfront","refs":["vepdegestrant","veritac-2","gedatolisib","camizestrant","serena-6","persevera"]}],"pipeline":["vepdegestrant","sacituzumab-tirumotecan","datopotamab-deruxtecan","artera-ai-breast","patritumab-deruxtecan","tqb2102","hrs-8080","ipatasertib","rc148","sph4336","yl202","tqb3616","jskn003","kn026","gotistobart","xzp-3287","pf-07248144","esg401","evorpacept","bebt-209","js105","jskn016","hlx22","tersolisib","glsi-100","d-0502","sim0270","zovegalisib","hlx11","rph-051","bgb-43395","ro7771950","tqb2930","avzo-021","serabelisib","sapanisertib","jk08","ep0062","env-501","sys6023","samuraciclib","camizestrant","giredestrant","atirmociclib","cambria","fourlight-1","lidera","evera","imlunestrant","gedatolisib","idea-ctdna-switch-generalised","idea-cdk4-selective-first-line","idea-late-recurrence-interception","mrd-testing"],"openProblems":["Late recurrence: half of relapses occur after year 5 and no test reliably identifies who needs extended or intensified therapy.","Adherence: a third of women stop adjuvant endocrine therapy early because of arthralgia, hot flushes, and sexual side effects.","Sequencing after CDK4/6: no head-to-head trials among oral SERDs, PI3K/AKT agents, everolimus combinations, and ADCs.","Does acting on ctDNA improve survival? SERENA-6 improved PFS; OS and patient-reported outcomes are unresolved, as the ODAC vote showed.","Palbociclib versus ribociclib versus abemaciclib: different survival results without a randomised comparison.","HER2-low scoring reproducibility at IHC 0/1+ determines T-DXd eligibility for millions of patients.","Invasive lobular carcinoma is under-represented in trials despite being 10-15% of cases.","Premenopausal women: whether chemotherapy's benefit in RxPONDER is simply ovarian suppression (NRG-BR009 / OFSET will answer)."],"parent":"breast-cancer"},{"id":"hr-positive-metastatic-post-cdk46","kind":"cancer","name":"HR-positive metastatic breast cancer after CDK4/6 inhibitors","aka":["Endocrine-resistant metastatic breast cancer","ESR1-mutant breast cancer","PIK3CA-mutant breast cancer","AKT pathway-altered breast cancer","Second-line HR-positive metastatic breast cancer"],"tldr":"When hormone-positive breast cancer grows through a CDK4/6 inhibitor, a blood test picks the next drug. Tumours with an acquired ESR1 mutation respond to the oral degraders elacestrant, camizestrant and imlunestrant; tumours with PIK3CA, AKT1 or PTEN changes to capivasertib, inavolisib or alpelisib; and once endocrine options run out, antibody-drug conjugates come before chemotherapy.","summary":"Resistance to first-line endocrine therapy with a CDK4/6 inhibitor follows a few well-mapped routes. Aromatase inhibitors select for mutations in the ligand-binding domain of ESR1 (Y537S, D538G and others) that make the oestrogen receptor active without oestrogen; these are rare in untreated tumours, appear in a third or more of patients at progression and are best detected in circulating tumour DNA. PIK3CA mutations are present from the outset in about 40 percent, and AKT1 mutations and PTEN loss in a further tenth; loss of RB1, cyclin E amplification and FGFR alterations drive CDK4/6 resistance itself. Guidelines now ask for an ESR1 test on plasma at each progression and a PIK3CA, AKT1 and PTEN test on tissue or plasma before the second line.\n\nFor ESR1-mutant disease the oral degraders replaced fulvestrant. EMERALD randomised 478 patients to elacestrant or standard endocrine therapy and halved the risk of progression in the ESR1-mutant group (hazard ratio 0.55), giving the first oral SERD approval in January 2023. SERENA-6 changed the timing: 315 patients on an aromatase inhibitor and CDK4/6 inhibitor whose plasma showed a new ESR1 mutation before any scan showed growth were switched to camizestrant while continuing the CDK4/6 inhibitor, and progression-free survival rose from 9.2 to 16.0 months (hazard ratio 0.44). EMBER-3 (874 patients) showed imlunestrant beat standard endocrine therapy in ESR1-mutant disease (hazard ratio 0.62) and that imlunestrant with abemaciclib beat imlunestrant alone whatever the ESR1 status (hazard ratio 0.57); postMONARCH showed a modest gain from continuing CDK4/6 inhibition with abemaciclib and fulvestrant after progression (6.0 against 5.3 months); the PROTAC degrader vepdegestrant followed in 2026, and giredestrant with everolimus improved progression-free survival in evERA.\n\nFor the PI3K and AKT pathway, SOLAR-1 showed alpelisib with fulvestrant extends progression-free survival from 5.7 to 11.0 months in PIK3CA-mutant tumours at the cost of severe hyperglycaemia in about 37 percent; CAPItello-291 (708 patients) showed capivasertib with fulvestrant helps after a CDK4/6 inhibitor with a hazard ratio of 0.60 overall and 0.50 in tumours with a PIK3CA, AKT1 or PTEN alteration, and was approved in November 2023; INAVO120 moved the mutant-selective inhibitor inavolisib into the first line for PIK3CA-mutant disease relapsing during or soon after adjuvant endocrine therapy, with palbociclib and fulvestrant, extending progression-free survival from 7.3 to 15.0 months and overall survival from 27.0 to 34.0 months. After endocrine therapy is exhausted, trastuzumab deruxtecan comes before chemotherapy for HER2-low and ultralow tumours (DESTINY-Breast06), sacituzumab govitecan extends survival after chemotherapy (TROPiCS-02, 14.4 against 11.2 months) and datopotamab deruxtecan is an alternative (TROPION-Breast01). The order in which to use degraders, pathway inhibitors and antibody-drug conjugates is the open question.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Breast_cancer","links":[{"label":"EMERALD (JCO 2022)","url":"https://doi.org/10.1200/JCO.22.00338"},{"label":"CAPItello-291 (NEJM 2023)","url":"https://doi.org/10.1056/NEJMoa2214131"},{"label":"INAVO120 (NEJM 2024)","url":"https://doi.org/10.1056/NEJMoa2404625"},{"label":"SERENA-6 on ClinicalTrials.gov","url":"https://clinicaltrials.gov/study/NCT04964934"}],"tags":["subtype-page"],"related":["hr-positive-early-high-risk"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["pten-loss"],"trials":["bolero-2"],"people":[],"bottlenecks":[],"keyPapers":["paper-destiny-breast06-nejm-2024","paper-emerald-elacestrant-jco-2022","paper-capitello-291-nejm-2023","paper-solar-1-alpelisib-nejm-2019"],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Nearly every patient treated with a CDK4/6 inhibitor and endocrine therapy for metastatic hormone receptor-positive disease eventually progresses, typically after two to three years; about four in ten tumours carry a PIK3CA mutation and a third or more acquire an ESR1 mutation under aromatase inhibitor pressure.","subtypes":["ESR1-mutant disease acquired under aromatase inhibitors (oral SERDs)","PIK3CA-mutant luminal disease (capivasertib, inavolisib, alpelisib)","AKT1-mutant or PTEN-altered disease (capivasertib)","Endocrine-sensitive relapse without a targetable mutation (fulvestrant with a second CDK4/6 inhibitor, or everolimus)","HER2-low or HER2-ultralow luminal disease (trastuzumab deruxtecan)","Endocrine-refractory disease (antibody-drug conjugates, then chemotherapy)"],"biomarkers":["ESR1 mutation on circulating tumour DNA, retested at each progression","PIK3CA, AKT1 and PTEN alterations on tissue or plasma","HER2 immunohistochemistry score (0, ultralow, 1+, 2+)","Oestrogen receptor persistence on rebiopsy of a metastasis","Germline BRCA1 and BRCA2 (PARP inhibitor eligibility)","Glycated haemoglobin and glucose before PI3K or AKT inhibitors"],"standardOfCare":[{"setting":"ESR1-mutant disease after a CDK4/6 inhibitor","approach":"Elacestrant (EMERALD), imlunestrant (EMBER-3) or vepdegestrant; where available, a switch to camizestrant at the moment ESR1 appears in plasma while continuing the CDK4/6 inhibitor (SERENA-6).","refs":["elacestrant","emerald","imlunestrant","ember-3","camizestrant","serena-6","vepdegestrant","liquid-biopsy"]},{"setting":"PIK3CA, AKT1 or PTEN alteration","approach":"Capivasertib with fulvestrant (CAPItello-291); alpelisib with fulvestrant for PIK3CA (SOLAR-1); inavolisib with palbociclib and fulvestrant for PIK3CA-mutant disease relapsing during or soon after adjuvant endocrine therapy (INAVO120).","refs":["capivasertib","capitello-291","alpelisib","solar-1","inavolisib","inavo120","fulvestrant"]},{"setting":"No targetable alteration","approach":"Fulvestrant with abemaciclib (postMONARCH), everolimus with exemestane, or another endocrine agent; giredestrant with everolimus is emerging (evERA).","refs":["abemaciclib","postmonarch","everolimus","exemestane","evera"]},{"setting":"Endocrine-refractory, HER2-low or ultralow","approach":"Trastuzumab deruxtecan before chemotherapy (DESTINY-Breast06), then sacituzumab govitecan (TROPiCS-02) or datopotamab deruxtecan (TROPION-Breast01) after chemotherapy.","refs":["trastuzumab-deruxtecan","destiny-breast06","sacituzumab-govitecan","tropics-02","datopotamab-deruxtecan","tropion-breast01","her2-low"]},{"setting":"Germline BRCA carriers","approach":"Olaparib (OlympiAD) or talazoparib (EMBRACA) in place of chemotherapy.","refs":["olaparib","olympiad","talazoparib","embraca","gbrca-mutation"]}],"stateOfArt":["A plasma ESR1 test now decides treatment, and SERENA-6 showed switching on the blood result before the scan changes works.","Three oral SERDs and a PROTAC degrader are approved within four years of the first.","Capivasertib and inavolisib brought the AKT and PI3K pathway under control with less hyperglycaemia than alpelisib.","Antibody-drug conjugates sit ahead of chemotherapy in HER2-low luminal disease."],"history":[{"year":2012,"title":"BOLERO-2: everolimus with exemestane after an aromatase inhibitor","refs":["everolimus","exemestane"]},{"year":2013,"title":"ESR1 ligand-binding domain mutations found as the cause of acquired endocrine resistance","refs":[]},{"year":2019,"title":"Alpelisib approved for PIK3CA-mutant disease (SOLAR-1)","refs":["solar-1","alpelisib"]},{"year":2023,"title":"Elacestrant (EMERALD) and capivasertib (CAPItello-291) approved","refs":["emerald","elacestrant","capitello-291","capivasertib"]},{"year":2024,"title":"Inavolisib approved in the first line for PIK3CA-mutant relapse (INAVO120)","refs":["inavo120","inavolisib"]},{"year":2025,"title":"SERENA-6: switch to camizestrant on circulating tumour DNA; imlunestrant approved (EMBER-3)","refs":["serena-6","camizestrant","ember-3","imlunestrant"]},{"year":2026,"title":"Vepdegestrant, the first PROTAC, approved","refs":["vepdegestrant"]}],"pipeline":["vepdegestrant","gedatolisib","giredestrant","camizestrant","cambria","evera","pik3ca-2","tersolisib","atirmociclib","samuraciclib","ipatasertib","liquid-biopsy"],"openProblems":["No trial has compared the sequence of oral SERD, pathway inhibitor and antibody-drug conjugate.","Whether to continue a CDK4/6 inhibitor after progression gives small gains and it is unclear for whom.","PIK3CA and ESR1 mutations often coexist and the combinations to treat both are unproven.","Hyperglycaemia, rash and diarrhoea limit pathway inhibitors in older patients."],"parent":"breast-hr-positive"},{"id":"hyperparathyroidism-jaw-tumour-syndrome","kind":"cancer","name":"Hyperparathyroidism-jaw tumour syndrome (CDC73-related parathyroid carcinoma)","aka":["HPT-JT","HPT-JT syndrome","Hyperparathyroidism-jaw tumour syndrome associated (germline CDC73)","CDC73-related disorder","HRPT2-related hyperparathyroidism"],"tldr":"Hyperparathyroidism-jaw tumour syndrome is an inherited condition in which a faulty CDC73 gene causes parathyroid tumours, and in about one in five people a parathyroid carcinoma, together with bony tumours of the jaw and kidney and womb growths. It matters because it is the commonest inherited route to parathyroid carcinoma and a reason to test the gene in anyone with that cancer.","summary":"The syndrome is autosomal dominant and is caused by germline inactivating mutations of CDC73 (formerly HRPT2), which encodes parafibromin; the gene was identified in 2002 by finding 13 different heterozygous germline mutations in 14 affected families, and somatic mutations in the same gene were then found in most sporadic parathyroid carcinomas (Carpten 2002). Primary hyperparathyroidism is the main finding, usually from a single parathyroid gland (80 percent of cases), unlike the multigland disease of MEN1; fibro-osseous (ossifying fibroma) tumours of the mandible or maxilla, renal cysts, hamartomas or Wilms tumour, and uterine tumours complete the picture (Torresan 2019). Loss of nuclear parafibromin on immunohistochemistry distinguishes parathyroid carcinomas and HPT-JT adenomas from sporadic adenomas (Gill 2006). The WHO endocrine classification lists the syndrome among the genetic tumour syndromes.\n\nHow it differs from its parent: the parent page covers parathyroid carcinoma of any cause, most of it sporadic; this page is the inherited setting in which the cancer arises early and can recur in other glands, so surgery, surveillance and family testing are planned differently. About 15 to 20 percent of people with the syndrome develop parathyroid carcinoma against about 1 percent of all hyperparathyroidism (Kelly 2015; Torresan 2019).\n\nTreatment: surgery is the treatment of choice for the hyperparathyroidism, and the extent, from focused removal of the affected gland to bilateral neck exploration, is debated because further glands can be affected later (Torresan 2019). Carcinoma is treated as on the parent page, with en bloc resection and cinacalcet for uncontrolled calcium; there is no drug trial in this syndrome. Carriers need lifelong calcium and parathyroid hormone monitoring, jaw and renal imaging, and their relatives should be offered CDC73 testing (Torresan 2019).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Hyperparathyroidism-jaw_tumor_syndrome","links":[{"label":"NCI PDQ: parathyroid cancer treatment","url":"https://www.cancer.gov/types/parathyroid/patient/parathyroid-treatment-pdq"},{"label":"Orphanet: hyperparathyroidism-jaw tumour syndrome (ORPHA:99880)","url":"https://www.orpha.net/en/disease/detail/99880"},{"label":"Carpten 2002, Nature Genetics: HRPT2 (CDC73), encoding parafibromin, is mutated in HPT-JT","url":"https://doi.org/10.1038/ng1048"},{"label":"Torresan 2019, Int J Endocrinol: clinical features, treatment and surveillance of HPT-JT (review)","url":"https://doi.org/10.1155/2019/1761030"},{"label":"Gill 2006, Am J Surg Pathol: loss of parafibromin distinguishes parathyroid carcinoma and HPT-JT adenomas","url":"https://doi.org/10.1097/01.pas.0000209827.39477.4f"},{"label":"Kelly 2015, J Oral Maxillofac Surg: HPT-JT case report and genetic review","url":"https://doi.org/10.1016/j.joms.2014.09.008"}],"tags":["subtype-page","wave4","rare"],"related":["parathyroid-carcinoma","men1-syndrome","wilms-tumor","multiple-endocrine-neoplasia"],"cancers":[],"sections":[],"technologies":["germline-testing"],"targets":["cdc73"],"drugs":["cinacalcet"],"companies":[],"institutions":[],"pathways":[],"terms":["hereditary-cancer-syndromes"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"Orphanet lists it as a rare disease (ORPHA:99880); about 100 cases had been published by 2015 and the true incidence is unknown (Kelly 2015). Parathyroid carcinoma develops in about 15 to 20 percent of affected people (Kelly 2015; Torresan 2019).","subtypes":["HPT-JT with parathyroid adenoma or atypical parathyroid tumour","HPT-JT with parathyroid carcinoma (about 15 to 20 percent of carriers)","CDC73-related familial isolated hyperparathyroidism"],"biomarkers":["Germline CDC73 mutation","Loss of nuclear parafibromin on immunohistochemistry","Calcium and parathyroid hormone","Jaw and renal imaging"],"standardOfCare":[{"setting":"Hyperparathyroidism and carcinoma","approach":"Parathyroid surgery for hyperparathyroidism; carcinoma treated as the parent page describes, with cinacalcet for uncontrolled calcium and CDC73 testing of relatives.","refs":["parathyroid-carcinoma","cinacalcet","germline-testing"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"parathyroid-carcinoma"},{"id":"hypopharyngeal-cancer","kind":"cancer","name":"Hypopharyngeal cancer","aka":["Hypopharynx cancer","Pyriform sinus cancer","Piriform fossa cancer","Postcricoid cancer"],"tldr":"Cancer of the hypopharynx, the funnel behind the voice box, is the head and neck cancer with the worst outlook because it grows silently and spreads to the neck early. Treatment is chemoradiation to keep the larynx where possible, or removal of the larynx and pharynx with reconstruction for the most extensive tumours.","summary":"Hypopharyngeal squamous cell carcinoma arises in the pyriform sinuses, the posterior pharyngeal wall or the postcricoid region, the mucosa-lined funnel between the oropharynx and the oesophagus that wraps around the back of the larynx. It causes few symptoms until it is large: a sore throat, pain referred to the ear, difficulty swallowing and, most often, a lump in the neck, so most patients present with stage III or IV disease, and many are malnourished. Tobacco and alcohol are the causes, and a second primary in the oesophagus or lung is common enough that panendoscopy is part of staging.\n\nThe landmark trial is EORTC 24891, reported by Lefebvre in 1996, which compared induction cisplatin and fluorouracil followed by radiotherapy in responders with total laryngectomy and partial pharyngectomy followed by radiotherapy: survival was no different and a proportion of survivors in the chemotherapy arm kept a working larynx, establishing larynx preservation as a legitimate aim. Concurrent cisplatin chemoradiation, shown in RTOG 91-11 to preserve the larynx best in laryngeal cancer, became the usual organ-preserving approach for hypopharyngeal cancer too, with cetuximab and radiotherapy (Bonner, which included hypopharyngeal tumours) for patients who cannot have cisplatin.\n\nTumours that have destroyed the laryngeal cartilage, fixed the vocal cords or extended into the cervical oesophagus, and those that recur after chemoradiation, are treated by laryngopharyngectomy, reconstructed with a free jejunal, anterolateral thigh or radial forearm flap, or a gastric pull-up when the oesophagus is involved, followed by postoperative radiotherapy or chemoradiation for extranodal extension or positive margins. Recurrent or metastatic disease is treated as for other head and neck squamous cell carcinoma with pembrolizumab-based therapy. Smoking cessation, nutritional support and swallowing rehabilitation are part of every plan.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Hypopharyngeal_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Hypopharyngeal_cancer"}],"tags":["subtype-page","head-and-neck"],"related":["laryngeal-cancer","oropharyngeal-cancer","hpv-negative-head-and-neck-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bonner-cetuximab-radiotherapy-nejm-2006","paper-eortc-24891-larynx-preservation-lefebvre-jnci-1996"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"About 84,000 new cases a year worldwide, overwhelmingly in men who smoke and drink heavily; it presents late, spreads to the neck early and has among the lowest survival of any head and neck site.","subtypes":["Pyriform (piriform) sinus cancer, the commonest hypopharyngeal site","Posterior pharyngeal wall cancer","Postcricoid cancer (historically linked to iron-deficiency Plummer-Vinson syndrome in women)","Hypopharyngeal cancer extending to the larynx or cervical oesophagus"],"biomarkers":["Stage, cartilage invasion and oesophageal extension on CT or MRI","Vocal cord fixation","Second primary in the oesophagus or lung at panendoscopy","Nutritional status","PD-L1 combined positive score (recurrent disease)"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Panendoscopy with biopsy, CT of the neck and chest, PET-CT for stage III to IV, and assessment of swallowing and nutrition before treatment.","refs":["pet-ct"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Early disease (T1 to T2, node-negative)","approach":"Radiotherapy alone, or transoral or open partial pharyngectomy in selected small tumours, with treatment of both sides of the neck.","refs":["imrt-igrt","tors"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Locally advanced, larynx preservable","approach":"Concurrent cisplatin chemoradiation to 70 Gy; induction cisplatin-fluorouracil (EORTC 24891) or docetaxel-cisplatin-fluorouracil followed by radiotherapy in some centres.","refs":["cisplatin","fluorouracil","docetaxel","chemoradiation","imrt-igrt","rtog-91-11"],"guideline":{"nccn":"Category 1 (concurrent chemoradiation)","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Cannot have cisplatin","approach":"Cetuximab with radiotherapy (Bonner), or carboplatin-based chemoradiation.","refs":["cetuximab","bonner-cetuximab-rt","carboplatin"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Extensive disease (cartilage destruction, oesophageal extension) or recurrence after radiotherapy","approach":"Total laryngopharyngectomy with neck dissection and free-flap or gastric pull-up reconstruction, then postoperative radiotherapy or cisplatin chemoradiation by pathology.","refs":["imrt-igrt","cisplatin","chemoradiation"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Recurrent or metastatic","approach":"Pembrolizumab alone or with platinum-fluorouracil (KEYNOTE-048).","refs":["pembrolizumab","keynote-048","recurrent-metastatic-hnscc"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Prevention","approach":"Smoking cessation and alcohol reduction; no screening programme exists.","refs":["smoking-cessation-after-diagnosis","alcohol-reduction-labelling"]}],"stateOfArt":["Organ preservation with chemoradiation is standard for most locally advanced tumours, but survival is poorer than for laryngeal cancer at the same stage.","Free-flap reconstruction has made laryngopharyngectomy safer and restored swallowing for many.","Immunotherapy around surgery (KEYNOTE-689, NIVOPOSTOP) applies to hypopharyngeal cancer, which was well represented in both trials."],"history":[{"year":1996,"title":"EORTC 24891: induction chemotherapy and radiotherapy preserve the larynx without loss of survival","refs":[]},{"year":2003,"title":"RTOG 91-11: concurrent cisplatin chemoradiation preserves the larynx best","refs":["rtog-91-11"]},{"year":2006,"title":"Cetuximab with radiotherapy (Bonner) includes hypopharyngeal tumours","refs":["bonner-cetuximab-rt"]},{"year":2019,"title":"KEYNOTE-048: pembrolizumab first line in recurrent disease","refs":["keynote-048"]},{"year":2025,"title":"NIVOPOSTOP: nivolumab after surgery for high-risk disease","refs":["nivopostop"]}],"pipeline":["nivopostop","keynote-689","adaptive-radiotherapy","pembrolizumab"],"openProblems":["Survival has barely improved in thirty years.","Choosing between preservation and laryngopharyngectomy in the most extensive tumours.","Swallowing, stricture and aspiration after chemoradiation.","Late presentation in the heavy smokers and drinkers who get the disease."],"parent":"laryngeal-cancer"},{"id":"aml-idh","kind":"cancer","name":"IDH1- and IDH2-mutated acute myeloid leukaemia","aka":["IDH-mutant AML","IDH1-mutated AML","IDH2-mutated AML"],"tldr":"IDH-mutated acute myeloid leukaemia has a faulty metabolic enzyme that floods cells with a chemical that blocks maturation. Pills that shut the enzyme off, ivosidenib for IDH1 and enasidenib or olutasidenib for IDH2 and IDH1, let the leukaemia cells mature, and ivosidenib with azacitidine tripled survival in older patients.","summary":"Mutant isocitrate dehydrogenase 1 or 2 makes the oncometabolite 2-hydroxyglutarate, which jams the DNA-demethylating enzymes that blood cells need to differentiate. IDH2 mutations (R140, R172) occur in roughly one in eight adult AML and IDH1 (R132) in about one in twelve. They co-occur with NPM1 and DNMT3A mutations and are enriched in older patients. Blocking the mutant enzyme does not kill the blast directly; it restores differentiation over weeks, and the price is differentiation syndrome in around a fifth of patients.\n\nEnasidenib, approved in 2017 for relapsed or refractory IDH2-mutated AML on a phase 1/2 study, was the first IDH inhibitor; its phase 3 IDHENTIFY trial against conventional care in older relapsed patients did not lengthen survival. Ivosidenib followed in 2018 for relapsed IDH1-mutated disease and, after AGILE (2022), for newly diagnosed patients unfit for intensive chemotherapy: ivosidenib plus azacitidine gave a median overall survival of 24.0 months against 7.9 months with azacitidine alone (hazard ratio 0.44). Olutasidenib, a second IDH1 inhibitor, was approved for relapsed disease in 2022.\n\nIDH-mutated leukaemias also respond unusually well to venetoclax with azacitidine, the VIALE-A subgroup showing the largest survival gain of any genotype, so the field now debates ivosidenib-azacitidine against venetoclax-azacitidine and tests triplets of all three. Resistance comes through second-site IDH mutations, isoform switching from IDH1 to IDH2, and emergence of RAS-pathway clones.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Isocitrate_dehydrogenase","links":[{"label":"Wikipedia: Isocitrate dehydrogenase","url":"https://en.wikipedia.org/wiki/Isocitrate_dehydrogenase"},{"label":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}],"tags":["subtype-page"],"related":["aml-flt3","aml-npm1-kmt2a","aml-older-unfit","aml-secondary"],"cancers":[],"sections":[],"technologies":["epigenetic-drugs"],"targets":["idh"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["differentiation-syndrome","eln-risk","hma"],"trials":["viale-a"],"people":[],"bottlenecks":[],"keyPapers":["paper-agile-ivosidenib-azacitidine-nejm-2022","paper-eln-2022-aml-dohner-blood-2022","paper-ivosidenib-idh1-dinardo-nejm-2018","paper-enasidenib-idh2-stein-blood-2017"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About one in five adults with acute myeloid leukaemia carries a mutation in IDH1 or IDH2, more often in older patients and in leukaemia arising from a prior marrow disorder.","subtypes":["IDH1 R132-mutated AML (ivosidenib, olutasidenib)","IDH2 R140- and R172-mutated AML (enasidenib)","IDH-mutated AML with NPM1 co-mutation","IDH-mutated secondary AML from myelodysplastic syndromes"],"biomarkers":["IDH1 R132 and IDH2 R140/R172 mutations","2-hydroxyglutarate level","NPM1, DNMT3A and RAS co-mutations","ELN 2022 risk group","IDH mutation clearance as MRD"],"standardOfCare":[{"setting":"Newly diagnosed IDH1-mutated, unfit for intensive chemotherapy","approach":"Ivosidenib plus azacitidine (AGILE) or venetoclax plus azacitidine; triplets in trials.","refs":["ivosidenib","azacitidine","agile","venetoclax","viale-a"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Newly diagnosed, fit for intensive chemotherapy","approach":"7+3 induction with consolidation and transplant by ELN risk; IDH inhibitors added in trials.","refs":["cytarabine-7-3","allogeneic-hsct","ivosidenib"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Relapsed or refractory","approach":"Ivosidenib or olutasidenib for IDH1, enasidenib for IDH2; venetoclax-based combinations; transplant in responders.","refs":["ivosidenib","olutasidenib","enasidenib","venetoclax","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}}],"stateOfArt":["Ivosidenib plus azacitidine is a first-line standard for unfit IDH1-mutated patients after AGILE tripled median survival.","Three approved IDH inhibitors cover both genes in relapsed disease.","Venetoclax-azacitidine is especially active in IDH-mutated leukaemia, so two targeted options compete in the same patients."],"history":[{"year":2009,"title":"IDH1 mutations found in AML after their discovery in glioma","refs":["idh"]},{"year":2017,"title":"Enasidenib: first IDH inhibitor approved, for relapsed IDH2-mutated AML","refs":["enasidenib"]},{"year":2018,"title":"Ivosidenib approved for relapsed IDH1-mutated AML","refs":["ivosidenib"]},{"year":2022,"title":"AGILE: ivosidenib plus azacitidine lengthens life in newly diagnosed unfit patients; olutasidenib approved","refs":["agile","ivosidenib","olutasidenib"]}],"pipeline":["olutasidenib","venetoclax","myelomatch","epigenetic-drugs"],"openProblems":["Ivosidenib-azacitidine or venetoclax-azacitidine first, or all three together.","Managing differentiation syndrome without stopping an effective drug.","Isoform switching and second-site mutations that escape a single IDH inhibitor."],"parent":"aml"},{"id":"gist-imatinib-resistant","kind":"cancer","name":"Imatinib-resistant GIST","aka":["Imatinib-refractory GIST","GIST with secondary KIT mutations","Advanced GIST after imatinib","Multidrug-resistant GIST"],"tldr":"Imatinib-resistant GIST is disease that has grown through the first drug, usually because the tumour has acquired a second KIT mutation that imatinib cannot block. Sunitinib, regorafenib and ripretinib are given in turn; ripretinib, in the INVICTUS trial, extended progression-free survival from 1 to 6 months in patients who had exhausted the other three.","summary":"Primary resistance to imatinib, progression within six months, is rare in KIT exon 11 disease and mostly seen in PDGFRA D842V and KIT or PDGFRA wild-type tumours. Secondary resistance is the rule in metastatic disease: after a median of around two years, clones with a second KIT mutation emerge, either in the ATP-binding pocket encoded by exons 13 and 14 or in the activation loop encoded by exons 17 and 18, and different metastases often carry different mutations. Tissue biopsy of one lesion therefore under-represents the disease, and circulating tumour DNA has become the way to map the resistant clones. Isolated progression in a single lesion can be treated with surgery, ablation or embolisation while imatinib continues.\n\nSunitinib, which inhibits KIT, PDGFRA and VEGF receptors, was approved in 2006 after a placebo-controlled trial in which it extended time to progression from 6 to 27 weeks; it works best against exon 13 and 14 secondary mutations and poorly against activation loop mutations. Regorafenib followed in 2013 after the GRID trial, extending progression-free survival from 0.9 to 4.8 months in the third line. Imatinib rechallenge (RIGHT) and continuation beyond progression slow growth because sensitive clones persist. Toxicity, hand-foot skin reaction, hypertension, fatigue and hypothyroidism, accumulates through the sequence.\n\nRipretinib, a switch-control inhibitor that locks KIT in the inactive conformation regardless of the secondary mutation, was tested fourth line in INVICTUS (Lancet Oncology 2020): median progression-free survival rose from 1.0 to 6.3 months and overall survival from 6.6 to 15.1 months, and the FDA approved it in May 2020. In INTRIGUE it was not superior to sunitinib in the second line overall, but patients with exon 11 primary and exon 17 or 18 secondary mutations did better on ripretinib and those with exon 13 or 14 mutations better on sunitinib, so the INSIGHT trial now tests mutation-directed choice, the first prospective genotype-guided sequencing in GIST. Next-generation KIT inhibitors, IDRX-42, NB003 and bezuclastinib with sunitinib, aim to cover all the secondary mutations at once.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Ripretinib","links":[{"label":"INVICTUS (Lancet Oncology 2020)","url":"https://pubmed.ncbi.nlm.nih.gov/32511981/"},{"label":"INTRIGUE (JCO 2022)","url":"https://pubmed.ncbi.nlm.nih.gov/35947817/"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Ripretinib"}],"tags":["subtype-page"],"related":["gist-kit-exon-11","gist-pdgfra-d842v"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["grid","nct03673501"],"people":[],"bottlenecks":[],"keyPapers":["paper-demetri-sunitinib-gist-lancet-2006","paper-grid-regorafenib-gist-lancet-2013","paper-invictus-ripretinib-lancet-oncol-2020","paper-intrigue-ripretinib-vs-sunitinib-jco-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Almost every patient with metastatic GIST eventually progresses on imatinib, most within two to three years, through secondary mutations in KIT; three further kinase inhibitors are approved for this stage, each adding months rather than years.","subtypes":["GIST with KIT exon 13 or 14 secondary mutation (ATP-binding pocket; sunitinib-sensitive)","GIST with KIT exon 17 or 18 secondary mutation (activation loop; ripretinib, regorafenib)","Polyclonal resistance with multiple secondary KIT mutations","Fourth-line GIST after imatinib, sunitinib and regorafenib (INVICTUS)","Isolated progression on imatinib (local treatment)"],"biomarkers":["Secondary KIT mutations by circulating tumour DNA (exons 13, 14, 17, 18)","Primary KIT or PDGFRA mutation (exon 11 versus 9 versus D842V)","Growth within a treated lesion on CT (nodule within a mass)","Imatinib plasma level to exclude underdosing","Thyroid function and blood pressure on sunitinib and regorafenib"],"standardOfCare":[{"setting":"Progression on imatinib 400 mg","approach":"Confirm adherence and plasma level; dose escalation to 800 mg (especially exon 9); local therapy for isolated progression while continuing imatinib.","refs":["imatinib","thermal-ablation","kit"]},{"setting":"Second line","approach":"Sunitinib; ripretinib as an alternative, preferred where the secondary mutation is in exon 17 or 18 (INTRIGUE subgroup; INSIGHT ongoing).","refs":["sunitinib","ripretinib","nct03673501","insight-gist","liquid-biopsy"]},{"setting":"Third line","approach":"Regorafenib (GRID).","refs":["regorafenib"]},{"setting":"Fourth line and beyond","approach":"Ripretinib (INVICTUS); imatinib rechallenge; trials of next-generation KIT inhibitors.","refs":["ripretinib","invictus","imatinib","idrx-42","nb003","bezuclastinib"]}],"stateOfArt":["Four approved kinase inhibitors give sequential control, and continuing some KIT inhibition to the end is standard.","Circulating tumour DNA genotyping is starting to choose the drug by the resistant clone rather than by line number.","Broad-spectrum KIT inhibitors in development aim to make resistance a single problem rather than a moving target."],"history":[{"year":2005,"title":"Secondary KIT mutations identified as the mechanism of imatinib resistance (Antonescu, Heinrich)","refs":["kit"]},{"year":2006,"title":"Sunitinib approved after imatinib failure","refs":["sunitinib"]},{"year":2013,"title":"GRID: regorafenib approved in the third line","refs":["regorafenib"]},{"year":2020,"title":"INVICTUS: ripretinib approved in the fourth line","refs":["invictus","ripretinib"]},{"year":2022,"title":"INTRIGUE: ripretinib not superior to sunitinib second line; genotype subgroups diverge","refs":["nct03673501","ripretinib","sunitinib"]}],"pipeline":["insight-gist","idrx-42","nb003","bezuclastinib","ripretinib","liquid-biopsy"],"openProblems":["Polyclonal resistance means no single inhibitor covers every metastasis.","Each later line adds months, not years, and toxicity accumulates.","Whether circulating tumour DNA-guided sequencing improves survival is unproven until INSIGHT reports."],"parent":"gist"},{"id":"tnbc-immunomodulatory","kind":"cancer","name":"Immunomodulatory triple-negative breast cancer (IM)","aka":["IM subtype","Immunomodulatory TNBC","Basal-like immune-activated (BLIA, Burstein)"],"tldr":"Immunomodulatory triple-negative breast cancers are the ones packed with immune cells. The 2016 re-analysis showed the signature comes from those lymphocytes rather than the tumour, so today the same idea is captured by counting tumour-infiltrating lymphocytes on the biopsy, which predicts a better outcome and is used to test whether some small tumours need less treatment.","summary":"The immunomodulatory (IM) subtype was enriched for immune cell processes, cytokine and antigen-processing pathways and immune signal transduction (Lehmann 2011). Laser-capture microdissection then showed those transcripts were contributed by infiltrating lymphocytes, so IM was removed as a tumour-intrinsic subtype in the four-way refinement (Lehmann 2016). Burstein's basal-like immune-activated (BLIA) subtype, defined by Stat signalling and cytokine expression, had the best disease-free and disease-specific survival of the four Burstein subtypes, and basal-like immunosuppressed (BLIS), marked by the immunosuppressing molecule VTCN1, the worst (Burstein 2015). In clinical practice the equivalent measurement is stromal tumour-infiltrating lymphocytes, and the parent page's biomarker and stage I rows carry the de-escalation cohorts; PD-L1 expression on immune cells is the treatment-selecting marker in metastatic disease (the glossary term for CPS 10 has the figures).\n\nA research classification by gene expression (Lehmann 2011, refined 2016), not a test the NHS runs; treatment follows the triple-negative rows on the parent page.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Tumor-infiltrating_lymphocytes","links":[{"label":"Lehmann, J Clin Invest 2011: identification of human triple-negative breast cancer subtypes (BL1, BL2, IM, M, MSL, LAR)","url":"https://doi.org/10.1172/jci45014"},{"label":"Lehmann, PLoS One 2016: refinement of triple-negative breast cancer molecular subtypes to four (TNBCtype-4)","url":"https://doi.org/10.1371/journal.pone.0157368"},{"label":"Burstein, Clin Cancer Res 2015: four triple-negative subtypes (LAR, MES, BLIS, BLIA) with distinct prognoses","url":"https://doi.org/10.1158/1078-0432.ccr-14-0432"},{"label":"Cortes, N Engl J Med 2022: KEYNOTE-355 overall survival by PD-L1 combined positive score","url":"https://doi.org/10.1056/nejmoa2202809"}],"tags":["breast","tnbc","subtype-page"],"related":["tnbc","tnbc-mesenchymal-stem-like","tnbc-basal-like-1"],"cancers":[],"sections":[],"technologies":[],"targets":["pdl1","pd1"],"drugs":[],"companies":[],"institutions":[],"pathways":["pd1-checkpoint"],"terms":["tils","pd-l1-cps-10-tnbc","cps"],"trials":["keynote-355"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"One of the six 2011 Lehmann subtypes, traced in 2016 to infiltrating lymphocytes; its clinical counterpart, high stromal tumour-infiltrating lymphocytes, is scored on routine slides.","subtypes":["Basal-like immune-activated (BLIA), best prognosis of the Burstein subtypes","Basal-like immunosuppressed (BLIS), worst prognosis"],"biomarkers":["Stromal tumour-infiltrating lymphocytes on the biopsy (prognostic; de-escalation trials)","PD-L1 combined positive score (metastatic pembrolizumab eligibility at 10 or more)","Immune gene expression (research)"],"standardOfCare":[{"setting":"Metastatic, PD-L1 CPS 10 or more","approach":"Pembrolizumab with chemotherapy (KEYNOTE-355; NICE TA801) or with sacituzumab govitecan (ASCENT-04); the rows on the parent page.","refs":["keynote-355","pembrolizumab","cps","pd-l1-cps-10-tnbc"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"tnbc"},{"id":"incidental-gallbladder-cancer","kind":"cancer","name":"Incidental gallbladder cancer (found after cholecystectomy)","aka":["Incidentally discovered gallbladder cancer","Unsuspected gallbladder cancer","Occult gallbladder cancer","IGBC"],"tldr":"Incidental gallbladder cancer is cancer the pathologist finds in a gallbladder removed for gallstones or inflammation, when nobody suspected it. It is the commonest way this cancer is found early enough to cure. Whether a second operation is needed depends on how deep the tumour went: none for the earliest layers, a radical operation at a specialist centre for T1b or deeper.","summary":"Between one in 400 and one in 110 gallbladders removed for presumed benign disease contains a cancer (0.25 to 0.89 percent; Soreide 2019), and the share rises steeply with age (0.08 percent under 60 versus 0.67 percent over 60 in Denmark, where every specimen is examined; the surgeon had noted macroscopic changes in 27 of 28 cancers, Lerche-Jorgensen 2025). About half are pT2 and a third pT1. Patients whose cancer is confined to the mucosa (T1a or less) have five-year survival of up to 100 percent after the cholecystectomy alone; for T1b or deeper tumours re-resection is recommended, though its type, extent and timing remain debated (Soreide 2019; AHPBA consensus, Aloia 2015). Ten US academic centres found re-resection between 4 and 8 weeks after the first operation gave the longest survival (median 40.4 months, against 17.4 months under 4 weeks and 22.4 months over 8 weeks), the interval allowing new CT or MRI and PET-CT, which can show residual or distant disease and prevent a futile operation (Ethun 2017; Soreide 2019). Perforation of the gallbladder at the first operation raises the risk of dissemination, and the risk of peritoneal spread rises with each T category. Port-site metastases occurred in 18.6 percent of laparoscopic cases before 2000 and 10.3 percent since (Berger-Richardson 2017); routine excision of the port sites does not improve survival (Soreide 2019). Routine staging laparoscopy before re-resection is not needed for every stage. Adjuvant chemotherapy after re-resection is poorly documented and probably underused (Soreide 2019).\n\nGetting patients to the right place is the weak link: in 27 Dutch secondary hospitals only 53.9 percent of 243 patients eligible for re-resection (pT1b to pT3, M0) were referred to a tertiary centre, and in nearly half of the non-referred the reason was not documented (van Dooren 2024). In the UK the specialist hepatobiliary multidisciplinary team is the route; two UK units have described their approach to suspected cancer, using intraoperative frozen section to decide on extending surgery at the first operation (Chan 2022, Liverpool; Banh 2024, London). The UK pathway page carries referral detail; this page covers what the finding means.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Cholecystectomy","links":[{"label":"Soreide, Br J Surg 2019: systematic review of incidental gallbladder cancer after cholecystectomy","url":"https://doi.org/10.1002/bjs.11035"},{"label":"Ethun, JAMA Surg 2017: timing of re-resection for incidental gallbladder cancer","url":"https://doi.org/10.1001/jamasurg.2016.3642"},{"label":"Berger-Richardson, Surgery 2017: trends in port-site metastasis after laparoscopic resection of incidental gallbladder cancer","url":"https://doi.org/10.1016/j.surg.2016.08.007"},{"label":"Lerche-Jorgensen, Dan Med J 2025: incidental gallbladder cancer in 9,698 cholecystectomies","url":"https://doi.org/10.61409/a11240787"},{"label":"van Dooren, BJS Open 2024: referral of incidental gallbladder cancer from 27 Dutch secondary centres","url":"https://doi.org/10.1093/bjsopen/zrae013"},{"label":"AHPBA expert consensus statement on gallbladder cancer (Aloia, HPB 2015)","url":"https://doi.org/10.1111/hpb.12444"},{"label":"Chan, J Surg Oncol 2022: intraoperative frozen section for suspected gallbladder cancer (Liverpool)","url":"https://doi.org/10.1002/jso.26726"},{"label":"Banh, Int J Surg 2024: single-stage management of suspected gallbladder cancer with frozen section (London)","url":"https://doi.org/10.1097/js9.0000000000001456"},{"label":"Cho, Ann Hepatobiliary Pancreat Surg 2026: extended versus simple cholecystectomy for T1b, meta-analysis","url":"https://doi.org/10.14701/ahbps.26-091"},{"label":"Rhodin, HPB 2024: simple versus radical cholecystectomy for T1b in the National Cancer Database","url":"https://doi.org/10.1016/j.hpb.2024.01.012"},{"label":"Roa, Nature Reviews Disease Primers 2022: gallbladder cancer","url":"https://doi.org/10.1038/s41572-022-00398-y"},{"label":"NHS: tests and next steps for gallbladder cancer","url":"https://www.nhs.uk/conditions/gallbladder-cancer/tests-and-next-steps/"}],"tags":["gallbladder","biliary","subtype-page"],"related":["gallbladder","gallbladder-carcinoma-in-situ-and-dysplasia","gallbladder-adenocarcinoma","cystic-duct-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["capecitabine"],"companies":[],"institutions":[],"pathways":[],"terms":["simple-cholecystectomy","radical-cholecystectomy","port-site-metastasis","cystic-duct-margin","segment-ivb-v-resection"],"trials":["bilcap"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"0.25 to 0.89 percent of all cholecystectomy specimens in the series reviewed by Soreide (2019); 0.29 percent of 9,698 in a Danish department, 0.08 percent under 60 and 0.67 percent over 60 (Lerche-Jorgensen 2025). Roa and colleagues say most gallbladder cancers are found this way.","subtypes":["Incidental gallbladder cancer, Tis or T1a (cholecystectomy alone is curative)","Incidental gallbladder cancer, T1b or deeper (re-resection recommended)","Incidental gallbladder cancer with a positive cystic duct margin (bile duct resection added)","Incidental gallbladder cancer with gallbladder perforation or bile spillage at the first operation (higher risk of peritoneal and port-site spread)"],"biomarkers":["T category on the specimen (the single decision-maker)","Cystic duct margin status","Whether the gallbladder was perforated or bile spilled at the first operation","Interval since cholecystectomy (4 to 8 weeks target)","Residual or distant disease on interval CT, MRI and PET-CT"],"standardOfCare":[{"setting":"Tis or T1a with a clear cystic duct margin","approach":"No further surgery; the simple cholecystectomy is treatment enough.","refs":["simple-cholecystectomy","cystic-duct-margin"]},{"setting":"T1b, T2 or T3, no metastases","approach":"Referral to a hepatobiliary centre; interval CT or MRI and PET-CT; radical cholecystectomy (liver bed plus portal lymphadenectomy) at 4 to 8 weeks, with bile duct resection only for a positive cystic duct margin; port sites not routinely excised; adjuvant capecitabine after.","refs":["radical-cholecystectomy","segment-ivb-v-resection","lymphadenectomy","cystic-duct-margin","port-site-metastasis","pet-ct","capecitabine","bilcap"],"guideline":{"version":"AHPBA consensus statement (HPB 2015); Soreide systematic review (Br J Surg 2019)","url":"https://doi.org/10.1002/bjs.11035"}},{"setting":"Residual disease found on interval imaging or at re-operation","approach":"Systemic treatment as for advanced gallbladder cancer.","refs":["gemcitabine-cisplatin","durvalumab","pembrolizumab"]}],"stateOfArt":["The 4 to 8 week window is the practical lesson of the last decade: long enough for imaging and referral, not so long that the disease progresses.","PET-CT before re-resection spares some patients an operation that would not have helped.","Port-site excision has been dropped from routine practice."],"history":[],"pipeline":[],"openProblems":["Whether T1b tumours need re-resection: two 2024 to 2026 analyses disagree on disease-specific benefit.","How many UK patients with an incidental cancer reach a hepatobiliary centre is not published.","Whether every gallbladder needs histological examination, or a selective policy based on age and the surgeon's inspection would be safe."],"parent":"gallbladder"},{"id":"indolent-systemic-mastocytosis","kind":"cancer","name":"Indolent and smouldering systemic mastocytosis","aka":["ISM","Indolent SM","Smouldering systemic mastocytosis","Bone marrow mastocytosis","Non-advanced systemic mastocytosis"],"tldr":"Indolent systemic mastocytosis is the common, slow form of this rare blood disorder, in which KIT-mutant mast cells build up in the marrow and skin and release histamine that causes flushing, itching, stomach pain, bone thinning and sometimes severe allergic reactions. Life expectancy is near normal, antihistamines and adrenaline control symptoms, and low-dose avapritinib was approved in 2023.","summary":"Systemic mastocytosis is a clonal myeloid neoplasm of mast cells driven in more than nine in ten patients by the KIT D816V mutation. The indolent form, which accounts for most cases, is defined by the WHO and ICC criteria of multifocal mast cell aggregates in the marrow with abnormal CD25 or CD2 or CD30 expression, raised serum tryptase and the KIT mutation, without the organ damage ('C findings') that defines advanced disease; smouldering disease has a higher mast cell burden ('B findings') but still no organ damage, and bone marrow mastocytosis lacks skin lesions. Patients suffer from mediator release: flushing, urticaria pigmentosa, pruritus, abdominal cramps, diarrhoea, brain fog, fatigue and, in a substantial minority, anaphylaxis, classically after insect stings; osteoporosis and fractures are common. Hereditary alpha-tryptasaemia, a common germline duplication of the tryptase gene, raises baseline tryptase and worsens symptoms in some patients and must be accounted for when interpreting tryptase levels. Progression to advanced disease is uncommon, and mutations in SRSF2, ASXL1 or RUNX1 identify the minority at risk.\n\nManagement for decades was symptomatic: H1 and H2 antihistamines, cromoglicate, leukotriene antagonists, proton-pump inhibitors, omalizumab for recurrent anaphylaxis, adrenaline autoinjectors for every patient, venom immunotherapy after sting anaphylaxis, and bisphosphonates for osteoporosis, with cladribine or interferon alfa for the few with intolerable symptoms. The KIT D816V-selective inhibitor avapritinib changed that: the PIONEER trial (NEJM Evidence 2023) randomised 212 patients with moderate to severe symptoms to avapritinib 25 mg daily or placebo on top of best supportive care and showed a greater fall in total symptom score, in serum tryptase, in KIT D816V allele burden and in marrow mast cells, and avapritinib was approved for indolent systemic mastocytosis in the United States in May 2023 and in Europe later that year; it does not carry the intracranial bleeding risk seen at higher doses in advanced disease but is avoided when platelets are low. Newer KIT D816V inhibitors, elenestinib (HARBOR) and bezuclastinib (Summit), are in randomised trials aiming for greater selectivity, and the disease is otherwise followed with tryptase, KIT allele burden and bone density.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Mastocytosis","links":[{"label":"PIONEER (NEJM Evidence 2023)","url":"https://doi.org/10.1056/EVIDoa2200339"},{"label":"NCCN Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Mastocytosis"}],"tags":["subtype-page","haematologic"],"related":["advanced-systemic-mastocytosis","systemic-mastocytosis","essential-thrombocythaemia"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","liquid-biopsy","histopathology-ihc","flow-cytometry-mrd"],"targets":["kit"],"drugs":["avapritinib","elenestinib","bezuclastinib","cladribine","interferon-alfa"],"companies":[],"institutions":[],"pathways":[],"terms":["driver-mutation","molecular-response"],"trials":["nct03731260","nct04910685","nct05186753"],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2022-myeloid-khoury-leukemia-2022","paper-pioneer-avapritinib-indolent-systemic-mastocytosis-nejm-evid-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"The large majority of systemic mastocytosis; life expectancy is close to normal, but symptoms from mast cell mediators, anaphylaxis risk and osteoporosis affect quality of life for years.","subtypes":["Indolent systemic mastocytosis with skin involvement (urticaria pigmentosa)","Indolent systemic mastocytosis without skin involvement","Bone marrow mastocytosis (marrow only, low tryptase, anaphylaxis-prone)","Smouldering systemic mastocytosis (high burden, B findings, no organ damage)","Indolent systemic mastocytosis with hereditary alpha-tryptasaemia","Indolent systemic mastocytosis with recurrent anaphylaxis (venom immunotherapy, omalizumab)"],"biomarkers":["Serum tryptase (adjusted for hereditary alpha-tryptasaemia copy number)","KIT D816V by high-sensitivity PCR in blood (allele burden tracks response)","Marrow mast cell aggregates with CD25, CD2 and CD30 expression","B findings (marrow burden over 30 percent, tryptase over 200 ng/mL, organomegaly) defining smouldering disease","SRSF2, ASXL1 and RUNX1 mutations (progression risk)","Bone density scan (osteoporosis)"],"standardOfCare":[{"setting":"Diagnosis","approach":"Serum tryptase, KIT D816V testing in peripheral blood, bone marrow biopsy with flow cytometry, tryptase gene copy number, bone density scan and screening for B and C findings.","refs":["histopathology-ihc","flow-cytometry-mrd","kit","driver-mutation"],"guideline":{"version":"NCCN Guidelines: Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Symptom control","approach":"H1 and H2 antihistamines, cromoglicate, leukotriene antagonists, proton-pump inhibitors; omalizumab for recurrent anaphylaxis; adrenaline autoinjectors for all; venom immunotherapy after sting anaphylaxis; bisphosphonates for osteoporosis.","refs":["epro-symptom-monitoring"],"guideline":{"version":"NCCN Guidelines: Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Moderate to severe symptoms despite supportive care","approach":"Avapritinib 25 mg daily (PIONEER, approved 2023), avoided when platelets are below 50 x 10^9/L; cladribine or interferon alfa as older cytoreductive options.","refs":["avapritinib","nct03731260","cladribine","interferon-alfa","kinase-inhibitors"],"guideline":{"version":"NCCN Guidelines: Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Trials","approach":"Elenestinib (HARBOR) and bezuclastinib (Summit) as more selective KIT D816V inhibitors.","refs":["elenestinib","nct04910685","bezuclastinib","nct05186753"],"guideline":{"version":"NCCN Guidelines: Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Monitoring","approach":"Tryptase, KIT allele burden and blood count yearly; bone density; marrow re-examination only if progression is suspected.","refs":["liquid-biopsy","molecular-response"],"guideline":{"version":"NCCN Guidelines: Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}}],"stateOfArt":["Avapritinib is the first disease-modifying drug approved for indolent systemic mastocytosis.","Peripheral blood KIT D816V testing has replaced marrow for diagnosis and monitoring in many centres.","Hereditary alpha-tryptasaemia testing explains discordant tryptase levels."],"history":[{"year":1949,"title":"Ellis describes systemic mastocytosis at autopsy","refs":[]},{"year":1995,"title":"KIT D816V identified as the driver mutation","refs":["kit"]},{"year":2016,"title":"Hereditary alpha-tryptasaemia described, explaining raised tryptase in some patients","refs":[]},{"year":2022,"title":"WHO and ICC classifications refine indolent, smouldering and bone marrow mastocytosis criteria","refs":[]},{"year":2023,"title":"PIONEER published; avapritinib approved for indolent systemic mastocytosis","refs":["avapritinib","nct03731260"]}],"pipeline":["avapritinib","elenestinib","bezuclastinib","nct04910685","nct05186753"],"openProblems":["Whether avapritinib alters the long-term course or only symptoms is unknown.","Anaphylaxis remains life-threatening and unpredictable.","Symptoms correlate poorly with mast cell burden.","Many patients wait years for a diagnosis."],"parent":"systemic-mastocytosis"},{"id":"all-infant","kind":"cancer","name":"Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year)","aka":["Infant ALL","KMT2A-rearranged infant leukaemia","MLL-rearranged infant ALL"],"tldr":"Leukaemia diagnosed in the first year of life is a different disease from leukaemia in older children: most cases carry a broken KMT2A gene and respond poorly to chemotherapy, and fewer than half of infants were cured for twenty years. One course of the immune drug blinatumomab after induction raised two-year disease-free survival from about half to over 80 percent in a pilot study.","summary":"Infant ALL presents with very high white counts, organomegaly, central nervous system involvement and often skin infiltrates. About 75 to 80 percent of cases carry a rearrangement of KMT2A (MLL) with one of many partner genes, commonly AFF1 (AF4), MLLT1 (ENL) or MLLT3 (AF9); the blasts are CD10-negative, express myeloid markers, and can switch lineage to a myeloid phenotype under CD19-directed therapy. KMT2A-rearranged infant leukaemia has one of the quietest genomes in cancer, with almost no other mutations, and depends on the fusion protein's partnership with menin and DOT1L to keep the HOXA gene programme switched on. Age under six months, a white count above 300 x 10^9/L and a poor response to a week of prednisone define the high-risk group.\n\nThe Interfant consortium has run the world's infant ALL trials since 1999. Interfant-99 reported four-year event-free survival of 47 percent with a hybrid ALL and AML regimen. Interfant-06, which randomised early intensification with AML-type courses against ALL-type courses, found no difference: six-year event-free survival was 46.1 percent and overall survival 58.2 percent overall, and allogeneic transplant helped only the high-risk group. In 2023 the consortium reported a pilot of 30 KMT2A-rearranged infants given one 28-day course of blinatumomab after Interfant-06 induction: two-year disease-free survival 81.6 percent against 49.4 percent in matched Interfant-06 controls, and overall survival 93.3 percent against 65.8 percent, with no infant relapsing during blinatumomab and no lineage switch in the first two years. Interfant-21 now gives blinatumomab to every KMT2A-rearranged infant.\n\nMenin inhibitors are the targeted therapy this disease waited for: revumenib produced remissions in heavily pretreated KMT2A-rearranged leukaemias in AUGMENT-101, which enrolled infants from 30 days of age, and was approved in November 2024 for relapsed or refractory KMT2A-rearranged acute leukaemia from the age of one; trials are moving it into first-line infant therapy alongside blinatumomab. The unsolved problems are the infants who relapse within the first year despite everything, the very young and very high-count infants for whom transplant remains a blunt tool, lineage switch to myeloid leukaemia under CD19 pressure, the neurotoxicity of intensive chemotherapy given to a developing brain, and the fact that trials in a disease with a few hundred cases a year worldwide take a decade each.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia","links":[{"label":"Wikipedia: Acute lymphoblastic leukaemia","url":"https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia"},{"label":"NCI PDQ: Childhood ALL Treatment","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}],"tags":["subtype-page","paediatric"],"related":["aml-npm1-kmt2a","all-paediatric-relapsed","all-paediatric-high-risk","all-ph-like","all-paediatric-ph-positive","all-paediatric-standard-risk"],"cancers":[],"sections":[],"technologies":["t-cell-engager","menin-inhibitors","allogeneic-hsct"],"targets":["kmt2a","menin","cd19"],"drugs":[],"companies":[],"institutions":[],"pathways":["menin-kmt2a"],"terms":["mrd","efs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-augment-101-revumenib-menin-nature-2023","paper-interfant-06-pieters-jco-2019","paper-blinatumomab-infant-all-van-der-sluis-nejm-2023","paper-interfant-99-lancet-2007"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Infants under one year make up 2 to 4 percent of childhood ALL; about three quarters of them carry a KMT2A rearrangement, and their cure rate has lagged the rest of childhood leukaemia for decades.","subtypes":["KMT2A-rearranged infant ALL, medium risk (aged 6 months or over, or younger with white count below 300 x 10^9/L and good prednisone response)","KMT2A-rearranged infant ALL, high risk (under 6 months with white count 300 x 10^9/L or more, or poor prednisone response)","KMT2A-germline infant ALL (about a quarter; treated like older-child ALL with a better outcome)","Infant ALL with lineage switch to acute myeloid leukaemia under CD19-directed therapy"],"biomarkers":["KMT2A rearrangement by FISH or RNA sequencing, and partner gene","Age at diagnosis (under or over 6 months)","Presenting white cell count","Prednisone response at day 8","Flow cytometry MRD at end of induction","CD10-negative B-cell immunophenotype with myeloid markers","CNS status"],"standardOfCare":[{"setting":"Induction","approach":"Interfant backbone: a week of prednisone, then dexamethasone, vincristine, cytarabine, daunorubicin and asparaginase with intrathecal therapy.","refs":["prednisone","dexamethasone","vincristine","cytarabine","daunorubicin","asparaginase","methotrexate","interfant-06"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Post-induction, KMT2A-rearranged","approach":"One 28-day course of blinatumomab after induction (Interfant-21), then Interfant-06 consolidation and maintenance.","refs":["blinatumomab","interfant-06","cytarabine","methotrexate","mercaptopurine","kmt2a"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"High risk","approach":"Allogeneic transplant in first remission after blinatumomab and consolidation.","refs":["allogeneic-hsct","blinatumomab"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Relapsed or refractory","approach":"Revumenib (approved from the age of one) or trials of menin inhibitors; blinatumomab or CD19 CAR T-cells; transplant.","refs":["revumenib","ziftomenib","blinatumomab","tisagenlecleucel","augment-101","idea-menin-infant-all","allogeneic-hsct"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}}],"stateOfArt":["A single blinatumomab course after induction raised two-year disease-free survival from about half to over 80 percent in the Interfant pilot, the first advance in infant ALL in twenty years.","Revumenib is the first targeted drug for KMT2A-rearranged leukaemia, approved for relapsed disease from the age of one.","Interfant-06 showed intensifying chemotherapy with AML-type courses does not help."],"history":[{"year":1999,"title":"Interfant-99 opens: the first international infant ALL trial","refs":[]},{"year":2007,"title":"Interfant-99 reports four-year event-free survival of 47 percent","refs":[]},{"year":2019,"title":"Interfant-06: AML-type intensification adds nothing; six-year event-free survival 46 percent","refs":["interfant-06"]},{"year":2023,"title":"Blinatumomab after induction: two-year disease-free survival 82 percent in the Interfant pilot","refs":["blinatumomab"]},{"year":2024,"title":"Revumenib approved for relapsed KMT2A-rearranged acute leukaemia after AUGMENT-101","refs":["revumenib","augment-101"]}],"pipeline":["blinatumomab","revumenib","ziftomenib","menin-inhibitors","idea-menin-infant-all","augment-101"],"openProblems":["Infants who relapse within the first year despite blinatumomab.","Lineage switch to myeloid leukaemia under CD19-directed therapy.","Fitting a menin inhibitor into first-line therapy without adding toxicity to a developing brain and marrow."],"parent":"all-leukemia"},{"id":"inflammatory-breast-cancer","kind":"cancer","name":"Inflammatory breast cancer","aka":["IBC","T4d breast cancer","Inflammatory carcinoma of the breast"],"tldr":"Inflammatory breast cancer does not usually form a lump. The breast becomes red, swollen, warm and heavy over weeks, with skin thickened like orange peel, because cancer cells have blocked the lymph channels in the skin. It is often mistaken for infection, is always at least stage III, and needs chemotherapy first, then mastectomy and radiotherapy, with HER2 or immune drugs added by subtype.","summary":"Inflammatory breast cancer is a clinical diagnosis, staged T4d: rapid onset over six months or less of erythema and oedema covering at least a third of the breast, often with warmth, heaviness and peau d'orange, with or without a palpable mass. Tumour emboli in the dermal lymphatics on a skin punch biopsy support the diagnosis but are not required, and their absence does not exclude it. Because the picture mimics mastitis, women are often given antibiotics first; any presumed infection that does not settle within a week or two in a woman who is not breastfeeding needs imaging and biopsy. Staging includes PET-CT or CT and bone scan, because roughly a third of patients in registry series have distant metastases at diagnosis. Compared with other breast cancers a higher share are HER2-positive or triple-negative and fewer are hormone receptor-positive, and no mutation unique to the inflammatory phenotype has been found.\n\nTreatment is trimodality and the order is fixed. Systemic therapy comes first: an anthracycline and taxane, with trastuzumab and pertuzumab throughout for HER2-positive disease and a pembrolizumab-based regimen for triple-negative disease by extrapolation from KEYNOTE-522, since inflammatory cases were few in the landmark trials. Response on examination and imaging then permits a modified radical mastectomy with axillary dissection; breast conservation, sentinel node biopsy alone, skin-sparing incisions and immediate reconstruction are avoided because the disease is in the skin lymphatics. Post-mastectomy radiotherapy to the chest wall and regional nodes follows in every patient, with bolus to bring the dose to the skin and a higher dose for poor responders. Endocrine therapy, completion of a year of HER2 therapy with trastuzumab emtansine or trastuzumab deruxtecan if disease remained, and olaparib or capecitabine for residual triple-negative disease follow the rules of non-inflammatory cancer.\n\nOutcomes have improved but remain the worst of any breast presentation: before chemotherapy almost no patient lived more than a few years after surgery, and even with trimodality treatment well under half of patients are alive at five years in registry series, with pathological complete response the strongest predictor of who will be. The MD Anderson programme that began giving chemotherapy before surgery in the 1970s and the dedicated inflammatory breast cancer clinics that followed have defined the standards, and an international expert consensus in 2011 fixed the diagnostic criteria; trials restricted to inflammatory disease remain scarce, so most evidence is borrowed. Whether immunotherapy and antibody-drug conjugates close the gap, whether radiotherapy can be intensified safely, and what drives the inflammatory phenotype are the open questions.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Inflammatory_breast_cancer","links":[{"label":"NCI: inflammatory breast cancer","url":"https://www.cancer.gov/types/breast/ibc-fact-sheet"},{"label":"International expert panel consensus (Annals of Oncology 2011)","url":"https://doi.org/10.1093/annonc/mdq345"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Inflammatory_breast_cancer"}],"tags":["subtype-page"],"related":["tnbc","breast-her2-positive","breast-hr-positive","paget-disease-of-the-nipple"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":["naoto-ueno","massimo-cristofanilli","gabriel-hortobagyi"],"bottlenecks":["b-rare-cancers","b-trial-diversity"],"keyPapers":["paper-keynote-522-nejm-2022","paper-dawood-inflammatory-breast-consensus-ann-oncol-2011","paper-rueth-inflammatory-breast-trimodality-jco-2014"],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"A rare form, about one to five percent of breast cancers in most series but commoner in younger women and in Black women, and responsible for a disproportionate share of breast cancer deaths.","subtypes":["HER2-positive inflammatory ductal carcinoma (trastuzumab and pertuzumab with chemotherapy)","Triple-negative inflammatory breast cancer (chemotherapy with immunotherapy by extrapolation)","Hormone receptor-positive inflammatory breast cancer (endocrine therapy after trimodality treatment)","Primary inflammatory breast cancer (new diagnosis) and secondary inflammatory recurrence","De novo metastatic inflammatory breast cancer (roughly a third at diagnosis)"],"biomarkers":["Clinical criteria: rapid onset, erythema and oedema over at least a third of the breast (T4d)","Dermal lymphatic tumour emboli on skin punch biopsy (supportive, not required)","Oestrogen receptor, progesterone receptor and HER2 (a higher share are HER2-positive or triple-negative)","PET-CT staging for distant disease at diagnosis","Response on examination and imaging after neoadjuvant chemotherapy","Germline BRCA1 and BRCA2 in younger and triple-negative cases"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Skin punch biopsy and core biopsy with receptor testing, clinical photography, bilateral mammography and ultrasound, and PET-CT or CT with bone scan because distant spread is common at presentation.","refs":["core-needle-biopsy","histopathology-ihc","mammography","ultrasound","pet"]},{"setting":"Systemic therapy first","approach":"Anthracycline and taxane chemotherapy; trastuzumab and pertuzumab throughout for HER2-positive disease; pembrolizumab-based chemotherapy for triple-negative disease by extrapolation from KEYNOTE-522.","refs":["doxorubicin","paclitaxel","trastuzumab","pertuzumab","pembrolizumab","keynote-522"]},{"setting":"Surgery","approach":"Modified radical mastectomy with axillary dissection after response to chemotherapy; breast conservation, sentinel node biopsy alone and skin-sparing approaches are avoided, and reconstruction is deferred until after radiotherapy.","refs":["mastectomy"]},{"setting":"Radiotherapy","approach":"Post-mastectomy radiotherapy to the chest wall and regional nodes in every patient, with bolus and often a higher dose for poor responders.","refs":["imrt-igrt"]},{"setting":"After trimodality treatment","approach":"Endocrine therapy for hormone receptor-positive disease; trastuzumab emtansine or trastuzumab deruxtecan for residual HER2-positive disease (KATHERINE, DESTINY-Breast05); olaparib or capecitabine for residual triple-negative disease as in non-inflammatory cancer.","refs":["tamoxifen","letrozole","trastuzumab-emtansine","trastuzumab-deruxtecan","katherine","destiny-breast05","olaparib","capecitabine","olympia"]}],"stateOfArt":["Trimodality treatment in a fixed order, chemotherapy then mastectomy then radiotherapy, is the standard everywhere.","HER2-positive inflammatory disease has gained most from dual antibody therapy and antibody-drug conjugates.","Dedicated inflammatory breast cancer clinics and an international consensus have standardised diagnosis.","Inflammatory disease is now written into breast trial eligibility rather than excluded."],"history":[{"year":1814,"title":"Charles Bell describes the purple, swollen breast that precedes death","refs":[]},{"year":1924,"title":"Lee and Tannenbaum coin the term inflammatory carcinoma","refs":[]},{"year":1974,"title":"MD Anderson gives chemotherapy before surgery in inflammatory breast cancer","refs":["gabriel-hortobagyi","doxorubicin"]},{"year":2006,"title":"First dedicated inflammatory breast cancer clinic and research programme opens at MD Anderson","refs":["massimo-cristofanilli","naoto-ueno"]},{"year":2011,"title":"International expert consensus on diagnosis and treatment","refs":[]},{"year":2021,"title":"Pembrolizumab-based regimen extended to triple-negative inflammatory disease","refs":["keynote-522","pembrolizumab"]}],"pipeline":["pembrolizumab","trastuzumab-deruxtecan","sacituzumab-govitecan","mrd-testing","liquid-biopsy"],"openProblems":["Diagnosis is delayed because the picture is mistaken for infection.","No molecular driver of the inflammatory phenotype has been found.","Trials restricted to inflammatory disease are rare, so treatment is extrapolated.","Local recurrence on the chest wall remains common in poor responders despite radiotherapy."],"parent":"breast-cancer"},{"id":"inflammatory-myofibroblastic-tumour","kind":"cancer","name":"Inflammatory myofibroblastic tumour (IMT)","aka":["IMT","Pulmonary inflammatory myofibroblastic tumour","Inflammatory pseudotumour","Epithelioid inflammatory myofibroblastic sarcoma"],"tldr":"IMT is a rare tumour, grouped with the sarcomas, of spindle cells mixed with inflammatory cells, most often in the lung or abdomen of children and young adults. Surgery cures most, and about half carry an ALK gene fusion, so the ALK-blocking pill crizotinib is approved for those that cannot be removed, one of the first targeted approvals for a childhood solid tumour.","summary":"IMT is an intermediate-grade mesenchymal neoplasm of myofibroblastic spindle cells with a plasma cell and lymphocyte infiltrate. Around half harbour ALK rearrangements with diverse partners (TPM3, TPM4, CLTC, RANBP2 and others); most ALK-negative cases carry ROS1, NTRK3, PDGFRB or RET fusions, so nearly every IMT has a druggable kinase fusion. The epithelioid inflammatory myofibroblastic sarcoma variant, driven by RANBP2-ALK or RRBP1-ALK, is aggressive and intra-abdominal. Presentation ranges from an incidental lung mass to fever, weight loss and anaemia from cytokine release.\n\nComplete surgical resection is curative for most patients and remains first line. For unresectable, recurrent or metastatic ALK-positive IMT, crizotinib produced objective responses in the EORTC 90101 CREATE phase 2 (Lancet Respir Med 2018) and in the Children's Oncology Group ADVL0912 study, leading to FDA approval in July 2022 for adults and children aged one year and older, the first approval of an ALK inhibitor for a non-lung indication in children. Second-generation ALK inhibitors (alectinib, ceritinib, lorlatinib) are used at resistance, and ROS1 or NTRK fusion cases respond to crizotinib, entrectinib, larotrectinib or repotrectinib respectively.\n\nOpen questions are treatment duration in children who reach complete response, whether neoadjuvant kinase inhibition can make surgery less mutilating, and how to manage the ALK-negative, fusion-negative minority.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Inflammatory_myofibroblastic_tumour","links":[{"label":"NCI PDQ: childhood soft tissue sarcoma (includes IMT)","url":"https://www.cancer.gov/types/soft-tissue-sarcoma/hp/child-soft-tissue-treatment-pdq"},{"label":"FDA approval of crizotinib for ALK-positive IMT (archived copy)","url":"https://web.archive.org/web/20260213082319/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizotinib-alk-positive-inflammatory-myofibroblastic-tumor"},{"label":"EORTC 90101 CREATE (Lancet Respir Med 2018)","url":"https://doi.org/10.1016/S2213-2600(18)30116-4"}],"tags":["nci-coverage","rare","sarcoma","paediatric"],"related":["gist","dermatofibrosarcoma-protuberans","desmoid-tumour","tenosynovial-giant-cell-tumour","pecoma"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","limb-salvage-surgery","rna-seq"],"targets":["alk","ros1","ntrk","pdgfra","ret"],"drugs":["crizotinib","alectinib","ceritinib","lorlatinib","entrectinib","larotrectinib","repotrectinib","imatinib"],"companies":["pfizer","childrens-oncology-group","curie-nki-eortc"],"institutions":[],"pathways":["rtk-activation","ras-mapk"],"terms":["gene-fusion","race-for-children-act","rare-cancers"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers"],"keyPapers":["paper-schoffski-lancet-respir-med"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"Rare at any age but the most common primary lung tumour of children; also arises in the mesentery, bladder and soft tissue.","subtypes":["Classic IMT (ALK-rearranged, about half)","ALK-negative IMT (ROS1, NTRK3, PDGFRB, RET fusions)","Epithelioid inflammatory myofibroblastic sarcoma (RANBP2-ALK or RRBP1-ALK)"],"biomarkers":["ALK immunohistochemistry and FISH or RNA fusion panel","ROS1, NTRK, PDGFRB, RET fusions in ALK-negative tumours","Inflammatory markers (anaemia, raised CRP) as systemic markers","Site and resectability"],"standardOfCare":[{"setting":"Resectable","approach":"Complete surgical excision; no adjuvant therapy in most cases, surveillance imaging for recurrence.","refs":["limb-salvage-surgery"],"guideline":{"version":"NCI PDQ: childhood soft tissue sarcoma","url":"https://www.cancer.gov/types/soft-tissue-sarcoma/hp/child-soft-tissue-treatment-pdq"}},{"setting":"Unresectable, recurrent or metastatic, ALK-positive","approach":"Crizotinib (FDA approval July 2022, children 1 year and older and adults); alectinib, ceritinib or lorlatinib at progression.","refs":["crizotinib","alectinib","lorlatinib","ceritinib"],"guideline":{"nccn":"Category 2A","version":"NCCN Soft Tissue Sarcoma"}},{"setting":"Unresectable, ALK-negative with other fusion","approach":"Match to fusion: entrectinib or crizotinib for ROS1, larotrectinib or entrectinib for NTRK, imatinib for PDGFRB; steroids or NSAIDs for symptom control in indolent disease.","refs":["entrectinib","larotrectinib","imatinib","repotrectinib"]}],"stateOfArt":["IMT is close to a fully genotype-directed disease: nearly every tumour carries a kinase fusion with an approved inhibitor.","The 2022 crizotinib approval used adult (CREATE) and paediatric (COG ADVL0912) data together, a model for age-agnostic approvals under the RACE for Children Act.","Epithelioid inflammatory myofibroblastic sarcoma, which no treatment used to touch, responds to ALK inhibition and is managed with sequential ALK inhibitors.","Surgery remains curative for the majority; drugs are for the minority with unresectable disease."],"history":[{"year":1939,"title":"First description as inflammatory pseudotumour of the lung","refs":[]},{"year":1999,"title":"ALK rearrangements found in IMT","note":"Griffin and colleagues identify 2p23 rearrangements, the first ALK fusions outside lymphoma.","refs":[]},{"year":2010,"title":"Crizotinib response in ALK-positive IMT","note":"Butrynski and colleagues, NEJM case report.","refs":[]},{"year":2018,"title":"EORTC 90101 CREATE phase 2","note":"Schöffski and colleagues, Lancet Respir Med: high response rate in ALK-positive IMT.","refs":["crizotinib"]},{"year":2022,"title":"Crizotinib approved for ALK-positive IMT","note":"FDA, 14 July 2022, adults and children aged 1 year and older.","refs":["crizotinib","race-for-children-act"]}],"pipeline":["crizotinib","lorlatinib","repotrectinib"],"openProblems":["How long to continue ALK inhibition in children with complete response, and whether surgery after response can allow stopping.","The fusion-negative minority: RNA sequencing to find drivers.","Rare aggressive epithelioid variants that develop resistance mutations to sequential ALK inhibitors."],"parent":"sarcoma"},{"id":"hcc-intermediate","kind":"cancer","name":"Intermediate hepatocellular carcinoma (BCLC B)","aka":["Intermediate-stage HCC","Multinodular HCC","TACE-eligible hepatocellular carcinoma","BCLC B"],"tldr":"Intermediate hepatocellular carcinoma is several tumours inside a working liver, too many to cut out but with no spread beyond it. The standard treatment for two decades has been chemoembolisation through the hepatic artery, and trials now show that adding immunotherapy and anti-angiogenic drugs to it delays progression.","summary":"BCLC stage B covers multinodular hepatocellular carcinoma with preserved liver function, no cancer-related symptoms and no macrovascular invasion or extrahepatic spread. The 2022 BCLC update split it into three groups: patients whose tumour burden allows downstaging or extended transplant criteria, those with well-defined nodules suited to transarterial chemoembolisation, and those with diffuse, infiltrative or bilobar disease who do better moving straight to systemic therapy, a change described as treatment stage migration.\n\nTransarterial chemoembolisation delivers chemotherapy-loaded particles or drug-eluting beads into the arteries feeding the tumours and blocks them; two randomised trials in 2002 (Llovet in Barcelona and Lo in Hong Kong) showed it prolongs survival, and it has been the standard since. Radioembolisation with yttrium-90 microspheres is an alternative with fewer post-procedure symptoms, though phase 3 trials against sorafenib in more advanced disease were negative. Repeated embolisation damages the liver, so the ART and other scores guide when to stop and switch.\n\nTwo phase 3 trials published in the Lancet in 2025 added systemic therapy to chemoembolisation: EMERALD-1 combined durvalumab and bevacizumab with TACE and extended median progression-free survival from 8.2 to 15.0 months, and LEAP-012 combined lenvatinib and pembrolizumab with TACE and extended it from 10.0 to 14.6 months; overall survival was immature in both at first analysis. EMERALD-3, testing durvalumab and tremelimumab with TACE, reported a benefit in 2026. The atezolizumab-bevacizumab and other advanced-stage regimens are also used directly in patients with high tumour burden, and ongoing trials compare systemic therapy alone with the combinations.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Transcatheter_arterial_chemoembolization","links":[{"label":"EMERALD-1 (Lancet 2025)","url":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02551-0/abstract"},{"label":"LEAP-012 (Lancet 2025)","url":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02575-3/abstract"},{"label":"BCLC 2022 update (J Hepatol)","url":"https://pubmed.ncbi.nlm.nih.gov/34801630/"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Transcatheter_arterial_chemoembolization"}],"tags":["subtype-page"],"related":["hcc-advanced","hcc-early"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-himalaya-nejm-evidence-2022","paper-llovet-tace-lancet-2002","paper-emerald-1-lancet-2025","paper-leap-012-lancet-2025"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Multiple tumours confined to a liver that still functions, without vein invasion or spread; the most heterogeneous BCLC stage, for which the 2022 update expects a median survival above two and a half years with chemoembolisation and now systemic therapy.","subtypes":["Multinodular HCC in a cirrhotic liver within the up-to-seven criteria (downstaging or extended transplant)","Well-defined nodules suitable for TACE","Diffuse or infiltrative bilobar HCC (systemic therapy first)","TACE-refractory HCC","BCLC B treated with TACE plus systemic therapy (EMERALD-1, LEAP-012)"],"biomarkers":["Tumour number and size (up-to-seven and other burden criteria)","Child-Pugh and ALBI liver function before and after each embolisation","Alpha-fetoprotein response","Modified RECIST response on contrast imaging","Absence of macrovascular invasion and extrahepatic spread (defines the stage)"],"standardOfCare":[{"setting":"Well-defined nodules, preserved liver function","approach":"Transarterial chemoembolisation, conventional or with drug-eluting beads, repeated on demand; radioembolisation as an alternative.","refs":["tace","tace-term","radioembolisation-tare","bclc-staging"]},{"setting":"TACE plus systemic therapy","approach":"Durvalumab with bevacizumab (EMERALD-1) or lenvatinib with pembrolizumab (LEAP-012) added to TACE, where approved; durvalumab-tremelimumab with TACE after EMERALD-3.","refs":["emerald-1","leap-012","emerald-3","durvalumab","bevacizumab","lenvatinib","pembrolizumab","tremelimumab","tace-plus-systemic"]},{"setting":"High burden or diffuse disease","approach":"Systemic therapy as for advanced disease (atezolizumab-bevacizumab or durvalumab-tremelimumab) instead of embolisation.","refs":["atezolizumab","bevacizumab","durvalumab","tremelimumab","imbrave150","himalaya"]},{"setting":"Within transplant criteria after downstaging","approach":"Chemoembolisation or radioembolisation as a bridge, then liver transplantation.","refs":["liver-transplant-oncology","bridging-therapy","tace"]}],"stateOfArt":["Chemoembolisation remains the backbone, but the 2022 BCLC update sends patients with diffuse or high-burden disease straight to systemic therapy.","EMERALD-1 and LEAP-012 are the first phase 3 trials to improve on TACE alone in twenty years.","Whether the combinations lengthen life, not just time to progression, is still awaited."],"history":[{"year":2002,"title":"Llovet and Lo randomised trials: chemoembolisation prolongs survival","refs":["tace"]},{"year":2010,"title":"Drug-eluting bead TACE (PRECISION V) matches conventional TACE with less toxicity","refs":["tace"]},{"year":2022,"title":"BCLC update subdivides intermediate stage and introduces treatment stage migration","refs":["bclc-staging"]},{"year":2025,"title":"EMERALD-1 and LEAP-012: systemic therapy plus TACE delays progression","refs":["emerald-1","leap-012"]},{"year":2026,"title":"EMERALD-3: durvalumab-tremelimumab plus TACE reported positive","refs":["emerald-3"]}],"pipeline":["emerald-3","tace-plus-systemic","radioembolisation-tare","durvalumab","lenvatinib"],"openProblems":["No overall survival gain yet shown for TACE combinations.","Which patients should skip embolisation and go straight to systemic therapy.","Liver damage from repeated embolisation limits later treatment options."],"parent":"hcc"},{"id":"neuroblastoma-intermediate-risk","kind":"cancer","name":"Intermediate-risk neuroblastoma","aka":["INRG intermediate-risk neuroblastoma","Unresectable localised neuroblastoma","Stage M neuroblastoma in infants"],"tldr":"Intermediate-risk neuroblastoma sits between the tumours that go away on their own and the high-risk disease that needs everything. A few cycles of moderate chemotherapy followed by surgery cure most children, and trials have spent twenty years showing how few cycles are enough.","summary":"The intermediate-risk group takes in L2 tumours in children with unfavourable histology or 11q aberration, L2 tumours in children over 18 months, metastatic stage M disease in infants under 18 months, and stage MS with unfavourable biology, all without MYCN amplification. These tumours will not regress reliably and cannot be removed safely at diagnosis, but they respond to chemotherapy and rarely relapse after it. The question the trials have asked is not which drug but how little: each cycle of carboplatin, etoposide, cyclophosphamide and doxorubicin adds hearing loss, infertility and cardiac risk to a child who will live for seventy years.\n\nCOG A3961, reported in the New England Journal of Medicine in 2010, gave 479 children four or eight cycles of that four-drug chemotherapy according to histology and ploidy and operated when the tumour became resectable: three-year overall survival was 96 percent and event-free survival 88 percent, establishing a biology-based reduction of therapy. ANBL0531 then cut further, giving two cycles to the most favourable subset and adding response-based escalation for the rest, with three-year event-free survival 83.2 percent and overall survival 94.9 percent; infants with stage M disease and children with 11q loss or unfavourable histology needed the longer course. SIOPEN's LINES trial applies the same approach in Europe, and infants with stage MS disease who need treatment for a bulky liver receive the same drugs briefly.\n\nRadiotherapy is used only for life-threatening disease that does not respond, and the residual mass after chemotherapy is often left in place when resection would risk the kidney or a nerve root. Children with 11q aberration or unfavourable histology, and infants with stage M disease and diploid tumours, are the ones who still relapse and the ones whose therapy the next trials will not shorten. Telomere maintenance mechanisms (ATRX, TERT) and ALK mutations are being tested as additions to the classification, and long-term follow-up of hearing, kidney function and fertility is what tells the groups whether the reductions were worth it.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Neuroblastoma","links":[{"label":"Wikipedia: Neuroblastoma","url":"https://en.wikipedia.org/wiki/Neuroblastoma"},{"label":"NCI PDQ: Neuroblastoma Treatment","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}],"tags":["subtype-page","paediatric"],"related":["neuroblastoma-low-risk","neuroblastoma-high-risk"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","mri","mibg-theranostics"],"targets":[],"drugs":[],"companies":["childrens-oncology-group"],"institutions":["siop-europe"],"pathways":[],"terms":["inrg-staging","mycn-amplification","late-effects","segmental-chromosomal-aberrations","urinary-catecholamines"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-inrg-cohn-jco-2009","paper-a3961-intermediate-risk-neuroblastoma-baker-nejm-2010","paper-anbl0531-twist-jco-2019"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About one neuroblastoma in ten is intermediate risk: unresectable localised disease or metastatic disease in infants, without MYCN amplification, cured in about nine in ten children with a few cycles of moderate chemotherapy.","subtypes":["L2 neuroblastoma over 18 months, or with unfavourable histology or 11q aberration, without MYCN amplification","Stage M neuroblastoma in infants under 18 months without MYCN amplification","Stage MS neuroblastoma with 11q aberration or unfavourable biology","Intermediate-risk neuroblastoma with favourable biology (two to four cycles)","Intermediate-risk neuroblastoma with unfavourable biology (up to eight cycles)"],"biomarkers":["INRG stage (L2, M in infants, MS)","MYCN amplification (must be absent)","11q aberration","DNA ploidy","INPC histology","ALK mutation","Urinary catecholamine metabolites"],"standardOfCare":[{"setting":"Chemotherapy","approach":"Two to eight cycles of carboplatin, etoposide, cyclophosphamide and doxorubicin by biology and response (A3961, ANBL0531), then surgery when resectable.","refs":["carboplatin","etoposide","cyclophosphamide","doxorubicin","cytotoxic-chemotherapy","inrg-staging","anbl0531"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}},{"setting":"Response assessment and surgery","approach":"MRI or CT and MIBG scan after chemotherapy; resection of the residual primary where safe, otherwise observation of the residual mass.","refs":["mri","mibg-theranostics","inrg-staging"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}},{"setting":"Non-responding or life-threatening disease","approach":"Radiotherapy to the primary or to a compressing lesion; escalation to high-risk therapy if biology proves unfavourable.","refs":["imrt-igrt","radiotherapy"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}},{"setting":"Follow-up","approach":"Hearing, kidney, cardiac and fertility follow-up for the chemotherapy given.","refs":["late-effects","cardio-oncology","fertility-preservation"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}}],"stateOfArt":["Four to eight cycles of moderate chemotherapy gave 96 percent three-year survival in A3961, and ANBL0531 cut therapy to two cycles for the most favourable children.","Biology (11q, ploidy, histology) sets the number of cycles; response allows escalation.","Radiotherapy and high-dose therapy are avoided altogether."],"history":[{"year":2009,"title":"INRG classification defines the intermediate-risk group by stage, age and biology","refs":["inrg-staging"]},{"year":2010,"title":"A3961: biology-based reduction to four or eight cycles gives 96 percent three-year survival","refs":["carboplatin","etoposide","cyclophosphamide","doxorubicin"]},{"year":2019,"title":"ANBL0531: further response-based reduction, two cycles for the most favourable children","refs":["inrg-staging"]}],"pipeline":["inrg-staging","idea-mfbg-pet-replaces-mibg","mibg-theranostics","cardio-oncology"],"openProblems":["Children with 11q aberration or unfavourable histology still relapse and cannot have therapy shortened.","Whether telomere maintenance and ALK status should change risk assignment.","Measuring the late effects of even moderate chemotherapy over decades."],"parent":"neuroblastoma"},{"id":"ipmn-cystic-precursors","kind":"cancer","name":"Intraductal papillary mucinous neoplasm and other pancreatic cystic precursors","aka":["IPMN","Pancreatic cyst","Mucinous cystic neoplasm","MCN","Pancreatic cystic neoplasm","Precancerous pancreatic cyst"],"tldr":"Intraductal papillary mucinous neoplasms are fluid-filled growths in the pancreatic ducts that make mucus and can slowly turn into pancreatic cancer, one of the few chances to catch pancreatic cancer before it starts. Most are watched with scans for years, and surgery is reserved for the ones with warning signs such as a widened main duct, a solid nodule inside the cyst or jaundice.","summary":"Intraductal papillary mucinous neoplasm (IPMN) is a mucin-producing epithelial neoplasm growing within the main pancreatic duct, its side branches or both. Main-duct and mixed-type IPMNs carry a substantial risk of high-grade dysplasia or invasive cancer at resection; branch-duct IPMNs, the commonest incidental cyst, progress in only a small minority over years. Mucinous cystic neoplasms (MCNs) occur almost only in women, in the body or tail, and have ovarian-type stroma; serous cystadenomas are benign and linked to VHL; solid pseudopapillary neoplasms are low-grade tumours of young women driven by CTNNB1. IPMNs carry KRAS and GNAS mutations early and acquire TP53, CDKN2A and SMAD4 changes as they progress, and cyst fluid analysis for CEA, glucose and mutations helps tell mucinous from non-mucinous cysts.\n\nManagement follows the international Fukuoka and Kyoto (2024) guidelines and the European consensus. High-risk stigmata (obstructive jaundice from a head cyst, an enhancing mural nodule of 5 mm or more, main duct of 10 mm or more, or positive cytology) call for resection in fit patients. Worrisome features (cyst of 3 cm or more, thickened enhancing wall, main duct 5 to 9 mm, smaller nodules, rapid growth, raised CA 19-9, new diabetes, pancreatitis) lead to endoscopic ultrasound with fluid sampling and closer surveillance. Cysts without these features are followed with MRI or endoscopic ultrasound at intervals set by size, and the question of when surveillance can stop in older patients with stable small cysts is unresolved.\n\nSurgery is pancreatoduodenectomy or distal pancreatectomy; invasive cancer arising in an IPMN is staged and treated as pancreatic ductal adenocarcinoma, though colloid-type invasive IPMN carcinomas have a better outcome, and the remaining pancreas needs continued surveillance because IPMN is a field disease. Research aims at cyst fluid and blood biomarkers that separate the cysts that will progress from the many that never will, at artificial intelligence reading of scans, and at the link between new-onset diabetes and early pancreatic cancer.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Intraductal_papillary_mucinous_neoplasm","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Intraductal_papillary_mucinous_neoplasm"},{"label":"Kyoto guidelines for IPMN (Pancreatology 2024)","url":"https://doi.org/10.1016/j.pan.2023.12.009"}],"tags":["subtype-page","gastrointestinal"],"related":["resectable-pdac","msi-high-pdac","kras-wild-type-pdac","pancreatic-acinar-cell-carcinoma","pancreatic-net","early-detection-roadmap","pancreatic-surveillance"],"cancers":[],"sections":[],"technologies":["mri","ct","endoscopic-ultrasound-systems","pancreatic-surveillance","robotic-surgery","mced","liquid-biopsy"],"targets":["kras","tp53"],"drugs":["galleri","folfirinox"],"companies":[],"institutions":[],"pathways":["pancreatic-cancer-signalling","wnt","p53-cell-cycle"],"terms":["ca19-9","obstructive-jaundice","whipple","resectability","tumour-grade","endoscopy"],"trials":[],"people":["anirban-maitra","marc-besselink","diane-simeone","bert-vogelstein","richard-schulick"],"bottlenecks":[],"keyPapers":["paper-fukuoka-2017-consensus-guidelines-ipmn-pancreatology-2017","paper-kyoto-2024-evidence-based-guidelines-ipmn-pancreatology-2024","paper-european-evidence-based-guidelines-pancreatic-cystic-neoplasms-gut-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Pancreatic cysts are found incidentally on scans in a few percent of adults and in a much larger share of people over 70; most are harmless, but intraductal papillary mucinous neoplasms and mucinous cystic neoplasms can progress to pancreatic cancer, and IPMNs are the precursor of a minority of pancreatic cancers.","subtypes":["Main-duct IPMN (high risk of high-grade dysplasia or invasive PDAC; resection in fit patients)","Branch-duct IPMN without worrisome features (surveillance)","Branch-duct IPMN with worrisome features or high-risk stigmata (endoscopic ultrasound, resection)","Invasive carcinoma arising in an IPMN (tubular or colloid type; treated as ductal PDAC)","Mucinous cystic neoplasm (women, body or tail, ovarian-type stroma; resection)","Serous cystadenoma (benign; VHL association) and solid pseudopapillary neoplasm (CTNNB1; resection)"],"biomarkers":["MRI with MRCP or pancreas-protocol CT: cyst size, main duct diameter, mural nodules, growth rate","Endoscopic ultrasound with cyst fluid CEA, glucose, cytology and KRAS, GNAS and other mutations","Serum CA 19-9 (worrisome feature when raised)","New-onset diabetes or pancreatitis (worrisome features)","Histological subtype of resected IPMN (gastric, intestinal, pancreatobiliary) and grade of dysplasia","TP53, SMAD4 and CDKN2A alterations in cyst fluid (investigational markers of progression)"],"standardOfCare":[{"setting":"Incidental cyst","approach":"Characterise with MRI and MRCP or pancreas-protocol CT; endoscopic ultrasound with fluid analysis when the cyst type is unclear or worrisome features are present.","refs":["mri","ct","endoscopic-ultrasound-systems","ca19-9"],"guideline":{"version":"Kyoto guidelines for the management of IPMN (Pancreatology 2024)","url":"https://doi.org/10.1016/j.pan.2023.12.009"}},{"setting":"High-risk stigmata","approach":"Resection (pancreatoduodenectomy or distal pancreatectomy) for obstructive jaundice, an enhancing mural nodule of 5 mm or more, a main duct of 10 mm or more, or positive cytology, in patients fit for surgery.","refs":["whipple","obstructive-jaundice","robotic-surgery"],"guideline":{"version":"Kyoto guidelines for the management of IPMN (Pancreatology 2024)","url":"https://doi.org/10.1016/j.pan.2023.12.009"}},{"setting":"Worrisome features","approach":"Endoscopic ultrasound and fluid sampling; resection or short-interval surveillance depending on findings, age and fitness.","refs":["endoscopic-ultrasound-systems","ca19-9","mri"],"guideline":{"version":"Kyoto guidelines for the management of IPMN (Pancreatology 2024)","url":"https://doi.org/10.1016/j.pan.2023.12.009"}},{"setting":"Surveillance","approach":"MRI or endoscopic ultrasound at intervals set by cyst size, continued while the patient remains a surgical candidate; the remaining pancreas is followed after resection.","refs":["mri","pancreatic-surveillance","endoscopic-ultrasound-systems"],"guideline":{"version":"Kyoto guidelines for the management of IPMN (Pancreatology 2024)","url":"https://doi.org/10.1016/j.pan.2023.12.009"}},{"setting":"Invasive carcinoma in an IPMN","approach":"Staged and treated as pancreatic ductal adenocarcinoma with resection and adjuvant chemotherapy.","refs":["whipple","folfirinox","prodige-24"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Risk-stratified surveillance under the Fukuoka and Kyoto guidelines avoids surgery for the large majority of cysts.","Cyst fluid mutation analysis separates mucinous from non-mucinous cysts and is entering routine use.","Artificial intelligence reading of CT and MRI and blood-based markers aim to predict which cysts progress.","The link between new-onset diabetes and early pancreatic cancer is being turned into a detection pathway."],"history":[{"year":1982,"title":"Ohhashi describes mucin-producing pancreatic tumours, later named IPMN","refs":["endoscopy"]},{"year":2006,"title":"Sendai consensus guidelines for the management of IPMN and MCN","refs":["resectability"]},{"year":2011,"title":"GNAS mutations found in IPMNs, distinguishing them from other cysts","refs":["cgp"]},{"year":2012,"title":"Fukuoka guidelines introduce high-risk stigmata and worrisome features","refs":["mri","endoscopic-ultrasound-systems"]},{"year":2018,"title":"European evidence-based guidelines on pancreatic cystic neoplasms","refs":["pancreatic-surveillance"]},{"year":2024,"title":"Kyoto guidelines revise surveillance intervals and add cyst fluid molecular markers","refs":["endoscopic-ultrasound-systems","ca19-9"]}],"pipeline":["idea-prev-ipmn-surveillance-stop-rule","idea-mced-new-onset-diabetes","idea-prev-new-onset-diabetes-pancreas-pathway","idea-prev-pancreas-ai-prediagnostic-ct","idea-prev-cgm-glycaemic-drift-pancreas","mced","galleri","pancreatic-surveillance"],"openProblems":["Most cysts never progress, and no test yet identifies the minority that will.","Surveillance of a common incidental finding is costly and causes anxiety, and when it can safely stop is unknown.","Surgery for cysts carries real morbidity, and a share of resected cysts turn out to be low grade.","IPMN is a field disease, so cancer can arise elsewhere in the gland after resection."],"parent":"pancreatic"},{"id":"intrahepatic-cholangiocarcinoma","kind":"cancer","name":"Intrahepatic cholangiocarcinoma","aka":["iCCA","Intrahepatic bile duct cancer","Peripheral cholangiocarcinoma","Mass-forming cholangiocarcinoma"],"tldr":"Intrahepatic cholangiocarcinoma starts in the small bile ducts inside the liver and usually appears as a liver mass rather than causing jaundice. It is the biliary cancer with the most drug targets: FGFR2 fusions treated with pemigatinib or futibatinib, IDH1 mutations with ivosidenib, and for everyone chemotherapy with the immunotherapy durvalumab or pembrolizumab.","summary":"Intrahepatic cholangiocarcinoma arises from the bile ducts beyond the second-order branches within the liver and presents as a mass, often found incidentally or with vague pain and weight loss, in contrast to the jaundice of extrahepatic tumours. Risk factors include cirrhosis, hepatitis B and C, primary sclerosing cholangitis, liver flukes in Thailand and neighbouring countries, and hepatolithiasis, but most cases in the West have none. Its genome differs from that of the rest of the biliary tree: FGFR2 fusions occur in about 10 to 15 percent, IDH1 mutations in about 15 percent, and BAP1 and ARID1A mutations are common, whereas KRAS and HER2 alterations are less frequent than in extrahepatic disease, so comprehensive sequencing at diagnosis is standard.\n\nResection is the only cure and is possible in a minority; hepatectomy with lymph node dissection is followed by six months of capecitabine after the BILCAP trial, whose per-protocol analysis showed longer survival. Recurrence is common. Liver transplantation for very early tumours in cirrhotic livers and after chemotherapy for locally advanced disease is under study, and for unresectable liver-confined disease radioembolisation, stereotactic radiotherapy and hepatic artery infusion chemotherapy are used in specialised centres.\n\nFor advanced disease gemcitabine with cisplatin (ABC-02, 2010) was the standard for a decade until TOPAZ-1 (2022) added durvalumab and KEYNOTE-966 (2023) added pembrolizumab, each modestly improving survival and producing a tail of long-term responders. After chemotherapy, targeted drugs matched to the tumour's mutation are given: pemigatinib (FIGHT-202, response rate 36 percent) and futibatinib (FOENIX-CCA2, response rate 42 percent) for FGFR2 fusions, and ivosidenib for IDH1 mutations, which in ClarIDHy extended progression-free survival from 1.4 to 2.7 months and gave a survival benefit once crossover was accounted for. Acquired resistance to FGFR inhibitors through gatekeeper mutations is tracked with circulating tumour DNA, and next-generation FGFR2 inhibitors such as tinengotinib are in trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Cholangiocarcinoma","links":[{"label":"FIGHT-202 (Lancet Oncology 2020)","url":"https://pubmed.ncbi.nlm.nih.gov/32203698/"},{"label":"ClarIDHy (Lancet Oncology 2020)","url":"https://pubmed.ncbi.nlm.nih.gov/32416072/"},{"label":"FOENIX-CCA2 (NEJM 2023)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2206834"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Cholangiocarcinoma"}],"tags":["subtype-page"],"related":["extrahepatic-cholangiocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["abc-06","fight-302"],"people":[],"bottlenecks":[],"keyPapers":["paper-bilcap-lancet-oncol-2019","paper-topaz-1-nejm-evidence-2022","paper-keynote-966-lancet-2023","paper-fight-202-pemigatinib-lancet-oncol-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Bile duct cancer arising within the liver, the second commonest primary liver cancer after hepatocellular carcinoma and rising in incidence worldwide; it carries most of the targetable mutations in biliary cancer, with FGFR2 fusions in about one in eight and IDH1 mutations in about one in seven.","subtypes":["Mass-forming intrahepatic cholangiocarcinoma (most)","Intrahepatic cholangiocarcinoma with FGFR2 fusion (pemigatinib, futibatinib)","Intrahepatic cholangiocarcinoma with IDH1 mutation (ivosidenib)","Small-duct versus large-duct type","Fluke-associated intrahepatic cholangiocarcinoma","Combined hepatocellular-cholangiocarcinoma"],"biomarkers":["FGFR2 fusions and rearrangements (RNA or DNA sequencing)","IDH1 mutation","BAP1, ARID1A and PBRM1 (small-duct type)","HER2, BRAF V600E, NRG1 and microsatellite instability (less common)","CA 19-9 for monitoring","Circulating tumour DNA for resistance mutations under FGFR inhibition"],"standardOfCare":[{"setting":"Diagnosis","approach":"Contrast MRI and CT, biopsy, and comprehensive genomic profiling including RNA-based fusion detection for every patient.","refs":["mri","ct","cgp","ngs","fgfr2-fusion"]},{"setting":"Resectable","approach":"Hepatectomy with lymph node dissection followed by six months of adjuvant capecitabine (BILCAP).","refs":["hepatectomy","lymphadenectomy","bilcap","capecitabine"]},{"setting":"Unresectable, liver-confined","approach":"Radioembolisation, stereotactic radiotherapy or hepatic artery infusion in specialised centres, usually with systemic therapy; liver transplantation in trials.","refs":["radioembolisation-tare","sbrt","liver-transplant-oncology"]},{"setting":"Advanced, first line","approach":"Gemcitabine and cisplatin with durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966).","refs":["topaz-1","keynote-966","abc-02","gemcitabine-cisplatin","durvalumab","pembrolizumab","gemcis-plus-io-btc"]},{"setting":"Advanced, FGFR2 fusion after chemotherapy","approach":"Pemigatinib (FIGHT-202) or futibatinib (FOENIX-CCA2); management of hyperphosphataemia and eye toxicity.","refs":["pemigatinib","futibatinib","fight-202","foenix-cca2","fgfr2","fgfr2-fusion"]},{"setting":"Advanced, IDH1 mutation after chemotherapy","approach":"Ivosidenib (ClarIDHy).","refs":["ivosidenib","claridhy","idh"]},{"setting":"Second line without a target","approach":"FOLFOX (ABC-06); trials.","refs":["folfox","cytotoxic-chemotherapy"]}],"stateOfArt":["Intrahepatic cholangiocarcinoma was the first gastrointestinal cancer with an approved FGFR inhibitor and the first solid tumour with an approved IDH1 inhibitor.","Immunotherapy added to gemcitabine-cisplatin is now first-line standard across biliary cancers.","Tracking resistance with circulating tumour DNA and switching FGFR inhibitors is becoming routine in specialist centres."],"history":[{"year":2010,"title":"ABC-02: gemcitabine plus cisplatin becomes the standard for advanced biliary cancer","refs":["abc-02","gemcitabine-cisplatin"]},{"year":2019,"title":"BILCAP: adjuvant capecitabine after resection","refs":["bilcap","capecitabine"]},{"year":2020,"title":"FIGHT-202: pemigatinib approved for FGFR2 fusion-positive cholangiocarcinoma","refs":["fight-202","pemigatinib"]},{"year":2021,"title":"ClarIDHy: ivosidenib approved for IDH1-mutant cholangiocarcinoma","refs":["claridhy","ivosidenib"]},{"year":2022,"title":"FOENIX-CCA2: futibatinib approved; TOPAZ-1: durvalumab added to chemotherapy","refs":["foenix-cca2","futibatinib","topaz-1","durvalumab"]},{"year":2023,"title":"KEYNOTE-966: pembrolizumab added to chemotherapy","refs":["keynote-966","pembrolizumab"]}],"pipeline":["tinengotinib","first-308","idea-btc-ctdna-fgfr-resistance","liquid-biopsy","liver-transplant-oncology","radioembolisation-tare","zanidatamab"],"openProblems":["Most patients present unresectable, and recurrence after resection is common.","FGFR inhibitor resistance develops within a year through kinase domain mutations.","Rising incidence in Western countries without a clear cause."],"parent":"cholangiocarcinoma"},{"id":"intravascular-large-b-cell-lymphoma","kind":"cancer","name":"Intravascular large B-cell lymphoma","aka":["IVLBCL","Intravascular lymphoma","Angiotropic large cell lymphoma","Malignant angioendotheliomatosis"],"tldr":"Intravascular large B-cell lymphoma is a rare form of large B-cell lymphoma in which the cancer cells grow inside small blood vessels rather than forming lumps, so it causes fevers, confusion, skin patches or breathlessness and is often found late or only after death. Rituximab-based chemotherapy with drugs that reach the brain has turned a nearly always fatal disease into one often controlled.","summary":"WHO-HAEM5 lists intravascular large B-cell lymphoma among the large B-cell lymphomas as an entity defined by selective growth of tumour cells within the lumina of small vessels, with a Western variant dominated by neurological and skin involvement and an Asian variant with haemophagocytic syndrome, marrow involvement and cytopenias (Alaggio 2022). In 182 published cases, one- and three-year overall survival were 42.3 and 11.5 percent with a median of 340 days; rituximab-containing regimens lengthened overall survival (450 against 180 days) and progression-free survival, while blood-brain-barrier-penetrating drugs gave no extra benefit for disease already in the central nervous system (Cancer Management and Research 2020). The Japanese phase 2 PRIMEUR-IVL trial gave R-CHOP with high-dose methotrexate and intrathecal chemotherapy to prevent central nervous system relapse in untreated patients without central nervous system disease (Shimada 2020, linked here).\n\nHow it differs from its parent: no mass and usually no lymphadenopathy, so diagnosis rests on random skin biopsy, marrow or organ biopsy; frequent central nervous system relapse, so prophylaxis is built into first-line treatment; and a high rate of haemophagocytic syndrome in the Asian variant.\n\nHow common: no registry figure; 182 published cases in a decade (Cancer Management and Research 2020).\n\nTreatment: R-CHOP with central nervous system-directed therapy (high-dose methotrexate and intrathecal chemotherapy) as in PRIMEUR-IVL; autologous transplant considered in first remission for fit patients; central nervous system disease treated as on the primary CNS lymphoma page.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Intravascular_lymphomas","links":[{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq"},{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"PRIMEUR-IVL (Shimada 2020, Lancet Oncology): R-CHOP with high-dose methotrexate and intrathecal chemotherapy in intravascular large B-cell lymphoma","url":"https://doi.org/10.1016/s1470-2045(20)30059-0"},{"label":"Cancer Management and Research 2020: prognosis of intravascular large B-cell lymphoma, 182 published cases","url":"https://doi.org/10.2147/cmar.s267825"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["dlbcl","primary-cns-lymphoma","lymphomatoid-granulomatosis","hiv-associated-lymphoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["rituximab","cyclophosphamide","methotrexate"],"companies":[],"institutions":[],"pathways":[],"terms":["r-chop","myd88-l265p"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Very rare: a review of the world literature over 2008 to 2018 found 182 pathologically confirmed cases in 103 publications (Cancer Management and Research 2020). No registry figure exists.","subtypes":["Intravascular large B-cell lymphoma, Western variant (neurological and cutaneous)","Intravascular large B-cell lymphoma, Asian variant (haemophagocytic syndrome, marrow, cytopenias)","Cutaneous variant (skin-limited, better prognosis)"],"biomarkers":["Random skin biopsy or organ biopsy showing intravascular CD20-positive large cells","Lactate dehydrogenase and ferritin (haemophagocytic variant)","Cerebrospinal fluid and MRI for central nervous system disease","MYD88 L265P and CD79B mutations (frequent)"],"standardOfCare":[{"setting":"All cases","approach":"R-CHOP with high-dose methotrexate and intrathecal chemotherapy (PRIMEUR-IVL); autologous transplant considered in first remission; CNS disease as on the primary CNS lymphoma page.","refs":["rituximab","cyclophosphamide","methotrexate","r-chop","primary-cns-lymphoma"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"dlbcl"},{"id":"invasive-breast-carcinoma-no-special-type","kind":"cancer","name":"Invasive breast carcinoma of no special type (invasive ductal carcinoma)","aka":["Invasive ductal carcinoma","IDC","Invasive carcinoma of no special type","NST","Infiltrating ductal carcinoma","Invasive ductal carcinoma not otherwise specified","Invasive breast cancer","ordinary breast cancer","usual type breast cancer","no special type","NST breast cancer","IDC NST"],"tldr":"Invasive carcinoma of no special type, still widely called invasive ductal carcinoma, is the ordinary form of breast cancer and by far the most common. The name means the tumour has no special pattern that would put it in one of the rarer types; everything on the main breast cancer page and its receptor subpages is written about this type unless it says otherwise.","summary":"The WHO classification uses invasive breast carcinoma of no special type for the large group of adenocarcinomas that cannot be classified as a special histological type; the 2019 edition keeps the term, treats the former medullary, oncocytic, lipid-rich, glycogen-rich, sebaceous and pleomorphic carcinomas as patterns within it, and grades it by the Nottingham system (Tan 2020). It is then divided clinically by oestrogen receptor, progesterone receptor and HER2 status and, in early disease, by genomic assays such as Oncotype DX, which is how the corpus's HR-positive, HER2-positive and triple-negative pages and their subpages are organised.\n\nHow it differs from its parent: it is not a subtype so much as the default; the special types on the sibling pages (lobular, tubular, mucinous, cribriform, papillary, secretory, adenoid cystic, apocrine, micropapillary, metaplastic, neuroendocrine) are defined against it and several carry a better or worse prognosis than grade-matched no special type disease.\n\nHow common: the most common type of breast cancer (Cancer Research UK); Cancer Research UK gives no percentage and this page does not estimate one.\n\nTreatment: entirely as the parent and its receptor pages describe (surgery, radiotherapy, endocrine therapy, chemotherapy, HER2-directed therapy and immunotherapy by receptor status and stage).","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Invasive_carcinoma_of_no_special_type","links":[{"label":"Cancer Research UK: types of breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/types"},{"label":"NCI PDQ: breast cancer treatment","url":"https://www.cancer.gov/types/breast/treatment"},{"label":"Tan 2020, Histopathology: the 2019 WHO classification of tumours of the breast","url":"https://doi.org/10.1111/his.14091"},{"label":"Ciriello 2015, Cell: comprehensive molecular portraits of invasive lobular breast cancer (TCGA)","url":"https://doi.org/10.1016/j.cell.2015.09.033"},{"label":"Quinn et al., Histopathology 2026;89(2):199 to 218: World Health Organization classification of tumours of the breast, 6th edition 2026","url":"https://doi.org/10.1111/his.70149"},{"label":"Royal College of Pathologists G148: dataset for histopathological reporting of breast disease in surgical excision specimens of breast cancer, version 3, November 2024 (full review due November 2026)","url":"https://www.rcpath.org/resourceLibrary/g148-dataset-for-histopathological-reporting-of-breast-disease-in-surgical-excision-specimens-of-breast-cancer.html"}],"tags":["subtype-page","wave4","breast"],"related":["breast-cancer","breast-hr-positive","breast-her2-positive","tnbc","invasive-lobular-carcinoma","medullary-pattern-breast-carcinoma","ductal-carcinoma-in-situ"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["oncotype-dx"],"companies":[],"institutions":[],"pathways":[],"terms":["who-breast-classification","nottingham-grade","grade-stage-receptor-breast","terminal-duct-lobular-unit","breast-tumour-size-on-the-report"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["This is the default, and the default is where the receptor result takes over. Invasive carcinoma of no special type is defined by not having a special pattern, so once a report says no special type, or invasive ductal carcinoma, everything that follows is decided by the grade, the stage and the receptors rather than by the type. The sixth edition of the WHO classification (April 2026) moves two groups into this category that used not to be here: mucinous carcinomas that are high grade, oestrogen receptor negative or HER2 positive become carcinoma of no special type with mucin production, and the unified neuroendocrine model the fifth edition applied to the breast is abandoned, with routine neuroendocrine staining of ordinary carcinoma no longer recommended."],"group":"breast","burden":"The most common type of breast cancer (Cancer Research UK); in the Cancer Genome Atlas breast series, 490 of 817 tumours were ductal (Ciriello 2015).","subtypes":["Invasive carcinoma of no special type, HR-positive and HER2-negative (luminal)","Invasive carcinoma of no special type, HER2-positive","Invasive carcinoma of no special type, triple-negative (basal-like)","Invasive carcinoma of no special type with medullary pattern (own page)","Oncocytic, lipid-rich, glycogen-rich and sebaceous patterns (rare, within no special type)"],"biomarkers":["Oestrogen receptor, progesterone receptor and HER2","Nottingham grade","Ki-67 and genomic assays (Oncotype DX and others) in early HR-positive disease"],"standardOfCare":[{"setting":"All stages","approach":"Treated as the parent's receptor pages describe.","refs":["breast-cancer","breast-hr-positive","breast-her2-positive","tnbc","oncotype-dx"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"breast-cancer"},{"id":"ipmn-associated-carcinoma","kind":"cancer","name":"Invasive carcinoma arising in an intraductal papillary mucinous neoplasm (IPMN-associated carcinoma)","aka":["Invasive carcinoma arising in an IPMN (tubular or colloid type; treated as ductal PDAC)","Invasive carcinoma arising in an IPMN (tubular or colloid type; 10 percent of resections; staged and treated as ductal adenocarcinoma)","IPMN with associated invasive carcinoma","Invasive IPMN","IPMN-associated invasive adenocarcinoma","IPMN-derived pancreatic cancer"],"tldr":"IPMN-associated carcinoma is pancreatic cancer that has grown out of a mucus-producing cyst in the pancreatic duct. Because the cyst is often being watched, the cancer is found smaller and earlier, and about four in ten patients are alive five years after surgery against two in ten for ordinary pancreatic cancer; the advantage belongs to the colloid type, not the tubular type.","summary":"What it is. Intraductal papillary mucinous neoplasms progress through low- and high-grade dysplasia to invasive carcinoma of two main types, tubular (which looks like ordinary ductal adenocarcinoma) and colloid (mucin pools), with a rarer oncocytic type; the 2015 Baltimore consensus asks pathologists to measure the distance between the IPMN and the invasive cancer and to sample the tissue between, because a carcinoma that is merely concomitant (arising separately in the same gland) should be genetically distinct from one associated with the IPMN (Basturk 2015). The parent cyst page carries the Fukuoka and Kyoto surveillance rules; this page is the cancer that surveillance is trying to pre-empt.\n\nHow it differs from its parent. In 1,260 consecutive resections for pancreatic adenocarcinoma, 132 (10 percent) were IPMN-associated and their five-year survival was 42 percent against 19 percent, explained by lower T stage, fewer node metastases, lower grade, fewer positive margins and less perineural and vascular invasion; when any one of those adverse features was present, survival fell to that of ordinary disease (Poultsides 2010). In 61 invasive IPMNs against 570 ductal adenocarcinomas, 62 percent were tubular, 26 percent colloid and 12 percent oncocytic; the favourable outcome (hazard ratio 0.58 after stage matching) held only for colloid and oncocytic carcinomas, while tubular carcinoma was no better than ordinary ductal cancer; colloid carcinomas arose from intestinal-type, mostly main-duct IPMNs and tubular carcinomas from gastric-type, often branch-duct IPMNs (Mino-Kenudson 2011). In a matched comparison of 59 patients, three- and five-year survival were 76 and 68 percent, and tubular histology carried 3.7 times the hazard of death of colloid histology (Yopp 2011).\n\nHow common it is. About 10 percent of resected adenocarcinomas in the Johns Hopkins series; no population count is published.\n\nHow it is treated. Staged by TNM and treated as pancreatic ductal adenocarcinoma: resection (pancreatoduodenectomy or distal pancreatectomy, sometimes total pancreatectomy for main-duct disease throughout the gland) with adjuvant chemotherapy, and lifelong surveillance of any remaining pancreas because IPMN is a field disease (the parent cyst page cites the Kyoto 2024 guideline). Whether colloid-type cancers need the same adjuvant treatment as tubular cancers has not been tested.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Intraductal_papillary_mucinous_neoplasm","links":[{"label":"Poultsides, Ann Surg 2010: histopathologic basis for the favourable survival of IPMN-associated invasive adenocarcinoma","url":"https://doi.org/10.1097/sla.0b013e3181cf8a19"},{"label":"Mino-Kenudson, Gut 2011: prognosis of invasive IPMN depends on histological and precursor epithelial subtypes","url":"https://doi.org/10.1136/gut.2010.232272"},{"label":"Yopp, Ann Surg 2011: invasive carcinoma arising in IPMN, matched comparison with ductal adenocarcinoma","url":"https://doi.org/10.1097/sla.0b013e318214bcb4"},{"label":"Basturk, Am J Surg Pathol 2015: Baltimore consensus, revised classification of pancreatic precursor lesions","url":"https://doi.org/10.1097/pas.0000000000000533"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"}],"tags":["gi","pancreatic","subtype-page"],"related":["pancreatic","ipmn-cystic-precursors","pancreatic-colloid-carcinoma","mcn-associated-carcinoma","resectable-pdac"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","histopathology-ihc","pancreatic-surveillance","mri","endoscopic-ultrasound-systems"],"targets":["kras","tp53","smad4"],"drugs":["folfirinox","gemcitabine-nab-paclitaxel","nalirifox"],"companies":[],"institutions":[],"pathways":["ras-mapk","pancreatic-cancer-signalling","p53-cell-cycle"],"terms":["pancreatic-cyst-high-risk-stigmata","panin","whipple","distal-pancreatectomy","resection-margins","tumour-grade"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 10 percent of resected pancreatic adenocarcinomas at a high-volume US centre (132 of 1,260, 1995 to 2006); the share of all pancreatic cancers is lower because many are unresectable at diagnosis and the precursor is not always recognisable.","subtypes":["Tubular-type invasive carcinoma in an IPMN (gastric-type, often branch-duct background; behaves like ductal PDAC)","Colloid-type invasive carcinoma in an IPMN (intestinal-type, mostly main-duct background; better outlook)","Oncocytic-type invasive carcinoma (intraductal oncocytic papillary neoplasm background; favourable)","Concomitant ductal adenocarcinoma separate from an IPMN in the same gland (genetically distinct; treated as ordinary PDAC)"],"biomarkers":["Histological type of the invasive component (tubular, colloid, oncocytic) and of the precursor epithelium (gastric, intestinal, pancreatobiliary, oncocytic)","Distance between the IPMN and the invasive carcinoma (associated versus concomitant, Baltimore 2015)","GNAS mutation (IPMN lineage) alongside KRAS; TP53 and SMAD4 changes with progression","CA 19-9 and cyst-fluid CEA before surgery"],"standardOfCare":[{"setting":"Resectable","approach":"Pancreatoduodenectomy, distal pancreatectomy or total pancreatectomy according to the extent of duct involvement, with regional lymphadenectomy and adjuvant chemotherapy as for ductal adenocarcinoma; surveillance of the remnant gland.","refs":["whipple","distal-pancreatectomy","folfirinox","neoadjuvant-adjuvant","pancreatic-surveillance","mri"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Advanced","approach":"Treated as pancreatic ductal adenocarcinoma: resection with adjuvant chemotherapy when removable, the chemotherapy rows of the parent page when not; the parent record carries the trials.","refs":["folfirinox","gemcitabine-nab-paclitaxel","nalirifox"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["The survival advantage of IPMN-associated cancer is explained by earlier stage and by colloid histology rather than by a different disease; tubular-type cancers need the full ductal adenocarcinoma pathway."],"history":[{"year":2010,"title":"Johns Hopkins series: 10 percent of resected adenocarcinomas are IPMN-associated, five-year survival 42 against 19 percent","refs":["whipple"]},{"year":2011,"title":"Colloid versus tubular histology shown to decide the outcome of invasive IPMN","refs":["pancreatic-colloid-carcinoma"]},{"year":2015,"title":"Baltimore consensus separates associated from concomitant carcinoma","refs":["panin"]}],"pipeline":[],"openProblems":["No trial has tested whether colloid-type cancers can be spared adjuvant chemotherapy.","Surveillance still misses cancers: the parent cyst page carries the unresolved questions of when to operate and when to stop watching."],"parent":"pancreatic"},{"id":"invasive-cribriform-carcinoma-breast","kind":"cancer","name":"Invasive cribriform carcinoma of the breast","aka":["Invasive cribriform carcinoma","Infiltrating cribriform carcinoma","Cribriform breast cancer"],"tldr":"Invasive cribriform carcinoma is a rare, low-grade type of breast cancer whose cells grow in sieve-like nests, closely related to tubular carcinoma. In its pure form it has an excellent outlook, with no deaths from the cancer in the defining series, and it is treated like other hormone-driven breast cancer with the least treatment possible.","summary":"The WHO classification defines invasive cribriform carcinoma by invasive nests with sieve-like spaces making up over 90 percent of the tumour (classical form) or over 50 percent with a tubular component (Tan 2020). In the Edinburgh review of 1,003 carcinomas, 51 were predominantly cribriform; of the 35 classical cases none had died of the carcinoma 10 to 21 years later and 30 remained alive, while the 16 mixed cases with less differentiated areas did worse but still better than invasive carcinoma in general (Page 1983). In the George Washington series pure and predominant cribriform carcinomas metastasised to axillary nodes frequently but almost never to more than three nodes, were oestrogen-receptor positive in 100 percent and progesterone-receptor positive in 69 percent, and had five-year survival of 100 percent for pure or at least 50 percent cribriform tumours (Venable 1990).\n\nHow it differs from its parent: with tubular carcinoma it forms the low-grade luminal special types with near-normal survival; it must be distinguished from cribriform ductal carcinoma in situ, which often accompanies it, and from adenoid cystic carcinoma.\n\nHow common: about 5 percent showed a predominant pattern in the 1983 series, and pure cases are fewer (Page 1983); no modern population figure was found in the sources read.\n\nTreatment: as HR-positive breast cancer following the parent page, with surgery, radiotherapy after breast conservation and endocrine therapy, and rarely chemotherapy; there is no trial in the type.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Breast_cancer_classification","links":[{"label":"Tan 2020, Histopathology: the 2019 WHO classification of tumours of the breast","url":"https://doi.org/10.1111/his.14091"},{"label":"Page 1983, Histopathology: invasive cribriform carcinoma of the breast, 51 of 1,003 carcinomas","url":"https://doi.org/10.1111/j.1365-2559.1983.tb02265.x"},{"label":"Venable 1990, Human Pathology: infiltrating cribriform carcinoma of the breast, a distinctive entity","url":"https://doi.org/10.1016/0046-8177(90)90235-w"}],"tags":["subtype-page","wave4","breast"],"related":["breast-cancer","breast-hr-positive","tubular-carcinoma-breast","adenoid-cystic-carcinoma-breast","ductal-carcinoma-in-situ"],"cancers":[],"sections":[],"technologies":["endocrine-therapy"],"targets":[],"drugs":["tamoxifen"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"51 of 1,003 invasive breast carcinomas (5 percent) in the Edinburgh series showed a predominantly cribriform pattern, 35 of them classical (Page 1983); the pure form is rarer than that share suggests.","subtypes":["Classical invasive cribriform carcinoma (over 90 percent cribriform; luminal A)","Mixed invasive cribriform carcinoma (with tubular or no special type areas)","Cribriform carcinoma with cribriform ductal carcinoma in situ"],"biomarkers":["Percentage of cribriform pattern","Oestrogen receptor (100 percent positive) and progesterone receptor","Node number (rarely more than three)"],"standardOfCare":[{"setting":"All stages","approach":"Treated as HR-positive breast cancer with the least treatment the parent page allows.","refs":["breast-hr-positive","endocrine-therapy","tamoxifen"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"breast-cancer"},{"id":"invasive-lobular-carcinoma","kind":"cancer","name":"Invasive lobular carcinoma of the breast","aka":["Invasive lobular carcinoma","ILC","Lobular breast cancer","Invasive lobular breast cancer","Infiltrating lobular carcinoma","Pleomorphic lobular carcinoma"],"tldr":"Invasive lobular carcinoma is the second most common type of breast cancer, about one in seven cases. Its cells have lost the glue protein E-cadherin, so they spread in single files rather than forming a lump, which makes it hard to see on mammograms and to measure. Almost all cases are hormone-receptor positive and are treated like other hormone-driven breast cancer.","summary":"Invasive lobular carcinoma is defined in the WHO classification by its discohesive growth, single cells and single-file cords infiltrating the stroma, and by loss of E-cadherin from inactivation of CDH1 (Tan 2020). The Cancer Genome Atlas profiled 817 breast tumours including 127 lobular, 490 ductal and 88 mixed: beyond E-cadherin loss, mutations of PTEN, TBX3 and FOXA1 were enriched in lobular disease, PTEN loss went with the highest AKT phosphorylation of any breast cancer subtype, proliferation and immune signatures defined three lobular transcriptional subtypes with different survival, and mixed ductal-lobular tumours were molecularly either lobular-like or ductal-like rather than true hybrids (Ciriello 2015).\n\nHow it differs from its parent: detection and surgery. Its diffuse growth makes it multicentric, multifocal and bilateral more often, with a high likelihood of incomplete excision after breast-conserving surgery; MRI and contrast-enhanced mammography surpass conventional imaging for its extent and improve surgical outcomes when added to the work-up (Healthcare 2023). Even mastectomy left positive margins in 10.6 percent of 357 patients, and in 18.7 percent of T3 tumours (American Journal of Surgery 2022). Metastases favour the peritoneum, ovaries, gut and meninges, and are often small foci needing immunohistochemistry to find in nodes; in 1,269 SEER patients meeting the Z0011 criteria, sentinel node dissection alone and full axillary dissection gave the same survival (PLoS One 2014). It is extremely uncommon in men (Breast Cancer 2017).\n\nHow common: about 15 percent of breast cancers (Cancer Research UK).\n\nTreatment follows the HR-positive breast cancer page, because almost all lobular cancers are hormone-receptor positive and HER2-negative: endocrine therapy with CDK4/6 inhibitors in advanced disease, and surgery with the imaging above. Whether lobular disease responds differently to chemotherapy or specific endocrine agents is under study; the fluoroestradiol PET trial linked here images its oestrogen receptors.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Invasive_lobular_carcinoma","links":[{"label":"Cancer Research UK: invasive lobular breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/types/invasive-lobular-breast-cancer"},{"label":"Tan 2020, Histopathology: the 2019 WHO classification of tumours of the breast","url":"https://doi.org/10.1111/his.14091"},{"label":"Ciriello 2015, Cell: comprehensive molecular portraits of invasive lobular breast cancer (TCGA)","url":"https://doi.org/10.1016/j.cell.2015.09.033"},{"label":"Healthcare 2023: invasive lobular carcinoma, a review of imaging modalities and pathology concordance","url":"https://doi.org/10.3390/healthcare11050746"},{"label":"American Journal of Surgery 2022: positive margins after mastectomy in 357 patients with invasive lobular carcinoma","url":"https://doi.org/10.1016/j.amjsurg.2021.05.021"},{"label":"PLoS One 2014: sentinel node dissection alone versus axillary dissection in early invasive lobular carcinoma, SEER","url":"https://doi.org/10.1371/journal.pone.0089778"},{"label":"Breast Cancer (Dove) 2017: invasive lobular carcinoma of the male breast, systematic review","url":"https://doi.org/10.2147/bctt.s126341"}],"tags":["subtype-page","wave4","breast"],"related":["breast-cancer","breast-hr-positive","invasive-breast-carcinoma-no-special-type","lobular-carcinoma-in-situ","tubular-carcinoma-breast","neuroendocrine-neoplasms-breast"],"cancers":[],"sections":[],"technologies":["endocrine-therapy","cdk46-inhibitor"],"targets":["cdh1"],"drugs":["tamoxifen","letrozole","fulvestrant","abemaciclib","palbociclib","ribociclib"],"companies":[],"institutions":[],"pathways":[],"terms":["mastectomy"],"trials":["nct04252859"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Around 15 in every 100 breast cancers, the second most common type (Cancer Research UK). GLOBOCAN counts it within the 2,296,840 breast cancers of 2022.","subtypes":["Classic invasive lobular carcinoma (single-file, E-cadherin negative, luminal A)","Pleomorphic lobular carcinoma (higher grade, sometimes HER2-positive)","Solid, alveolar and tubulolobular variants","Mixed ductal and lobular carcinoma (molecularly one or the other)","Lobular carcinoma in situ (own page)"],"biomarkers":["E-cadherin loss on immunohistochemistry and CDH1 inactivation","Oestrogen and progesterone receptor (almost always positive), HER2 (usually negative)","PTEN, TBX3 and FOXA1 mutations (enriched)","Extent on MRI or contrast-enhanced mammography before surgery"],"standardOfCare":[{"setting":"All stages","approach":"Treated as HR-positive breast cancer: surgery planned with MRI, endocrine therapy, CDK4/6 inhibitors in advanced disease; sentinel node biopsy as in ductal disease.","refs":["breast-hr-positive","endocrine-therapy","cdk46-inhibitor","tamoxifen","letrozole","mastectomy"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"breast-cancer"},{"id":"invasive-micropapillary-carcinoma-breast","kind":"cancer","name":"Invasive micropapillary carcinoma of the breast","aka":["Invasive micropapillary carcinoma","IMPC","Micropapillary breast cancer"],"tldr":"Invasive micropapillary carcinoma is a rare type of breast cancer in which small clusters of cells float inside-out in empty spaces. It spreads to the lymph nodes far more often than ordinary breast cancer of the same size, but once that is allowed for its survival is similar, and it is treated by receptor status like other breast cancer, usually hormone-driven.","summary":"The WHO classification defines invasive micropapillary carcinoma by morule-like clusters of cells without fibrovascular cores lying in clear stromal spaces, with reversed polarity shown by the inside-out staining of epithelial membrane antigen and sialyl Lewis X (Tan 2020; Archives of Pathology 2016). It is a variant of luminal B breast cancer, hormone-receptor positive with HER2 positivity in a proportion, with frequent lymphovascular invasion and nodal metastasis; molecular studies show distinct profiles supporting its status as an entity but no single genomic aberration explaining its morphology (Archives of Pathology 2016). Laboratory work using MCF7 spheroids modelled the chemoresistance described in the tumour through HIF-1-driven P-glycoprotein expression (BMC Cancer 2012).\n\nHow it differs from its parent: its nodal spread is out of proportion to its size, so imaging of the axilla and node surgery matter more; mixed tumours (micropapillary with no special type) are common and the threshold for calling a tumour micropapillary is not agreed.\n\nHow common: no reliable share was found in the sources read.\n\nTreatment: by receptor status on the parent's pages, most often as HR-positive breast cancer with endocrine therapy, and with HER2-directed therapy when HER2-positive; there is no trial in the type.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Breast_cancer_classification","links":[{"label":"Tan 2020, Histopathology: the 2019 WHO classification of tumours of the breast","url":"https://doi.org/10.1111/his.14091"},{"label":"Archives of Pathology 2016: invasive micropapillary carcinoma of the breast, an update","url":"https://doi.org/10.5858/arpa.2016-0040-ra"},{"label":"BMC Cancer 2012: a spheroid model of the chemoresistance of invasive micropapillary carcinoma","url":"https://doi.org/10.1186/1471-2407-12-4"}],"tags":["subtype-page","wave4","breast"],"related":["breast-cancer","breast-hr-positive","papillary-carcinoma-breast","mucinous-carcinoma-breast","invasive-breast-carcinoma-no-special-type"],"cancers":[],"sections":[],"technologies":["endocrine-therapy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Rare in its pure form; the criteria separating pure from mixed micropapillary carcinoma remain imprecise, so published shares vary (Archives of Pathology 2016). No population figure is given in the sources read.","subtypes":["Pure invasive micropapillary carcinoma (luminal B, HR-positive)","Mixed micropapillary and no special type carcinoma","HER2-positive micropapillary carcinoma","Mucinous carcinoma with micropapillary pattern (classification debated)"],"biomarkers":["Inside-out EMA or MUC1 staining","Oestrogen and progesterone receptor (usually positive), HER2 (positive in a proportion)","Lymphovascular invasion and node status"],"standardOfCare":[{"setting":"All stages","approach":"Treated by receptor status on the parent's pages, with careful axillary staging.","refs":["breast-hr-positive","breast-her2-positive","endocrine-therapy"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"breast-cancer"},{"id":"invasive-mucinous-adenocarcinoma-lung","kind":"cancer","name":"Invasive mucinous adenocarcinoma of the lung","aka":["Invasive mucinous adenocarcinoma","IMA","Mucinous bronchioloalveolar carcinoma (term retired in 2011)","Mucinous adenocarcinoma of the lung"],"tldr":"Invasive mucinous adenocarcinoma is a type of lung cancer whose cells look like stomach or bowel lining and fill the air spaces with mucus, often appearing as pneumonia-like shadows on a scan. Most cases carry a KRAS mutation, and many of the rest carry a gene fusion, including NRG1, that new drugs can target.","summary":"The IASLC/ATS/ERS classification of 2011 separated invasive mucinous adenocarcinoma from the non-mucinous lepidic tumours because of its distinct cells (goblet or columnar with abundant mucin), its tendency to spread through the airways as multifocal or lobar consolidation, and its biology (Travis 2011). Sequencing of 72 cases found KRAS mutations in 63 percent, with a distribution of nucleotide changes closer to gastrointestinal than to other lung tumours; among the KRAS wild-type cases were the fusions CD74-NRG1, VAMP2-NRG1, TRIM4-BRAF, TPM3-NTRK1 and EML4-ALK and mutations in ERBB2 and other genes (Shim 2015). Expression profiling identified a 143-gene mucinous signature, shared with mucin-producing gastrointestinal, pancreatic and breast cancers, in which the transcription factors FOXA3, SPDEF and HNF4A drive MUC5AC and MUC5B, and in which the checkpoint VTCN1 rather than PD-L1 is expressed (EMBO Molecular Medicine 2017).\n\nHow it differs from its parent: it is TTF-1-negative and expresses gut markers, so it can be mistaken for a metastasis; it is EGFR-mutant only rarely; and it is the lung cancer richest in NRG1 fusions, for which the HER2-HER3 bispecific antibody zenocutuzumab is approved.\n\nHow common: no share is given in the sources read; it is a minority of adenocarcinomas.\n\nTreatment: as lung adenocarcinoma by stage, with KRAS G12C inhibitors for that mutation, zenocutuzumab for NRG1 fusions, and the matching inhibitors for ALK, BRAF and NTRK fusions; multifocal disease that stays in the lung is sometimes resected repeatedly.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Adenocarcinoma_of_the_lung","links":[{"label":"Travis 2011, JTO: IASLC/ATS/ERS international multidisciplinary classification of lung adenocarcinoma","url":"https://doi.org/10.1097/jto.0b013e318206a221"},{"label":"Nicholson 2022, JTO: the 2021 WHO classification of lung tumours","url":"https://doi.org/10.1016/j.jtho.2021.11.003"},{"label":"Shim 2015, JTO: unique genetic and survival characteristics of invasive mucinous adenocarcinoma of the lung","url":"https://doi.org/10.1097/jto.0000000000000579"},{"label":"EMBO Molecular Medicine 2017: gene signature driving invasive mucinous adenocarcinoma of the lung","url":"https://doi.org/10.15252/emmm.201606711"}],"tags":["subtype-page","wave4","lung"],"related":["nsclc","lung-adenocarcinoma","kras-g12c-nsclc","lung-adenocarcinoma-in-situ-and-minimally-invasive"],"cancers":[],"sections":[],"technologies":[],"targets":["kras","nrg1"],"drugs":["zenocutuzumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"A minority of lung adenocarcinomas; the defining genomic series studied 72 cases from the United States and Korea (Shim 2015). No registry share was found in the sources read.","subtypes":["KRAS-mutant invasive mucinous adenocarcinoma (63 percent)","NRG1 fusion-positive invasive mucinous adenocarcinoma","Invasive mucinous adenocarcinoma with ALK, BRAF or NTRK fusion","Mixed invasive mucinous and non-mucinous adenocarcinoma"],"biomarkers":["KRAS mutation (G12C and non-G12C)","NRG1 fusion","ALK, BRAF, NTRK1 and ERBB2 alterations in KRAS wild-type cases","TTF-1 negative, HNF4A and gut markers positive"],"standardOfCare":[{"setting":"All stages","approach":"Treated as lung adenocarcinoma by stage, with KRAS G12C inhibitors, zenocutuzumab for NRG1 fusions and matched inhibitors for other fusions when found.","refs":["lung-adenocarcinoma","kras-g12c-nsclc","zenocutuzumab"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"nsclc"},{"id":"kaposi-sarcoma","kind":"cancer","name":"Kaposi sarcoma","aka":["KS","HHV-8-associated sarcoma"],"tldr":"Kaposi sarcoma is a blood-vessel cancer caused by the herpesvirus HHV-8, made famous by the AIDS epidemic. In people with HIV, antiretroviral therapy alone often shrinks it; liposomal doxorubicin or paclitaxel treat advanced disease, and it remains among the commonest cancers in sub-Saharan Africa, where paclitaxel is often unaffordable.","summary":"Kaposi sarcoma is a KSHV/HHV-8-driven vascular tumour with four epidemiologic forms: classic (elderly Mediterranean/Eastern European men, indolent), endemic African (including an aggressive lymphadenopathic childhood form), iatrogenic (transplant immunosuppression), and epidemic (AIDS-associated), plus KS in men who have sex with men with controlled HIV. Lesions involve skin, mucosa, lymph nodes and viscera (lung, gut); KSHV also causes primary effusion lymphoma and multicentric Castleman disease, and KS inflammatory cytokine syndrome (KICS).\n\nAIDS-KS: antiretroviral therapy is the foundation and suffices for limited disease; advanced disease (visceral, oedema, rapid progression, T1 by ACTG staging) adds pegylated liposomal doxorubicin (first line) or paclitaxel, both approved in the 1990s; pomalidomide (2020) was the first new KS drug in two decades and works in HIV-positive and -negative patients. Iatrogenic KS responds to reducing immunosuppression or switching to mTOR inhibitors (sirolimus). Classic KS is treated with local therapy (radiotherapy, intralesional vincristine, cryotherapy) or the same systemic agents. In Africa, where paclitaxel is often unaffordable, bleomycin-vincristine regimens remain in use and ACTG A5263 showed paclitaxel superior to oral etoposide and BV. Immune checkpoint inhibitors show activity in small series.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Kaposi%27s_sarcoma","links":[{"label":"NCCN Guidelines: Kaposi Sarcoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1447"},{"label":"ACTG A5263 (Lancet 2020)","url":"https://doi.org/10.1016/S0140-6736(19)33222-2"},{"label":"NCI PDQ: Kaposi sarcoma","url":"https://www.cancer.gov/types/soft-tissue-sarcoma/patient/kaposi-treatment-pdq"}],"tags":["gap-fill","skin","viral","global"],"related":["vascular-tumours","angiosarcoma","dermatofibrosarcoma-protuberans"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","imrt-igrt","checkpoint-inhibitor","global-oncology-access"],"targets":["pd1","vegf"],"drugs":["pegylated-liposomal-doxorubicin","paclitaxel","pomalidomide","vincristine","bleomycin","everolimus","pembrolizumab","nivolumab"],"companies":["bms","johnson-johnson"],"institutions":[],"pathways":["vegf-angiogenesis","pi3k-akt-mtor"],"terms":["irae","hhv8-kshv"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["tumour-virus-research"],"dependsOn":[],"notes":[],"group":"skin","burden":"About 35,000 cases per year worldwide, most in sub-Saharan Africa where it is among the commonest cancers; caused by Kaposi sarcoma herpesvirus (KSHV/HHV-8), with HIV the major cofactor.","subtypes":["Classic (sporadic) KS","Endemic African KS (including lymphadenopathic childhood form)","Iatrogenic (post-transplant) KS","Epidemic (AIDS-associated) KS","KS in HIV-negative MSM","KSHV-associated: primary effusion lymphoma, multicentric Castleman disease, KICS"],"biomarkers":["HHV-8 LANA-1 immunohistochemistry","HIV status, CD4 count, viral load","ACTG TIS staging (tumour, immune, systemic)","KSHV viral load (KICS, MCD)","Visceral involvement (endoscopy, imaging)"],"standardOfCare":[{"setting":"AIDS-KS, limited (T0)","approach":"Antiretroviral therapy; observe for regression (watch for IRIS-KS flare); local therapy for cosmetically or functionally important lesions.","refs":["imrt-igrt"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: AIDS-Related Kaposi Sarcoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1447"}},{"setting":"AIDS-KS, advanced (T1) or symptomatic","approach":"ART plus pegylated liposomal doxorubicin (preferred) or paclitaxel; pomalidomide as an oral option; continue until maximal response.","refs":["pegylated-liposomal-doxorubicin","paclitaxel","pomalidomide"],"guideline":{"nccn":"Category 1 (PLD, paclitaxel); 2A (pomalidomide)","version":"NCCN Guidelines: AIDS-Related Kaposi Sarcoma"}},{"setting":"Classic or HIV-negative KS","approach":"Local radiotherapy, intralesional vincristine or cryotherapy for few lesions; pegylated liposomal doxorubicin, paclitaxel or pomalidomide for extensive disease.","refs":["pegylated-liposomal-doxorubicin","paclitaxel","pomalidomide","vincristine"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Kaposi Sarcoma"}},{"setting":"Iatrogenic KS","approach":"Reduce immunosuppression; switch calcineurin inhibitor to sirolimus/everolimus; chemotherapy if progressive.","refs":["everolimus"]},{"setting":"Resource-limited settings","approach":"ART plus paclitaxel where available (ACTG A5263); bleomycin-vincristine otherwise; task-shifted oncology nursing models.","refs":["paclitaxel","bleomycin","vincristine","actg-a5263"],"guideline":{"version":"ACTG A5263 (Lancet 2020)"}}],"stateOfArt":["ART transformed AIDS-KS from a leading cause of death into a treatable condition in high-income countries; incidence fell >80% after 1996.","Pomalidomide (2020) is the first new approved KS drug since 1997 and the first that also covers HIV-negative KS.","Africa carries the burden: KS is a top-five cancer in many countries, and access to paclitaxel or liposomal doxorubicin is the limiting factor.","Immunotherapy (PD-1) shows activity and is being tested; KSHV-targeted therapy remains investigational."],"history":[{"year":1872,"title":"Moritz Kaposi describes 'idiopathic multiple pigmented sarcoma of the skin'","refs":[]},{"year":1981,"title":"KS in young gay men heralds the AIDS epidemic (CDC MMWR)","refs":[]},{"year":1994,"title":"KSHV/HHV-8 discovered (Chang and Moore, Science)","refs":[]},{"year":1995,"title":"Liposomal doxorubicin approved for AIDS-KS","refs":["pegylated-liposomal-doxorubicin"]},{"year":1996,"title":"Combination ART causes KS regression; incidence collapses","refs":[]},{"year":1997,"title":"Paclitaxel approved for AIDS-KS","refs":["paclitaxel"]},{"year":2020,"title":"Pomalidomide approved for KS (HIV-positive and -negative)","refs":["pomalidomide"]},{"year":2020,"title":"ACTG A5263: paclitaxel superior to oral etoposide and bleomycin-vincristine in Africa (Lancet)","refs":["paclitaxel","bleomycin"]}],"pipeline":["pomalidomide","pembrolizumab","nivolumab"],"openProblems":["Access to effective chemotherapy and ART-linked cancer care in sub-Saharan Africa.","KS in people with suppressed HIV and normal CD4 counts (unexplained).","No antiviral therapy targets latent KSHV.","Endemic childhood KS in Africa still lacks access to the chemotherapy that treats it."],"parent":"sarcoma"},{"id":"gist-kit-exon-11","kind":"cancer","name":"KIT exon 11-mutant GIST","aka":["Imatinib-sensitive GIST","KIT-mutant gastrointestinal stromal tumour","Classic GIST"],"tldr":"Most GISTs are driven by a mutation in exon 11 of the KIT gene, which keeps the KIT growth receptor switched on. Imatinib blocks it: given for three years after surgery in higher-risk tumours it prevents relapse and extends life, and in metastatic disease it controls the tumour for years before resistance develops.","summary":"Gastrointestinal stromal tumours arise from the interstitial cells of Cajal in the gut wall, and in 1998 Hirota showed that most carry activating mutations of KIT. Exon 11 mutations, which affect the juxtamembrane domain that normally holds the receptor inactive, account for around two thirds of all GISTs, occur at every site, and are the most sensitive to imatinib at 400 mg daily. Deletions involving codons 557 and 558 carry a worse prognosis than substitutions. Mutation testing is required before treatment because exon 9, PDGFRA D842V and wild-type tumours behave differently, and risk of relapse after surgery is estimated from size, mitotic count and site using the Miettinen or modified NIH criteria.\n\nSurgery removes localised tumours with clear margins and without lymph node dissection, since GIST rarely spreads to nodes. Adjuvant imatinib for one year improved recurrence-free survival in ACOSOG Z9001 (2009), and the Scandinavian SSG XVIII trial (JAMA 2012) showed that three years beat one in high-risk tumours, with five-year overall survival of 92 percent against 82 percent; three years is standard for high-risk disease, and trials of five years are ongoing. Neoadjuvant imatinib shrinks large or awkwardly placed tumours, at the rectum or gastro-oesophageal junction, to allow organ-sparing surgery.\n\nIn metastatic disease imatinib controls the tumour for a median of around two years before secondary mutations, in the ATP-binding pocket (exons 13 and 14) or activation loop (exons 17 and 18), cause resistance; the drug is continued indefinitely because stopping it leads to rapid progression. Response is judged on CT with Choi criteria, since tumours may become cystic without shrinking. On progression, dose escalation to 800 mg, then sunitinib, regorafenib and ripretinib follow, and circulating tumour DNA is increasingly used to identify the secondary mutation and choose between them.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Gastrointestinal_stromal_tumor","links":[{"label":"SSG XVIII (JAMA 2012)","url":"https://pubmed.ncbi.nlm.nih.gov/22453568/"},{"label":"ACOSOG Z9001 (Lancet 2009)","url":"https://pubmed.ncbi.nlm.nih.gov/19303137/"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Gastrointestinal_stromal_tumor"}],"tags":["subtype-page"],"related":["gist-imatinib-resistant","gist-pdgfra-d842v"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["gist-risk-stratification","bap1-loss"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-demetri-imatinib-gist-nejm-2002","paper-hirota-kit-gist-science-1998","paper-ssg-xviii-adjuvant-imatinib-joensuu-jama-2012","paper-heinrich-kit-mutation-imatinib-response-jco-2003"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About two thirds of gastrointestinal stromal tumours carry a mutation in exon 11 of KIT, the juxtamembrane domain; this is the imatinib-sensitive majority in whom the drug turned a lethal sarcoma into a chronic disease.","subtypes":["KIT exon 11 deletion (codons 557-558; higher risk)","KIT exon 11 substitution or duplication (lower risk)","Localised KIT exon 11-mutant GIST, high risk (three years of adjuvant imatinib)","Metastatic KIT exon 11-mutant GIST on imatinib","Gastric versus small bowel KIT-mutant GIST"],"biomarkers":["KIT exon 11 mutation type (deletion versus substitution)","Mitotic count, size and site (Miettinen risk)","KIT (CD117) and DOG1 immunohistochemistry","Secondary KIT mutations on progression (tissue or circulating tumour DNA)","Imatinib plasma level in poor responders"],"standardOfCare":[{"setting":"Localised, resectable","approach":"Complete surgical resection without lymphadenectomy; laparoscopic for smaller gastric tumours; neoadjuvant imatinib for large or poorly placed tumours.","refs":["imatinib","robotic-surgery","kit"]},{"setting":"After resection, high risk","approach":"Three years of adjuvant imatinib 400 mg (SSG XVIII); trials of longer courses.","refs":["imatinib","kit"]},{"setting":"Metastatic, first line","approach":"Imatinib 400 mg continued until progression, with CT response assessment by Choi criteria.","refs":["imatinib","ct","kit"]},{"setting":"Progression on imatinib","approach":"Dose escalation to 800 mg, then sunitinib, regorafenib and ripretinib, ideally guided by the secondary mutation on circulating tumour DNA.","refs":["imatinib","sunitinib","regorafenib","ripretinib","liquid-biopsy","ctdna"]}],"stateOfArt":["Imatinib in KIT-mutant GIST was the first targeted therapy for a solid tumour defined by its driver mutation and remains the model for the field.","Three years of adjuvant imatinib is one of the few adjuvant targeted therapies proven to extend overall survival.","Genotype now dictates dose and drug sequence, with circulating tumour DNA replacing repeat biopsy."],"history":[{"year":1998,"title":"Hirota identifies gain-of-function KIT mutations in GIST","refs":["kit"]},{"year":2001,"title":"First GIST patient treated with imatinib responds (Joensuu)","refs":["imatinib"]},{"year":2002,"title":"B2222 phase 2 and FDA approval of imatinib for metastatic GIST","refs":["imatinib"]},{"year":2009,"title":"ACOSOG Z9001: one year of adjuvant imatinib reduces recurrence","refs":["imatinib"]},{"year":2012,"title":"SSG XVIII: three years of adjuvant imatinib extends overall survival","refs":["imatinib"]}],"pipeline":["idrx-42","nb003","bezuclastinib","liquid-biopsy","insight-gist"],"openProblems":["Whether adjuvant imatinib should continue for five years or longer.","Resistance through secondary KIT mutations in nearly every metastatic patient.","Tumours that recur after stopping adjuvant therapy despite years of control."],"parent":"gist"},{"id":"kras-g12c-colorectal","kind":"cancer","name":"KRAS G12C-mutant colorectal cancer","aka":["KRAS G12C colorectal cancer","G12C-mutant bowel cancer","RAS-mutant colorectal cancer (G12C subset)"],"tldr":"KRAS G12C bowel cancer carries a mutation that was undruggable for forty years. The first KRAS drugs work only weakly on their own in the bowel, because the tumour switches EGFR back on, so they are given with an anti-EGFR antibody: sotorasib with panitumumab and adagrasib with cetuximab are both approved after chemotherapy.","summary":"KRAS was the first human oncogene identified in colorectal cancer, and RAS mutations, found in about 45 percent of tumours, predict failure of cetuximab and panitumumab, which is why RAS testing precedes any anti-EGFR therapy. G12C is a minority RAS allele in the bowel (3 to 4 percent, against 13 percent for G12D) but it was the first to be drugged, because the mutant cysteine can be trapped covalently by inhibitors of the inactive GDP-bound state, a chemistry described by Ostrem and Shokat in 2013.\n\nSotorasib and adagrasib alone produced responses in only about a fifth of colorectal patients, far fewer than in lung cancer, because inhibition triggers rapid EGFR-driven reactivation of the pathway. Combining with an anti-EGFR antibody fixed this: in KRYSTAL-1 adagrasib plus cetuximab produced a response rate of 34 percent with median progression-free survival of 6.9 months and overall survival of 15.9 months, leading to FDA accelerated approval in June 2024; in the randomised CodeBreaK 300 trial sotorasib 960 mg plus panitumumab lengthened progression-free survival to 5.6 months against 2.2 months with trifluridine-tipiracil or regorafenib, with a response rate of 26 percent against none, and the FDA approved the combination in January 2025.\n\nCodeBreaK 301 (sotorasib, panitumumab and FOLFIRI first line) and KRYSTAL-10 (adagrasib plus cetuximab against chemotherapy in second line) are the phase 3 trials that will decide when the combinations are given. Next-generation G12C inhibitors (divarasib, olomorasib, glecirasib), G12D inhibitors and the pan-RAS and RAS(ON) inhibitors such as daraxonrasib aim at the far larger group of other RAS-mutant colorectal cancers.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/KRAS","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/KRAS"},{"label":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}],"tags":["subtype-page"],"related":["braf-v600e-colorectal","early-onset-colorectal","her2-amplified-colorectal","msi-high-colorectal","rectal-cancer"],"cancers":[],"sections":[],"technologies":["kras-inhibitors","monoclonal-antibody","liquid-biopsy"],"targets":["kras","egfr","vegf"],"drugs":["sotorasib","adagrasib","panitumumab","cetuximab","divarasib","olomorasib","glecirasib","daraxonrasib"],"companies":[],"institutions":[],"pathways":["ras-mapk","colorectal-cancer-signalling"],"terms":["ctdna","ngs","sidedness"],"trials":["codebreak-300","nct03785249","nct06252649","nct04793958","sunlight","fresco-2","nct05194995","nct07259590"],"people":[],"bottlenecks":[],"keyPapers":["paper-codebreak-300-nejm-2023","paper-krystal-1-crc-yaeger-nejm-2023","paper-prager-sunlight-trifluridine-tipiracil-bevacizumab-nejm-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 3 to 4 percent of colorectal cancers carry KRAS G12C, a small slice of the 45 percent that are RAS-mutant; they behave like other RAS-mutant tumours, resistant to anti-EGFR antibodies, with a somewhat worse outlook.","subtypes":["KRAS G12C with an anti-EGFR combination (sotorasib-panitumumab, adagrasib-cetuximab)","Other KRAS mutations (G12D, G12V, G13D): RAS(ON) and pan-RAS inhibitors in trials","RAS-mutant colorectal cancer, left-sided or right-sided, in which anti-EGFR antibodies do not work","NRAS-mutant colorectal cancer (about 4 percent; no targeted therapy)"],"biomarkers":["KRAS G12C by tumour or circulating tumour DNA sequencing","Extended RAS testing (KRAS and NRAS exons 2, 3 and 4) before any anti-EGFR antibody","Co-mutations (TP53, APC, PIK3CA) and acquired RAS or MAPK alterations at progression","Mismatch repair status"],"standardOfCare":[{"setting":"Metastatic, previously treated","approach":"Sotorasib plus panitumumab (CodeBreaK 300) or adagrasib plus cetuximab (KRYSTAL-1) after fluoropyrimidine, oxaliplatin and irinotecan.","refs":["codebreak-300","nct03785249","sotorasib","panitumumab","adagrasib","cetuximab","kras-inhibitors"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Metastatic, first line","approach":"FOLFOX, FOLFIRI or CAPOX with bevacizumab, as for any RAS-mutant colorectal cancer; anti-EGFR antibodies are not used; KRAS G12C combinations are under test first line (CodeBreaK 301).","refs":["folfox","folfiri","capox","bevacizumab","nct06252649"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Later lines","approach":"Trifluridine-tipiracil with bevacizumab (SUNLIGHT), fruquintinib (FRESCO-2) or regorafenib; clinical trials of next-generation RAS inhibitors.","refs":["sunlight","fresco-2","trifluridine-tipiracil","fruquintinib","regorafenib"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}}],"stateOfArt":["Two approved KRAS G12C plus anti-EGFR combinations after chemotherapy (2024 and 2025).","The EGFR-feedback lesson from BRAF-mutant disease was reused to make KRAS inhibitors work in the bowel.","Pan-RAS and RAS(ON) inhibitors are the first drugs to reach the far commoner G12D and G12V mutations."],"history":[{"year":1982,"title":"KRAS identified as a human oncogene","refs":["kras"]},{"year":2008,"title":"KRAS mutations shown to predict failure of cetuximab and panitumumab","refs":["cetuximab","panitumumab","kras"]},{"year":2013,"title":"Ostrem and Shokat describe covalent inhibitors of KRAS G12C","refs":["kras","kras-inhibitors"]},{"year":2021,"title":"Sotorasib becomes the first approved KRAS inhibitor (lung cancer)","refs":["sotorasib"]},{"year":2023,"title":"KRYSTAL-1 and CodeBreaK 300 show that adding an anti-EGFR antibody makes KRAS G12C inhibitors work in the bowel","refs":["nct03785249","codebreak-300","adagrasib","sotorasib"]},{"year":2024,"title":"FDA accelerated approval of adagrasib with cetuximab","refs":["adagrasib","cetuximab"]},{"year":2025,"title":"FDA approves sotorasib with panitumumab","refs":["sotorasib","panitumumab"]}],"pipeline":["nct06252649","nct04793958","divarasib","olomorasib","glecirasib","daraxonrasib","zoldonrasib","elironrasib","nct05194995","nct07259590","vs-7375"],"openProblems":["Responses last months, not years; acquired RAS and MAPK alterations drive resistance.","G12D, the commonest colorectal KRAS allele, has no approved drug.","First-line use of the combinations awaits CodeBreaK 301 and KRYSTAL-10.","Anti-EGFR skin and magnesium toxicity limits the combinations for some patients."],"parent":"colorectal"},{"id":"kras-g12c-nsclc","kind":"cancer","name":"KRAS G12C-mutant non-small-cell lung cancer","aka":["KRAS G12C lung cancer","KRAS-mutant NSCLC","KRAS p.G12C non-small-cell lung cancer"],"tldr":"KRAS G12C lung cancer carries a mutation that was thought impossible to drug for forty years. Sotorasib and adagrasib now shrink about four in ten tumours after chemotherapy and immunotherapy, though the benefit is measured in months, and newer inhibitors and first-line combinations with immunotherapy are in trials.","summary":"KRAS was the first human oncogene identified in a solid tumour, but its smooth surface and picomolar affinity for GTP defeated every attempt at a drug until 2013, when Kevan Shokat's laboratory showed that the mutant cysteine of G12C could be trapped by a covalent inhibitor in a pocket that exists only in the inactive, GDP-bound state. Unlike EGFR or ALK disease, KRAS-mutant lung cancer occurs in smokers, carries a high mutation burden, often expresses PD-L1 and responds to checkpoint inhibitors, so first-line treatment is chemoimmunotherapy or pembrolizumab alone as for driver-negative disease; co-mutations in STK11 and KEAP1, present in a quarter to a third, blunt that response.\n\nSotorasib produced a 37 percent response rate in previously treated patients in CodeBreaK 100 and received accelerated approval in May 2021, the first KRAS inhibitor; CodeBreaK 200 (2023) then showed it beat docetaxel on progression-free survival (5.6 versus 4.5 months, hazard ratio 0.66) but not overall survival, and the FDA required a new dose-comparison study. Adagrasib produced a 43 percent response rate in KRYSTAL-1 with activity in brain metastases and was approved in December 2022; KRYSTAL-12 (2024) showed progression-free survival of 5.5 versus 3.8 months against docetaxel (hazard ratio 0.58). Resistance emerges within months through secondary KRAS mutations, amplification, bypass through receptor tyrosine kinases and histological transformation, and both drugs have liver toxicity that is worse soon after immunotherapy.\n\nThe field is moving in three directions: more potent or better tolerated G12C inhibitors (divarasib, with a 53 percent response rate in phase 1 and the Krascendo 1 phase 3; olomorasib; glecirasib and garsorasib approved in China), first-line combinations with pembrolizumab (KRYSTAL-7, SUNRAY-01), and pan-RAS inhibitors such as daraxonrasib that bind the active state. Open questions are why lung tumours respond better than colorectal tumours, how to overcome STK11 and KEAP1 co-mutations, and whether a KRAS inhibitor can be combined safely with a checkpoint inhibitor from the start.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/KRAS","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/KRAS"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":["egfr-mutant-nsclc","alk-positive-nsclc","braf-v600e-nsclc","her2-mutant-nsclc","pdl1-high-nsclc","met-altered-nsclc"],"cancers":[],"sections":[],"technologies":["kras-inhibitors","kinase-inhibitors","checkpoint-inhibitor","liquid-biopsy","cgp"],"targets":["kras","pd1","pdl1"],"drugs":["sotorasib","adagrasib","divarasib","olomorasib","glecirasib","garsorasib","daraxonrasib","calderasib","pembrolizumab","docetaxel"],"companies":["amgen","bms","roche-genentech","eli-lilly","merck"],"institutions":[],"pathways":["ras-mapk","nsclc-signalling","pd1-checkpoint"],"terms":["kras-mutation-subtypes","driver-mutation","resistance","hepatotoxicity","brain-metastases","tps"],"trials":["codebreak-200","krystal-12","krascendo-1","nct06119581","nct04613596","nct07190248"],"people":["kevan-shokat","ferdinandos-skoulidis","pasi-janne","tony-mok","ramaswamy-govindan"],"bottlenecks":[],"keyPapers":["paper-ostrem-kras-g12c-nature-2013","paper-codebreak-200-lancet-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"KRAS is mutated in about a quarter of lung adenocarcinomas in Europe and North America, and G12C, the smoking-associated variant, accounts for about 13 percent of adenocarcinomas, making it the single commonest targetable driver in Western patients. It is rarer in East Asia.","subtypes":["KRAS G12C adenocarcinoma with high PD-L1 (chemoimmunotherapy or pembrolizumab first, inhibitor second)","KRAS G12C adenocarcinoma with STK11 or KEAP1 co-mutation (poor immunotherapy response)","KRAS G12C with brain metastases (adagrasib has intracranial activity)","Non-G12C KRAS mutations (G12D, G12V; pan-RAS inhibitors in trials)"],"biomarkers":["KRAS G12C by tissue or plasma sequencing","PD-L1 tumour proportion score (first-line choice)","STK11 and KEAP1 co-mutations (prognostic, immunotherapy resistance)","TP53 co-mutation","Acquired KRAS mutations, MET amplification or bypass alterations at progression","Liver enzymes on a G12C inhibitor, especially soon after immunotherapy"],"standardOfCare":[{"setting":"Advanced, first line","approach":"As for driver-negative disease: pembrolizumab plus platinum doublet, or pembrolizumab alone if PD-L1 is 50 percent or more; KRAS inhibitors are not yet approved first line.","refs":["pembrolizumab","keynote-024-189","carboplatin","pemetrexed","paclitaxel","tps"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, after chemoimmunotherapy","approach":"Sotorasib (CodeBreaK 200) or adagrasib (KRYSTAL-12), preferred to docetaxel; adagrasib for active brain metastases; docetaxel with or without ramucirumab afterwards.","refs":["sotorasib","codebreak-200","adagrasib","krystal-12","docetaxel","ramucirumab","kras-inhibitors"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, clinical trials","approach":"Divarasib versus sotorasib or adagrasib (Krascendo 1); olomorasib or adagrasib with pembrolizumab first line (SUNRAY-01, KRYSTAL-7); pan-RAS inhibitors.","refs":["divarasib","krascendo-1","olomorasib","nct06119581","nct04613596","daraxonrasib"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Two approved covalent G12C inhibitors after chemoimmunotherapy, both with progression-free survival gains over docetaxel of one to two months and response rates around 40 percent.","Divarasib, olomorasib and the Chinese inhibitors glecirasib and garsorasib aim at deeper and longer responses.","First-line KRAS inhibitor plus pembrolizumab combinations in phase 3.","Pan-RAS and RAS(ON) inhibitors extend the approach to G12D and G12V."],"history":[{"year":1982,"title":"KRAS identified as a human oncogene in lung cancer cell lines","refs":["kras","oncogene"]},{"year":2013,"title":"Ostrem and Shokat trap mutant G12C cysteine in the switch-II pocket","refs":["kevan-shokat","kras","paper-ostrem-kras-g12c-nature-2013"]},{"year":2021,"title":"Sotorasib approved after CodeBreaK 100: the first KRAS inhibitor","refs":["sotorasib","ferdinandos-skoulidis","amgen"]},{"year":2022,"title":"Adagrasib approved after KRYSTAL-1, with brain activity","refs":["adagrasib","pasi-janne"]},{"year":2023,"title":"CodeBreaK 200: sotorasib beats docetaxel on progression-free but not overall survival","refs":["codebreak-200","sotorasib","paper-codebreak-200-lancet-2023"]},{"year":2024,"title":"KRYSTAL-12: adagrasib beats docetaxel; divarasib enters phase 3 (Krascendo 1)","refs":["krystal-12","adagrasib","divarasib","krascendo-1"]}],"pipeline":["divarasib","krascendo-1","olomorasib","nct06119581","nct04613596","glecirasib","garsorasib","daraxonrasib","calderasib","nct07190248","idea-bio1-pmhc-bispecifics-public-drivers","idea-shared-kras-vaccine-adjuvant"],"openProblems":["Responses to G12C inhibitors are shallower and shorter in lung cancer than EGFR or ALK inhibitors achieve, and no overall survival benefit over docetaxel has been shown.","Liver toxicity when a G12C inhibitor follows or accompanies a checkpoint inhibitor limits first-line combinations.","STK11 and KEAP1 co-mutations predict poor outcome with every treatment and have no targeted therapy.","Resistance is polyclonal and mechanistically diverse, arguing for combinations from the start."],"parent":"nsclc"},{"id":"kras-g12c-pdac","kind":"cancer","name":"KRAS G12C-mutant pancreatic ductal adenocarcinoma","aka":["KRAS G12C pancreatic cancer","KRAS p.G12C PDAC","G12C-mutant pancreatic adenocarcinoma"],"tldr":"KRAS G12C pancreatic cancer is the small slice of pancreatic cancer whose KRAS mutation happens to be the one that the first KRAS drugs were built for. Sotorasib and adagrasib, approved for lung cancer, shrink a share of these tumours after chemotherapy and are listed as options, and newer inhibitors such as elironrasib, olomorasib and the pan-RAS drug daraxonrasib are being tested in this group.","summary":"KRAS is mutated in more than nine out of ten pancreatic ductal adenocarcinomas, but the covalent inhibitors that reached the clinic first bind only the cysteine of the G12C variant, which is rare in the pancreas. The G12C subgroup otherwise resembles other KRAS-mutant pancreatic cancers in its presentation, its TP53, CDKN2A and SMAD4 co-alterations and its response to chemotherapy; it is found only by tumour or plasma sequencing, which is why guidelines ask for it at diagnosis in advanced disease.\n\nSotorasib in the pancreatic cohort of CodeBreaK 100 (2023) and adagrasib in KRYSTAL-1 (2023) produced responses in a minority of previously treated patients with disease control in most, durable for some months. Both are NCCN-listed options after first-line chemotherapy and are used off label or through access schemes, since neither has a pancreatic indication. Resistance arises through secondary KRAS mutations, amplification and bypass through receptor tyrosine kinases, and pancreatic tumours appear to depend more on wild-type RAS and on EGFR-family signalling than lung tumours do, which is the rationale for combining G12C inhibitors with EGFR antibodies or with pan-RAS drugs.\n\nThe pan-RAS inhibitor daraxonrasib, active against G12C alongside the other variants, lengthened survival in RASolute 302 and is approved after first-line chemotherapy regardless of KRAS subtype, so G12C-mutant patients now have a RAS inhibitor with pancreatic-specific evidence. Elironrasib (a RAS(ON) G12C-selective inhibitor) is being combined with daraxonrasib, olomorasib is in a pancreatic cohort, glecirasib has a pancreatic phase 2 in China, and divarasib, garsorasib and FMC-376 are in earlier studies. Open questions are whether a G12C-selective drug adds anything to a pan-RAS inhibitor, how to sequence them with chemotherapy, and whether responses in the pancreas can be made as deep as in the lung.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/KRAS","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/KRAS"},{"label":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}],"tags":["subtype-page","gastrointestinal"],"related":["metastatic-pdac","kras-wild-type-pdac","locally-advanced-pdac","brca-palb2-pdac","kras-g12c-nsclc","kras-g12c-colorectal","kras-roadmap"],"cancers":[],"sections":[],"technologies":["kras-inhibitors","cgp","liquid-biopsy","cytotoxic-chemotherapy"],"targets":["kras","egfr"],"drugs":["sotorasib","adagrasib","daraxonrasib","elironrasib","olomorasib","glecirasib","divarasib","garsorasib","folfirinox","gemcitabine-nab-paclitaxel"],"companies":["amgen","bms","revolution-medicines","eli-lilly","jacobio-pharmaceuticals","roche-genentech"],"institutions":[],"pathways":["ras-mapk","pancreatic-cancer-signalling","rtk-activation"],"terms":["kras-mutation-subtypes","driver-mutation","oncogene","resistance","ca19-9"],"trials":["rasolute-302","nct06128551","nct04956640","nct06008288","nct06244771","nct07491445"],"people":["kevan-shokat","frank-mccormick","tanios-bekaii-saab","eileen-oreilly","andrew-aguirre"],"bottlenecks":[],"keyPapers":["paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023","paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023","paper-ostrem-kras-g12c-nature-2013","paper-codebreak-200-lancet-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 1 to 2 percent of pancreatic ductal adenocarcinomas carry KRAS G12C, far fewer than the G12D, G12V and G12R mutations that make up most of the rest, so it is a small group even in a common cancer.","subtypes":["KRAS G12C PDAC after first-line chemotherapy (sotorasib or adagrasib listed; daraxonrasib approved)","KRAS G12C PDAC in trials of G12C-selective inhibitors (elironrasib, olomorasib, glecirasib, divarasib)","KRAS G12C PDAC with acquired resistance (secondary KRAS mutations, bypass signalling)","KRAS G12C PDAC treated first line with chemotherapy as for other KRAS-mutant disease"],"biomarkers":["KRAS G12C by tissue or plasma next-generation sequencing (about 1 to 2 percent of pancreatic adenocarcinomas)","Co-alterations in TP53, CDKN2A and SMAD4","Acquired KRAS mutations, KRAS amplification or receptor tyrosine kinase bypass at progression","CA 19-9 for response monitoring","Liver enzymes on a G12C inhibitor"],"standardOfCare":[{"setting":"First line","approach":"Chemotherapy as for other pancreatic adenocarcinoma: modified FOLFIRINOX, NALIRIFOX or gemcitabine plus nab-paclitaxel; G12C inhibitors are not approved first line.","refs":["folfirinox","nalirifox","gemcitabine-nab-paclitaxel","kras-mutation-subtypes"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"After first-line chemotherapy","approach":"Daraxonrasib (RASolute 302, approved for pancreatic cancer irrespective of KRAS subtype); sotorasib or adagrasib as NCCN-listed options on the CodeBreaK 100 and KRYSTAL-1 cohorts.","refs":["daraxonrasib","rasolute-302","sotorasib","adagrasib","kras-inhibitors"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Clinical trials","approach":"Elironrasib with daraxonrasib, olomorasib, glecirasib and other G12C-selective inhibitors alone or with chemotherapy or EGFR antibodies.","refs":["elironrasib","nct06128551","olomorasib","nct04956640","glecirasib","nct06008288"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Sotorasib and adagrasib give responses in a minority and disease control in most previously treated patients, and are guideline-listed options.","Daraxonrasib gives the G12C group, like every other KRAS subgroup, an approved RAS inhibitor with pancreatic phase 3 evidence.","RAS(ON) G12C-selective inhibitors such as elironrasib are being combined with pan-RAS inhibition to deepen responses."],"history":[{"year":1988,"title":"KRAS mutations found in almost all pancreatic adenocarcinomas (Almoguera and Perucho)","refs":["kras","oncogene"]},{"year":2013,"title":"Ostrem and Shokat show the G12C cysteine can be trapped by a covalent inhibitor","refs":["kevan-shokat","paper-ostrem-kras-g12c-nature-2013"]},{"year":2021,"title":"Sotorasib approved for KRAS G12C lung cancer, the first KRAS inhibitor","refs":["sotorasib","amgen"]},{"year":2023,"title":"CodeBreaK 100 pancreatic cohort (sotorasib) and KRYSTAL-1 (adagrasib) report activity in previously treated pancreatic cancer","refs":["sotorasib","adagrasib","tanios-bekaii-saab"]},{"year":2026,"title":"RASolute 302: daraxonrasib, active against all RAS variants, lengthens survival after chemotherapy","refs":["rasolute-302","daraxonrasib"]}],"pipeline":["elironrasib","nct06128551","olomorasib","nct04956640","glecirasib","nct06008288","divarasib","garsorasib","nct06244771","daraxonrasib","nct07491445"],"openProblems":["Responses to G12C-selective inhibitors are shallower and shorter in the pancreas than in the lung.","Neither sotorasib nor adagrasib has a pancreatic indication, so access depends on off-label use and trials.","Whether adding a G12C-selective drug to a pan-RAS inhibitor improves on the pan-RAS drug alone is untested.","The group is too small for large randomised trials of its own."],"parent":"pancreatic"},{"id":"kras-wild-type-pdac","kind":"cancer","name":"KRAS wild-type pancreatic ductal adenocarcinoma","aka":["KRAS wild-type pancreatic cancer","KRAS-negative PDAC","Fusion-driven pancreatic cancer","BRAF-altered pancreatic cancer"],"tldr":"KRAS wild-type pancreatic cancer is the one in ten pancreatic cancers without the KRAS mutation that drives the rest. Instead many carry a different switched-on gene, often a fusion involving NRG1, NTRK, ALK, ROS1, FGFR2 or RET, or a BRAF change, and several of these have approved pills or antibodies, so these tumours must be sequenced with a test that detects fusions.","summary":"The absence of a KRAS mutation in a pancreatic ductal adenocarcinoma is a signal to look harder. Some cases are misclassified ampullary, distal bile duct or duodenal cancers, some are mismatch repair deficient, and a substantial share carry an alternative driver: fusions of NRG1 (the commonest), NTRK1 to 3, ALK, ROS1, FGFR2, RET, MET or BRAF, BRAF V600E mutations and in-frame BRAF deletions, or less often ERBB2 amplification or GNAS mutation in a cancer arising from an intraductal papillary mucinous neoplasm. Because fusions are missed by DNA panels with limited intron coverage, RNA-based sequencing or a comprehensive panel with fusion detection is recommended for every KRAS wild-type tumour.\n\nSeveral of these drivers have drugs. Zenocutuzumab, a bispecific antibody blocking HER2 and HER3 that prevents NRG1 from signalling, produced durable responses in the eNRGy trial and was approved in December 2024 for NRG1 fusion-positive pancreatic cancer, the first targeted drug approved for a pancreatic driver. Larotrectinib and entrectinib are approved for NTRK fusions in any tumour, dabrafenib plus trametinib for BRAF V600E in any tumour, and ALK, ROS1, RET and FGFR2 inhibitors are used on the strength of their activity in other cancers; BRAF in-frame deletions respond to MEK inhibitors in case series. Chemotherapy remains the first-line standard while sequencing is arranged, and NOTABLE, a Chinese phase 3, showed that adding the EGFR antibody nimotuzumab to gemcitabine lengthened survival in KRAS wild-type disease, leading to a Chinese approval.\n\nKRAS wild-type tumours also differ in biology: they are less dependent on the MAPK pathway, less likely to carry CDKN2A or SMAD4 loss, and their prognosis with chemotherapy is somewhat better. Open problems are that fusion testing is still not universal, that each driver is too rare for pancreatic-specific trials, and that resistance to the targeted drugs follows the patterns seen in lung cancer.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Pancreatic_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Pancreatic_cancer"},{"label":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}],"tags":["subtype-page","gastrointestinal"],"related":["kras-g12c-pdac","metastatic-pdac","msi-high-pdac","brca-palb2-pdac","pancreatic-acinar-cell-carcinoma","ampullary","cholangiocarcinoma"],"cancers":[],"sections":[],"technologies":["cgp","liquid-biopsy","bispecific-antibody","cytotoxic-chemotherapy","checkpoint-inhibitor"],"targets":["her3","her2","ntrk","braf","alk","ros1","fgfr2","egfr","kras"],"drugs":["zenocutuzumab","larotrectinib","entrectinib","repotrectinib","dabrafenib-trametinib","nimotuzumab","pembrolizumab","gemcitabine","folfirinox"],"companies":["merck","pfizer","roche-genentech","bms"],"institutions":[],"pathways":["rtk-activation","ras-mapk","pancreatic-cancer-signalling"],"terms":["gene-fusion","driver-mutation","kras-mutation-subtypes","braf-v600-mutation","msi","resistance"],"trials":["notable-trial"],"people":["eileen-oreilly","anirban-maitra","shen-lin","eric-van-cutsem"],"bottlenecks":[],"keyPapers":["paper-heining-nrg1-fusions-kras-wild-type-pancreatic-cancer-discov-2018","paper-jones-nrg1-fusions-recurrent-actionable-kras-wild-type-pdac-ccr-2019","paper-enrgy-zenocutuzumab-nrg1-fusion-positive-cancer-nejm-2025"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Roughly one in ten pancreatic ductal adenocarcinomas has no KRAS mutation. The group is younger on average and is where most of the gene fusions and BRAF alterations that can be targeted with existing drugs are found.","subtypes":["NRG1 fusion-positive KRAS wild-type PDAC (zenocutuzumab)","NTRK fusion-positive KRAS wild-type PDAC (larotrectinib, entrectinib)","BRAF V600E-mutant or BRAF in-frame deletion KRAS wild-type PDAC (BRAF plus MEK or MEK inhibitors)","ALK, ROS1, RET or FGFR2 fusion-positive KRAS wild-type PDAC","Mismatch repair deficient KRAS wild-type PDAC (pembrolizumab)","KRAS wild-type PDAC without an identified driver (chemotherapy; nimotuzumab in China)"],"biomarkers":["KRAS wild-type status on tumour or plasma sequencing (prompts fusion testing)","RNA-based or comprehensive fusion testing for NRG1, NTRK, ALK, ROS1, FGFR2, RET, MET and BRAF fusions","BRAF V600E and in-frame deletion status","Mismatch repair immunohistochemistry or microsatellite instability testing","ERBB2 amplification and GNAS mutation (IPMN-derived cancers)","Review of histology and site to exclude ampullary, bile duct or duodenal primaries"],"standardOfCare":[{"setting":"Diagnosis","approach":"Comprehensive genomic profiling with fusion detection (RNA sequencing where DNA panels are negative) for every KRAS wild-type tumour; pathology review to exclude a periampullary primary.","refs":["cgp","liquid-biopsy","gene-fusion","msi"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"First line","approach":"Chemotherapy as for other pancreatic adenocarcinoma while sequencing is completed; a targeted drug first line only for NTRK or NRG1 fusions where the patient is unfit for chemotherapy.","refs":["folfirinox","nalirifox","gemcitabine-nab-paclitaxel"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"NRG1 fusion","approach":"Zenocutuzumab (eNRGy), approved December 2024 for pancreatic cancer with an NRG1 fusion after prior systemic therapy.","refs":["zenocutuzumab","her3","her2"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"NTRK fusion","approach":"Larotrectinib or entrectinib, approved for NTRK fusion-positive solid tumours; repotrectinib after resistance.","refs":["larotrectinib","entrectinib","repotrectinib","ntrk"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"BRAF alteration","approach":"Dabrafenib plus trametinib for BRAF V600E (tumour-agnostic approval); MEK inhibitors for BRAF in-frame deletions on case-series evidence.","refs":["dabrafenib-trametinib","braf-v600-mutation","braf"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Other fusions","approach":"ALK, ROS1, RET and FGFR2 inhibitors extrapolated from other cancers; mismatch repair deficient tumours receive pembrolizumab.","refs":["repotrectinib","pembrolizumab","alk","ros1","fgfr2"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"No identified driver","approach":"Chemotherapy; nimotuzumab plus gemcitabine approved in China after NOTABLE.","refs":["nimotuzumab","notable-trial","gemcitabine"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Zenocutuzumab is the first drug approved for a pancreatic cancer driver mutation, for NRG1 fusions.","Tumour-agnostic approvals for NTRK fusions and BRAF V600E cover the other common actionable drivers.","Guidelines now ask for fusion testing in every KRAS wild-type pancreatic cancer.","NOTABLE gave KRAS wild-type disease its first positive phase 3 of an EGFR antibody, in China."],"history":[{"year":2015,"title":"Sequencing studies show that KRAS wild-type pancreatic cancers are enriched for alternative drivers","refs":["cgp","kras"]},{"year":2018,"title":"NRG1 fusions described as a recurrent driver of KRAS wild-type pancreatic cancer","refs":["gene-fusion","her3"]},{"year":2018,"title":"Larotrectinib approved for NTRK fusion-positive solid tumours, pancreatic cancer included","refs":["larotrectinib","ntrk"]},{"year":2022,"title":"Dabrafenib plus trametinib approved for BRAF V600E solid tumours regardless of site","refs":["dabrafenib-trametinib","braf"]},{"year":2023,"title":"NOTABLE: nimotuzumab plus gemcitabine lengthens survival in KRAS wild-type pancreatic cancer","refs":["notable-trial","nimotuzumab"]},{"year":2024,"title":"Zenocutuzumab approved for NRG1 fusion-positive pancreatic cancer","refs":["zenocutuzumab"]}],"pipeline":["zenocutuzumab","repotrectinib","nimotuzumab","notable-trial","cgp","liquid-biopsy","idea-prev-reflex-germline-testing"],"openProblems":["Fusion testing is still missed when DNA panels are used alone, so many actionable tumours go unrecognised.","Each driver is too rare for pancreatic-specific randomised trials; evidence is extrapolated from lung cancer and basket studies.","Resistance to fusion-targeted drugs follows lung cancer patterns and second-line options are thin.","Some KRAS wild-type cases are misclassified periampullary cancers, which confounds every series."],"parent":"pancreatic"},{"id":"lactotroph-pitnet","kind":"cancer","name":"Lactotroph pituitary neuroendocrine tumour (prolactinoma)","aka":["Prolactinoma","Lactotroph tumour","Lactotroph tumour (prolactinoma)","Prolactin-secreting pituitary adenoma","Lactotroph adenoma"],"tldr":"A prolactinoma is a pituitary tumour of the cells that make prolactin, the milk hormone; it is the commonest hormone-producing pituitary tumour and causes missed periods, infertility, milk production or, in men, low testosterone. Almost uniquely among tumours it is treated first with a tablet, cabergoline, which shrinks it in most people; surgery is kept for those the drug fails.","summary":"The 2022 WHO classification of endocrine tumours reclassifies pituitary adenomas as pituitary neuroendocrine tumours (PitNETs) and types them by transcription factor lineage, the lactotroph tumour belonging to the PIT1 lineage with sparsely or densely granulated subtypes, defined by prolactin and oestrogen receptor alpha expression (Asa 2022). The Pituitary Society's 2023 international consensus covers epidemiology, biochemical evaluation of hyperprolactinaemia, imaging, treatment with dopamine agonists including efficacy, adverse effects and withdrawal, indications for surgery and radiotherapy, and management in pregnancy, children, psychiatric illness, postmenopausal women, transgender people and kidney disease; it concludes that treatment resistance is rare but that new options and international registries are needed (Petersenn 2023).\n\nHow it differs from its parent: the parent page covers all pituitary tumours; the lactotroph tumour is the one treated medically first, the one whose macroadenomas in women and men respond to cabergoline with tumour shrinkage, and the one where surgery has become a first-line alternative for small well-defined tumours in some guidelines.\n\nHow common: the most prevalent functioning pituitary tumour (Petersenn 2023); no separate incidence figure in the sources read.\n\nTreatment: cabergoline (or bromocriptine) as first-line therapy with attempted withdrawal after prolonged normalisation and tumour shrinkage; transsphenoidal surgery for intolerance, resistance, cystic tumours or patient preference; radiotherapy and temozolomide for the rare aggressive or giant prolactinoma, as on the parent page (Petersenn 2023).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Prolactinoma","links":[{"label":"NCI PDQ: pituitary tumours treatment","url":"https://www.cancer.gov/types/pituitary/treatment"},{"label":"Asa 2022, Endocrine Pathology: overview of the 2022 WHO classification of pituitary tumours","url":"https://doi.org/10.1007/s12022-022-09703-7"},{"label":"Petersenn 2023, Nature Reviews Endocrinology: Pituitary Society international consensus on prolactin-secreting pituitary adenomas","url":"https://doi.org/10.1038/s41574-023-00886-5"}],"tags":["subtype-page","wave4","rare"],"related":["pituitary-tumours","somatotroph-pitnet","corticotroph-pitnet","gonadotroph-pitnet","thyrotroph-pitnet","men1-syndrome"],"cancers":[],"sections":[],"technologies":["radiosurgery-srs"],"targets":[],"drugs":["cabergoline","bromocriptine","temozolomide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"The most prevalent functioning pituitary tumour (Pituitary Society consensus 2023); the parent page gives the pituitary tumour figures, and GLOBOCAN does not count pituitary tumours.","subtypes":["Sparsely granulated lactotroph pituitary tumour (the common prolactinoma)","Densely granulated lactotroph pituitary tumour","Giant or aggressive prolactinoma (dopamine agonist-resistant)","Mixed somatotroph-lactotroph or mammosomatotroph tumour (PIT1 lineage)"],"biomarkers":["Serum prolactin (with macroprolactin and hook-effect checks)","PIT1 and oestrogen receptor alpha lineage markers; prolactin immunostaining","Pituitary MRI (micro- versus macroadenoma; cavernous sinus invasion)","Ki-67 and mitoses (aggressiveness)"],"standardOfCare":[{"setting":"First line","approach":"Cabergoline (or bromocriptine), with attempted withdrawal after prolonged normalisation and shrinkage.","refs":["cabergoline","bromocriptine","pituitary-tumours"]},{"setting":"Resistant, intolerant or aggressive","approach":"Transsphenoidal surgery; radiotherapy and temozolomide for aggressive or giant tumours as on the parent page.","refs":["radiosurgery-srs","temozolomide","pituitary-tumours"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"pituitary-tumours"},{"id":"langerhans-cell-histiocytosis","kind":"cancer","name":"Langerhans cell histiocytosis (LCH)","aka":["LCH","Histiocytosis X","Eosinophilic granuloma","Hand-Schuller-Christian disease","Letterer-Siwe disease"],"tldr":"Langerhans cell histiocytosis is a disorder in which a small group of immune cells with a faulty growth signal (most often a BRAF mutation) pile up in bone, skin, pituitary or organs. It ranges from a single bone lesion that heals after biopsy to a life-threatening disease of infants. A year of gentle chemotherapy cures most children, and BRAF or MEK inhibitors rescue those with resistant disease.","summary":"LCH is now understood as an inflammatory myeloid neoplasm: clonal cells of the mononuclear phagocyte lineage carry activating MAPK-pathway mutations, most often BRAF V600E (about half of cases) and MAP2K1, with the remainder having other RAS-MAPK lesions. The cell of origin, a bone-marrow or blood myeloid precursor versus a tissue dendritic cell, determines extent: mutations arising early give multisystem disease with risk-organ involvement (liver, spleen, marrow), while later lesions give single bone or skin disease. Pituitary involvement causes diabetes insipidus, and a minority of children develop a late neurodegenerative syndrome from mutated cells in the brain.\n\nTreatment is stratified. Single-system bone or skin disease often needs only biopsy or curettage, observation or local therapy. Multisystem disease is treated with vinblastine and prednisone: the Histiocyte Society trials LCH-I to LCH-III showed that early response predicts survival and that prolonging therapy to 12 months reduces reactivation (LCH-III, Blood 2013); LCH-IV is refining duration and testing intensification for non-responders. Children with risk-organ involvement who do not respond quickly move to salvage (cladribine and cytarabine, or clofarabine). For refractory BRAF V600E disease, vemurafenib produces rapid responses in almost all children (Donadieu, JCO 2019), and dabrafenib with or without trametinib is used; MEK inhibitors cover MAP2K1 and other mutations. Responses to targeted therapy are near universal but reactivation on stopping is common, so the durability and safety of long-term inhibitors in young children is the central question.\n\nAdult LCH, including smoking-related pulmonary LCH, is managed with cladribine or cytarabine and MAPK inhibitors, and is now covered by the same Histiocyte Society and NCCN guidance. Neurodegenerative LCH, which had no treatment at all, responds partially to MAPK inhibition, giving a reason to detect it early with MRI.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosis","links":[{"label":"NCI PDQ: Langerhans cell histiocytosis","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"},{"label":"LCH-III: prolonged therapy in multisystem LCH (Blood 2013)","url":"https://doi.org/10.1182/blood-2012-09-455774"},{"label":"Vemurafenib in refractory BRAF V600E LCH (JCO 2019)","url":"https://doi.org/10.1200/JCO.19.00456"},{"label":"Histiocyte Society","url":"https://histiocytesociety.org/"}],"tags":["nci-coverage","paediatric","haematologic"],"related":["histiocytoses","bpdcn","aml"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","cytotoxic-chemotherapy","mri","liquid-biopsy","survivorship-care-plan"],"targets":["braf"],"drugs":["vinblastine","vemurafenib","dabrafenib-trametinib","cladribine"],"companies":["childrens-oncology-group"],"institutions":["histiocyte-society","siop-europe"],"pathways":["ras-mapk"],"terms":["late-effects"],"trials":["lch-iii"],"people":[],"bottlenecks":["b-rare-cancers"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Roughly 5 cases per million children per year, most under ten; also occurs in adults, often in the lung of smokers (NCI PDQ).","subtypes":["Single-system LCH (bone, skin, lymph node)","Multisystem LCH without risk-organ involvement","Multisystem LCH with risk-organ involvement (liver, spleen, haematopoietic)","CNS-risk lesions and pituitary LCH (diabetes insipidus)","Neurodegenerative LCH","Pulmonary LCH (adults, smoking-related)","Mixed LCH / Erdheim-Chester disease (adults)"],"biomarkers":["BRAF V600E in lesion tissue and cell-free DNA (disease burden and monitoring)","MAP2K1 and other MAPK alterations","Risk-organ involvement at diagnosis","Response at week 6 (predicts outcome in LCH-III)","Pituitary MRI and posterior pituitary function","Brain MRI for neurodegenerative change"],"standardOfCare":[{"setting":"Single-system bone or skin","approach":"Biopsy or curettage with observation; intralesional steroid, topical therapy or indomethacin for symptomatic lesions; systemic therapy for multifocal bone or CNS-risk lesions.","refs":["active-surveillance","vinblastine"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}},{"setting":"Multisystem LCH (first line)","approach":"Vinblastine and prednisone for 12 months (LCH-III), with response assessment at 6 weeks; LCH-IV tests further tailoring of duration and intensity.","refs":["vinblastine","lch-iii"],"guideline":{"version":"LCH-III (Blood 2013); LCH-IV protocol","url":"https://doi.org/10.1182/blood-2012-09-455774"}},{"setting":"Refractory risk-organ disease or reactivation","approach":"Cladribine plus cytarabine or clofarabine salvage; BRAF inhibitor (vemurafenib or dabrafenib, with trametinib) for BRAF V600E, MEK inhibitor for MAP2K1-mutant disease.","refs":["cladribine","vemurafenib","dabrafenib-trametinib"],"guideline":{"version":"Donadieu 2019 (JCO); NCCN histiocytic neoplasms","url":"https://doi.org/10.1200/JCO.19.00456"}},{"setting":"Neurodegenerative LCH","approach":"MAPK-pathway inhibition (BRAF or MEK inhibitor) with neurological monitoring; early MRI detection in children with pituitary or craniofacial disease.","refs":["dabrafenib-trametinib","mri"]}],"stateOfArt":["LCH is a MAPK-driven myeloid neoplasm; BRAF V600E in tissue and blood is a diagnostic, prognostic and monitoring marker.","Twelve months of vinblastine-prednisone cures most children with multisystem disease and early response is the key prognostic signal (LCH-III).","BRAF and MEK inhibitors rescue nearly every child with refractory BRAF-mutant disease, but reactivation after stopping means duration is unresolved.","Neurodegenerative LCH, the most feared late complication, is partially reversible with MAPK inhibition if caught early."],"history":[{"year":1953,"title":"Lichtenstein unifies eosinophilic granuloma, Hand-Schuller-Christian and Letterer-Siwe disease as histiocytosis X","refs":[]},{"year":1973,"title":"Langerhans cell identified as the lesional cell","note":"Nezelof finds Birbeck granules in the lesions.","refs":[]},{"year":1991,"title":"Histiocyte Society launches LCH-I","note":"First international randomised trial in LCH.","refs":[]},{"year":2010,"title":"BRAF V600E discovered in LCH","note":"Badalian-Very and colleagues (Blood) show LCH is a clonal MAPK-driven neoplasm.","refs":["braf","ras-mapk"]},{"year":2013,"title":"LCH-III: 12 months of therapy reduces reactivation","note":"Gadner and colleagues (Blood 2013).","refs":["vinblastine","lch-iii"]},{"year":2014,"title":"Cell of origin explains extent","note":"Berres and colleagues (JEM) show BRAF V600E in myeloid precursors in high-risk disease.","refs":[]},{"year":2019,"title":"Vemurafenib in refractory childhood LCH","note":"Donadieu and colleagues (JCO) report responses in nearly all BRAF V600E children, with reactivation after stopping.","refs":["vemurafenib"]}],"pipeline":["dabrafenib-trametinib","vemurafenib","lch-iii"],"openProblems":["How long to give BRAF or MEK inhibitors and how to stop them without reactivation; combination with chemotherapy to allow cessation is being tested in the Histiocyte Society and NACHO networks.","Preventing and treating neurodegenerative LCH; MRI surveillance and early MAPK inhibition are the current approach.","Permanent sequelae (diabetes insipidus, growth failure, hearing loss, sclerosing cholangitis) in survivors of risk-organ disease.","Adult LCH is under-recognised and under-studied; shared paediatric-adult guidelines are a first step."]},{"id":"large-cell-lung-carcinoma","kind":"cancer","name":"Large cell carcinoma of the lung","aka":["Large-cell lung carcinoma","Large cell lung carcinoma","Large-cell carcinoma","Large-cell / NOS","Large cell lung carcinoma with rhabdoid phenotype (variant retired in 2015)","Undifferentiated non-small-cell lung cancer"],"tldr":"Large cell carcinoma is the name for a non-small-cell lung cancer whose cells look neither glandular nor squamous under the microscope. Since 2015 pathologists use protein stains to sort most of these tumours into adenocarcinoma or squamous cell carcinoma, so a true large cell diagnosis is now rare and is treated like adenocarcinoma.","summary":"The WHO classification defines large cell carcinoma as an undifferentiated non-small-cell carcinoma that lacks the cytological, architectural and immunohistochemical features of small cell carcinoma, adenocarcinoma or squamous cell carcinoma; since 2015 the diagnosis can be made only on a resection specimen after immunohistochemistry (TTF-1, napsin A, p40, p63, neuroendocrine markers) is negative or inconclusive (Travis 2015). In a study of 121 tumours across the historical spectrum of large cell carcinoma, all 47 large cell neuroendocrine carcinomas showed neuroendocrine lineage, all 24 basaloid and both lymphoepithelioma-like carcinomas showed squamous markers, and 18 of 22 clear cell carcinomas had glandular differentiation with KRAS mutations in 39 percent (Pelosi 2014); tumours with no marker at all are clinically and genomically indistinguishable from solid adenocarcinoma (Rekhtman 2014). Large cell neuroendocrine carcinoma is now classified with the neuroendocrine neoplasms.\n\nHow it differs from its parent: this is a diagnosis of exclusion within non-small-cell lung cancer rather than a lineage. Its former variants (clear cell, rhabdoid, basaloid, lymphoepithelioma-like) were reassigned in 2015, and the rhabdoid phenotype no longer exists as a category.\n\nHow common: about 10 percent of lung cancers in the PDQ figure, which predates the reclassification; no current registry figure for the narrowed category was found in the sources read.\n\nTreatment: no trial has enrolled large cell carcinoma alone. Guidelines and the PDQ summary treat it with non-squamous (adenocarcinoma) regimens, including pemetrexed-based chemotherapy with pembrolizumab, and recommend the same driver testing as adenocarcinoma because null-immunophenotype tumours carry adenocarcinoma-type alterations (Rekhtman 2014).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Large-cell_lung_carcinoma","links":[{"label":"NCI PDQ (health professional): non-small cell lung cancer treatment, histological shares","url":"https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq"},{"label":"Travis 2015, JTO: the 2015 WHO classification of lung tumours","url":"https://doi.org/10.1097/jto.0000000000000630"},{"label":"Pelosi 2014, Virchows Archiv: large cell carcinoma of the lung reclassified by immunohistochemistry and molecular biology","url":"https://doi.org/10.1007/s00428-013-1501-6"},{"label":"Rekhtman 2014, Curr Opin Pulm Med: large cell carcinoma redefined by immunohistochemistry and genomics","url":"https://doi.org/10.1097/mcp.0000000000000068"}],"tags":["subtype-page","wave4","lung"],"related":["nsclc","lung-adenocarcinoma","lung-squamous-cell-carcinoma","pulmonary-sarcomatoid-carcinoma","lung-net"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["pemetrexed","pembrolizumab","carboplatin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"About 10 percent of lung cancers in the NCI PDQ figures, but the category has shrunk since 2015 because most tumours once called large cell are reassigned to adenocarcinoma or squamous cell carcinoma by immunohistochemistry (Travis 2015).","subtypes":["Large cell carcinoma, null immunophenotype (treated as solid adenocarcinoma)","Large cell carcinoma with unclear staining (TTF-1 and p40 both weak or focal)","Former variants reassigned in 2015: clear cell (to adenocarcinoma), basaloid and lymphoepithelioma-like (to squamous), large cell neuroendocrine carcinoma (to neuroendocrine)"],"biomarkers":["Negative or inconclusive TTF-1, napsin A, p40 and p63","Neuroendocrine markers negative (otherwise large cell neuroendocrine carcinoma)","Driver testing as for adenocarcinoma (KRAS most often)","PD-L1"],"standardOfCare":[{"setting":"All stages","approach":"Treated as lung adenocarcinoma: non-squamous chemotherapy with pembrolizumab, driver testing, and the parent's stage-based pathway.","refs":["lung-adenocarcinoma","pemetrexed","pembrolizumab","nsclc"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"nsclc"},{"id":"lung-lcnec","kind":"cancer","name":"Large cell neuroendocrine carcinoma of the lung","aka":["Pulmonary large cell neuroendocrine carcinoma","LCNEC","Large-cell neuroendocrine carcinoma","Large cell neuroendocrine carcinoma (a WHO 2021 lung neuroendocrine carcinoma, between small-cell and non-small-cell disease)","High-grade pulmonary neuroendocrine carcinoma, non-small-cell type"],"tldr":"Large cell neuroendocrine carcinoma is a lung cancer that looks like a large-cell tumour under the microscope but has the neuroendocrine markers and the fast, aggressive behaviour of small-cell lung cancer. It sits between the two halves of the usual split, which is why teams disagree about whether to treat it as one or the other.","summary":"What it is. The fifth edition of the World Health Organization classification of thoracic tumours (2021) places large cell neuroendocrine carcinoma in the lung neuroendocrine neoplasm chapter, alongside typical carcinoid, atypical carcinoid and small cell carcinoma, rather than among the non-small-cell types it resembles by size and architecture (Nicholson 2022). The diagnosis needs both a neuroendocrine morphology, organoid nesting, rosettes or a trabecular pattern with a high mitotic count and necrosis, and confirmation of neuroendocrine differentiation by immunohistochemistry, which is why it is rarely diagnosed confidently on a small biopsy.\n\nWhere it sits in the family. It belongs to neither side of the clinical split that organises every other page in this family. The IASLC's ninth-edition staging work analysed pulmonary neuroendocrine carcinoma as its own group within the lung database, and clinical practice has run it both ways, as a non-small-cell cancer eligible for resection and adjuvant chemotherapy and as a small-cell cancer given platinum and etoposide. On this site it is a child of the lung cancer family page rather than of non-small-cell or small-cell lung cancer; the reasoning is set out in the taxonomy section of docs/CANCER-PAGES.md.\n\nHow it is treated. No randomised trial has settled it and this record does not claim one. Localised disease is resected where it can be, as for other non-small-cell tumours of the same stage, and advanced disease is generally given a platinum doublet, with the choice between the small-cell and the non-small-cell backbone decided case by case. The parent record carries the staging, the diagnostic pathway and the screening and prevention material that apply here unchanged.\n\nWhat it is not. It is not large cell carcinoma, which by the 2021 definition is an undifferentiated tumour with no glandular, squamous or neuroendocrine features and is a diagnosis of exclusion made on a resection specimen. It is not small cell carcinoma, whose cells are small with scant cytoplasm and finely granular chromatin. It is not a carcinoid: typical and atypical carcinoids are low and intermediate-grade tumours with a very different course, and sit under the neuroendocrine family page in this corpus.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Large-cell_lung_carcinoma","links":[{"label":"Nicholson, J Thorac Oncol 2022: the 2021 WHO classification of lung tumours, impact of advances since 2015","url":"https://doi.org/10.1016/j.jtho.2021.11.003"},{"label":"Lancet Respir Med 2025: estimated worldwide variation and trends in incidence of lung cancer by histological subtype in 2022 and over time (GLOBOCAN 2022 with Cancer Incidence in Five Continents)","url":"https://doi.org/10.1016/s2213-2600(24)00428-4"},{"label":"J Thorac Oncol 2023: IASLC lung cancer staging project, the new database to inform revisions in the ninth edition of the TNM classification","url":"https://doi.org/10.1016/j.jtho.2023.01.088"},{"label":"NICE NG122: lung cancer, diagnosis and staging (published 28 March 2019, last updated 8 March 2024)","url":"https://www.nice.org.uk/guidance/ng122/chapter/Diagnosis-and-staging"}],"tags":["lung","subtype-page"],"related":["lung-cancer","sclc","nsclc","large-cell-lung-carcinoma","lung-net","neuroendocrine"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","ct","pet"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["tnm-9-lung-cancer","ttf1-p40","resectability-lung-cancer","performance-status"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"Rare, and counted differently depending on which classification a registry uses. GLOBOCAN does not report it, and registry series that separate the four main histological types put large cell carcinoma as a whole at 6.5 percent of lung cancers in both men and women worldwide (101,861 cases in men and 59,271 in women in 2022, Lancet Respiratory Medicine 2025); large cell neuroendocrine carcinoma is a subset of that group, so no separate incidence figure can be quoted from the sources read here.","subtypes":["Pure large cell neuroendocrine carcinoma of the lung","Combined large cell neuroendocrine carcinoma (with an adenocarcinoma, squamous or small-cell component)"],"biomarkers":["Neuroendocrine morphology with a high mitotic count and necrosis, recorded in the pathology report","Neuroendocrine differentiation confirmed by immunohistochemistry","TTF-1 and p40 to exclude adenocarcinoma and squamous cell carcinoma"],"standardOfCare":[{"setting":"Localised disease","approach":"Resection where the tumour is resectable, staged by TNM 9 as for any other lung cancer, with adjuvant chemotherapy decided case by case; no randomised trial establishes the regimen, and teams differ over whether to use the small-cell or the non-small-cell backbone.","refs":["resectability-lung-cancer","tnm-9-lung-cancer"]},{"setting":"Advanced disease","approach":"A platinum doublet, with the choice between the small-cell and the non-small-cell backbone made case by case; the parent and the small-cell page carry the regimens.","refs":["sclc","nsclc"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"lung-cancer"},{"id":"laryngeal-cancer","kind":"cancer","name":"Laryngeal and hypopharyngeal cancer","aka":["Larynx cancer","Voice box cancer","Glottic cancer","Supraglottic cancer","Hypopharynx cancer"],"tldr":"Cancer of the voice box, a head and neck cancer, announces itself with hoarseness and is highly curable when caught early, by laser surgery or radiotherapy that preserve the voice. Advanced disease is treated with chemoradiation to keep the larynx where possible, with total laryngectomy for the most extensive tumours or when other treatment fails.","summary":"Laryngeal squamous cell carcinoma arises in the glottis (vocal cords), supraglottis or subglottis; hypopharyngeal cancer arises just behind and below and is grouped with it. Persistent hoarseness leads to early diagnosis of glottic tumours, which are treated with transoral laser microsurgery or radiotherapy alone with excellent cure rates. Locally advanced disease is treated with concurrent cisplatin chemoradiation, established by RTOG 91-11 as the best way to keep the larynx, while tumours that have destroyed cartilage or the larynx's function are best treated with total laryngectomy and postoperative radiotherapy, followed by voice rehabilitation with a voice prosthesis. Hypopharyngeal cancer presents late, with swallowing difficulty and neck nodes, and often needs laryngopharyngectomy. Smoking cessation is the most important single intervention.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Laryngeal_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Laryngeal_cancer"}],"tags":["subtype-page"],"related":["hpv-negative-head-and-neck-cancer","oral-cavity-cancer","oropharyngeal-cancer","recurrent-metastatic-hnscc"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-keynote-048-lancet-2019","paper-rtog-91-11-forastiere-nejm-2003","paper-rtog-91-11-long-term-forastiere-jco-2013","paper-va-larynx-induction-chemotherapy-nejm-1991"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"About 190,000 new cases a year worldwide, overwhelmingly in smokers and heavy drinkers; early vocal cord cancers are cured in more than nine in ten patients, while hypopharyngeal cancer has among the worst outlooks in head and neck oncology.","subtypes":["Glottic (vocal cord) cancer","Supraglottic cancer","Subglottic cancer (rare)","Hypopharyngeal cancer (pyriform sinus, postcricoid, posterior wall)"],"biomarkers":["Stage and cartilage invasion on CT","Vocal cord mobility","Smoking and alcohol exposure","PD-L1 (recurrent disease)"],"standardOfCare":[{"setting":"Early glottic cancer","approach":"Transoral laser microsurgery or radiotherapy alone; both cure most patients and preserve the voice.","refs":["imrt-igrt","hypofractionated-radiotherapy"]},{"setting":"Locally advanced, larynx preservable","approach":"Concurrent cisplatin chemoradiation (RTOG 91-11); induction chemotherapy for selection in some centres.","refs":["cisplatin","rtog-91-11"]},{"setting":"Extensive disease or non-functioning larynx","approach":"Total laryngectomy with neck dissection and postoperative radiotherapy or chemoradiation; voice prosthesis rehabilitation.","refs":["imrt-igrt"]},{"setting":"Recurrent or metastatic","approach":"Salvage laryngectomy after radiotherapy failure; pembrolizumab-based therapy for metastatic disease (KEYNOTE-048).","refs":["pembrolizumab","keynote-048","cetuximab"]},{"setting":"Prevention","approach":"Smoking cessation and alcohol reduction; no screening programme exists.","refs":["smoking-cessation-after-diagnosis","alcohol-reduction-labelling"]}],"stateOfArt":["Larynx preservation with chemoradiation cures most locally advanced cancers while keeping the voice, but late toxicity and non-cancer deaths have tempered enthusiasm for it in the most extensive tumours.","Transoral laser surgery and single-fraction-savvy radiotherapy schedules give early glottic cancer cure rates above 90 percent.","Voice prostheses after laryngectomy restore intelligible speech for most patients."],"history":[{"year":1873,"title":"Billroth performs the first total laryngectomy","refs":[]},{"year":1991,"title":"VA Larynx trial: induction chemotherapy and radiotherapy preserve the larynx in two thirds","refs":[]},{"year":2003,"title":"RTOG 91-11: concurrent cisplatin chemoradiation best for larynx preservation","refs":["rtog-91-11"]},{"year":2013,"title":"Long-term RTOG 91-11 data show more non-cancer deaths after concurrent treatment","refs":["rtog-91-11"]}],"pipeline":["pembrolizumab","adaptive-radiotherapy"],"openProblems":["Hypopharyngeal cancer survival has barely improved.","Choosing between preservation and laryngectomy in T4 disease.","Long-term swallowing and airway function after chemoradiation.","Persistently high incidence where smoking remains common."],"parent":"head-and-neck"},{"id":"leiomyosarcoma","kind":"cancer","name":"Leiomyosarcoma","aka":["LMS","Uterine leiomyosarcoma","Smooth muscle sarcoma"],"tldr":"Leiomyosarcoma is a cancer of smooth muscle, most often in the womb, the abdomen behind the bowel or the wall of a large vein. Surgery is the only cure; for spread disease, doxorubicin-based chemotherapy, trabectedin and gemcitabine-docetaxel are the standards, with no targeted drug yet.","summary":"Leiomyosarcoma arises from smooth muscle and is genomically complex, with TP53, RB1 and ATRX loss and no recurrent fusion. Uterine leiomyosarcoma is usually found unexpectedly after surgery for presumed fibroids, which is why morcellation of unsuspected tumours is avoided; retroperitoneal and vascular tumours present late. Complete surgical resection, with radiotherapy for limb tumours, is the only curative treatment and adjuvant chemotherapy has not proven benefit. Metastatic disease is treated with doxorubicin, alone or with trabectedin (LMS-04) or dacarbazine, gemcitabine-docetaxel, trabectedin and pazopanib; responses are modest and median survival is about two years. Immunotherapy has little activity, and trials target the disease's DNA repair and cell-cycle vulnerabilities.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Leiomyosarcoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Leiomyosarcoma"}],"tags":["subtype-page"],"related":["liposarcoma","undifferentiated-pleomorphic-sarcoma","uterine-sarcoma","retroperitoneal-sarcoma","extremity-soft-tissue-sarcoma","myxofibrosarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-eortc-62012-doxorubicin-ifosfamide-judson-lancet-oncol-2014","paper-esmo-sts-guideline-gronchi-ann-oncol-2021","paper-lms-04-doxorubicin-trabectedin-lancet-oncol-2022","paper-hensley-gemcitabine-docetaxel-leiomyosarcoma-jco-2002"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"One of the two commonest soft-tissue sarcomas in adults, arising in the uterus, the retroperitoneum, large veins and limbs; about half of patients with deep tumours eventually develop metastases, most often to the lungs.","subtypes":["Uterine leiomyosarcoma","Retroperitoneal and intra-abdominal leiomyosarcoma","Vascular leiomyosarcoma (inferior vena cava, large veins)","Limb and cutaneous leiomyosarcoma (better outlook)"],"biomarkers":["TP53, RB1 and ATRX alterations","Grade (FNCLCC) and size","Smooth muscle markers (desmin, h-caldesmon, SMA)","Oestrogen and progesterone receptor in uterine tumours (hormone therapy in low-grade disease)"],"standardOfCare":[{"setting":"Localised","approach":"Wide surgical resection; radiotherapy for limb and trunk tumours; no morcellation of uterine masses that could be sarcoma; adjuvant chemotherapy not standard.","refs":["imrt-igrt"]},{"setting":"Metastatic, first line","approach":"Doxorubicin plus trabectedin (LMS-04) or doxorubicin alone; gemcitabine-docetaxel as an alternative, especially in uterine disease.","refs":["doxorubicin","trabectedin","gemcitabine","docetaxel"]},{"setting":"Later lines","approach":"Trabectedin, pazopanib, dacarbazine-based regimens, aromatase inhibitors in hormone receptor-positive low-grade uterine disease; metastasectomy for limited lung spread.","refs":["trabectedin","pazopanib","letrozole"]}],"stateOfArt":["LMS-04 gave the first randomised progression-free survival gain in a decade by combining doxorubicin with trabectedin.","Lung metastasectomy in selected patients produces long survival that chemotherapy alone does not.","Genomic profiling has defined the disease but not yet yielded a targeted drug."],"history":[{"year":1994,"title":"Doxorubicin-ifosfamide becomes the reference first-line regimen for soft-tissue sarcoma","refs":["doxorubicin","ifosfamide"]},{"year":2007,"title":"Trabectedin approved in Europe for soft-tissue sarcoma","refs":["trabectedin"]},{"year":2014,"title":"Morcellation warnings after unsuspected uterine leiomyosarcoma spread","refs":[]},{"year":2022,"title":"LMS-04: doxorubicin plus trabectedin improves progression-free survival","refs":["trabectedin"]}],"pipeline":["trabectedin"],"openProblems":["No targeted or immune therapy works in most patients.","Uterine tumours are still discovered by accident after fibroid surgery.","Adjuvant chemotherapy remains unproven."],"parent":"sarcoma"},{"id":"leukaemia","kind":"cancer","name":"Leukaemia (all types)","aka":["Leukemia","Blood cancer (leukaemias)"],"tldr":"Leukaemia means cancer of the blood-forming cells, but the four main types share little beyond the name: acute lymphoblastic and acute myeloid leukaemia are emergencies treated with intensive therapy, while chronic lymphocytic and chronic myeloid leukaemia are slow diseases controlled for years with pills. Each has its own page.","summary":"Leukaemias arise when a blood stem cell or its progeny acquires mutations that block maturation and drive proliferation, flooding the marrow and blood with abnormal cells. They are classified by speed (acute or chronic) and lineage (lymphoid or myeloid). Acute lymphoblastic leukaemia is the commonest childhood cancer and is cured in about 90 percent of children; acute myeloid leukaemia is mainly a disease of older adults treated with intensive chemotherapy, venetoclax combinations and transplant; chronic lymphocytic leukaemia is often watched for years and then controlled with BTK and BCL2 inhibitors; chronic myeloid leukaemia became the model of targeted therapy with imatinib. Rarer forms include hairy cell leukaemia and chronic myelomonocytic leukaemia. CAR-T cells and bispecific antibodies are changing the acute leukaemias.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Leukemia","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Leukemia"},{"label":"NCI PDQ","url":"https://www.cancer.gov/types/leukemia"}],"tags":["parent-page"],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About 490,000 new cases and 300,000 deaths a year worldwide; the commonest cancer of childhood, where most cases are now cured, and a group of very different diseases in adults.","subtypes":["Acute lymphoblastic leukaemia (ALL)","Acute myeloid leukaemia (AML)","Chronic lymphocytic leukaemia (CLL)","Chronic myeloid leukaemia (CML)","Hairy cell leukaemia","Chronic myelomonocytic leukaemia (CMML)","Blastic plasmacytoid dendritic cell neoplasm (BPDCN)"],"biomarkers":["Flow cytometry immunophenotype","Cytogenetics and fusion genes (BCR-ABL1, PML-RARA, KMT2A)","Mutations (FLT3, NPM1, IDH1/2, TP53, IGHV status)","Measurable residual disease by flow or PCR"],"standardOfCare":[{"setting":"Diagnosis","approach":"Blood count and film, bone marrow aspirate and biopsy, flow cytometry, cytogenetics and molecular panel; the subtype then sets the pathway.","refs":["flow-cytometry-mrd","cytogenetics-fish"]},{"setting":"Treatment","approach":"By type on the subtype pages: intensive chemotherapy and transplant for acute leukaemias, tyrosine kinase inhibitors for CML, BTK and BCL2 inhibitors for CLL.","refs":["all-leukemia","aml","cll","cml"]},{"setting":"Supportive care","approach":"Growth factor support, transfusion, infection prevention and tumour lysis prophylaxis around intensive treatment.","refs":["g-csf-growth-factors","transfusion-support"]}],"stateOfArt":["Childhood ALL cure rates near 90 percent through risk-adapted chemotherapy and measurable residual disease monitoring.","CML patients live near-normal lifespans on tyrosine kinase inhibitors, and many can stop treatment.","Venetoclax made AML treatable in older adults; CAR-T and blinatumomab rescued relapsed ALL.","Treatment-free remission and measurable residual disease guide therapy across the chronic leukaemias."],"history":[{"year":1845,"title":"Virchow names leukaemia","note":"White blood in a patient's vessels described as a disease of the blood itself.","refs":[]},{"year":1948,"title":"Farber induces remissions in childhood ALL with aminopterin","refs":[]},{"year":1960,"title":"Philadelphia chromosome discovered in CML","refs":[]},{"year":2001,"title":"Imatinib approved","note":"The first kinase inhibitor and the model for targeted therapy.","refs":["imatinib"]},{"year":2017,"title":"Tisagenlecleucel: the first CAR-T approval, for childhood ALL","refs":["tisagenlecleucel"]}],"pipeline":["menin-inhibitors","car-t"],"openProblems":["Adult ALL and TP53-mutated AML still have poor outcomes.","Infant and relapsed childhood leukaemias.","Access to CAR-T and transplant outside rich countries.","Late effects of childhood treatment."]},{"id":"leydig-cell-tumour","kind":"cancer","name":"Leydig cell tumour of the testis","aka":["Leydig cell tumour","Leydig cell tumor","Interstitial cell tumour of the testis","Malignant Leydig cell tumour"],"tldr":"Leydig cell tumour is the commonest testicular tumour that is not a germ cell tumour; it grows from the hormone-making cells between the tubules. It often makes testosterone or oestrogen, causing early puberty in boys or breast growth in men, and nine in ten are benign and cured by surgery. No chemotherapy works in the malignant tenth, managed case by case at a specialist centre.","summary":"Leydig cell tumours are sex cord-stromal tumours of the testis, listed in the WHO classification apart from the germ cell tumours that make up most testicular cancer (Moch 2016). They are the most common non-germ cell neoplasms of the testis and are often hormonally active, producing precocious virilisation in boys or feminisation in adults (JCEM 2006). Malignancy, defined by metastasis rather than by histology alone, occurs in up to 10 percent, with large size, necrosis, vascular invasion, atypia and high mitotic count as warning features; the main differential in boys with congenital adrenal hyperplasia is the testicular adrenal rest tumour, which responds to steroid suppression (Avicenna Journal of Medicine 2013). Germline fumarate hydratase mutations, the cause of the HLRCC syndrome, were found in two of 30 adult Leydig cell tumours, with loss of the wild-type allele and activation of the hypoxia pathway (JCEM 2006).\n\nHow it differs from its parent: the testicular page describes germ cell tumours, cured by cisplatin; Leydig cell tumours do not respond to that chemotherapy, do not raise the germ cell markers, and are staged and managed as a sex cord-stromal tumour, with testis-sparing surgery possible for small benign tumours.\n\nHow common: no incidence figure in the sources read.\n\nTreatment: radical or testis-sparing orchidectomy for benign tumours; retroperitoneal lymph node dissection for tumours with malignant features or nodal disease; metastatic disease has no effective chemotherapy and is managed case by case (NCI PDQ testicular summary for the germ cell comparison).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Leydig_cell_tumour","links":[{"label":"NCI PDQ: testicular cancer treatment","url":"https://www.cancer.gov/types/testicular/treatment"},{"label":"Moch 2016, European Urology: the 2016 WHO classification of urinary and male genital tumours, part A","url":"https://doi.org/10.1016/j.eururo.2016.02.029"},{"label":"JCEM 2006: adult Leydig cell tumours of the testis caused by germline fumarate hydratase mutations","url":"https://doi.org/10.1210/jc.2006-0183"},{"label":"Avicenna Journal of Medicine 2013: testicular adrenal rest tumour or Leydig cell tumour, case and review","url":"https://doi.org/10.4103/2231-0770.112789"}],"tags":["subtype-page","wave4","testicular","rare"],"related":["testicular","sertoli-cell-tumour","granulosa-cell-tumour","seminoma"],"cancers":[],"sections":[],"technologies":[],"targets":["fh"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"The most common non-germ cell tumour of the testis (JCEM 2006), yet a small minority of testicular tumours; up to 10 percent behave malignantly (Avicenna Journal of Medicine 2013). No registry figure was found in the sources read.","subtypes":[],"biomarkers":["Inhibin and calretinin positive; germ cell markers negative","Testosterone, oestradiol and gonadotrophins","Size, necrosis, vascular invasion, atypia and mitotic count (malignancy risk)","Fumarate hydratase (rare germline cases)"],"standardOfCare":[{"setting":"All cases","approach":"Orchidectomy (testis-sparing for small benign tumours); retroperitoneal node dissection for malignant features; no chemotherapy has shown benefit in metastatic disease, which is planned case by case at a specialist centre with trials considered.","refs":["testicular"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"testicular"},{"id":"limited-stage-sclc","kind":"cancer","name":"Limited-stage small-cell lung cancer","aka":["LS-SCLC","Limited-disease small-cell lung cancer","Stage I to III small-cell lung cancer"],"tldr":"Small-cell lung cancer that is still confined to one side of the chest is treated to cure with chemotherapy and radiotherapy given together. Adding two years of the immunotherapy antibody durvalumab afterwards lengthened median survival from under three years to over four and a half, the first improvement in this disease in decades.","summary":"Small-cell lung cancer grows fast, spreads early and responds dramatically but briefly to chemotherapy. Limited-stage disease, defined since the 1950s as disease encompassable in one radiation field, is treated with four cycles of cisplatin or carboplatin plus etoposide and concurrent thoracic radiotherapy started with the first or second cycle. Turrisi's trial (1999) showed that 45 Gy in twice-daily fractions over three weeks improved five-year survival from 16 to 26 percent compared with the same dose once daily, and CONVERT (2017) found that 66 Gy once daily was not better than the twice-daily schedule, so both are accepted. Prophylactic cranial irradiation for patients in response cut brain relapse and improved three-year survival from 15 to 21 percent in the 1999 Aupérin meta-analysis, though MRI surveillance is being tested as an alternative because of its effect on memory.\n\nFor twenty-five years nothing improved on this until ADRIATIC (2024): 730 patients without progression after chemoradiation were randomised to durvalumab for up to two years, placebo, or durvalumab plus tremelimumab. Durvalumab alone lengthened median overall survival from 33.4 to 55.9 months (hazard ratio 0.73) and progression-free survival from 9.2 to 16.6 months, with pneumonitis of any grade in about a third of patients in both arms. The FDA approved durvalumab consolidation in December 2024 and it has become the standard.\n\nThe next steps are testing the DLL3 T-cell engager tarlatamab after chemoradiation (DeLLphi-306) and checkpoint inhibitors given during rather than after chemoradiation; surgery is limited to the rare stage I tumour found incidentally. Open questions are whether prophylactic cranial irradiation is still needed with modern MRI surveillance, the best radiotherapy dose and schedule with immunotherapy, and how to treat the majority who still relapse.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Small-cell_carcinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Small-cell_carcinoma"},{"label":"NCCN Guidelines: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}],"tags":["subtype-page","lung"],"related":["extensive-stage-sclc"],"cancers":[],"sections":[],"technologies":["imrt-igrt","checkpoint-inhibitor","prophylactic-cranial-irradiation","cytotoxic-chemotherapy","platinum","pet-ct","mri","t-cell-engager"],"targets":["pdl1","dll3","tp53"],"drugs":["durvalumab","platinum-etoposide","cisplatin","carboplatin","etoposide","tremelimumab","tarlatamab","lurbinectedin","topotecan"],"companies":["astrazeneca","amgen"],"institutions":[],"pathways":["sclc-signalling","p53-cell-cycle","pd1-checkpoint"],"terms":["limited-extensive-stage","chemoradiation","pci-term","consolidation-therapy","radiation-pneumonitis","histologic-transformation","sclc-molecular-subtypes"],"trials":["adriatic","convert","nct06117774","dellphi-304"],"people":["cheng-ying","fiona-blackhall","charles-rudin","luis-paz-ares"],"bottlenecks":[],"keyPapers":["paper-adriatic-nejm-2024"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"About 30 percent of small-cell lung cancers are limited stage, confined to one side of the chest and its regional nodes so that they fit in a single radiotherapy field; almost all patients are current or former heavy smokers. Median survival was 25 to 30 months with chemoradiation and about a fifth to a quarter were cured.","subtypes":["Limited-stage small-cell lung cancer, stage I to III, fit for concurrent chemoradiation (durvalumab consolidation)","Very limited stage I small-cell lung cancer (surgery then chemotherapy)","Limited-stage small-cell disease unfit for concurrent treatment (sequential chemoradiation)","Small-cell lung cancer transformed from EGFR-mutated adenocarcinoma"],"biomarkers":["Stage by PET-CT and brain MRI (limited versus extensive is the main decision)","Response after chemoradiation (eligibility for durvalumab)","Pulmonary function and radiation dose constraints","Neuroendocrine markers on pathology (synaptophysin, chromogranin, INSM1)","Transcription factor subtype (ASCL1, NEUROD1, POU2F3; research)"],"standardOfCare":[{"setting":"Limited stage, fit","approach":"Four cycles of cisplatin or carboplatin plus etoposide with concurrent thoracic radiotherapy (45 Gy twice daily or 60 to 66 Gy once daily) started by cycle two, then durvalumab for up to two years in patients without progression (ADRIATIC).","refs":["platinum-etoposide","cisplatin","carboplatin","etoposide","imrt-igrt","chemoradiation","convert","durvalumab","adriatic","consolidation-therapy"],"guideline":{"version":"NCCN Guidelines: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}},{"setting":"After response: brain","approach":"Prophylactic cranial irradiation (25 Gy in 10 fractions) or MRI surveillance every three months in patients who decline it or are older; hippocampal avoidance where available.","refs":["prophylactic-cranial-irradiation","pci-term","mri","idea-mri-surveillance-replaces-pci"],"guideline":{"version":"NCCN Guidelines: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}},{"setting":"Stage I, node-negative, found incidentally","approach":"Lobectomy with node dissection then four cycles of platinum-etoposide; radiotherapy if nodes are positive.","refs":["lobectomy","platinum-etoposide"],"guideline":{"version":"NCCN Guidelines: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}},{"setting":"Relapse","approach":"As for extensive-stage disease: tarlatamab, lurbinectedin or topotecan, or rechallenge with platinum-etoposide if relapse is late.","refs":["tarlatamab","dellphi-304","lurbinectedin","topotecan","platinum-etoposide"],"guideline":{"version":"NCCN Guidelines: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}}],"stateOfArt":["Durvalumab consolidation after chemoradiation (ADRIATIC): median survival 55.9 versus 33.4 months.","Twice-daily 45 Gy or once-daily 60 to 66 Gy thoracic radiotherapy, both accepted (CONVERT).","MRI surveillance under test as an alternative to prophylactic cranial irradiation.","Tarlatamab after chemoradiation in phase 3 (DeLLphi-306)."],"history":[{"year":1957,"title":"Veterans Administration Lung Study Group defines limited and extensive stage","refs":["limited-extensive-stage"]},{"year":1992,"title":"Meta-analysis: adding thoracic radiotherapy to chemotherapy improves survival in limited stage","refs":["chemoradiation","imrt-igrt"]},{"year":1999,"title":"Turrisi: twice-daily 45 Gy improves five-year survival to 26 percent; Aupérin meta-analysis: prophylactic cranial irradiation improves survival","refs":["prophylactic-cranial-irradiation","platinum-etoposide"]},{"year":2017,"title":"CONVERT: 66 Gy once daily not superior to 45 Gy twice daily","refs":["convert","fiona-blackhall"]},{"year":2024,"title":"ADRIATIC: durvalumab after chemoradiation lengthens survival by almost two years; FDA approval","refs":["adriatic","durvalumab","cheng-ying","paper-adriatic-nejm-2024"]}],"pipeline":["nct06117774","tarlatamab","idea-mri-surveillance-replaces-pci","idea-sclc-subtype-directed","t-cell-engager"],"openProblems":["Whether prophylactic cranial irradiation still helps when MRI surveillance is available is being tested in randomised trials.","The best radiotherapy dose and schedule to combine with immunotherapy is unknown.","Most patients still relapse after chemoradiation and durvalumab, and there is no biomarker for who will be cured.","Transformed small-cell disease arising from EGFR-mutated adenocarcinoma is treated as limited or extensive stage without evidence specific to it."],"parent":"sclc"},{"id":"lip-cancer","kind":"cancer","name":"Lip cancer","aka":["Lower lip squamous cell carcinoma","Cancer of the lip vermilion"],"tldr":"Cancer of the lip is really a skin cancer of the sun-exposed lower lip, usually found early because it can be seen. A small operation or radiotherapy cures most people, and reconstruction keeps the mouth working.","summary":"Lip cancer is squamous cell carcinoma of the vermilion, the red part of the lip, and the great majority arise on the lower lip, which faces the sun, in fair-skinned men who work outdoors or smoke, often from a precursor patch of actinic cheilitis. Upper lip tumours are more often basal cell carcinomas spreading from the skin. Because the eighth edition of the staging system moved vermilion lip cancer into the skin cancer chapter, only cancer of the inner mucosal lip is now staged with the oral cavity, though lip cancer is still treated by head and neck teams.\n\nMost tumours are small when found and are cured by wedge excision, closed directly or, for larger defects, with Abbe, Estlander or Karapandzic flaps that keep the mouth competent and mobile. Radiotherapy, by external beam or brachytherapy, is an equally effective alternative, chosen for tumours at the commissure or in patients unfit for surgery. Nodal spread is uncommon in small tumours, so the neck is observed or staged with sentinel node biopsy and dissected only when nodes are found or the primary is large, thick or has perineural invasion.\n\nAdvanced tumours invading the jaw or with nodal spread are treated with resection, neck dissection and postoperative radiotherapy, with cisplatin for extranodal extension or positive margins, and unresectable or metastatic disease is treated as cutaneous squamous cell carcinoma with cemiplimab or as head and neck squamous cell carcinoma with pembrolizumab. Sun protection and smoking cessation prevent most cases, and treating actinic cheilitis prevents progression.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Lip_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Lip_cancer"}],"tags":["subtype-page","head-and-neck"],"related":["buccal-mucosa-cancer","oral-tongue-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["empower-cscc-1"],"people":[],"bottlenecks":[],"keyPapers":["paper-keynote-048-lancet-2019","paper-bonner-cetuximab-radiotherapy-nejm-2006","paper-bernier-eortc-22931-nejm-2004","paper-empower-cscc-1-cemiplimab-migden-nejm-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"Mostly squamous cell carcinoma of the lower lip in fair-skinned outdoor workers and smokers; it is caught early because it is visible, and excision or radiotherapy cures the great majority.","subtypes":["Lower lip squamous cell carcinoma (sun and tobacco related)","Upper lip cancer (often basal cell carcinoma)","Commissure (corner of the mouth) cancer","Mucosal lip cancer staged with the oral cavity","Actinic cheilitis (precursor)"],"biomarkers":["Tumour thickness and depth","Perineural invasion","Margin status","Immunosuppression (transplant recipients)","PD-L1 (advanced disease)"],"standardOfCare":[{"setting":"Early disease","approach":"Wedge or V excision with local flap reconstruction, or radiotherapy (external beam or brachytherapy) for commissure tumours or unfit patients.","refs":["imrt-igrt","brachytherapy"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Large, thick or node-positive disease","approach":"Resection with flap reconstruction, sentinel node biopsy or neck dissection, and postoperative radiotherapy; cisplatin for extranodal extension or positive margins.","refs":["imrt-igrt","sentinel-node","cisplatin","chemoradiation"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Unresectable or metastatic","approach":"Cemiplimab as for cutaneous squamous cell carcinoma, or pembrolizumab-based treatment as for head and neck squamous cell carcinoma.","refs":["cemiplimab","pembrolizumab","keynote-048"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Prevention","approach":"Sun protection of the lips, smoking cessation, and treatment of actinic cheilitis.","refs":["smoking-cessation-after-diagnosis"]}],"stateOfArt":["Local flap techniques a century old still give the best functional results.","Radiotherapy and surgery cure similar proportions, so the choice rests on function and cosmesis.","Immunotherapy for cutaneous squamous cell carcinoma now covers the rare advanced lip cancer."],"history":[{"year":1898,"title":"Abbe describes the cross-lip flap","refs":[]},{"year":1974,"title":"Karapandzic describes the neurovascular flap that keeps the mouth working","refs":[]},{"year":2017,"title":"Vermilion lip cancer moves to the skin cancer staging chapter (AJCC 8th edition)","refs":[]}],"pipeline":["cemiplimab"],"openProblems":["Lip cancer in outdoor workers in sunny countries is under-recognised and under-protected.","Function and appearance after resection of more than half the lip.","Whether sentinel node biopsy should be routine for thicker tumours."],"parent":"oral-cavity-cancer"},{"id":"liposarcoma","kind":"cancer","name":"Liposarcoma","aka":["Well-differentiated liposarcoma (atypical lipomatous tumour)","Dedifferentiated liposarcoma","Myxoid liposarcoma","Pleomorphic liposarcoma"],"tldr":"Liposarcoma is a cancer of fat cells that comes in four different forms: two driven by extra copies of the MDM2 gene, one by a fusion gene that makes it unusually sensitive to radiotherapy and trabectedin, and one that behaves like other aggressive sarcomas. Surgery is the mainstay and MDM2 inhibitors are the most promising drugs in trials.","summary":"Well-differentiated and dedifferentiated liposarcoma share amplification of MDM2 and CDK4 on chromosome 12 and arise mostly in the retroperitoneum and thigh; the well-differentiated form does not metastasise but recurs locally, and the dedifferentiated form is aggressive. Myxoid liposarcoma carries the FUS-DDIT3 fusion, occurs in younger adults, spreads to unusual soft-tissue and bone sites and is strikingly sensitive to radiotherapy and to trabectedin. Pleomorphic liposarcoma is genomically complex and treated like other high-grade sarcomas. Surgery is the mainstay, with radiotherapy for limb tumours and, for retroperitoneal disease, the STRASS trial failed to show a benefit of preoperative radiotherapy overall. Eribulin improved survival in advanced liposarcoma, trabectedin is effective in myxoid disease, and MDM2 inhibitors such as brigimadlin and CDK4/6 inhibitors are in late trials for the MDM2-amplified forms.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Liposarcoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Liposarcoma"}],"tags":["subtype-page"],"related":["leiomyosarcoma","retroperitoneal-sarcoma","undifferentiated-pleomorphic-sarcoma","myxofibrosarcoma","extremity-soft-tissue-sarcoma","synovial-sarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["brigimadlin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["sarc028"],"people":[],"bottlenecks":[],"keyPapers":["paper-esmo-sts-guideline-gronchi-ann-oncol-2021","paper-strass-lancet-oncol-2020","paper-eribulin-liposarcoma-schoffski-lancet-2016","paper-trabectedin-vs-dacarbazine-demetri-jco-2016"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"The commonest soft-tissue sarcoma of adults, about a fifth of the total; outcomes range from near-benign well-differentiated tumours of the limbs to dedifferentiated retroperitoneal tumours that recur repeatedly and are often fatal.","subtypes":["Well-differentiated liposarcoma (atypical lipomatous tumour; MDM2-amplified)","Dedifferentiated liposarcoma (MDM2-amplified, aggressive)","Myxoid and round cell liposarcoma (FUS-DDIT3)","Pleomorphic liposarcoma"],"biomarkers":["MDM2 and CDK4 amplification (FISH; separates from lipoma)","FUS-DDIT3 fusion (myxoid)","Round cell component (myxoid prognosis)","Grade and site (retroperitoneal versus limb)"],"standardOfCare":[{"setting":"Well-differentiated, limb","approach":"Marginal excision; no radiotherapy or systemic therapy; surveillance for local recurrence.","refs":["sarcoma"]},{"setting":"Retroperitoneal well- and dedifferentiated","approach":"Complete en bloc resection in a sarcoma centre; preoperative radiotherapy not routine after STRASS; repeat surgery for recurrence.","refs":["sarcoma","imrt-igrt"]},{"setting":"Myxoid liposarcoma","approach":"Surgery with preoperative radiotherapy (highly radiosensitive); trabectedin for advanced disease.","refs":["imrt-igrt","trabectedin"]},{"setting":"Advanced disease","approach":"Doxorubicin-based chemotherapy, eribulin (overall survival benefit in liposarcoma), trabectedin; MDM2 and CDK4 inhibitors in trials for amplified tumours.","refs":["doxorubicin","eribulin","trabectedin","mdm2"]}],"stateOfArt":["MDM2 amplification is both the diagnostic test and the therapeutic target, with brigimadlin in a phase 3 trial against doxorubicin.","Eribulin was the first drug to lengthen survival specifically in liposarcoma.","Myxoid liposarcoma's radiosensitivity allows reduced-dose preoperative radiotherapy."],"history":[{"year":1962,"title":"Enzinger and Winslow classify liposarcoma","refs":[]},{"year":1993,"title":"MDM2 amplification found in well-differentiated and dedifferentiated liposarcoma","refs":["mdm2"]},{"year":2016,"title":"Eribulin approved for liposarcoma after a survival benefit","refs":["eribulin"]},{"year":2020,"title":"STRASS: preoperative radiotherapy does not improve retroperitoneal sarcoma outcomes overall","refs":[]}],"pipeline":["mdm2-inhibitors","eribulin"],"openProblems":["Retroperitoneal dedifferentiated disease recurs in most patients despite complete surgery.","MDM2 inhibitors cause low platelets that limit dosing.","No systemic therapy is proven in the adjuvant setting."],"parent":"sarcoma"},{"id":"lobular-carcinoma-in-situ","kind":"cancer","name":"Lobular carcinoma in situ (LCIS)","aka":["LCIS","Lobular neoplasia","Classic lobular carcinoma in situ","Pleomorphic lobular carcinoma in situ","Florid lobular carcinoma in situ","Atypical lobular hyperplasia (lesser form)","Tis (LCIS)","stage 0 lobular","lobular neoplasia","in situ lobular carcinoma"],"tldr":"Lobular carcinoma in situ is not an invasive breast cancer but a marker that a woman is at higher risk of one: abnormal cells fill the milk-producing lobules without spreading. About one in five women develop breast cancer within ten years, in either breast and of any type; preventive tamoxifen cuts that to about one in fourteen, and the pleomorphic form is excised like ductal carcinoma in situ.","summary":"The WHO classification lists lobular carcinoma in situ among the lobular neoplasias, with atypical lobular hyperplasia as its lesser form and the pleomorphic and florid variants as higher-risk forms; like invasive lobular carcinoma it has lost E-cadherin (Tan 2020). In the Memorial Sloan Kettering cohort of 1,060 women with LCIS alone, 5 percent chose bilateral prophylactic mastectomy and 1,004 chose surveillance, 173 of them with chemoprevention; at a median follow-up of 81 months, 150 women developed 168 breast cancers (63 percent in the same breast, 25 percent in the other, 12 percent both), with no dominant histology (ductal carcinoma in situ 35 percent, invasive ductal 29 percent, invasive lobular 27 percent), and the ten-year cumulative risk was 7 percent with chemoprevention against 21 percent without (King 2015). Pleomorphic LCIS behaves differently: of 21 patients with pure pleomorphic LCIS on biopsy who had excision, 33.3 percent were found to have invasive carcinoma and 19 percent ductal carcinoma in situ, and the lesion was extensive or multifocal in 47.6 percent (Annals of Surgical Oncology 2015).\n\nHow it differs from its parent: it is a risk lesion and precursor rather than a cancer, is not staged, and its management is surveillance and prevention rather than treatment of a tumour, which is why it sits beside ductal carcinoma in situ under the breast cancer page.\n\nHow common: no incidence figure is given in the sources read.\n\nTreatment: for classic LCIS found on core biopsy, surveillance with annual imaging and consideration of chemoprevention with tamoxifen or an aromatase inhibitor (the low-dose tamoxifen trial TAM-01 included lobular carcinoma in situ among its intraepithelial neoplasias); excision to clear margins for pleomorphic or florid LCIS, given the upgrade rate; bilateral mastectomy only by informed choice (King 2015).","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Lobular_carcinoma_in_situ","links":[{"label":"Tan 2020, Histopathology: the 2019 WHO classification of tumours of the breast","url":"https://doi.org/10.1111/his.14091"},{"label":"King 2015, JCO: lobular carcinoma in situ, a 29-year longitudinal experience of 1,060 patients","url":"https://doi.org/10.1200/jco.2015.61.4743"},{"label":"Annals of Surgical Oncology 2015: pleomorphic lobular carcinoma in situ, features and management","url":"https://doi.org/10.1245/s10434-015-4552-x"},{"label":"Cancer Research UK: types of breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/types"},{"label":"Royal College of Pathologists G148: dataset for histopathological reporting of breast disease in surgical excision specimens of breast cancer, version 3, November 2024 (full review due November 2026)","url":"https://www.rcpath.org/resourceLibrary/g148-dataset-for-histopathological-reporting-of-breast-disease-in-surgical-excision-specimens-of-breast-cancer.html"}],"tags":["subtype-page","wave4","breast"],"related":["breast-cancer","ductal-carcinoma-in-situ","invasive-lobular-carcinoma","breast-hr-positive"],"cancers":[],"sections":[],"technologies":[],"targets":["cdh1"],"drugs":["tamoxifen"],"companies":[],"institutions":[],"pathways":[],"terms":["aromatase-inhibitor","carcinoma-in-situ","mastectomy","tnm-breast-cancer-editions","terminal-duct-lobular-unit","who-breast-classification"],"trials":["tam-01"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Why lobular carcinoma in situ is on its own page rather than under a receptor subtype. It is staged Tis (LCIS) and, unlike ductal carcinoma in situ, classical lobular carcinoma in situ behaves more as a marker of risk in both breasts than as a lesion that will become an invasive cancer where it sits. The 2024 UK dataset expanded its description to cover the florid and pleomorphic forms, which are treated more like ductal carcinoma in situ."],"group":"breast","burden":"Found in a minority of breast biopsies, usually by chance; Memorial Sloan Kettering followed 1,060 women with LCIS and no concurrent cancer over 29 years, median age at diagnosis 50 (King 2015). No population incidence is given in the sources read.","subtypes":["Classic lobular carcinoma in situ (surveillance and chemoprevention)","Pleomorphic lobular carcinoma in situ (excised like ductal carcinoma in situ)","Florid lobular carcinoma in situ","Atypical lobular hyperplasia (lesser lobular neoplasia)"],"biomarkers":["E-cadherin loss","Oestrogen receptor (positive in classic LCIS)","Pleomorphic or florid morphology (upgrade risk)","Extent on MRI when considering excision"],"standardOfCare":[{"setting":"Classic LCIS on biopsy","approach":"Surveillance and chemoprevention (tamoxifen or an aromatase inhibitor); TAM-01 tested low-dose tamoxifen in intraepithelial neoplasia.","refs":["tamoxifen","tam-01","aromatase-inhibitor"]},{"setting":"Pleomorphic or florid LCIS","approach":"Excision to clear margins because of the upgrade rate to invasive cancer or ductal carcinoma in situ.","refs":["ductal-carcinoma-in-situ","mastectomy"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"breast-cancer"},{"id":"localised-adrenocortical-carcinoma","kind":"cancer","name":"Localised adrenocortical carcinoma (ENSAT stage I to III, resectable)","aka":["Resectable adrenocortical carcinoma","Early-stage ACC","Non-metastatic adrenal cortical carcinoma","Adrenocortical carcinoma after complete resection"],"tldr":"Localised adrenocortical carcinoma is adrenal cortex cancer still confined to the adrenal gland and its surroundings that surgery can remove, the only treatment that cures it. Afterwards the adrenal-specific drug mitotane is given to patients whose tumour has a high risk of returning, judged by the Ki-67 index and whether it was completely removed, while low-risk patients are watched.","summary":"Adrenocortical carcinoma is a rare cancer of the steroid-producing adrenal cortex. About six in ten tumours secrete hormones, most often cortisol (Cushing's syndrome) or androgens (virilisation in women), and the rest are found as incidental or symptomatic masses; a full hormone work-up before surgery both establishes the diagnosis and prepares the patient for adrenal insufficiency afterwards. The Weiss score confirms malignancy on pathology, the Ki-67 index grades it, and the ENSAT system stages it: stage I and II tumours are confined to the adrenal, stage III has invaded surrounding tissue or nodes, and stage IV has metastasised. Children with adrenocortical carcinoma nearly always carry a germline TP53 mutation, including the R337H founder mutation of southern Brazil, and do better than adults when the tumour is resected; adults are tested for Lynch syndrome and Li-Fraumeni syndrome.\n\nOpen adrenalectomy with en bloc removal of adherent structures and regional nodes by an experienced surgeon is the standard for suspected carcinoma; laparoscopic surgery is reserved for small tumours and tumour rupture must be avoided because it seeds the peritoneum. Even after complete resection the disease often returns, so the 2018 ESE/ENSAT guideline recommends adjuvant mitotane, the adrenolytic drug approved in 1970, for patients at high risk of recurrence (Ki-67 above 10 percent, stage III or incomplete resection), titrated to plasma levels of 14 to 20 mg/L and given for at least two years alongside hydrocortisone replacement. The ADIUVO trial (Lancet Diabetes and Endocrinology 2023) randomised low-risk patients (stage I to III, complete resection, Ki-67 of 10 percent or less) to mitotane or observation and found no benefit, so observation is now the standard for that group. Postoperative radiotherapy to the tumour bed is considered for incomplete resection, and platinum-based chemotherapy is added to mitotane for very high-risk tumours in some centres, although the randomised ADIUVO-2 trial addressing that question is still recruiting. Follow-up imaging every three months in the first years catches recurrences that can sometimes be resected again.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Adrenocortical_carcinoma","links":[{"label":"ADIUVO (Lancet Diabetes and Endocrinology 2023)","url":"https://doi.org/10.1016/S2213-8587(23)00193-6"},{"label":"ESE/ENSAT guideline 2018","url":"https://doi.org/10.1530/EJE-18-0608"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Adrenocortical_carcinoma"}],"tags":["subtype-page","endocrine"],"related":["advanced-adrenocortical-carcinoma","adrenocortical","hereditary-ppgl"],"cancers":[],"sections":[],"technologies":["robotic-surgery","imrt-igrt","germline-testing","thermal-ablation","sbrt","ct","mri","fdg-pet"],"targets":["tp53"],"drugs":["mitotane","cisplatin","etoposide"],"companies":[],"institutions":[],"pathways":[],"terms":["adrenalectomy","germline-vs-somatic","lymphadenectomy","staging-systems"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-adiuvo-adjuvant-mitotane-low-grade-acc-terzolo-lancet-diabetes-endocrinol-2023","paper-ese-ensat-adrenocortical-carcinoma-guideline-eur-j-endocrinol-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"Roughly half to two thirds of adrenocortical carcinomas are found without distant metastases, often as a large adrenal mass causing Cushing's syndrome or virilisation, or incidentally on a scan; recurrence after surgery is nonetheless common.","subtypes":["ENSAT stage I to II adrenocortical carcinoma (confined to the adrenal)","ENSAT stage III adrenocortical carcinoma (local invasion or regional nodes)","Low-risk resected adrenocortical carcinoma (Ki-67 of 10 percent or less, R0; observation after ADIUVO)","High-risk resected adrenocortical carcinoma (Ki-67 above 10 percent, stage III or R1; adjuvant mitotane)","Cortisol-secreting adrenocortical carcinoma (Cushing's syndrome; steroid replacement after surgery)","Paediatric adrenocortical carcinoma (germline TP53, virilising, better prognosis when localised)"],"biomarkers":["Weiss score of three or more (malignancy)","Ki-67 index (10 and 20 percent thresholds for risk)","ENSAT stage and resection status","Hormone profile (cortisol, DHEAS, androgens, aldosterone, steroid precursors)","Urinary steroid metabolomics (diagnosis, emerging)","Germline TP53 in all children; Lynch syndrome testing in adults","Plasma mitotane level (14 to 20 mg/L target)"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Hormone work-up, contrast CT or MRI of the adrenal, chest CT and FDG-PET; no biopsy of a resectable adrenal mass; germline testing.","refs":["ct","mri","fdg-pet","germline-testing","germline-vs-somatic"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}},{"setting":"Resectable disease","approach":"Open adrenalectomy with en bloc resection of adherent structures and locoregional lymphadenectomy by an experienced surgeon; laparoscopic surgery only for small tumours; perioperative hydrocortisone for cortisol-secreting tumours.","refs":["adrenalectomy","lymphadenectomy","robotic-surgery"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}},{"setting":"After complete resection, low risk","approach":"Observation with imaging every three months (ADIUVO showed no benefit from mitotane).","refs":["mitotane","ct","adiuvo"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}},{"setting":"After resection, high risk","approach":"Adjuvant mitotane titrated to 14 to 20 mg/L for at least two years with glucocorticoid replacement; tumour-bed radiotherapy after incomplete resection; platinum-based chemotherapy considered for very high-risk tumours (ADIUVO-2).","refs":["mitotane","imrt-igrt","etoposide","cisplatin","adiuvo","adiuvo-2"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}},{"setting":"Local recurrence","approach":"Repeat resection when feasible after a disease-free interval of a year or more, with mitotane; ablation or radiotherapy for small unresectable recurrences.","refs":["adrenalectomy","thermal-ablation","sbrt","mitotane"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}}],"stateOfArt":["Complete open resection by an experienced surgeon remains the only cure.","ADIUVO showed that low-risk patients can be spared mitotane.","Ki-67 and resection status now steer adjuvant treatment more than stage alone."],"history":[{"year":1960,"title":"Mitotane (o,p'-DDD) first used for adrenocortical carcinoma","refs":["mitotane"]},{"year":1970,"title":"Mitotane approved in the United States","refs":["mitotane"]},{"year":2007,"title":"Retrospective Italian-German study associates adjuvant mitotane with longer recurrence-free survival","refs":["mitotane"]},{"year":2009,"title":"ENSAT staging system published","refs":["staging-systems"]},{"year":2018,"title":"ESE/ENSAT guideline sets Ki-67 and resection status as the basis for adjuvant mitotane","refs":["mitotane"]},{"year":2023,"title":"ADIUVO: no benefit from adjuvant mitotane in low-risk resected disease","refs":["mitotane"]}],"pipeline":["mitotane","cisplatin","etoposide"],"openProblems":["Whether adjuvant chemotherapy adds to mitotane in high-risk disease awaits ADIUVO-2.","Mitotane is slow to reach therapeutic levels and causes neurological and gastrointestinal toxicity in many patients.","Adrenal incidentalomas are common and distinguishing early carcinoma from adenoma on imaging is imperfect.","Surgical expertise is concentrated in few centres."],"parent":"adrenocortical"},{"id":"localised-anal-cancer","kind":"cancer","name":"Localised anal squamous cell carcinoma (stage I to III)","aka":["Non-metastatic anal cancer","Locoregional anal squamous cell carcinoma","Anal canal cancer treated with chemoradiotherapy","Stage I to III anal cancer"],"tldr":"Localised anal cancer is squamous cell cancer of the anal canal that has not spread beyond the pelvis and groin, one of the few cancers cured mainly by chemotherapy and radiotherapy together rather than by surgery. Fluorouracil with mitomycin during radiotherapy has been standard since the ACT II trial; surgery to remove the anus is kept for the minority whose cancer persists or returns.","summary":"Anal squamous cell carcinoma confined to the anal canal, the pelvic nodes and the groin nodes is treated to keep the anus. Before 1974 the standard was abdominoperineal resection with a permanent colostomy; Norman Nigro then showed that fluorouracil and mitomycin given during radiotherapy made most tumours disappear, and the UKCCCR ACT I and EORTC trials in the 1990s proved chemoradiotherapy beat radiotherapy alone. ACT II (Lancet Oncology 2013), the largest anal cancer trial with 940 patients, found that cisplatin was no better than mitomycin alongside fluorouracil and radiotherapy, that maintenance chemotherapy added nothing, and that tumours keep regressing for months, so response should be judged at 26 weeks rather than 11 before anyone is sent for surgery. RTOG 98-11 had likewise found induction cisplatin inferior to mitomycin-based treatment.\n\nToday's treatment is intensity-modulated radiotherapy with concurrent fluorouracil (or capecitabine) and mitomycin, with the dose scaled to stage; very small well-differentiated perianal tumours can be excised alone. Salvage abdominoperineal resection is offered when biopsy confirms persistent or recurrent disease. HPV or p16 status is favourable and HIV is no longer a bar to full-dose treatment when CD4 counts are adequate. The UK PLATO programme (ACT3, ACT4 and ACT5) is testing lower doses for early tumours and higher doses for locally advanced ones, EA2165 tests nivolumab after chemoradiotherapy for high-risk disease, and circulating HPV DNA is being studied as a way to tell early who is cured.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Anal_cancer","links":[{"label":"ACT II (Lancet Oncology 2013)","url":"https://doi.org/10.1016/S1470-2045(13)70086-X"},{"label":"NCCN Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Anal_cancer"}],"tags":["subtype-page","gastrointestinal"],"related":["anal-hsil-precursor","metastatic-anal-cancer","anal","locally-advanced-cervical-cancer"],"cancers":[],"sections":[],"technologies":["imrt-igrt","cytotoxic-chemotherapy","cthpv-dna","mri","pet-ct"],"targets":[],"drugs":["fluorouracil","mitomycin","capecitabine","nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":["hpv-p16","clinical-complete-response","chemoradiation"],"trials":["act-ii"],"people":[],"bottlenecks":[],"keyPapers":["paper-act-ii-anal-cancer-chemoradiation-lancet-oncol-2013","paper-esmo-anal-cancer-guideline-ann-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"The large majority of anal cancers are diagnosed without distant spread, and most are cured without losing the anus.","subtypes":["Stage I anal canal squamous cell carcinoma (T1 N0, lower radiotherapy dose)","Stage II anal squamous cell carcinoma (T2 to T3 N0)","Stage III node-positive or T4 anal squamous cell carcinoma (locally advanced, higher dose)","Perianal (anal margin) squamous cell carcinoma (small tumours excised alone)","HPV-negative anal squamous cell carcinoma (worse prognosis)","Anal cancer in people living with HIV"],"biomarkers":["HPV and p16 status (favourable)","T and N stage on MRI and PET-CT","HIV status and CD4 count","Clinical complete response at 26 weeks (ACT II)","Circulating HPV DNA (investigational)","PD-L1 (not required)"],"standardOfCare":[{"setting":"Staging","approach":"Pelvic MRI, PET-CT, examination of the groins, HIV testing and HPV or p16 status; biopsy of suspicious groin nodes.","refs":["mri","pet-ct","hpv-p16"],"guideline":{"version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}},{"setting":"Stage I to III","approach":"Intensity-modulated radiotherapy with concurrent fluorouracil (or capecitabine) and mitomycin, dose scaled to stage (ACT II, RTOG 98-11); small perianal tumours may be excised alone.","refs":["imrt-igrt","fluorouracil","mitomycin","act-ii","chemoradiation"],"guideline":{"version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}},{"setting":"Response assessment","approach":"Clinical assessment at 26 weeks; biopsy only if disease persists or grows, because regression continues for months (ACT II).","refs":["clinical-complete-response","act-ii"],"guideline":{"version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}},{"setting":"Persistent or recurrent disease","approach":"Salvage abdominoperineal resection with permanent colostomy; inguinal node dissection or radiotherapy for isolated groin recurrence.","refs":["robotic-surgery"],"guideline":{"version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}},{"setting":"High-risk locally advanced disease","approach":"Trials of dose escalation (PLATO ACT5) and adjuvant nivolumab (EA2165); standard care remains chemoradiotherapy alone.","refs":["imrt-igrt","nivolumab"],"guideline":{"version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}}],"stateOfArt":["Organ-preserving chemoradiotherapy cures most patients and has been standard for fifty years.","ACT II settled the chemotherapy partner (mitomycin), the futility of maintenance and the timing of response assessment.","Radiotherapy dose is now being tailored to stage in the PLATO trials."],"history":[{"year":1974,"title":"Nigro reports complete responses to fluorouracil, mitomycin and radiotherapy, sparing the anus","refs":["fluorouracil","mitomycin"]},{"year":1996,"title":"UKCCCR ACT I: chemoradiotherapy beats radiotherapy alone","refs":["chemoradiation"]},{"year":2008,"title":"RTOG 98-11: mitomycin-based chemoradiotherapy beats induction cisplatin","refs":["mitomycin"]},{"year":2013,"title":"ACT II published: mitomycin equals cisplatin, no maintenance, assess response at 26 weeks","refs":["act-ii","clinical-complete-response"]},{"year":2016,"title":"Intensity-modulated radiotherapy becomes standard after RTOG 0529 reduces toxicity","refs":["imrt-igrt"]},{"year":2019,"title":"PLATO trials open to personalise radiotherapy dose by stage","refs":["imrt-igrt"]}],"pipeline":["cthpv-dna","nivolumab","imrt-igrt"],"openProblems":["Radiotherapy dose for early and for locally advanced tumours is still being settled in PLATO.","About a quarter of patients with locally advanced disease relapse and need major surgery.","Late bowel, sexual and bladder effects of pelvic chemoradiotherapy are common and under-measured.","Whether adding a PD-1 antibody to chemoradiotherapy improves cure is untested outside EA2165."],"parent":"anal"},{"id":"localised-penile-cancer","kind":"cancer","name":"Localised penile cancer (organ-confined, node-negative)","aka":["Early penile squamous cell carcinoma","Organ-confined penile cancer","Penile intraepithelial neoplasia and T1 to T2 penile cancer","cN0 penile cancer"],"tldr":"Localised penile cancer is squamous cell cancer confined to the penis with no spread to the groin lymph nodes, and the aim of treatment is to remove the tumour while keeping as much of the penis as possible. Precancer and small tumours are treated with creams, laser or glans-sparing surgery, and the groin nodes are checked by sentinel node biopsy or surveillance rather than removed wholesale.","summary":"Penile squamous cell carcinoma begins on the glans, the inner foreskin or the coronal sulcus, in roughly a third to a half of cases driven by HPV (basaloid and warty types, p16 positive) and otherwise by chronic inflammation, lichen sclerosus and phimosis (usual, verrucous and sarcomatoid types, often TP53 mutant). Penile intraepithelial neoplasia (PeIN) is its precursor. The 2023 EAU-ASCO guideline places organ preservation at the centre of care: PeIN and superficial tumours are treated with topical fluorouracil or imiquimod, laser ablation, circumcision or glans resurfacing; T1 and T2 tumours with glansectomy or partial penectomy with a margin of a few millimetres, which oncological series have shown to be safe; and brachytherapy is an alternative for small distal tumours. Total penectomy is kept for large or proximal tumours.\n\nWhat decides survival is the groin. Palpably normal nodes still hide metastases in about a fifth of patients with tumours of intermediate or high risk (T1 with grade 2 or higher, lymphovascular invasion, or any T2 or worse), so the guideline recommends dynamic sentinel node biopsy for those patients rather than surveillance, and surveillance only for low-risk tumours; if the sentinel node is positive the patient moves into node-positive management. Circumcision and HPV vaccination prevent much of the disease, and the rarity of penile cancer means that referral to a specialised centre, as required in the United Kingdom since 2002, improves organ preservation and survival.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Penile_cancer","links":[{"label":"EAU-ASCO penile cancer guideline 2023","url":"https://doi.org/10.1016/j.eururo.2023.02.027"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Penile_cancer"}],"tags":["subtype-page","genitourinary"],"related":["node-positive-penile-cancer","penile","localised-anal-cancer"],"cancers":[],"sections":[],"technologies":["sentinel-node","brachytherapy","hpv-vaccine","precancer-ablation"],"targets":[],"drugs":["fluorouracil","gardasil-9"],"companies":[],"institutions":[],"pathways":[],"terms":["hpv-p16","hpv-status","mohs-surgery","lymphadenectomy"],"trials":["nct06465914"],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2022-gu-moch-eur-urol-2022","paper-eau-asco-penile-cancer-guideline-eur-urol-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Most penile cancers in high-income countries are diagnosed while confined to the glans or foreskin; the disease is far commoner in parts of South America, Africa and Asia where circumcision is rare and HPV vaccination low.","subtypes":["Penile intraepithelial neoplasia (PeIN, precursor; topical therapy, laser or circumcision)","HPV-associated penile squamous cell carcinoma (basaloid, warty; p16 positive)","HPV-independent penile squamous cell carcinoma (usual type, verrucous, sarcomatoid)","Ta to T1 low-grade penile cancer (organ-sparing surgery, groin surveillance)","T1 high-grade to T2 penile cancer with clinically negative groins (organ-sparing surgery plus sentinel node biopsy)"],"biomarkers":["p16 immunohistochemistry and HPV DNA","Grade and lymphovascular invasion of the primary (decide sentinel node biopsy)","Depth and stage (Ta, T1, T2) of the primary","Surgical margin status","Dynamic sentinel node biopsy result"],"standardOfCare":[{"setting":"Penile intraepithelial neoplasia","approach":"Circumcision if the foreskin is involved; topical fluorouracil or imiquimod, laser ablation or glans resurfacing; close follow-up because recurrence is common.","refs":["fluorouracil","precancer-ablation"],"guideline":{"version":"EAU-ASCO Collaborative Guideline on Penile Cancer 2023","url":"https://doi.org/10.1016/j.eururo.2023.02.027"}},{"setting":"T1 to T2 tumours","approach":"Organ-sparing surgery (wide local excision, glansectomy, partial penectomy) with narrow margins; brachytherapy for small distal tumours; total penectomy only for large or proximal disease.","refs":["mohs-surgery","brachytherapy"],"guideline":{"version":"EAU-ASCO Collaborative Guideline on Penile Cancer 2023","url":"https://doi.org/10.1016/j.eururo.2023.02.027"}},{"setting":"Clinically negative groins","approach":"Surveillance for low-risk tumours (Ta, T1 grade 1 without lymphovascular invasion); dynamic sentinel node biopsy for intermediate- and high-risk tumours, with inguinal lymphadenectomy if positive.","refs":["sentinel-node","lymphadenectomy"],"guideline":{"version":"EAU-ASCO Collaborative Guideline on Penile Cancer 2023","url":"https://doi.org/10.1016/j.eururo.2023.02.027"}},{"setting":"Prevention","approach":"HPV vaccination (now offered to boys in many countries and being tested in Chinese men) and treatment of phimosis and lichen sclerosus.","refs":["hpv-vaccine","gardasil-9","nct06465914"],"guideline":{"version":"EAU-ASCO Collaborative Guideline on Penile Cancer 2023","url":"https://doi.org/10.1016/j.eururo.2023.02.027"}}],"stateOfArt":["Organ-sparing surgery with narrow margins is standard and preserves sexual and urinary function in most men.","Dynamic sentinel node biopsy finds hidden groin metastases without the morbidity of prophylactic node dissection.","Centralisation of care has improved outcomes in the United Kingdom and the Netherlands."],"history":[{"year":1994,"title":"Dynamic sentinel node biopsy for penile cancer introduced in Amsterdam","refs":["sentinel-node"]},{"year":2002,"title":"England centralises penile cancer surgery in supra-regional centres","refs":[]},{"year":2009,"title":"HPV vaccination shown to prevent external genital lesions in men","refs":["hpv-vaccine","gardasil-9"]},{"year":2022,"title":"WHO classification separates HPV-associated and HPV-independent penile squamous cell carcinoma","refs":["hpv-p16"]},{"year":2023,"title":"EAU-ASCO collaborative guideline sets organ preservation and sentinel node biopsy as standards","refs":["sentinel-node","mohs-surgery"]}],"pipeline":["hpv-vaccine","nct06465914"],"openProblems":["Local recurrence after organ-sparing surgery is common and needs long follow-up.","Sentinel node biopsy misses some metastases, and the false-negative rate depends on centre experience.","Whether HPV status should change treatment is unknown.","Most of the world's patients present late in places without specialist centres."],"parent":"penile"},{"id":"prostate-high-risk","kind":"cancer","name":"Localised prostate cancer, high and very high risk","aka":["High-risk prostate cancer","Very high risk prostate cancer","Locally advanced prostate cancer","Grade Group 4 and 5 prostate cancer","Non-metastatic high-risk prostate cancer","Cambridge Prognostic Group 4","Cambridge Prognostic Group 5","CPG 4","CPG 5","CPG4 prostate cancer","CPG5 prostate cancer"],"tldr":"High-risk prostate cancer has Grade Group 4 or 5 disease, a PSA above 20 or a tumour growing beyond the gland. It is still curable, but needs radiotherapy with two to three years of hormone therapy, or surgery followed by radiotherapy, and adding abiraterone to hormone therapy now lengthens life in the highest-risk men.","summary":"High-risk localised prostate cancer is defined by the NCCN as any of clinical stage T3a, Grade Group 4 or 5, or PSA above 20 ng/mL; very high risk adds T3b to T4 disease, primary Gleason pattern 5, more than four cores of Grade Group 4 or 5, or two or more high-risk features. It is found by PSA and biopsy and staged with PSMA PET, which proPSMA showed is far more accurate than CT and bone scan. Standard treatment is external beam radiotherapy to the prostate and pelvic nodes with 18 to 36 months of androgen deprivation, often with a brachytherapy boost, or radical prostatectomy with extended node dissection followed by radiotherapy when the pathology warrants it. STAMPEDE showed that adding two years of abiraterone to androgen deprivation and radiotherapy in men with very high risk or node-positive disease cuts metastasis and death, and this is now guideline care for the highest-risk group. Salvage options after failure are covered under biochemical recurrence.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Prostate_cancer_staging","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Prostate_cancer_staging"},{"label":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"},{"label":"NICE NG131: prostate cancer, diagnosis and management (recommendations, including the Cambridge Prognostic Group table at 1.2.15)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"},{"label":"Royal College of Pathologists G084: dataset for histopathology reports for prostatic carcinoma, version 4, October 2024","url":"https://www.rcpath.org/static/8cc88604-2c8d-4df4-a99542df41c102af/G084-dataset-for-histopathology-reports-for-prostatic-carcinoma.pdf"}],"tags":["subtype-page"],"related":["prostate-intermediate-risk","prostate-low-risk","prostate-bcr","prostate-mhspc","prostate-ductal-adenocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["cambridge-prognostic-group","tnm-prostate-cancer","extraprostatic-extension","intraductal-carcinoma-prostate","cribriform-prostate-cancer","metastasis-free-survival","other-cause-mortality","chromoplexy","pi-rads","whole-mount-pathology","polygenic-risk-score"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-stampede-abiraterone-nejm-2017","paper-propsma-hofman-lancet-2020","paper-stampede-abiraterone-high-risk-attard-lancet-2022","paper-bolla-eortc-22863-nejm-1997"],"journals":[],"dependsOn":[],"notes":["What this page is called in the NHS: Cambridge Prognostic Groups 4 and 5. NICE NG131 1.2.15 defines group 4 as any one of Gleason 8 (grade group 4), PSA above 20 or stage T3, and group 5 as two or more of those three, or Gleason 9 to 10 (grade group 5), or stage T4. Active surveillance is not offered in either (1.3.11); radical prostatectomy or radical radiotherapy is offered where the cancer is likely to be controlled in the long term (1.3.12); radiotherapy is combined with androgen deprivation, and continuing it for up to three years is considered in CPG 4 and 5 (1.3.23); brachytherapy alone is not offered (1.3.25).","Note what puts a man in group 4 on its own: a single T3, which means extraprostatic extension or seminal vesicle invasion. A stage found on MRI rather than by examination will be written cT3(mr) under the ninth edition of TNM, and the TNM committee's reason for introducing the suffix is precisely that imaging finds T3 disease a finger would have called T2."],"group":"genitourinary","burden":"About one in five newly diagnosed localised cancers and most of the deaths from disease found before it spreads; ten-year cancer-specific survival is around 85 percent with combined treatment.","subtypes":["High risk (T3a, or Grade Group 4 or 5, or PSA above 20)","Very high risk (T3b to T4, primary pattern 5, more than 4 high-grade cores, or 2 or more high-risk features)","Locally advanced adenocarcinoma with seminal vesicle invasion (T3b)","Clinically node-positive (N1) non-metastatic disease"],"biomarkers":["Gleason Grade Group 4 or 5","PSA above 20 ng/mL","PSMA PET staging","Germline and tumour HRR testing (BRCA2 in particular)","Decipher genomic classifier"],"standardOfCare":[{"setting":"High risk","approach":"External beam radiotherapy to prostate and pelvic nodes with 18 to 36 months of androgen deprivation, with or without brachytherapy boost; or radical prostatectomy with extended lymph node dissection.","refs":["imrt-igrt","androgen-deprivation","leuprolide","degarelix","relugolix","brachytherapy","robotic-surgery","hypo-rt-pc"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Very high risk and node-positive","approach":"Radiotherapy plus androgen deprivation with two years of abiraterone (STAMPEDE); PSMA PET staging before treatment.","refs":["abiraterone","stampede","psma-pet","propsma"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"After prostatectomy with adverse pathology","approach":"Adjuvant or early salvage radiotherapy guided by PSA, with hormone therapy for higher-risk features.","refs":["imrt-igrt","androgen-deprivation","psa","biochemical-recurrence"]}],"stateOfArt":["PSMA PET has replaced bone scan and CT for staging, reclassifying about a quarter of men.","Abiraterone with radiotherapy and hormone therapy is the first drug to improve survival in high-risk non-metastatic disease.","Genomic classifiers and AI pathology are being tested to choose hormone therapy duration."],"history":[{"year":1997,"title":"EORTC 22863: adding three years of hormone therapy to radiotherapy improves survival","refs":["androgen-deprivation"]},{"year":2009,"title":"Long-course beats short-course androgen deprivation with radiotherapy in high-risk disease","refs":["androgen-deprivation"]},{"year":2020,"title":"proPSMA: PSMA PET more accurate than conventional staging","refs":["propsma","psma-pet"]},{"year":2022,"title":"STAMPEDE: abiraterone improves survival in high-risk non-metastatic disease","refs":["stampede","abiraterone"]}],"pipeline":["psma-pet","artera-ai-prostate","decipher-prostate","abiraterone"],"openProblems":["How long hormone therapy should last when abiraterone is added.","Whether PSMA PET-detected nodes should change treatment when the trials were staged conventionally.","Which men with high-risk disease are better served by surgery than radiotherapy."],"parent":"prostate"},{"id":"prostate-intermediate-risk","kind":"cancer","name":"Localised prostate cancer, intermediate risk","aka":["Intermediate-risk prostate cancer","Favourable intermediate risk","Unfavourable intermediate risk","Grade Group 2 and 3 prostate cancer","Cambridge Prognostic Group 2","Cambridge Prognostic Group 3","CPG 2","CPG 3","CPG2 prostate cancer","CPG3 prostate cancer"],"tldr":"Intermediate-risk prostate cancer has Grade Group 2 or 3 disease, a PSA between 10 and 20 or a tumour that fills more of the gland. Surgery or radiotherapy cure most men; the favourable half can sometimes be watched, and the unfavourable half is given a few months of hormone therapy with radiotherapy.","summary":"Intermediate-risk localised prostate cancer, in the NCCN scheme, has one or more of clinical stage T2b to T2c, Grade Group 2 or 3, or PSA 10 to 20 ng/mL, without high-risk features. It is split into favourable (one factor, Grade Group 1 or 2, under half of cores positive) and unfavourable (two or more factors, Grade Group 3, or more than half of cores positive), because the two behave differently. It is found by PSA, MRI and biopsy and staged clinically; bone scan and CT are reserved for unfavourable disease. Favourable disease is treated by radical prostatectomy, external beam radiotherapy or brachytherapy alone, and active surveillance is an option for selected men. Unfavourable disease is treated by prostatectomy with lymph node dissection, or radiotherapy with four to six months of androgen deprivation, or external beam radiotherapy plus a brachytherapy boost. CHHiP established 60 Gy in 20 fractions, HYPO-RT-PC showed seven fractions are equivalent, and PACE-B showed five stereotactic fractions match conventional radiotherapy at five years. Genomic classifiers and the ArteraAI pathology test are used to decide whether hormone therapy adds anything.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Prostate_cancer_staging","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Prostate_cancer_staging"},{"label":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"},{"label":"NICE NG131: prostate cancer, diagnosis and management (recommendations, including the Cambridge Prognostic Group table at 1.2.15)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"},{"label":"Royal College of Pathologists G084: dataset for histopathology reports for prostatic carcinoma, version 4, October 2024","url":"https://www.rcpath.org/static/8cc88604-2c8d-4df4-a99542df41c102af/G084-dataset-for-histopathology-reports-for-prostatic-carcinoma.pdf"}],"tags":["subtype-page"],"related":["prostate-low-risk","prostate-high-risk","prostate-bcr","prostate-ductal-adenocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["cambridge-prognostic-group","percentage-gleason-pattern-4","cribriform-prostate-cancer","intraductal-carcinoma-prostate","tnm-prostate-cancer","lead-time-bias","overtreatment","number-needed-to-screen","pi-rads","template-mapping-biopsy","polygenic-risk-score","whole-mount-pathology"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-damico-risk-groups-jama-1998","paper-protect-nejm-2016","paper-chhip-lancet-oncol-2016","paper-rtog-9408-short-term-adt-jones-nejm-2011"],"journals":[],"dependsOn":[],"notes":["What this page is called in the NHS: Cambridge Prognostic Groups 2 and 3, the two halves of intermediate risk. NICE NG131 1.2.15 defines group 2 as Gleason 3+4=7 (grade group 2) or PSA 10 to 20, at stage T1 to T2, and group 3 as Gleason 3+4=7 and PSA 10 to 20 and stage T1 to T2, or Gleason 4+3=7 (grade group 3) at stage T1 to T2. The split exists because the old three-tier model could not tell 3+4 from 4+3. The treatment differs across the line: in CPG 2 active surveillance, radical prostatectomy and radical radiotherapy are offered as a choice (1.3.9); in CPG 3 radical treatment is offered and active surveillance is only considered for people who choose not to have it (1.3.10). Radiotherapy is combined with six months of androgen deprivation from CPG 2 upwards (1.3.28 and the radical radiotherapy recommendations).","Within these two groups, two things on the pathology report move a man towards treatment rather than surveillance: the percentage of Gleason pattern 4, a core reporting item in UK core biopsies since October 2024, and the presence of invasive cribriform or intraductal carcinoma, which both ISUP and the Genitourinary Pathology Society treat as a reason to exclude a man from active surveillance."],"group":"genitourinary","burden":"About four in ten newly diagnosed localised prostate cancers; ten-year cancer-specific survival is above 95 percent with treatment.","subtypes":["Favourable intermediate risk (one factor, Grade Group 1 or 2, under half of cores)","Unfavourable intermediate risk (two or more factors, Grade Group 3, or more than half of cores)","Localised acinar adenocarcinoma, Grade Group 2 or 3","Cribriform or intraductal pattern (behaves as unfavourable)"],"biomarkers":["Gleason Grade Group 2 or 3","PSA 10 to 20 ng/mL","Percentage of positive cores","Cribriform or intraductal carcinoma","Decipher genomic classifier and ArteraAI Prostate for hormone therapy decisions"],"standardOfCare":[{"setting":"Favourable intermediate risk","approach":"Radical prostatectomy, external beam radiotherapy (moderate or ultra-hypofractionated) or brachytherapy alone; active surveillance for selected men with low volume Grade Group 2 disease.","refs":["robotic-surgery","hypofractionated-radiotherapy","sbrt","brachytherapy","active-surveillance","chhip","pace-b"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Unfavourable intermediate risk","approach":"Radical prostatectomy with pelvic lymph node dissection, or external beam radiotherapy with four to six months of androgen deprivation, or external beam plus brachytherapy boost.","refs":["robotic-surgery","androgen-deprivation","leuprolide","brachytherapy","imrt-igrt","hypo-rt-pc"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Deciding on hormone therapy","approach":"ArteraAI Prostate predicts benefit from short-course androgen deprivation with radiotherapy; Decipher stratifies risk.","refs":["artera-ai-prostate","decipher-prostate","digital-pathology-ai"]}],"stateOfArt":["Radiotherapy has shrunk from eight weeks to one to two, with the same control and side effects.","The favourable and unfavourable split lets half of these men avoid hormone therapy.","AI pathology trained on trial specimens now tells which men gain from hormone therapy."],"history":[{"year":2014,"title":"Zumsteg proposes favourable and unfavourable intermediate risk","refs":["gleason-grade-group"]},{"year":2016,"title":"CHHiP: 60 Gy in 20 fractions non-inferior to 74 Gy in 37","refs":["chhip"]},{"year":2019,"title":"HYPO-RT-PC: seven fractions match 39","refs":["hypo-rt-pc"]},{"year":2024,"title":"PACE-B: stereotactic radiotherapy in five fractions non-inferior","refs":["pace-b"]},{"year":2025,"title":"ArteraAI Prostate: first predictive AI pathology test","refs":["artera-ai-prostate"]}],"pipeline":["artera-ai-prostate","decipher-prostate","sbrt"],"openProblems":["Whether favourable intermediate risk can be safely watched in the long term.","How to select men for hormone therapy without giving it to everyone in the unfavourable group.","Cribriform and intraductal patterns are prognostic but not yet in the risk groups."],"parent":"prostate"},{"id":"prostate-low-risk","kind":"cancer","name":"Localised prostate cancer, very low and low risk","aka":["Low-risk prostate cancer","Very low risk prostate cancer","Grade Group 1 prostate cancer","NCCN very low and low risk","Cambridge Prognostic Group 1","CPG 1","CPG1 prostate cancer","Grade group 1 prostate cancer"],"tldr":"Low-risk prostate cancer is Grade Group 1 disease confined to the gland with a PSA under 10. It grows so slowly that watching it closely is the recommended first choice, and most men who choose surveillance never need treatment.","summary":"Very low and low risk localised prostate cancer is defined by the NCCN as clinical stage T1 to T2a, Grade Group 1 (Gleason 3+3) and PSA below 10 ng/mL; very low risk adds fewer than three positive cores, under half of any core involved and a PSA density below 0.15. It is found by PSA testing followed by MRI and targeted biopsy, the pathway PRECISION showed finds more dangerous cancers with fewer needles. Active surveillance, with PSA every six months, repeat MRI and repeat biopsy, is the preferred option: ProtecT followed 1,643 men for fifteen years and found prostate cancer deaths of around 3 percent in every arm, whether monitored, operated on or irradiated. Men who prefer or later need treatment have radical prostatectomy, external beam radiotherapy (now moderately hypofractionated after CHHiP, or five fractions of stereotactic radiotherapy after PACE-B) or brachytherapy, without hormone therapy. Genomic classifiers and AI pathology can refine who is safe to watch, and germline testing is offered when the family history suggests it.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Active_surveillance_of_prostate_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Active_surveillance_of_prostate_cancer"},{"label":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"},{"label":"NICE NG131: prostate cancer, diagnosis and management (recommendations, including the Cambridge Prognostic Group table at 1.2.15)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"},{"label":"Royal College of Pathologists G084: dataset for histopathology reports for prostatic carcinoma, version 4, October 2024","url":"https://www.rcpath.org/static/8cc88604-2c8d-4df4-a99542df41c102af/G084-dataset-for-histopathology-reports-for-prostatic-carcinoma.pdf"}],"tags":["subtype-page"],"related":["prostate-intermediate-risk","prostate-high-risk","prostate-bcr","prostate-ductal-adenocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["cambridge-prognostic-group","percentage-gleason-pattern-4","cribriform-prostate-cancer","psa-density","watchful-waiting","tnm-prostate-cancer","lead-time-bias","overtreatment","number-needed-to-screen","pi-rads","template-mapping-biopsy","polygenic-risk-score","whole-mount-pathology"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-damico-risk-groups-jama-1998","paper-protect-15-year-nejm-2023","paper-klotz-active-surveillance-jco-2015","paper-precision-mri-targeted-biopsy-nejm-2018"],"journals":[],"dependsOn":[],"notes":["What this page is called in the NHS: Cambridge Prognostic Group 1. NICE NG131 recommendation 1.2.15 defines it as Gleason score 6 (grade group 1) and PSA under 10 micrograms per litre and stage T1 to T2, all three together. For CPG 1, NG131 1.3.8 offers active surveillance, and says to consider radical prostatectomy or radical radiotherapy only if active surveillance is not suitable or not acceptable to the person. Isotope bone scans are not routinely offered (1.2.16). The NCCN's very low and low risk bands cover roughly the same ground but add PSA density and the number of positive cores, so the two systems do not select identical men."],"group":"genitourinary","burden":"Roughly a third of prostate cancers diagnosed in screened populations; fewer than one in a hundred men with low-risk disease die of it within fifteen years whether monitored or treated.","subtypes":["Very low risk (T1c, Grade Group 1, PSA under 10, fewer than 3 cores, PSA density under 0.15)","Low risk (T1 to T2a, Grade Group 1, PSA under 10)","Localised acinar adenocarcinoma, Grade Group 1"],"biomarkers":["PSA and PSA density","Gleason Grade Group 1 on biopsy","MRI PI-RADS score","Genomic classifier (Decipher, Oncotype DX GPS, Prolaris)","Germline BRCA2 testing when family history warrants"],"standardOfCare":[{"setting":"Very low and low risk, preferred","approach":"Active surveillance with PSA every six months, MRI and repeat biopsy; treatment only on progression to Grade Group 2 or more.","refs":["active-surveillance","protect","mp-mri","psa","gleason-grade-group"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Low risk, men who prefer treatment","approach":"Radical prostatectomy, moderately hypofractionated external beam radiotherapy, five-fraction stereotactic radiotherapy or brachytherapy, without hormone therapy.","refs":["robotic-surgery","hypofractionated-radiotherapy","sbrt","brachytherapy","chhip","pace-b"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Diagnosis","approach":"MRI before biopsy and targeted plus systematic cores; genomic classifiers or AI pathology to refine surveillance decisions.","refs":["mp-mri","precision-mri","decipher-prostate","artera-ai-prostate"]}],"stateOfArt":["ProtecT settled that low-risk disease can be watched: fifteen-year cancer mortality was around 3 percent in every arm.","MRI-first diagnosis finds fewer of these indolent cancers and more of the dangerous ones.","Surveillance uptake for low-risk disease has risen from a fifth to more than half of eligible men in a decade."],"history":[{"year":1966,"title":"Gleason describes his grading system","refs":["gleason-grade-group"]},{"year":1994,"title":"PSA approved for early detection in the United States","refs":["psa"]},{"year":2016,"title":"ProtecT: ten-year mortality about 1 percent whether monitored or treated","refs":["protect"]},{"year":2018,"title":"PRECISION: MRI-targeted biopsy beats systematic biopsy","refs":["precision-mri"]},{"year":2023,"title":"ProtecT fifteen-year results confirm surveillance","refs":["protect"]},{"year":2024,"title":"PACE-B: five-fraction stereotactic radiotherapy non-inferior at five years","refs":["pace-b"]}],"pipeline":["artera-ai-prostate","decipher-prostate","mp-mri"],"openProblems":["Which Grade Group 1 cancers will upgrade, and whether Grade Group 1 should be called cancer at all.","How often to repeat biopsy on surveillance and whether MRI alone can replace it.","Overdiagnosis by PSA screening against the deaths screening prevents."],"parent":"prostate"},{"id":"localised-small-bowel-adenocarcinoma","kind":"cancer","name":"Localised small bowel adenocarcinoma (stage I to III, resected)","aka":["Resectable small bowel adenocarcinoma","Duodenal adenocarcinoma, localised","Jejunal and ileal adenocarcinoma, localised","Stage I to III SBA"],"tldr":"Localised small bowel adenocarcinoma is cancer of the duodenum, jejunum or ileum that has not spread beyond nearby lymph nodes and can be removed by surgery, the only cure. Duodenal tumours need a Whipple operation and tumours further along a segmental resection; chemotherapy afterwards is offered for node-positive disease by analogy with colon cancer while the BALLAD trial tests whether it helps.","summary":"Small bowel adenocarcinoma is rare because the small intestine, despite making up most of the length of the gut, produces few cancers. About half arise in the duodenum, where they present with obstruction, bleeding or jaundice and are found at endoscopy, and the rest in the jejunum and ileum, where they are found late after months of obstruction or anaemia; capsule endoscopy, CT enterography and double-balloon enteroscopy have shortened that delay. Predisposing conditions matter: Crohn's disease causes ileal tumours, coeliac disease jejunal ones, familial adenomatous polyposis duodenal and ampullary ones, and Lynch syndrome tumours anywhere, so germline testing and mismatch repair testing are recommended for all patients. Mismatch repair deficiency is found in a larger share than in colon cancer, and HER2 amplification and KRAS mutations in others.\n\nSurgery follows the site: pancreaticoduodenectomy (Whipple procedure) for tumours of the first and second parts of the duodenum, segmental resection with wide lymphadenectomy for the distal duodenum, jejunum and ileum, and right hemicolectomy for terminal ileal tumours, with at least eight nodes examined for accurate staging. Node involvement is the main prognostic factor. No randomised trial had ever tested adjuvant chemotherapy until the international BALLAD trial, which randomised patients with resected stage I to III disease to observation or to fluoropyrimidine chemotherapy with or without oxaliplatin; pending its final results, the NCCN guideline recommends adjuvant CAPOX or FOLFOX for stage III and high-risk stage II disease on the colon cancer model, and considers observation for stage I and low-risk stage II tumours. Mismatch-repair-deficient tumours may gain less from fluoropyrimidines, and neoadjuvant or adjuvant checkpoint inhibition for them is under study. Circulating tumour DNA is being tested to identify patients with residual disease after surgery.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Small_intestine_cancer","links":[{"label":"NCCN Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"},{"label":"BALLAD (NCT02502370)","url":"https://clinicaltrials.gov/study/NCT02502370"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Small_intestine_cancer"}],"tags":["subtype-page","gastrointestinal"],"related":["advanced-small-bowel-adenocarcinoma","small-bowel","small-intestinal-net","ampullary"],"cancers":[],"sections":[],"technologies":["endoscopy","ct","germline-testing","cytotoxic-chemotherapy","mri"],"targets":["kras","her2"],"drugs":["capox","folfox"],"companies":[],"institutions":[],"pathways":[],"terms":["whipple","lymphadenectomy","msi","lynch-syndrome","hereditary-cancer-syndromes","colectomy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-overman-capox-small-bowel-adenocarcinoma-jco-2009","paper-who-2019-digestive-system-tumours-nagtegaal-histopathology-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About half of small bowel adenocarcinomas are found before distant spread, most often in the duodenum; many are linked to Crohn's disease, coeliac disease, Lynch syndrome or familial adenomatous polyposis.","subtypes":["Localised duodenal adenocarcinoma (Whipple procedure; FAP-associated in some)","Localised jejunal adenocarcinoma (coeliac-associated in some)","Localised ileal adenocarcinoma (Crohn's-associated in some)","Stage I to low-risk stage II small bowel adenocarcinoma (observation after surgery)","Stage III or high-risk stage II small bowel adenocarcinoma (adjuvant CAPOX or FOLFOX)","Mismatch-repair-deficient localised small bowel adenocarcinoma (Lynch syndrome screening)"],"biomarkers":["Mismatch repair and microsatellite status (all patients)","Node status and number of nodes examined (at least eight)","Germline testing for Lynch syndrome, FAP and Peutz-Jeghers where indicated","HER2 amplification and KRAS status (baseline for later therapy)","Circulating tumour DNA after surgery (investigational)","Crohn's disease or coeliac disease history"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Endoscopy or enteroscopy with biopsy, CT of chest, abdomen and pelvis, mismatch repair testing and germline assessment.","refs":["endoscopy","ct","msi","germline-testing","lynch-syndrome"],"guideline":{"version":"NCCN Guidelines: Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"}},{"setting":"Duodenal tumours","approach":"Pancreaticoduodenectomy for proximal duodenal tumours; segmental resection for distal duodenal tumours; endoscopic resection only for adenomas.","refs":["whipple","lymphadenectomy"],"guideline":{"version":"NCCN Guidelines: Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"}},{"setting":"Jejunal and ileal tumours","approach":"Segmental resection with wide mesenteric lymphadenectomy; right hemicolectomy for terminal ileal tumours.","refs":["lymphadenectomy","colectomy"],"guideline":{"version":"NCCN Guidelines: Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"}},{"setting":"After surgery","approach":"Observation for stage I and low-risk stage II; adjuvant CAPOX or FOLFOX for stage III and high-risk stage II, extrapolated from colon cancer pending BALLAD.","refs":["capox","folfox","cytotoxic-chemotherapy","ballad"],"guideline":{"version":"NCCN Guidelines: Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"}},{"setting":"Surveillance","approach":"CT and CEA every six to twelve months; endoscopic surveillance of the remaining duodenum in FAP.","refs":["ct","endoscopy"],"guideline":{"version":"NCCN Guidelines: Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"}}],"stateOfArt":["Surgery cures a good share of patients with node-negative disease.","BALLAD is the first randomised adjuvant trial in the disease.","Universal mismatch repair testing finds Lynch syndrome families and identifies candidates for immunotherapy."],"history":[{"year":1935,"title":"Whipple describes pancreaticoduodenectomy","refs":["whipple"]},{"year":2014,"title":"Retrospective series suggest a benefit from adjuvant chemotherapy in node-positive disease","refs":["capox","folfox"]},{"year":2015,"title":"BALLAD opens as an international trial of adjuvant chemotherapy versus observation","refs":[]},{"year":2019,"title":"NCCN publishes its first guideline for small bowel adenocarcinoma","refs":[]}],"pipeline":["capox","folfox","signatera"],"openProblems":["Whether adjuvant chemotherapy improves survival awaits the full BALLAD results.","Diagnosis is often delayed by months because the small bowel is hard to image.","The optimal extent of lymphadenectomy is undefined.","Patients with Crohn's disease are hard to screen."],"parent":"small-bowel"},{"id":"locally-advanced-bcc","kind":"cancer","name":"Locally advanced and metastatic basal cell carcinoma","aka":["Advanced basal cell carcinoma","Unresectable basal cell carcinoma","Metastatic basal cell carcinoma","Hedgehog inhibitor-treated basal cell carcinoma"],"tldr":"Locally advanced basal cell carcinoma is a skin cancer that has grown so large or deep, usually on the face, that surgery or radiotherapy can no longer remove it without unacceptable damage. Almost all these tumours depend on the hedgehog growth pathway, and the pills vismodegib and sonidegib shrink about four in ten of them; cemiplimab is used when the pills fail or cannot be tolerated.","summary":"Nearly every basal cell carcinoma is driven by the hedgehog pathway, through loss of the receptor PTCH1 in most tumours or activating mutations of SMO in about one in ten; germline PTCH1 mutations cause Gorlin syndrome with dozens to hundreds of tumours. Locally advanced disease means a tumour that is not amenable to surgery or radiotherapy because of size, depth, invasion of bone, orbit or nerves, or because repeated recurrence has exhausted local options; metastatic disease, to nodes, lung or bone, is very rare. Surgery with margin control, radiotherapy and, for superficial tumours, topical or photodynamic therapy cure the vast majority before this point.\n\nVismodegib, the first inhibitor of SMO, produced responses in 43 percent of locally advanced and 30 percent of metastatic tumours in ERIVANCE (2012) and was approved in January 2012 as the first systemic drug for the disease; sonidegib produced responses in 43 percent of locally advanced tumours at 200 mg in BOLT (2015). Responses are often deep and durable, but muscle cramps, hair loss, loss of taste and weight loss affect nearly everyone and lead many to stop within a year; intermittent dosing (MIKIE) keeps much of the benefit with fewer side effects, and neoadjuvant use to shrink tumours before surgery is established. Both drugs are teratogenic. Resistance arises through SMO mutations that block drug binding.\n\nCemiplimab, tested in patients whose disease had progressed on or could not tolerate hedgehog inhibitors, produced responses in 31 percent of locally advanced tumours and was approved in February 2021, giving the disease a second line. Because basal cell carcinoma carries a very high ultraviolet mutation burden, PD-1 blockade may be more active than the modest response rate suggests in patients not selected for hedgehog-inhibitor failure, and first-line immunotherapy and intratumoural agents are in trials; topical patidegib is being tested to prevent new tumours in Gorlin syndrome.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Basal-cell_carcinoma","links":[{"label":"ERIVANCE (NEJM 2012)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa1113713"},{"label":"Cemiplimab after hedgehog inhibitors (Lancet Oncology 2021)","url":"https://doi.org/10.1016/S1470-2045(21)00126-1"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Basal-cell_carcinoma"}],"tags":["subtype-page"],"related":["basal-cell-carcinoma","advanced-cutaneous-scc","merkel-cell-carcinoma"],"cancers":[],"sections":[],"technologies":["hedgehog-inhibitors","checkpoint-inhibitor","mohs-surgery","superficial-radiotherapy","electron-beam-therapy-systems"],"targets":["smoothened","pd1"],"drugs":["vismodegib","sonidegib","cemiplimab","patidegib"],"companies":[],"institutions":[],"pathways":["hedgehog","basal-cell-carcinoma-signalling"],"terms":["hedgehog-inhibitor-tolerability"],"trials":["erivance","bolt","stevie","vismoneo","cemiplimab-advanced-bcc"],"people":[],"bottlenecks":[],"keyPapers":["paper-erivance-vismodegib-sekulic-nejm-2012","paper-bolt-sonidegib-migden-lancet-oncol-2015","paper-cemiplimab-bcc-stratigos-lancet-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"skin","burden":"Basal cell carcinoma is the commonest human cancer, with millions of cases a year, but fewer than one in a hundred becomes locally advanced beyond surgery and radiotherapy and metastasis is rarer still; most advanced cases are neglected or repeatedly recurrent tumours of the head and neck, or arise in Gorlin syndrome.","subtypes":["Locally advanced basal cell carcinoma (unresectable or not suitable for radiotherapy)","Metastatic basal cell carcinoma (nodes, lung, bone)","Hedgehog inhibitor-resistant basal cell carcinoma (cemiplimab candidates)","Infiltrative and morphoeic basal cell carcinoma with perineural invasion","Basosquamous carcinoma (behaves like squamous cell carcinoma)","Gorlin syndrome with multiple basal cell carcinomas (germline PTCH1)"],"biomarkers":["PTCH1 loss or SMO activation (nearly universal; testing not needed for treatment)","Germline PTCH1 or SUFU (Gorlin syndrome)","SMO resistance mutations after hedgehog inhibitors (research)","Perineural invasion and bone or orbital involvement on imaging","High ultraviolet-signature tumour mutational burden"],"standardOfCare":[{"setting":"Locally advanced, first line","approach":"Vismodegib (ERIVANCE) or sonidegib (BOLT); intermittent dosing to limit cramps, hair loss and taste loss; surgery or radiotherapy after response where feasible.","refs":["erivance","bolt","vismodegib","sonidegib","hedgehog-inhibitors"],"guideline":{"version":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}},{"setting":"Neoadjuvant","approach":"Vismodegib for several months to shrink large facial tumours before surgery and reduce the defect.","refs":["vismodegib","mohs-surgery"],"guideline":{"version":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}},{"setting":"After hedgehog inhibitor failure or intolerance","approach":"Cemiplimab (approved 2021); clinical trials of intratumoural agents and immunotherapy combinations.","refs":["cemiplimab","nct06422936","nct04349436"],"guideline":{"version":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}},{"setting":"Metastatic disease","approach":"Vismodegib or sonidegib; cemiplimab after progression; platinum chemotherapy has only case-series support.","refs":["vismodegib","sonidegib","cemiplimab"],"guideline":{"version":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}},{"setting":"Radiotherapy and local options","approach":"Radiotherapy for tumours not resectable but still confined; electron beam and superficial radiotherapy for suitable sites; multidisciplinary review of all advanced cases.","refs":["imrt-igrt","superficial-radiotherapy","electron-beam-therapy-systems"],"guideline":{"version":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}},{"setting":"Gorlin syndrome","approach":"Surveillance and surgery, avoidance of radiotherapy, hedgehog inhibitors for multiple advanced tumours, topical patidegib in trials.","refs":["vismodegib","nct06050122"],"guideline":{"version":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}}],"stateOfArt":["Hedgehog inhibitors shrink about four in ten locally advanced tumours, many for years, in a disease that had no systemic drug before 2012.","Cemiplimab gives a second line after hedgehog inhibitor failure.","Intermittent dosing and neoadjuvant use have made the pills more tolerable and more useful."],"history":[{"year":1996,"title":"PTCH1 identified as the Gorlin syndrome gene, linking basal cell carcinoma to hedgehog signalling","refs":["hedgehog"]},{"year":2009,"title":"Vismodegib phase 1: responses in advanced basal cell carcinoma (NEJM)","refs":["vismodegib"]},{"year":2012,"title":"ERIVANCE: vismodegib approved, the first hedgehog inhibitor","refs":["erivance","vismodegib"]},{"year":2015,"title":"BOLT: sonidegib approved","refs":["bolt","sonidegib"]},{"year":2017,"title":"MIKIE: intermittent vismodegib keeps efficacy with fewer side effects","refs":["vismodegib"]},{"year":2021,"title":"Cemiplimab approved after hedgehog inhibitor failure","refs":["cemiplimab"]}],"pipeline":["cemiplimab","nct06344052","nct06422936","nct06050122","nct04349436","hedgehog-inhibitors"],"openProblems":["Hedgehog inhibitor side effects lead many patients to stop before the tumour is controlled.","Only about a third of patients respond to cemiplimab after hedgehog inhibitor failure and there is no third line.","Advanced disease is largely a failure of access and neglect, since almost every tumour is curable when small."],"parent":"basal-cell-carcinoma"},{"id":"locally-advanced-cervical-cancer","kind":"cancer","name":"Locally advanced cervical cancer","aka":["Stage IB3 to IVA cervical cancer","LACC (disease state, not the surgical trial)","Node-positive cervical cancer","Bulky cervical cancer"],"tldr":"Locally advanced cervical cancer has grown beyond the cervix or into the pelvic lymph nodes but not to distant organs. It is treated with cisplatin chemotherapy given alongside external radiotherapy and brachytherapy, and two recent trials have improved on that: adding pembrolizumab, and giving six weeks of chemotherapy before the radiotherapy starts.","summary":"The group spans FIGO 2018 stage IB3 (tumour over four centimetres), IIA2 and IIB (vaginal or parametrial extension), III (lower vagina, pelvic sidewall, hydronephrosis or pelvic and para-aortic nodes, which FIGO 2018 now stages as IIIC) and IVA (bladder or rectal invasion). Squamous carcinoma predominates; adenocarcinoma responds slightly less well. MRI defines the primary tumour and PET-CT the nodes, and nodal status has become the strongest prognostic factor. In 1999 five trials reported together and the National Cancer Institute issued a clinical alert that cisplatin given weekly during radiotherapy improved survival; concurrent chemoradiation, delivered as external-beam radiotherapy to the pelvis followed by image-guided brachytherapy to a high dose in the cervix within eight weeks, has been the standard since. Intensity-modulated radiotherapy reduces bowel toxicity and the EMBRACE studies showed that MRI-guided adaptive brachytherapy gives local control above ninety percent.\n\nAttempts to add more chemotherapy after chemoradiation failed: OUTBACK's four cycles of adjuvant carboplatin-paclitaxel gave five-year survival of 72 percent against 71 percent with chemoradiation alone, while adding toxicity. INTERLACE instead gave six weeks of induction carboplatin-paclitaxel before chemoradiation and improved five-year overall survival from 72 to 80 percent, with a hazard ratio of 0.60; the short, dose-dense induction schedule is now a guideline option, especially where immunotherapy is unavailable. KEYNOTE-A18 added pembrolizumab to chemoradiation for high-risk disease, defined as node-positive stage IB2 to IIB or stage III to IVA, and improved progression-free survival with a hazard ratio of 0.70 and overall survival at thirty-six months from 74.8 to 82.6 percent, leading to approval in January 2024. CALLA, which tested durvalumab in the same setting, was negative, a reminder that the antibody and the trial population both matter.\n\nHow to combine induction chemotherapy and immunotherapy, whether to add para-aortic radiotherapy for high pelvic nodes, and how to bring MRI-guided brachytherapy to low-income countries where most patients live are the current questions. Circulating HPV DNA after chemoradiation predicts relapse and may allow response-adapted follow-up or consolidation. Surgery has a small role: completion hysterectomy after chemoradiation does not improve survival, but exenteration can salvage central pelvic recurrence.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Cervical_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Cervical_cancer"}],"tags":["subtype-page"],"related":["early-cervical-cancer","recurrent-metastatic-cervical-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["calla"],"people":[],"bottlenecks":[],"keyPapers":["paper-keynote-a18-pfs-lancet-2024","paper-keynote-a18-os-lancet-2024","paper-interlace-lancet-2024","paper-outback-lancet-oncol-2023","paper-rose-cisplatin-chemoradiation-cervical-nejm-1999"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"Most cervical cancers worldwide present at this stage because screening is absent; even with chemoradiation about a third of women relapse, so it is the stage where the disease kills most of its victims and where the newest trials have made the largest gains.","subtypes":["FIGO 2018 stage IB3 and IIA2 (bulky, confined to cervix and upper vagina)","Stage IIB (parametrial invasion)","Stage IIIA to IIIB (lower vagina, pelvic wall, hydronephrosis)","Stage IIIC1 and IIIC2 (pelvic and para-aortic node-positive)","Stage IVA (bladder or rectal invasion)","High-risk locally advanced (KEYNOTE-A18 population: node-positive IB2 to IIB, or III to IVA)","Squamous cell carcinoma and adenocarcinoma of the cervix"],"biomarkers":["FIGO 2018 stage including nodal status on PET-CT","Tumour volume on MRI","Para-aortic node involvement","Haemoglobin before and during radiotherapy","HPV type and p16","PD-L1 (not required for pembrolizumab in this setting)","Circulating HPV DNA after treatment (investigational)"],"standardOfCare":[{"setting":"Standard chemoradiation","approach":"Weekly cisplatin with pelvic external-beam radiotherapy followed by image-guided brachytherapy, completed within eight weeks.","refs":["cisplatin","imrt-igrt","brachytherapy","chemoradiation","radiotherapy"]},{"setting":"High-risk disease (node-positive IB2 to IIB, III to IVA)","approach":"Pembrolizumab with chemoradiation and for up to two years afterwards (KEYNOTE-A18).","refs":["pembrolizumab","keynote-a18","io-plus-crt-cervical","cisplatin","brachytherapy"]},{"setting":"Induction option","approach":"Six weekly cycles of carboplatin-paclitaxel before chemoradiation (INTERLACE), particularly where immunotherapy is not available.","refs":["carboplatin","paclitaxel","interlace","induction-chemo-then-crt"]},{"setting":"Not recommended","approach":"Adjuvant carboplatin-paclitaxel after chemoradiation gave no benefit in OUTBACK.","refs":["outback","carboplatin","paclitaxel"]},{"setting":"Staging","approach":"Pelvic MRI and whole-body PET-CT; surgical para-aortic staging in selected cases.","refs":["mri","pet-ct","staging-laparoscopy"]},{"setting":"Central pelvic recurrence after radiotherapy","approach":"Pelvic exenteration in selected patients; re-irradiation with brachytherapy or protons in specialist centres.","refs":["brachytherapy","proton-therapy","robotic-surgery"]}],"stateOfArt":["KEYNOTE-A18 made pembrolizumab part of chemoradiation for high-risk disease, the first systemic advance in this setting since 1999.","INTERLACE showed that a short induction course of cheap chemotherapy adds eight percentage points of five-year survival.","MRI-guided adaptive brachytherapy (EMBRACE) achieves local control above ninety percent."],"history":[{"year":1999,"title":"NCI clinical alert: cisplatin chemoradiation improves survival in five trials","refs":["cisplatin","chemoradiation"]},{"year":2021,"title":"OUTBACK: adjuvant chemotherapy after chemoradiation gives no benefit","refs":["outback"]},{"year":2021,"title":"EMBRACE-I: MRI-guided adaptive brachytherapy gives local control above ninety percent","refs":["brachytherapy"]},{"year":2023,"title":"INTERLACE: induction carboplatin-paclitaxel improves five-year survival from 72 to 80 percent","refs":["interlace"]},{"year":2023,"title":"KEYNOTE-A18: pembrolizumab with chemoradiation improves progression-free and overall survival","refs":["keynote-a18"]},{"year":2024,"title":"Pembrolizumab approved with chemoradiation for high-risk locally advanced disease","refs":["pembrolizumab"]}],"pipeline":["idea-hpv-ctdna-cervical","pembrolizumab","proton-therapy","mrd-testing"],"openProblems":["Whether induction chemotherapy and pembrolizumab should be combined.","Access to brachytherapy and PET-CT where most patients live.","Why durvalumab (CALLA) failed where pembrolizumab succeeded."],"parent":"cervical"},{"id":"locally-advanced-pdac","kind":"cancer","name":"Locally advanced unresectable pancreatic ductal adenocarcinoma","aka":["Locally advanced pancreatic cancer","LAPC","Unresectable non-metastatic pancreatic cancer","Stage III pancreatic adenocarcinoma"],"tldr":"Locally advanced pancreatic cancer has grown around the arteries or veins behind the pancreas so that it cannot be removed, but it has not spread to other organs. Chemotherapy is the main treatment, joined in 2026 by a device that delivers electric fields to the tumour; radiotherapy controls pain and local growth, and a minority of tumours shrink enough to be operated on after all.","summary":"Locally advanced pancreatic ductal adenocarcinoma is defined by encasement of the superior mesenteric or coeliac artery beyond 180 degrees, an unreconstructable portal or superior mesenteric vein, or aortic involvement, with no metastases on CT. It behaves as a systemic disease: most patients who die of it have metastases at the time, which is why chemotherapy is the first treatment and why trials of adding local therapy have struggled to show a survival gain. Patients present with pain, weight loss, jaundice and new diabetes, and supportive care (biliary stenting, pancreatic enzymes, nutrition, coeliac plexus block for pain) is part of the treatment from the start.\n\nInduction chemotherapy is modified FOLFIRINOX or gemcitabine plus nab-paclitaxel for four to six months, extrapolated from the metastatic trials and supported by the NEOLAP and other phase 2 studies. Consolidation chemoradiation after induction did not lengthen survival in LAP07 (2016) but did delay local progression and reduce the need for further chemotherapy, so it remains an option, along with stereotactic body radiotherapy and MR-guided ablative radiotherapy, which deliver high doses to tumours abutting the bowel. Irreversible electroporation and other ablative techniques are used in a few centres without randomised evidence. PANOVA-3 (2025) was the first positive phase 3 trial in this stage in a decade: adding tumour treating fields to gemcitabine plus nab-paclitaxel lengthened survival, and the device was approved in 2026.\n\nAfter induction, patients are restaged and a minority with stable or responding disease, especially those whose CA 19-9 has normalised, are explored with a view to resection, sometimes with arterial resection; this conversion surgery is the goal of the whole strategy but remains uncommon. Trials in this stage now add RAS inhibitors, stroma-directed agents and immunotherapy combinations to chemotherapy and test whether ablative radiotherapy can replace surgery for tumours that do not become resectable.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Pancreatic_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Pancreatic_cancer"},{"label":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}],"tags":["subtype-page","gastrointestinal"],"related":["borderline-resectable-pdac","resectable-pdac","metastatic-pdac","kras-g12c-pdac","kras-wild-type-pdac","msi-high-pdac"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","ttfields","sbrt","mr-linac","hypofractionated-radiotherapy","irreversible-electroporation","biliary-stenting-drainage","kras-inhibitors","fapi-pet","pet-ct"],"targets":["kras","fap"],"drugs":["folfirinox","gemcitabine-nab-paclitaxel","gemcitabine","capecitabine","optune","daraxonrasib","zoldonrasib"],"companies":["novocure","revolution-medicines"],"institutions":[],"pathways":["pancreatic-cancer-signalling","caf-activation-desmoplasia","cachexia-biology"],"terms":["locally-advanced","resectability","chemoradiation","sbrt-term","ca19-9","obstructive-jaundice","biliary-stent","cachexia","desmoplasia"],"trials":["panova-3","nct05653453","nct05466799","nct06850623","nct07157033","nct04390399"],"people":["theodore-hong","albert-koong","theodore-lawrence","eileen-oreilly","tobias-janowitz","hedy-kindler"],"bottlenecks":[],"keyPapers":["paper-conroy-folfirinox-pancreatic-nejm-2011","paper-mpact-nab-paclitaxel-gemcitabine-nejm-2013","paper-lap07-chemoradiotherapy-locally-advanced-pancreatic-jama-2016"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About a third of pancreatic cancers are found when the tumour has grown around the major arteries or blocked the main vein without spreading elsewhere; it is the stage where local treatments other than surgery have been tested hardest.","subtypes":["Locally advanced PDAC with arterial encasement (superior mesenteric or coeliac artery)","Locally advanced PDAC with unreconstructable venous occlusion","Locally advanced PDAC converted to resection after induction chemotherapy","Locally advanced PDAC progressing locally without metastases (ablative radiotherapy candidates)","Locally advanced PDAC in patients unfit for combination chemotherapy (gemcitabine alone or chemoradiation)"],"biomarkers":["Pancreas-protocol CT with arterial encasement (defines the stage)","CA 19-9 at baseline and during induction (normalisation predicts a useful operation)","Restaging CT and PET-CT after induction (occult metastases in a share of patients)","Germline BRCA1, BRCA2 and PALB2 status (platinum choice)","KRAS and other somatic alterations by tissue or plasma sequencing (trial eligibility)","Nutritional status, pancreatic exocrine function and glycaemic control"],"standardOfCare":[{"setting":"Induction chemotherapy","approach":"Modified FOLFIRINOX or gemcitabine plus nab-paclitaxel for four to six months, with biliary stenting, pancreatic enzyme replacement and pain control alongside.","refs":["folfirinox","gemcitabine-nab-paclitaxel","biliary-stenting-drainage","cachexia"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Tumour treating fields","approach":"Alternating electric fields delivered through skin arrays added to gemcitabine plus nab-paclitaxel (PANOVA-3), approved in 2026.","refs":["ttfields","optune","panova-3","gemcitabine-nab-paclitaxel"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Consolidation local therapy","approach":"Chemoradiation with capecitabine, stereotactic body radiotherapy or MR-guided ablative radiotherapy after induction chemotherapy for disease that has not spread; LAP07 shows better local control without longer survival.","refs":["chemoradiation","sbrt","mr-linac","capecitabine","hypofractionated-radiotherapy","lap07"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Conversion surgery","approach":"Exploration and resection, sometimes with arterial reconstruction, for the minority with stable or responding disease and a normalised CA 19-9 after induction.","refs":["whipple","resectability","ca19-9","resection-margins"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Ablation","approach":"Irreversible electroporation in selected centres after induction chemotherapy; no randomised evidence.","refs":["irreversible-electroporation"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Progression","approach":"Treat as metastatic disease: switch backbone, daraxonrasib after first-line chemotherapy, clinical trials.","refs":["nalirifox","daraxonrasib","rasolute-302"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Induction chemotherapy with modified FOLFIRINOX or gemcitabine plus nab-paclitaxel is standard, with local therapy chosen afterwards by response.","PANOVA-3 made tumour treating fields the first approved addition to chemotherapy in this stage.","Ablative radiotherapy on MR-guided linear accelerators aims to control tumours that do not become resectable after induction.","Conversion to surgery after induction is the aim, achieved in a minority."],"history":[{"year":1981,"title":"Gastrointestinal Tumor Study Group: fluorouracil chemoradiation lengthens survival over radiotherapy alone in locally advanced disease","refs":["fluorouracil","chemoradiation"]},{"year":2011,"title":"FOLFIRINOX result in metastatic disease is adopted as induction for locally advanced tumours","refs":["folfirinox","paper-conroy-folfirinox-pancreatic-nejm-2011"]},{"year":2016,"title":"LAP07: chemoradiation after induction gemcitabine controls local growth but does not lengthen survival","refs":["chemoradiation","gemcitabine"]},{"year":2019,"title":"Ablative MR-guided radiotherapy for locally advanced disease enters trials","refs":["mr-linac","sbrt"]},{"year":2025,"title":"PANOVA-3: tumour treating fields with gemcitabine plus nab-paclitaxel lengthen survival","refs":["panova-3","ttfields","gemcitabine-nab-paclitaxel"]},{"year":2026,"title":"Tumour treating fields device approved for locally advanced pancreatic cancer","refs":["optune","novocure"]}],"pipeline":["nct05653453","nct05466799","nct06850623","nct07157033","nct04390399","daraxonrasib","zoldonrasib","mr-linac","irreversible-electroporation","idea-reg-losartan-pancreatic-stroma","idea-fund-adaptive-radiotherapy-evidence"],"openProblems":["No local therapy after chemotherapy has lengthened survival in a randomised trial apart from tumour treating fields.","Conversion surgery is uncommon and its benefit over continued non-surgical treatment is unproven.","CT cannot distinguish fibrosis from living tumour after induction, so restaging is unreliable.","Cachexia, pain and biliary complications limit how much treatment patients can receive."],"parent":"pancreatic"},{"id":"locoregionally-advanced-nasopharyngeal-carcinoma","kind":"cancer","name":"Locoregionally advanced nasopharyngeal carcinoma (stage III to IVA)","aka":["Locally advanced NPC","Stage III to IVA nasopharyngeal carcinoma","Non-metastatic advanced nasopharyngeal carcinoma","Endemic EBV-associated nasopharyngeal carcinoma, locoregionally advanced"],"tldr":"Locoregionally advanced nasopharyngeal carcinoma is nasopharyngeal cancer, the Epstein-Barr-virus-driven cancer behind the nose, that has grown into nearby structures or neck lymph nodes but not further. It is treated without surgery, by precise radiotherapy with cisplatin, usually after gemcitabine and cisplatin chemotherapy and in recent trials with PD-1 immunotherapy; most patients are cured.","summary":"Nasopharyngeal carcinoma in its endemic form is a non-keratinising carcinoma driven by Epstein-Barr virus, concentrated in southern China, South East Asia, North Africa and the Arctic, and it presents late because the nasopharynx is silent: a neck mass, unilateral hearing loss or blood-stained nasal discharge are the usual first signs, and by then most tumours have reached the skull base or the neck nodes. Plasma EBV DNA is a tumour marker that screens populations (a Hong Kong trial detected early tumours in asymptomatic men), stages the disease and, when still detectable after radiotherapy, identifies patients at high risk of relapse. The tumour is exquisitely sensitive to radiotherapy and chemotherapy, so surgery has no role in primary treatment.\n\nThe Intergroup 0099 trial (1998) established concurrent cisplatin chemoradiotherapy over radiotherapy alone, and intensity-modulated radiotherapy, which spares the parotids, brainstem and optic pathways around this awkward target, became standard in the 2000s. Induction chemotherapy was then shown to add benefit: the Sun Yat-sen phase 3 trial of gemcitabine and cisplatin before chemoradiotherapy (New England Journal of Medicine 2019) improved three-year recurrence-free survival from 76.5 to 85.3 percent and overall survival, and docetaxel-cisplatin-fluorouracil (TPF) induction had shown a similar effect, so induction gemcitabine-cisplatin followed by cisplatin chemoradiotherapy is the CSCO-ASCO and NCCN standard for stage III to IVA disease. Metronomic capecitabine for a year after chemoradiotherapy improved failure-free survival in a further Chinese phase 3 (Lancet 2021), and adjuvant therapy directed by post-treatment plasma EBV DNA is being tested in NRG-HN001. PD-1 antibodies have entered the curative setting: the CONTINUUM trial (Lancet 2024) added sintilimab to induction chemotherapy and chemoradiotherapy and improved three-year event-free survival from 76 to 86 percent, and trials of toripalimab and camrelizumab in the same setting are reporting. De-escalation is the other direction: trials omit concurrent cisplatin in low-risk stage II to III patients after induction, reduce radiotherapy dose in good responders and use proton therapy to cut late toxicity, because survivors live for decades with xerostomia, hearing loss, cranial neuropathy and the risk of carotid disease.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Nasopharyngeal_carcinoma","links":[{"label":"Induction gemcitabine-cisplatin (NEJM 2019)","url":"https://doi.org/10.1056/NEJMoa1905287"},{"label":"CSCO-ASCO NPC guideline 2021","url":"https://doi.org/10.1200/JCO.20.03237"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Nasopharyngeal_carcinoma"}],"tags":["subtype-page","head-and-neck"],"related":["recurrent-metastatic-nasopharyngeal-carcinoma","nasopharyngeal","hpv-positive-oropharyngeal-cancer"],"cancers":[],"sections":[],"technologies":["imrt-igrt","proton-therapy","checkpoint-inhibitor","platinum","liquid-biopsy","mri","pet-ct","acupuncture-xerostomia"],"targets":["pd1"],"drugs":["gemcitabine-cisplatin","cisplatin","capecitabine","toripalimab","camrelizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["plasma-ebv-dna","ebv-term","chemoradiation","head-neck-subsites"],"trials":["nct07258979"],"people":[],"bottlenecks":[],"keyPapers":["paper-zhang-gemcitabine-cisplatin-induction-nasopharyngeal-nejm-2019","paper-intergroup-0099-chemoradiotherapy-nasopharyngeal-jco-1998","paper-csco-asco-nasopharyngeal-carcinoma-guideline-jco-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"About two thirds of nasopharyngeal carcinoma in endemic southern China and South East Asia presents at stage III or IVA because the tumour site is hidden; it is curable in most patients with chemoradiotherapy.","subtypes":["Stage III nasopharyngeal carcinoma (T3 or N2)","Stage IVA nasopharyngeal carcinoma (T4 or N3)","Non-keratinising undifferentiated EBV-associated nasopharyngeal carcinoma (endemic; most cases)","Keratinising squamous nasopharyngeal carcinoma (non-endemic, smoking-related, less radiosensitive)","Nasopharyngeal carcinoma with detectable plasma EBV DNA after chemoradiotherapy (high relapse risk)","Low-risk locoregionally advanced nasopharyngeal carcinoma (de-escalation trials)"],"biomarkers":["Plasma EBV DNA (baseline load and post-treatment clearance)","EBER in situ hybridisation on biopsy","TNM stage on MRI of the nasopharynx and neck and PET-CT","Response to induction chemotherapy on MRI (adaptive treatment)","PD-L1 (not required for PD-1 therapy)","Hearing, thyroid and pituitary baselines for late toxicity"],"standardOfCare":[{"setting":"Staging","approach":"MRI of the nasopharynx and neck, PET-CT or CT of chest and abdomen with bone scan, plasma EBV DNA, dental and audiological assessment.","refs":["mri","pet-ct","plasma-ebv-dna","ebv-term"],"guideline":{"version":"CSCO/ASCO guideline on nasopharyngeal carcinoma 2021; NCCN Head and Neck Cancers","url":"https://doi.org/10.1200/JCO.20.03237"}},{"setting":"Stage III to IVA, standard","approach":"Induction gemcitabine and cisplatin for three cycles followed by intensity-modulated radiotherapy (70 Gy) with concurrent cisplatin; TPF induction as an alternative.","refs":["gemcitabine-cisplatin","cisplatin","imrt-igrt","proton-therapy","chemoradiation"],"guideline":{"version":"CSCO/ASCO guideline on nasopharyngeal carcinoma 2021; NCCN Head and Neck Cancers","url":"https://doi.org/10.1200/JCO.20.03237"}},{"setting":"After chemoradiotherapy","approach":"Metronomic capecitabine for one year in high-risk patients; EBV DNA-directed adjuvant therapy in trials (NRG-HN001).","refs":["capecitabine","plasma-ebv-dna"],"guideline":{"version":"CSCO/ASCO guideline on nasopharyngeal carcinoma 2021; NCCN Head and Neck Cancers","url":"https://doi.org/10.1200/JCO.20.03237"}},{"setting":"Immunotherapy in the curative setting","approach":"PD-1 antibody (sintilimab in CONTINUUM; toripalimab and camrelizumab in trials) added to induction and chemoradiotherapy in high-risk disease, adopted in China.","refs":["camrelizumab","toripalimab","checkpoint-inhibitor","nct07258979","continuum"],"guideline":{"version":"CSCO/ASCO guideline on nasopharyngeal carcinoma 2021; NCCN Head and Neck Cancers","url":"https://doi.org/10.1200/JCO.20.03237"}},{"setting":"Follow-up","approach":"Plasma EBV DNA, MRI and nasopharyngoscopy; management of xerostomia, hearing loss, hypothyroidism and hypopituitarism.","refs":["plasma-ebv-dna","mri","acupuncture-xerostomia"],"guideline":{"version":"CSCO/ASCO guideline on nasopharyngeal carcinoma 2021; NCCN Head and Neck Cancers","url":"https://doi.org/10.1200/JCO.20.03237"}}],"stateOfArt":["Induction gemcitabine-cisplatin plus cisplatin chemoradiotherapy cures most patients.","Plasma EBV DNA stages, monitors and now directs adjuvant therapy.","PD-1 antibodies have improved event-free survival when added to curative treatment in China."],"history":[{"year":1966,"title":"Old and colleagues link Epstein-Barr virus to nasopharyngeal carcinoma","refs":["ebv-term"]},{"year":1998,"title":"Intergroup 0099: concurrent cisplatin chemoradiotherapy improves survival","refs":["cisplatin","chemoradiation"]},{"year":2010,"title":"Intensity-modulated radiotherapy shown to reduce xerostomia and improve control","refs":["imrt-igrt"]},{"year":2017,"title":"Plasma EBV DNA screening detects early nasopharyngeal carcinoma in Hong Kong","refs":["plasma-ebv-dna"]},{"year":2019,"title":"Induction gemcitabine-cisplatin improves survival in locoregionally advanced disease","refs":["gemcitabine-cisplatin"]},{"year":2021,"title":"Metronomic adjuvant capecitabine improves failure-free survival; CSCO-ASCO guideline published","refs":["capecitabine"]},{"year":2024,"title":"CONTINUUM: sintilimab added to chemoradiotherapy improves event-free survival","refs":["checkpoint-inhibitor"]}],"pipeline":["toripalimab","camrelizumab","proton-therapy","nct07258979","plasma-ebv-dna"],"openProblems":["Which patients can safely have less chemotherapy or radiotherapy is being defined trial by trial.","Late toxicities of skull-base radiotherapy last for life.","Non-endemic keratinising disease responds less well and is under-studied.","PD-1 antibodies in the curative setting are approved and affordable mainly in China."],"parent":"nasopharyngeal"},{"id":"low-grade-appendiceal-mucinous-neoplasm","kind":"cancer","name":"Low-grade appendiceal mucinous neoplasm and pseudomyxoma peritonei","aka":["LAMN","Pseudomyxoma peritonei","PMP","Low-grade mucinous carcinoma peritonei","Disseminated peritoneal adenomucinosis","Jelly belly"],"tldr":"Low-grade appendiceal mucinous neoplasm is a slow-growing appendiceal cancer that makes mucus, and when it bursts it spreads jelly through the abdomen as pseudomyxoma peritonei. It rarely spreads through blood or lymph, so it is treated by stripping all visible disease from the abdomen and washing the cavity with heated chemotherapy, an operation that gives most patients many years of life.","summary":"Low-grade appendiceal mucinous neoplasms (LAMN) are villous or flat mucinous tumours that grow inside the appendix without invading its wall in the way a carcinoma does, distend it into a mucocele and, if they perforate, release mucin and tumour cells into the peritoneal cavity. There they redistribute along the flow of peritoneal fluid to the omentum, pelvis, right diaphragm and liver surface, producing pseudomyxoma peritonei, a slowly enlarging accumulation of mucin that eventually compresses the bowel and starves the patient. The PSOGI consensus of 2016 classifies the peritoneal disease as acellular mucin, low-grade, high-grade or high-grade with signet ring cells, and grade is the strongest predictor of survival; GNAS mutations are typical of low-grade disease, while TP53 and SMAD4 mark high-grade change. A LAMN confined to the appendix without perforation is cured by appendicectomy, and right hemicolectomy adds nothing.\n\nOnce the peritoneum is involved the treatment is cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), developed by Paul Sugarbaker in the 1980s and 1990s: every visible deposit is removed by peritonectomy and organ resection, and the abdomen is then perfused with heated mitomycin (or oxaliplatin) for 60 to 90 minutes. A multi-institutional registry of 2,298 patients (Journal of Clinical Oncology 2012) reported a median survival of 16.3 years and 10-year survival of 63 percent after complete cytoreduction, and the operation is standard in specialist centres although it has never been compared with lesser surgery in a randomised trial. Systemic chemotherapy has little effect on low-grade disease, and a randomised trial at MD Anderson found no benefit from fluoropyrimidine-based chemotherapy over observation in unresectable low-grade mucinous adenocarcinoma, so it is kept for high-grade histology. Patients with recurrence can be operated again, and those with unresectable disease are managed by debulking for symptoms, and in trials by mucolytic agents such as bromelain with acetylcysteine and by pressurised intraperitoneal aerosol chemotherapy.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Pseudomyxoma_peritonei","links":[{"label":"PMP registry (JCO 2012)","url":"https://doi.org/10.1200/JCO.2011.39.7166"},{"label":"PSOGI classification (Am J Surg Pathol 2016)","url":"https://doi.org/10.1097/PAS.0000000000000535"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Pseudomyxoma_peritonei"}],"tags":["subtype-page","gastrointestinal"],"related":["appendiceal-adenocarcinoma","goblet-cell-adenocarcinoma","appendiceal","peritoneal-mesothelioma"],"cancers":[],"sections":[],"technologies":["hipec","hipec-pipac-devices","ct","mri"],"targets":["kras"],"drugs":["mitomycin","folfox","capox"],"companies":[],"institutions":[],"pathways":[],"terms":["hipec-procedure","peritoneal-metastasis","debulking","colectomy","peritoneum"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-psogi-pseudomyxoma-appendiceal-classification-am-j-surg-pathol-2016","paper-who-2019-digestive-system-tumours-nagtegaal-histopathology-2020","paper-chua-j-clin-oncol"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"The commonest appendiceal neoplasm; most low-grade mucinous neoplasms are cured by appendicectomy, and the minority that rupture and seed the abdomen with mucin cause pseudomyxoma peritonei, which affects only a few people per million each year.","subtypes":["Low-grade appendiceal mucinous neoplasm confined to the appendix (cured by appendicectomy)","LAMN with acellular mucin outside the appendix (low recurrence risk, surveillance)","Low-grade pseudomyxoma peritonei (low-grade mucinous carcinoma peritonei)","High-grade appendiceal mucinous neoplasm (HAMN) and high-grade pseudomyxoma peritonei","Pseudomyxoma peritonei with signet ring cells (worst grade)","Recurrent pseudomyxoma peritonei after cytoreductive surgery"],"biomarkers":["PSOGI grade of the peritoneal disease (acellular, low, high, signet ring)","Peritoneal cancer index (extent) and completeness of cytoreduction score","GNAS mutation (low grade), KRAS; TP53 and SMAD4 (high grade)","CEA, CA 19-9 and CA-125 (prognosis and surveillance)","Perforation and extra-appendiceal mucin on the appendicectomy specimen"],"standardOfCare":[{"setting":"LAMN confined to the appendix","approach":"Appendicectomy with clear margin; no right hemicolectomy; surveillance imaging if mucin was found outside the appendix.","refs":["colectomy","ct"],"guideline":{"version":"NCCN Guidelines: Colon Cancer (appendiceal section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Pseudomyxoma peritonei, resectable","approach":"Complete cytoreductive surgery (peritonectomy and organ resection) with hyperthermic intraperitoneal chemotherapy, mitomycin or oxaliplatin, in a specialist centre.","refs":["hipec","hipec-procedure","mitomycin","peritoneal-metastasis","debulking"],"guideline":{"version":"NCCN Guidelines: Colon Cancer (appendiceal section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"High-grade pseudomyxoma peritonei","approach":"Cytoreductive surgery with HIPEC, with perioperative systemic chemotherapy (FOLFOX or CAPOX) as for appendiceal adenocarcinoma.","refs":["hipec","folfox","capox"],"guideline":{"version":"NCCN Guidelines: Colon Cancer (appendiceal section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Unresectable or recurrent disease","approach":"Repeat cytoreduction where feasible; debulking for symptoms; systemic chemotherapy only for high-grade histology; trials of mucolytics and pressurised intraperitoneal aerosol chemotherapy.","refs":["debulking","hipec-pipac-devices","folfox"],"guideline":{"version":"NCCN Guidelines: Colon Cancer (appendiceal section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}}],"stateOfArt":["Cytoreductive surgery with HIPEC gives long survival in low-grade pseudomyxoma peritonei and is the model for peritoneal surface oncology.","The PSOGI classification made grade the basis of treatment decisions across centres.","Chemotherapy has no proven role in low-grade disease, sparing patients its toxicity."],"history":[{"year":1884,"title":"Werth coins the term pseudomyxoma peritonei","refs":[]},{"year":1995,"title":"Sugarbaker describes peritonectomy procedures and heated intraperitoneal chemotherapy","refs":["hipec","hipec-procedure"]},{"year":2012,"title":"International registry of 2,298 patients: median survival 16.3 years after cytoreduction and HIPEC","refs":["hipec"]},{"year":2016,"title":"PSOGI consensus classification of appendiceal mucinous neoplasms and pseudomyxoma peritonei","refs":[]},{"year":2023,"title":"Randomised trial finds no benefit from systemic chemotherapy in unresectable low-grade mucinous appendiceal adenocarcinoma","refs":["folfox"]}],"pipeline":["hipec","hipec-pipac-devices"],"openProblems":["Cytoreduction with HIPEC has never been compared with cytoreduction alone in this disease.","Recurrence after complete cytoreduction is common and criteria for reoperation vary.","No effective systemic therapy exists for low-grade disease.","Patients are often diagnosed late after years of abdominal distension."],"parent":"appendiceal"},{"id":"low-grade-serous-ovarian-cancer","kind":"cancer","name":"Low-grade serous ovarian cancer","aka":["LGSOC","Low-grade serous carcinoma"],"tldr":"Low-grade serous cancer is the slow-growing, chemotherapy-resistant cousin of the common ovarian cancer. Surgery and hormone therapy are its mainstays, and MEK inhibitors, alone or combined with a FAK inhibitor, are the first drugs shown to shrink it reliably.","summary":"Low-grade serous carcinoma is a distinct disease with wild-type TP53 and mutations in the MAPK pathway (KRAS, BRAF, NRAS) in about half of cases; it often arises from a serous borderline tumour and expresses oestrogen receptors. Complete surgical removal matters more than in high-grade disease because chemotherapy response rates are low; letrozole or other aromatase inhibitors are used as maintenance and for recurrence. The GOG 281 trial showed that the MEK inhibitor trametinib nearly doubled progression-free survival compared with standard chemotherapy or hormone therapy in recurrent disease, and the combination of avutometinib and defactinib was approved in the United States in 2025 for KRAS-mutant recurrent disease after the RAMP 201 trial.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Ovarian_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Ovarian_cancer"}],"tags":["subtype-page"],"related":["high-grade-serous-ovarian-cancer","clear-cell-ovarian-cancer","mucinous-ovarian-cancer","granulosa-cell-tumour"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-gog-281-trametinib-lgsoc-gershenson-lancet-2022","paper-gershenson-hormonal-maintenance-lgsoc-jco-2017","paper-ramp-201-avutometinib-defactinib-lgsoc-jco-2025"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"About one in twenty ovarian cancers, affecting younger women, with a median age in the forties; it grows slowly but resists chemotherapy, so patients live for years with disease that is hard to eradicate.","subtypes":["KRAS-mutant (most responsive to MEK and RAF/MEK inhibition)","BRAF or NRAS-mutant","MAPK wild-type","Arising from serous borderline tumour"],"biomarkers":["KRAS, BRAF and NRAS mutations","Oestrogen and progesterone receptor expression","Wild-type TP53 (distinguishes it from high-grade)","CA-125 (less reliable than in high-grade disease)"],"standardOfCare":[{"setting":"First line","approach":"Complete cytoreductive surgery; carboplatin-paclitaxel followed by letrozole maintenance, or letrozole alone in selected patients.","refs":["carboplatin","paclitaxel","letrozole"]},{"setting":"Recurrent disease","approach":"Trametinib (GOG 281) or avutometinib plus defactinib for KRAS-mutant tumours; aromatase inhibitors; secondary surgery where complete resection is possible.","refs":["trametinib","avutometinib-defactinib","letrozole"]},{"setting":"Maintenance","approach":"Letrozole after first-line treatment, continued for years while tolerated.","refs":["letrozole"]}],"stateOfArt":["GOG 281 was the first randomised trial in this rare disease and made trametinib a standard option.","Avutometinib-defactinib is the first approval specific to low-grade serous cancer.","Hormone maintenance is replacing chemotherapy in first-line care."],"history":[{"year":2004,"title":"Two-tier grading separates low-grade from high-grade serous cancer (MD Anderson)","refs":[]},{"year":2022,"title":"GOG 281: trametinib doubles progression-free survival","refs":["trametinib"]},{"year":2025,"title":"Avutometinib plus defactinib approved for KRAS-mutant disease","refs":["avutometinib-defactinib"]}],"pipeline":["avutometinib-defactinib","trametinib"],"openProblems":["Whether first-line chemotherapy adds anything to surgery and hormone therapy.","Options for MAPK wild-type tumours.","Living for decades with a slow but incurable disease."],"parent":"ovarian"},{"id":"low-risk-gtn","kind":"cancer","name":"Low-risk gestational trophoblastic neoplasia (FIGO score 0 to 6)","aka":["Low-risk GTN","Post-molar gestational trophoblastic neoplasia","Persistent trophoblastic disease","Invasive mole and low-risk choriocarcinoma"],"tldr":"Low-risk gestational trophoblastic neoplasia is the mild form of this rare pregnancy-related cancer, usually found when the pregnancy hormone hCG fails to fall after removal of a molar pregnancy. It is cured in almost every woman with a single chemotherapy drug, methotrexate or actinomycin D, given until the hormone level is normal, and most go on to have normal pregnancies afterwards.","summary":"Gestational trophoblastic neoplasia arises from the placental trophoblast of a pregnancy, most often a complete or partial hydatidiform mole, and is unique among cancers in producing a near-perfect tumour marker, human chorionic gonadotropin (hCG), which is used for diagnosis, staging, monitoring and follow-up. After evacuation of a complete mole about 15 percent of women, and after a partial mole under 1 percent, develop neoplasia, detected by a plateau or rise in serial hCG without any need for biopsy. The FIGO 2000 scoring system combines age, antecedent pregnancy, interval, hCG level, tumour size, site and number of metastases and prior chemotherapy into a score; 6 or below is low risk and predicts response to single-agent chemotherapy. Low-risk disease is typically an invasive mole or choriocarcinoma confined to the uterus or with small lung metastases.\n\nSingle-agent chemotherapy cures nearly all patients. Methotrexate, the first drug ever to cure a metastatic cancer when Min Chiu Li used it for choriocarcinoma in 1956, is given as an eight-day regimen alternating with folinic acid (the Charing Cross schedule) or weekly, and actinomycin D as a pulsed fortnightly dose; the GOG 174 trial (Journal of Clinical Oncology 2011) found pulsed actinomycin D produced more complete responses than weekly methotrexate, though methotrexate remains first choice in many centres for its low toxicity. Treatment continues until hCG is normal and then for three consolidation cycles, and women who develop resistance switch to the other single agent or, if hCG is high, to multi-agent EMA-CO; overall survival in low-risk disease is close to 100 percent whatever the sequence. Second-curettage cures a minority with low hCG, and hysterectomy is an option for women who have completed their families. Because trophoblast expresses PD-L1 almost universally, the anti-PD-L1 antibody avelumab cured eight of fifteen women with single-agent-resistant low-risk disease in the TROPHIMMUN trial (Journal of Clinical Oncology 2020), and pembrolizumab has similar case-series support, so checkpoint inhibitors are now an option to avoid multi-agent chemotherapy. Follow-up hCG monitoring continues for a year and pregnancy is deferred until it is complete; subsequent pregnancies are normal in most cases, with a small risk of a further mole.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Gestational_trophoblastic_disease","links":[{"label":"GOG 174 (JCO 2011)","url":"https://doi.org/10.1200/JCO.2010.30.4386"},{"label":"TROPHIMMUN (JCO 2020)","url":"https://doi.org/10.1200/JCO.20.00803"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Gestational_trophoblastic_disease"}],"tags":["subtype-page","gynaecologic"],"related":["high-risk-gtn","placental-site-trophoblastic-tumour","gestational-trophoblastic"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","checkpoint-inhibitor","ultrasound","fertility-preservation","serum-tumour-markers"],"targets":["pdl1"],"drugs":["methotrexate","dactinomycin","avelumab","pembrolizumab","etoposide","cyclophosphamide","vincristine"],"companies":[],"institutions":[],"pathways":[],"terms":["tumour-markers","staging-systems"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-gog-174-methotrexate-vs-dactinomycin-low-risk-gtn-jco-2011","paper-trophimmun-avelumab-chemoresistant-gtn-you-jco-2020","paper-figo-2000-staging-gestational-trophoblastic-neoplasia-ijgo-2002"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"The large majority of gestational trophoblastic neoplasia, usually detected by a rising or plateauing hCG after evacuation of a molar pregnancy; cure approaches 100 percent and fertility is preserved.","subtypes":["Post-molar gestational trophoblastic neoplasia with hCG plateau or rise (commonest presentation)","Invasive mole (chorioadenoma destruens)","Low-risk gestational choriocarcinoma (FIGO score 6 or below)","Low-risk disease with lung metastases (still single-agent)","Single-agent-resistant low-risk disease (switch agent, EMA-CO or avelumab)","Quiescent gestational trophoblastic disease (low persistent hCG, observation)"],"biomarkers":["Serial serum hCG (diagnosis, response, surveillance)","FIGO 2000 prognostic score (0 to 6 low risk)","Pelvic ultrasound and chest imaging for staging","Pretreatment hCG level (predicts single-agent resistance)","Genotyping to confirm gestational origin where uncertain","PD-L1 expression (near universal; checkpoint inhibitor rationale)"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Serial hCG after molar evacuation; pelvic Doppler ultrasound and chest X-ray or CT; FIGO scoring; no biopsy needed.","refs":["ultrasound","tumour-markers","staging-systems"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}},{"setting":"First line","approach":"Single-agent methotrexate with folinic acid (eight-day regimen) or pulsed actinomycin D (GOG 174), continued until hCG normalises plus three consolidation cycles.","refs":["methotrexate","dactinomycin","cytotoxic-chemotherapy"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}},{"setting":"Resistance to first agent","approach":"Switch to the alternative single agent if hCG is low; EMA-CO if hCG is high; avelumab or pembrolizumab as chemotherapy-sparing options (TROPHIMMUN).","refs":["dactinomycin","methotrexate","etoposide","cyclophosphamide","vincristine","avelumab","pembrolizumab","trophimmun"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}},{"setting":"Surgery","approach":"Second uterine evacuation in selected women with low hCG; hysterectomy for women who have completed their families or with uncontrolled bleeding.","refs":["fertility-preservation"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}},{"setting":"Follow-up","approach":"hCG monitoring for twelve months after remission, contraception during follow-up, and hCG after every future pregnancy.","refs":["tumour-markers"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}}],"stateOfArt":["Cure with fertility preserved is the norm using a single drug.","hCG monitoring makes it the only cancer routinely diagnosed and followed without imaging or biopsy of the tumour.","Avelumab offers a chemotherapy-sparing option when the first drug fails."],"history":[{"year":1956,"title":"Min Chiu Li cures metastatic choriocarcinoma with methotrexate, the first chemotherapy cure of a solid tumour","refs":["methotrexate"]},{"year":1964,"title":"Actinomycin D established as a second single agent","refs":["dactinomycin"]},{"year":1973,"title":"Charing Cross Hospital centralises registration and treatment in the United Kingdom","refs":["tumour-markers"]},{"year":2000,"title":"FIGO adopts the combined anatomical stage and prognostic score","refs":["staging-systems"]},{"year":2011,"title":"GOG 174: pulsed actinomycin D beats weekly methotrexate on complete response","refs":["dactinomycin","methotrexate"]},{"year":2020,"title":"TROPHIMMUN: avelumab cures most women with single-agent-resistant low-risk disease","refs":["avelumab"]}],"pipeline":["avelumab","pembrolizumab"],"openProblems":["Methotrexate and actinomycin D have never been compared head to head with the regimens most centres use.","Which resistant patients should receive immunotherapy rather than EMA-CO is not settled.","Overtreatment of quiescent disease with persistently low hCG is a risk.","Care is centralised in only a few countries."],"parent":"gestational-trophoblastic"},{"id":"neuroblastoma-low-risk","kind":"cancer","name":"Low-risk neuroblastoma (INRG very low and low risk, including stage MS)","aka":["Very low-risk neuroblastoma","Stage MS neuroblastoma","Stage 4S neuroblastoma","Localised neuroblastoma in infants"],"tldr":"Low-risk neuroblastoma is the form found in infants and young children whose tumour has not spread beyond its site or, in the special stage MS pattern, has spread only to the liver, skin and a little marrow. Many of these tumours shrink and disappear on their own, so treatment is surgery, or simply watching, and almost every child survives.","summary":"Neuroblastoma arises from sympathetic nervous system precursors, most often in the adrenal, and the same histology spans one of the widest ranges of behaviour in oncology. The International Neuroblastoma Risk Group (INRG) classification of 2009 assigns pretreatment risk from image-defined risk factors (stage L1 or L2), metastatic pattern (M or MS), age, MYCN status, 11q aberration, ploidy and histology. Very low and low risk covers L1 tumours without MYCN amplification at any age, L2 tumours in infants without unfavourable biology, and stage MS in infants under 18 months: metastases confined to skin, liver and less than 10 percent of marrow, which regress spontaneously. Screening programmes in Japan, Quebec and Germany in the 1980s and 1990s found many more infant tumours than ever came to clinical attention and did not reduce deaths, proof that a large fraction of infant neuroblastoma regresses unseen.\n\nThe Children's Oncology Group trial P9641 treated children with low-risk disease by surgery alone, reserving chemotherapy for symptoms or incomplete resection with unfavourable biology: five-year event-free survival was 89 percent and overall survival 97 percent, with almost every child who relapsed rescued. The German NB97 trial observed infants with localised unresected tumours and saw spontaneous regression in around half. COG ANBL1232 then went further, observing small adrenal masses in infants under six months without biopsy, and expectant observation of L2 tumours in children under 18 months with favourable biology; the SIOPEN LINES study runs the same strategy in Europe. Stage MS infants are watched unless a rapidly enlarging liver threatens breathing or the kidneys, when a short course of carboplatin and etoposide or low-dose cyclophosphamide is given.\n\nThe problems are of judgement rather than drugs: telling a tumour that will regress from one that will grow, deciding when the surgical risk to the kidney or spinal cord of an L2 tumour outweighs the risk of watching, and recognising the minority of infants with MS disease who carry MYCN amplification or 11q loss and behave as high risk. Telomere maintenance status and segmental chromosomal aberrations are being added to the biology, urinary catecholamines and ultrasound carry the follow-up, and the late effects of the chemotherapy given to the small group who need it, particularly hearing and fertility, are being tracked so that even that can be reduced.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Neuroblastoma","links":[{"label":"Wikipedia: Neuroblastoma","url":"https://en.wikipedia.org/wiki/Neuroblastoma"},{"label":"NCI PDQ: Neuroblastoma Treatment","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}],"tags":["subtype-page","paediatric"],"related":["neuroblastoma-intermediate-risk","neuroblastoma-high-risk"],"cancers":[],"sections":[],"technologies":["active-surveillance","ultrasound","mri"],"targets":[],"drugs":[],"companies":["childrens-oncology-group"],"institutions":["siop-europe"],"pathways":[],"terms":["inrg-staging","mycn-amplification","late-effects","segmental-chromosomal-aberrations","urinary-catecholamines"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-inrg-cohn-jco-2009","paper-anbl00p2-expectant-observation-nuchtern-ann-surg-2012","paper-p9641-low-risk-neuroblastoma-strother-jco-2012"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Roughly a third of neuroblastoma, mostly in infants, is low risk: localised disease or the special metastatic pattern of infancy, without MYCN amplification, and cured in almost every case with little or no treatment.","subtypes":["INRG very low risk: L1 neuroblastoma without MYCN amplification (surgery or observation)","INRG low risk: L2 neuroblastoma in infants without unfavourable biology (observation or surgery)","Stage MS neuroblastoma in infants under 18 months without MYCN amplification (observation, short chemotherapy if symptomatic)","Ganglioneuroblastoma intermixed and ganglioneuroma (maturing spectrum; surgery or observation)","Perinatal adrenal neuroblastoma found on antenatal or postnatal ultrasound (expectant observation)"],"biomarkers":["INRG stage (L1, L2, MS) from image-defined risk factors","MYCN amplification (must be absent)","11q aberration","DNA ploidy","INPC histology","Urinary catecholamine metabolites (HVA, VMA)","Age at diagnosis"],"standardOfCare":[{"setting":"L1 tumours and small adrenal masses in infants","approach":"Observation with serial ultrasound and urinary catecholamines, or surgical resection; no chemotherapy.","refs":["inrg-staging","active-surveillance","ultrasound","mri","mycn-amplification"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}},{"setting":"L2 tumours in infants with favourable biology","approach":"Expectant observation or surgery; short carboplatin and etoposide or cyclophosphamide only for symptoms or threat to organs.","refs":["active-surveillance","carboplatin","etoposide","cyclophosphamide","inrg-staging"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}},{"setting":"Stage MS","approach":"Observation; carboplatin and etoposide or low-dose cyclophosphamide for a rapidly enlarging liver or respiratory compromise.","refs":["active-surveillance","carboplatin","etoposide","cyclophosphamide","ultrasound"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}},{"setting":"Follow-up","approach":"Ultrasound and urinary catecholamines, tapering over years; late-effects follow-up for the few who received chemotherapy.","refs":["ultrasound","mri","late-effects"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (health professional version)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}}],"stateOfArt":["Surgery alone, or observation alone, cures almost every child with low-risk neuroblastoma; five-year overall survival was 97 percent in P9641.","Small adrenal masses in young infants are observed without biopsy, and about half regress.","Biology (MYCN, 11q, ploidy) rather than stage decides who is watched and who is treated."],"history":[{"year":1971,"title":"Evans staging of neuroblastoma introduced; stage IV-S recognised as regressing disease","refs":[]},{"year":2008,"title":"German NB97: spontaneous regression in about half of observed infant tumours","refs":[]},{"year":2009,"title":"International Neuroblastoma Risk Group classification published","refs":["inrg-staging"]},{"year":2012,"title":"P9641: surgery alone gives 97 percent survival in low-risk disease; expectant observation of small adrenal masses reported","refs":["active-surveillance"]}],"pipeline":["active-surveillance","inrg-staging","idea-mfbg-pet-replaces-mibg","ultrasound"],"openProblems":["Distinguishing tumours that will regress from those that will grow without biopsy.","When surgery to the kidney or spinal canal is riskier than watching.","Identifying the few stage MS infants with MYCN amplification or 11q loss who behave as high risk."],"parent":"neuroblastoma"},{"id":"mds-lower-risk","kind":"cancer","name":"Lower-risk myelodysplastic syndromes","aka":["Low-risk MDS","IPSS-R very low, low and intermediate MDS","Lower-risk myelodysplastic neoplasms","Transfusion-dependent lower-risk MDS"],"tldr":"Lower-risk myelodysplastic syndromes rarely turn into leukaemia quickly; the problem is anaemia and the transfusions it demands. Erythropoietin, then luspatercept (COMMANDS) and the telomerase blocker imetelstat (IMerge), free many patients from transfusions for months or years, and lenalidomide does the same for the del(5q) subtype.","summary":"Risk in myelodysplastic syndromes is scored by IPSS-R (blasts, cytogenetics and depth of cytopenias) and now IPSS-M, which adds mutations such as SF3B1 (favourable) and TP53 (adverse). Very low, low and intermediate IPSS-R groups, or IPSS-M low and moderate-low, are lower risk: median survival is measured in years and leukaemic transformation is uncommon, so treatment aims at the cytopenias and their consequences, chiefly transfusion-dependent anaemia with iron overload, and at quality of life. Watchful waiting is right for patients without symptoms.\n\nAnaemia treatment is stepwise. Erythropoiesis-stimulating agents help around half of patients with a serum erythropoietin below 500 U/L. Lenalidomide gives transfusion independence to most patients with del(5q). Luspatercept, a TGF-beta superfamily ligand trap that releases late-stage red cell maturation, was approved in 2020 after MEDALIST for ring-sideroblast disease after erythropoietin failure, and COMMANDS (2023) moved it to first line: 58.5 percent of transfusion-dependent, erythropoietin-naive patients became transfusion independent for at least 12 weeks with a haemoglobin rise, against 31.2 percent on epoetin alfa. Imetelstat, the first telomerase inhibitor, was approved in 2024 after IMerge: in erythropoietin-refractory patients, 39.8 percent became transfusion independent for eight weeks and 28 percent for 24 weeks, against 15 and 3.3 percent on placebo, at the cost of neutropenia and thrombocytopenia.\n\nOther cytopenias have fewer options: thrombopoietin agonists in trials, G-CSF for neutropenic infection, and iron chelation for transfusional iron overload (TELESTO). Allogeneic transplant is deferred until the disease progresses. Elritercept and other activin traps, oral hypomethylating agents at low dose, and drugs against the SF3B1 spliceosome defect are in trials, and IPSS-M is revealing that some patients labelled lower risk carry higher-risk mutations and should be treated accordingly.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Myelodysplastic_syndrome","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Myelodysplastic_syndrome"},{"label":"NCCN Guidelines: Myelodysplastic Syndromes","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}],"tags":["subtype-page"],"related":["mds-higher-risk"],"cancers":[],"sections":[],"technologies":["transfusion-support"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["anaemia","staging-systems","ageing-tissue-field-theory","ipss-m-ipss-r","del5q","sf3b1-mutation"],"trials":["commands","imerge","medalist"],"people":[],"bottlenecks":[],"keyPapers":["paper-commands-luspatercept-mds-lancet-2023","paper-imerge-imetelstat-mds-lancet-2024"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About two-thirds of people with myelodysplastic syndromes have lower-risk disease by IPSS-R; most are over 70, and anaemia rather than leukaemia is what shapes their lives, with many needing regular transfusions.","subtypes":["MDS with low blasts, IPSS-R very low or low","MDS with SF3B1 mutation and ring sideroblasts (luspatercept)","MDS with isolated del(5q) (lenalidomide)","Transfusion-dependent lower-risk MDS after erythropoietin failure (imetelstat, luspatercept)","Hypoplastic MDS (immunosuppression)","IPSS-R intermediate MDS reclassified by IPSS-M"],"biomarkers":["IPSS-R and IPSS-M scores","Serum erythropoietin level","Ring sideroblasts and SF3B1 mutation","del(5q)","Transfusion burden","Serum ferritin and iron overload","TP53 and other adverse mutations on IPSS-M"],"standardOfCare":[{"setting":"Asymptomatic, no transfusions","approach":"Observation with blood counts every three to six months; no treatment.","refs":["transfusion-support"],"guideline":{"version":"NCCN Guidelines: Myelodysplastic Syndromes","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}},{"setting":"Anaemia, first line","approach":"Luspatercept for ring-sideroblast or SF3B1-mutated disease and for transfusion-dependent patients (COMMANDS); erythropoiesis-stimulating agent where serum erythropoietin is below 500 U/L; lenalidomide for del(5q).","refs":["luspatercept","epoetin-alfa","darbepoetin-alfa","lenalidomide"],"guideline":{"version":"NCCN Guidelines: Myelodysplastic Syndromes","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}},{"setting":"Anaemia after erythropoietin or luspatercept failure","approach":"Imetelstat (IMerge); luspatercept if not yet used; low-dose hypomethylating agent; trials of elritercept and other agents.","refs":["imetelstat","luspatercept","azacitidine","nct06499285","nct05308264","nct06243458"],"guideline":{"version":"NCCN Guidelines: Myelodysplastic Syndromes","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}},{"setting":"Supportive care","approach":"Red cell transfusion to symptoms, iron chelation once ferritin is persistently high, G-CSF for recurrent neutropenic infection, platelet transfusion for bleeding.","refs":["transfusion-support","g-csf-growth-factors"],"guideline":{"version":"NCCN Guidelines: Myelodysplastic Syndromes","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}}],"stateOfArt":["Luspatercept is first-line treatment for transfusion-dependent anaemia after COMMANDS, and imetelstat gives a second line that works after erythropoietin fails.","IPSS-M has shifted treatment for many patients by finding high-risk mutations in disease that looked lower risk.","Transfusion independence, not survival, is the endpoint that has driven every approval."],"history":[{"year":1997,"title":"International Prognostic Scoring System for MDS","refs":["staging-systems"]},{"year":2005,"title":"Lenalidomide produces transfusion independence in del(5q) MDS","refs":["lenalidomide"]},{"year":2012,"title":"IPSS-R revised scoring system","refs":["staging-systems"]},{"year":2020,"title":"Luspatercept approved after MEDALIST","refs":["luspatercept"]},{"year":2022,"title":"IPSS-M adds mutations to risk scoring","refs":[]},{"year":2023,"title":"COMMANDS: luspatercept beats epoetin alfa in first line","refs":["luspatercept","epoetin-alfa"]},{"year":2024,"title":"Imetelstat approved after IMerge: the first telomerase inhibitor","refs":["imetelstat"]}],"pipeline":["luspatercept","imetelstat","nct06499285","nct05308264","nct06243458","nct05320198"],"openProblems":["No approved treatment for thrombocytopenia or neutropenia in lower-risk disease.","Whether early disease-modifying treatment changes the natural history rather than the transfusion count.","Iron overload management and quality of life are under-studied."],"parent":"mds"},{"id":"tnbc-luminal-androgen-receptor","kind":"cancer","name":"Luminal androgen receptor triple-negative breast cancer (LAR)","aka":["LAR subtype","Luminal androgen receptor TNBC","Molecular apocrine breast cancer (overlapping)","AR-positive triple-negative breast cancer"],"tldr":"Luminal androgen receptor cancers are triple-negative breast cancers that behave like hormone-driven tumours run by the male hormone receptor instead of oestrogen. They are less proliferative, respond less well to chemotherapy, and have shown modest benefit from prostate cancer drugs that block the androgen receptor in phase 2 trials; none is approved for breast cancer.","summary":"The luminal androgen receptor (LAR) subtype was characterised by androgen receptor signalling and luminal gene expression despite ER negativity, included patients with decreased relapse-free survival, and its cell lines were uniquely sensitive to bicalutamide (Lehmann 2011); it survived the 2016 refinement as one of four tumour-intrinsic subtypes, with a pathological complete response rate of 29 percent across five neoadjuvant datasets against 41 percent for BL1 (Lehmann 2016) and 10 percent in the MD Anderson series (Masuda 2013). Burstein's LAR subtype carries the androgen receptor and the mucin MUC1 as candidate targets and separates from the other three subtypes on DNA copy number (Burstein 2015). The molecular apocrine tumours described in France are the same entity approached from ER-negative disease: ESR1-negative, AR- and FOXA1-positive by transcript, with 67 percent HER2 3+ and 57 percent GCDFP15-positive by immunohistochemistry and a clinically aggressive course (Lehmann-Che 2013); the histological apocrine carcinoma, ER and PR negative and androgen receptor positive, is on its own page. Androgen blockade has been tested in two phase 2 trials: bicalutamide 150 mg daily gave a six-month clinical benefit rate of 19 percent and median progression-free survival of 12 weeks in 26 AR-positive, ER- and PR-negative patients (Gucalp 2013); enzalutamide 160 mg daily gave a 16-week clinical benefit rate of 25 percent in all 118 enrolled and 33 percent in the 78 with 10 percent or more nuclear AR, median progression-free survival 2.9 and 3.3 months and median overall survival 12.7 and 17.6 months, with fatigue the only grade 3 or higher treatment-related event above 2 percent (Traina 2018). Neither drug is approved for breast cancer; PIK3CA mutations are enriched in this subtype, the basis for trials combining androgen blockade with PI3K-pathway inhibitors.\n\nA research classification by gene expression (Lehmann 2011, refined 2016), not a test the NHS runs; treatment follows the triple-negative rows on the parent page.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Androgen_receptor","links":[{"label":"Lehmann, J Clin Invest 2011: identification of human triple-negative breast cancer subtypes (BL1, BL2, IM, M, MSL, LAR)","url":"https://doi.org/10.1172/jci45014"},{"label":"Lehmann, PLoS One 2016: refinement of triple-negative breast cancer molecular subtypes to four (TNBCtype-4)","url":"https://doi.org/10.1371/journal.pone.0157368"},{"label":"Masuda, Clin Cancer Res 2013: differential response to neoadjuvant chemotherapy among 7 triple-negative subtypes","url":"https://doi.org/10.1158/1078-0432.ccr-13-0799"},{"label":"Burstein, Clin Cancer Res 2015: four triple-negative subtypes (LAR, MES, BLIS, BLIA) with distinct prognoses","url":"https://doi.org/10.1158/1078-0432.ccr-14-0432"},{"label":"Lehmann-Che, Breast Cancer Res 2013: molecular apocrine breast cancers overexpress HER2 or GCDFP15","url":"https://doi.org/10.1186/bcr3421"},{"label":"Gucalp, Clin Cancer Res 2013: phase II bicalutamide in androgen receptor-positive, ER-negative metastatic breast cancer","url":"https://doi.org/10.1158/1078-0432.ccr-12-3327"},{"label":"Traina, J Clin Oncol 2018: enzalutamide for androgen receptor-expressing triple-negative breast cancer","url":"https://doi.org/10.1200/jco.2016.71.3495"}],"tags":["breast","tnbc","subtype-page"],"related":["tnbc","apocrine-carcinoma-breast","tnbc-basal-like-1"],"cancers":[],"sections":[],"technologies":[],"targets":["androgen-receptor"],"drugs":["bicalutamide","enzalutamide"],"companies":[],"institutions":[],"pathways":["pi3k-akt-mtor"],"terms":["androgen-receptor-positive-tnbc","pcr"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"One of the four tumour-intrinsic triple-negative subtypes; androgen receptor was expressed by immunohistochemistry (over 10 percent of nuclei) in 12 percent of 424 ER- and PR-negative breast cancers screened for a trial (Gucalp 2013).","subtypes":["Luminal-type gene expression with androgen receptor signalling (LAR)","Molecular apocrine carcinoma, HER2-enriched or GCDFP15-positive","Apocrine carcinoma by histology (own page)"],"biomarkers":["Androgen receptor by immunohistochemistry (more than 10 percent nuclear staining in the trials; over 0 percent in the enzalutamide trial's intent-to-treat group)","FOXA1 and GCDFP15 expression","PIK3CA mutation (enriched)","Lower Ki-67 than basal-like tumours"],"standardOfCare":[{"setting":"Stage II to III","approach":"As for triple-negative disease; the subtype's lower pathological complete response rate is a research observation.","refs":["keynote-522","pembrolizumab"]},{"setting":"Metastatic, androgen receptor-positive (trials only)","approach":"Bicalutamide or enzalutamide showed clinical benefit rates of 19 to 33 percent in phase 2; not approved for breast cancer, so within a trial or after the approved options.","refs":["bicalutamide","enzalutamide","androgen-receptor"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"tnbc"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","aka":["Bronchogenic carcinoma","Lung carcinoma","Cancer of the lung","Trachea, bronchus and lung cancer","Lung and bronchus cancer","Carcinoma of the lung"],"tldr":"Lung cancer splits into non-small-cell disease, about 85 percent of it, and small-cell disease, which was 6.6 percent of English cases in 2024 and 9.1 percent of Welsh ones (National Lung Cancer Audit, State of the Nation 2026); the two behave and are treated very differently. Screening, staging and the things both types share are common ground; the rest belongs to each subtype.","summary":"Lung cancer is divided by histology into non-small-cell lung cancer, itself split into adenocarcinoma, squamous and large-cell carcinoma, and small-cell lung cancer, a fast-growing neuroendocrine tumour almost always linked to smoking. Non-small-cell disease has more than a dozen targetable driver mutations and is treated with surgery, radiotherapy, targeted drugs and immunotherapy by stage and biology; small-cell disease is treated with chemotherapy, immunotherapy and radiotherapy and relapses quickly. Low-dose CT screening of heavy smokers cuts lung cancer deaths by about a fifth, and tobacco control remains the largest lever. Mesothelioma and thymic tumours are separate thoracic cancers.\n\nHow the family is organised. Four classifications of lung cancer are in daily use at once and they do not nest. The World Health Organization's Classification of Thoracic Tumours, fifth edition (2021), names the tumour types: adenocarcinoma and its patterns, squamous cell carcinoma, large cell carcinoma, the sarcomatoid carcinomas, adenosquamous carcinoma, the salivary-gland-type tumours, and a separate chapter of neuroendocrine neoplasms holding typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma. The NCI's PDQ summaries use the clinical split instead, one summary for non-small-cell lung cancer and one for small-cell lung cancer, because that split decides the first fork of treatment. The molecular subsets (EGFR-mutant, ALK-rearranged, ROS1, KRAS G12C, MET exon 14, RET, BRAF, HER2, NTRK, NRG1) decide the second fork but are states a tumour is in rather than types of tumour, and no classification lists them as entities. On this site the family reads: lung cancer, then non-small-cell and small-cell, then the histologies under non-small-cell, with large cell neuroendocrine carcinoma sitting beside the clinical split rather than inside it because it belongs to neither. Mesothelioma arises from the pleura and is not a lung cancer, however close it sits in the chest.\n\nHow common it is, worldwide. Lung cancer is the commonest cancer in the world and the commonest cause of cancer death, and it is the only cancer that tops both lists. The IARC fact sheet, served with the GLOBOCAN 2024 estimates, counts 2,637,005 new cases a year (age-standardised rate 23.9 per 100,000) and 1,861,839 deaths (16.3 per 100,000). Asia carries 1,730,334 of the cases (65.6 percent) and 1,196,664 of the deaths (64.3 percent); Europe 478,683 and 369,740 (18.2 and 19.9 percent); Northern America 258,423 and 151,406 (9.8 and 8.1 percent); Latin America and the Caribbean 103,726 and 89,548; Africa 47,006 and 41,045; Oceania 18,833 and 13,436. The highest national rate in men is Hungary at 61.8 per 100,000, and in women Hungary and Denmark at 36.0. Five-year prevalence is lower relative to yearly incidence than for most cancers, because survival after a lung cancer diagnosis is shorter: 2,345,582 of the world's prevalent cases are in Asia (65.7 percent).\n\nWhich types, and in what proportion. Using the GLOBOCAN 2022 base with the recorded incidence of Cancer Incidence in Five Continents volume XII, of 1,572,045 lung cancers in men worldwide 717,211 (45.6 percent) were adenocarcinoma, 461,171 (29.4 percent) squamous cell carcinoma, 180,063 (11.5 percent) small-cell carcinoma and 101,861 (6.5 percent) large-cell carcinoma; of 908,630 in women, 541,971 (59.7 percent) were adenocarcinoma, 155,598 (17.1 percent) squamous, 87,902 (9.7 percent) small-cell and 59,271 (6.5 percent) large-cell (Lancet Respiratory Medicine 2025). Adenocarcinoma is now the commonest type in both sexes everywhere the data allow the question to be asked, and the highest adenocarcinoma rates are in east Asia (27.12 per 100,000 men, 19.04 per 100,000 women). The same study attributed 114,486 male and 80,378 female adenocarcinomas in 2022 to ambient particulate matter pollution.\n\nThe United Kingdom. Lung cancer is the 3rd commonest cancer in the UK, with around 50,200 new cases a year, nearly 140 a day, 11 percent of all new cancer cases: about 25,500 in males and 24,700 in females (Cancer Research UK, 2019 and 2021 to 2022). It is the commonest cause of cancer death, with around 32,800 deaths a year, 90 a day (2022 to 2024). Almost half of new cases (46 percent) are in people aged 75 and over, and rates are highest at 80 to 84. Incidence has fallen about 11 percent since the early 1990s and 5 percent in the last decade; mortality has fallen 40 percent since the early 1970s and 22 percent in the last decade. The lifetime risk of a diagnosis is nearly 1 in 13 for females and 1 in 14 for males born in 1961 (both about 7 percent).\n\nThe United States. The SEER programme projects 229,410 new cases (10.8 percent of all cancers) and 124,990 deaths (20.0 percent of all cancer deaths) for 2026, which makes lung and bronchus cancer the 3rd commonest cancer diagnosed and by a wide margin the commonest cause of cancer death. The rate of new cases is 47.2 per 100,000 a year (2019 to 2023) and the death rate 30.2 (2020 to 2024); both are falling, incidence by 1.9 percent a year over 2014 to 2023 and mortality by 4.1 percent a year over 2015 to 2024, the fastest fall of any common cancer. The median age at diagnosis is 71 and at death 73; about 5.2 percent of Americans will be diagnosed in their lifetime; 661,853 people were living with the disease in 2023. Rates differ by group: 63.7 per 100,000 in non-Hispanic Black men and 57.0 in non-Hispanic White men against 29.8 in Hispanic men; 50.9 in non-Hispanic White women and 48.6 in non-Hispanic American Indian and Alaska Native women against 23.2 in Hispanic women.\n\nScreening, in one paragraph. Two randomised trials carry the case. The National Lung Screening Trial randomised 53,454 Americans aged 55 to 74 with at least 30 pack-years to three annual low-dose CT scans or chest radiographs and found 20.0 percent fewer lung cancer deaths (95 percent confidence interval 6.8 to 26.7) and 6.7 percent fewer deaths from any cause. NELSON randomised 13,195 men and 2,594 women aged 50 to 74 in the Netherlands and Belgium to volume CT at baseline and years 1, 3 and 5.5 or to nothing, and found a death rate ratio of 0.76 (0.61 to 0.94) in men at ten years and 0.67 (0.38 to 1.14) in women. The UK National Screening Committee recommended targeted screening at 55 to 74 for people at high risk in June 2022; England's Targeted Lung Health Check programme, running since 2019, became the national Lung Cancer Screening Programme and by March 2025 had invited over two million people and diagnosed 7,193 lung cancers, 63.1 percent at stage 1 and 12.6 percent at stage 2, with full coverage expected in 2030.\n\nWhat the family shares, and what it does not. Every type is staged by the same system, the ninth edition of the TNM classification, in force since 1 January 2025; every type is investigated down the same pathway of chest X-ray, contrast-enhanced CT, PET-CT and needle sampling of mediastinal nodes through the airway wall; and every type is caused overwhelmingly by the same exposure, so the same prevention works on all of them. What the family does not share is treatment: the driver-matched pills that transformed adenocarcinoma do nothing for squamous or small-cell disease, and the surgery that cures early non-small-cell disease is rarely the right operation for small-cell disease. The subtype pages carry the treatment; this page carries what is common.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Lung_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Lung_cancer"},{"label":"NCI PDQ","url":"https://www.cancer.gov/types/lung"},{"label":"GLOBOCAN trachea, bronchus and lung fact sheet (IARC Global Cancer Observatory, 2024 estimates)","url":"https://gco.iarc.who.int/media/globocan/factsheets/cancers/15-trachea-bronchus-and-lung-fact-sheet.pdf"},{"label":"SEER Cancer Stat Facts: lung and bronchus cancer (rates, stage distribution, survival by stage, age and race)","url":"https://seer.cancer.gov/statfacts/html/lungb.html"},{"label":"CRUK: lung cancer statistics (incidence, mortality, survival, early diagnosis, treatment)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer"},{"label":"CRUK: lung cancer incidence statistics","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/incidence"},{"label":"CRUK: lung cancer mortality statistics (including mortality by deprivation)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/mortality"},{"label":"CRUK: lung cancer survival statistics (by age, deprivation and over time)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/survival"},{"label":"CRUK: lung cancer risk factors (attributable fractions for the UK)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/risk-factors"},{"label":"NHS: lung cancer","url":"https://www.nhs.uk/conditions/lung-cancer/"},{"label":"NHS: symptoms of lung cancer (when to see a GP, when to call 111 and when to call 999)","url":"https://www.nhs.uk/conditions/lung-cancer/symptoms/"},{"label":"NHS: lung cancer screening (who is invited to a lung health check and what happens)","url":"https://www.nhs.uk/tests-and-treatments/lung-cancer-screening/"},{"label":"NICE NG12: suspected cancer, recommendations by site (lung and pleural cancers 1.1.1 to 1.1.6)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"},{"label":"NICE NG122: lung cancer, diagnosis and staging (published 28 March 2019, last updated 8 March 2024)","url":"https://www.nice.org.uk/guidance/ng122/chapter/Diagnosis-and-staging"},{"label":"NICE NG209: tobacco, preventing uptake, promoting quitting and treating dependence (published 30 November 2021, last updated 4 February 2025)","url":"https://www.nice.org.uk/guidance/ng209"},{"label":"UK National Screening Committee: lung cancer screening recommendation (June 2022 review)","url":"https://view-health-screening-recommendations.service.gov.uk/lung-cancer/"},{"label":"GOV.UK: new lung cancer screening roll out to detect cancer sooner (26 June 2023)","url":"https://www.gov.uk/government/news/new-lung-cancer-screening-roll-out-to-detect-cancer-sooner"},{"label":"National Lung Screening Trial Research Team, N Engl J Med 2011: reduced lung-cancer mortality with low-dose computed tomographic screening (53,454 people)","url":"https://doi.org/10.1056/nejmoa1102873"},{"label":"de Koning, N Engl J Med 2020: NELSON, reduced lung-cancer mortality with volume CT screening in a randomised trial (13,195 men and 2,594 women)","url":"https://doi.org/10.1056/nejmoa1911793"},{"label":"US Preventive Services Task Force, JAMA 2021: screening for lung cancer, recommendation statement (annual low-dose CT at 50 to 80 with 20 pack-years, grade B)","url":"https://doi.org/10.1001/jama.2021.1117"},{"label":"Jonas, JAMA 2021: screening for lung cancer with low-dose computed tomography, updated evidence report for the US Preventive Services Task Force (223 publications, 7 randomised trials, 86,486 people)","url":"https://doi.org/10.1001/jama.2021.0377"},{"label":"Nature Medicine 2026: implementation of the NHS England Lung Cancer Screening Programme over 5 years (over two million invited, 7,193 cancers to March 2025)","url":"https://doi.org/10.1038/s41591-026-04292-y"},{"label":"Br J Radiol 2025: something old something new, introduction to the ninth edition TNM classification of lung cancer (effective 1 January 2025)","url":"https://doi.org/10.1093/bjr/tqaf161"},{"label":"Rami-Porta, J Thorac Oncol 2024: IASLC lung cancer staging project, proposals for revision of the TNM stage groups in the forthcoming ninth edition (76,518 patients analysed of 124,581 registered)","url":"https://doi.org/10.1016/j.jtho.2024.02.011"},{"label":"Nicholson, J Thorac Oncol 2022: the 2021 WHO classification of lung tumours, impact of advances since 2015","url":"https://doi.org/10.1016/j.jtho.2021.11.003"},{"label":"Lancet Respir Med 2025: estimated worldwide variation and trends in incidence of lung cancer by histological subtype in 2022 and over time (GLOBOCAN 2022 with Cancer Incidence in Five Continents)","url":"https://doi.org/10.1016/s2213-2600(24)00428-4"},{"label":"BJC Reports 2023: lung cancer in never smokers, development of a UK national research strategy (127 surveys, 190 attendees)","url":"https://doi.org/10.1038/s44276-023-00006-w"},{"label":"NHS: tests and next steps for lung cancer","url":"https://www.nhs.uk/conditions/lung-cancer/tests-and-next-steps/"},{"label":"NHS: treatment for lung cancer","url":"https://www.nhs.uk/conditions/lung-cancer/treatment/"},{"label":"NHS: coughing up blood (blood in phlegm)","url":"https://www.nhs.uk/symptoms/coughing-up-blood/"},{"label":"NHS Better Health: quit smoking","url":"https://www.nhs.uk/better-health/quit-smoking/"},{"label":"NHS: genetic and genomic testing","url":"https://www.nhs.uk/tests-and-treatments/genetic-and-genomic-testing/"},{"label":"NHS: clinical trials","url":"https://www.nhs.uk/tests-and-treatments/clinical-trials/"},{"label":"NICE NG122: lung cancer, management","url":"https://www.nice.org.uk/guidance/ng122/chapter/Management"},{"label":"NICE NG122: lung cancer, palliative interventions and supportive and palliative care","url":"https://www.nice.org.uk/guidance/ng122/chapter/Palliative-interventions-and-supportive-and-palliative-care"},{"label":"NICE NG122: lung cancer, support from clinical nurse specialists","url":"https://www.nice.org.uk/guidance/ng122/chapter/Support-from-clinical-nurse-specialists"},{"label":"NICE NG122: lung cancer, follow-up and patient perspectives","url":"https://www.nice.org.uk/guidance/ng122/chapter/Follow-up-and-patient-perspectives"},{"label":"NICE NG234: spinal metastases and metastatic spinal cord compression, recommendations","url":"https://www.nice.org.uk/guidance/ng234/chapter/Recommendations"},{"label":"Roy Castle Lung Cancer Foundation: living with lung cancer","url":"https://roycastle.org/learn-about-lung-cancer/living-with-cancer/"},{"label":"Roy Castle Lung Cancer Foundation: the support available to you","url":"https://roycastle.org/our-support/"},{"label":"Roy Castle Lung Cancer Foundation: stop smoking","url":"https://roycastle.org/our-support/stop-smoking/"},{"label":"Roy Castle Lung Cancer Foundation: getting diagnosed","url":"https://roycastle.org/learn-about-lung-cancer/getting-diagnosed/"},{"label":"Roy Castle Lung Cancer Foundation: lung cancer treatments","url":"https://roycastle.org/learn-about-lung-cancer/lung-cancer-treatments/"},{"label":"Macmillan: lung cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/lung-cancer"},{"label":"Macmillan: non-small cell lung cancer (NSCLC)","url":"https://www.macmillan.org.uk/cancer-information-and-support/lung-cancer/non-small-cell-lung-cancer"},{"label":"Macmillan: breathlessness","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/breathlessness"},{"label":"Macmillan: superior vena cava obstruction (SVCO)","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/superior-vena-cava-obstruction"},{"label":"Cancer Research UK: living with lung cancer","url":"https://www.cancerresearchuk.org/about-cancer/lung-cancer/living-with"},{"label":"Cancer Research UK: coping with breathlessness when you have lung cancer","url":"https://www.cancerresearchuk.org/about-cancer/lung-cancer/living-with/coping-with-breathlessness"},{"label":"Cancer Research UK: coping and support when you have lung cancer","url":"https://www.cancerresearchuk.org/about-cancer/lung-cancer/living-with/coping"},{"label":"Cancer Research UK: fluid on the lungs (pleural effusion)","url":"https://www.cancerresearchuk.org/about-cancer/coping/physically/breathing-problems/fluid-on-lungs-pleural-effusion"},{"label":"Cancer Research UK: treatments to help you breathe when you have lung cancer","url":"https://www.cancerresearchuk.org/about-cancer/lung-cancer/treatment/help-you-breathe"},{"label":"Cancer Research UK: symptoms of metastatic lung cancer","url":"https://www.cancerresearchuk.org/about-cancer/lung-cancer/metastatic/symptoms"},{"label":"Cancer Research UK: oxygen at home","url":"https://www.cancerresearchuk.org/about-cancer/coping/physically/breathing-problems/treatment/oxygen-at-home"},{"label":"Cancer Research UK: lung cancer resources and support organisations","url":"https://www.cancerresearchuk.org/about-cancer/lung-cancer/living-with/resources-books"},{"label":"Asthma + Lung UK: breathlessness","url":"https://www.asthmaandlung.org.uk/symptoms-tests-treatments/symptoms/breathlessness"},{"label":"Asthma + Lung UK: how can I manage my breathlessness?","url":"https://www.asthmaandlung.org.uk/symptoms-tests-treatments/symptoms/breathlessness/how-can-i-manage-my-breathlessness"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Marie Curie: what is palliative care?","url":"https://www.mariecurie.org.uk/information/getting-care/palliative-care"},{"label":"Temel et al., early palliative care for patients with metastatic non-small-cell lung cancer (NEJM 2010)","url":"https://doi.org/10.1056/NEJMoa1000678"}],"tags":["parent-page"],"related":["nsclc","sclc","lung-lcnec","lung-net","mesothelioma","pleuropulmonary-blastoma","lung-adenocarcinoma","lung-squamous-cell-carcinoma","lung-cancer-evidence-roadmap","idea-lung-screening-eligibility-by-risk-not-pack-years","idea-lung-never-smoker-disease-its-own-programme","idea-lung-resistance-directed-sequencing-at-every-progression","idea-lung-brain-metastasis-prevention-as-a-primary-endpoint","idea-lung-deprivation-gradient-treated-as-a-defect-in-delivery","idea-lung-small-cell-platform-with-shared-controls-and-subtypes","idea-lung-uk-screening-testing-and-access-gaps"],"cancers":[],"sections":[],"technologies":["low-dose-ct-screening","nhs-targeted-lung-health-check","ct","pet","histopathology-ihc","palliative-care","palliative-radiotherapy","psycho-oncology","peer-support-groups","oncology-nutrition","pain-management","prehabilitation","eras-perioperative-nutrition","survivorship-care-plan","multidisciplinary-tumour-board","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","liquid-biopsy","sbrt","pet-ct","checkpoint-inhibitor","radiotherapy","imrt-igrt","ngs","wes-wgs","ihc","fish","bronchoscopy","kinase-inhibitors","t-cell-engager","adc","stereotactic-radiosurgery"],"targets":["egfr","alk","ros1","ret","met","kras","braf","her2","ntrk","dll3","tp53","rb1","pd1"],"drugs":["osimertinib","amivantamab","lazertinib","gefitinib","erlotinib","afatinib","crizotinib","alectinib","lorlatinib","brigatinib","entrectinib","selpercatinib","capmatinib","tepotinib","sotorasib","adagrasib","dabrafenib","trametinib","trastuzumab-deruxtecan","pembrolizumab","nivolumab","atezolizumab","durvalumab","cemiplimab","tarlatamab","bevacizumab","ivonescimab","zongertinib","datopotamab-deruxtecan","tremelimumab","ceritinib","pralsetinib","vinorelbine","gemcitabine","paclitaxel","pemetrexed","cisplatin","carboplatin","etoposide","docetaxel","topotecan","lurbinectedin"],"companies":[],"institutions":[],"pathways":[],"terms":["targeted-lung-health-check","pack-year","never-smoker-lung-cancer","tnm-9-lung-cancer","radon","asbestos","smoking-cessation","haemoptysis","pulmonary-nodule","lung-rads","pancoast-tumour","ttf1-p40","tnm-staging","performance-status","malignant-pleural-effusion","superior-vena-cava-obstruction","lobectomy","segmentectomy","pneumonectomy","bronchoscopy","radiation-pneumonitis","irae","immune-colitis","pleural-effusion","pleurodesis","brain-metastases","bone-metastases","cancer-related-fatigue","anaemia","cachexia","curative-intent","late-effects","ngs","ctdna","neutropenia","febrile-neutropenia","pdl1","tps","tmb","driver-mutation","oncogene-addiction","resistance","mrd","prophylactic-cranial-irradiation","chemoradiation","neoadjuvant-adjuvant","histology","clonal-evolution","overdiagnosis","oligometastatic","screening","lung-trials-open-today","lung-palliation-breathlessness-effusion-obstruction","lung-failed-programmes","lung-uk-drug-access"],"trials":["nlst-nelson","pacific","flaura2","mariposa","laura","alina","alex","crown","adriatic","caspian","impower133","dellphi-304","codebreak-200","geometry-mono-1","lung-map"],"people":[],"bottlenecks":["b-early-detection","b-prevention-adoption","b-resistance","b-immunotherapy-response","b-brain-delivery","b-tumor-heterogeneity","b-rare-cancers","b-global-access","b-biomarker-validation","b-care-fragmentation","b-toxicity-qol","b-trial-diversity"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Is lung cancer one disease? No, and the ways of dividing it do not nest. Pathologists use the World Health Organization's classification of tumour types; oncologists use the split between small-cell and non-small-cell disease, because that decides the first fork of treatment; and within non-small-cell disease a set of driver mutations decides the second fork. This page is the family; the type pages carry the treatment. Mesothelioma, which grows from the lining around the lung rather than from the lung, is a different cancer and is not on this page.","How common is it? It is the commonest cancer in the world and the commonest cause of cancer death, the only cancer that leads both lists: 2,637,005 new cases and 1,861,839 deaths a year (GLOBOCAN 2024). In the UK there are around 50,200 cases and 32,800 deaths a year, the 3rd commonest cancer and the commonest cause of cancer death (Cancer Research UK). In the United States 229,410 cases and 124,990 deaths are projected for 2026 (SEER).","What proportion is caused by smoking? Cancer Research UK attributes 72 percent of UK cases to tobacco, 71 percent to active smoking and 1 percent to second-hand smoke, and about 86 percent of UK lung cancer deaths. Seventy-nine percent of UK cases are judged preventable altogether once workplace exposures, air pollution and radon are counted.","Does stopping help once you have smoked for years? Yes, and the earlier the better. Of British men who smoke all their lives 15.9 percent die of lung cancer by 75; of those who stop by 60, 9.9 percent; by 50, 6 percent; by 40, 3 percent; by 30, 1.7 percent. In women the figures are 9.5 percent for lifelong smokers, 5.3 percent for stopping by 60 and 2.2 percent by 50 (Cancer Research UK).","I have never smoked. Can I still get lung cancer? Yes. Fifteen percent of UK lung cancers are in people who have never smoked, which would make it the 8th commonest cancer in the UK on its own, and worldwide the figure is 15 to 25 percent (BJC Reports 2023; Health Science Reports 2026). It is usually adenocarcinoma, it is commoner in women, and it is more likely to carry a mutation a drug can target. Second-hand smoke accounts for an estimated 15 percent of never-smoker cases, radon and air pollution for more.","Who is offered NHS lung screening, and what happens? In England, people aged 55 to 74 whose GP record shows they smoke or used to are invited to a lung health check, by phone, online or in person. The check asks about breathing, lifestyle and family history and measures height and weight; a risk model then decides whether a CT scan follows. Scans may be in a mobile unit in a car park or at a hospital, take a few minutes, and results arrive within four weeks. Anyone who still smokes is offered help to stop at the same appointment. The programme is being rolled out area by area, starting where lung cancer rates are highest, with full coverage expected in 2030 (NHS; Nature Medicine 2026).","Does screening actually save lives? Yes, shown in randomised trials rather than inferred. Three annual low-dose CT scans cut lung cancer deaths by 20.0 percent in 53,454 Americans (National Lung Screening Trial 2011), and four rounds of volume CT cut them by 24 percent in Dutch and Belgian men at ten years (NELSON 2020). It takes 323 people screened over 6.5 years, or 130 over ten years, to prevent one lung cancer death.","What are the harms of screening? In the National Lung Screening Trial 24.2 percent of CT screens were called positive and 96.4 percent of those were false alarms; false positives led to 17 invasive procedures per 1,000 people screened, with fewer than one major complication. Incidental findings turned up in 4.4 to 40.7 percent of people screened. Overdiagnosis, finding a cancer that would never have caused harm, has been estimated at anywhere from 0 to 67 percent, which is the least settled number in the field. NELSON's protocol, which measures nodule volume and growth rather than diameter, referred only 2.1 percent of participants, and modern nodule protocols are expected to reduce the false-positive burden.","Why do I keep hearing the staging has changed? Because it has. The ninth edition of the TNM classification came into force on 1 January 2025. The T categories are unchanged; N2 was split into N2a (one mediastinal station) and N2b (several), M1c was split by the number of organ systems involved, and several stage groups moved as a result. A person staged in 2024 and a person staged in 2025 can carry different stage labels for the same disease, which matters when comparing survival figures.","What is the outlook? Averages hide a wide range and are dominated by how late the disease is found. In the United States 29.5 percent of people are alive at five years, which rises to 65.5 percent for the 24 percent found while the cancer is still confined to the lung and falls to 10.5 percent for the 51 percent found after it has spread (SEER). In the UK 11.1 percent survive ten years or more, up from 3.3 percent in the 1970s, and survival is higher in women than men and falls steeply with age (Cancer Research UK). These figures predate the drugs and the screening programme now in use.","Living with lung cancer, care and decisions: This is orientation from public patient pages and guidelines, not advice for your case: your own team's instructions and 24-hour number come first. The nine decision rows above, the question sets for the respiratory physician, thoracic surgeon, oncologist, genomics and palliative care appointments, the first 60 days checklist and the red cards were written from NICE NG122 and NG234 and the NHS, Roy Castle Lung Cancer Foundation, Macmillan, Cancer Research UK, Asthma + Lung UK, Maggie's and Marie Curie patient pages, all read on 25 September 2026.","On smoking and stigma. Lung cancer is the cancer people are most often asked whether they smoked, and the question reaches people who smoke, people who stopped decades ago and people who never smoked. Nothing in this record treats the diagnosis as a consequence. Stopping smoking appears here as a treatment recommendation with a named benefit, because NICE NG122 (1.3.1 and 1.3.2) says smoking increases the risk of lung complications after surgery and that people should be advised to stop as soon as the diagnosis is suspected and told why; the same section (1.3.3) says not to postpone surgery to allow people to stop, which means treatment is not conditional on it. Roy Castle Lung Cancer Foundation says quitting after a diagnosis may help you respond better to treatment and lists what is available. Nobody has to earn their treatment."],"group":"lung","burden":"The commonest cancer in the world and the commonest cause of cancer death, the only cancer that tops both lists: 2,637,005 new cases and 1,861,839 deaths a year (GLOBOCAN 2024), with 65.6 percent of cases in Asia. Around 50,200 UK cases and 32,800 UK deaths a year, the 3rd commonest cancer and the commonest cause of cancer death (Cancer Research UK); 229,410 US cases and 124,990 deaths projected for 2026 (SEER). Adenocarcinoma is the commonest type in both sexes, and 72 percent of UK cases are caused by smoking.","subtypes":["Non-small-cell lung cancer (adenocarcinoma, squamous, large cell)","Small-cell lung cancer","Carcinoid and other neuroendocrine tumours of the lung","Pleuropulmonary blastoma (childhood)","Large cell neuroendocrine carcinoma of the lung"],"biomarkers":["EGFR, ALK, ROS1, KRAS G12C, BRAF V600E, MET exon 14, RET, NTRK, HER2 mutations (non-small-cell)","PD-L1 expression","Stage by TNM and PET-CT","Circulating tumour DNA for minimal residual disease","Histological type on a small biopsy, decided by TTF-1 and p40 immunohistochemistry before anything else"],"standardOfCare":[{"setting":"Referral when symptoms suggest lung cancer (UK)","approach":"Refer on the suspected cancer pathway for chest X-ray findings that suggest lung cancer, or for unexplained haemoptysis at 40 and over. Offer an urgent direct access chest X-ray at 40 and over for two or more of cough, fatigue, shortness of breath, chest pain, weight loss and appetite loss, or for one of them in anyone who has ever smoked. Consider one for persistent or recurrent chest infection, finger clubbing, supraclavicular or persistent cervical lymphadenopathy, chest signs consistent with lung cancer, or thrombocytosis. Mesothelioma has its own rules in the same section, with asbestos exposure lowering the threshold.","refs":["haemoptysis","ct"],"guideline":{"version":"NICE NG12: suspected cancer, recognition and referral (lung and pleural cancers 1.1.1 to 1.1.6)","url":"https://www.nice.org.uk/guidance/ng12"}},{"setting":"Prevention and stopping smoking","approach":"Tobacco control and stopping smoking, which is the only lever that reaches the 72 percent of UK cases caused by smoking. NICE NG209 covers preventing uptake in people aged 24 and under and treating dependence in everyone aged 12 and over, and was updated in February 2025 to add cytisinicline. Screening services carry smoking cessation with them, as the UK National Screening Committee required. Radon can be measured in a home and reduced; workplace exposures are regulated.","refs":["smoking-cessation","radon","asbestos"],"guideline":{"version":"NICE NG209: tobacco, preventing uptake, promoting quitting and treating dependence","url":"https://www.nice.org.uk/guidance/ng209"}},{"setting":"Early lung cancer: surgery, radiotherapy or both, and what your lung function means for the choice","approach":"For lung cancer that has not spread, the first question is not which treatment is strongest but which treatment your lungs can afford. NICE NG122 (1.5.1) says that for people who are well enough and for whom treatment with curative intent is suitable, offer lobectomy, either open or thoracoscopic, and (1.5.2) offer more extensive surgery only where it is needed to get clear margins. NICE's own explanation is that lobectomy gives better survival than stereotactic ablative radiotherapy and is a good compromise between preserving lung function and removing the cancer. The fitness assessment runs on numbers rather than on impressions: spirometry and transfer factor before any treatment with curative intent (1.4.9), a functional segment count to predict lung function after the operation (1.4.11), a shuttle walk test with 400 m as the cut-off for good function or an exercise test with 15 ml/kg/minute where the risk of breathlessness afterwards is moderate to high (1.4.13 and 1.4.14), and a global risk score such as Thoracoscore with the person told the risk before they consent (1.4.1). Where predicted lung function after surgery is low, the guideline does not close the door: it says to offer people with a predicted postoperative FEV1 or transfer factor below 30 percent the option of treatment with curative intent if they accept the risks of breathlessness and associated complications (1.4.12). Two branches follow. If you decline a lobectomy or it is contraindicated, NICE offers stereotactic ablative radiotherapy or a sublobar resection (1.5.5), and says the evidence does not establish which of those two is better. If you decline any surgery or none is possible, it offers stereotactic ablative radiotherapy, and conventional or hyperfractionated radiotherapy if that is contraindicated (1.5.8). Stereotactic radiotherapy is outpatient treatment over a handful of visits, which is why people often prefer it. Smoking sits inside this row rather than beside it: NICE says to explain that smoking increases the risk of lung complications after surgery and to advise stopping as soon as the diagnosis is suspected, and in the same section says not to postpone surgery to allow people to stop (1.3.1 to 1.3.3).","refs":["lobectomy","segmentectomy","pneumonectomy","sbrt","pet-ct","prehabilitation","performance-status"],"guideline":{"version":"NICE NG122 (2019, updated March 2024)","url":"https://www.nice.org.uk/guidance/ng122/chapter/Management"}},{"setting":"Treatment before or after surgery, and which results have to come back first","approach":"An operation is rarely the whole of the treatment for anything above the smallest tumours, and the order matters. Before surgery, NICE NG122 (1.6.8) recommends nivolumab with chemotherapy for neoadjuvant treatment of resectable disease at least 4 cm or node positive, and (1.6.9 and 1.6.10) durvalumab or pembrolizumab with platinum chemotherapy given before and then continued after the operation, durvalumab restricted to disease without EGFR mutations or ALK rearrangements. That restriction is why the molecular result has to be back before this decision is made rather than after it. After surgery, NICE (1.6.11) says to offer systemic anticancer therapy to people with good performance status and T1a to 4, N1 to 2, M0 disease, (1.6.12) to consider it for T2b to 4, N0, M0 tumours larger than 4 cm, and (1.6.13) to use a platinum-based combination. Where a targetable change is present the adjuvant treatment is a tablet instead: osimertinib after complete resection of stage 1b to 3a EGFR exon 19 deletion or L858R disease, stopped at 3 years or earlier on recurrence or unacceptable toxicity (1.6.14), and alectinib after complete resection of stage 1b (at least 4 cm) to 3a ALK-positive disease (1.6.15). For operable stage 3a N2 disease NICE (1.6.3 to 1.6.6) says to consider chemoradiotherapy with surgery, to discuss the benefits and risks first including that it improves progression-free survival and may improve overall survival, to schedule the operation 3 to 5 weeks after the chemoradiotherapy finishes so there is time to recover, and to do it only in teams with expertise in the combined treatment and in each of its parts. The practical questions this row generates are about sequence and waiting: what has to come back before we decide, how long the treatment before surgery adds, and what the pathology report will change afterwards.","refs":["nivolumab","durvalumab","pembrolizumab","osimertinib","alectinib","checkmate-816","keynote-671","adaura","alina","egfr","alk"],"guideline":{"version":"NICE NG122 (2019, updated March 2024)","url":"https://www.nice.org.uk/guidance/ng122/chapter/Management"}},{"setting":"Locally advanced lung cancer that cannot be removed: chemoradiotherapy, then a year of immunotherapy","approach":"Locally advanced lung cancer is the stage where the treatment is hardest and the intent is still cure. NICE NG122 (1.6.17) says to consider chemoradiotherapy for people with stage 2 or 3 disease whose condition is not suitable for surgery or who decline it, and to balance the potential survival benefit against the risk of additional toxicities, which is an unusually honest sentence for a guideline and worth quoting back in clinic. What follows the chemoradiotherapy is now part of the plan rather than an afterthought: NICE (1.6.18) recommends durvalumab for locally advanced unresectable disease with PD-L1 expression on 1 percent or more of tumour cells where the disease has not progressed after concurrent platinum-based chemoradiation; the schedule this came from, PACIFIC, gave it for a year. For people whose tumour carries an EGFR change, the corpus records LAURA, which tested osimertinib in the same position after chemoradiotherapy, so what is offered depends on both the PD-L1 result and the gene result and is worth asking about by name. Where chemoradiotherapy is too much, NICE (1.5.9 and 1.5.10) says to consider radical radiotherapy, conventional or hyperfractionated, for people with stage 3a or 3b disease who are eligible, while saying plainly that some people who cannot tolerate chemoradiotherapy will not manage radical radiotherapy either. The side effect that defines this row is inflammation of the lung: both the radiotherapy and the immunotherapy can cause it, the symptoms are identical (breathlessness, a cough that does not go away, wheezing, a fever over 37.5 C), and Macmillan's instruction for all of them is the same, which is to ring the 24-hour number straight away rather than wait for the next clinic.","refs":["durvalumab","pacific","laura","osimertinib","radiation-pneumonitis","checkpoint-inhibitor","pdl1"],"guideline":{"version":"NICE NG122 (2019, updated March 2024)","url":"https://www.nice.org.uk/guidance/ng122/chapter/Management"}},{"setting":"What a biomarker result changes once the cancer has spread, and why waiting for it is usually right","approach":"Once lung cancer has spread, the tumour's genes decide the first treatment more completely than in almost any other cancer, and the honest advice is usually to wait for the result. NICE NG122 (1.2.12) says to see the National Genomics Test Directory for guidance on next-generation sequencing panels to guide treatment, and (1.2.11) that samples must be adequate, without unacceptable risk to the person, to permit subtyping and assessment of molecular markers. The genes with a treatment attached that the record carries are EGFR, ALK, ROS1, KRAS G12C, BRAF V600, MET exon 14 skipping, RET fusions, HER2 mutations and NTRK fusions, and for most of them the matched tablet does better than what would otherwise be given first. The case for waiting is not only that a targeted drug might be missed. Some of the immunotherapy recommendations are written to exclude EGFR and ALK disease (NICE 1.6.9 does so explicitly for durvalumab around surgery), and a treatment started in the wrong lane is harder to undo than a fortnight of waiting. The case against waiting is real too, and belongs in the conversation: if someone is unwell, losing weight quickly or in pain, a team may sensibly start something now and change when the result lands. That is a judgement about the person, not a failure of the system, and the question to ask is what would be started and how fast the switch could happen. Where tissue is short, a blood test for circulating tumour DNA can sometimes answer sooner; it cannot show a change in how the cancer looks under the microscope, so it complements a biopsy rather than replacing it.","refs":["ngs","liquid-biopsy","ctdna","egfr","alk","ros1","kras-g12c","braf","met","ret","osimertinib","alectinib"],"guideline":{"version":"NICE NG122 (2019, updated March 2024)","url":"https://www.nice.org.uk/guidance/ng122/chapter/Diagnosis-and-staging"}},{"setting":"Which immunotherapy, and whether with chemotherapy, by the PD-L1 score","approach":"Where no targetable change is found, the first treatment for advanced lung cancer is immunotherapy, and the PD-L1 score decides whether it is given alone or with chemotherapy. NICE NG122 organises its published treatment pathways for advanced disease around exactly this split, separately for squamous and non-squamous cancer: no targetable mutations with PD-L1 below 50 percent, and no targetable mutations with PD-L1 at 50 percent or higher, with further pathways for RET fusion, KRAS G12C, MET exon 14 skipping and BRAF V600 disease at each PD-L1 level. In practice a high score opens the option of a checkpoint antibody on its own, which is a gentler treatment with fewer visits and no hair loss; adding chemotherapy works faster and is usually preferred when there is a lot of disease, when symptoms are pressing, or when the score is low. Neither is a better treatment in the abstract, and the question worth asking is which of those considerations is driving the recommendation for you. The trade-off in side effects is different in kind rather than in degree. Chemotherapy's effects are mostly predictable and temporary; immune effects are less predictable, can affect any organ, and Macmillan says they can begin during treatment or after it ends, which is why the alert card is issued and why the same short list is repeated at every visit: breathlessness, a new cough, wheezing or a fever over 37.5 C; more stools than is normal for you or stools at night; a spreading, blistering or peeling rash with flu-like symptoms; and feeling unwell even with a normal temperature.","refs":["pembrolizumab","atezolizumab","cemiplimab","nivolumab","ipilimumab","pdl1","keynote-042","keynote-407","checkmate-227","irae","checkpoint-inhibitor"],"guideline":{"version":"NICE NG122 (2019, updated March 2024)","url":"https://www.nice.org.uk/guidance/ng122/chapter/Management"}},{"setting":"When a targeted drug stops working (resistance): the second biopsy and what comes next","approach":"Targeted tablets work until the cancer finds a way round them, and planning for that in advance makes the day it happens less frightening. The first thing to establish is the pattern. One growing area with everything else stable is often treated locally, with stereotactic radiotherapy to that spot and the tablet continued; growth in several places usually means changing treatment. The second is whether to look at the cancer again. NICE NG122 (1.2.11) asks for samples adequate to permit pathological diagnosis including subtyping and assessment of molecular markers, and (1.2.13) to choose investigations that give the most information with the least risk to the person, thinking carefully before performing a test that gives only diagnostic pathology when other information is needed too. Applied at resistance, that is the argument for and against a repeat biopsy: it can show a new resistance mutation, an amplified second gene, or that the cancer has transformed into a different type entirely, and each of those points somewhere different. A blood test for tumour DNA is quicker and can find a new mutation, but it cannot see a transformation, so where that is the question tissue is still needed. What follows depends on what is found: a next-generation inhibitor of the same target, chemotherapy with or without an antibody, an antibody drug conjugate such as patritumab deruxtecan in the HERTHENA-Lung02 setting, or a trial. Trials usually require you to be well enough to take part, so this is the point at which to ask for the referral rather than several months later.","refs":["osimertinib","lorlatinib","patritumab-deruxtecan","herthena-lung02","liquid-biopsy","ctdna","sbrt","bronchoscopy"],"guideline":{"version":"NICE NG122 (2019, updated March 2024)","url":"https://www.nice.org.uk/guidance/ng122/chapter/Diagnosis-and-staging"}},{"setting":"Lung cancer that has spread to the brain","approach":"Lung cancer reaches the brain more often than most cancers, and the treatment has changed enough that old assumptions are worth putting down. NICE NG122 (1.16.1) says to offer dexamethasone to people with symptomatic brain metastases and to reduce to the minimum necessary maintenance dose for symptomatic response, and (1.16.2) refers the treatment itself to the section on management of confirmed brain metastases in its brain tumours guideline rather than repeating it. The practical choice is between focused radiotherapy to a small number of spots, whole-brain radiotherapy, surgery for a single accessible lesion, and, increasingly, a targeted tablet chosen because it crosses into the brain: several of the modern drugs recorded here were designed to do so, which can mean treating brain disease with tablets rather than radiotherapy. NICE is willing to say out loud that radiotherapy to the whole brain has a cost: writing about preventive brain radiotherapy in small-cell disease it says the treatment can adversely affect quality of life and that the survival benefits are limited. Which approach is proposed, and why, is therefore a reasonable question. The symptoms to know, from Cancer Research UK, are memory problems, mood or personality changes, seizures, confusion, severe headaches often with sickness, and weakness of an arm or a leg. Two practical matters usually go unmentioned until they bite. Driving is governed by DVLA rules after a seizure or a brain metastasis and is worth asking about before it is assumed either way. Steroids lift symptoms quickly but have their own effects, and NICE NG122 (1.16.1) says to reduce to the minimum necessary maintenance dose for symptomatic response, so the plan to come down matters as much as the plan to start.","refs":["brain-metastases","dexamethasone","sbrt","osimertinib","lorlatinib","palliative-radiotherapy"],"guideline":{"version":"NICE NG122 (2019, updated March 2024)","url":"https://www.nice.org.uk/guidance/ng122/chapter/Palliative-interventions-and-supportive-and-palliative-care"}},{"setting":"A clinical trial or standard treatment","approach":"Lung cancer has more trials open than almost any other cancer, because the targets keep multiplying, and at several points a trial is a reasonable choice beside standard treatment rather than a last resort. The open questions this record follows are the ones a trial would answer for you: whether immunotherapy before surgery should be continued afterwards and for how long; whether stereotactic radiotherapy matches surgery for a small tumour in someone fit for either, which NICE itself has written as a research recommendation; what to give after a third-generation EGFR inhibitor stops working; whether treating a single growing spot buys more time on the same tablet; and whether preventive brain radiotherapy in small-cell disease can be replaced by regular MRI scans, another NICE research recommendation. The NHS is the plainest source on what taking part involves: you can ask your doctor or a patient organisation about trials you may be eligible to join; you will usually be randomly assigned either to the treatment being assessed or to a control group given standard treatment, or a placebo where no proven standard exists; trials can be time consuming, with screening and follow-up visits and sometimes overnight stays; some cover travel expenses; and you can choose to leave at any point without giving a reason and without it affecting the care you receive. Ask early rather than late, because most trials require you to be well enough to take part.","refs":["multidisciplinary-tumour-board","herthena-lung02","laura","sbrt","liquid-biopsy"],"guideline":{"version":"NICE NG122 (2019, updated March 2024)","url":"https://www.nice.org.uk/guidance/ng122/chapter/Recommendations-for-research"}},{"setting":"When to talk about palliative care","approach":"Palliative care means symptom control and support, and it is not a stage of the illness. In lung cancer this is not an opinion: it is one of the few places in oncology where starting supportive care early was tested in a randomised trial and improved survival. Temel and colleagues (NEJM 2010) randomly assigned 151 people with newly diagnosed metastatic non-small-cell lung cancer to early palliative care integrated with standard oncology care, or to standard oncology care alone. At 12 weeks the early palliative care group had better quality of life (mean FACT-L 98.0 against 91.5, P equals 0.03) and fewer depressive symptoms (16 against 38 percent, P equals 0.01); fewer received aggressive care at the end of life (33 against 54 percent, P equals 0.05), and median survival was longer (11.6 against 8.9 months, P equals 0.02). That result is why the referral is offered alongside treatment rather than after it. NICE NG122 fills in what the service does: palliative radiotherapy as symptoms arise or immediately for people who cannot have curative treatment (1.13.1); radiotherapy, debulking or a stent for an airway that is closing (1.14.2); draining a pleural effusion and talc pleurodesis where that would give lasting benefit (1.15.1 and 1.15.2); breathing control, psychosocial support and coping strategies for breathlessness, delivered by people with expertise in the techniques and available in all care settings (1.15.3 and 1.15.4); opioids such as codeine or morphine to reduce cough (1.15.5); chemotherapy and radiotherapy, and a stent where symptoms are severe, for superior vena cava obstruction (1.15.7 and 1.15.8); dexamethasone for symptomatic brain metastases (1.16.1); single-fraction radiotherapy for bone pain that ordinary painkillers are not controlling (1.17.1); and multidisciplinary management of weight loss, appetite, swallowing and depression (1.18.1). Marie Curie adds that it can start at any point and can run alongside chemotherapy or radiotherapy, and that it also supports the people close to you.","refs":["palliative-care","palliative-radiotherapy","pleurodesis","pleural-effusion","pain-management","psycho-oncology","curative-intent"],"guideline":{"version":"NICE NG122 (2019, updated March 2024)","url":"https://www.nice.org.uk/guidance/ng122/chapter/Palliative-interventions-and-supportive-and-palliative-care"}},{"setting":"Screening for lung cancer in people who have smoked","approach":"Annual low-dose CT of the chest in current and former smokers of the eligible age and pack-year range, with volume-based nodule management. NLST (53,454 participants) showed a 20 percent relative reduction in lung cancer mortality against chest radiography, and NELSON (15,789) a 24 percent reduction in men at ten years with a lower false-positive rate. In England the Targeted Lung Health Check programme invites people aged 55 to 74 with a smoking history. Screening is the single intervention with the largest effect on lung cancer mortality, and uptake, not evidence, is the limiting factor.","refs":["nlst-nelson","low-dose-ct-screening","ct","nhs-galleri"],"guideline":{"version":"NICE NG122; USPSTF; NHS Targeted Lung Health Check","url":"https://www.nice.org.uk/guidance/ng122"}},{"setting":"Stage I non-small-cell lung cancer, fit for surgery","approach":"Anatomical resection with mediastinal lymph node dissection or sampling. For a peripheral tumour 2 cm or smaller, sublobar resection is now a standard option rather than a compromise: JCOG0802/WJOG4607L found segmentectomy superior to lobectomy for overall survival (in the radiologically pure-solid subgroup, five-year overall survival 92.4 against 86.1 percent, hazard ratio 0.64), and CALGB 140503 found sublobar resection non-inferior for disease-free survival in 697 patients. Adjuvant chemotherapy is not given: the LACE pooled analysis found a hazard ratio of 1.40 in stage IA, so it is avoided, and stage IB gains little. Video-assisted or robotic access is preferred where expertise exists.","refs":["jcog0802","calgb-140503","lace-pooled-analysis","robotic-surgery","lobectomy","segmentectomy","minimally-invasive-surgery"],"guideline":{"version":"NICE NG122; NCCN Non-Small Cell Lung Cancer; ESMO","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Stage I non-small-cell lung cancer, not fit for surgery","approach":"Stereotactic ablative radiotherapy, typically 54 Gy in three fractions or an equivalent schedule adapted to tumour position. CHISEL randomised 101 patients with inoperable peripheral stage I disease to stereotactic or conventional radiotherapy and found better local control and overall survival with the stereotactic schedule. Whether it can replace an operation in fit patients is unsettled: the pooled STARS and ROSEL analysis favoured radiotherapy (three-year overall survival 95 against 79 percent), but on 58 patients from two trials that closed early, and the larger randomised comparisons have not reported. Thermal ablation is an alternative for small tumours where radiotherapy is not possible.","refs":["chisel","stars-rosel","sbrt","thermal-ablation"],"guideline":{"version":"NICE NG122; NCCN Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Resected stage II to IIIA non-small-cell lung cancer, adjuvant chemotherapy","approach":"Four cycles of cisplatin with vinorelbine, or another cisplatin doublet, starting six to twelve weeks after surgery. IALT (1,867 patients) gave five-year survival 44.5 against 40.4 percent, JBR.10 established the cisplatin and vinorelbine regimen, and ANITA gave median survival 65.7 against 43.7 months. The LACE pooled analysis of 4,584 patients set the modern indication: hazard ratio 0.89 overall, a 5.4 percent absolute five-year benefit, rising with stage (stage II 0.83, stage III 0.83) and absent, with a point estimate favouring observation, in stage IA. Carboplatin is substituted where cisplatin is contraindicated, on weaker evidence. Postoperative mediastinal radiotherapy is not given for N2 disease after a complete resection: Lung ART did not improve three-year disease-free survival and increased cardiopulmonary toxicity.","refs":["ialt","jbr-10","anita","lace-pooled-analysis","lung-art","cisplatin","vinorelbine","cytotoxic-chemotherapy"],"guideline":{"nccn":"Category 1 (stage II-IIIA)","version":"NICE NG122; NCCN Non-Small Cell Lung Cancer; LACE","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Resected EGFR-mutant or ALK-positive non-small-cell lung cancer, adjuvant targeted therapy","approach":"For an EGFR exon 19 deletion or L858R, osimertinib after resection and any adjuvant chemotherapy. ADAURA improved disease-free and overall survival, and the 2026 exploratory long-term analysis gives eight-year overall survival of 74 against 58 percent in stage II to IIIA (hazard ratio 0.53) and 79 against 64 percent in stage IB to IIIA (0.52), with the benefit larger for exon 19 deletions (0.45) than L858R (0.72). In England NICE TA1043 funds it but requires that it stops at three years. For ALK-positive disease, two years of alectinib after resection of stage IB (4 cm or more) to IIIA disease, on ALINA (disease-free survival hazard ratio 0.24), FDA-approved in 2024; overall survival is immature. Adjuvant immunotherapy is not given alongside either: EGFR- and ALK-altered tumours were excluded from or did not benefit in the immunotherapy trials.","refs":["adaura","alina","osimertinib","alectinib","egfr-exon19-l858r","lung-uk-drug-access"],"guideline":{"version":"NICE TA1043; NCCN Non-Small Cell Lung Cancer","url":"https://www.nice.org.uk/guidance/ta1043"}},{"setting":"Resectable stage II to IIIB non-small-cell lung cancer without a driver, perioperative immunotherapy","approach":"Three or four cycles of platinum doublet chemotherapy with a checkpoint inhibitor before surgery, and in most schedules the checkpoint inhibitor alone for a year afterwards. CheckMate 816 gave neoadjuvant nivolumab with chemotherapy alone (median event-free survival 31.6 against 20.8 months, hazard ratio 0.63; pathological complete response 24.0 against 2.2 percent). The perioperative schedule adds adjuvant treatment: KEYNOTE-671 with pembrolizumab, AEGEAN with durvalumab (event-free survival hazard ratio 0.69), CheckMate 77T with nivolumab (18-month event-free survival 70.2 against 50.0 percent, hazard ratio 0.58), Neotorch with toripalimab in stage III disease (hazard ratio 0.40) and RATIONALE-315 with tislelizumab (overall survival hazard ratio 0.65). Whether the adjuvant half adds anything to the neoadjuvant half is the open question; no trial has tested it directly. Tumours with EGFR or ALK alterations are excluded. Adjuvant-only immunotherapy after chemotherapy remains an option where surgery came first: atezolizumab in PD-L1-positive stage II to IIIA disease (IMpower010) or pembrolizumab (KEYNOTE-091).","refs":["checkmate-816","keynote-671","nct03800134","nct04025879","neotorch","nct04379635","nct02486718","keynote-091","neoadjuvant-adjuvant","pcr","major-pathological-response","efs"],"guideline":{"nccn":"Category 1","version":"NICE TA1127, TA1017, TA1030, TA876, TA1037, TA1071; NCCN","url":"https://www.nice.org.uk/guidance/ta1127"}},{"setting":"Unresectable stage III non-small-cell lung cancer","approach":"Concurrent platinum-based chemoradiotherapy to 60 Gy, then consolidation. RTOG 0617 showed that raising the dose to 74 Gy shortens survival, so 60 Gy is the ceiling. For disease without an EGFR mutation, a year of durvalumab: PACIFIC gave 24-month overall survival 66.3 against 55.6 percent (hazard ratio for death 0.68) and median progression-free survival 17.2 against 5.6 months, with the benefit holding at five years. Concurrent, rather than consolidation, immunotherapy failed in PACIFIC-2. Where chemoradiotherapy had to be given sequentially, GEMSTONE-301 showed consolidation sugemalimab still works (median progression-free survival 9.0 against 5.8 months), although that drug is licensed only in China and the EU. For EGFR-mutant stage III disease, osimertinib instead of durvalumab, on LAURA, funded in England under NICE TA1156.","refs":["pacific","pacific-2","laura","rtog-0617","gemstone-301","durvalumab","osimertinib","chemoradiation","consolidation-therapy"],"guideline":{"nccn":"Category 1","version":"NICE TA798, TA1156; NCCN Non-Small Cell Lung Cancer","url":"https://www.nice.org.uk/guidance/ta798"}},{"setting":"Metastatic non-small-cell lung cancer: what must be tested before treatment","approach":"Comprehensive molecular profiling, by next-generation sequencing of tissue and, where tissue is inadequate or time is short, of plasma, plus PD-L1 immunohistochemistry. The minimum set is EGFR (including exon 20 insertions and the uncommon G719X, L861Q and S768I), ALK, ROS1, KRAS G12C, MET exon 14 skipping, RET, BRAF V600E, HER2 and NTRK, with NRG1 where a targetable fusion is suspected and none is found. Starting immunotherapy before the result is known is the commonest avoidable error: an EGFR- or ALK-driven tumour rarely responds to it, and giving a checkpoint inhibitor shortly before osimertinib raises the risk of severe pneumonitis and hepatotoxicity. PD-L1 assays are not interchangeable: KEYNOTE-024 used 22C3 with a tumour proportion score, IMpower110 used SP142 scoring both tumour and immune cells.","refs":["cgp","liquid-biopsy","pd-l1-testing","tps","companion-diagnostic","driver-mutation","impower110","keynote-024-189"],"guideline":{"version":"NICE NG122; NCCN Non-Small Cell Lung Cancer; ESMO","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Metastatic disease, EGFR exon 19 deletion or L858R","approach":"Osimertinib alone (FLAURA: median progression-free survival 18.9 against 10.2 months, hazard ratio 0.46; median overall survival 38.6 against 31.8 months), or intensified first-line treatment for patients with heavier disease: osimertinib with pemetrexed and platinum chemotherapy (FLAURA2) or amivantamab with lazertinib (MARIPOSA), both funded in England under TA1060 and TA1122. Dacomitinib (ARCHER 1050: 14.7 against 9.2 months against gefitinib) and afatinib (LUX-Lung 3: 13.6 against 6.9 months in the common mutations) remain licensed alternatives. At progression, plasma or tissue is re-tested for MET amplification, C797S, small-cell transformation and other mechanisms; historically T790M after a first-generation drug was treated with osimertinib (AURA3: 10.1 against 4.4 months), a sequence first-line osimertinib has largely removed.","refs":["flaura","flaura2","mariposa","aura3","nct01774721","lux-lung-3","osimertinib","amivantamab","lazertinib","egfr-exon19-l858r","resistance","met-amplification"],"guideline":{"nccn":"Category 1","version":"NICE TA654, TA1060, TA1122; NCCN","url":"https://www.nice.org.uk/guidance/ta654"}},{"setting":"Metastatic disease, EGFR exon 20 insertions and uncommon mutations","approach":"Exon 20 insertions do not respond to osimertinib. First line, amivantamab with carboplatin and pemetrexed (PAPILLON), available in England only through a managed access period under NICE TA1158; amivantamab alone after platinum chemotherapy is approved by the FDA but not recommended by NICE (TA850). Mobocertinib was withdrawn worldwide in 2023 after its confirmatory trial failed. For the non-resistant uncommon mutations G719X, L861Q and S768I, afatinib holds a specific FDA indication granted in January 2018 on a pooled analysis of LUX-Lung 2, 3 and 6, and is preferred to osimertinib.","refs":["nct04538664","amivantamab","afatinib","mobocertinib","egfr-exon20-insertion","egfr-mutation-subtypes","lux-lung-3"],"guideline":{"version":"NICE TA1158, TA850; NCCN Non-Small Cell Lung Cancer","url":"https://www.nice.org.uk/guidance/ta1158"}},{"setting":"Metastatic disease, ALK-positive","approach":"A later-generation ALK inhibitor first, never crizotinib. Lorlatinib has the longest disease control recorded for any targeted lung cancer drug: in CROWN, five-year progression-free survival was 60 against 8 percent with crizotinib (hazard ratio 0.19), with intracranial progression close to abolished, at the cost of neurocognitive, mood, weight and lipid effects. Alectinib (ALEX: median progression-free survival 34.8 against 10.9 months; ALESIA in Asian patients) and brigatinib (ALTA-1L) are the alternatives. Crizotinib, which PROFILE 1014 established against chemotherapy (10.9 against 7.0 months), is now the control arm rather than a treatment. In England NICE funds lorlatinib (TA1103), brigatinib (TA670), alectinib (TA536) and ceritinib (TA500) first line, and lorlatinib (TA628) or brigatinib after crizotinib (TA571) later.","refs":["crown","alex","alesia","j-alex","alta-1l","profile-1014","lorlatinib","alectinib","brigatinib","brain-metastases","gene-fusion"],"guideline":{"nccn":"Category 1","version":"NICE TA1103, TA670, TA536, TA500; NCCN","url":"https://www.nice.org.uk/guidance/ta1103"}},{"setting":"Metastatic disease, ROS1-positive","approach":"Repotrectinib or entrectinib first line, because both cross into the brain. TRIDENT-1 gave a 79 percent response rate and median progression-free survival of 35.7 months in ROS1 inhibitor-naive patients, and responses in 59 percent of those with the G2032R solvent-front mutation after an earlier inhibitor. Crizotinib, which defined the subtype (72 percent response, median progression-free survival 19.2 months in the PROFILE 1001 expansion cohort), penetrates the brain poorly and is a second choice; taletrectinib is approved in China and the United States. In England NICE recommends crizotinib (TA1021) and entrectinib (TA643) and asks for the least expensive; there is no appraisal of repotrectinib for this indication.","refs":["nct03093116","profile-1001-ros1","nct02568267","repotrectinib","entrectinib","crizotinib","taletrectinib","gene-fusion","gatekeeper-mutation"],"guideline":{"version":"NICE TA1021, TA643; NCCN Non-Small Cell Lung Cancer","url":"https://www.nice.org.uk/guidance/ta1021"}},{"setting":"Metastatic disease, KRAS G12C","approach":"Chemotherapy with immunotherapy first line, then a KRAS G12C inhibitor. Sotorasib (CodeBreaK 200) and adagrasib (KRYSTAL-12) both beat docetaxel on progression-free survival in the second line without an overall survival gain, which is why the class is second line rather than first. In England sotorasib is available only through the Cancer Drugs Fund under a managed access agreement (NICE TA781) and adagrasib has no recommendation. Divarasib and olomorasib, which bind the same pocket with better exposure, and the RAS(ON) inhibitors that also cover the non-G12C alleles, are in phase 3. Liver enzyme rises are the characteristic toxicity and are worse when a KRAS inhibitor follows a checkpoint inhibitor closely.","refs":["codebreak-200","krystal-12","codebreak-100","sotorasib","adagrasib","divarasib","olomorasib","kras-inhibitors","hepatotoxicity"],"guideline":{"version":"NICE TA781 (Cancer Drugs Fund); NCCN Non-Small Cell Lung Cancer","url":"https://www.nice.org.uk/guidance/ta781"}},{"setting":"Metastatic disease, MET exon 14 skipping and MET amplification","approach":"Tepotinib or capmatinib for MET exon 14 skipping, on the single-arm VISION and GEOMETRY mono-1 trials; in England NICE TA789 recommends tepotinib and there is no appraisal of capmatinib. Peripheral oedema is the characteristic and often dose-limiting toxicity. For MET-amplified disease arising as resistance to an EGFR inhibitor, savolitinib with osimertinib is approved in China; telisotuzumab vedotin, an antibody-drug conjugate against c-Met, was approved by the FDA in 2025 for previously treated c-Met-high non-squamous disease.","refs":["nct02864992","geometry-mono-1","tepotinib","capmatinib","savolitinib","telisotuzumab-vedotin","met-exon-14-skipping","met-amplification","luminosity"],"guideline":{"version":"NICE TA789; NCCN Non-Small Cell Lung Cancer","url":"https://www.nice.org.uk/guidance/ta789"}},{"setting":"Metastatic disease, RET fusion-positive","approach":"Selpercatinib. LIBRETTO-431 established it against platinum chemotherapy with or without pembrolizumab in untreated disease, and LIBRETTO-001 gave an objective response of 85 percent in the untreated and 64 percent in the previously treated, with 91 percent intracranial response. In England NICE TA911 gives untreated patients access through managed access and TA1042 recommends it routinely after previous treatment. Pralsetinib produced a 61 percent response in the previously treated cohort of ARROW but is not recommended by NICE (TA812), so selpercatinib is effectively the only funded option in England.","refs":["libretto-431","nct03157128","arrow-thyroid","selpercatinib","pralsetinib","gene-fusion","brain-metastases"],"guideline":{"version":"NICE TA911, TA1042; NCCN Non-Small Cell Lung Cancer","url":"https://www.nice.org.uk/guidance/ta1042"}},{"setting":"Metastatic disease, BRAF V600E, HER2-mutant, NTRK and NRG1","approach":"BRAF V600E: dabrafenib with trametinib (64 percent response in the untreated cohort of BRF113928) or encorafenib with binimetinib (PHAROS); both are funded in England first line only, under NICE TA898 and TA1150. HER2 (ERBB2) mutation: trastuzumab deruxtecan at 5.4 mg/kg (DESTINY-Lung02), with interstitial lung disease as the risk that defines the drug, or zongertinib, a HER2-selective tyrosine kinase inhibitor approved by the FDA in 2025 and moved to first line in 2026. NTRK fusion: larotrectinib or entrectinib, tumour-agnostically. NRG1 fusion: zenocutuzumab, which gave a 29 percent response rate in the 93 patients with non-small-cell lung cancer in the eNRGy study and holds FDA accelerated approval from 4 December 2024. None of the HER2, NTRK or NRG1 options has a lung-specific NICE recommendation.","refs":["brf113928","pharos","destiny-lung02","destiny-lung01","nct02912949","navigate","dabrafenib-trametinib","trastuzumab-deruxtecan","zongertinib","zenocutuzumab","larotrectinib","ild","tumour-agnostic"],"guideline":{"version":"NICE TA898, TA1150; NCCN Non-Small Cell Lung Cancer","url":"https://www.nice.org.uk/guidance/ta898"}},{"setting":"Metastatic disease without a driver, PD-L1 tumour proportion score 50 percent or more","approach":"Pembrolizumab alone (KEYNOTE-024), atezolizumab alone (IMpower110: median overall survival 20.2 against 13.1 months in the PD-L1-highest group, hazard ratio 0.59) or cemiplimab alone (EMPOWER-Lung 1), with chemotherapy added where the disease burden is high or a fast response is needed. The threshold matters: CheckMate 026, which used 5 percent, failed outright (progression-free survival hazard ratio 1.15). In England NICE funds pembrolizumab (TA531, stopped at two years), atezolizumab (TA705) and cemiplimab with chemotherapy (TA1165).","refs":["keynote-024-189","impower110","empower-lung-1","keynote-042","checkmate-026","pembrolizumab","atezolizumab","cemiplimab","tps","pd-l1-testing"],"guideline":{"nccn":"Category 1","version":"NICE TA531, TA705, TA1165; NCCN","url":"https://www.nice.org.uk/guidance/ta531"}},{"setting":"Metastatic disease without a driver, PD-L1 below 50 percent","approach":"Platinum doublet chemotherapy with a checkpoint inhibitor: pemetrexed and platinum with pembrolizumab for non-squamous disease (KEYNOTE-189; NICE TA683) or carboplatin and paclitaxel with pembrolizumab for squamous disease (KEYNOTE-407; NICE TA770). Alternatives are atezolizumab with bevacizumab, carboplatin and paclitaxel (IMpower150; NICE TA584), durvalumab with tremelimumab and chemotherapy (POSEIDON: median overall survival 14.0 against 11.7 months, hazard ratio 0.77) and nivolumab with ipilimumab and two cycles of chemotherapy (CheckMate 9LA: 14.1 against 10.7 months, hazard ratio 0.69), the last of which NICE does not recommend (TA724), so it is not routinely funded in England. Where immunotherapy is contraindicated, chemotherapy alone with maintenance pemetrexed in non-squamous disease.","refs":["keynote-024-189","keynote-407","squire","impower150","nct03164616","checkmate-9la","checkmate-227","pembrolizumab","pemetrexed","carboplatin","maintenance-therapy"],"guideline":{"nccn":"Category 1","version":"NICE TA683, TA770, TA584; NCCN","url":"https://www.nice.org.uk/guidance/ta683"}},{"setting":"Metastatic non-small-cell lung cancer, later lines","approach":"Docetaxel, with nintedanib in adenocarcinoma after first-line chemotherapy (LUME-Lung 1: median progression-free survival 3.4 against 2.7 months; NICE TA347), or single-agent chemotherapy. Where a checkpoint inhibitor was not given first line, nivolumab (CheckMate 017: median overall survival 9.2 against 6.0 months; CheckMate 057: 12.2 against 9.4 months), atezolizumab (OAK: 13.8 against 9.6 months) or pembrolizumab in PD-L1-positive disease (KEYNOTE-010: 10.4 against 8.5 months at 2 mg/kg, hazard ratio 0.71) each beat docetaxel. Ramucirumab with docetaxel (REVEL: median overall survival 10.5 against 9.1 months) is licensed but not recommended by NICE (TA403). Antibody-drug conjugates are entering this space: datopotamab deruxtecan holds an FDA approval from 2025 for EGFR-mutant disease after a tyrosine kinase inhibitor and platinum chemotherapy, and patritumab deruxtecan and sacituzumab tirumotecan are in phase 3. Re-treatment with a checkpoint inhibitor after progression on one is not supported by evidence.","refs":["checkmate-017","checkmate-057","oak","keynote-010","revel","lume-lung-1","tropion-lung01","herthena-lung02","docetaxel","nintedanib","ramucirumab","datopotamab-deruxtecan","patritumab-deruxtecan","adc"],"guideline":{"version":"NICE TA655, TA713, TA520, TA347, TA403; NCCN","url":"https://www.nice.org.uk/guidance/ta347"}},{"setting":"Antibody-drug conjugates and bispecific antibodies entering the field","approach":"The two formats that will decide the next five years. Antibody-drug conjugates: datopotamab deruxtecan against TROP2 improved progression-free but not overall survival in TROPION-Lung01 (hazard ratios 0.75 and 0.94) and holds a 2025 FDA approval for EGFR-mutant disease after a tyrosine kinase inhibitor and platinum chemotherapy; patritumab deruxtecan against HER3 improved progression-free survival in HERTHENA-Lung02 (5.8 against 5.4 months, hazard ratio 0.77) without an overall survival gain and its application was withdrawn; telisotuzumab vedotin against c-Met gave a 28.6 percent response rate in LUMINOSITY, 34.6 percent where c-Met expression was high, and was approved by the FDA in 2025; trastuzumab deruxtecan holds the HER2-mutant indication on DESTINY-Lung02. Bispecific antibodies: ivonescimab, which binds PD-1 and VEGF in one molecule, beat pembrolizumab on progression-free survival in HARMONi-2 (hazard ratio 0.51) with a significant overall survival result announced in 2026, and beat chemotherapy after EGFR inhibition in HARMONi-A (7.1 against 4.8 months, hazard ratio 0.46), but its first global trial, HARMONi-3, missed statistical significance for progression-free survival at interim in May 2026; amivantamab, which binds EGFR and MET, is already standard first line with lazertinib; and tarlatamab, which binds DLL3 and CD3, is the first T-cell engager to improve survival in a common solid tumour (DeLLphi-304, overall survival hazard ratio 0.60). None of these regimens is funded in England outside amivantamab with lazertinib, and the pattern to watch is the one TROPION-Lung01 and HERTHENA-Lung02 set: a progression-free survival gain that does not become an overall survival gain.","refs":["tropion-lung01","herthena-lung02","luminosity","harmoni-2","harmoni-3","harmoni-a","dellphi-304","dellphi-305","destiny-lung02","datopotamab-deruxtecan","patritumab-deruxtecan","telisotuzumab-vedotin","ivonescimab","tarlatamab","amivantamab","adc","bispecific-antibody","t-cell-engager"],"guideline":{"version":"No United Kingdom funding outside amivantamab with lazertinib; NCCN lists datopotamab deruxtecan and telisotuzumab vedotin as options after progression","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Limited-stage small-cell lung cancer","approach":"Four cycles of cisplatin with etoposide and concurrent thoracic radiotherapy starting with cycle 1, then consolidation durvalumab for up to two years and, in most patients, prophylactic cranial irradiation. The radiotherapy schedule is 45 Gy twice daily over three weeks (Intergroup 0096: median survival 23 against 19 months, five-year survival 26 against 16 percent, grade 3 oesophagitis 27 against 11 percent) or 66 Gy once daily, which CONVERT found equivalent. ADRIATIC added durvalumab after chemoradiotherapy and gave median overall survival 55.9 against 33.4 months (hazard ratio 0.73, p=0.01), the largest single gain recorded in this disease; NICE TA1099 funds it in England. Prophylactic cranial irradiation rests on the Auperin meta-analysis of 987 patients (three-year survival 20.7 against 15.3 percent, relative risk of death 0.84), qualified by the Japanese trial of Takahashi, which found no benefit when brain MRI surveillance replaced it.","refs":["adriatic","convert","turrisi-intergroup-0096","pci-overview-1999","takahashi-pci","durvalumab","platinum-etoposide","chemoradiation","curative-intent"],"guideline":{"nccn":"Category 1","version":"NICE TA1099; NCCN Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}},{"setting":"Extensive-stage small-cell lung cancer, first line","approach":"Four to six cycles of platinum and etoposide with a checkpoint inhibitor, continued as maintenance. IMpower133 added atezolizumab (NICE TA638, performance status 0 or 1 only), CASPIAN added durvalumab (NICE TA1041, same restriction) and ASTRUM-005 added serplulimab (NICE TA1167); adebrelimab and benmelstobart are approved in China. IMforte showed that adding lurbinectedin to atezolizumab maintenance prolongs survival, and the FDA converted lurbinectedin's accelerated approval on it. Consolidation thoracic radiotherapy is offered where thoracic disease remains: CREST missed its one-year endpoint (33 against 28 percent, p=0.066) but tripled two-year survival (13 against 3 percent, p=0.004). Prophylactic cranial irradiation is now a discussion rather than a rule, because MRI surveillance is available.","refs":["impower133","caspian","astrum-005","imforte","crest-thoracic-rt","slotman-pci-es-sclc","takahashi-pci","atezolizumab","durvalumab","serplulimab","lurbinectedin","platinum-etoposide"],"guideline":{"nccn":"Category 1","version":"NICE TA638, TA1041, TA1167; NCCN Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}},{"setting":"Relapsed small-cell lung cancer","approach":"Whether the relapse is platinum-sensitive (more than 90 days, and often more than 180) decides the first choice. Platinum-sensitive relapse is re-treated with platinum and etoposide. Otherwise: tarlatamab, a DLL3 and CD3 bispecific T-cell engager, gave a 40 percent response rate at 10 mg in DeLLphi-301 and beat chemotherapy in DeLLphi-304, with cytokine release syndrome in about half and a mandatory monitored first dose; lurbinectedin gave a 35.2 percent response rate in its basket cohort; topotecan, oral or intravenous, remains the long-standing option. England is restrictive here: NICE TA1091 does not recommend tarlatamab, lurbinectedin has no United Kingdom marketing authorisation, and TA184 recommends oral topotecan only where re-treatment is inappropriate and CAV is contraindicated.","refs":["nct05060016","dellphi-304","dellphi-305","lurbinectedin-basket-sclc","atlantis","tarlatamab","lurbinectedin","topotecan","t-cell-engager"],"guideline":{"version":"NICE TA1091 (not recommended), TA184; NCCN Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}},{"setting":"Oligometastatic and oligoprogressive disease","approach":"Where metastases are few, local treatment of all of them alongside systemic therapy. SABR-COMET randomised 99 patients with one to five oligometastatic lesions to stereotactic ablative radiotherapy plus standard care or standard care alone and found longer overall survival, with lung primaries well represented. In oncogene-driven disease, a single progressing site during an otherwise effective targeted drug is treated with radiotherapy or surgery and the drug continued, rather than changing line. The evidence is from small randomised trials and the definition of oligometastatic disease is still argued over.","refs":["sabr-comet","sbrt","oligometastatic","oligoprogression","radiosurgery-srs"],"guideline":{"version":"NCCN Non-Small Cell Lung Cancer; ESMO","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Palliation: breathlessness, pleural effusion and a blocked airway","approach":"Breathlessness is treated by cause and by symptom at once: a handheld fan, low-dose oral morphine, a benzodiazepine only where anxiety is prominent, oxygen only where the patient is hypoxic, and a breathlessness service where one exists. A malignant pleural effusion is drained and then either pleurodesed with talc or managed with an indwelling pleural catheter: TIME2 found breathlessness relief identical (24.7 against 24.4 mm on a 100 mm scale, p=0.96) and AMPLE found the catheter reduced total hospital days (10.0 against 12.0, p=0.03), so the choice turns on trapped lung, home support and how much hospital time the patient will accept. An obstructing endobronchial tumour is debulked at rigid bronchoscopy with cryotherapy, argon plasma or laser and held open with an airway stent, then treated with external beam or endobronchial brachytherapy. Superior vena cava obstruction is relieved with an endovascular stent within a day. Early integrated palliative care from diagnosis of incurable disease improves quality of life and mood.","refs":["time2","ample","lung-palliation-breathlessness-effusion-obstruction","palliative-care","brachytherapy","pleural-effusion","palliative-treatment"],"guideline":{"version":"NICE NG122; BTS pleural disease guideline","url":"https://www.nice.org.uk/guidance/ng122"}},{"setting":"Palliation: bone and brain metastases","approach":"A single 8 Gy fraction of radiotherapy for an uncomplicated painful bone metastasis: the Dutch Bone Metastasis Study found response to initial treatment 71 against 73 percent for a multi-fraction course (p=0.84), and retreatment, needed more often after a single fraction, worked in 63 percent. A bisphosphonate or denosumab reduces skeletal events. Spinal cord compression is treated with dexamethasone, same-day whole-spine MRI and surgery or radiotherapy within 24 hours. For one to four brain metastases, stereotactic radiosurgery alone with MRI surveillance: JROSG 99-1 found adding whole-brain radiotherapy did not lengthen life (7.5 against 8.0 months, p=0.42) though it halved twelve-month brain recurrence (46.8 against 76.4 percent), and QUARTZ found whole-brain radiotherapy added nothing to steroids and supportive care in patients unfit for either. In driver-positive disease, the brain-penetrant drug often controls the metastases without radiotherapy.","refs":["dutch-bone-metastasis-study","jrosg-99-1","quartz","crown","denosumab","zoledronic-acid","palliative-radiotherapy","radiosurgery-srs","bone-metastases","brain-metastases"],"guideline":{"version":"NICE NG122; NICE NG59 (metastatic spinal cord compression)","url":"https://www.nice.org.uk/guidance/ng122"}}],"stateOfArt":["Immunotherapy and targeted drugs have doubled or tripled survival in metastatic non-small-cell disease over a decade.","CT screening is recommended in the United States and, since June 2022, across the four UK nations; in Europe it is still mostly not a programme, and uptake is low where it is.","Small-cell lung cancer has gained immunotherapy and the DLL3 T-cell engager tarlatamab after decades without progress."],"history":[{"year":1950,"title":"Smoking is linked to lung cancer","note":"Doll and Hill's case-control study of London hospital patients, published in the British Medical Journal in the same year as Wynder and Graham's American series, found the association that tobacco control has rested on since; the British Doctors Study that followed it ran for fifty years.","refs":[]},{"year":1954,"title":"Doll and Hill follow British doctors forward","note":"The 1950 case-control studies were called artefacts, so a cohort was assembled before anybody was ill and followed to death. Wynder and Graham's 684 proven cases had appeared in JAMA four months before Doll and Hill's BMJ paper.","refs":["paper-doll-hill-mortality-of-doctors-smoking-bmj-1954","paper-wynder-graham-tobacco-bronchiogenic-carcinoma-jama-1950","paper-doll-peto-50-year-doctors-bmj-2004"]},{"year":1995,"title":"Chemotherapy is shown to help, a little","note":"9,387 patients from 52 randomised trials: a 27 percent reduction in the risk of death when chemotherapy was added to supportive care, and 5 percent absolute benefit at five years after surgery.","refs":["paper-nsclc-collaborative-group-chemotherapy-meta-analysis-bmj-1995"]},{"year":1996,"title":"A prevention trial finds harm","note":"CARET gave beta carotene and retinol to 18,314 smokers and asbestos workers and was stopped 21 months early: relative risk of lung cancer 1.28 and of lung cancer death 1.46.","refs":["paper-caret-beta-carotene-retinol-lung-cancer-nejm-1996"]},{"year":1999,"title":"Small-cell lung cancer gets its two advances","note":"Twice-daily thoracic radiotherapy raised five-year survival from 16 to 26 percent in limited-stage disease, and the prophylactic cranial irradiation overview of 987 patients showed treating a brain with no visible disease raises three-year survival from 15.3 to 20.7 percent.","refs":["paper-turrisi-twice-daily-thoracic-radiotherapy-limited-sclc-nejm-1999","paper-auperin-prophylactic-cranial-irradiation-sclc-nejm-1999"]},{"year":2002,"title":"E1594: four chemotherapy regimens, one result","note":"1,207 patients, a 19 percent response rate and a median survival of 7.9 months whichever platinum doublet was used. That was as far as undirected cytotoxic treatment could go, and it is the baseline every entry after it is measured against.","refs":["paper-schiller-ecog-1594-four-chemotherapy-regimens-nejm-2002"]},{"year":2004,"title":"EGFR mutations explain gefitinib responses","refs":["gefitinib"]},{"year":2006,"title":"Median survival passes twelve months","note":"ECOG 4599 added bevacizumab to chemotherapy in 878 patients with non-squamous disease: 12.3 against 10.3 months, with a risk of increased treatment-related deaths.","refs":["paper-sandler-ecog-4599-bevacizumab-nsclc-nejm-2006"]},{"year":2007,"title":"EML4-ALK: the second driver","note":"A small inversion on chromosome 2p, found in 5 of 75 tumours, transformed fibroblasts. Crizotinib, built as a MET inhibitor, gave a 57 percent response rate in 2010 after 1,500 patients were screened to find 82.","refs":["paper-soda-eml4-alk-fusion-nature-2007","paper-kwak-crizotinib-alk-nsclc-nejm-2010"]},{"year":2008,"title":"Histology chooses the drug, and the adjuvant rule is fixed","note":"Pemetrexed beat gemcitabine in adenocarcinoma (12.6 against 10.9 months) and lost in squamous disease (9.4 against 10.8); LACE pooled 4,584 resected patients for a 5.4 percent five-year gain concentrated in stage II and III.","refs":["paper-scagliotti-cisplatin-pemetrexed-histology-jco-2008","paper-lace-adjuvant-cisplatin-pooled-analysis-jco-2008"]},{"year":2009,"title":"IPASS: the biomarker, not the population","note":"1,217 East Asian never-smokers and light former smokers randomised between gefitinib and chemotherapy; the benefit lived entirely in the EGFR-mutant subgroup, and EGFR testing became standard.","refs":["paper-mok-ipass-gefitinib-pulmonary-adenocarcinoma-nejm-2009","paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004","paper-paez-egfr-mutations-gefitinib-science-2004"]},{"year":2011,"title":"The National Lung Screening Trial proves screening works","note":"53,454 Americans aged 55 to 74 with 30 or more pack-years were randomised to three annual low-dose CT scans or chest radiographs: 20.0 percent fewer lung cancer deaths and 6.7 percent fewer deaths from any cause. It also measured the cost: 24.2 percent of CT screens were positive and 96.4 percent of those positives were false.","refs":["ct","low-dose-ct-screening"]},{"year":2011,"title":"Chest radiography is shown to do nothing","note":"PLCO randomised 154,901 people to four annual chest X-rays or usual care: 1,213 lung cancer deaths against 1,230 after 13 years. It is why low-dose computed tomography had to be proved separately.","refs":["paper-plco-chest-radiograph-lung-cancer-mortality-jama-2011","paper-nlst-nejm-2011"]},{"year":2015,"title":"Nivolumab approved: immunotherapy enters lung cancer","refs":["nivolumab"]},{"year":2017,"title":"Stage III moves, and so does the way tumours are read","note":"PACIFIC put durvalumab after chemoradiotherapy, reaching 42.9 percent five-year survival against 33.4; ALEX moved first-line ALK treatment to a brain-penetrant drug; TRACERx showed copy-number heterogeneity carries a hazard ratio of 4.9 for recurrence or death.","refs":["paper-spigel-pacific-five-year-survival-jco-2022","paper-peters-alex-alectinib-crizotinib-nejm-2017","paper-tracerx-100-nejm-2017","paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017"]},{"year":2019,"title":"England starts the Targeted Lung Health Check programme","note":"Mobile CT scanners parked in supermarket car parks in the areas with the highest lung cancer rates, inviting ever-smokers aged 55 to 74 through their GP records and scanning those a risk model placed above threshold. The first phase invited about 900,000 people and found more than 2,000 cancers, 76 percent of them early stage against 29 percent outside the programme.","refs":["nhs-targeted-lung-health-check","targeted-lung-health-check"]},{"year":2020,"title":"NELSON confirms the mortality benefit in Europe","note":"Volume CT at baseline and years 1, 3 and 5.5 in 13,195 men and 2,594 women aged 50 to 74 in the Netherlands and Belgium: a lung cancer death rate ratio of 0.76 at ten years in men and 0.67 in women, with only 2.1 percent referred for a suspicious nodule, a tenth of the American false-positive burden.","refs":["low-dose-ct-screening"]},{"year":2021,"title":"WHO's fifth edition reclassifies lung tumours","note":"The 2021 WHO Classification of Thoracic Tumours added a chapter on classifying small diagnostic samples, graded invasive non-mucinous adenocarcinoma by growth pattern, recognised spread through air spaces and thoracic SMARCA4-deficient undifferentiated tumour, and moved lymphoepithelial carcinoma into the squamous cell carcinomas.","refs":[]},{"year":2021,"title":"Screening widens, and adjuvant immunotherapy arrives","note":"The United States task force lowered eligibility to age 50 and 20 pack-years, two years after Aldrich showed 31 percent of white smokers qualified against 17 percent of Black smokers; IMpower010 showed adjuvant atezolizumab delays recurrence, mainly in PD-L1-positive stage II to IIIA disease.","refs":["paper-uspstf-lung-cancer-screening-jama-2021","paper-aldrich-uspstf-screening-african-american-smokers-jama-oncol-2019","paper-felip-impower010-adjuvant-atezolizumab-lancet-2021"]},{"year":2022,"title":"The UK National Screening Committee recommends targeted screening","note":"After an evidence review and a health economic model, the committee recommended in June 2022 that all four UK nations move towards targeted lung cancer screening at 55 to 74 with integrated smoking cessation, and named the Targeted Lung Health Check programme as a feasible starting point.","refs":[]},{"year":2023,"title":"England announces a national lung cancer screening programme","note":"Announced on 26 June 2023 at a cost of £270 million a year once fully implemented, expected to deliver almost one million scans and find as many as 9,000 cancers a year, using GP records to identify ever-smokers aged 55 to 74 and a risk model to decide who is scanned every two years.","refs":["nhs-targeted-lung-health-check"]},{"year":2023,"title":"Air pollution gets a mechanism, and first-line treatment is intensified","note":"PM2.5 was shown to promote rather than initiate EGFR-driven lung cancer, with oncogenic EGFR mutations in 18 percent of histologically normal lungs; FLAURA2 and AEGEAN reported, and tarlatamab gave a 40 percent response rate in twice-treated small-cell disease.","refs":["paper-hill-lung-adenocarcinoma-air-pollutants-nature-2023","paper-planchard-flaura2-osimertinib-chemotherapy-nejm-2023","paper-heymach-aegean-perioperative-durvalumab-nejm-2023","paper-dellphi-301-nejm-2023"]},{"year":2024,"title":"Tarlatamab: first targeted drug for small-cell lung cancer","refs":["tarlatamab"]},{"year":2024,"title":"Genotype reaches the operating theatre and stage III","note":"ALINA gave adjuvant alectinib after resection of ALK-positive disease (93.8 against 63.0 percent disease-free at two years), LAURA gave osimertinib after chemoradiotherapy in EGFR-mutant stage III (39.1 against 5.6 months), MARIPOSA beat osimertinib in first line, and ADRIATIC lifted limited-stage small-cell survival from 33.4 to 55.9 months.","refs":["paper-wu-alina-adjuvant-alectinib-nejm-2024","paper-lu-laura-osimertinib-stage-iii-nejm-2024","paper-mariposa-nejm-2024","paper-adriatic-nejm-2024"]},{"year":2025,"title":"TNM 9 comes into force","note":"From 1 January 2025 lung cancer is staged by the ninth edition: the T descriptors unchanged, N2 split into N2a and N2b by the number of mediastinal stations involved, M1c split into M1c1 and M1c2 by the number of organ systems, and the stage groups moved to follow (T1N1 to IIA, T1N2a to IIB, T3N2a to IIIA, T2aN2b and T2bN2b to IIIB).","refs":["tnm-9-lung-cancer","tnm-staging"]},{"year":2026,"title":"Five years of the NHS England programme reported","note":"Over two million people invited and 7,193 lung cancers diagnosed to March 2025, 63.1 percent at stage 1 and 12.6 percent at stage 2, with the early-stage share of all lung cancer in England rising over the five years and rising most in the most deprived regions. Full national coverage is expected in 2030.","refs":["nhs-targeted-lung-health-check"]},{"year":2032,"title":"The perioperative and first-line trials complete","note":"ADRIATIC's study completion is listed for 23 October 2026, IMpower010 for 31 August 2027, FLAURA2 for 30 September 2027, LAURA for 29 October 2027, MARIPOSA for 16 February 2028, DeLLphi-304 for 26 March 2028, AEGEAN for 11 September 2028, CROWN for 31 December 2028 and ALINA for 19 November 2031; TRACERx runs to November 2035.","refs":["lung-cancer-evidence-roadmap","alina","crown","mariposa"]}],"pipeline":["tarlatamab","datopotamab-deruxtecan","idea-lung-screening-eligibility-by-risk-not-pack-years","idea-lung-never-smoker-disease-its-own-programme","idea-lung-resistance-directed-sequencing-at-every-progression","idea-lung-brain-metastasis-prevention-as-a-primary-endpoint","idea-lung-deprivation-gradient-treated-as-a-defect-in-delivery","idea-lung-small-cell-platform-with-shared-controls-and-subtypes","idea-lung-uk-screening-testing-and-access-gaps"],"openProblems":["Most of the world's lung cancer is in countries with no screening. Asia carries 65.6 percent of cases and 64.3 percent of deaths (GLOBOCAN 2024), and of the ten European countries surveyed in 2026 only three had a formal programme. A screening benefit demonstrated in the Netherlands and the United States has to be re-earned in each health system that tries to deliver it.","The risk models that select people for screening cannot see never-smokers. Fifteen percent of UK lung cancers, and 15 to 25 percent worldwide, arise in people who have never smoked, and every eligibility rule in use starts from smoking history. Nothing currently offered would find those cancers early.","Overdiagnosis has never been measured well enough to quote. Estimates across the trials range from 0 to 67 percent (US Preventive Services Task Force evidence report, 2021), which is the widest range for any screened cancer, and the number decides how much of the screening benefit is real.","Deprivation drives both the disease and the outcome. UK lung cancer mortality is 102 percent higher in women and 93 percent higher in men in the most deprived fifth than in the least, around 13,400 UK deaths a year are linked with deprivation, and five-year survival in England is 20.1 percent in the most deprived group against 27.6 percent in the least. Screening programmes sited in deprived areas narrow the first gap and may widen the second if uptake does not follow.","Screening eligibility is written in pack-years, which excludes high-risk groups systematically: 31 percent of white smokers qualified against 17 percent of Black smokers in one United States cohort (Aldrich 2019), so a rule built to find the highest risk misses hardest where the risk is highest.","Resistance arrives within one to three years for every targeted drug and is a heterogeneous set of diagnoses, including transformation into small-cell lung cancer in about one in seven, yet most patients move to the next line without a re-biopsy or a plasma profile to say what the tumour became.","Four perioperative immunotherapy schedules (before surgery, after surgery, on both sides, and with chemotherapy) are all standard somewhere and none has been compared with another, so nobody knows which one to choose or whether the adjuvant half adds anything.","Brain metastases are the dominant failure pattern in driver-positive disease and the newest inhibitors appear to prevent them, but prevention is measured as a secondary endpoint on inconsistent imaging schedules, so the size of the effect is unknown.","Extensive-stage small-cell lung cancer gained two to three months of median survival from immunotherapy and still has no predictive biomarker; the four transcription-factor subtypes that might supply one have never been used prospectively to assign treatment.","At the same stage and in systems free at the point of use, patients in more deprived circumstances are less likely to receive any lung cancer treatment (odds ratio 0.79), less likely to have surgery and less likely to have chemotherapy."],"basics":{"symptoms":["A cough that is not going away, shortness of breath, coughing up blood, chest or shoulder pain, repeated chest infections or one that will not clear, losing weight without trying, loss of appetite, feeling tired all the time (NHS)","Less common: swelling of the face or neck, difficulty swallowing, a hoarse voice that does not go away, finger clubbing where the fingertips look wider or curve downwards (NHS)","Early lung cancer often causes no symptoms at all, which is why screening finds cancers that presentation does not (NHS)","See a GP for a cough lasting longer than 3 weeks or any other symptom; ask for an urgent GP appointment or use NHS 111 if you cough up blood; call 999 or go to A&E if you are struggling to breathe or have pain in the chest or upper back (NHS)","GP referral rules (NICE NG12 1.1.1 to 1.1.3): suspected cancer pathway referral for chest X-ray findings suggesting lung cancer or unexplained haemoptysis at 40 and over; urgent direct access chest X-ray at 40 and over for two or more of cough, fatigue, shortness of breath, chest pain, weight loss and appetite loss, or one of them in anyone who has ever smoked; consider an urgent chest X-ray for persistent or recurrent chest infection, finger clubbing, supraclavicular or persistent cervical lymphadenopathy, chest signs consistent with lung cancer, or thrombocytosis","In England in 2019, about 26 percent of lung cancers were diagnosed after an urgent suspected cancer referral and 33 percent after an emergency presentation (Cancer Research UK)"],"diagnosis":["Chest X-ray first in primary care; contrast-enhanced CT of the chest, liver, adrenals and lower neck before any biopsy (NICE NG122 1.2.2, 1.2.14)","PET-CT for everyone who could have treatment with curative intent (NICE NG122 1.2.4)","Mediastinal nodes sampled through the airway or oesophageal wall by endobronchial ultrasound-guided needle aspiration, endoscopic ultrasound-guided needle aspiration, or both, with surgical staging kept for a negative result and continuing suspicion (NICE NG122 1.2.8, 1.2.20 to 1.2.22)","Brain imaging by stage: none for clinical stage 1 without neurological symptoms, contrast-enhanced CT for stage 2, contrast-enhanced MRI for stage 3 (NICE NG122 1.2.24 to 1.2.26)","The biopsy must be big enough for subtyping and molecular markers; the panel is set by the National Genomics Test Directory (NICE NG122 1.2.11, 1.2.12)"],"staging":["The ninth edition of the TNM classification has been in force since 1 January 2025, built on 124,581 patients diagnosed from 2011 to 2019 (British Journal of Radiology 2025; IASLC staging project)","T descriptors are unchanged from the eighth edition: the T subcommittee tested them against the new database and proposed no change","N changed: N2 is split into N2a, a single ipsilateral mediastinal or subcarinal station, and N2b, multiple ipsilateral mediastinal stations with or without the subcarinal station","M changed at the far end: M1c is split into M1c1, several metastases in one extrathoracic organ system, and M1c2, several metastases across organ systems; both remain stage IVB","Stage groups moved to follow: T1N1 to IIA, T1N2a to IIB, T3N2a to IIIA, T2aN2b and T2bN2b to IIIB","Small-cell lung cancer is also staged by TNM, and the older limited and extensive stage labels are still used alongside it because they decide whether radiotherapy is given to the chest","In England 34 percent of staged cases in 2022 were stage I or II; in the United States 24 percent are localised at diagnosis, 21 percent regional and 51 percent distant (Cancer Research UK; SEER)"],"sources":[]},"prognosis":{"text":"Population averages for the whole family, not a personal prognosis, and they lag the treatments now in use. In the United States 29.5 percent of people diagnosed with lung and bronchus cancer in 2016 to 2022 were alive five years later relative to people of the same age without the disease; by stage that is 65.5 percent for localised disease, which is 24 percent of cases, 38.2 percent for regional (21 percent), 10.5 percent for distant (51 percent) and 17.5 percent for unstaged (4 percent) (SEER). In the UK 11.1 percent of people are predicted to survive ten years or more, against 3.3 percent in the 1970s, and 18.1 percent of people diagnosed in England survive five years, rising to 43.5 percent among those who have already survived a year. Survival is higher in women than men and falls steeply with age, from 32.7 percent of women and 22.2 percent of men diagnosed at 15 to 44 to 9.2 percent of women and 5.2 percent of men diagnosed at 75 to 99, and it tracks deprivation: 20.1 percent at five years in the most deprived group in England against 27.6 percent in the least (Cancer Research UK). The averages differ sharply by type, which is why each type page carries its own.","sources":[{"label":"SEER Cancer Stat Facts: lung and bronchus cancer (rates, stage distribution, survival by stage, age and race)","url":"https://seer.cancer.gov/statfacts/html/lungb.html"},{"label":"CRUK: lung cancer survival statistics (by age, deprivation and over time)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/survival"}]}},{"id":"lung-net","kind":"cancer","name":"Lung neuroendocrine tumours (typical and atypical carcinoid)","aka":["Bronchial carcinoid","Pulmonary carcinoid","Typical carcinoid","Atypical carcinoid","Lung NET","Bronchopulmonary neuroendocrine tumour"],"tldr":"Lung neuroendocrine tumours, called typical and atypical carcinoids, are slow-growing tumours of the airways that are usually cured by surgery. When they spread, everolimus is the one drug tested in a randomised trial for this site, cabozantinib was approved in 2025, and somatostatin analogues and lutetium radioligand therapy are borrowed from gut tumours.","summary":"Lung neuroendocrine tumours are graded differently from their gut counterparts: the WHO lung classification separates typical carcinoid (fewer than two mitoses per two square millimetres and no necrosis) from atypical carcinoid (two to ten mitoses or foci of necrosis), with Ki-67 used to support the count rather than define it, and places both alongside small-cell and large-cell neuroendocrine carcinoma in a single neuroendocrine group. Most typical carcinoids sit centrally in a main or lobar bronchus and present with cough, wheeze, haemoptysis or recurrent pneumonia behind an obstructed airway; peripheral tumours are found incidentally. A few produce ectopic ACTH and Cushing's syndrome, carcinoid syndrome is uncommon without liver metastases, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is a rare precursor that seeds multiple tumourlets. About a twentieth arise in patients with MEN1.\n\nSurgery is the treatment for localised disease and usually the cure: lobectomy or a parenchyma-sparing sleeve resection with systematic nodal dissection, with endobronchial resection reserved for patients who cannot tolerate an operation. Adjuvant therapy has no proven benefit and follow-up is prolonged because atypical carcinoids can recur years later. For advanced disease the evidence is thin. RADIANT-4 (Lancet 2016) is the only randomised trial to include lung tumours in numbers: 302 patients with non-functional lung or gastrointestinal neuroendocrine tumours were randomised to everolimus or placebo and progression-free survival lengthened from 3.9 to 11.0 months, and the FDA approved everolimus for lung neuroendocrine tumours in 2016. The phase 2 LUNA trial (2017) tested pasireotide, everolimus and the combination in lung and thymic tumours and found each active, without a randomised comparison against placebo.\n\nThe rest of the sequence is borrowed. Somatostatin analogues are used for somatostatin receptor-positive tumours on the strength of gut trials and the small SPINET study of lanreotide, and lutetium-177 dotatate is given off-label to receptor-positive lung tumours on series data, since NETTER-1 and NETTER-2 enrolled only gastroenteropancreatic disease. CABINET (New England Journal of Medicine 2024) included lung and thymic tumours in its extra-pancreatic cohort, where cabozantinib lengthened progression-free survival from 3.9 to 8.4 months, and a subgroup analysis presented in 2025 showed a large reduction in progression risk in the lung and thymic tumours; cabozantinib's 2025 approval covers them. Temozolomide-based chemotherapy is used for atypical carcinoids that need shrinkage, and platinum-etoposide is reserved for tumours behaving like carcinoma.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor","links":[{"label":"RADIANT-4 (Lancet 2016)","url":"https://doi.org/10.1016/S0140-6736(15)00817-X"},{"label":"CABINET (NEJM 2024)","url":"https://doi.org/10.1056/NEJMoa2403991"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor"},{"label":"Nicholson, J Thorac Oncol 2022: the 2021 WHO classification of lung tumours, impact of advances since 2015","url":"https://doi.org/10.1016/j.jtho.2021.11.003"}],"tags":["subtype-page","endocrine","lung"],"related":["extrapulmonary-nec","grade-3-net","pancreatic-net","small-intestinal-net"],"cancers":["lung-cancer"],"sections":[],"technologies":["sstr-pet","prrt","bronchoscopy","ct"],"targets":["sstr2","mtor"],"drugs":["everolimus","cabozantinib","octreotide-lanreotide","lutathera","ga68-dotatate","pasireotide"],"companies":[],"institutions":[],"pathways":[],"terms":["lobectomy","net-grade-ki67","carcinoid-syndrome","chromogranin-a","tnm-9-lung-cancer","ttf1-p40"],"trials":["radiant-3-4","cabinet","nct03972488","spinet"],"people":[],"bottlenecks":[],"keyPapers":["paper-radiant-4-everolimus-lancet-2016","paper-cabinet-cabozantinib-nejm-2024","paper-enets-lung-net-consensus-caplin-ann-oncol-2015"],"journals":[],"dependsOn":[],"notes":["Where carcinoid sits in the lung family. The 2021 WHO classification of thoracic tumours puts typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma in one neuroendocrine chapter, so the neuroendocrine spectrum crosses the clinical small-cell and non-small-cell split that organises the rest of the lung family. This corpus keeps the carcinoids under the neuroendocrine family page, where the somatostatin-analogue and peptide receptor radionuclide pages sit beside them, and keeps small cell carcinoma and large cell neuroendocrine carcinoma under lung cancer; all three are cross-linked. The reasoning is set out in the taxonomy section of docs/CANCER-PAGES.md."],"group":"lung","burden":"A small minority of lung cancers, occurring in younger patients and non-smokers more often than other lung cancers; typical carcinoids are usually cured by surgery, atypical carcinoids recur more often.","subtypes":["Typical carcinoid of the central bronchus (low mitotic count, no necrosis)","Atypical carcinoid (two to ten mitoses or necrosis, higher recurrence)","Peripheral lung neuroendocrine tumour (incidental, sometimes multiple)","Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) with tumourlets","Lung carcinoid with ectopic ACTH and Cushing's syndrome","MEN1-associated lung neuroendocrine tumour","Thymic neuroendocrine tumour (grouped with lung in trials)"],"biomarkers":["Mitotic count and necrosis (WHO typical versus atypical)","Ki-67 index (supportive, not definitional in the lung)","Somatostatin receptor PET (staging and somatostatin analogue or radioligand eligibility)","Chromogranin A (monitoring)","ACTH and cortisol where Cushing's syndrome is suspected","Germline MEN1 in young or multiple tumours"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Bronchoscopy with biopsy for central tumours, CT of the chest and abdomen, somatostatin receptor PET, and pathology graded by mitotic count and necrosis.","refs":["bronchoscopy","ct","sstr-pet","ga68-dotatate","net-grade-ki67"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Localised disease","approach":"Lobectomy or sleeve resection with systematic nodal dissection; endobronchial resection for patients unfit for surgery; no adjuvant therapy.","refs":["lobectomy","robotic-surgery"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Advanced, somatostatin receptor-positive, slow tempo","approach":"Octreotide or lanreotide, by extrapolation from gut trials and the SPINET study.","refs":["octreotide-lanreotide","clarinet"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Advanced, progressive","approach":"Everolimus (RADIANT-4); cabozantinib (CABINET); lutetium-177 dotatate off-label for receptor-positive tumours; temozolomide-based chemotherapy for atypical carcinoids needing shrinkage.","refs":["everolimus","radiant-3-4","cabozantinib","cabinet","lutathera","prrt","capecitabine-temozolomide"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Hormone syndromes","approach":"Somatostatin analogues for carcinoid syndrome; steroidogenesis inhibitors or resection for ectopic ACTH.","refs":["octreotide-lanreotide","carcinoid-syndrome"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}}],"stateOfArt":["Surgery cures most typical carcinoids, and parenchyma-sparing sleeve resection preserves lung function.","Everolimus is the only drug with randomised evidence specific to lung neuroendocrine tumours, and cabozantinib joined it in 2025 through the CABINET extra-pancreatic cohort.","The lung classification by mitotic count and necrosis, rather than Ki-67, still governs treatment, and the two systems are being reconciled."],"history":[{"year":1972,"title":"Arrigoni defines atypical carcinoid as a separate entity","refs":[]},{"year":2015,"title":"WHO lung classification groups carcinoids with small-cell and large-cell neuroendocrine carcinoma as neuroendocrine tumours","refs":["net-grade-ki67"]},{"year":2016,"title":"RADIANT-4: everolimus approved for lung neuroendocrine tumours","refs":["radiant-3-4","everolimus"]},{"year":2017,"title":"LUNA: pasireotide and everolimus active in lung and thymic tumours","refs":[]},{"year":2024,"title":"CABINET published with lung and thymic tumours in the extra-pancreatic cohort","refs":["cabinet"]},{"year":2025,"title":"Cabozantinib approved for previously treated neuroendocrine tumours including lung; ESMO subgroup analysis","refs":["cabozantinib","cabinet"]}],"pipeline":["cabinet","nct06943755","prrt","sstr-pet"],"openProblems":["No randomised trial has tested somatostatin analogues or radioligand therapy specifically in lung neuroendocrine tumours.","Lung and gastroenteropancreatic grading systems disagree, so trial eligibility and guideline advice do not map cleanly.","Atypical carcinoids relapse late and there is no proven adjuvant therapy."],"parent":"neuroendocrine"},{"id":"lymphoepithelial-carcinoma-lung","kind":"cancer","name":"Lymphoepithelial carcinoma of the lung","aka":["Lymphoepithelioma-like carcinoma of the lung","Pulmonary lymphoepithelioma-like carcinoma","LELC of the lung","EBV-associated lung carcinoma"],"tldr":"Lymphoepithelial carcinoma of the lung is a rare lung cancer, seen mostly in East Asian non-smokers, in which cancer cells sit in a dense crowd of immune cells and usually carry the Epstein-Barr virus, like nasopharyngeal cancer. It is treated as a squamous lung cancer, and its high PD-L1 levels have made immunotherapy a natural choice.","summary":"The 2021 WHO classification moved lymphoepithelial carcinoma from the large cell group into squamous cell carcinoma, on the strength of its squamous immunophenotype (Nicholson 2022). Histologically it is a poorly differentiated carcinoma with a heavy lymphocytic infiltrate, and in East Asian patients it is nearly always associated with Epstein-Barr virus. In 66 patients from Taiwan, PD-L1 was overexpressed in 75.8 percent of tumours and EGFR mutation found in 12.1 percent, with no KRAS, BRAF, ALK or ROS1 alterations (Chang 2015). Targeted sequencing of 27 Chinese cases found no classic lung driver apart from one ERBB2 amplification and one KRAS mutation, but mutations in epigenetic regulators in 78 percent (Modern Pathology 2020).\n\nHow it differs from its parent: it lacks the smoking-related mutational burden of ordinary squamous cell carcinoma, is virus-associated, and has a better reported prognosis in the series above; its biology is closer to nasopharyngeal carcinoma, which the corpus covers.\n\nHow common: no incidence figure is published.\n\nTreatment: as squamous cell carcinoma of the lung by stage, with platinum chemotherapy and, given the PD-L1 findings, checkpoint inhibitors in advanced disease; the sources read are pathology series rather than treatment trials, and no trial has been run in the entity itself, so it is treated as squamous cell carcinoma of the lung by stage.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Lymphoepithelioma-like_carcinoma","links":[{"label":"Nicholson 2022, JTO: the 2021 WHO classification of lung tumours","url":"https://doi.org/10.1016/j.jtho.2021.11.003"},{"label":"Chang 2015, Lung Cancer: PD-L1 is highly expressed in 66 lung lymphoepithelioma-like carcinomas","url":"https://doi.org/10.1016/j.lungcan.2015.03.017"},{"label":"Modern Pathology 2020: genomic profiles and PD-L1 expression of 29 primary lymphoepithelioma-like carcinomas of the lung","url":"https://doi.org/10.1038/s41379-019-0391-9"}],"tags":["subtype-page","wave4","lung"],"related":["nsclc","lung-squamous-cell-carcinoma","basaloid-squamous-cell-carcinoma-lung","nasopharyngeal"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"Rare and concentrated in East Asia: the largest series in the sources read hold 66 patients (Chang 2015) and 29 patients (Modern Pathology 2020), both from China or Taiwan. No registry share exists.","subtypes":["EBV-positive lymphoepithelial carcinoma of the lung (the usual form in East Asia)","EBV-negative lymphoepithelial carcinoma of the lung"],"biomarkers":["EBV-encoded RNA in situ hybridisation","PD-L1 (overexpressed in about three quarters)","p40 positive, TTF-1 negative","Epigenetic regulator mutations (research)"],"standardOfCare":[{"setting":"All stages","approach":"Treated as squamous cell carcinoma of the lung; checkpoint inhibitors in advanced disease on the PD-L1 findings, without a dedicated trial.","refs":["lung-squamous-cell-carcinoma","pembrolizumab"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"nsclc"},{"id":"lymphomatoid-granulomatosis","kind":"cancer","name":"Lymphomatoid granulomatosis","aka":["LYG","EBV-positive B-cell lymphoproliferative disorder of the lung","Angiocentric immunoproliferative lesion"],"tldr":"Lymphomatoid granulomatosis is a rare Epstein-Barr virus-driven disease of B cells that invades and destroys blood vessels, almost always in the lungs and often the brain and skin, in people whose immune control of the virus is weak. Low-grade disease can be treated with interferon and high-grade disease as a large B-cell lymphoma with rituximab-based chemotherapy.","summary":"WHO-HAEM5 lists lymphomatoid granulomatosis among the EBV-positive B-cell lymphoproliferative disorders, graded 1 to 3 by the number of large EBV-positive B cells, with grade 3 overlapping large B-cell lymphoma (Alaggio 2022; Katzenstein 2010). It affects mainly middle-aged adults, men almost twice as often as women, with multiple bilateral lung nodules and extrapulmonary involvement of skin and nervous system in more than a third; mortality has been high and treatment was not well established (Katzenstein 2010). In the National Cancer Institute series of 55 patients, all had lung involvement, 38 percent central nervous system involvement, none nodal or marrow disease, and all had past EBV exposure with a low median viral load; the lesions were angiocentric and rich in T cells with variable EBV-positive B cells (Song 2015).\n\nHow it differs from its parent: it is a spectrum from a virus-driven immunodeficiency disorder to a lymphoma, defined by grade; it spares nodes and marrow; and its low-grade forms are treated by restoring immune control (interferon alfa) rather than by chemotherapy.\n\nHow common: no registry figure in the sources read.\n\nTreatment: on the National Cancer Institute approach, interferon alfa for grade 1 and 2 disease and rituximab-based chemotherapy (such as dose-adjusted EPOCH-R) for grade 3, with withdrawal of iatrogenic immunosuppression where present; relapse can move between grades (Song 2015 for the series behind the approach).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Lymphomatoid_granulomatosis","links":[{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq"},{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"Katzenstein 2010, Am J Surg Pathol: lymphomatoid granulomatosis, insights over four decades","url":"https://doi.org/10.1097/pas.0b013e3181fd8781"},{"label":"Song 2015, Am J Surg Pathol: lymphomatoid granulomatosis, the National Cancer Institute series of 55 patients","url":"https://doi.org/10.1097/pas.0000000000000328"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["non-hodgkin-lymphoma","dlbcl","intravascular-large-b-cell-lymphoma","post-transplant-lymphoproliferative-disorder","hiv-associated-lymphoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["interferon-alfa","rituximab","cyclophosphamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare: the National Cancer Institute reviewed 55 patients referred over 1995 to 2010, median age 46, men 2.2 times as often as women (Song 2015). No registry figure exists.","subtypes":["Lymphomatoid granulomatosis, grade 1 and 2 (few EBV-positive large B cells; interferon)","Lymphomatoid granulomatosis, grade 3 (overlaps EBV-positive large B-cell lymphoma; chemotherapy)","Lymphomatoid granulomatosis with central nervous system involvement (38 percent)"],"biomarkers":["EBV-encoded RNA in situ hybridisation in large B cells","Grade by number of EBV-positive B cells","Lung and brain imaging","Underlying immunodeficiency (iatrogenic, HIV, primary)"],"standardOfCare":[{"setting":"Grade 1 and 2","approach":"Interferon alfa, with withdrawal of iatrogenic immunosuppression.","refs":["interferon-alfa","non-hodgkin-lymphoma"]},{"setting":"Grade 3","approach":"Rituximab-based chemotherapy as for large B-cell lymphoma.","refs":["rituximab","cyclophosphamide","dlbcl"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"non-hodgkin-lymphoma"},{"id":"lymphomatoid-papulosis","kind":"cancer","name":"Lymphomatoid papulosis","aka":["LyP","Primary cutaneous CD30-positive T-cell lymphoproliferative disorder: lymphomatoid papulosis","Lymphomatoid papulosis type A","Mucha-Habermann disease"],"tldr":"A skin condition that keeps producing crops of small red bumps which ulcerate, crust and heal on their own over a few weeks, leaving small scars, and then come back. The biopsy looks like an aggressive lymphoma and the disease behaves nothing like one: nobody in the published series has died of it, but it carries a raised risk of a second lymphoma.","summary":"What it is. A chronic, relapsing condition of the skin in which crops of papules and small nodules appear, sometimes dozens at a time, go through a cycle of ulceration and crusting over three to twelve weeks, and heal on their own, often leaving a small scar. New crops follow. It can go on for years or decades, and it can stop.\n\nThe gap between the biopsy and the person. Under the microscope the lesions contain large, atypical CD30-positive cells that look like those of an aggressive lymphoma, and a pathologist who is given the slide without the history can reasonably report anaplastic large cell lymphoma. The diagnosis is made by putting the two together: lesions that come and go in crops and heal spontaneously, with that biopsy, are lymphomatoid papulosis. This is the clearest example in the lymphoma family of a diagnosis that cannot be made on the biopsy alone, and WHO-HAEM5 says as much of the skin lymphomas generally, that dermatological examination and clinical photographs are indispensable.\n\nWhere it sits in the classification. WHO-HAEM5 lists it among the primary cutaneous T-cell lymphomas as one of the two primary cutaneous CD30-positive T-cell lymphoproliferative disorders, the other being primary cutaneous anaplastic large cell lymphoma. The two are ends of one spectrum: the same person may have both, and the same T-cell clone can be found in both. Several histological types of lymphomatoid papulosis are described, named by letters, and they do not change the treatment or the outlook.\n\nThe risk that justifies follow-up. People with lymphomatoid papulosis have a raised risk of developing a second lymphoma, most often mycosis fungoides, primary cutaneous anaplastic large cell lymphoma or Hodgkin lymphoma, which may come before, with or after the skin lesions. That is the reason for continuing dermatological follow-up in a condition that is otherwise harmless, and it is the reason a new lump that behaves differently from the usual crops is biopsied.\n\nHow it is treated, which is often not at all. No treatment has been shown to prevent the second lymphoma or to change the course, so the aim is to control the lesions that bother the person. Observation with emollients and reassurance is a legitimate plan for somebody with a few lesions. Low-dose weekly methotrexate, phototherapy and potent topical steroids are used where the crops are frequent, numerous or scarring. Treatment suppresses the lesions and they return when it stops. Combination chemotherapy has no place.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Lymphomatoid_papulosis","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"EORTC, ISCL and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma (Kempf, Blood 2011)","url":"https://doi.org/10.1182/blood-2011-05-351346"},{"label":"CD30-positive cutaneous lymphoproliferative disorders: the Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma, 56 patients (Liu, J Am Acad Dermatol 2003)","url":"https://doi.org/10.1016/S0190-9622(03)02484-8"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"}],"tags":["heme","lymphoma","subtype-page"],"related":["primary-cutaneous-anaplastic-large-cell-lymphoma","cutaneous-t-cell-lymphoma","mycosis-fungoides","hodgkin-lymphoma","sezary-syndrome"],"cancers":[],"sections":[],"technologies":["histopathology-ihc"],"targets":["cd30"],"drugs":["methotrexate"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-classification-2022","lymphoma-tx-skin-directed-therapy","lymphoma-indolent-versus-aggressive","lymphoma-nodal-versus-extranodal"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"In the United Kingdom population series that reports lymphoma by subtype, the primary cutaneous CD30-positive lymphoproliferative disorders, which group this condition with primary cutaneous anaplastic large cell lymphoma, accounted for 37 of 5,796 lymphomas, a European age-standardised rate of 0.13 per 100,000 a year, a median age at diagnosis of 52.9 years and five-year relative survival of 88.3 per cent. In the Stanford series of 56 patients with CD30-positive skin disease, no patient with lymphomatoid papulosis died of the disease and overall survival was 92 per cent at five and ten years.","subtypes":["Type A, the commonest, with scattered large CD30-positive cells in a mixed inflammatory background","Type B, which resembles mycosis fungoides down the microscope","Type C, which resembles anaplastic large cell lymphoma","Other described types, which do not change the treatment or the outlook"],"biomarkers":["CD30-positive large atypical cells on the biopsy, which on their own would suggest an aggressive lymphoma","The clinical course, which is the diagnosis: crops of lesions that ulcerate and heal on their own over weeks","A clonal T-cell receptor rearrangement in many cases, which does not make it a cancer in the way it would elsewhere","Absence of ALK","Continuing surveillance for a second lymphoma, most often mycosis fungoides, primary cutaneous anaplastic large cell lymphoma or Hodgkin lymphoma"],"standardOfCare":[{"setting":"Making the diagnosis, which needs the history as much as the biopsy","approach":"The biopsy shows large atypical CD30-positive cells that on their own would suggest an aggressive lymphoma. What makes the diagnosis is the course: crops of papules that ulcerate, crust and heal on their own over three to twelve weeks, often leaving small scars, recurring over years. Photographs and a dated history are part of the diagnostic record, not an extra. Staging confirms there is no disease outside the skin.","refs":["histopathology-ihc","cd30","lymphoma-tx-skin-directed-therapy","fdg-pet"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Treatment, which is often none","approach":"No treatment has been shown to change the course or to reduce the risk of a second lymphoma, so treatment is for the lesions that bother the person. Observation with emollients and an explanation is a legitimate plan for somebody with a few lesions, and in the published series nobody has died of this condition. Where crops are frequent, numerous or scarring, low-dose weekly methotrexate, phototherapy or potent topical steroids suppress them, and the lesions return when treatment stops. Combination chemotherapy has no place.","refs":["methotrexate","lymphoma-tx-skin-directed-therapy","lymphoma-tx-watch-and-wait"],"guideline":{"version":"EORTC, ISCL and USCLC consensus recommendations for primary cutaneous CD30-positive lymphoproliferative disorders (Blood 2011)","url":"https://doi.org/10.1182/blood-2011-05-351346"}},{"setting":"Why follow-up continues in a condition that does not shorten life","approach":"People with lymphomatoid papulosis have a raised risk of a second lymphoma, most often mycosis fungoides, primary cutaneous anaplastic large cell lymphoma or Hodgkin lymphoma, which may come before, alongside or after the skin lesions. Continuing dermatological review, and biopsy of any lump that behaves differently from the usual crops, is the reason for follow-up. Nothing prevents the second lymphoma, so the aim is to find it early.","refs":["mycosis-fungoides","primary-cutaneous-anaplastic-large-cell-lymphoma","hodgkin-lymphoma","histopathology-ihc"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":1968,"title":"Named","note":"Macaulay described a self-healing eruption whose biopsy looked malignant and whose course did not, and called it lymphomatoid papulosis.","refs":[]},{"year":2003,"title":"No deaths from the disease in a single-centre series","note":"In the Stanford series of CD30-positive skin lymphoproliferative disorders, no patient with lymphomatoid papulosis died of the disease, and overall survival was 92 per cent at five and ten years.","refs":[]},{"year":2011,"title":"International consensus recommendations","note":"The EORTC, International Society for Cutaneous Lymphomas and United States Cutaneous Lymphoma Consortium panel set out definitions, endpoints and treatment recommendations, and recorded that the level of evidence for most treatments is low.","refs":[]}],"pipeline":[],"openProblems":["No treatment has been shown to reduce the risk of a second lymphoma, so treatment is for symptoms only and over-treatment is a real harm in a condition that does not shorten life.","There is no way to predict which patient will develop a second lymphoma, so everybody is followed up indefinitely.","The consensus recommendations state that the evidence behind nearly every treatment is retrospective and small."],"parent":"cutaneous-t-cell-lymphoma"},{"id":"lynch-associated-colorectal-cancer","kind":"cancer","name":"Lynch syndrome-associated colorectal cancer","aka":["Lynch syndrome-associated colorectal cancer (inherited mismatch repair variant; about 1 to 4 percent of colon cancers)","Lynch syndrome (hereditary dMMR, ~3%)","Hereditary non-polyposis colorectal cancer","HNPCC","Lynch syndrome bowel cancer","Mismatch repair germline colorectal cancer"],"tldr":"Lynch syndrome-associated bowel cancer is bowel cancer in someone born with a fault in one of the genes that proofread DNA copying errors. The tumours tend to arise younger and on the right side, they carry the mismatch repair defect that makes immunotherapy work, and the diagnosis changes the care of the whole family as well as the care of the patient.","summary":"What it is. Lynch syndrome is an inherited condition caused by a germline variant in one of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2, or by a deletion in EPCAM that silences MSH2. The proofreading system that corrects copying errors in repetitive DNA fails, the tumour accumulates insertions and deletions at those repeats, and the result is a mismatch repair-deficient, microsatellite-unstable cancer. The World Health Organization lists it among the genetic tumour syndromes of the digestive system, and it is the commonest inherited cause of bowel cancer (Nagtegaal 2020).\n\nHow it differs from its parent. Two things distinguish it from mismatch repair-deficient bowel cancer in general. The defect is inherited rather than acquired, so relatives are at risk and cascade testing follows the diagnosis; and the cancers behave differently by gene. In the Prospective Lynch Syndrome Database, 1,942 carriers without previous cancer were followed for 13,782 observation years under colonoscopic surveillance: cancers appeared from age 25 in MLH1 and MSH2 carriers but only from about 40 in MSH6 and PMS2 carriers, and the cumulative incidence of colorectal cancer by age 70 was 46 percent for MLH1, 35 percent for MSH2, 20 percent for MSH6 and 10 percent for PMS2. Endometrial cancer reached 34, 51, 49 and 24 percent by the same age. Colorectal cancer occurred despite surveillance but killed few people: ten-year crude survival was 91 percent when the first cancer was colorectal (Moller 2017). Sporadic mismatch repair-deficient cancers, by contrast, usually arise through methylation of the MLH1 promoter in older people through the serrated pathway, and have no implication for relatives.\n\nHow common it is. Modelling of 5,744 families put the population prevalence of a mismatch repair variant at 1 in 279 (Win 2017); Cancer Research UK records that hereditary non-polyposis colorectal cancer accounts for 1 to 4 percent of colon cancers, and that around 9 in 10 men and 7 in 10 women with it develop bowel cancer by age 70.\n\nHow it is treated. The cancer itself is treated as colorectal cancer of the same stage and molecular profile, which in practice means the mismatch repair-deficient pathways: checkpoint inhibitors in metastatic disease, and the neoadjuvant and adjuvant immunotherapy strategies the parent record carries. What is specific to Lynch syndrome is everything around the tumour. NICE NG151 (1.1.1) says to consider daily aspirin for more than two years to reduce colorectal cancer risk, on the strength of CAPP2, in which 600 mg daily cut colorectal cancer over ten years (hazard ratio 0.65 by intention to treat, 0.56 in those who completed two years) (Burn 2020). Colonoscopic surveillance, the extent of surgery when a cancer is found, gynaecological risk-reducing surgery and cascade testing of relatives follow the British Society of Gastroenterology, ACPGBI and UK Cancer Genetics Group guidelines (Monahan 2020).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Lynch_syndrome","links":[{"label":"Win, Cancer Epidemiol Biomarkers Prev 2017: prevalence and penetrance of major genes and polygenes for colorectal cancer (5,744 families)","url":"https://doi.org/10.1158/1055-9965.epi-16-0693"},{"label":"Moller, Gut 2017: cancer incidence and survival in Lynch syndrome under surveillance, the Prospective Lynch Syndrome Database (1,942 carriers)","url":"https://doi.org/10.1136/gutjnl-2015-309675"},{"label":"Burn, Lancet 2020: CAPP2, cancer prevention with aspirin in Lynch syndrome, 10-year follow-up (861 patients randomised)","url":"https://doi.org/10.1016/s0140-6736(20)30366-4"},{"label":"Monahan, Gut 2020: BSG, ACPGBI and UKCGG guidelines for the management of hereditary colorectal cancer","url":"https://doi.org/10.1136/gutjnl-2019-319915"},{"label":"NICE NG151: colorectal cancer, recommendations (Lynch 1.1, local disease 1.3, biomarkers 1.4, metastatic disease 1.5, ongoing care and support including follow-up 1.6)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"},{"label":"CRUK: bowel cancer risk factors (professional)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer/risk-factors"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"}],"tags":["gi","colorectal","subtype-page"],"related":["colorectal","msi-high-colorectal","fap-associated-colorectal-cancer","early-onset-colorectal","endometrial","colon-cancer","rectal-cancer"],"cancers":[],"sections":[],"technologies":["msi-mmr-testing","germline-testing","histopathology-ihc","aspirin-cancer-prevention","chemoprevention"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["lynch-syndrome","msi","mlh1-promoter-methylation","germline-vs-somatic","colonoscopy-surveillance-intervals","serrated-pathway"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 1 in 279 people carry a mismatch repair variant (MLH1 1 in 1,946, MSH2 1 in 2,841, MSH6 1 in 758, PMS2 1 in 714), and hereditary non-polyposis colorectal cancer accounts for 1 to 4 percent of colon cancers (Win 2017; Cancer Research UK).","subtypes":["MLH1-associated Lynch syndrome (colorectal cancer in 46 percent by age 70)","MSH2-associated Lynch syndrome, including EPCAM deletions (colorectal cancer in 35 percent by age 70)","MSH6-associated Lynch syndrome (colorectal cancer in 20 percent by age 70; later onset)","PMS2-associated Lynch syndrome (colorectal cancer in 10 percent by age 70; later onset)","Constitutional mismatch repair deficiency (biallelic variants; childhood tumours)"],"biomarkers":["Mismatch repair protein loss on immunohistochemistry, or microsatellite instability, on every colorectal cancer at diagnosis","MLH1 promoter methylation and BRAF V600E testing to separate sporadic from inherited mismatch repair loss","Germline testing of MLH1, MSH2, MSH6, PMS2 and EPCAM to confirm the diagnosis and to test relatives"],"standardOfCare":[{"setting":"Finding the syndrome","approach":"Mismatch repair immunohistochemistry or microsatellite instability testing on every colorectal cancer; MLH1 promoter methylation testing where MLH1 is lost, because most of those cancers are sporadic; germline testing when methylation is absent, then cascade testing of relatives.","refs":["msi-mmr-testing","histopathology-ihc","germline-testing","lynch-syndrome","mlh1-promoter-methylation"],"guideline":{"version":"NICE NG151: colorectal cancer (published January 2020, last updated December 2021, last reviewed April 2026)","url":"https://www.nice.org.uk/guidance/ng151"}},{"setting":"Risk reduction in carriers","approach":"Consider daily aspirin for more than two years (NICE NG151 1.1.1, from CAPP2); colonoscopic surveillance at intervals set by gene and age; discussion of the extent of colectomy when a cancer is found; gynaecological risk-reducing surgery after childbearing for women.","refs":["aspirin-cancer-prevention","colonoscopy","colonoscopy-surveillance-intervals","colectomy","chemoprevention"],"guideline":{"version":"NICE NG151: colorectal cancer (published January 2020, last updated December 2021, last reviewed April 2026)","url":"https://www.nice.org.uk/guidance/ng151"}}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"colorectal"},{"id":"male-breast-cancer","kind":"cancer","name":"Male breast cancer","aka":["Breast cancer in men"],"tldr":"Men get breast cancer too, usually a hormone-sensitive kind found as a lump near the nipple. It is treated much as in women, with surgery, radiotherapy and tamoxifen, and inherited BRCA2 mutations are found often enough that every man diagnosed is offered genetic testing. The main fix under way is including men in trials so their care stops being borrowed from women.","summary":"Male breast cancer is almost always invasive ductal carcinoma, oestrogen-receptor positive (in the large majority) and HER2-negative; lobular carcinoma is rare because men lack terminal lobules, and triple-negative disease is uncommon. Germline BRCA2 mutations are the strongest hereditary factor (BRCA1 less so), and testing is recommended for every man with breast cancer regardless of age or family history; other risks are Klinefelter syndrome, oestrogen exposure, radiation, obesity and liver disease. Men present later and with higher stage than women because there is no screening and awareness is low, and the tumour sits close to the skin and nipple.\n\nTreatment follows the female algorithm with adjustments. Mastectomy is usual because of tumour position, though breast-conserving surgery is feasible in some; sentinel node biopsy, radiotherapy and chemotherapy indications mirror women's. Endocrine therapy differs: tamoxifen is the preferred adjuvant agent, because aromatase inhibitors used alone in men raise testosterone and oestradiol through feedback and appear less effective, so if used they should be combined with a GnRH agonist. CDK4/6 inhibitors, HER2-directed therapy and PARP inhibitors for germline BRCA carriers are used in men on the basis of extrapolation and small cohorts. The EORTC 10085 / International Male Breast Cancer Program (Ann Oncol 2018) was the largest characterisation effort, and the FDA's 2020 guidance 'Male Breast Cancer: Developing Drugs for Treatment' instructs sponsors to include men in breast cancer trials rather than excluding them by default.\n\nOpen problems are adjuvant endocrine adherence and side effects in men, the biology of male-specific ER-positive disease, and the paucity of prospective data.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Male_breast_cancer","links":[{"label":"NCI PDQ: male breast cancer","url":"https://www.cancer.gov/types/breast/male-breast-cancer"},{"label":"ASCO guideline: management of male breast cancer (JCO 2020)","url":"https://doi.org/10.1200/JCO.19.03120"},{"label":"FDA guidance: Male Breast Cancer, Developing Drugs for Treatment (2020)","url":"https://www.fda.gov/regulatory-information/search-fda-guidance-documents/male-breast-cancer-developing-drugs-treatment"},{"label":"International Male Breast Cancer Program (Ann Oncol 2018)","url":"https://doi.org/10.1093/annonc/mdx651"}],"tags":["nci-coverage","rare","breast"],"related":["breast-hr-positive","breast-her2-positive","tnbc","ductal-carcinoma-in-situ"],"cancers":[],"sections":[],"technologies":["endocrine-therapy","germline-testing","sentinel-node","parp-inhibitor","cdk46-inhibitor","mammography"],"targets":["estrogen-receptor","her2","brca","cdk4-6","parp"],"drugs":["tamoxifen","letrozole","fulvestrant","goserelin","palbociclib","ribociclib","abemaciclib","olaparib","talazoparib","trastuzumab"],"companies":[],"institutions":[],"pathways":["er-signaling","homologous-recombination-repair"],"terms":["hormone-receptor-status","mastectomy","gbrca-mutation","hereditary-cancer-syndromes"],"trials":["olympia","nct04842617"],"people":[],"bottlenecks":["b-trial-diversity","b-hereditary-risk","b-rare-cancers"],"keyPapers":["paper-cardoso-ann-oncol","paper-hassett-j-clin-oncol"],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"About one in a hundred breast cancers occurs in a man; the lifetime risk is roughly one in a thousand men, higher with a BRCA2 mutation, Klinefelter syndrome or a strong family history (SEER; NCI).","subtypes":["Invasive ductal carcinoma, ER-positive / HER2-negative (most)","HER2-positive (minority)","Triple-negative (rare)","Ductal carcinoma in situ (often papillary)","Hereditary (BRCA2, BRCA1, PALB2, CHEK2)"],"biomarkers":["ER, PR, HER2 (as in women)","Germline BRCA1/2 and multigene panel (recommended for all men with breast cancer)","Ki-67 and genomic assays (Oncotype DX validated mainly in women)","Nodal status","Testosterone and oestradiol if aromatase inhibitors are considered"],"standardOfCare":[{"setting":"Early stage","approach":"Mastectomy (or breast conservation where feasible) with sentinel node biopsy; adjuvant radiotherapy by the same criteria as women; chemotherapy and HER2-directed therapy as indicated.","refs":["mastectomy","sentinel-node","trastuzumab"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Breast Cancer (special considerations for men); ASCO guideline on management of male breast cancer 2020","url":"https://doi.org/10.1200/JCO.19.03120"}},{"setting":"Adjuvant endocrine, ER-positive","approach":"Tamoxifen for five to ten years; aromatase inhibitor only with GnRH agonist suppression if tamoxifen is contraindicated.","refs":["tamoxifen","goserelin","letrozole"],"guideline":{"version":"ASCO 2020 male breast cancer guideline","url":"https://doi.org/10.1200/JCO.19.03120"}},{"setting":"Advanced, ER-positive","approach":"Endocrine therapy (tamoxifen, or aromatase inhibitor or fulvestrant with GnRH agonist) with a CDK4/6 inhibitor by extrapolation; chemotherapy for visceral crisis.","refs":["tamoxifen","fulvestrant","palbociclib","ribociclib","abemaciclib"],"guideline":{"version":"NCCN Guidelines: Breast Cancer"}},{"setting":"Germline BRCA carriers","approach":"PARP inhibitor (olaparib adjuvant per OlympiA; olaparib or talazoparib for metastatic disease) and cascade testing of relatives.","refs":["olaparib","talazoparib","germline-testing","olympia"]}],"stateOfArt":["Guidelines (ASCO 2020, NCCN) now state explicitly how to treat men rather than leaving it to inference from women's trials.","Universal germline testing in men with breast cancer finds BRCA2 mutations often and opens PARP inhibitor therapy and family cascade testing.","The FDA's 2020 guidance pushes sponsors to include men in breast cancer trials; labels for CDK4/6 inhibitors and other agents increasingly cover men.","The International Male Breast Cancer Program built the first large prospective registry, showing high ER positivity, low HER2 rates and under-treatment with adjuvant endocrine therapy."],"history":[{"year":1927,"title":"First large series of male breast cancer","note":"Wainwright's review of published cases.","refs":[]},{"year":1976,"title":"Tamoxifen shown active in men","note":"Early case series establish tamoxifen as the endocrine backbone.","refs":["tamoxifen"]},{"year":1995,"title":"BRCA2 linked to male breast cancer","note":"Wooster and colleagues identify BRCA2; male breast cancer is one of its hallmark phenotypes.","refs":["brca"]},{"year":2018,"title":"International Male Breast Cancer Program (EORTC 10085)","note":"Cardoso and colleagues (Ann Oncol 2018) characterise 1,483 men treated 1990 to 2010.","refs":[]},{"year":2020,"title":"ASCO guideline and FDA guidance","note":"First ASCO guideline on male breast cancer; FDA guidance on including men in breast cancer drug development.","refs":[]},{"year":2021,"title":"OlympiA: adjuvant olaparib for germline BRCA carriers","note":"Trial included men.","refs":["olaparib","olympia"]}],"pipeline":["olaparib","palbociclib","ribociclib","trastuzumab-deruxtecan"],"openProblems":["Men are still under-enrolled in breast cancer trials; regulatory guidance and label harmonisation are the response.","Aromatase inhibitor efficacy and the need for GnRH co-treatment rest on small studies; registries are collecting outcomes.","Later diagnosis from low awareness; education campaigns and rapid referral pathways are the levers.","Adjuvant endocrine adherence and side effects in men are poorly studied."],"parent":"breast-cancer"},{"id":"malignant-peripheral-nerve-sheath-tumour","kind":"cancer","name":"Malignant peripheral nerve sheath tumour (MPNST)","aka":["MPNST","Neurofibrosarcoma (historic)","Malignant schwannoma (historic)"],"tldr":"Malignant peripheral nerve sheath tumour is a sarcoma that grows from the covering of a nerve, most often in people with neurofibromatosis type 1 when a benign plexiform neurofibroma turns malignant. Surgery with radiotherapy is the only cure; chemotherapy with doxorubicin and ifosfamide shrinks some tumours, and drugs targeting the tumour's lost NF1 and PRC2 brakes are in trials.","summary":"Malignant peripheral nerve sheath tumour arises from Schwann cell lineage in a peripheral nerve or a pre-existing neurofibroma, sporadically, after radiotherapy or, in half of cases, in neurofibromatosis type 1, where atypical neurofibromatous neoplasms of uncertain biological potential are the recognised precursor. Its genome shows loss of NF1, then CDKN2A, then the polycomb repressive complex 2 components SUZ12 or EED, producing global loss of H3K27 trimethylation that pathologists now use as a diagnostic marker, alongside TP53 loss in high-grade tumours.\n\nTreatment of localised disease is wide resection with radiotherapy, which controls local disease but does not prevent metastasis; the tumours are large, deep and often involve major nerves and the spine, so margins are frequently compromised. Chemotherapy activity is modest: the SARC006 phase 2 trial of neoadjuvant doxorubicin-ifosfamide followed by ifosfamide-etoposide produced responses in a minority, more often in sporadic than NF1-associated tumours, and adjuvant chemotherapy is offered to fit patients with high-grade disease on the general sarcoma evidence.\n\nTargeted approaches follow the biology: MEK inhibitors such as selumetinib and mirdametinib, approved for the precursor plexiform neurofibromas, are being combined with mTOR inhibitors (SARC031) and other agents in MPNST; PRC2 loss confers sensitivity to some epigenetic and DNA-damaging strategies in models; and surveillance of people with neurofibromatosis by whole-body MRI and PET to catch transformation early is the most practical current advance.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Malignant_peripheral_nerve_sheath_tumor","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Malignant_peripheral_nerve_sheath_tumor"}],"tags":["subtype-page"],"related":["extremity-soft-tissue-sarcoma","desmoid-tumour","synovial-sarcoma","undifferentiated-pleomorphic-sarcoma","epithelioid-sarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-kroep-mpnst-first-line-chemotherapy-ann-oncol-2011","paper-lee-prc2-mpnst-nat-genet-2014","paper-eortc-62012-doxorubicin-ifosfamide-judson-lancet-oncol-2014","paper-esmo-sts-guideline-gronchi-ann-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"About five percent of soft tissue sarcomas; half occur in people with neurofibromatosis type 1, whose lifetime risk is around one in ten, and it is the leading cause of death in that condition. Outcomes are poor, with five-year survival below half in most series.","subtypes":["NF1-associated MPNST (about half; arises in plexiform neurofibroma)","Sporadic MPNST","Radiation-associated MPNST","Epithelioid MPNST (SMARCB1 loss; not NF1-associated)","MPNST with heterologous differentiation (malignant Triton tumour)"],"biomarkers":["Loss of H3K27 trimethylation on immunohistochemistry (PRC2 loss)","NF1, CDKN2A, SUZ12 or EED alterations","TP53 loss (high grade)","FDG-PET uptake in neurofibromas (transformation)","Germline NF1 status"],"standardOfCare":[{"setting":"Localised","approach":"Wide resection with preoperative or postoperative radiotherapy; nerve sacrifice and reconstruction as needed; consider neoadjuvant or adjuvant anthracycline-ifosfamide for large high-grade tumours.","refs":["limb-salvage-surgery","imrt-igrt","doxorubicin","ifosfamide"]},{"setting":"Advanced","approach":"Doxorubicin plus ifosfamide (EORTC 62012), then ifosfamide-etoposide or trials; response rates lower in NF1-associated tumours.","refs":["doxorubicin","ifosfamide","eortc-62012","etoposide"]},{"setting":"Neurofibromatosis type 1 surveillance","approach":"Whole-body MRI and FDG-PET for growing or painful plexiform neurofibromas; biopsy of atypical lesions; MEK inhibitors for symptomatic plexiform neurofibromas.","refs":["mri","pet-ct","selumetinib","mirdametinib"]}],"stateOfArt":["H3K27me3 loss made a difficult diagnosis reproducible.","MEK inhibitors control the benign precursor but have not yet been proven in MPNST, where combinations with mTOR inhibitors are in trials.","Whole-body MRI surveillance in neurofibromatosis aims to catch transformation before it becomes incurable."],"history":[{"year":1990,"title":"NF1 gene cloned","refs":[]},{"year":2014,"title":"PRC2 (SUZ12, EED) loss found in most MPNST","refs":[]},{"year":2016,"title":"H3K27me3 loss adopted as a diagnostic marker","refs":[]},{"year":2017,"title":"SARC006: neoadjuvant chemotherapy responses in a minority, fewer in NF1-associated tumours","refs":["doxorubicin","ifosfamide"]},{"year":2020,"title":"Selumetinib approved for NF1 plexiform neurofibromas, the precursor lesion","refs":["selumetinib"]},{"year":2025,"title":"Mirdametinib approved for NF1 plexiform neurofibromas in adults and children","refs":["mirdametinib"]}],"pipeline":["selumetinib","mirdametinib","mek","ras-mapk"],"openProblems":["Metastasis is common even after complete local treatment.","Chemotherapy works less well in the NF1-associated tumours that make up half of cases.","No targeted drug has yet been proven in MPNST itself."],"parent":"sarcoma"},{"id":"mantle-cell-lymphoma","kind":"cancer","name":"Mantle cell lymphoma","aka":[],"tldr":"An uncommon B-cell lymphoma driven by cyclin D1 that used to behave badly in almost everyone. BTK inhibitors, CAR-T and now BCL2 drugs have changed it from chemotherapy-plus-transplant to targeted combinations.","summary":"Mantle cell lymphoma (MCL) carries t(11;14) with cyclin D1 overexpression (SOX11-positive in classical MCL). Risk is set by MIPI, Ki-67, blastoid morphology and TP53 mutation, the last defining a group that fails chemo-immunotherapy and transplant. A leukaemic non-nodal variant behaves indolently.\n\nYounger fit patients traditionally received cytarabine-containing induction and autologous transplant with rituximab maintenance; TRIANGLE (2024) showed adding ibrutinib to induction and maintenance is at least as good as transplant, and transplant is being abandoned. Older patients receive bendamustine-rituximab or R-CHOP; ECHO (2024) added acalabrutinib to BR first line (FDA approval 2025). Relapse is treated with covalent BTK inhibitors (ibrutinib 2013, acalabrutinib 2017, zanubrutinib 2019; ibrutinib's US MCL approval was withdrawn in 2023 after SHINE), then brexucabtagene autoleucel (ZUMA-2, 2020), the non-covalent BTKi pirtobrutinib (2023), or the BCL2 inhibitor sonrotoclax (2026); venetoclax-ibrutinib (SYMPATICO) is another option. Lisocabtagene was approved for MCL in 2024.\n\nTP53-mutant MCL still does poorly with everything except CAR-T and bispecifics; glofitamab and CD20×CD3 agents are in phase 3.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Mantle_cell_lymphoma","links":[{"label":"TRIANGLE (Lancet 2024)","url":"https://doi.org/10.1016/S0140-6736(24)00184-3"},{"label":"NCCN Guidelines: B-Cell Lymphomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1480"},{"label":"NCI PDQ: adult NHL","url":"https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq"},{"label":"Lymphoma Action: helpline services","url":"https://lymphoma-action.org.uk/information-and-support/support-you/helpline-services"},{"label":"Lymphoma Action: questions to ask your medical team about lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/questions-ask-your-medical-team-about-lymphoma"},{"label":"Lymphoma Action: follow-up after lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/follow-after-lymphoma-treatment"},{"label":"Lymphoma Action: infections, risk and prevention","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/infections-risk-and-prevention"},{"label":"Lymphoma Action: neutropenia (low neutrophils)","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/neutropenia-low-neutrophils"},{"label":"Lymphoma Action: cancer-related fatigue","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/cancer-related-fatigue"},{"label":"Lymphoma Action: lymphoma, work and you","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/day-day-living/lymphoma-work-and-you"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Lymphoma Action: active monitoring (watch and wait)","url":"https://lymphoma-action.org.uk/information-and-support/lymphoma-treatment/active-monitoring-watch-and-wait"},{"label":"Lymphoma Action: CAR-T cell therapy","url":"https://lymphoma-action.org.uk/information-and-support/lymphoma-treatment/car-t-cell-therapy"},{"label":"Lymphoma Action: when lymphoma comes back, or does not respond","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/lymphoma-comes-back-relapses-or-doesnt-respond"},{"label":"Macmillan: non-Hodgkin lymphoma","url":"https://www.macmillan.org.uk/cancer-information-and-support/lymphoma/non-hodgkin-lymphoma"}],"tags":["gap-fill","haematologic"],"related":["follicular-lymphoma","marginal-zone-lymphoma","dlbcl","waldenstrom","tp53-del17p","btk-c481s","bcl2-g101v","cyclin-d1-t11-14","lymphoma-roadmap","lymphoma-ev-fixed-duration-chemotherapy-free-first-line"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","car-t","autologous-stem-cell-transplant","t-cell-engager","monoclonal-antibody","palliative-care","psycho-oncology","peer-support-groups","survivorship-care-plan","fertility-preservation","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","multidisciplinary-tumour-board","oncology-nutrition","prehabilitation","bispecific-antibody","cytogenetics-fish","histopathology-ihc","cgp","clonality-testing"],"targets":["btk","bcl2","cd19","cd20","cd3","cdk4-6","ccnd1","tp53","atm","plcg2","notch1","notch2","kmt2d","birc3","cdkn2a"],"drugs":["ibrutinib","acalabrutinib","zanubrutinib","pirtobrutinib","brexucabtagene-autoleucel","lisocabtagene-maraleucel","sonrotoclax","venetoclax","bendamustine","rituximab","glofitamab","clonoseq","bortezomib"],"companies":["abbvie","astrazeneca","beone","gilead","eli-lilly","bms"],"institutions":[],"pathways":["apoptosis-bcl2","p53-cell-cycle","cell-cycle-engine-cdks","bcr-signalling","p53-mdm2-axis"],"terms":["del17p-tp53","mrd","lugano-classification","mipi","cyclin-d1-t11-14","lymphoma-tx-transplant-role","lymphoma-tx-maintenance","lymphoma-tx-car-t-pathway","lymphoma-tx-crs-icans","lymphoma-tx-uk-versus-us","lymphoma-tx-regimen-alphabet","lymphoma-tx-tumour-lysis","cancer-related-fatigue","late-effects","febrile-neutropenia","neutropenia","financial-toxicity","central-venous-access","hypogammaglobulinaemia","performance-status","quality-of-life","lymphoma-decision-watch-and-wait","lymphoma-decision-local-or-car-t-centre","lymphoma-decision-trial","lymphoma-living-indolent-lymphoma","lymphoma-living-infection-years-after","lymphoma-living-vaccinations","lymphoma-living-fatigue","watchful-waiting","lymphoma-bio-antigen-escape","lymphoma-bio-germinal-centre","resistance","cross-resistance"],"trials":["nct07377578","nct04002297","nct01804686","nct06742996","nct06363994","nct04662255","nct02972840","zuma-2","triangle","sympatico","shine","enrich","lyma"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Living with mantle cell lymphoma: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the 24-hour number they gave you come first, and no figure here is a prediction about you. The decision records, the question sets, the first 60 days checklist and the red cards on this page were written from the NHS, Lymphoma Action, Macmillan and Cancer Research UK patient pages, from NICE NG52, NG47, CG151 and NG234, from the NHS Breast Screening Programme protocols and the Green Book, and from the trial reports named beside each figure, all read on 1 October 2026."],"group":"haematologic","burden":"Mantle cell lymphoma makes up about 5-7% of non-Hodgkin lymphomas; incidence ~1 per 100,000 per year, median age ~68, 3:1 male.","subtypes":["Classical nodal MCL (SOX11+)","Leukaemic non-nodal MCL (indolent)","Blastoid / pleomorphic variant","TP53-mutant MCL","In situ mantle cell neoplasia"],"biomarkers":["t(11;14) / cyclin D1 IHC","SOX11","MIPI and MIPI-c","Ki-67 (≥30% high risk)","TP53 mutation / del(17p)","Blastoid morphology","MRD (ctDNA/clonoSEQ, investigational)"],"standardOfCare":[{"setting":"First line, fit (<65-70)","approach":"Rituximab + high-dose cytarabine-based induction (e.g. R-CHOP/R-DHAP or Nordic) with ibrutinib and 2 years ibrutinib maintenance; autologous transplant no longer adds benefit when ibrutinib is used (TRIANGLE).","refs":["rituximab","ibrutinib","autologous-stem-cell-transplant","triangle"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: B-Cell Lymphomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1480"}},{"setting":"First line, older or unfit","approach":"Bendamustine-rituximab + acalabrutinib (ECHO, approved 2025) or BR alone with rituximab maintenance; R-CHOP alternative.","refs":["bendamustine","rituximab","acalabrutinib"],"guideline":{"nccn":"Category 1 (BR + acalabrutinib)","version":"NCCN Guidelines: B-Cell Lymphomas"}},{"setting":"Relapsed, BTKi-naive","approach":"Covalent BTK inhibitor (acalabrutinib, zanubrutinib; ibrutinib ex-US) ± venetoclax (SYMPATICO).","refs":["acalabrutinib","zanubrutinib","ibrutinib","venetoclax","sympatico"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: B-Cell Lymphomas"}},{"setting":"Relapsed after BTKi","approach":"Brexucabtagene or lisocabtagene CAR-T; pirtobrutinib; sonrotoclax (2026); allogeneic HSCT in selected patients; bispecific trials.","refs":["brexucabtagene-autoleucel","lisocabtagene-maraleucel","pirtobrutinib","sonrotoclax","allogeneic-hsct"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: B-Cell Lymphomas"}},{"setting":"Mantle cell lymphoma: the three things to establish before choosing treatment","approach":"Mantle cell lymphoma is not one disease. Classical nodal disease behaves aggressively and needs treatment. Leukaemic non-nodal mantle cell lymphoma, with SOX11-negative, hypermutated immunoglobulin genes, splenomegaly and circulating cells but no lymphadenopathy, can be watched for years, and treating it early does harm without benefit. Blastoid and pleomorphic variants behave much more aggressively.\n\nThree things to establish. First, the growth pattern and Ki-67 index: above about 30 per cent signals aggressive disease. Second, TP53 mutation status, which is the single strongest adverse factor and predicts poor response to intensive chemotherapy and to autologous transplant; a TP53-mutated patient is a candidate for a novel-agent regimen or a trial rather than for intensification. Third, the MIPI score, which combines age, performance status, LDH and white cell count. Gastrointestinal involvement is near-universal at a microscopic level and colonoscopy is not required in every patient.","refs":["mipi","lymphoma-tx-watch-and-wait","lymphoma-tx-regimen-alphabet","fdg-pet"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; BSH","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"First-line mantle cell lymphoma in younger, fitter patients after TRIANGLE: ibrutinib in, transplant optional","approach":"TRIANGLE randomised 870 patients up to 65 who were fit for transplant to three arms: alternating R-CHOP and R-DHAP induction with autologous transplant (arm A); the same with ibrutinib added to induction and as two-year maintenance (arm A+I); or ibrutinib-containing induction and maintenance without transplant (arm I). Three-year failure-free survival was 88 per cent for arm A+I against 72 per cent for arm A (hazard ratio 0.52). Transplant was not shown to be superior to the ibrutinib-containing regimen without it: 72 per cent for arm A against 86 per cent for arm I. Adding ibrutinib to transplant increased grade 3 to 5 haematological events during maintenance and follow-up (50 per cent in arm A+I against 21 per cent in arm A) and infections (25 against 13 per cent).\n\nWhat changed in practice: a covalent BTK inhibitor belongs in first-line treatment of younger patients, and autologous transplant is no longer automatic. Many units now give ibrutinib-containing induction and maintenance without transplant, particularly in TP53-mutated disease where transplant has never worked well. Where transplant is used, rituximab maintenance afterwards improves survival: LyMa randomised 240 patients after transplant to three years of rituximab or observation and found four-year event-free survival of 79 against 61 per cent, with overall survival also improved.\n\nCytarabine-containing induction (R-DHAP or the Nordic regimen) remains the backbone where an intensive approach is chosen. In England, NICE TA1193 allows exactly the TRIANGLE schedule: ibrutinib with R-CHOP alternating with R-DHAP or R-DHAOx, followed by ibrutinib alone, for untreated disease in adults for whom an autologous transplant is suitable.","refs":["triangle","ibrutinib","rituximab","cytarabine","cisplatin","dexamethasone","oxaliplatin","r-chop","autologous-stem-cell-transplant","lymphoma-tx-transplant-role","lymphoma-tx-maintenance","lymphoma-tx-uk-access","mipi","paper-triangle-ibrutinib-mantle-cell-lymphoma-dreyling-lancet-2024"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; TRIANGLE, LyMa","url":"https://doi.org/10.1056/NEJMoa1701769"}},{"setting":"First-line mantle cell lymphoma in older patients: the British answer and the international one","approach":"Two randomised trials, two different regimens, and a real difference between British and American practice.\n\nENRICH, run at 66 sites in the United Kingdom and the Nordic countries, randomised 397 patients aged 60 and over to ibrutinib with rituximab or to the investigator's choice of immunochemotherapy (R-CHOP or bendamustine-rituximab), both followed by two years of rituximab maintenance, with ibrutinib continued until progression. At a median follow-up of 47.9 months the adjusted hazard ratio for progression-free survival was 0.69 in favour of ibrutinib-rituximab. The benefit was concentrated where the comparator was R-CHOP (hazard ratio 0.37) and was not demonstrated against bendamustine-rituximab (0.91). Grade 3 or worse adverse events were similar (67 against 70 per cent). This is the first randomised trial in untreated mantle cell lymphoma to show a chemotherapy-free combination beating immunochemotherapy, and it is British practice.\n\nSHINE took the other route and added ibrutinib to bendamustine-rituximab in 523 patients aged 65 and over: median progression-free survival 80.6 against 52.9 months (hazard ratio 0.75) with no overall survival difference and grade 3 or 4 adverse events in 81.5 against 77.3 per cent.\n\nSo: ibrutinib-rituximab without chemotherapy for a patient in whom bendamustine is unattractive, and bendamustine-rituximab with or without a BTK inhibitor otherwise. Acalabrutinib and zanubrutinib are the second-generation covalent BTK inhibitors, with less atrial fibrillation and hypertension than ibrutinib, and are substituted in patients with cardiac risk. Acalabrutinib with bendamustine and rituximab received traditional United States approval on 16 January 2025 on the ECHO trial for untreated mantle cell lymphoma in people not eligible for an autologous transplant, and NICE TA1184 recommends the same combination in England for the same group. VR-CAP, which replaces vincristine with bortezomib, is an alternative backbone.","refs":["ibrutinib","rituximab","bendamustine","acalabrutinib","zanubrutinib","bortezomib","r-chop","lymphoma-tx-uk-versus-us","lymphoma-tx-maintenance","lymphoma-tx-regimen-alphabet"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; ENRICH, SHINE","url":"https://doi.org/10.1016/S0140-6736(25)01432-1"}},{"setting":"Relapsed mantle cell lymphoma that has not yet had a BTK inhibitor","approach":"A covalent BTK inhibitor is the standard next treatment and produces responses in about two thirds. Acalabrutinib and zanubrutinib are preferred over ibrutinib on cardiovascular toxicity where both are available. Adding venetoclax lengthens remission: SYMPATICO randomised 366 patients after one to five prior lines to ibrutinib with venetoclax or ibrutinib with placebo and gave median progression-free survival of 31.9 against 22.1 months (hazard ratio 0.629), with a complete response of 69.2 per cent in a separate open-label arm of treatment-naive TP53-mutated disease. Venetoclax carries a tumour lysis risk that requires a ramp-up and monitoring.\n\nOther options at this point are lenalidomide with rituximab, bortezomib-containing regimens, bendamustine with rituximab if not used before, and a clinical trial. Autologous transplant is rarely useful at relapse; allogeneic transplant is reserved for young, fit patients with chemosensitive disease.","refs":["sympatico","ibrutinib","acalabrutinib","zanubrutinib","venetoclax","lenalidomide","rituximab","bortezomib","bendamustine","lymphoma-tx-tumour-lysis","allogeneic-hsct"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; SYMPATICO","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Mantle cell lymphoma after a BTK inhibitor has failed: brexucabtagene autoleucel and pirtobrutinib","approach":"Progression on a covalent BTK inhibitor was, until 2020, the point at which there was little left. Two treatments changed it.\n\nBrexucabtagene autoleucel, a CD19 CAR-T product, was tested in ZUMA-2 in 105 patients who had all had a BTK inhibitor: objective response 93 per cent and complete response 67 per cent in the primary efficacy analysis, 85 per cent by intention to treat, with progression-free survival of 61 per cent and overall survival of 83 per cent at twelve months. The toxicity is real: grade 3 or higher cytokine release syndrome in 15 per cent and grade 3 or higher neurological events in 31 per cent, higher than the CD19 products used in large B-cell lymphoma. Referral should happen as the BTK inhibitor starts to fail, not after the next line, because apheresis quality falls with further treatment.\n\nPirtobrutinib, a non-covalent BTK inhibitor, works after covalent BTK inhibitor failure including in the presence of the C481S resistance mutation, and is an option for patients who are not candidates for CAR-T or who need disease control while a CAR-T product is manufactured.\n\nLisocabtagene maraleucel is the second CAR-T option, approved in the United States on 30 May 2024 for relapsed or refractory mantle cell lymphoma after at least two prior lines including a BTK inhibitor. Other options are venetoclax-based combinations, glofitamab with pirtobrutinib in a trial, allogeneic transplant in selected younger patients, and palliative radiotherapy to a symptomatic site. This is a point at which a trial is often the best available treatment.","refs":["zuma-2","brexucabtagene-autoleucel","lisocabtagene-maraleucel","pirtobrutinib","venetoclax","glofitamab","car-t","lymphoma-tx-car-t-pathway","lymphoma-tx-crs-icans","allogeneic-hsct","palliative-radiotherapy","paper-zuma-2-brexu-cel-mantle-cell-nejm-2020"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; ZUMA-2","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":["Transplant is leaving first-line MCL: TRIANGLE made ibrutinib-containing induction and maintenance the new fit-patient standard.","BTK inhibitors sit in first line for older patients (ECHO) and at relapse; pirtobrutinib rescues covalent-BTKi failures.","CAR-T (ZUMA-2) gives long remissions after BTKi failure, including in TP53-mutant disease.","BCL2 inhibition is back: sonrotoclax approved for relapsed MCL in 2026 with venetoclax combinations close behind.","One founding translocation, and everything else is secondary. The t(11;14) puts CCND1 under the immunoglobulin heavy-chain locus and is considered the first oncogenic hit in virtually all mantle cell lymphomas. Sequencing of 29 genomes with validation in 172 more found 25 significantly mutated genes on top of it, including ATM, TP53, BIRC3, KMT2D and NOTCH2.","TP53 is the result that changes the plan. Among 183 younger patients on the Nordic protocols, TP53 mutation was present in 11% and carried a hazard ratio of 6.2 for overall survival, a median overall survival of 1.8 years against 12.7 years, half relapsing within a year, and worse responses to both induction and high-dose chemotherapy. No label depends on it, and in practice it is the usual reason to go to a BTK inhibitor, venetoclax or CAR-T rather than intensive chemotherapy and transplant.","A minority of cases are cyclin D1-negative and carry CCND2 or CCND3 rearrangements instead; SOX11 identifies most of them, and its absence marks the indolent leukaemic non-nodal form that is often watched rather than treated.","Resistance to a BTK inhibitor is read in the kinase. BTK C481S is answered by a non-covalent inhibitor; PLCG2 gain of function is not, because it sits below the drug; and L528W defeats both."],"history":[{"year":1992,"title":"Cyclin D1 and t(11;14) define MCL","note":"Mantle cell lymphoma recognised as a distinct entity (REAL classification 1994).","refs":[]},{"year":2008,"title":"MIPI prognostic index","refs":[]},{"year":2013,"title":"Ibrutinib: first BTK inhibitor approved","note":"68% response in relapsed MCL; the first indication for any BTK inhibitor.","refs":["ibrutinib"]},{"year":2017,"title":"Acalabrutinib approved (ACE-LY-004)","refs":["acalabrutinib"]},{"year":2019,"title":"Zanubrutinib approved","refs":["zanubrutinib"]},{"year":2020,"title":"Brexucabtagene autoleucel (ZUMA-2)","note":"First CAR-T for MCL: 93% response after BTKi failure.","refs":["brexucabtagene-autoleucel"]},{"year":2023,"title":"Pirtobrutinib approved; ibrutinib US MCL indication withdrawn","refs":["pirtobrutinib","ibrutinib"]},{"year":2024,"title":"TRIANGLE and ECHO","note":"Ibrutinib replaces transplant in fit patients; acalabrutinib + BR improves PFS first line in older patients.","refs":["ibrutinib","acalabrutinib"]},{"year":2026,"title":"Sonrotoclax approved for relapsed MCL","refs":["sonrotoclax"]}],"pipeline":["sonrotoclax","glofitamab","pirtobrutinib","venetoclax","bgb-16673","nemtabrutinib","rocbrutinib","icp-248","zamtocabtagene-autoleucel","ctx112"],"openProblems":["TP53-mutant and blastoid MCL fail chemo-immunotherapy; need CAR-T or bispecific-based first-line trials.","MRD-guided treatment duration.","Whether CAR-T should precede pirtobrutinib or follow it.","Cost and access of indefinite BTK-inhibitor therapy.","TRIANGLE showed that adding ibrutinib to induction and maintenance improves failure-free survival and that transplant is not superior to an ibrutinib-containing regimen without it, but it did not answer which of the three arms is best for a given patient, and the arm that omits transplant has the shortest follow-up.","TP53-mutated mantle cell lymphoma responds poorly to every intensive chemotherapy strategy tested, including autologous transplant, and there is no regimen with randomised evidence in this group.","ENRICH showed ibrutinib-rituximab beats R-CHOP in older patients but not bendamustine-rituximab, so the right first treatment for an older patient depends on which comparator a clinician would otherwise have chosen, which is an uncomfortable basis for a recommendation."],"parent":"non-hodgkin-lymphoma"},{"id":"marginal-zone-lymphoma","kind":"cancer","name":"Marginal zone lymphoma","aka":["MZL","MALT lymphoma","Extranodal marginal zone lymphoma","Splenic marginal zone lymphoma","Nodal marginal zone lymphoma"],"tldr":"Marginal zone lymphoma is a slow B-cell lymphoma that often grows where the body has been fighting a chronic infection: the stomach with Helicobacter pylori, the eye, the skin or the spleen. Curing the infection cures many early cases; the rest are treated with rituximab, chemotherapy or BTK inhibitors.","summary":"Marginal zone lymphomas come in three forms. Extranodal (MALT) lymphoma arises in mucosal tissue chronically stimulated by infection or autoimmunity: gastric MALT lymphoma from Helicobacter pylori, ocular adnexal from Chlamydia in some regions, salivary gland in Sjogren's syndrome and thyroid in Hashimoto's disease; eradicating H. pylori puts most early gastric cases into remission, and localised disease elsewhere is cured with low-dose radiotherapy. Splenic marginal zone lymphoma presents with a large spleen and circulating villous lymphocytes and is linked to hepatitis C, whose treatment can induce remission; rituximab has replaced splenectomy. Nodal marginal zone lymphoma behaves like follicular lymphoma. Systemic treatment when needed is rituximab alone or with bendamustine or chlorambucil, lenalidomide-rituximab, and the BTK inhibitors ibrutinib and zanubrutinib for relapsed disease.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Marginal_zone_B-cell_lymphoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Marginal_zone_B-cell_lymphoma"},{"label":"Lymphoma Action: helpline services","url":"https://lymphoma-action.org.uk/information-and-support/support-you/helpline-services"},{"label":"Lymphoma Action: questions to ask your medical team about lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/questions-ask-your-medical-team-about-lymphoma"},{"label":"Lymphoma Action: follow-up after lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/follow-after-lymphoma-treatment"},{"label":"Lymphoma Action: infections, risk and prevention","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/infections-risk-and-prevention"},{"label":"Lymphoma Action: neutropenia (low neutrophils)","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/neutropenia-low-neutrophils"},{"label":"Lymphoma Action: cancer-related fatigue","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/cancer-related-fatigue"},{"label":"Lymphoma Action: lymphoma, work and you","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/day-day-living/lymphoma-work-and-you"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Lymphoma Action: active monitoring (watch and wait)","url":"https://lymphoma-action.org.uk/information-and-support/lymphoma-treatment/active-monitoring-watch-and-wait"},{"label":"Lymphoma Action: the emotional impact of living with lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/emotional-impact-living-lymphoma"},{"label":"Macmillan: non-Hodgkin lymphoma","url":"https://www.macmillan.org.uk/cancer-information-and-support/lymphoma/non-hodgkin-lymphoma"}],"tags":["subtype-page"],"related":["follicular-lymphoma","waldenstrom","mantle-cell-lymphoma","dlbcl","ig-tcr-clonality","myd88-l265p","lymphoma-roadmap","lymphoma-ev-fixed-duration-chemotherapy-free-first-line"],"cancers":[],"sections":[],"technologies":["palliative-care","psycho-oncology","peer-support-groups","survivorship-care-plan","fertility-preservation","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","multidisciplinary-tumour-board","oncology-nutrition","prehabilitation","clonality-testing","cytogenetics-fish","flow-cytometry-mrd"],"targets":["malt1","bcl10","tnfaip3","notch2","klf2","birc3","cd20","myd88"],"drugs":["zanubrutinib","chlorambucil","lisocabtagene-maraleucel"],"companies":[],"institutions":[],"pathways":["inflammation-nfkb","notch","microbiome-tumour"],"terms":["myd88-l265p","ss18-ssx-fusion","lymphoma-tx-h-pylori-eradication","lymphoma-tx-watch-and-wait","lymphoma-tx-radiotherapy","cancer-related-fatigue","late-effects","febrile-neutropenia","neutropenia","financial-toxicity","central-venous-access","hypogammaglobulinaemia","performance-status","quality-of-life","lymphoma-decision-watch-and-wait","lymphoma-decision-trial","lymphoma-living-indolent-lymphoma","lymphoma-living-scanxiety-and-surveillance","lymphoma-living-infection-years-after","lymphoma-living-fatigue","watchful-waiting","lymphoma-bio-lymphgen","lymphoma-bio-transformation"],"trials":["augment","zuma-5","ielsg-19","mosun-len-mzl"],"people":[],"bottlenecks":[],"keyPapers":["paper-wotherspoon-h-pylori-malt-lancet-1993","paper-esmo-marginal-zone-lymphoma-zucca-ann-oncol-2020","paper-magnolia-zanubrutinib-mzl-ccr-2021","paper-augment-lenalidomide-rituximab-leonard-jco-2019"],"journals":[],"dependsOn":[],"notes":["Living with marginal zone lymphoma: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the 24-hour number they gave you come first, and no figure here is a prediction about you. The decision records, the question sets, the first 60 days checklist and the red cards on this page were written from the NHS, Lymphoma Action, Macmillan and Cancer Research UK patient pages, from NICE NG52, NG47, CG151 and NG234, from the NHS Breast Screening Programme protocols and the Green Book, and from the trial reports named beside each figure, all read on 1 October 2026."],"group":"haematologic","burden":"About one in ten non-Hodgkin lymphomas, the second commonest indolent type after follicular lymphoma; most patients live for many years and many are cured by treating the infection or inflammation that drove the disease.","subtypes":["Extranodal marginal zone lymphoma of MALT (gastric, ocular adnexal, salivary, thyroid, lung, skin)","Splenic marginal zone lymphoma","Nodal marginal zone lymphoma","Paediatric nodal marginal zone lymphoma (indolent)"],"biomarkers":["Helicobacter pylori status (gastric MALT)","t(11;18) MALT1 translocation (predicts failure of eradication therapy)","Hepatitis C serology (splenic)","MYD88 wild-type (distinguishes from Waldenstrom)","Plasmacytic differentiation and paraprotein"],"standardOfCare":[{"setting":"Gastric MALT lymphoma, H. pylori-positive","approach":"Eradication therapy and endoscopic follow-up; radiotherapy if the lymphoma persists or carries t(11;18).","refs":["non-hodgkin-lymphoma"]},{"setting":"Localised extranodal disease","approach":"Low-dose involved-site radiotherapy (as little as 4 Gy in two fractions for some sites); surgery rarely.","refs":["imrt-igrt","hypofractionated-radiotherapy"]},{"setting":"Splenic marginal zone lymphoma","approach":"Watch and wait if asymptomatic; antiviral therapy if hepatitis C-positive; rituximab alone or with chemotherapy; splenectomy now rare.","refs":["rituximab"]},{"setting":"Advanced or relapsed","approach":"Rituximab with bendamustine or chlorambucil, lenalidomide-rituximab; zanubrutinib or ibrutinib for relapsed disease.","refs":["rituximab","bendamustine","chlorambucil","lenalidomide","zanubrutinib","ibrutinib"]},{"setting":"Marginal zone lymphoma: three different diseases under one name","approach":"Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) arises at a site of chronic inflammation, most often the stomach, and is the one that can sometimes be cured with antibiotics. Splenic marginal zone lymphoma presents with a large spleen, cytopenias and circulating villous lymphocytes, and is associated with hepatitis C. Nodal marginal zone lymphoma behaves much like follicular lymphoma and is treated like it. The three share a cell of origin and very little else in the way of treatment, so the first question is which one it is.\n\nTwo tests change the plan at diagnosis. Helicobacter pylori status in gastric MALT, because eradication is the first treatment. Hepatitis C status in splenic and nodal disease, because antiviral treatment alone can produce lymphoma remission in hepatitis C-associated cases. Other site-specific associations are recorded and occasionally actionable: Chlamydia psittaci in ocular adnexal MALT, Borrelia burgdorferi in cutaneous MALT, Campylobacter jejuni in immunoproliferative small intestinal disease.","refs":["paper-esmo-marginal-zone-lymphoma-zucca-ann-oncol-2020","lymphoma-tx-h-pylori-eradication","lymphoma-tx-watch-and-wait","rituximab"],"guideline":{"version":"ESMO marginal zone lymphomas (Zucca et al.); NCCN B-Cell Lymphomas","url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-haematological-malignancies"}},{"setting":"Marginal zone lymphoma that is advanced, symptomatic or has relapsed","approach":"Treatment is indicated for symptoms, organ compromise, cytopenias or rapid progression, not for the presence of disease. Rituximab alone produces responses in about half. Chemoimmunotherapy with bendamustine and rituximab is the usual choice when more is needed, and rituximab with chlorambucil has the only randomised evidence in MALT (IELSG-19: five-year event-free survival 68 per cent for the combination against 51 per cent for chlorambucil and 50 per cent for rituximab alone, with five-year overall survival about 90 per cent in each arm, so the combination delays events without changing survival).\n\nAt relapse, the BTK inhibitors are the newest class: MAGNOLIA treated relapsed or refractory marginal zone lymphoma of all subtypes with zanubrutinib and reported an objective response of 68 per cent, complete response 26 per cent and 15-month progression-free survival of 83 per cent, with fewer cardiac events than ibrutinib. Lenalidomide with rituximab is an option and marginal zone patients were included in AUGMENT. Lisocabtagene maraleucel received United States approval for relapsed or refractory marginal zone lymphoma after two or more prior lines on 4 December 2025. Local radiotherapy at 24 Gy remains the right answer for a single symptomatic site whatever the line.","refs":["rituximab","bendamustine","chlorambucil","zanubrutinib","ibrutinib","lenalidomide","lisocabtagene-maraleucel","augment","lymphoma-tx-radiotherapy","paper-magnolia-zanubrutinib-mzl-ccr-2021","paper-esmo-marginal-zone-lymphoma-zucca-ann-oncol-2020"],"guideline":{"version":"ESMO marginal zone lymphomas; NCCN B-Cell Lymphomas; IELSG-19, MAGNOLIA","url":"https://doi.org/10.1200/JCO.2016.70.6994"}}],"stateOfArt":["Gastric MALT lymphoma is the clearest example of a cancer cured by treating an infection.","Very low-dose radiotherapy controls localised disease with almost no side effects.","BTK inhibitors give durable responses in relapsed disease with zanubrutinib's approval in 2021.","Marginal zone lymphomas are united by chronic antigenic stimulation and by NF-kB activation reached through several different lesions: the API2-MALT1 fusion of t(11;18), BCL10 and MALT1 translocations, TNFAIP3 inactivation, and NOTCH2 and KLF2 mutations in the splenic form.","In the genetic taxonomy of large B-cell lymphoma, the BN2 subtype, defined by BCL6 fusions and NOTCH2 mutations, shares a pathogenesis with marginal zone lymphoma, which is one of the clearest demonstrations that the genetic classification is tracking biology rather than clustering noise.","Clonality testing earns its place here more than almost anywhere, because the differential at the small-biopsy stage is a reactive marginal zone expansion, and that question is not answered by morphology alone."],"history":[{"year":1983,"title":"Isaacson and Wright describe MALT lymphoma","refs":[]},{"year":1993,"title":"H. pylori eradication induces regression of gastric MALT lymphoma (Wotherspoon)","refs":[]},{"year":2021,"title":"Zanubrutinib approved for relapsed marginal zone lymphoma","refs":["zanubrutinib"]}],"pipeline":["zanubrutinib","lenalidomide"],"openProblems":["Transformation to diffuse large B-cell lymphoma in a minority.","No standard sequence of therapies is proven by randomised trials.","Rare sites (lung, skin, dura) are managed by extrapolation."],"parent":"non-hodgkin-lymphoma"},{"id":"mediastinal-germ-cell-tumour","kind":"cancer","name":"Mediastinal germ cell tumour","aka":["Primary mediastinal germ cell tumour","Mediastinal seminoma","Primary mediastinal non-seminomatous germ cell tumour","PMNSGCT","Mediastinal teratoma"],"tldr":"A mediastinal germ cell tumour is a germ cell tumour that starts in the chest, between the lungs, rather than in the testis. Seminomas here are cured almost as often as testicular seminoma, but non-seminomas of the chest are the hardest germ cell tumours to cure, so they get four cycles of chemotherapy and surgery for what is left.","summary":"Germ cell tumours of the mediastinum arise in the anterior mediastinum, in or beside the thymus, from germ cells that stayed behind in the midline during development. The WHO classification of tumours of the thymus and mediastinum (5th edition, 2021) lists them with the same histological types as testicular disease: seminoma, embryonal carcinoma, yolk sac tumour, choriocarcinoma, teratoma (mature and immature) and mixed tumours, plus germ cell tumours with somatic-type malignancy or an associated haematological malignancy (Marx 2022). Diagnosis rests on imaging, the serum markers alpha-fetoprotein and beta-hCG, and biopsy where the markers are not raised.\n\nHow it differs from its parent: site decides the outlook. In the pooled analysis of 635 extragonadal germ cell tumours, 49 percent of patients with mediastinal non-seminoma were alive after platinum chemotherapy with or without surgery, against 63 percent with retroperitoneal non-seminoma, while seminoma had an 88 percent overall survival whatever the site (Bokemeyer 2002). A mediastinal non-seminomatous primary alone places a patient in the poor-risk group of the International Germ Cell Cancer Collaborative Group classification (Rosti 2019). Haematological malignancies (17 cases, above all acute leukaemias) occurred only in the 287 patients with mediastinal non-seminoma, an incidence of 2.0 percent a year and a standardised incidence ratio of 250 against the general population; none of those 17 survived two years (Hartmann 2000).\n\nHow common: no incidence figure is published for the mediastinal site alone; the parent page gives the share of germ cell tumours that arise outside the gonads.\n\nTreatment follows the parent's poor-risk pathway: four cycles of cisplatin-based chemotherapy (BEP or VIP), then resection of residual disease (NCI PDQ; EAU and ESMO testicular guidance as cited on the parent page). Surgery after chemotherapy is major: in 158 patients operated on over 25 years at Indiana, mean age 29, operative mortality was 6 percent, nine of the ten deaths from respiratory failure (Kesler 2008). Relapse is treated with the salvage regimens tested in the TIGER trial, which names primary mediastinal non-seminoma among its poorest-risk entrants.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Germ_cell_tumor","links":[{"label":"NCI PDQ: extragonadal germ cell tumours treatment","url":"https://www.cancer.gov/types/extragonadal-germ-cell/patient/extragonadal-treatment-pdq"},{"label":"WHO Classification of Tumours of the thymus and mediastinum, 5th edition (Marx 2022, JTO summary)","url":"https://doi.org/10.1016/j.jtho.2021.10.010"},{"label":"Bokemeyer 2002, JCO: extragonadal germ cell tumours of the mediastinum and retroperitoneum, 635 patients","url":"https://doi.org/10.1200/jco.2002.07.062"},{"label":"Hartmann 2000, JNCI: haematological disorders with primary mediastinal non-seminomatous germ cell tumours","url":"https://doi.org/10.1093/jnci/92.1.54"},{"label":"Kesler 2008, Ann Thorac Surg: 25 years of surgery for primary mediastinal non-seminomatous germ cell tumours","url":"https://doi.org/10.1016/j.athoracsur.2007.09.020"},{"label":"Rosti 2019, Seminars in Oncology: primary mediastinal germ cell tumours (review)","url":"https://doi.org/10.1053/j.seminoncol.2019.04.001"}],"tags":["subtype-page","wave4","rare"],"related":["extragonadal-germ-cell-tumour","retroperitoneal-germ-cell-tumour","cns-germ-cell-tumours","non-seminoma","seminoma","thymic-epithelial","hyperparathyroidism-jaw-tumour-syndrome"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["bleomycin","etoposide","cisplatin","ifosfamide"],"companies":[],"institutions":[],"pathways":[],"terms":["afp","tumour-markers","autologous-transplant"],"trials":["tiger-trial"],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2021-thymus-mediastinum-classification-marx-jto-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Rare and not counted separately by GLOBOCAN. In the international analysis of 635 extragonadal germ cell tumours treated at 11 centres from 1975 to 1996, 341 (54 percent) arose in the mediastinum; 83 percent of the whole series were non-seminomas (Bokemeyer 2002).","subtypes":["Mediastinal seminoma","Mediastinal non-seminomatous germ cell tumour (embryonal carcinoma, yolk sac tumour, choriocarcinoma, mixed)","Mediastinal teratoma (mature and immature)","Germ cell tumour with associated haematological malignancy"],"biomarkers":["Alpha-fetoprotein and beta-hCG at diagnosis and after each cycle","Lactate dehydrogenase","Isochromosome 12p on the biopsy","Blood count during follow-up, for the leukaemia risk in non-seminoma"],"standardOfCare":[{"setting":"Mediastinal seminoma","approach":"Treated as extragonadal seminoma: cisplatin-based chemotherapy, with PET to judge residual masses.","refs":["extragonadal-germ-cell-tumour","cisplatin","etoposide"]},{"setting":"Mediastinal non-seminoma","approach":"Four cycles of BEP or VIP, then resection of residual disease in a centre that does this surgery often; salvage as in the TIGER trial.","refs":["extragonadal-germ-cell-tumour","bleomycin","etoposide","cisplatin","ifosfamide","tiger-trial"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"extragonadal-germ-cell-tumour"},{"id":"mediastinal-grey-zone-lymphoma","kind":"cancer","name":"Mediastinal grey zone lymphoma","aka":["Mediastinal gray zone lymphoma","MGZL","Grey zone lymphoma","Gray zone lymphoma","B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma","B-cell lymphoma unclassifiable","Intermediate DLBCL/CHL"],"tldr":"A lymphoma of the chest that sits between two diseases: it has some of the features of primary mediastinal B-cell lymphoma and some of classic Hodgkin lymphoma, and a pathologist cannot put it cleanly in either. It is recognised as an entity of its own, and the 2022 classifications restricted the name to lymphomas that involve the mediastinum.","summary":"What it is. The mediastinum is the space in the middle of the chest between the lungs, and it contains the thymus. Two lymphomas grow there in young adults: primary mediastinal large B-cell lymphoma and nodular sclerosis classic Hodgkin lymphoma. They are biologically related, and some tumours fall between them, with the cell size and sheet-like growth of one and the surface markers of the other. WHO-HAEM5 describes it as a single biological group with a spectrum running from classic Hodgkin lymphoma to primary mediastinal B-cell lymphoma, with mediastinal grey zone lymphoma straddling the two.\n\nHow it differs from its neighbours. The distinguishing feature is the mismatch between what the cells look like and what they express. Classic Hodgkin lymphoma has rare large cells in a sea of immune cells and has lost most of its B-cell programme; grey zone lymphoma keeps a high density of tumour cells and keeps the B-cell markers. The International Consensus Classification writes that requirement down: a diagnosis needs both a high density of tumour cells and strong expression of at least two B-cell markers. A tumour that looks like nodular sclerosis Hodgkin lymphoma and happens to express CD20 variably is still Hodgkin lymphoma.\n\nWhat changed in 2022, and it is the whole of the name. The previous name was B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma, and it could be applied anywhere in the body. Both 2022 classifications restricted it to the mediastinum, because cases with the same appearance arising elsewhere turned out to have different gene expression and different DNA changes. Those are now classified as diffuse large B-cell lymphoma, not otherwise specified. This is one of the few places where the two classifications agree completely, and it changes the diagnosis of a real group of patients.\n\nHow it presents. Almost always as a large mass in the front of the chest in a young adult, more often a man, sometimes causing swelling of the face and arms and breathlessness from pressure on the great veins, which is an emergency. Sequential cases of primary mediastinal B-cell lymphoma and nodular sclerosis Hodgkin lymphoma in the same person have been shown to share a clonal origin, which is part of the evidence that the three diseases are one biological family.\n\nHow it is treated. As an aggressive B-cell lymphoma rather than as Hodgkin lymphoma: regimens built for large B-cell lymphoma, with rituximab, are preferred, because the tumour keeps its B-cell markers. There is no randomised trial in this entity and the series are small. The treatment layer of this family and the primary mediastinal B-cell lymphoma page carry the regimens.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Primary_mediastinal_B-cell_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["primary-mediastinal-b-cell-lymphoma","hodgkin-lymphoma","dlbcl","non-hodgkin-lymphoma","ebv-positive-dlbcl"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","fdg-pet"],"targets":["cd30","cd20"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-classification-2022","lymphoma-indolent-versus-aggressive","lugano-classification","deauville-score","lymphoma-tx-radiotherapy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"In the United Kingdom population series that reports lymphoma by subtype, 24 of 5,796 lymphomas (0.4 per cent) were recorded in the category then called intermediate between diffuse large B-cell and classic Hodgkin lymphoma: a crude incidence of 0.22 per 100,000 a year and a European age-standardised rate of 0.08, with men affected about twice as often as women and a median age at diagnosis of 59.3 years. Five-year relative survival in that series was 84.0 per cent, although the numbers are small and the confidence interval ran from 61 to 94 per cent.","subtypes":[],"biomarkers":["A high density of tumour cells, which separates it from classic Hodgkin lymphoma","Strong expression of at least two B-cell markers (CD20, CD79a, PAX5), which the International Consensus Classification requires for the diagnosis","CD30 and often CD15, shared with classic Hodgkin lymphoma","Involvement of the mediastinum, which both 2022 classifications now require","Epstein-Barr virus, which is usually negative; an EBV-positive tumour with Hodgkin-like cells is classified as EBV-positive diffuse large B-cell lymphoma instead"],"standardOfCare":[{"setting":"Making the diagnosis, and the trap in it","approach":"The diagnosis needs a generous biopsy, because the appearance varies across a single tumour and a core needle may sample only the part that looks like one of the neighbouring diseases. Both 2022 classifications require involvement of the mediastinum: an identical-looking tumour elsewhere in the body is diffuse large B-cell lymphoma, not otherwise specified. A nodular sclerosis classic Hodgkin lymphoma with variable CD20 expression remains Hodgkin lymphoma and is not reclassified here.","refs":["histopathology-ihc","cd30","cd20","lymphoma-classification-2022"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Treatment","approach":"Treated with regimens designed for aggressive large B-cell lymphoma and containing rituximab, rather than with Hodgkin lymphoma chemotherapy, because the tumour retains its B-cell programme and the surface target with it. Radiotherapy to the residual mediastinal mass is used in some series. There is no randomised trial in this entity, the published series number in the tens, and the regimen is chosen in a multidisciplinary meeting; the detail sits on the primary mediastinal B-cell lymphoma page and in the treatment layer of this family.","refs":["primary-mediastinal-b-cell-lymphoma","rituximab","lymphoma-tx-regimen-alphabet","lymphoma-tx-radiotherapy","r-chop"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":2008,"title":"Named as an unclassifiable category","note":"The fourth edition of the WHO classification created B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma, which could be diagnosed at any site.","refs":["hodgkin-lymphoma"]},{"year":2021,"title":"The mutational landscape of grey zone lymphoma","note":"Sequencing showed that cases arising outside the mediastinum carry different gene expression profiles and DNA alterations from those arising in it, which is the evidence both 2022 classifications used to restrict the name.","refs":["primary-mediastinal-b-cell-lymphoma"]},{"year":2022,"title":"Renamed and restricted to the mediastinum","note":"WHO-HAEM5 and the International Consensus Classification both adopted the name mediastinal grey zone lymphoma and both reassigned non-mediastinal cases to diffuse large B-cell lymphoma, not otherwise specified.","refs":["lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["No randomised trial has been run in this entity and none is likely: it is about one lymphoma in 250, so the evidence will stay observational.","Pathologists disagree about the boundary with nodular sclerosis classic Hodgkin lymphoma more often than about almost any other lymphoma boundary, and the treatment that follows the two diagnoses is different.","Whether radiotherapy to a residual mediastinal mass adds anything after modern immunochemotherapy has not been tested here."],"parent":"non-hodgkin-lymphoma"},{"id":"colorectal-medullary-carcinoma","kind":"cancer","name":"Medullary carcinoma of the colon","aka":["Medullary carcinoma of the large intestine","Medullary colorectal carcinoma","Medullary adenocarcinoma of the colon"],"tldr":"Medullary carcinoma is a very rare form of bowel cancer in which sheets of poorly formed cells are packed with immune cells; almost all cases are mismatch-repair deficient and it occurs mostly in older women on the right side. Despite its ugly appearance it does at least as well as ordinary bowel cancer, and because of its immune features it is a natural candidate for immunotherapy.","summary":"The WHO classification lists medullary carcinoma as a distinct colorectal adenocarcinoma type with solid sheets of poorly differentiated cells, vesicular nuclei and a prominent intraepithelial lymphocytic infiltrate, nearly always mismatch-repair deficient (Nagtegaal 2020). In SEER it was extremely rare (5 to 8 per 10,000 colon cancers), most common in the proximal colon, twice as common in women who presented at a lower stage with a trend to favourable prognosis, and no case was reliably identified in the rectum or appendix (International Journal of Oncology 2010). Loss of MLH1 and PMS2 was found in more than 80 percent of 18 cases, most were negative for CK7, CK20 and CDX2, and cadherin-17 and SATB2 were expressed in 89 percent, which matters when it presents as a carcinoma of unknown primary (Archives of Pathology 2014). In 105 cases the microenvironment showed strong interferon-gamma-induced immunoregulatory gene expression, including IDO-1, distinct from other microsatellite-unstable carcinomas (Modern Pathology 2016).\n\nHow it differs from its parent: it is the extreme of the mismatch-repair deficient, right-sided, immune-rich colon cancer that the MSI-high page describes, with a distinctive marker profile (CDX2-negative) that can mislead the pathologist.\n\nHow common: 5 to 8 per 10,000 colon cancers (International Journal of Oncology 2010).\n\nTreatment: as the colorectal and MSI-high pages by stage, with checkpoint inhibitors for mismatch-repair deficient disease; there is no trial in the type.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Colorectal_cancer","links":[{"label":"Nagtegaal 2020, Histopathology: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"International Journal of Oncology 2010: medullary carcinoma of the large intestine, SEER population analysis","url":"https://doi.org/10.3892/ijo_00000741"},{"label":"Archives of Pathology 2014: cadherin-17 and SATB2 in medullary carcinoma of the large intestine","url":"https://doi.org/10.5858/arpa.2013-0452-oa"},{"label":"Modern Pathology 2016: medullary carcinoma of the colon, immunoregulatory microenvironment in 105 cases","url":"https://doi.org/10.1038/modpathol.2016.54"}],"tags":["subtype-page","wave4","colorectal"],"related":["colorectal","msi-high-colorectal","colon-cancer","colorectal-mucinous-adenocarcinoma","cancer-of-unknown-primary"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab","nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 5 to 8 cases for every 10,000 colon cancers, a mean annual incidence of 3.47 per 10 million population in SEER 1973 to 2006; mean age 69.3, twice as common in women, 74 percent in the proximal colon (International Journal of Oncology 2010).","subtypes":["Medullary carcinoma, mismatch-repair deficient (the usual form; right-sided, MSI-high)","Medullary carcinoma, mismatch-repair proficient (rare)"],"biomarkers":["MLH1 and PMS2 loss (over 80 percent)","Cadherin-17 and SATB2 positive; CK7, CK20 and CDX2 usually negative","Tumour-infiltrating lymphocytes and IDO-1 expression","BRAF V600E (sporadic MSI-high)"],"standardOfCare":[{"setting":"All stages","approach":"Treated as MSI-high colorectal cancer by stage, with checkpoint inhibitors for mismatch-repair deficient disease.","refs":["msi-high-colorectal","colorectal","pembrolizumab","nivolumab"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"colorectal"},{"id":"medullary-thyroid-cancer","kind":"cancer","name":"Medullary thyroid cancer","aka":["Medullary thyroid carcinoma","MTC"],"tldr":"Medullary thyroid cancer comes from the calcitonin-making C cells, not the thyroid hormone cells, so radioactive iodine does not work. Surgery is the only cure, a quarter of cases run in families through the RET gene, and the RET-selective drug selpercatinib has transformed treatment of advanced disease.","summary":"Medullary thyroid cancer arises from the parafollicular C cells and secretes calcitonin, which serves as its tumour marker. Germline RET mutations cause the hereditary forms (MEN2A, MEN2B and familial medullary thyroid cancer), and children who inherit them have the thyroid removed before cancer develops, timed by the mutation's risk level; most sporadic tumours carry a somatic RET M918T mutation, and a minority RAS mutations. Total thyroidectomy with central neck dissection is the only curative treatment, and calcitonin doubling time guides follow-up. For progressive advanced disease, vandetanib (2011) and cabozantinib (2012) were the first approved kinase inhibitors; selpercatinib, a RET-selective inhibitor, beat them in the LIBRETTO-531 trial and is now the standard for RET-mutant disease, with pralsetinib as an alternative. Phaeochromocytoma must be excluded before any thyroid surgery in MEN2.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Medullary_thyroid_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Medullary_thyroid_cancer"}],"tags":["subtype-page"],"related":["anaplastic-thyroid-cancer","follicular-thyroid-cancer","papillary-thyroid-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["exam","zeta"],"people":[],"bottlenecks":[],"keyPapers":["paper-libretto-531-nejm-2023","paper-ata-medullary-thyroid-guideline-wells-thyroid-2015","paper-exam-cabozantinib-mtc-elisei-jco-2013","paper-zeta-vandetanib-mtc-wells-jco-2012"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"Two to four percent of thyroid cancers; a quarter are inherited through a RET mutation in the multiple endocrine neoplasia type 2 syndromes; ten-year survival ranges from above 95 percent for disease confined to the thyroid to under half once distant spread has occurred.","subtypes":["Sporadic (about 75 percent)","Hereditary: MEN2A (with phaeochromocytoma and hyperparathyroidism)","Hereditary: MEN2B (mucosal neuromas, marfanoid habitus, early aggressive disease)","Familial medullary thyroid cancer only"],"biomarkers":["Calcitonin and CEA (diagnosis, follow-up and doubling time)","Germline RET testing in every patient","Somatic RET M918T","RAS mutations in RET-negative tumours"],"standardOfCare":[{"setting":"Hereditary RET carriers","approach":"Prophylactic total thyroidectomy in childhood, timed by the RET codon risk category (before age one in MEN2B).","refs":["ret","multiple-endocrine-neoplasia"]},{"setting":"Localised disease","approach":"Total thyroidectomy with central compartment dissection, lateral dissection when nodes are involved; no radioactive iodine; levothyroxine replacement only.","refs":["thyroid"]},{"setting":"Advanced RET-mutant disease","approach":"Selpercatinib first line (LIBRETTO-531 beat cabozantinib and vandetanib); pralsetinib as an alternative.","refs":["selpercatinib","pralsetinib","ret"]},{"setting":"Advanced RET-negative disease","approach":"Cabozantinib or vandetanib; external radiotherapy for local control; somatostatin analogues for diarrhoea from calcitonin.","refs":["cabozantinib","vandetanib"]}],"stateOfArt":["Selpercatinib gave a response rate near 70 percent and much longer progression-free survival than the older multikinase drugs, with fewer side effects.","Genetic testing and prophylactic surgery have made hereditary medullary cancer a preventable disease in tested families.","Calcitonin doubling time is one of the most reliable prognostic tools in any cancer."],"history":[{"year":1959,"title":"Hazard describes medullary thyroid carcinoma as a distinct tumour","refs":[]},{"year":1993,"title":"RET mutations found to cause MEN2","refs":["ret"]},{"year":2011,"title":"Vandetanib approved","refs":["vandetanib"]},{"year":2012,"title":"Cabozantinib approved (EXAM trial)","refs":["cabozantinib"]},{"year":2020,"title":"Selpercatinib approved for RET-mutant disease","refs":["selpercatinib"]},{"year":2023,"title":"LIBRETTO-531: selpercatinib beats the multikinase drugs first line","refs":["selpercatinib"]}],"pipeline":["selpercatinib"],"openProblems":["No cure once the disease has spread beyond the neck.","Resistance mutations to RET inhibitors (G810) are emerging.","RET-negative sporadic disease has no targeted option."],"parent":"thyroid"},{"id":"medulloblastoma","kind":"cancer","name":"Medulloblastoma","aka":[],"tldr":"Medulloblastoma is the most common malignant childhood brain tumour, arising in the cerebellum. Surgery, radiation to the whole brain and spine, and chemotherapy cure about 70%, at a heavy cost to thinking and growth; treatment is now being tailored to four molecular subgroups so that the low-risk children get less.","summary":"Medulloblastoma is an embryonal tumour of the posterior fossa with four consensus molecular subgroups (WNT, SHH, Group 3, Group 4) that differ in age, genetics, metastatic tendency and survival: WNT (~10%, CTNNB1 mutations, >95% survival), SHH (~30%, PTCH1/SUFU/SMO, TP53-mutant subset with shorter survival; infants and adults), Group 3 (~25%, MYC amplification, worst prognosis) and Group 4 (~35%, most common, intermediate). WHO 2021 integrates histology and molecular group.\n\nStandard therapy is maximal safe resection, craniospinal irradiation (CSI; 23.4 Gy for average risk, 36 Gy for high risk) with posterior fossa/tumour bed boost, and adjuvant cisplatin-based chemotherapy (cisplatin, vincristine, cyclophosphamide, lomustine). Infants under 3 receive radiation-sparing intensive chemotherapy (with high-dose chemotherapy/autologous rescue or intraventricular methotrexate) because CSI causes lasting harm to the developing brain. Risk-adapted trials (SJMB12, ACNS1422, SIOP PNET5) are reducing CSI dose for WNT tumours and testing SMO inhibitors for SHH tumours in skeletally mature patients. Proton therapy reduces exit dose to cochlea, heart and thyroid. Relapse is rarely curable outside infants; MRI-based surveillance, cfDNA in CSF, and survivorship (neurocognition, endocrine, hearing, second cancers, cerebellar mutism) dominate follow-up.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Medulloblastoma","links":[{"label":"NCI PDQ: childhood medulloblastoma","url":"https://www.cancer.gov/types/brain/patient/child-medulloblastoma-treatment-pdq"},{"label":"Taylor 2012 consensus subgroups","url":"https://doi.org/10.1007/s00401-011-0922-z"},{"label":"Children's Oncology Group","url":"https://childrensoncologygroup.org/"}],"tags":["gap-fill","paediatric","cns"],"related":["national-brain-tumor-society","atrt","ependymoma","cns-germ-cell-tumours","glioblastoma"],"cancers":[],"sections":[],"technologies":["proton-therapy","imrt-igrt","methylation-profiling","autologous-stem-cell-transplant","cytotoxic-chemotherapy","mri","survivorship-care-plan","antineoplastons"],"targets":["smoothened","tp53"],"drugs":["cisplatin","carboplatin","vincristine","cyclophosphamide","lomustine","methotrexate","temozolomide","irinotecan","vismodegib","carmustine"],"companies":["roche-genentech","childrens-oncology-group"],"institutions":[],"pathways":["wnt","p53-cell-cycle"],"terms":["blood-brain-barrier"],"trials":["ccss","acns0332"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"The most common malignant brain tumour of childhood (~20% of paediatric CNS tumours; ~500 cases per year in the US), peak age 3-8; also occurs in adults.","subtypes":["WNT-activated (best prognosis)","SHH-activated, TP53-wild-type","SHH-activated, TP53-mutant (poor)","Group 3 (MYC-amplified subset very poor)","Group 4","Adult medulloblastoma (mostly SHH)"],"biomarkers":["Molecular subgroup (methylation profiling; IHC surrogates β-catenin, GAB1, YAP1)","MYC / MYCN amplification","TP53 mutation (SHH)","Metastatic stage (Chang M0-M4) by MRI and CSF cytology","Extent of resection (residual >1.5 cm²)","Histology (desmoplastic/nodular, large cell/anaplastic)","Germline testing (SUFU, PTCH1, TP53, BRCA2, PALB2, APC)"],"standardOfCare":[{"setting":"Average risk (≥3 years, M0, <1.5 cm² residual, no MYC amp)","approach":"Resection, CSI 23.4 Gy with boost to 54 Gy (proton where available), then cisplatin/vincristine/cyclophosphamide or lomustine-based chemotherapy (ACNS0331); WNT tumours receive reduced CSI in trials.","refs":["cisplatin","vincristine","cyclophosphamide","lomustine","proton-therapy","imrt-igrt"],"guideline":{"version":"COG ACNS0331; SIOP PNET5","url":"https://doi.org/10.1200/JCO.20.02730"}},{"setting":"High risk (metastatic, residual, anaplastic, MYC)","approach":"CSI 36 Gy ± concurrent carboplatin (ACNS0332 for Group 3), then multi-agent chemotherapy; high-dose chemotherapy with stem-cell rescue in some protocols.","refs":["carboplatin","cisplatin","cyclophosphamide","autologous-stem-cell-transplant"],"guideline":{"version":"COG ACNS0332"}},{"setting":"Infants (<3 years)","approach":"Radiation-avoiding intensive chemotherapy (Head Start, HIT-SKK with intraventricular methotrexate); desmoplastic/SHH infants do well, Group 3 infants poorly.","refs":["methotrexate","cyclophosphamide","autologous-stem-cell-transplant"]},{"setting":"Relapsed","approach":"Re-irradiation, temozolomide-irinotecan ± bevacizumab, SMO inhibitor (vismodegib/sonidegib) for SHH in post-pubertal patients, clinical trials; cure is rare.","refs":["temozolomide","irinotecan","bevacizumab","vismodegib"]}],"stateOfArt":["Four molecular subgroups (2012) now define trials; the goal is to de-escalate for WNT and SHH-favourable tumours and intensify for MYC-amplified Group 3.","Proton CSI reduces long-term hearing, endocrine and cardiac toxicity without loss of control.","Survival is ~70-75% overall but neurocognitive decline of 2-4 IQ points per year after CSI in young children is the price.","Targeted therapy exists only for SHH (SMO inhibitors) and only after skeletal maturity, because of growth-plate fusion."],"history":[{"year":1925,"title":"Bailey and Cushing name medulloblastoma","refs":[]},{"year":1953,"title":"Craniospinal irradiation introduced (Paterson and Farr)","note":"First cures.","refs":[]},{"year":1990,"title":"Chemotherapy after radiation improves survival (Packer)","refs":["cisplatin","vincristine"]},{"year":2006,"title":"Reduced-dose CSI (23.4 Gy) safe for average risk with chemotherapy (CCG 9892/ACNS0331)","refs":[]},{"year":2012,"title":"Four molecular subgroups agreed (Taylor et al., Acta Neuropathol)","refs":[]},{"year":2016,"title":"WHO integrates molecular groups into classification","refs":[]},{"year":2017,"title":"Proton CSI: equivalent control, fewer toxicities (Yock, Lancet Oncol)","refs":["proton-therapy"]},{"year":2021,"title":"SJMB03 subgroup outcomes; ACNS0331 shows CSI dose reduction below 23.4 Gy unsafe for most","refs":[]}],"pipeline":["proton-therapy","vismodegib","methylation-profiling"],"openProblems":["Group 3 MYC-amplified and SHH TP53-mutant tumours: survival under 50%.","Relapse after craniospinal irradiation is rarely curable; it is where new approaches are most needed.","Neurocognitive, endocrine and hearing sequelae in survivors.","Infants: curing Group 3 without radiation.","Access to proton therapy and methylation profiling globally."],"parent":"brain-tumours"},{"id":"melanoma","kind":"cancer","name":"Melanoma","aka":[],"tldr":"The skin cancer that proved immunotherapy works: half of advanced patients now live 10 years. Also the first with an approved TIL therapy, an oncolytic virus, and a positive phase 3 personalised vaccine.","summary":"Melanoma arises from pigment cells; most cases are cured by excision when found early, and it is the skin cancer most likely to spread when it is not. Risk is driven by ultraviolet exposure and fair skin; the tumour carries the highest mutation burden of any common cancer, which is why it became the proving ground for immunotherapy. About half of cutaneous melanomas carry BRAF V600 mutations, a quarter NRAS, and acral and mucosal subtypes carry KIT alterations; uveal melanoma is a distinct disease driven by GNAQ/GNA11 and BAP1.\n\nThe treatment revolution began in 2011 with ipilimumab and vemurafenib and accelerated with PD-1 blockade (2014). Nivolumab-ipilimumab now delivers ~50% melanoma-specific survival at ten years in advanced disease (CheckMate 067), pembrolizumab 34% overall survival at ten years (KEYNOTE-006), and nivolumab-relatlimab offers a gentler doublet. For BRAF-mutant disease, DREAMseq settled that immunotherapy should come first. In resectable stage III disease, NADINA and SWOG S1801 moved immunotherapy to before surgery with response-adapted follow-on treatment, and adjuvant PD-1 or BRAF/MEK covers stage IIB-III. After immunotherapy fails, lifileucel TIL therapy (2024) and the oncolytic virus RP1 with nivolumab (2026) are approved; tebentafusp is the first survival-extending drug in metastatic uveal melanoma. Intismeran autogene plus pembrolizumab became the first personalised mRNA vaccine to pass a phase 3 in August 2026.\n\nOpen problems: roughly 40% of advanced patients never respond to immunotherapy, and second-line options after PD-1 failure remain limited; LAG-3 blockade failed as adjuvant therapy and with a different PD-1 partner; adjuvant treatment of stage II over-treats most patients; uveal, mucosal, and acral subtypes lag far behind; brain metastases affect up to half of advanced patients; and half the world's population lacks the HLA type required by the T-cell-receptor drugs.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Melanoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Melanoma"}],"tags":["skin","spike"],"related":["basal-cell-carcinoma","cutaneous-scc","merkel-cell-carcinoma","immunotherapy-roadmap","io-first-then-braf-mek","neoadjuvant-io-response-adapted","lag3-adjuvant-caution","io-then-til","oncolytic-plus-pd1","vaccine-plus-pd1"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","til-therapy","oncolytic-virus","neoantigen-mrna-vaccine","kinase-inhibitors","t-cell-engager","tcr-t","mistletoe-extracts","gerson-therapy-detox-regimens","dermoscopy-ai","sentinel-node","sbrt","mrd-testing"],"targets":["pd1","ctla4","lag3","braf","kit","gp100","mage-a4","prame"],"drugs":["vemurafenib","binimetinib","cobimetinib","brenetafusp","fianlimab","caris-mi-cancer-seek","dacarbazine","tasonermin"],"companies":["microbiotica","philogen-s-p-a","bioinvent-international","multitude-therapeutics","neonc-technologies","shanghai-kechow-pharma","aura-biosciences","georgiamune","hangzhou-hanx-biopharmaceuticals","ionctura","krystal-biotech","mabxience-research-s-l","scancell","vyriad","bms","merck","regeneron","immunocore","iovance","replimune","moderna","roche-genentech","pfizer","novartis","immatics","swog","ecog-acrin"],"institutions":["nki","moffitt","ucla-jonsson"],"pathways":["pd1-checkpoint","ras-mapk","melanoma-signalling"],"terms":["breslow-thickness","ulceration-melanoma","major-pathological-response","hla-a02-restriction","irae"],"trials":["nct06697301","nct05155254","nct05732805","nct05751928","nct06743126","nct06624644","seacraft-2","nct06054555","nct06581406","nct06246916","nct05727904","nct04674683","nct06640530","nct05608291","nct05625399","nct02362594","nct05270044","nct04099251","nct05022901","nct05549297","nct04657991","nct05987332","nct02938299","nct03567889","nct07221734","checkmate-915","keynote-006","relativity-047","nadina","swog-s1801","keynote-716","combi-ad","columbus","dreamseq","c-144-01","imcgp100-202","mslt-ii","prism-mel-301","fianlimab-phase3-melanoma","relativity-098"],"people":[],"bottlenecks":[],"keyPapers":["paper-esteva-skin-cancer-deep-learning-nature-2017"],"journals":["melanoma-research","pigment-cell-and-melanoma-research"],"dependsOn":[],"notes":[],"group":"skin","burden":"Melanoma causes about 330,000 cases per year, and incidence is rising in fair-skinned populations.","subtypes":["Superficial spreading (most common cutaneous)","Nodular","Lentigo maligna (chronically sun-damaged skin)","Acral lentiginous (palms, soles, nails; KIT/NRAS; not UV-driven)","Mucosal (KIT, low TMB, poor IO response)","Uveal (GNAQ/GNA11, BAP1; HLA-A*02 tebentafusp)","Desmoplastic (very high TMB, IO-sensitive)","BRAF V600-mutant (~50%)","NRAS-mutant (~25%)","Triple wild-type"],"biomarkers":["BRAF V600","NRAS","KIT (acral/mucosal)","PD-L1 (weak)","TMB","HLA-A*02:01 (tebentafusp)","Breslow thickness and ulceration (staging)","Sentinel node status","BRAF V600E/K (targeted therapy eligibility)","NRAS, KIT (subtype and trial eligibility)","HLA-A*02:01 (tebentafusp, brenetafusp)","PRAME (diagnostic IHC; TCR target)","LDH (prognostic in stage IV)","ctDNA (investigational for MRD and response)","TMB and interferon signatures (research predictors of IO response)"],"standardOfCare":[{"setting":"Stage II-III","approach":"Adjuvant pembrolizumab/nivolumab; neoadjuvant IO for resectable stage III.","refs":["pembrolizumab","nivolumab","sentinel-node"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Metastatic first line","approach":"Nivolumab-ipilimumab or nivolumab-relatlimab; BRAF/MEK if rapid control needed.","refs":["checkmate-067","relatlimab-nivolumab","encorafenib"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"After PD-1","approach":"Lifileucel, RP1 + nivolumab, ipilimumab-based, trials; tebentafusp (uveal).","refs":["lifileucel","vusolimogene-oderparepvec","tebentafusp"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Screening and diagnosis","approach":"Dermoscopy, total-body photography for high-risk patients, excisional biopsy with Breslow thickness and ulceration reported; AI decision support emerging.","refs":["dermoscopy-ai","breslow-thickness","ulceration-melanoma"]},{"setting":"Stage I-II primary","approach":"Wide local excision with margins by thickness (1-2 cm); sentinel lymph node biopsy from ~0.8 mm Breslow or with ulceration; nodal ultrasound surveillance rather than completion dissection if positive (MSLT-II).","refs":["sentinel-node","mslt-ii","ultrasound"],"guideline":{"nccn":"Category 1 for SLNB thresholds","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Stage IIB-IIC (thick or ulcerated, node-negative)","approach":"Adjuvant pembrolizumab or nivolumab for one year (KEYNOTE-716, CheckMate 76K); discuss modest absolute benefit and irAE risk; ctDNA-guided trials.","refs":["keynote-716","pembrolizumab","nivolumab"],"guideline":{"nccn":"2A","esmoMcbs":"A","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Resectable stage III (macroscopic nodes)","approach":"Neoadjuvant ipilimumab + nivolumab (two cycles) then surgery with response-adapted adjuvant therapy (NADINA), or neoadjuvant pembrolizumab (SWOG S1801); alternative adjuvant-only PD-1 or, if BRAF-mutant, dabrafenib-trametinib.","refs":["nadina","swog-s1801","combi-ad","major-pathological-response"],"guideline":{"nccn":"Preferred (neoadjuvant IO)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Stage III after surgery (adjuvant)","approach":"Nivolumab or pembrolizumab for one year; dabrafenib-trametinib for BRAF V600 (COMBI-AD, 10-year RFS 48%); relatlimab adds nothing (RELATIVITY-098).","refs":["combi-ad","dabrafenib-trametinib","relativity-098"],"guideline":{"nccn":"1","esmoMcbs":"A"}},{"setting":"Unresectable or metastatic, first line","approach":"Nivolumab + ipilimumab (highest long-term survival; ~59% grade 3-4 events) or nivolumab + relatlimab (Opdualag; ~21%) or anti-PD-1 alone; for BRAF-mutant disease, immunotherapy first (DREAMseq) unless rapid control is needed.","refs":["checkmate-067","relativity-047","keynote-006","dreamseq","io-first-then-braf-mek"],"guideline":{"nccn":"1 (preferred)","esmoMcbs":"4-5"}},{"setting":"BRAF V600-mutant, after immunotherapy or needing rapid response","approach":"BRAF + MEK doublet: encorafenib-binimetinib, dabrafenib-trametinib, or vemurafenib-cobimetinib; triplet with atezolizumab is approved but little used.","refs":["columbus","encorafenib","binimetinib","vemurafenib","cobimetinib","braf-plus-mek"],"guideline":{"nccn":"1"}},{"setting":"After anti-PD-1 failure","approach":"Lifileucel TIL therapy (accelerated approval 2024), RP1 oncolytic virus + nivolumab (2026), ipilimumab-based rechallenge, brenetafusp trials; clinical trials strongly encouraged.","refs":["lifileucel","c-144-01","vusolimogene-oderparepvec","prism-mel-301","brenetafusp"],"guideline":{"nccn":"2A"}},{"setting":"Metastatic uveal melanoma (HLA-A*02:01-positive)","approach":"Tebentafusp (OS benefit, IMCgp100-202); liver-directed therapy for hepatic-dominant disease; ipilimumab-nivolumab has modest activity.","refs":["tebentafusp","imcgp100-202","hla-a02-restriction"],"guideline":{"nccn":"1"}},{"setting":"Brain metastases","approach":"Nivolumab + ipilimumab for asymptomatic disease (~50% intracranial response, CheckMate 204); stereotactic radiosurgery; BRAF/MEK for symptomatic BRAF-mutant disease.","refs":["nivolumab","ipilimumab","sbrt"]}],"stateOfArt":["10-year survival ~50% with IO doublet.","First cell therapy for a solid tumour.","First positive phase 3 personalised vaccine.","About half of patients with advanced melanoma treated with nivolumab-ipilimumab are alive at ten years, and a third of those on pembrolizumab; durable remissions persist off treatment.","Neoadjuvant immunotherapy with response-adapted follow-on treatment (NADINA, SWOG S1801) is the new standard for resectable stage III disease and lets most patients skip a year of adjuvant therapy.","Sequencing is settled for BRAF-mutant disease: immunotherapy first, targeted therapy in reserve.","Post-PD-1 options now exist: TIL therapy, an oncolytic virus with nivolumab, and PRAME-directed T-cell engagers in phase 3.","The first personalised mRNA vaccine to pass a phase 3 (intismeran, August 2026) did so in melanoma.","Completion lymph node dissection has been abandoned after MSLT-II, sparing most stage III patients lymphoedema."],"history":[{"year":1975,"title":"Dacarbazine: ~10% response, standard for 35 years","refs":[]},{"year":1992,"title":"High-dose interleukin-2 produces rare durable cures","note":"The first evidence that the immune system alone could eradicate metastatic melanoma.","refs":["cytokine-therapy"]},{"year":2002,"title":"BRAF V600E mutations discovered in ~50% of melanomas","note":"Davies et al., Nature.","refs":["braf"]},{"year":2010,"title":"Ipilimumab is the first drug to extend survival in metastatic melanoma","note":"Hodi et al., NEJM.","refs":["ipilimumab"]},{"year":2011,"title":"Ipilimumab and vemurafenib approved","refs":["ipilimumab"]},{"year":2011,"title":"Ipilimumab and vemurafenib approved","note":"Immunotherapy and targeted therapy arrive in the same year.","refs":["vemurafenib","ipilimumab"]},{"year":2014,"title":"PD-1 inhibitors approved","refs":["pembrolizumab","nivolumab"]},{"year":2014,"title":"Pembrolizumab and nivolumab approved; first BRAF/MEK combination (dabrafenib-trametinib)","refs":["pembrolizumab","nivolumab","dabrafenib-trametinib"]},{"year":2015,"title":"T-VEC: first oncolytic virus","refs":["talimogene-laherparepvec"]},{"year":2015,"title":"CheckMate 067 combination and KEYNOTE-006; T-VEC first oncolytic virus; cobimetinib","refs":["checkmate-067","keynote-006","talimogene-laherparepvec","cobimetinib"]},{"year":2017,"title":"COMBI-AD and CheckMate 238 establish adjuvant therapy for stage III; MSLT-II ends completion dissection","refs":["combi-ad","mslt-ii"]},{"year":2018,"title":"Encorafenib + binimetinib approved (COLUMBUS); Nobel Prize to Allison and Honjo","refs":["columbus","encorafenib","binimetinib"]},{"year":2021,"title":"DREAMseq sets sequencing; KEYNOTE-716 extends adjuvant IO to stage II; tebentafusp phase 3 positive","refs":["dreamseq","keynote-716","imcgp100-202"]},{"year":2022,"title":"Nivolumab-relatlimab (Opdualag) approved; tebentafusp approved; SWOG S1801 shows neoadjuvant benefit","refs":["relativity-047","relatlimab-nivolumab","tebentafusp","swog-s1801"]},{"year":2024,"title":"Lifileucel: first TIL therapy","refs":["lifileucel"]},{"year":2024,"title":"NADINA neoadjuvant phase 3; lifileucel first TIL therapy; KEYNOTE-006 ten-year data; COMBI-AD ten-year data","refs":["nadina","lifileucel","c-144-01","keynote-006","combi-ad"]},{"year":2025,"title":"RELATIVITY-098 adjuvant LAG-3 negative; CheckMate 067 ten-year survival ~50%","refs":["relativity-098","checkmate-067"]},{"year":2026,"title":"Intismeran phase 3 positive; RP1 approved","refs":["interpath-001","vusolimogene-oderparepvec"]},{"year":2026,"title":"Intismeran autogene phase 3 positive; RP1 approved with nivolumab; fianlimab-cemiplimab phase 3 misses; brenetafusp phase 3 enrolling","refs":["interpath-001","intismeran-autogene","vusolimogene-oderparepvec","fianlimab-phase3-melanoma","prism-mel-301"]}],"pipeline":["intismeran-autogene","vusolimogene-oderparepvec","lifileucel","tebentafusp","ceralasertib","darovasertib","eik1001","gotistobart","io102-io103","bcd-217","cobolimab","bcd-100","ima203","lns8801","naporafenib","ibi363","t3011","trk-950","jk08","gc101-til","ba3071","env-501","enb003","prtx007","au-007","or502","doc1021","interpath-001","brenetafusp","prism-mel-301","prame","fianlimab","idea-ctdna-guided-adjuvant-melanoma","idea-prame-tcr-beyond-a02","mrd-testing","dermoscopy-ai","neoadjuvant-io-response-adapted","immuno-pet","tcr-t"],"openProblems":["Primary IO resistance in ~40%.","Uveal and mucosal subtypes.","Brain metastases.","Primary resistance: about 40% of advanced patients never respond to PD-1-based therapy, and predictive biomarkers (PD-L1, TMB, interferon signatures) remain too weak to guide choices.","After PD-1 failure, the approved options (TIL therapy, RP1 with nivolumab) respond in ~30% at best; for the rest melanoma remains life-limiting, and PRAME-directed T-cell engagers are the next attempt.","LAG-3 blockade is not a class effect: it failed as adjuvant therapy and with cemiplimab, so the biology of when it helps is unresolved.","Adjuvant therapy in stage IIB/IIC treats many to benefit few; ctDNA-guided selection is unproven.","Uveal, mucosal, and acral melanomas respond poorly to checkpoint inhibitors and have few targeted options.","Brain metastases occur in up to half of advanced patients; no treatment reliably controls leptomeningeal disease.","T-cell-receptor drugs require HLA-A*02:01, excluding most people of African and East Asian ancestry.","Long-term immune toxicity (endocrinopathies, arthritis) in cured patients is under-studied."],"prognosis":{"text":"In the United States, 94.7% of people diagnosed with melanoma of the skin in 2016-2022 were alive five years later, relative to people of the same age without the disease. 77% of melanomas are found while still confined to the skin, with five-year relative survival of 100%; it is 76% for regional disease (10% of cases) and 34% for distant disease (5% of cases). The distant-stage figure describes people diagnosed in 2016-2022 and only partly reflects the immunotherapy combinations that now keep a growing share of people with advanced melanoma alive long term.","sources":[{"label":"SEER Cancer Stat Facts: Melanoma of the Skin","url":"https://seer.cancer.gov/statfacts/html/melan.html"}]},"parent":"skin-cancer"},{"id":"urethral-melanoma","kind":"cancer","name":"Melanoma of the urethra","aka":["Urethral melanoma","Primary malignant melanoma of the urethra","Urethral melanoma (very rare)","Genitourinary mucosal melanoma"],"tldr":"Melanoma of the urethra is a very rare urethral cancer that starts in pigment cells of the urethral lining, usually near its outer opening, in older adults. It is a form of mucosal melanoma, so it is removed surgically and, when it spreads, treated with the immunotherapy drugs used for melanoma elsewhere.","summary":"Primary melanoma of the urethra is a mucosal melanoma. In the series of 15 cases, the tumour involved the distal urethra in all six men and the distal urethra or meatus in eight of nine women; tumours were typically polypoid, 0.8 to 6 cm (mean 2.6 cm), every one had a vertical growth phase and the depth of invasion ranged from 2 to 17 mm (Oliva 2000). Among 11 women treated surgically at the Mayo Clinic over five decades (mean age 68), the study examined which tumour features predicted recurrence and disease-specific survival (DiMarco 2004). Men present with penile or urethral involvement and the outlook has classically been poor (Sanchez-Ortiz 2005).\n\nHow it differs from its parent: it is not a carcinoma at all, so none of the parent's bladder-cancer or anal-cancer analogies apply; staging and systemic therapy come from the mucosal melanoma page instead, and the WHO skin and genitourinary classifications treat mucosal melanoma as one entity across sites.\n\nHow common: no incidence figure is published; the case series above are the published evidence.\n\nTreatment: complete excision (partial urethrectomy or, for proximal or bulky tumours, radical surgery) as reported in the surgical series (DiMarco 2004; Sanchez-Ortiz 2005), then the mucosal melanoma page's pathway for recurrent or metastatic disease, which rests on checkpoint inhibitors (nivolumab, pembrolizumab) and KIT testing; there is no trial in urethral melanoma itself.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Mucosal_melanoma","links":[{"label":"NCI PDQ: urethral cancer treatment","url":"https://www.cancer.gov/types/urethral/patient/urethral-treatment-pdq"},{"label":"Oliva 2000, Am J Surg Pathol: primary malignant melanoma of the urethra, 15 cases","url":"https://doi.org/10.1097/00000478-200006000-00003"},{"label":"DiMarco 2004, J Urol: surgical treatment of primary melanoma of the female urethra","url":"https://doi.org/10.1097/01.ju.0000104671.20863.47"},{"label":"Sanchez-Ortiz 2005, J Urol: melanoma of the penis, scrotum and male urethra","url":"https://doi.org/10.1097/01.ju.0000159207.91737.53"}],"tags":["subtype-page","wave4","rare"],"related":["urethral","mucosal-melanoma","melanoma","urethral-squamous-cell-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["nivolumab","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Very rare: the largest pathology series holds 15 cases, nine women and six men, aged 44 to 96 (mean 73) (Oliva 2000); a 40-year single-institution series found ten patients with penile or urethral melanoma (Sanchez-Ortiz 2005). No registry figure exists.","subtypes":["Melanoma of the distal urethra and meatus (the usual site)","Melanoma of the proximal urethra (rare)"],"biomarkers":["Depth of invasion and vertical growth phase","KIT, NRAS and BRAF mutation testing as in mucosal melanoma","Node status"],"standardOfCare":[{"setting":"All stages","approach":"Excision as reported in the surgical series; recurrent or metastatic disease treated as mucosal melanoma with checkpoint inhibitors.","refs":["mucosal-melanoma","nivolumab","pembrolizumab"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"urethral"},{"id":"meningioma","kind":"cancer","name":"Meningioma","aka":["Meningeal tumour","Atypical meningioma","Anaplastic meningioma","Malignant meningioma"],"tldr":"Meningiomas grow from the membranes covering the brain and spinal cord rather than from the brain itself. Most are slow and benign and are either watched or removed; radiotherapy or radiosurgery treats what surgery cannot reach or what grows back, and no drug has yet been approved for them.","summary":"Meningiomas arise from arachnoid cap cells and are graded 1 to 3 in WHO 2021 by mitotic count, brain invasion and specific histological patterns, with two molecular criteria that assign grade 3 regardless of appearance: homozygous CDKN2A/B deletion and TERT promoter mutation. About half of sporadic tumours carry NF2 loss with monosomy 22, and most of the rest carry mutually exclusive mutations in TRAF7, KLF4, AKT1, SMO, PIK3CA or POLR2A that cluster at the skull base (Clark and Brastianos, 2013). DNA methylation classes and integrated molecular grading (Sahm 2017, Nassiri 2021) predict recurrence better than histology alone. Radiation exposure is the only established environmental cause; progesterone and oestrogen receptors explain the female excess and the link to some progestogens.\n\nIncidental small meningiomas are watched with MRI. Symptomatic or growing tumours are resected, with completeness graded by the Simpson scale, and complete resection of a grade 1 tumour is usually curative. Radiosurgery controls most small tumours (under about 3 cm) and is the usual choice for skull base and cavernous sinus lesions that cannot be safely removed. Fractionated radiotherapy is given after incomplete resection of grade 2 tumours and after any resection of grade 3 tumours, following the phase 2 EORTC 22042-26042 and RTOG 0539 studies; whether completely resected grade 2 tumours need radiotherapy is the question of the ROAM/EORTC 1308 and NRG BN003 randomised trials. Proton therapy is used for large skull base and re-irradiation cases.\n\nNo systemic therapy is approved. Hydroxyurea, somatostatin analogues, interferon and mifepristone have all failed or shown marginal activity; bevacizumab and sunitinib produce modest control in recurrent high-grade disease, everolimus with octreotide has phase 2 activity (CEVOREM), and Alliance A071401 is testing mutation-matched drugs (the FAK inhibitor GSK2256098 in NF2-mutant tumours, SMO and AKT inhibitors, CDK inhibitors). Somatostatin receptor 2 expression makes DOTATATE PET useful for imaging and has led to trials of peptide receptor radionuclide therapy. Grade 3 and recurrent unresectable meningiomas remain a real unmet need.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Meningioma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Meningioma"},{"label":"EANO guideline on meningiomas (Neuro-Oncology 2021)","url":"https://doi.org/10.1093/neuonc/noab150"}],"tags":["subtype-page","cns"],"related":["brain-tumours","vestibular-schwannoma","spinal-cord-tumours","pituitary-tumours","glioblastoma","craniopharyngioma"],"cancers":[],"sections":[],"technologies":["radiosurgery-srs","gamma-knife","cyberknife","imrt-igrt","proton-therapy","methylation-profiling","prrt","active-surveillance","mri"],"targets":["mtor"],"drugs":["bevacizumab","sunitinib","everolimus","gsk2256098","mifepristone"],"companies":[],"institutions":[],"pathways":[],"terms":["stereotactic-radiosurgery","cdkn2a-homozygous-deletion"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2021-cns-louis-neuro-oncology-2021","paper-eano-meningioma-goldbrunner-neuro-oncology-2021","paper-sahm-meningioma-methylation-lancet-oncol-2017"],"journals":[],"dependsOn":[],"notes":[],"group":"central nervous system","burden":"The commonest primary intracranial tumour, found in about one in a hundred adults on imaging, mostly women; the great majority are grade 1 and never threaten life, while grade 3 tumours behave like cancers and have no approved drug.","subtypes":["Meningioma, grade 1 (meningothelial, fibrous, transitional, psammomatous and other benign patterns)","Meningioma, grade 2 (atypical; chordoid and clear cell patterns)","Meningioma, grade 3 (anaplastic; or any meningioma with CDKN2A/B homozygous deletion or TERT promoter mutation)","NF2-related meningioma (multiple, often with schwannoma)","Skull base meningioma with TRAF7, KLF4, AKT1, SMO or PIK3CA mutation (convexity tumours are mostly NF2-driven)","Spinal meningioma (intradural extramedullary)"],"biomarkers":["WHO grade with mitotic count and brain invasion","CDKN2A/B homozygous deletion and TERT promoter mutation (assign grade 3)","NF2 loss and monosomy 22","TRAF7, KLF4, AKT1, SMO, PIK3CA and POLR2A mutations","DNA methylation class and integrated molecular grade","Somatostatin receptor 2 expression (DOTATATE PET)","Simpson grade of resection"],"standardOfCare":[{"setting":"Incidental or small asymptomatic","approach":"Observation with serial MRI; many never grow. Treatment when growth or symptoms appear.","refs":["active-surveillance","mri"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Symptomatic or growing, accessible","approach":"Surgical resection as complete as safely possible; complete resection of a grade 1 tumour is usually curative and needs no adjuvant treatment.","refs":["mri","methylation-profiling"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Small, skull base or surgically inaccessible","approach":"Stereotactic radiosurgery (Gamma Knife, CyberKnife or linac) or fractionated stereotactic radiotherapy, with high long-term control rates for grade 1 tumours.","refs":["radiosurgery-srs","gamma-knife","cyberknife","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Grade 2, incompletely resected, and all grade 3","approach":"Fractionated radiotherapy after surgery (EORTC 22042-26042, RTOG 0539); proton therapy for large or re-irradiated skull base tumours; observation versus radiotherapy after complete resection of grade 2 tumours is under trial (ROAM/EORTC 1308, NRG BN003).","refs":["imrt-igrt","proton-therapy"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Recurrent, no surgical or radiotherapy option","approach":"No approved drug. Bevacizumab, sunitinib or everolimus with a somatostatin analogue on phase 2 evidence; mutation-matched trials (Alliance A071401) and peptide receptor radionuclide therapy studies preferred.","refs":["bevacizumab","sunitinib","everolimus","prrt"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}}],"stateOfArt":["Two molecular markers now assign grade 3 regardless of histology, and methylation classes forecast recurrence better than the microscope.","Radiosurgery controls most small meningiomas without an operation and has become the default for skull base disease.","Meningioma is the commonest brain tumour and still has no approved systemic therapy; mutation-matched and radionuclide trials are the first rational attempts."],"history":[{"year":1922,"title":"Cushing coins the term meningioma","note":"Cushing and Eisenhardt's 1938 monograph followed, with the first large surgical series.","refs":[]},{"year":1957,"title":"Simpson grades completeness of resection and links it to recurrence","refs":[]},{"year":1993,"title":"NF2 gene identified on chromosome 22","note":"Trofatter and Rouleau clone the gene whose loss drives most meningiomas and schwannomas.","refs":[]},{"year":2013,"title":"Exome sequencing finds TRAF7, KLF4, AKT1 and SMO mutations in NF2-intact meningiomas","note":"Clark and colleagues (Science) and Brastianos and colleagues (Nature Genetics).","refs":[]},{"year":2017,"title":"DNA methylation classes of meningioma predict recurrence","note":"Sahm and colleagues (Lancet Oncology).","refs":["methylation-profiling"]},{"year":2021,"title":"WHO 2021 adds CDKN2A/B deletion and TERT promoter mutation as grade 3 criteria","refs":[]}],"pipeline":["prrt","bevacizumab","everolimus","methylation-profiling"],"openProblems":["No approved systemic therapy; grade 3 and recurrent unresectable tumours have few options.","Whether completely resected grade 2 meningiomas need radiotherapy (ROAM, NRG BN003).","Which incidental meningiomas will grow; most never do.","Long-term cognitive and endocrine effects of radiotherapy to the skull base."],"parent":"brain-tumours"},{"id":"merkel-cell-carcinoma","kind":"cancer","name":"Merkel cell carcinoma","aka":[],"tldr":"Merkel cell carcinoma is a rare, fast-growing skin cancer, usually caused by a common virus (Merkel cell polyomavirus) or by sun damage. Once it had spread there was no treatment that worked; PD-1/PD-L1 immunotherapy now gives lasting responses in about half of patients.","summary":"Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer of older, fair-skinned and immunosuppressed people. About 80% of cases in the Northern Hemisphere are driven by clonally integrated Merkel cell polyomavirus (MCPyV, discovered 2008); the remainder are UV-induced with a very high tumour mutational burden. Both forms are immunogenic, which explains why MCC responded to checkpoint blockade when chemotherapy gave only brief responses.\n\nLocalised disease is treated with wide excision, sentinel node biopsy and adjuvant radiotherapy; the STAMP and ADMEC-O trials tested adjuvant PD-1 blockade, with ADMEC-O (nivolumab) showing a disease-free survival benefit in 2023. Metastatic disease is treated first line with avelumab (JAVELIN Merkel 200, first approval 2017), pembrolizumab (KEYNOTE-017, 2018) or retifanlimab (POD1UM-201, 2023); durable responses occur in about half, and chemotherapy is reserved for immunotherapy failure. Circulating MCPyV oncoprotein antibodies (AMERK) allow surveillance in seropositive patients.\n\nUnsolved: primary and acquired immunotherapy resistance (about half of patients), immunosuppressed patients (transplant, CLL) who cannot receive checkpoint blockade safely, and the adjuvant standard.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Merkel-cell_carcinoma","links":[{"label":"NCCN Guidelines: Merkel Cell Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1444"},{"label":"Merkelcell.org (UW/Fred Hutch)","url":"https://merkelcell.org/"},{"label":"NCI PDQ: Merkel cell carcinoma","url":"https://www.cancer.gov/types/skin/patient/merkel-cell-treatment-pdq"},{"label":"Keohane, Proby, Newlands, Motley, Nasr and Mohd Mustapa, British Journal of Dermatology 2018;179:824 to 828: the new 8th edition of TNM staging and its implications for skin cancer, a review by the British Association of Dermatologists and the Royal College of Pathologists, UK","url":"https://doi.org/10.1111/bjd.16892"},{"label":"van Bodegraven et al., British Journal of Dermatology 2023;188(6):777 to 784: 'Get Data Out' Skin, national cancer registry incidence and survival rates for all registered skin tumour groups for 2013 to 2019 in England","url":"https://doi.org/10.1093/bjd/ljad033"}],"tags":["gap-fill","skin","rare"],"related":["basal-cell-carcinoma","cutaneous-scc","melanoma"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","sentinel-node","imrt-igrt","oncolytic-virus","tcr-t"],"targets":["pd1","pdl1","ctla4"],"drugs":["avelumab","pembrolizumab","retifanlimab","nivolumab","ipilimumab","platinum-etoposide","talimogene-laherparepvec"],"companies":["merck","pfizer","incyte","bms","neonc-technologies"],"institutions":[],"pathways":["pd1-checkpoint","p53-cell-cycle"],"terms":["tmb","irae","mcpyv-status","keratinocyte-cancer","keratinocyte-cancer-counting","tnm-skin-carcinoma","skin-cancer-high-risk-features","radiotherapy-for-skin-cancer","skin-cancer-after-organ-transplant","surgical-margins-keratinocyte-cancer"],"trials":["nct06947928","stamp-merkel","checkmate-358","pod1um-201","admec-o"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Merkel cell carcinoma is not a keratinocyte cancer, and it is staged by a different chapter. It arises from Merkel cells rather than keratinocytes, and both the UICC and AJCC give it its own staging chapter, separate from the cutaneous carcinoma chapters that cover basal cell, squamous cell and adnexal carcinoma; the UK skin carcinoma staging appendix excludes it in terms. Sentinel node biopsy is written into its pathological nodal staging, and for both melanoma and Merkel cell carcinoma the clinician must state whether involved nodes were clinically occult or clinically detected (Keohane 2018). It is caught by the phrase non-melanoma skin cancer in some statistics, including mortality figures published for that group, which is one reason the field is moving to the more precise term keratinocyte cancer for the two common ones."],"group":"skin","burden":"Merkel cell carcinoma causes about 3,000 cases per year in the US and rising; median age is ~75; it is roughly 40 times rarer than melanoma and more likely to spread stage for stage, which is why immunotherapy's durable responses mattered so much.","subtypes":["Virus-positive MCC (MCPyV, ~80%)","Virus-negative UV-driven MCC (high TMB, RB1/TP53 mutations)","MCC in immunosuppressed patients (transplant, CLL, HIV)"],"biomarkers":["CK20 perinuclear dot staining; TTF-1 negative","MCPyV large T antigen (IHC/PCR)","MCPyV oncoprotein antibody titre (surveillance)","Sentinel lymph node status","PD-L1 (not required for treatment)","Tumour mutational burden (virus-negative)"],"standardOfCare":[{"setting":"Localised (stage I-II)","approach":"Wide local excision with sentinel node biopsy; adjuvant radiotherapy to the primary site (and nodal basin if node-positive); adjuvant nivolumab supported by ADMEC-O in selected patients.","refs":["sentinel-node","imrt-igrt","nivolumab"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Merkel Cell Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1444"}},{"setting":"Regional nodal disease (stage III)","approach":"Lymphadenectomy and/or nodal radiotherapy; neoadjuvant nivolumab (CheckMate 358) produced pathological complete responses in about half.","refs":["nivolumab","imrt-igrt"]},{"setting":"Metastatic, first line","approach":"Avelumab, pembrolizumab or retifanlimab; ~50% response with most responses durable.","refs":["avelumab","pembrolizumab","retifanlimab"],"guideline":{"nccn":"Category 2A (preferred)","version":"NCCN Guidelines: Merkel Cell Carcinoma"}},{"setting":"Immunotherapy-refractory","approach":"Platinum-etoposide chemotherapy (brief responses), radiotherapy, clinical trials (ipilimumab-nivolumab, T-VEC, adoptive T cells).","refs":["platinum-etoposide","ipilimumab","talimogene-laherparepvec"]},{"setting":"Choosing among the three PD-1 pathway antibodies","approach":"Avelumab, pembrolizumab and retifanlimab are all approved and none has been compared with another. First-line response was 39.7 per cent with avelumab in 116 patients, 56 per cent with pembrolizumab in 50 and 54.5 per cent with retifanlimab in 101. The retifanlimab study is the most fully reported: 17.8 per cent complete responses, median duration of response not reached in complete responders and 25.3 months in partial responders, median progression-free survival 16.0 months, and 63 per cent of patients alive at three years, in a disease where chemotherapy responses were measured in months. Grade 3 immune-related adverse events occurred in 10.9 per cent. Which antibody is used matters far less than that roughly half of patients respond and most responders keep responding.","refs":["pod1um-201","javelin-merkel-200","keynote-017","retifanlimab","avelumab","pembrolizumab","irae"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Merkel Cell Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1444"}},{"setting":"After complete resection: what the adjuvant evidence does and does not show","approach":"ADMEC-O randomised 179 patients with completely resected Merkel cell carcinoma 2 to 1 to a year of nivolumab or to observation. Disease-free survival was 85 per cent at 12 months and 84 per cent at 24 with nivolumab against 77 and 73 per cent with observation, a hazard ratio of 0.58 whose 95 per cent confidence interval, 0.30 to 1.12, crosses one; the authors state it as an absolute risk reduction of 9 and 10 percentage points. Grade 3 or 4 adverse events occurred in 42 per cent against 11 per cent. Overall survival had ten events against six in a group half the size and is not mature. This is a phase 2 signal in a rare disease, not a proven standard, and the randomised phase 3 that would settle it, STAMP, has not reported.","refs":["admec-o","stamp-merkel","nivolumab","irae"],"guideline":{"version":"ADMEC-O interim analysis (The Lancet 2023)","url":"https://doi.org/10.1016/s0140-6736(23)00769-9"}},{"setting":"What is available in England","approach":"NICE technology appraisal TA691 recommendation 1.1 recommends avelumab for metastatic Merkel cell carcinoma in adults who have not had chemotherapy for metastatic disease, under a commercial arrangement, on evidence collected in the Cancer Drugs Fund under TA517. TA517 recommendation 1.1 continues to cover its use after one or more lines of chemotherapy. Pembrolizumab and retifanlimab have no NICE appraisal for this disease.","refs":["avelumab","pembrolizumab","retifanlimab","javelin-merkel-200"],"guideline":{"version":"NICE TA691 recommendation 1.1 and NICE TA517 recommendation 1.1 (avelumab recommended)","url":"https://www.nice.org.uk/guidance/ta691"}}],"stateOfArt":["Three approved PD-1/PD-L1 antibodies; about half of metastatic patients respond and most responders stay in remission for years.","Virus-driven biology makes MCPyV antigens an appealing target for vaccines and TCR-T.","Adjuvant immunotherapy has its first positive trial (ADMEC-O) and is entering guidelines.","Serologic surveillance (MCPyV oncoprotein antibodies) reduces imaging in seropositive patients."],"history":[{"year":1972,"title":"Toker describes 'trabecular carcinoma of the skin'","refs":[]},{"year":2008,"title":"Merkel cell polyomavirus discovered","note":"Feng, Chang and Moore find clonally integrated MCPyV in most MCC using digital transcriptome subtraction.","refs":[]},{"year":2016,"title":"Pembrolizumab first-line phase 2 (KEYNOTE-017, NEJM)","refs":["pembrolizumab"]},{"year":2017,"title":"Avelumab: first approved therapy for MCC","note":"JAVELIN Merkel 200; accelerated approval March 2017.","refs":["avelumab"]},{"year":2018,"title":"Pembrolizumab approved","refs":["pembrolizumab"]},{"year":2023,"title":"Retifanlimab approved; ADMEC-O adjuvant nivolumab positive","refs":["retifanlimab","nivolumab"]},{"year":2023,"title":"ADMEC-O: the first randomised adjuvant signal","note":"179 patients randomised 2 to 1 to a year of nivolumab or observation; disease-free survival 84 against 73 per cent at 24 months, hazard ratio 0.58 with a confidence interval crossing one, and overall survival not mature.","refs":["admec-o"]},{"year":2025,"title":"POD1UM-201: a third PD-1 antibody with three-year follow-up","note":"Objective response 54.5 per cent in 101 chemotherapy-naive patients, median progression-free survival 16.0 months and 63 per cent alive at three years.","refs":["pod1um-201"]}],"pipeline":["nivolumab","retifanlimab","ipilimumab"],"openProblems":["Half of patients do not respond to PD-1 blockade and have no effective second line.","Immunosuppressed patients: high incidence, poor outcomes, contraindications to immunotherapy.","No validated adjuvant standard yet despite ADMEC-O.","Rarity limits trial size; registries (e.g. Seattle) carry much of the evidence.","Three PD-1 pathway antibodies are approved for this disease and none has ever been compared with another; the choice is made on availability and schedule rather than on evidence.","The adjuvant question rests on a phase 2 trial whose hazard ratio crosses one and whose survival data are not mature, and the phase 3 that would settle it has not reported."],"parent":"skin-cancer"},{"id":"tnbc-mesenchymal-stem-like","kind":"cancer","name":"Mesenchymal stem-like triple-negative breast cancer (MSL)","aka":["MSL subtype","Mesenchymal stem-like TNBC"],"tldr":"Mesenchymal stem-like was one of the six original subtypes of triple-negative breast cancer, marked by stem-cell and low-proliferation genes. Five years later the same group showed the signal came from stromal cells mixed into the sample rather than the cancer cells, so the label describes a tumour environment rather than a tumour.","summary":"Lehmann 2011 separated a mesenchymal stem-like (MSL) cluster from the mesenchymal cluster by lower expression of proliferation genes and enrichment for genes of mesenchymal stem cells, angiogenesis and growth factor signalling; representative cell lines responded to the PI3K/mTOR inhibitor NVP-BEZ235 and to dasatinib (Lehmann 2011). Using histopathological quantification and laser-capture microdissection, the 2016 refinement showed that the MSL transcripts were contributed by tumour-associated stromal cells, as the immunomodulatory transcripts were by infiltrating lymphocytes, and collapsed the classification to four tumour-specific subtypes (Lehmann 2016). The page stays because the label persists in papers and reports; a tumour once called MSL would now be assigned to the mesenchymal or another intrinsic subtype, and its low proliferation and stromal richness match the claudin-low phenotype described by Fougner 2020.\n\nA research classification by gene expression (Lehmann 2011, refined 2016), not a test the NHS runs; treatment follows the triple-negative rows on the parent page.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Triple-negative_breast_cancer","links":[{"label":"Lehmann, J Clin Invest 2011: identification of human triple-negative breast cancer subtypes (BL1, BL2, IM, M, MSL, LAR)","url":"https://doi.org/10.1172/jci45014"},{"label":"Lehmann, PLoS One 2016: refinement of triple-negative breast cancer molecular subtypes to four (TNBCtype-4)","url":"https://doi.org/10.1371/journal.pone.0157368"},{"label":"Fougner, Nat Commun 2020: re-definition of claudin-low as a breast cancer phenotype","url":"https://doi.org/10.1038/s41467-020-15574-5"}],"tags":["breast","tnbc","subtype-page"],"related":["tnbc","tnbc-mesenchymal","tnbc-immunomodulatory"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["emt"],"terms":["claudin-low"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"One of the six 2011 Lehmann subtypes; dropped as a tumour-intrinsic subtype in 2016 when its signal was traced to stromal cells.","subtypes":["Mesenchymal tumours with a stromal, low-proliferation signature (claudin-low phenotype)"],"biomarkers":["Stromal and mesenchymal stem-cell gene expression (a sample-composition signal, research only)"],"standardOfCare":[{"setting":"Any stage","approach":"As for triple-negative disease; the label has no treatment consequence.","refs":["pembrolizumab","keynote-522"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"tnbc"},{"id":"tnbc-mesenchymal","kind":"cancer","name":"Mesenchymal triple-negative breast cancer (M)","aka":["M subtype","Mesenchymal TNBC","MES subtype (Burstein)","Claudin-low triple-negative breast cancer (overlapping phenotype)"],"tldr":"Mesenchymal triple-negative breast cancers have switched on the programme cells use to migrate (epithelial-to-mesenchymal transition). They overlap with claudin-low and metaplastic tumours, respond to chemotherapy less well than basal-like 1 tumours, and are the subtype the parent page names as resisting every drug class.","summary":"The mesenchymal (M) and mesenchymal stem-like (MSL) subtypes were enriched for epithelial-to-mesenchymal transition and growth factor pathway genes, and their cell lines responded to a PI3K/mTOR inhibitor and to dasatinib in the defining study (Lehmann 2011). In the 2016 refinement the stem-like signal proved to come from tumour-associated stromal cells, leaving M as the tumour-intrinsic mesenchymal subtype (Lehmann 2016). Burstein's mesenchymal (MES) subtype carries growth factor receptor targets (PDGFR alpha, c-KIT) (Burstein 2015). The claudin-low intrinsic subtype describes much of the same biology from the whole-breast-cancer side: low luminal differentiation markers, high epithelial-to-mesenchymal transition and stem-cell features, mostly triple-negative invasive carcinomas with frequent metaplastic and medullary differentiation, and a preoperative chemotherapy response between basal-like and luminal tumours (Prat 2010); a 2020 re-analysis found claudin-low is better understood as a phenotype with low genomic instability, low proliferation and high immune and stromal infiltration that can overlay any intrinsic subtype (Fougner 2020). Metaplastic carcinoma, the histological type most often mesenchymal, is on its own page.\n\nA research classification by gene expression (Lehmann 2011, refined 2016), not a test the NHS runs; treatment follows the triple-negative rows on the parent page.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Triple-negative_breast_cancer","links":[{"label":"Lehmann, J Clin Invest 2011: identification of human triple-negative breast cancer subtypes (BL1, BL2, IM, M, MSL, LAR)","url":"https://doi.org/10.1172/jci45014"},{"label":"Lehmann, PLoS One 2016: refinement of triple-negative breast cancer molecular subtypes to four (TNBCtype-4)","url":"https://doi.org/10.1371/journal.pone.0157368"},{"label":"Burstein, Clin Cancer Res 2015: four triple-negative subtypes (LAR, MES, BLIS, BLIA) with distinct prognoses","url":"https://doi.org/10.1158/1078-0432.ccr-14-0432"},{"label":"Prat, Breast Cancer Res 2010: phenotypic and molecular characterisation of the claudin-low intrinsic subtype","url":"https://doi.org/10.1186/bcr2635"},{"label":"Fougner, Nat Commun 2020: re-definition of claudin-low as a breast cancer phenotype","url":"https://doi.org/10.1038/s41467-020-15574-5"}],"tags":["breast","tnbc","subtype-page"],"related":["tnbc","tnbc-mesenchymal-stem-like","metaplastic-breast-carcinoma","tnbc-basal-like-2"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["emt","pi3k-akt-mtor"],"terms":["claudin-low","basal-like"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"One of the four tumour-intrinsic triple-negative subtypes; overlaps the claudin-low phenotype and the metaplastic histological type.","subtypes":["Claudin-low phenotype (low luminal markers, epithelial-to-mesenchymal transition, stem-cell features)","Metaplastic carcinoma with spindle cell or matrix-producing components (own page)"],"biomarkers":["Epithelial-to-mesenchymal transition gene expression (research)","Low claudin 3, 4 and 7 and E-cadherin expression (claudin-low)","PDGFR alpha and c-KIT (Burstein MES)"],"standardOfCare":[{"setting":"Stage II to III and metastatic","approach":"As for triple-negative disease; no mesenchymal-specific treatment is approved. PI3K/mTOR inhibitors and dasatinib were active in cell lines only.","refs":["keynote-522","pembrolizumab"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"tnbc"},{"id":"mesothelioma","kind":"cancer","name":"Mesothelioma","aka":[],"tldr":"An asbestos-caused cancer of the lung lining. Immunotherapy doublets replaced chemotherapy in 2020, and mesothelin CAR-T is under study.","summary":"Malignant pleural mesothelioma arises from the lining of the lung, almost always decades after asbestos exposure, and is rising in countries that banned asbestos late or not at all. It grows along surfaces rather than as a mass, is hard to image and stage, and resists most systemic therapy. Histology is the dominant biological variable: epithelioid tumours are slower and chemosensitive; sarcomatoid and biphasic tumours are aggressive, chemoresistant, and paradoxically more immunotherapy-responsive.\n\nFor 16 years after pemetrexed-cisplatin (2004) nothing improved survival except, modestly, adding bevacizumab (MAPS, 2016). Immunotherapy then changed the first line twice: nivolumab-ipilimumab (CheckMate 743, approved 2020) and pembrolizumab with chemotherapy (IND.227/KEYNOTE-483, approved September 2024). Tumour treating fields hold a device approval on single-arm data. Radical surgery, long assumed beneficial, was shown by MARS 2 (2024) to shorten survival and worsen quality of life, and is now largely confined to trials.\n\nWhat comes next is biology-led: PRMT5 and MAT2A inhibitors for the ~40-50% of tumours with MTAP deletion, mesothelin-directed CAR-T delivered into the pleural space, ADCs and T-cell engagers against mesothelin, and better use of histology and BAP1/CDKN2A status to choose therapy. Prevention remains the biggest lever: asbestos is still mined and used in parts of Asia, Russia, and Brazil.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Mesothelioma","links":[{"label":"NCI PDQ: malignant mesothelioma treatment","url":"https://www.cancer.gov/types/mesothelioma/hp/mesothelioma-treatment-pdq"},{"label":"NICE NG12: suspected cancer, recommendations by site (lung and pleural cancers 1.1.1 to 1.1.6)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"}],"tags":["thoracic"],"related":[],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","car-t","ttfields","synthetic-lethality-approaches","pleurectomy-decortication","hipec","histopathology-ihc","antiangiogenic"],"targets":["mesothelin","pd1","ctla4","pdl1","vegf"],"drugs":["talc-sclerosant"],"companies":["orion-orion-pharma","bms","merck","novocure","boehringer-ingelheim"],"institutions":["mskcc","royal-marsden","the-christie","nki"],"pathways":["pd1-checkpoint","vegf-angiogenesis","p53-cell-cycle"],"terms":["epithelioid-vs-sarcomatoid","synthetic-lethality","irae","asbestos","tnm-9-lung-cancer"],"trials":["nct06097728"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Why mesothelioma is not a lung cancer. It arises from the mesothelial lining of the pleura rather than from the lung, the WHO classification gives it its own chapter, the IASLC runs a separate staging project for it whose ninth-edition proposals differ from the lung ones, and NICE NG12 gives it its own referral rules, lowering the threshold for an urgent chest X-ray in anyone aged 40 and over with a single unexplained respiratory symptom and a history of asbestos exposure. It shares the organ drawing with lung cancer because the drawing is anatomy, not taxonomy, and it shares asbestos as a cause; it is not a subtype of lung cancer on this site and is not listed as one."],"group":"thoracic","burden":"Mesothelioma causes about 30,000 cases a year worldwide, ~3,000 in the US, almost all from asbestos exposure 20-50 years earlier, so incidence is still rising in Asia and parts of Europe. Immunotherapy has produced the first tail of long-term survivors: in CheckMate 743 five-year survival was 14% against 6% with chemotherapy. Median survival across series is 12-18 months, which means half of the people in those series lived longer.","subtypes":["Epithelioid (~60-70%)","Biphasic (~20%)","Sarcomatoid (~10-20%, includes desmoplastic)","Peritoneal mesothelioma (~10-15% of all mesothelioma; treated with cytoreductive surgery and HIPEC)","Pericardial and testicular (rare)"],"biomarkers":["Histology (epithelioid vs sarcomatoid)","BAP1","CDKN2A/MTAP deletion","Mesothelin","Histology (epithelioid vs non-epithelioid) drives first-line choice","BAP1 loss (diagnostic; germline BAP1 syndrome)","CDKN2A/MTAP deletion (diagnostic; PRMT5-inhibitor target)","Mesothelin (CAR-T, ADC, engager target)","PD-L1 (weakly predictive)","Soluble mesothelin-related peptides and fibulin-3 (research)","Asbestos exposure history"],"standardOfCare":[{"setting":"Unresectable","approach":"Nivolumab-ipilimumab or chemo-IO; TTFields.","refs":["nivolumab","ipilimumab","pembrolizumab","optune"],"guideline":{"version":"NCCN Guidelines: Mesothelioma (Pleural)","url":"https://www.nccn.org/guidelines/category_1"}},{"setting":"Diagnosis and staging","approach":"CT and PET/CT; thoracoscopic biopsy with IHC panel (calretinin, WT1, D2-40; BAP1 and MTAP loss support malignancy); histology and BAP1/MTAP status recorded for treatment planning.","refs":["histopathology-ihc","pet-ct","ct"],"guideline":{"nccn":"MPM guideline","version":"NCCN Mesothelioma: Pleural v1.2026"}},{"setting":"First line, non-epithelioid","approach":"Nivolumab + ipilimumab (CheckMate 743) preferred; pembrolizumab + platinum-pemetrexed alternative.","refs":["nivolumab","ipilimumab","checkmate-743","pembrolizumab","keynote-483","histology-directs-first-line-meso"],"guideline":{"nccn":"1 (preferred)","esmoMcbs":"4"}},{"setting":"First line, epithelioid","approach":"Pembrolizumab + platinum-pemetrexed, nivolumab + ipilimumab, or platinum-pemetrexed ± bevacizumab, chosen by fitness and preference.","refs":["pembrolizumab","keynote-483","nivolumab","ipilimumab","pemetrexed","maps"],"guideline":{"nccn":"1 (chemo-IO and IO doublet); 2A (bevacizumab)","esmoMcbs":"3"}},{"setting":"Maintenance","approach":"Continue immunotherapy per regimen; TTFields (Optune Lua) with pemetrexed-platinum under HDE approval; no maintenance chemotherapy standard.","refs":["optune","ttfields","stellar"],"guideline":{"nccn":"2B (TTFields)"}},{"setting":"Second line","approach":"Nivolumab (CONFIRM: OS benefit vs placebo) or nivolumab-ipilimumab if not given first line; platinum-pemetrexed rechallenge or gemcitabine/vinorelbine if IO given first; trials.","refs":["nivolumab","pemetrexed"],"guideline":{"nccn":"2A"}},{"setting":"Surgery","approach":"Not recommended for cure outside trials after MARS 2; VATS pleurodesis or indwelling pleural catheter for effusion; extended pleurectomy/decortication (P/D) only in clinical trials.","refs":["pleurectomy-decortication","mars-2"],"guideline":{"nccn":"Selected centres/trials only"}},{"setting":"Radiotherapy","approach":"Palliative for chest wall pain; prophylactic tract irradiation not beneficial (SMART/PIT trials); hemithoracic IMRT after surgery only in trials.","refs":["imrt-igrt"]},{"setting":"Peritoneal mesothelioma","approach":"Cytoreductive surgery with HIPEC in selected patients; systemic therapy extrapolated from pleural disease.","refs":["hipec"]}],"stateOfArt":["IO doublet first line.","Two immunotherapy-based first-line standards (nivolumab-ipilimumab; pembrolizumab-chemotherapy), chosen by histology.","Radical surgery removed from routine care after MARS 2 showed harm.","Five-year survival with nivolumab-ipilimumab 14% vs 6% with chemotherapy: a small but real tail of long-term survivors.","MTAP deletion and BAP1 loss are routine diagnostic markers and emerging therapeutic handles.","Mesothelin CAR-T delivered regionally has produced long survivors in phase 1."],"history":[{"year":1960,"title":"Wagner links mesothelioma to asbestos in South African miners","refs":[]},{"year":1989,"title":"US EPA asbestos ban partly overturned (1991); many countries ban asbestos over the following decades","refs":[]},{"year":2003,"title":"EMPHACIS: pemetrexed-cisplatin improves survival","refs":["pemetrexed"]},{"year":2004,"title":"Pemetrexed-cisplatin approved","refs":[]},{"year":2004,"title":"Pemetrexed approved: first mesothelioma drug","refs":["pemetrexed"]},{"year":2011,"title":"MARS 1: extrapleural pneumonectomy shows harm; practice shifts to lung-sparing surgery","refs":["pleurectomy-decortication"]},{"year":2016,"title":"MAPS: bevacizumab adds ~3 months","refs":["maps"]},{"year":2019,"title":"TTFields device approval (HDE) on STELLAR","refs":["stellar","optune"]},{"year":2019,"title":"LUME-Meso fails; nintedanib abandoned in mesothelioma","refs":["lume-meso","nintedanib"]},{"year":2020,"title":"Nivolumab-ipilimumab first line","refs":[]},{"year":2020,"title":"CheckMate 743: nivolumab-ipilimumab approved, first new first line in 16 years","refs":["checkmate-743","nivolumab","ipilimumab"]},{"year":2021,"title":"CONFIRM: nivolumab improves survival in relapsed disease","refs":["nivolumab"]},{"year":2023,"title":"IND.227/KEYNOTE-483 positive for pembrolizumab-chemotherapy","refs":["keynote-483"]},{"year":2024,"title":"MARS 2: surgery worsens survival; pembrolizumab-chemotherapy approved (September)","refs":["mars-2","pembrolizumab"]},{"year":2024,"title":"BEAT-meso misses OS; non-epithelioid subgroup benefits","refs":["beat-meso"]},{"year":2025,"title":"CheckMate 743 five-year data: 14% vs 6% alive","refs":["checkmate-743"]},{"year":2026,"title":"DREAM3R stopped early; PRMT5 inhibitors and mesothelin cell therapies advance","refs":["dream3r","idea-mtap-prmt5-mesothelioma","idea-mesothelin-car-t-regional"]}],"pipeline":["synthetic-lethality-approaches","eb-mf-car-nk-01","anetumab-ravtansine","idea-adc-for-mesothelioma","anetumab-vs-vinorelbine-mpm","nci-anetumab-pembrolizumab-mpm","ucl-proton-hemithoracic-mpm","proton-therapy","idea-mtap-prmt5-mesothelioma","idea-mesothelin-car-t-regional","car-t","armored-car","mesothelin","t-cell-engager","adc","checkpoint-inhibitor","ttfields","histology-directs-first-line-meso","fapi-pet"],"openProblems":["Sarcomatoid subtype.","No early detection despite known exposure.","Even the best first-line regimens give a median survival under two years; the tail of long survivors on immunotherapy is what to build on.","Epithelioid disease gains little from immunotherapy over chemotherapy; no predictive biomarker beyond histology.","No approved targeted therapy despite recurrent BAP1, CDKN2A/MTAP, and NF2 alterations.","Once immunotherapy has been used first line, the second-line options are platinum-pemetrexed rechallenge, gemcitabine or vinorelbine, none with a randomised survival trial behind it in that sequence; mesothelin CAR-T, mesothelin ADCs and engagers, and PRMT5 inhibitors for MTAP-deleted tumours are the trials addressing it.","Surgery's role is now unclear for the small group of early, epithelioid, node-negative patients.","Response assessment is hard (modified RECIST for pleural rind); trials are small and slow.","Asbestos is still produced and used in several large countries; incidence will rise there for decades.","Peritoneal and rarer sites lack dedicated evidence."]},{"id":"met-altered-nsclc","kind":"cancer","name":"MET exon 14 and MET-amplified non-small-cell lung cancer","aka":["MET exon 14 skipping lung cancer","METex14 NSCLC","MET-amplified lung cancer","c-Met overexpressing NSCLC"],"tldr":"MET-driven lung cancer comes in three forms: an exon 14 skipping mutation treated with the pills capmatinib or tepotinib, MET amplification that often arises as an escape route from EGFR drugs, and high c-Met protein levels that the antibody-drug conjugate telisotuzumab vedotin targets.","summary":"MET exon 14 skipping mutations remove the domain that marks the receptor for degradation, so it accumulates and signals persistently; they were shown to be targetable in 2015 when patients responded to crizotinib. Capmatinib (GEOMETRY mono-1, 2020) produced response rates of 68 percent in treatment-naive and 41 percent in previously treated patients and received accelerated approval in May 2020, and tepotinib (VISION, 2020) a 46 percent response rate with approval in February 2021; both are brain-penetrant and cause peripheral oedema. Savolitinib is approved in China for the same mutation, including sarcomatoid tumours. Checkpoint inhibitors work poorly despite frequent PD-L1 expression, and exon 14 patients who are fit and untreated are usually given the MET inhibitor first.\n\nMET amplification behaves differently by context. De novo high-level amplification (gene copy number 10 or more) responds to capmatinib in about a third of patients; low-level amplification does not. As acquired resistance to osimertinib, MET amplification is treated by adding a MET inhibitor to osimertinib: the SAVANNAH and SACHI trials of osimertinib plus savolitinib showed high response rates in patients selected by MET testing, and SACHI led to approval of the combination in China in 2025. Amivantamab, the EGFR-MET bispecific antibody, covers MET-mediated resistance in EGFR-mutated disease as well.\n\nc-Met protein overexpression without a MET genomic alteration is the target of telisotuzumab vedotin, an antibody-drug conjugate with a microtubule payload: LUMINOSITY reported a 35 percent response rate in non-squamous EGFR wild-type tumours with high c-Met expression, and the drug received accelerated approval in May 2025, with TeliMET NSCLC-01 comparing it with docetaxel. Open questions are the best MET inhibitor sequence, whether MET inhibitors should be combined with chemotherapy or immunotherapy first line, and how to define MET amplification consistently across assays.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/C-Met","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/C-Met"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":["egfr-mutant-nsclc","alk-positive-nsclc","ret-fusion-nsclc","ros1-positive-nsclc","kras-g12c-nsclc","her2-mutant-nsclc"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","adc","bispecific-antibody","cgp"],"targets":["met","egfr"],"drugs":["capmatinib","tepotinib","capmatinib-tepotinib","savolitinib","telisotuzumab-vedotin","telisotuzumab-adizutecan","amivantamab","crizotinib"],"companies":["novartis","merck-kgaa","astrazeneca","abbvie","hengrui"],"institutions":[],"pathways":["nsclc-signalling","rtk-activation"],"terms":["met-amplification","resistance","driver-mutation","tki-term","met-exon-14-skipping"],"trials":["geometry-mono-1","nct02864992","luminosity","telimet-nsclc-01","nct03778229"],"people":["ross-camidge","alexander-drilon"],"bottlenecks":[],"keyPapers":["paper-wolf-geometry-mono-1-capmatinib-nejm-2020","paper-vision-tepotinib-paik-nejm-2020","paper-frampton-met-exon-14-cancer-discov-2015"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"MET exon 14 skipping mutations occur in 3 to 4 percent of non-small-cell lung cancers, typically in older patients and enriched in sarcomatoid tumours; de novo high-level MET amplification in 1 to 2 percent; and MET amplification appears as a resistance mechanism in about 15 percent of EGFR-mutated cancers after osimertinib. About a quarter of non-squamous lung cancers overexpress the c-Met protein.","subtypes":["MET exon 14 skipping adenocarcinoma or sarcomatoid carcinoma (capmatinib, tepotinib)","De novo high-level MET amplification (gene copy number 10 or more)","MET amplification as acquired resistance in EGFR-mutated adenocarcinoma (osimertinib plus savolitinib, amivantamab)","c-Met protein overexpression without a genomic alteration (telisotuzumab vedotin)"],"biomarkers":["MET exon 14 skipping by RNA or DNA sequencing (DNA panels miss some intronic variants)","MET gene copy number by fluorescence in situ hybridisation or sequencing","c-Met immunohistochemistry (3+ in 50 percent or more of cells for telisotuzumab vedotin)","MET amplification in plasma or tissue at progression on osimertinib","Peripheral oedema and creatinine on MET inhibitors"],"standardOfCare":[{"setting":"Advanced MET exon 14, first line or later","approach":"Capmatinib (GEOMETRY mono-1) or tepotinib (VISION); platinum-pemetrexed with or without pembrolizumab if the inhibitor is not tolerated or after it.","refs":["capmatinib","geometry-mono-1","tepotinib","nct02864992","capmatinib-tepotinib","pemetrexed","carboplatin"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"MET amplification after osimertinib in EGFR-mutated disease","approach":"Osimertinib plus savolitinib (SAVANNAH, SACHI) where available; amivantamab plus chemotherapy; platinum-pemetrexed.","refs":["osimertinib","savolitinib","nct03778229","amivantamab","nct04988295","met-amplification"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"c-Met overexpression, previously treated non-squamous","approach":"Telisotuzumab vedotin (LUMINOSITY) after platinum chemotherapy; TeliMET NSCLC-01 versus docetaxel is confirmatory.","refs":["telisotuzumab-vedotin","luminosity","telimet-nsclc-01","docetaxel"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Two approved brain-penetrant MET inhibitors for exon 14 skipping with response rates of 40 to 70 percent.","Osimertinib plus savolitinib for MET-amplified resistance in EGFR-mutated disease (SACHI, approved in China).","Telisotuzumab vedotin, the first antibody-drug conjugate for a lung cancer selected by protein expression, approved in 2025."],"history":[{"year":2015,"title":"MET exon 14 skipping shown to be a targetable driver with crizotinib responses","refs":["met","crizotinib"]},{"year":2020,"title":"GEOMETRY mono-1: capmatinib approved; VISION: tepotinib reported","refs":["geometry-mono-1","capmatinib","nct02864992","tepotinib"]},{"year":2021,"title":"Tepotinib approved; savolitinib approved in China","refs":["tepotinib","savolitinib"]},{"year":2024,"title":"LUMINOSITY: telisotuzumab vedotin response rate 35 percent in c-Met high tumours","refs":["luminosity","telisotuzumab-vedotin"]},{"year":2025,"title":"Telisotuzumab vedotin approved; SACHI: osimertinib plus savolitinib for MET-amplified resistance","refs":["telisotuzumab-vedotin","savolitinib","osimertinib"]}],"pipeline":["telimet-nsclc-01","telisotuzumab-adizutecan","savolitinib","nct03778229","amivantamab"],"openProblems":["MET amplification has no agreed threshold and results differ between assays.","Peripheral oedema limits the dose of every MET inhibitor and has no good treatment.","Whether MET inhibitors should be combined with chemotherapy or immunotherapy first line in exon 14 disease is untested."],"parent":"nsclc"},{"id":"metaplastic-breast-carcinoma","kind":"cancer","name":"Metaplastic breast carcinoma","aka":["Metaplastic carcinoma of the breast","MpBC","Spindle cell carcinoma of the breast","Matrix-producing carcinoma","Squamous cell carcinoma of the breast","Low-grade adenosquamous carcinoma","Fibromatosis-like metaplastic carcinoma","Carcinosarcoma of the breast"],"tldr":"Metaplastic breast cancer is a rare form in which part of the tumour has changed into another tissue type, such as squamous skin-like cells, spindle cells or bone and cartilage. Most are triple-negative and they do worse than other triple-negative cancers, resisting chemotherapy; the low-grade forms are an exception with an excellent outlook.","summary":"Metaplastic breast cancer is defined by the histological presence of at least two cellular types, typically epithelial and mesenchymal components, and the WHO classification (5th edition, 2019) lists low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, squamous cell carcinoma, spindle cell carcinoma, metaplastic carcinoma with heterologous mesenchymal differentiation (chondroid, osseous) and mixed forms (Tan 2020; Cserni 2020). It carries a triple-negative phenotype yet a worse prognosis and shorter survival than triple-negative disease of no special type, with recurrent alterations in epithelial-to-mesenchymal transition, EGFR amplification, PI3K/Akt, Wnt/beta-catenin and cell-cycle pathways, and no standardised treatment guideline of its own (Reddy 2020). In the National Cancer Data Base, five-year overall survival was 72.7 percent for metaplastic against 87.5 percent for non-metaplastic disease overall and 71.1 against 77.8 percent among triple-negative patients; within metaplastic disease receptor status did not change survival (hazard ratio 1.16); patients more often had mastectomy (59.0 against 44.9 percent), chemotherapy (74.1 against 43.1 percent) and axillary dissection, and more often had negative nodes (20.0 against 10.6 percent); chemotherapy (hazard ratio 0.69) and radiotherapy (0.52) were associated with better survival, axillary dissection with worse (Ong 2018). The claudin-low intrinsic subtype has a high frequency of metaplastic differentiation (Prat 2010). Two members of the family are indolent: fibromatosis-like metaplastic carcinoma and low-grade adenosquamous carcinoma, which the European Working Group for Breast Screening Pathology lists among the triple-negative special types unlikely to benefit from chemotherapy (Cserni 2021).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Metaplastic_carcinoma","links":[{"label":"Reddy, Breast Cancer Res 2020: a comprehensive overview of metaplastic breast cancer","url":"https://doi.org/10.1186/s13058-020-01353-z"},{"label":"Ong, Ann Surg Oncol 2018: metaplastic breast cancer treatment and outcomes in 2,500 patients (National Cancer Data Base)","url":"https://doi.org/10.1245/s10434-018-6533-3"},{"label":"Tan, Histopathology 2020: the 2019 WHO classification of tumours of the breast","url":"https://doi.org/10.1111/his.14091"},{"label":"Cserni, Pathologica 2020: histological type and typing of breast carcinomas and WHO classification changes","url":"https://doi.org/10.32074/1591-951x-1-20"},{"label":"Cserni, Cancers 2021: triple-negative breast cancer histological subtypes with a favourable prognosis (European Working Group for Breast Screening Pathology)","url":"https://doi.org/10.3390/cancers13225694"},{"label":"Prat, Breast Cancer Res 2010: phenotypic and molecular characterisation of the claudin-low intrinsic subtype","url":"https://doi.org/10.1186/bcr2635"}],"tags":["breast","tnbc","subtype-page"],"related":["tnbc","tnbc-mesenchymal","medullary-pattern-breast-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":["egfr"],"drugs":[],"companies":[],"institutions":[],"pathways":["emt","pi3k-akt-mtor"],"terms":["claudin-low","tumour-grade"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Under 1 percent of breast cancers: 2,451 metaplastic against 568,057 non-metaplastic stage I to III cases in the US National Cancer Data Base, 2010 to 2014, of which 70.3 percent were triple-negative (Ong 2018).","subtypes":["Squamous cell carcinoma of the breast (ductal origin, no special type component often present)","Spindle cell carcinoma","Metaplastic carcinoma with chondroid or osseous (matrix-producing) differentiation","Low-grade adenosquamous carcinoma (indolent)","Fibromatosis-like metaplastic carcinoma (indolent)","Mixed metaplastic carcinoma"],"biomarkers":["Triple-negative receptor status (70.3 percent)","Mesenchymal or squamous component on histology (with cytokeratin and p63 immunostains)","EGFR amplification, PIK3CA and TP53 mutations (research)"],"standardOfCare":[{"setting":"Early disease","approach":"Surgery and radiotherapy, with chemotherapy as for triple-negative disease of no special type; chemotherapy and radiotherapy were associated with better survival in the national database, and axillary dissection was not. Low-grade adenosquamous and fibromatosis-like forms are treated by surgery alone in the European working group's consensus.","refs":["mastectomy","lumpectomy","sentinel-node","carboplatin","paclitaxel"]},{"setting":"Advanced disease","approach":"As for metastatic triple-negative disease (pembrolizumab where PD-L1 positive, TROP2 ADCs); response to chemotherapy is poorer than in other triple-negative cancers.","refs":["pembrolizumab","sacituzumab-govitecan"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"tnbc"},{"id":"metastatic-anal-cancer","kind":"cancer","name":"Metastatic and recurrent anal squamous cell carcinoma","aka":["Advanced anal cancer","Stage IV anal squamous cell carcinoma","Inoperable recurrent anal cancer","Metastatic SCAC"],"tldr":"Metastatic anal cancer is squamous cell anal cancer that has spread to the liver, lungs or distant lymph nodes, or come back where surgery can no longer remove it. Carboplatin with paclitaxel became the standard first treatment after the InterAACT trial, the PD-1 antibody retifanlimab was added to it in 2025 after POD1UM-303, and nivolumab or pembrolizumab are options after chemotherapy.","summary":"Anal squamous cell carcinoma that has spread beyond the pelvis was for decades treated with cisplatin and fluorouracil on the strength of small series alone. InterAACT (Journal of Clinical Oncology 2020), the first randomised trial in advanced anal cancer, compared that regimen with carboplatin and paclitaxel in 91 patients: response rates were similar, carboplatin and paclitaxel caused fewer serious adverse events and was associated with longer survival, and it became the reference first-line regimen in the NCCN and ESMO guidelines. Because almost all these tumours are HPV-driven and carry PD-L1, checkpoint inhibitors were tested early: the NCI9673 trial of nivolumab (Lancet Oncology 2017) reported responses in 24 percent of 37 previously treated patients, and pembrolizumab showed durable responses in the KEYNOTE-028 and KEYNOTE-158 anal cohorts, so both are guideline options after chemotherapy.\n\nPOD1UM-303, also called InterAACT 2 (Lancet 2025), randomised 308 patients with inoperable locally recurrent or metastatic disease to carboplatin and paclitaxel with retifanlimab or placebo and lengthened progression-free survival from 7.4 to 9.3 months, with overall survival favouring the antibody; the United States approved retifanlimab with carboplatin and paclitaxel in May 2025, the first drug approval specific to anal cancer. Oligometastatic disease is sometimes treated with resection or stereotactic radiotherapy of liver or lung metastases, and isolated pelvic recurrence after chemoradiotherapy is treated by salvage surgery rather than as metastatic disease. Circulating HPV DNA is being studied to follow response, and trials of HPV-directed T-cell therapies and vaccines enrol anal cancer alongside cervical and oropharyngeal cancer.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Anal_cancer","links":[{"label":"InterAACT (JCO 2020)","url":"https://doi.org/10.1200/JCO.19.03266"},{"label":"POD1UM-303 (Lancet 2025)","url":"https://doi.org/10.1016/S0140-6736(25)00631-2"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Anal_cancer"}],"tags":["subtype-page","gastrointestinal"],"related":["localised-anal-cancer","anal-hsil-precursor","anal","recurrent-metastatic-cervical-cancer"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","cytotoxic-chemotherapy","cthpv-dna","sbrt"],"targets":["pd1","pdl1"],"drugs":["carboplatin","paclitaxel","retifanlimab","nivolumab","pembrolizumab","fluorouracil"],"companies":[],"institutions":[],"pathways":[],"terms":["hpv-p16","re-irradiation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-interaact-carboplatin-paclitaxel-advanced-anal-cancer-rao-jco-2020","paper-esmo-anal-cancer-guideline-ann-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"A minority of patients present with distant spread or relapse beyond the pelvis after chemoradiotherapy; the liver, lungs and distant nodes are the usual sites.","subtypes":["Synchronous metastatic anal squamous cell carcinoma (liver, lung, distant nodes)","Metachronous relapse after chemoradiotherapy","Inoperable locally recurrent anal cancer","Oligometastatic anal cancer (local treatment considered)","HPV-negative metastatic anal squamous cell carcinoma"],"biomarkers":["HPV and p16 status","PD-L1 (not required for retifanlimab)","Circulating HPV DNA (investigational monitoring)","HIV status and CD4 count","Mismatch repair and tumour mutational burden (rarely relevant)"],"standardOfCare":[{"setting":"First line","approach":"Carboplatin and paclitaxel with retifanlimab (POD1UM-303, approved 2025); carboplatin and paclitaxel alone (InterAACT) where the antibody is unavailable or contraindicated.","refs":["carboplatin","paclitaxel","retifanlimab","checkpoint-inhibitor","interaact","pod1um-303"],"guideline":{"version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}},{"setting":"After platinum chemotherapy","approach":"Nivolumab (NCI9673) or pembrolizumab (KEYNOTE-158) if no prior PD-1 antibody; fluorouracil-based or taxane chemotherapy otherwise.","refs":["nivolumab","pembrolizumab","fluorouracil","nci9673"],"guideline":{"version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}},{"setting":"Oligometastatic disease","approach":"Resection or stereotactic radiotherapy of limited liver or lung metastases alongside systemic therapy, on a case basis.","refs":["sbrt"],"guideline":{"version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}},{"setting":"Isolated pelvic recurrence","approach":"Salvage abdominoperineal resection when the tumour is resectable; re-irradiation is rarely possible.","refs":["robotic-surgery","re-irradiation"],"guideline":{"version":"NCCN Guidelines: Anal Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1414"}}],"stateOfArt":["Retifanlimab with carboplatin and paclitaxel is the first regimen approved specifically for anal cancer.","InterAACT gave the disease its first randomised first-line standard.","PD-1 antibodies produce durable responses in a minority after chemotherapy."],"history":[{"year":2017,"title":"NCI9673: nivolumab responses in refractory anal cancer","refs":["nivolumab"]},{"year":2020,"title":"InterAACT: carboplatin and paclitaxel becomes the first-line standard","refs":["carboplatin","paclitaxel"]},{"year":2025,"title":"POD1UM-303 published; retifanlimab with carboplatin and paclitaxel approved in the United States","refs":["retifanlimab","carboplatin","paclitaxel"]}],"pipeline":["retifanlimab","cthpv-dna","nivolumab","pembrolizumab"],"openProblems":["Median survival remains under two years even with a PD-1 antibody added to chemotherapy.","No second-line standard exists after chemo-immunotherapy.","Whether local treatment of oligometastases improves survival has never been randomised.","HPV-directed cell therapies and vaccines are promising but early."],"parent":"anal"},{"id":"metastatic-cancer","kind":"cancer","name":"Metastatic cancer (cancer that has spread)","aka":["Metastatic Cancer","Secondary cancer","Advanced cancer","Stage 4 cancer","Stage IV cancer","Cancer that has spread"],"tldr":"Metastatic cancer means the original cancer has spread to other parts of the body, most often the bones, liver, lungs or brain. It keeps the name of where it started, is treated with therapies that reach the whole body, and can increasingly be controlled for years; with limited spread it is sometimes treated with the aim of cure.","summary":"Metastasis is the process by which cancer cells leave the original tumour, travel through blood or lymph and grow in another organ. A breast cancer that has spread to the liver is still breast cancer and is treated with breast cancer drugs, which is why this page points to the cancer-specific pages for treatment. What metastatic cancers share is the intent and the tools: systemic therapy (chemotherapy, targeted drugs, hormone therapy, immunotherapy) rather than surgery alone; radiotherapy and bone-strengthening drugs for bone metastases; radiosurgery or surgery for brain metastases; and early palliative care alongside treatment, which improves quality of life and in some studies survival. Two ideas have changed the outlook: many metastatic cancers are now chronic conditions controlled for years, and oligometastatic disease, spread limited to a few sites, is increasingly treated with stereotactic radiotherapy or surgery to every site with the aim of long remission, as the SABR-COMET trial suggested. Circulating tumour DNA is beginning to detect and monitor spread from a blood sample.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Metastasis","links":[{"label":"NCI: Metastatic cancer","url":"https://www.cancer.gov/types/metastatic-cancer"}],"tags":["umbrella"],"related":["cancer-of-unknown-primary","secondary-brain-tumours","bone-metastases","brain-metastases","leptomeningeal-disease","oligometastatic","sabr-comet"],"cancers":[],"sections":[],"technologies":["sbrt","stereotactic-radiosurgery","palliative-radiotherapy","bone-modifying-agents","palliative-care","ctdna"],"targets":[],"drugs":["zoledronic-acid","denosumab","radium-223"],"companies":[],"institutions":[],"pathways":[],"terms":["metastasis","oligometastatic","bone-metastases","brain-metastases","leptomeningeal-disease","palliative-treatment"],"trials":["alliance-n0574","nrg-cc001","horrad","nct06174987","nct06506955","nct04914598","nct06081959","nct04464226","nct05501886","nct06994507","nct05774951","nct04906395","nct05296798","nct07648264","nct05814354","nct07672236","nct02763566","nct06312176","nct06062810","nct06343948","nct05696626","nct03148418","nct07060807","nct05262010","nct06635447","nct05112965","nct06652633","nct07541079","nct02320435","nct06492616","nct04895358","nct07499674","nct04170283","nct04862663","nct05909397","nct05514054","nct03315364","nct06867705","nct05629234","nct07405164","nct06313983","nct06764186","nct07290088","nct05257395","nct06041061","nct05864014","nct05827081","nct04514419","nct03435796","nct07648914","nct07071337","nct06632912","nct03815643","nct04639986","nct04851613","nct03980054","nct06072612"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"other","burden":"Most cancer deaths follow metastasis rather than growth of the original tumour; how often a cancer spreads, and where, depends on the primary site.","subtypes":[],"biomarkers":["Imaging (CT, PET, MRI) and biopsy of a metastatic site to confirm the primary and re-test targets","Circulating tumour DNA","Site-specific markers such as bone scan uptake or alkaline phosphatase"],"standardOfCare":[{"setting":"Widespread metastatic disease","approach":"Systemic therapy chosen by the primary cancer and its biomarkers, with early palliative care; see the individual cancer pages.","refs":["palliative-care"]},{"setting":"Oligometastatic disease","approach":"Stereotactic ablative radiotherapy or surgery to all sites in addition to systemic therapy, in selected patients and ideally in trials.","refs":["sbrt"]},{"setting":"Bone metastases","approach":"Palliative radiotherapy for pain, bone-modifying agents (zoledronic acid or denosumab) to prevent fractures, radium-223 in prostate cancer.","refs":["palliative-radiotherapy","bone-modifying-agents","zoledronic-acid","denosumab","radium-223"]},{"setting":"Brain metastases","approach":"Stereotactic radiosurgery for limited lesions, surgery for large symptomatic ones, and brain-penetrant targeted drugs where a driver exists.","refs":["stereotactic-radiosurgery"]}],"stateOfArt":["Oligometastatic disease can be treated for long-term control: in SABR-COMET, adding stereotactic radiotherapy to every metastasis (one to five sites) raised five-year overall survival from 17.7 to 42.3 percent, at the cost of some serious toxicity; phase 3 trials are confirming it.","Treatment is chosen by the tumour's biology, not only its origin: pembrolizumab for mismatch-repair-deficient or high-mutation-burden tumours (2017), larotrectinib and entrectinib for NTRK fusions, dabrafenib with trametinib for BRAF V600E, selpercatinib for RET, and trastuzumab deruxtecan for HER2-positive tumours of any site are approved regardless of where the cancer began.","Metastases to bone and brain have their own standards: bone-modifying agents and single-fraction palliative radiotherapy for bone, stereotactic radiosurgery rather than whole-brain radiotherapy for limited brain metastases, and brain-penetrant targeted drugs where a driver exists.","Early palliative care alongside cancer treatment improves quality of life and mood and does not shorten life; guidelines now recommend it from diagnosis of advanced disease."],"history":[{"year":1995,"title":"Oligometastasis proposed","note":"Hellman and Weichselbaum argue that some patients have a limited metastatic state that local treatment could control, the idea SABR-COMET later tested.","refs":["sbrt"]},{"year":2010,"title":"Early palliative care trial","note":"Temel and colleagues randomise newly diagnosed metastatic lung cancer patients to early palliative care with standard oncology: better quality of life, less depression and no loss of survival.","refs":["palliative-care"]},{"year":2017,"title":"First tissue-agnostic approval","note":"Pembrolizumab is approved for any solid tumour with mismatch-repair deficiency or microsatellite instability, the first cancer drug approved by biomarker rather than organ.","refs":["pembrolizumab"]},{"year":2020,"title":"SABR-COMET long-term results","note":"Five-year survival more than doubles with stereotactic radiotherapy to all metastases in the randomised phase 2 trial.","refs":["sabr-comet"]},{"year":1889,"title":"Paget's seed and soil hypothesis","note":"Stephen Paget proposed that cancers spread to organs whose environment suits them, the founding idea of metastasis research.","refs":[]},{"year":2002,"title":"Zoledronic acid approved for bone metastases","note":"Bisphosphonates, then denosumab, cut fractures and other skeletal events from bone metastases.","refs":["zoledronic-acid","denosumab"]},{"year":2019,"title":"SABR-COMET reports","note":"Randomised phase 2 trial in which stereotactic radiotherapy to all sites of oligometastatic disease was associated with longer survival, launching phase 3 trials of the approach.","refs":["sbrt"]}],"pipeline":["sabr-comet","sbrt","ctdna","pembrolizumab","larotrectinib","entrectinib","dabrafenib","trametinib","selpercatinib","dostarlimab","trastuzumab-deruxtecan","tst001","merestinib","au-007","or502","wjb001","mhb039a","mhb036c","samuraciclib","camonsertib","selicrelumab","fluzoparib","evexomostat","obi-902","farletuzumab-ecteribulin","imp1734","skb105","avzo-023","tqb3909","obi-992","rnk05047","inlexisertib","ipg1094","hst-1011","evm14"],"openProblems":["Metastasis itself has no approved drug: treatments target the growing cells, not the spreading.","Which patients with limited spread truly benefit from treating every site is still being tested in phase 3 trials."]},{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","aka":["mCRPC","Metastatic CRPC","Castration-resistant metastatic prostate cancer","Hormone-refractory prostate cancer (older term)","Hormone-relapsed metastatic prostate cancer","Hormone-refractory prostate cancer"],"tldr":"Metastatic castration-resistant prostate cancer is disease that grows despite castrate testosterone. Sequenced treatments now include androgen receptor inhibitors, docetaxel and cabazitaxel, PARP inhibitors for men with BRCA-type mutations, the radioligand 177Lu-PSMA-617 and radium-223 for bone-predominant disease.","summary":"Metastatic castration-resistant prostate cancer is defined by progression on scans or PSA, or new metastases, with castrate testosterone. Nearly every man reaches it from hormone-sensitive disease, and the treatment chosen depends on what he has already had. Men who have not had an androgen receptor pathway inhibitor receive abiraterone or enzalutamide; PROpel, TALAPRO-2 and MAGNITUDE showed that adding olaparib, talazoparib or niraparib helps men with BRCA and other homologous recombination repair mutations, and PROfound showed olaparib alone beats a second hormonal agent in these men. Docetaxel and then cabazitaxel remain the chemotherapies. VISION established 177Lu-PSMA-617 after chemotherapy and PSMAfore moved it before, for PSMA PET-positive disease; 177Lu-PSMA-I&T (SPLASH, ECLIPSE) follows the same path. Radium-223 lengthens life in symptomatic bone-predominant disease without visceral metastases (ALSYMPCA), sipuleucel-T is still approved for minimally symptomatic disease, and pembrolizumab is used for the rare mismatch repair-deficient tumour. Tumour and germline testing for HRR genes and mismatch repair is standard. Actinium-225 PSMA agents, the STEAP1 T-cell engager xaluritamig and the EZH2 inhibitor mevrometostat are in phase 3.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Castration-resistant_prostate_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Castration-resistant_prostate_cancer"},{"label":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"},{"label":"NICE NG131: prostate cancer, diagnosis and management (recommendations, including the Cambridge Prognostic Group table at 1.2.15)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"}],"tags":["subtype-page"],"related":["prostate-mhspc","prostate-nmcrpc","prostate-nepc","prostate-bcr"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["brca-reversion-mutations","tnm-prostate-cancer","castration-resistance","radiographic-progression-free-survival","bipolar-androgen-therapy","genome-wide-loss-of-heterozygosity","neuroendocrine-differentiation","chromoplexy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-vision-nejm-2021","paper-profound-nejm-2020","paper-cou-aa-301-abiraterone-de-bono-nejm-2011","paper-alsympca-radium-223-nejm-2013"],"journals":[],"dependsOn":[],"notes":["NICE calls this hormone-relapsed metastatic prostate cancer, which is the heading its own recommendations use; castration-resistant is the term of the trials, the labels and the American guidelines. A British patient will meet both words for the same disease."],"group":"genitourinary","burden":"The state in which nearly all prostate cancer deaths occur, about 400,000 a year worldwide; median survival from first treatment is now around three years, longer for men who have not had an androgen receptor inhibitor.","subtypes":["mCRPC, androgen receptor pathway inhibitor-naive","mCRPC after an androgen receptor pathway inhibitor, chemotherapy-naive","mCRPC after taxane chemotherapy","HRR-mutant mCRPC (BRCA1, BRCA2, ATM and others; PARP inhibitors)","PSMA PET-positive mCRPC (radioligand therapy)","Bone-predominant mCRPC without visceral metastases (radium-223)","Mismatch repair-deficient mCRPC (pembrolizumab)"],"biomarkers":["Tumour and germline HRR genes (BRCA2 above all)","PSMA PET uptake and FDG discordance","Mismatch repair deficiency and tumour mutational burden","PSA and alkaline phosphatase","Circulating tumour DNA (AR amplification, BRCA2 reversion)","AR-V7 in circulating tumour cells (research)"],"standardOfCare":[{"setting":"First line, androgen receptor pathway inhibitor-naive","approach":"Abiraterone or enzalutamide; add olaparib, talazoparib or niraparib for HRR-mutant, above all BRCA-mutant, disease (PROpel, TALAPRO-2, MAGNITUDE).","refs":["abiraterone","enzalutamide","olaparib","talazoparib","niraparib","propel","talapro-2","magnitude"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"After an androgen receptor pathway inhibitor","approach":"Docetaxel; olaparib or rucaparib for BRCA-mutant disease (PROfound); 177Lu-PSMA-617 for PSMA-positive disease before chemotherapy (PSMAfore); pembrolizumab for mismatch repair-deficient tumours.","refs":["docetaxel","olaparib","rucaparib","profound","pluvicto","psmafore","pembrolizumab"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"After docetaxel","approach":"177Lu-PSMA-617 (VISION), cabazitaxel, radium-223 for symptomatic bone-only disease (ALSYMPCA), or a PARP inhibitor if not yet used.","refs":["pluvicto","vision","cabazitaxel","radium-223","alsympca","therap"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Bone health","approach":"Denosumab or zoledronic acid to prevent skeletal events, with calcium and vitamin D; palliative radiotherapy to painful metastases.","refs":["denosumab","zoledronic-acid","sbrt"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Phase 3 options","approach":"Actinium-225 PSMA radioligands, the STEAP1 T-cell engager xaluritamig, the EZH2 inhibitor mevrometostat and 177Lu-PSMA-I&T within trials.","refs":["ac225-psma","xaluritamig","mevrometostat","lu177-psma-it","alphabreak","xalute","mevpro-1","splash","eclipse-psma"]}],"stateOfArt":["PSMA PET and 177Lu-PSMA-617 make prostate cancer the model for theranostics.","PARP inhibitors gave prostate cancer its first genotype-directed treatment.","Survival in this once six-month setting is now measured in years, built from sequenced drugs rather than one breakthrough."],"history":[{"year":2004,"title":"TAX 327: docetaxel is the first drug to lengthen life in castration-resistant disease","refs":["docetaxel"]},{"year":2010,"title":"Cabazitaxel and sipuleucel-T approved","refs":["cabazitaxel","sipuleucel-t"]},{"year":2011,"title":"Abiraterone approved after docetaxel","refs":["abiraterone"]},{"year":2012,"title":"Enzalutamide approved","refs":["enzalutamide"]},{"year":2013,"title":"ALSYMPCA: radium-223, the first alpha emitter","refs":["alsympca","radium-223"]},{"year":2020,"title":"PROfound: olaparib for HRR-mutant disease","refs":["profound","olaparib"]},{"year":2021,"title":"VISION: 177Lu-PSMA-617 lengthens life","refs":["vision","pluvicto"]},{"year":2022,"title":"PROpel and MAGNITUDE: PARP inhibitor plus abiraterone","refs":["propel","magnitude"]},{"year":2023,"title":"PSMAfore and TALAPRO-2","refs":["psmafore","talapro-2"]},{"year":2025,"title":"ECLIPSE: 177Lu-PSMA-I&T meets its endpoint","refs":["eclipse-psma"]}],"pipeline":["ac225-psma","xaluritamig","mevrometostat","lu177-psma-it","pasritamig","opevesostat","saruparib","bms-986365","fpi-2265","ifinatamab-deruxtecan","hs-20093"],"openProblems":["The best sequence of radioligand, PARP inhibitor and chemotherapy is untested.","Actinium-225 supply and the lack of alpha-emitter dosimetry.","Lineage plasticity to neuroendocrine disease under androgen receptor blockade.","Resistance to 177Lu-PSMA-617 in PSMA-low or FDG-discordant disease."],"parent":"prostate"},{"id":"prostate-mhspc","kind":"cancer","name":"Metastatic hormone-sensitive prostate cancer","aka":["mHSPC","Metastatic castration-sensitive prostate cancer","mCSPC","De novo metastatic prostate cancer","Hormone-naive metastatic prostate cancer","Hormone-sensitive prostate cancer"],"tldr":"Metastatic hormone-sensitive prostate cancer is disease that has spread but still responds to lowering testosterone. Hormone therapy alone is no longer enough: adding an androgen receptor inhibitor, and docetaxel for high-volume disease, lengthens life by years.","summary":"Metastatic hormone-sensitive prostate cancer has spread to bone, nodes or organs and has not yet been exposed to, or is still controlled by, androgen deprivation. It is found by PSA, biopsy and imaging, increasingly PSMA PET, and is split into high volume (four or more bone metastases with one outside the spine and pelvis, or visceral disease) and low volume, and into de novo and recurrent disease. Androgen deprivation with a GnRH agonist or antagonist is the backbone. CHAARTED and STAMPEDE showed docetaxel added to it lengthens life, mainly in high-volume disease; LATITUDE and STAMPEDE showed the same for abiraterone; TITAN (apalutamide), ENZAMET and ARCHES (enzalutamide) and ARANOTE (darolutamide) extended the benefit to every androgen receptor pathway inhibitor. PEACE-1 and ARASENS proved triplet therapy with docetaxel plus abiraterone or darolutamide for men fit for chemotherapy with high-volume disease. Radiotherapy to the prostate improves survival in low-volume disease (STAMPEDE). CAPItello-281 added capivasertib for PTEN-deficient tumours in 2026, and PSMAddition brought 177Lu-PSMA-617 into this setting the same year. Hormone therapy alone is now reserved for frail men.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Prostate_cancer#Metastatic_disease","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Prostate_cancer"},{"label":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"},{"label":"Brierley et al., International Journal of Cancer 2026: the 9th edition of the UICC TNM classification of malignant tumours, updates and rationale for change (prostate at section 10.1)","url":"https://doi.org/10.1002/ijc.70561"}],"tags":["subtype-page"],"related":["prostate-mcrpc","prostate-nmcrpc","prostate-bcr","prostate-high-risk"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["tnm-prostate-cancer","cambridge-prognostic-group","intermittent-androgen-deprivation","other-cause-mortality","genome-wide-loss-of-heterozygosity","radiographic-progression-free-survival"],"trials":["aranote","enzamet","nct02489318"],"people":[],"bottlenecks":[],"keyPapers":["paper-stampede-abiraterone-nejm-2017","paper-latitude-nejm-2017","paper-arasens-nejm-2022","paper-chaarted-nejm-2015"],"journals":[],"dependsOn":[],"notes":["A word of caution about what stage IV means now. The ninth edition of TNM asks that a node or metastasis found on PSMA PET be written N1(PET) or M1(PET), because prostate is the malignancy most affected by stage migration: imaging now finds small-volume disease that older staging could not see, so a man diagnosed with metastatic disease on a PSMA PET may have much less cancer than a man given the same label before those scans existed, and the older survival figures were measured on the older label (Brierley 2026)."],"group":"genitourinary","burden":"About one in twenty prostate cancers are metastatic at diagnosis in high-income countries and far more elsewhere; median survival has risen from under four years to more than five with combination therapy.","subtypes":["De novo high-volume mHSPC (4 or more bone metastases or visceral disease)","De novo low-volume mHSPC (oligometastatic, prostate radiotherapy helps)","Recurrent metastatic hormone-sensitive disease after local therapy","PTEN-deficient mHSPC (capivasertib)","PSMA-positive mHSPC (177Lu-PSMA-617)"],"biomarkers":["Disease volume (CHAARTED criteria)","De novo versus recurrent","PTEN loss by immunohistochemistry","PSMA PET positivity","Germline and tumour HRR genes","PSA fall to below 0.2 at seven months (prognostic)"],"standardOfCare":[{"setting":"All patients, backbone","approach":"Continuous androgen deprivation with a GnRH agonist, GnRH antagonist or orchiectomy; never alone in fit men.","refs":["androgen-deprivation","leuprolide","degarelix","relugolix","adt"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Doublet therapy","approach":"Androgen deprivation plus abiraterone (LATITUDE, STAMPEDE), enzalutamide (ARCHES, ENZAMET), apalutamide (TITAN) or darolutamide (ARANOTE).","refs":["abiraterone","enzalutamide","apalutamide","darolutamide","latitude","stampede","arches"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Triplet therapy, high volume, fit for chemotherapy","approach":"Androgen deprivation plus docetaxel plus darolutamide (ARASENS) or abiraterone (PEACE-1).","refs":["docetaxel","darolutamide","abiraterone","arasens","peace-1","chaarted"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Low-volume disease","approach":"Doublet therapy plus radiotherapy to the prostate (STAMPEDE); metastasis-directed radiotherapy within trials.","refs":["stampede","imrt-igrt","sbrt","oligometastatic"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Biomarker-selected additions (2026)","approach":"Capivasertib with abiraterone for PTEN-deficient tumours (CAPItello-281); 177Lu-PSMA-617 with androgen receptor pathway inhibitor for PSMA-positive disease (PSMAddition).","refs":["capivasertib","capitello-281","pluvicto","psmaddition"]}],"stateOfArt":["Combination therapy from diagnosis has lifted median survival past five years, and past eight in low-volume disease.","Triplet therapy is standard for high-volume disease in men fit for docetaxel.","The first biomarker-selected drugs, capivasertib and 177Lu-PSMA-617, entered this setting in 2026."],"history":[{"year":1941,"title":"Huggins shows castration controls metastatic prostate cancer","refs":["androgen-deprivation"]},{"year":2015,"title":"CHAARTED: docetaxel with hormone therapy lengthens life","refs":["chaarted","docetaxel"]},{"year":2016,"title":"STAMPEDE confirms docetaxel at first diagnosis","refs":["stampede"]},{"year":2017,"title":"LATITUDE and STAMPEDE: abiraterone at first diagnosis","refs":["latitude","stampede","abiraterone"]},{"year":2019,"title":"TITAN, ENZAMET and ARCHES: androgen receptor inhibitors for all","refs":["arches","apalutamide","enzalutamide"]},{"year":2021,"title":"PEACE-1: European triplet therapy","refs":["peace-1"]},{"year":2022,"title":"ARASENS: darolutamide triplet cuts death by a third","refs":["arasens","darolutamide"]},{"year":2026,"title":"Capivasertib for PTEN-deficient and 177Lu-PSMA-617 for PSMA-positive disease approved","refs":["capitello-281","psmaddition","capivasertib","pluvicto"]}],"pipeline":["capivasertib","pluvicto","psmaddition","relugolix","psma-pet"],"openProblems":["Who needs triplet therapy and who is overtreated by it.","Whether intermittent or de-escalated therapy is safe after a deep PSA response.","PSMA PET restages many men the trials called non-metastatic, and the evidence has not caught up."],"parent":"prostate"},{"id":"metastatic-pdac","kind":"cancer","name":"Metastatic pancreatic ductal adenocarcinoma","aka":["Metastatic pancreatic cancer","Stage IV pancreatic adenocarcinoma","Advanced pancreatic cancer","mPDAC"],"tldr":"Metastatic pancreatic cancer has spread beyond the pancreas, usually to the liver, and is treated with chemotherapy rather than surgery. Three combination regimens lengthen life, a minority of patients qualify for targeted drugs chosen by tumour or inherited mutations, and in 2026 the pan-RAS inhibitor daraxonrasib became the first drug against the KRAS mutation that drives almost every case.","summary":"Metastatic pancreatic ductal adenocarcinoma is diagnosed by CT with biopsy of the primary or a metastasis, usually under endoscopic ultrasound or CT guidance. Nearly every tumour carries a KRAS mutation (G12D, G12V and G12R most often, G12C in a small minority) alongside TP53, CDKN2A and SMAD4 loss, and every patient should have germline testing and tumour sequencing at diagnosis, because roughly one in ten has an actionable finding: a germline BRCA or PALB2 variant, mismatch repair deficiency, or, in KRAS wild-type tumours, a gene fusion or BRAF alteration. Supportive care runs in parallel: biliary stenting, pancreatic enzyme replacement, nutrition, pain control and treatment of thrombosis.\n\nGemcitabine became the standard in 1997 by improving symptoms and survival modestly over fluorouracil. Two combinations then beat it: FOLFIRINOX in PRODIGE 4/ACCORD 11 (2011) for fit patients, and gemcitabine plus nab-paclitaxel in MPACT (2013) for a broader group. NAPOLI 3 (2023) showed that NALIRIFOX, which replaces irinotecan with its liposomal form, beats gemcitabine plus nab-paclitaxel, and it was approved in 2024. Choice between them turns on fitness, neuropathy, biliary drainage and patient preference. Olaparib maintenance after platinum chemotherapy is approved for germline BRCA carriers (POLO), pembrolizumab for mismatch repair deficient tumours, zenocutuzumab for NRG1 fusions, and NTRK, BRAF and other targeted drugs for the rare tumours that carry them. Second-line chemotherapy switches backbone: liposomal irinotecan with fluorouracil after gemcitabine (NAPOLI-1), gemcitabine-based treatment after FOLFIRINOX.\n\nThe field changed in 2026 when RASolute 302 showed that daraxonrasib, an inhibitor of the active form of all RAS proteins, lengthened survival over chemotherapy after first-line treatment; it is now approved and is being tested first line with and without chemotherapy and in the adjuvant setting. G12D-selective inhibitors (zoldonrasib, MRTX1133 and others) are in phase 3 first line, G12C inhibitors are used off label or in trials for the small G12C group, and shared KRAS vaccines, personalised mRNA vaccines, claudin 18.2 and mesothelin-directed antibodies, antibody-drug conjugates and CAR-T cells are in trials. Immune checkpoint inhibitors alone do not work outside mismatch repair deficient disease, and the search for combinations that make this immunologically cold tumour respond continues.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Pancreatic_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Pancreatic_cancer"},{"label":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}],"tags":["subtype-page","gastrointestinal"],"related":["locally-advanced-pdac","kras-g12c-pdac","kras-wild-type-pdac","brca-palb2-pdac","msi-high-pdac","resectable-pdac","kras-roadmap"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","kras-inhibitors","parp-inhibitor","checkpoint-inhibitor","neoantigen-mrna-vaccine","shared-antigen-vaccine","car-t","adc","bispecific-antibody","cgp","liquid-biopsy","biliary-stenting-drainage"],"targets":["kras","brca","cldn18-2","mesothelin","her3","ntrk","pd1","fap"],"drugs":["folfirinox","nalirifox","gemcitabine-nab-paclitaxel","gemcitabine","irinotecan","fluorouracil","olaparib","pembrolizumab","zenocutuzumab","daraxonrasib","zoldonrasib","mrtx1133","eli-002-7p","autogene-cevumeran","ibi343","cmg901","satricabtagene-autoleucel","fap-2286","devimistat","pamrevlumab","eryaspase","algenpantucel-l"],"companies":["ipsen","revolution-medicines","astrazeneca","merck","bms","biontech","elicio-therapeutics","innovent","astellas","carsgen"],"institutions":[],"pathways":["pancreatic-cancer-signalling","ras-mapk","immune-desert-exclusion","cachexia-biology"],"terms":["kras-mutation-subtypes","ca19-9","metastasis","peritoneal-metastasis","gbrca-mutation","msi","gene-fusion","resistance","cachexia","obstructive-jaundice","platinum-sensitivity"],"trials":["napoli-3","polo","rasolute-302","nct07491445","nct07805954","nct07621718","nct07522073","g-hope-002","nct04404595","nct06051695","nct07562152","nct06608927","mountaintap-30","precision-promise","avenger-500","lapis-trial","trybeca-1","impress-trial","notable-trial"],"people":["daniel-von-hoff","thierry-conroy","zev-wainberg","eileen-oreilly","talia-golan","tanios-bekaii-saab","eric-van-cutsem","volker-heinemann","hedy-kindler","kevan-shokat","frank-mccormick"],"bottlenecks":[],"keyPapers":["paper-conroy-folfirinox-pancreatic-nejm-2011","paper-mpact-nab-paclitaxel-gemcitabine-nejm-2013","paper-napoli-3-lancet-2023","paper-burris-gemcitabine-pancreatic-jco-1997","paper-rahib-projecting-cancer-deaths-2030-cancerres-2014"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About half of pancreatic cancers have already spread, most often to the liver and peritoneum, when they are found; this stage accounts for most of the disease's deaths and most of its trials.","subtypes":["Metastatic PDAC, fit for combination chemotherapy (FOLFIRINOX, NALIRIFOX or gemcitabine plus nab-paclitaxel)","Metastatic PDAC, unfit for combination chemotherapy (gemcitabine alone or best supportive care)","Metastatic PDAC with a KRAS G12D, G12V or G12R mutation (pan-RAS and G12D inhibitors)","Metastatic PDAC with an actionable non-KRAS finding (BRCA or PALB2, mismatch repair deficiency, NRG1 or NTRK fusion, BRAF)","Metastatic PDAC after first-line chemotherapy (daraxonrasib, switch of backbone)","Liver-dominant versus peritoneal-dominant metastatic PDAC"],"biomarkers":["KRAS mutation subtype by tissue or plasma sequencing (G12D, G12V, G12R, G12C; wild-type prompts fusion testing)","Germline BRCA1, BRCA2, PALB2 and ATM (platinum and PARP inhibitor choice)","Mismatch repair status by immunohistochemistry or sequencing (pembrolizumab)","NRG1, NTRK, ALK, ROS1, FGFR2 and RET fusions and BRAF alterations in KRAS wild-type tumours","CA 19-9 for response monitoring (uninformative in Lewis-negative patients)","Claudin 18.2 and mesothelin expression (trial eligibility)","Performance status, bilirubin and neuropathy (regimen choice)"],"standardOfCare":[{"setting":"First line, fit patients","approach":"Modified FOLFIRINOX or NALIRIFOX (NAPOLI 3); gemcitabine plus nab-paclitaxel as the alternative, chosen by fitness, biliary drainage and neuropathy.","refs":["folfirinox","nalirifox","napoli-3","gemcitabine-nab-paclitaxel"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"First line, less fit patients","approach":"Gemcitabine plus nab-paclitaxel at reduced dose or gemcitabine alone; best supportive care when chemotherapy would do harm.","refs":["gemcitabine-nab-paclitaxel","gemcitabine","cachexia"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Maintenance and biomarker-directed therapy","approach":"Olaparib after at least sixteen weeks of platinum without progression in germline BRCA carriers (POLO); pembrolizumab for mismatch repair deficient tumours; zenocutuzumab for NRG1 fusions; NTRK and BRAF inhibitors where present.","refs":["olaparib","polo","pembrolizumab","zenocutuzumab","larotrectinib","dabrafenib-trametinib"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Second line","approach":"Daraxonrasib after first-line chemotherapy (RASolute 302); otherwise switch backbone, liposomal irinotecan with fluorouracil after gemcitabine or a gemcitabine-based regimen after FOLFIRINOX.","refs":["daraxonrasib","rasolute-302","irinotecan","fluorouracil","gemcitabine-nab-paclitaxel"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Supportive care throughout","approach":"Biliary stenting, pancreatic enzyme replacement, dietetic support, early palliative care, anticoagulation for thrombosis and coeliac plexus block for pain.","refs":["biliary-stenting-drainage","cachexia","obstructive-jaundice"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Clinical trials","approach":"First-line daraxonrasib with or without chemotherapy; G12D inhibitors with chemotherapy; KRAS vaccines; claudin 18.2 and mesothelin-directed antibodies and CAR-T; platform trials such as Precision Promise.","refs":["nct07491445","zoldonrasib","nct07805954","eli-002-7p","g-hope-002","nct04404595","precision-promise"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Three combination regimens lengthen life first line and NALIRIFOX is the newest (NAPOLI 3, approved 2024).","Daraxonrasib is the first RAS inhibitor to lengthen survival in pancreatic cancer (RASolute 302, 2026) and is approved after first-line chemotherapy.","Biomarker testing at diagnosis finds an actionable target in about one in ten patients.","G12D-selective inhibitors, KRAS vaccines and claudin 18.2 or mesothelin-directed cell and antibody therapies are in late trials."],"history":[{"year":1997,"title":"Gemcitabine approved after showing clinical benefit over fluorouracil (Burris)","refs":["gemcitabine","paper-burris-gemcitabine-pancreatic-jco-1997"]},{"year":2011,"title":"PRODIGE 4/ACCORD 11: FOLFIRINOX lengthens survival over gemcitabine in fit patients","refs":["folfirinox","thierry-conroy","paper-conroy-folfirinox-pancreatic-nejm-2011"]},{"year":2013,"title":"MPACT: gemcitabine plus nab-paclitaxel lengthens survival over gemcitabine","refs":["gemcitabine-nab-paclitaxel","daniel-von-hoff","paper-mpact-nab-paclitaxel-gemcitabine-nejm-2013"]},{"year":2019,"title":"POLO: olaparib maintenance delays progression in germline BRCA carriers","refs":["polo","olaparib","talia-golan"]},{"year":2023,"title":"NAPOLI 3: NALIRIFOX beats gemcitabine plus nab-paclitaxel first line","refs":["napoli-3","nalirifox","zev-wainberg","paper-napoli-3-lancet-2023"]},{"year":2024,"title":"Zenocutuzumab approved for NRG1 fusion-positive pancreatic cancer","refs":["zenocutuzumab"]},{"year":2026,"title":"RASolute 302: daraxonrasib lengthens survival after first-line chemotherapy, the first RAS inhibitor to do so","refs":["rasolute-302","daraxonrasib","revolution-medicines"]}],"pipeline":["nct07491445","zoldonrasib","nct07805954","nct07621718","nct07522073","mrtx1133","eli-002-7p","autogene-cevumeran","g-hope-002","ibi343","cmg901","nct04404595","satricabtagene-autoleucel","nct06051695","fap-2286","nct07562152","nct06608927","nct07259317","nct07450859","mountaintap-30","elraglusib","precision-promise","idea-bio1-pan-ras-covalent-g12d","idea-shared-kras-vaccine-adjuvant"],"openProblems":["Resistance to RAS inhibitors emerges within months and the best partner drugs are unknown.","Checkpoint inhibitors fail outside mismatch repair deficient disease because the tumour excludes T cells.","Most patients are too unwell for FOLFIRINOX-type regimens and trials under-represent them.","Cachexia and thrombosis kill many patients before the cancer itself is the limiting problem.","Late diagnosis: half of patients present with metastases and no screening test exists for the general population."],"parent":"pancreatic"},{"id":"metastatic-ppgl","kind":"cancer","name":"Metastatic pheochromocytoma and paraganglioma","aka":["Malignant pheochromocytoma","Metastatic paraganglioma","Advanced PPGL","Unresectable pheochromocytoma and paraganglioma"],"tldr":"Metastatic pheochromocytoma and paraganglioma is disease that has spread to bone, lymph nodes, liver or lungs, the only way these adrenaline-producing tumours are called malignant. It is often slow, so treatment starts with blood pressure control and watching, then moves through radioactive drugs that home to the tumour, the kinase inhibitor sunitinib, chemotherapy and, since 2025, belzutifan.","summary":"No pathological feature reliably separates benign from malignant pheochromocytoma and paraganglioma; malignancy is defined by metastases at sites where chromaffin tissue does not normally occur, above all bone, lymph nodes, liver and lung. Metastatic disease occurs in about a tenth of adrenal tumours and a much larger share of extra-adrenal sympathetic paragangliomas, and SDHB mutation, large size, extra-adrenal site and a noradrenergic or dopaminergic profile are the main risk factors. The course is heterogeneous: some patients live for decades with stable bone metastases, others progress within months, so the first decision is whether to treat at all. Catecholamine excess is controlled throughout with alpha-blockade (phenoxybenzamine or doxazosin) and beta-blockade added second, with metyrosine for refractory cases, and any procedure, including biopsy and embolisation, is done under blockade to avoid a hypertensive crisis. Somatostatin receptor PET (68Ga-DOTATATE) and 123I-MIBG scintigraphy stage the disease and, by showing uptake, select patients for the corresponding radionuclide therapy.\n\nTreatment is sequenced by pace. Indolent disease is watched or treated locally with surgery, radiotherapy, ablation or embolisation of dominant lesions. For progressive disease, radionuclide therapy is the first systemic step: high-specific-activity 131I-MIBG (iobenguane, Azedra) was approved in 2018 after a phase 2 trial in which a quarter of patients halved their antihypertensive medication and about a fifth had tumour responses, though the manufacturer withdrew it from the market in 2024, and lutetium-177 dotatate, approved for gastroenteropancreatic neuroendocrine tumours, is used for somatostatin-receptor-positive disease on the strength of retrospective series and phase 2 trials. Sunitinib is the one systemic drug with randomised evidence: FIRSTMAPPP (Lancet 2024), an academic phase 2 trial that took twelve years to enrol 78 patients, showed 12-month progression-free survival of 36 percent against 19 percent on placebo. Cyclophosphamide, vincristine and dacarbazine (CVD) chemotherapy, in use since 1988, and temozolomide, which is active particularly in SDHB-mutant tumours, are the cytotoxic options, and cabozantinib showed activity in the phase 2 NATALIE trial. Belzutifan, the HIF-2 alpha inhibitor, was approved in the United States in May 2025 for adults and children over 12 with locally advanced, unresectable or metastatic disease after a response rate of 26 percent in the LITESPARK-015 cohort, the first approval for the disease in seven years and the first to exploit the pseudohypoxia biology of cluster 1 tumours; the imipridone ONC206 and radioligand combinations are in trials. Bone metastases, the commonest site, are treated with denosumab or bisphosphonates and palliative radiotherapy.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Pheochromocytoma","links":[{"label":"FIRSTMAPPP (Lancet 2024)","url":"https://doi.org/10.1016/S0140-6736(23)02554-0"},{"label":"Endocrine Society PPGL guideline 2014","url":"https://doi.org/10.1210/jc.2014-1498"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Pheochromocytoma"}],"tags":["subtype-page","endocrine"],"related":["hereditary-ppgl","pheochromocytoma-paraganglioma","advanced-adrenocortical-carcinoma","small-intestinal-net"],"cancers":[],"sections":[],"technologies":["radioligand-therapy","prrt","mibg-theranostics","sstr-pet","fdg-pet","kinase-inhibitors","cytotoxic-chemotherapy","thermal-ablation","sbrt","active-surveillance"],"targets":["hif2a","sstr2","vegf"],"drugs":["belzutifan","sunitinib","cabozantinib","lutathera","i131-mibg","temozolomide","cyclophosphamide","vincristine"],"companies":[],"institutions":[],"pathways":[],"terms":["adrenalectomy","rare-cancers","sdh-deficiency"],"trials":["nct04924075","nct07282587"],"people":[],"bottlenecks":[],"keyPapers":["paper-firstmappp-sunitinib-metastatic-ppgl-baudin-lancet-2024","paper-pryma-high-specific-activity-i131-mibg-ppgl-jnm-2019","paper-endocrine-society-pheochromocytoma-paraganglioma-guideline-jcem-2014"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"About one in ten pheochromocytomas and up to a third or more of sympathetic paragangliomas, especially SDHB-related ones, metastasise to bone, lymph nodes, liver and lung; the course ranges from indolent over decades to rapidly fatal.","subtypes":["Indolent metastatic pheochromocytoma or paraganglioma (bone-predominant, observation or local therapy)","Progressive somatostatin-receptor-positive metastatic paraganglioma (lutetium-177 dotatate)","MIBG-avid metastatic pheochromocytoma (131I-MIBG where available)","SDHB-related metastatic paraganglioma (temozolomide-sensitive, belzutifan candidate)","Rapidly progressive metastatic pheochromocytoma or paraganglioma (CVD chemotherapy)","Metastatic pheochromocytoma or paraganglioma with uncontrolled catecholamine excess"],"biomarkers":["Plasma or urinary metanephrines and 3-methoxytyramine (secretory profile, monitoring)","Germline and somatic SDHB, VHL and other cluster status (prognosis, belzutifan and temozolomide sensitivity)","68Ga-DOTATATE PET uptake (lutetium-177 dotatate eligibility)","123I-MIBG uptake (131I-MIBG eligibility)","Rate of progression on serial imaging (decides when to treat)","Bone scan or FDG-PET for skeletal disease"],"standardOfCare":[{"setting":"All patients","approach":"Alpha-blockade with beta-blockade added second; metyrosine for refractory symptoms; blockade before every procedure; bone-protective agents for skeletal metastases.","refs":["adrenalectomy"],"guideline":{"version":"Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors","url":"https://doi.org/10.1210/jc.2014-1498"}},{"setting":"Staging","approach":"68Ga-DOTATATE PET, 123I-MIBG scintigraphy where 131I-MIBG is available, CT or MRI, FDG-PET for SDHB-related disease; germline testing.","refs":["sstr-pet","mibg-theranostics","fdg-pet","mri","germline-testing"],"guideline":{"version":"Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors","url":"https://doi.org/10.1210/jc.2014-1498"}},{"setting":"Indolent disease","approach":"Active surveillance; resection, radiotherapy, thermal ablation or embolisation of dominant or symptomatic lesions.","refs":["active-surveillance","sbrt","thermal-ablation","imrt-igrt"],"guideline":{"version":"Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors","url":"https://doi.org/10.1210/jc.2014-1498"}},{"setting":"Progressive disease, radionuclide therapy","approach":"Lutetium-177 dotatate for somatostatin-receptor-positive disease; 131I-MIBG for MIBG-avid disease where still available (approved 2018, withdrawn from market 2024).","refs":["lutathera","prrt","radioligand-therapy","i131-mibg","mibg-theranostics"],"guideline":{"version":"Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors","url":"https://doi.org/10.1210/jc.2014-1498"}},{"setting":"Progressive disease, systemic drugs","approach":"Belzutifan (approved 2025); sunitinib (FIRSTMAPPP); cabozantinib; cyclophosphamide, vincristine and dacarbazine or temozolomide for rapidly progressive or SDHB-related disease.","refs":["belzutifan","sunitinib","cabozantinib","cyclophosphamide","vincristine","temozolomide","kinase-inhibitors","cytotoxic-chemotherapy","firstmappp"],"guideline":{"version":"Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors","url":"https://doi.org/10.1210/jc.2014-1498"}},{"setting":"Trials","approach":"ONC206, radioligand combinations and next-generation HIF-2 alpha inhibitors.","refs":["nct07282587","nct04924075"],"guideline":{"version":"Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors","url":"https://doi.org/10.1210/jc.2014-1498"}}],"stateOfArt":["Belzutifan is the first approved targeted drug and the first to act on the tumour's own hypoxia biology.","FIRSTMAPPP proved that randomised trials are possible in this ultra-rare disease and validated sunitinib.","Radionuclide therapy gives durable control to patients whose tumours take up the tracer."],"history":[{"year":1988,"title":"Cyclophosphamide, vincristine and dacarbazine chemotherapy reported at the NIH","refs":["cyclophosphamide","vincristine"]},{"year":1991,"title":"131I-MIBG therapy in malignant pheochromocytoma reported","refs":["i131-mibg","mibg-theranostics"]},{"year":2018,"title":"High-specific-activity 131I-MIBG (Azedra) approved in the United States","refs":["i131-mibg"]},{"year":2024,"title":"FIRSTMAPPP: sunitinib improves progression-free survival; Azedra withdrawn from the market","refs":["sunitinib","i131-mibg"]},{"year":2025,"title":"Belzutifan approved for advanced pheochromocytoma and paraganglioma","refs":["belzutifan","nct04924075"]}],"pipeline":["belzutifan","nct04924075","nct07282587","lutathera","prrt","sunitinib","cabozantinib"],"openProblems":["No randomised trial has compared radionuclide therapy with drugs or defined their order.","Azedra's withdrawal leaves MIBG-avid, somatostatin-receptor-negative patients without a radionuclide option in many countries.","Catecholamine crises during treatment remain dangerous.","The disease is too rare and too slow for conventional trial designs."],"parent":"pheochromocytoma-paraganglioma"},{"id":"tnbc-metastatic","kind":"cancer","name":"Metastatic triple-negative breast cancer","aka":["Advanced triple-negative breast cancer","Stage IV TNBC","Recurrent triple-negative breast cancer"],"tldr":"The treatment of triple-negative breast cancer that has spread has been transformed since 2020, though it is not yet curable. By PD-L1 score, first treatment is pembrolizumab with chemotherapy or with sacituzumab govitecan, or datopotamab deruxtecan or sacituzumab govitecan alone; BRCA carriers can take a PARP inhibitor tablet; and trastuzumab deruxtecan reaches the third of tumours with low HER2.","summary":"Metastatic triple-negative disease spreads early to lung, liver and brain and grows fast, so the first line matters more than in other breast cancers. At relapse the tumour is retested, because receptors can change, and three results steer treatment: PD-L1 by combined positive score (10 or more in roughly four in ten patients), germline BRCA status and the HER2 immunohistochemistry score that identifies HER2-low disease. Until 2018 the options were taxanes, anthracyclines, platinum, capecitabine and eribulin, with platinum favoured in BRCA carriers after the TNT trial.\n\nImmunotherapy came first. IMpassion130 showed atezolizumab with nab-paclitaxel delays progression in PD-L1-positive disease and won an accelerated approval that was withdrawn in 2021 when IMpassion131 with paclitaxel failed. KEYNOTE-355 (847 patients) showed pembrolizumab with chemotherapy extends survival in tumours with a combined positive score of 10 or more (hazard ratio 0.73) and became the first-line standard for that group. The TROP2 antibody-drug conjugates then moved into the first line: ASCENT-04 showed sacituzumab govitecan with pembrolizumab beats chemotherapy with pembrolizumab in PD-L1-positive disease, ASCENT-03 showed sacituzumab govitecan beats chemotherapy in PD-L1-negative disease, and TROPION-Breast02 (644 patients) showed datopotamab deruxtecan extends overall survival from 18.7 to 23.7 months in patients who cannot have immunotherapy, the first first-line antibody-drug conjugate to do so; all three were approved in 2026.\n\nLater lines were transformed earlier. ASCENT (529 patients with at least two prior lines) showed sacituzumab govitecan nearly doubles survival against chemotherapy (12.1 against 6.7 months, hazard ratio 0.48), the first antibody-drug conjugate approval in triple-negative disease in 2020. For germline BRCA carriers OlympiAD (302 patients) and EMBRACA (431) showed olaparib and talazoparib extend progression-free survival over chemotherapy (7.0 against 4.2 months, hazard ratio 0.58; 8.6 against 5.6 months, hazard ratio 0.54) without a significant survival gain. DESTINY-Breast04 included a small HER2-low triple-negative cohort that pointed the same way as the main result, and trastuzumab deruxtecan is an option for the third of tumours that are HER2-low; the bispecific antibody-drug conjugate izalontamab brengitecan posted a positive phase 3 in 2026. Whether a second topoisomerase-payload conjugate works after the first, how to select patients for TROP2 drugs, and what to do about brain metastases, present in up to a third to nearly half of patients, are the open questions.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Triple-negative_breast_cancer","links":[{"label":"ASCENT (NEJM 2021)","url":"https://doi.org/10.1056/NEJMoa2028485"},{"label":"KEYNOTE-355 (NEJM 2022)","url":"https://doi.org/10.1056/NEJMoa2202809"},{"label":"OlympiAD (NEJM 2017)","url":"https://doi.org/10.1056/NEJMoa1706450"}],"tags":["subtype-page"],"related":["tnbc-early"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-ascent-nejm-2021","paper-destiny-breast04-nejm-2022","paper-keynote-355-nejm-2022","paper-olympiad-nejm-2017"],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Many women with early triple-negative disease relapse, most within three years, joining those diagnosed with spread from the outset; median survival was about a year to eighteen months on chemotherapy alone and now approaches two years in first-line trials.","subtypes":["PD-L1-positive basal-like disease (combined positive score 10 or more; pembrolizumab combinations)","PD-L1-negative or immunotherapy-ineligible disease (antibody-drug conjugate first)","Germline BRCA-mutant metastatic triple-negative disease (olaparib, talazoparib, platinum)","HER2-low triple-negative disease (trastuzumab deruxtecan)","Early relapse within twelve months of curative chemotherapy (excluded from many first-line trials)","Triple-negative disease with brain metastases"],"biomarkers":["PD-L1 by 22C3 combined positive score (10 or more for pembrolizumab)","Germline BRCA1 and BRCA2 (PARP inhibitors)","HER2 immunohistochemistry to identify HER2-low disease","Repeat receptor testing on a metastatic biopsy (receptor conversion)","TROP2 expression (not required for TROP2 antibody-drug conjugates)","Tumour mutational burden and microsatellite instability (tumour-agnostic immunotherapy)"],"standardOfCare":[{"setting":"First line, combined positive score 10 or more","approach":"Pembrolizumab with chemotherapy (KEYNOTE-355) or with sacituzumab govitecan (ASCENT-04).","refs":["pembrolizumab","keynote-355","sacituzumab-govitecan","ascent-04","cps"]},{"setting":"First line, PD-L1-negative or immunotherapy-ineligible","approach":"Datopotamab deruxtecan (TROPION-Breast02) or sacituzumab govitecan (ASCENT-03); a taxane or platinum where antibody-drug conjugates are unavailable.","refs":["datopotamab-deruxtecan","tropion-breast02","sacituzumab-govitecan","ascent-03","paclitaxel","carboplatin"]},{"setting":"Germline BRCA carriers","approach":"Olaparib (OlympiAD) or talazoparib (EMBRACA) after or instead of first-line chemotherapy; platinum chemotherapy is also more active.","refs":["olaparib","olympiad","talazoparib","embraca","carboplatin","gbrca-mutation"]},{"setting":"Second line and beyond","approach":"Whichever TROP2 antibody-drug conjugate has not been used (ASCENT); trastuzumab deruxtecan for HER2-low tumours (DESTINY-Breast04); izalontamab brengitecan where available; eribulin, capecitabine or gemcitabine with carboplatin.","refs":["sacituzumab-govitecan","ascent","trastuzumab-deruxtecan","destiny-breast04","izalontamab-brengitecan","eribulin","capecitabine","gemcitabine"]},{"setting":"Brain metastases","approach":"Stereotactic radiosurgery or whole-brain radiotherapy with continued systemic therapy; antibody-drug conjugates have early evidence of intracranial activity.","refs":["radiosurgery-srs","brain-metastases"]}],"stateOfArt":["Antibody-drug conjugates are first-line therapy for every PD-L1 group, alone or with pembrolizumab.","Median survival in first-line trials approaches two years, roughly double the chemotherapy era.","PARP inhibitors give BRCA carriers a chemotherapy-free option.","A bispecific antibody-drug conjugate has succeeded in phase 3."],"history":[{"year":2014,"title":"TNT: carboplatin beats docetaxel in germline BRCA carriers","refs":["carboplatin"]},{"year":2017,"title":"OlympiAD: olaparib beats chemotherapy in germline BRCA disease","refs":["olympiad","olaparib"]},{"year":2018,"title":"EMBRACA and IMpassion130","refs":["embraca","talazoparib","impassion130","atezolizumab"]},{"year":2020,"title":"ASCENT and KEYNOTE-355","refs":["ascent","sacituzumab-govitecan","keynote-355","pembrolizumab"]},{"year":2021,"title":"IMpassion131 fails and atezolizumab is withdrawn in breast cancer","refs":["impassion131"]},{"year":2022,"title":"DESTINY-Breast04 includes HER2-low triple-negative tumours","refs":["destiny-breast04","trastuzumab-deruxtecan"]},{"year":2025,"title":"ASCENT-03, ASCENT-04 and TROPION-Breast02 positive in the first line","refs":["ascent-03","ascent-04","tropion-breast02"]},{"year":2026,"title":"First-line antibody-drug conjugate approvals; izalontamab brengitecan phase 3 positive","refs":["datopotamab-deruxtecan","sacituzumab-govitecan","bl-b01d1-307"]}],"pipeline":["izalontamab-brengitecan","bl-b01d1-307","sacituzumab-tirumotecan","tropion-breast05","izabright-breast01","trop2-pet","ivonescimab","patritumab-deruxtecan","dual-payload-adc"],"openProblems":["Cross-resistance between antibody-drug conjugates sharing a topoisomerase I payload.","No biomarker selects patients for TROP2 drugs.","Brain metastases remain undertreated and are excluded from most trials.","Access: the new first-line drugs cost many times more than chemotherapy."],"parent":"tnbc"},{"id":"micronodular-thymoma","kind":"cancer","name":"Micronodular thymoma with lymphoid stroma","aka":["Micronodular thymoma","MNT","Micronodular thymoma with lymphoid stroma (rare, indolent)","Micronodular thymoma with lymphoid stroma (thymoma, thymic-epithelial)"],"tldr":"Micronodular thymoma with lymphoid stroma is a rare, benign-behaving thymoma made of small nests of spindle-shaped epithelial cells separated by abundant B lymphocytes, unlike other thymomas whose lymphocytes are T cells. It is cured by surgery; its curiosity is that a third harbour a clonal B-cell population, and a few develop a low-grade lymphoma within the tumour.","summary":"Micronodular thymoma with lymphoid stroma is an uncommon thymoma variant in the WHO classification, characterised by multiple small nodules of type A thymoma-like cells separated by a B-cell-rich lymphoid stroma with follicles (Histopathology 2015). Monoclonal B-cell populations were found in 6 of 18 cases (33 percent), with an intratumoural lymphoma in three, against consistently polyclonal B cells in thymic follicular hyperplasia and other thymomas; the neoplastic epithelium expresses chemokines that recruit dendritic and B cells, setting the stage for lymphoma (Journal of Pathology 2005). Langerhans cells are abundant within the tumour nests and mature dendritic cells cluster with T cells in the stroma, suggesting how the lymphoid follicles form (Histopathology 2015).\n\nHow it differs from its parent: its lymphocytes are B rather than immature T cells, myasthenia gravis is rare, behaviour is indolent, and the only complication of note is a MALT-type lymphoma arising within it.\n\nHow common: no registry figure; a rare variant (Histopathology 2015).\n\nTreatment: complete resection, which is curative in the reported cases; any associated lymphoma is treated on the MALT lymphoma page; no adjuvant therapy is indicated.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Thymoma","links":[{"label":"NCI PDQ: thymoma and thymic carcinoma treatment","url":"https://www.cancer.gov/types/thymus-cancer/thymoma-thymic-carcinoma"},{"label":"Journal of Pathology 2005: micronodular thymoma, abnormal chemokine expression and lymphoma development","url":"https://doi.org/10.1002/path.1808"},{"label":"Histopathology 2015: micronodular thymoma with lymphoid stroma, Langerhans and dendritic cells in six patients","url":"https://doi.org/10.1111/his.12428"}],"tags":["subtype-page","wave4","rare"],"related":["thymoma","thymoma-type-a-ab","thymoma-type-b1-b2","malt-lymphoma","thymic-epithelial"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"thoracic","burden":"Rare: the two pathology series in the sources read hold 18 and 6 cases (Journal of Pathology 2005; Histopathology 2015). No registry figure exists.","subtypes":["Micronodular thymoma with lymphoid stroma without a clonal B-cell population","Micronodular thymoma with a monoclonal B-cell population (a third of cases)","Micronodular thymoma with an intratumoural MALT-type lymphoma"],"biomarkers":["Type A-like epithelial nests with B-cell-rich stroma and follicles","B-cell clonality (IgH rearrangement)","Langerhans and dendritic cell distribution","Stage (almost always encapsulated)"],"standardOfCare":[{"setting":"All cases","approach":"Complete resection; associated lymphoma treated on the MALT lymphoma page; no adjuvant therapy.","refs":["thymoma","malt-lymphoma"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"thymoma"},{"id":"colorectal-micropapillary-carcinoma","kind":"cancer","name":"Micropapillary adenocarcinoma of the colon and rectum","aka":["Micropapillary adenocarcinoma of the colon and rectum (small tumour nests with reversed polarity; heavy lymphatic and vascular invasion)","Colorectal micropapillary carcinoma","Micropapillary colorectal cancer","Colorectal carcinoma with micropapillary pattern"],"tldr":"Micropapillary adenocarcinoma is bowel cancer in which some of the tumour grows as tiny clusters of cells floating in empty spaces, with the cells turned inside out so the surface that normally faces the bowel faces outwards instead. It is a pattern that goes with heavier invasion of lymph and blood vessels and more involved lymph nodes, and it is graded and treated like ordinary bowel cancer.","summary":"What it is. The 2019 World Health Organization classification of digestive tumours lists micropapillary adenocarcinoma among the histological subtypes of colorectal adenocarcinoma (Nagtegaal 2020). Under the microscope the tumour forms small morula-like nests of cells without a fibrovascular core, sitting in empty lacunar spaces, and the cells show reversed polarity: the apical membrane faces the stroma rather than a lumen, which can be shown by staining for villin or epithelial membrane antigen (Oncol Lett 2021).\n\nHow it differs from its parent. The micropapillary component is almost never the whole tumour. Reported proportions range from 5 to 80 percent of a lesion and are usually under 30 percent (J Gastrointest Cancer 2026). Where it is present, tumours show more lymphatic and vascular invasion, a higher ratio of involved to examined lymph nodes and a higher pathological T category than colorectal cancers without it, and more invasion again as the proportion rises (Hum Pathol 2018). KRAS, BRAF and TP53 mutations are described in the pattern and are read as driving invasiveness and the loss of polarity rather than defining a separate disease (J Gastrointest Cancer 2026).\n\nHow common it is. In 266 colorectal cancers the pattern was found in 27.8 percent at any extent and in 9.4 percent at 5 percent or more of the tumour (Hum Pathol 2018); in 453 tumours the 5 percent threshold was met in 19.8 percent (Oncol Lett 2021). Counts depend entirely on the threshold used, and no national registry records it.\n\nHow it is treated. No trial has been run in this histology. Treated as colorectal adenocarcinoma: resection with adjuvant chemotherapy by stage when removable, the systemic rows of the parent page when not; the parent record carries the trials. The practical consequence of the report is staging: the pattern travels with node involvement, so it is a reason to look carefully at the nodes and the margins rather than a reason to change the drugs.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Colorectal_cancer","links":[{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"Hum Pathol 2018: the clinicopathological significance of micropapillary pattern in colorectal cancers (266 tumours)","url":"https://doi.org/10.1016/j.humpath.2018.02.027"},{"label":"Oncol Lett 2021: villin as a biomarker for reverse polarity in colorectal micropapillary carcinoma (453 tumours)","url":"https://doi.org/10.3892/ol.2020.12333"},{"label":"J Gastrointest Cancer 2026: colorectal micropapillary adenocarcinoma, molecular mechanisms and clinical implications (review)","url":"https://doi.org/10.1007/s12029-025-01372-z"},{"label":"NICE NG151: colorectal cancer, recommendations (Lynch 1.1, local disease 1.3, biomarkers 1.4, metastatic disease 1.5, ongoing care and support including follow-up 1.6)","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"}],"tags":["gi","colorectal","subtype-page"],"related":["colorectal","colorectal-adenoma-like-adenocarcinoma","colorectal-mucinous-adenocarcinoma","colorectal-serrated-adenocarcinoma","colon-cancer","rectal-cancer"],"cancers":[],"sections":[],"technologies":["histopathology-ihc"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["tumour-grade","tnm-staging","circumferential-resection-margin"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"A pattern rather than a separate tumour in most series. In 266 Korean colorectal cancers a micropapillary pattern of any extent was present in 27.8 percent and made up 5 percent or more of the tumour in 9.4 percent; in a later series of 453 tumours the 5 percent threshold was met in 19.8 percent. No UK or registry count is published.","subtypes":["Colorectal adenocarcinoma with a focal micropapillary component (under 5 percent of the tumour)","Colorectal adenocarcinoma with a substantial micropapillary component (5 percent or more, the threshold most series use)","Micropapillary pattern arising within mucin pools (distinguished from pure micropapillary pattern)"],"biomarkers":["Micropapillary component as a percentage of the tumour, recorded in the pathology report","Reversed polarity shown by villin, epithelial membrane antigen or E-cadherin staining","Lymphatic and vascular invasion, which travel with the pattern"],"standardOfCare":[{"setting":"Localised disease","approach":"Resection with the usual nodal harvest; adjuvant chemotherapy decided by stage as for colorectal adenocarcinoma of no special type, with the node involvement that travels with this pattern taken into account.","refs":["colectomy","total-mesorectal-excision","capox","folfox"],"guideline":{"version":"NICE NG151: colorectal cancer (published January 2020, last updated December 2021, last reviewed April 2026)","url":"https://www.nice.org.uk/guidance/ng151"}}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"colorectal"},{"id":"gastric-msi-high","kind":"cancer","name":"Microsatellite-unstable (MSI-high) gastric cancer","aka":["MSI-H gastric cancer","Mismatch repair-deficient gastric cancer","dMMR gastric cancer"],"tldr":"Microsatellite-unstable gastric cancer has lost its DNA mismatch repair machinery, carries thousands of mutations and is unusually visible to the immune system. It responds strongly to checkpoint antibodies, may gain little from chemotherapy, and in early-stage disease immunotherapy before surgery is making many tumours disappear entirely.","summary":"Mismatch repair deficiency in stomach cancer usually comes from methylation of the MLH1 promoter in older patients rather than from Lynch syndrome, though germline testing is offered when the family history suggests it. The tumours are intestinal type, distal, less likely to involve nodes and carry a better prognosis stage for stage; they are one of the four TCGA molecular groups and overlap with high PD-L1 expression. Testing by immunohistochemistry for the four repair proteins or by polymerase chain reaction or sequencing is now recommended for every gastric cancer at diagnosis.\n\nIn advanced disease the microsatellite-unstable subgroups of KEYNOTE-062, CheckMate 649 and KEYNOTE-859 showed the largest benefit of any group from PD-1 blockade, with response rates and survival far above those of chemotherapy alone, and pembrolizumab has had a tumour-agnostic approval for mismatch repair-deficient cancers since 2017. Whether chemotherapy adds anything to the antibody in these patients is uncertain, and many clinicians give a PD-1 antibody alone or with a CTLA-4 antibody.\n\nIn resectable disease post hoc analyses of the MAGIC and CLASSIC trials and a 2019 meta-analysis suggested that perioperative chemotherapy gives little or no benefit in microsatellite-unstable tumours, and neoadjuvant immunotherapy trials have followed: NEONIPIGA (nivolumab and ipilimumab) produced pathological complete responses in 59 percent of patients, and INFINITY (durvalumab and tremelimumab) and DANTE reported similar findings. Organ-preserving strategies that omit surgery after a complete response are being tested, following the same path as rectal cancer.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Microsatellite_instability","links":[{"label":"Pietrantonio meta-analysis (JCO 2019)","url":"https://pubmed.ncbi.nlm.nih.gov/31513484/"},{"label":"NEONIPIGA (JCO 2023)","url":"https://pubmed.ncbi.nlm.nih.gov/36179271/"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Microsatellite_instability"}],"tags":["subtype-page"],"related":["gastric-cldn18-2-positive","early-gastric-cancer","gastric-her2-positive","gastric-pdl1-high"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-062"],"people":[],"bottlenecks":[],"keyPapers":["paper-le-mmr-deficiency-science-2017","paper-keynote-062-shitara-jama-oncol-2020","paper-pietrantonio-msi-gastric-meta-analysis-jco-2019","paper-tcga-gastric-nature-2014"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Around one in five localised gastric cancers in Western series but only about one in twenty at the metastatic stage, because these tumours spread less; they occur in older patients, in the distal stomach and in intestinal-type histology.","subtypes":["Sporadic MSI-high gastric cancer (MLH1 promoter methylation, older patients, distal stomach)","Lynch syndrome-associated gastric cancer","MSI-high intestinal type","Localised MSI-high (neoadjuvant immunotherapy trials)","Metastatic MSI-high (checkpoint blockade)"],"biomarkers":["Mismatch repair proteins by immunohistochemistry (MLH1, MSH2, MSH6, PMS2)","Microsatellite instability by polymerase chain reaction or sequencing","Tumour mutational burden (high)","PD-L1 combined positive score (often high)","Germline mismatch repair genes where Lynch syndrome is suspected"],"standardOfCare":[{"setting":"Advanced, first line","approach":"PD-1 antibody with or without chemotherapy (nivolumab or pembrolizumab); nivolumab with ipilimumab in selected patients; the benefit exceeds that in any other subgroup.","refs":["pembrolizumab","nivolumab","ipilimumab","checkmate-649","keynote-859","msi","mismatch-repair-msi"]},{"setting":"Advanced, after chemotherapy","approach":"Pembrolizumab under its tumour-agnostic approval for mismatch repair-deficient cancers.","refs":["pembrolizumab","tumour-agnostic","msi"]},{"setting":"Resectable","approach":"Surgery with or without perioperative chemotherapy, whose benefit is doubtful here; neoadjuvant immunotherapy (nivolumab-ipilimumab, durvalumab-tremelimumab) in trials or where available.","refs":["gastrectomy","nivolumab","ipilimumab","durvalumab","tremelimumab","flot"]},{"setting":"Hereditary risk","approach":"Germline testing and Lynch syndrome surveillance where the pattern suggests it.","refs":["germline-testing","lynch-syndrome"]}],"stateOfArt":["Microsatellite-unstable gastric cancer is the clearest immunotherapy success story in the disease, with long remissions in metastatic patients.","Neoadjuvant checkpoint blockade produces complete pathological responses in more than half of localised tumours.","The evidence that chemotherapy adds little has changed how these patients are treated before surgery."],"history":[{"year":2014,"title":"TCGA classifies gastric cancer into four molecular groups including MSI-high","refs":[]},{"year":2017,"title":"Pembrolizumab receives tumour-agnostic approval for mismatch repair-deficient cancers","refs":["pembrolizumab","tumour-agnostic"]},{"year":2019,"title":"Meta-analysis of MAGIC, CLASSIC, ARTIST and ITACA-S: no chemotherapy benefit in MSI-high tumours","refs":[]},{"year":2021,"title":"CheckMate 649 and KEYNOTE-062 subgroups: large gains from PD-1 blockade in MSI-high disease","refs":["checkmate-649","nivolumab"]},{"year":2023,"title":"NEONIPIGA: neoadjuvant nivolumab and ipilimumab give pathological complete response in 59 percent","refs":["nivolumab","ipilimumab"]}],"pipeline":["nivolumab","ipilimumab","durvalumab","tremelimumab","mrd-testing","liquid-biopsy"],"openProblems":["Whether surgery can be omitted after a complete response to neoadjuvant immunotherapy.","Whether chemotherapy should be dropped altogether in metastatic disease.","A minority of MSI-high tumours do not respond, and the reasons are unclear."],"parent":"gastric"},{"id":"msi-high-pdac","kind":"cancer","name":"Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma","aka":["MSI-high pancreatic cancer","dMMR pancreatic cancer","Mismatch repair deficient PDAC","Lynch syndrome-associated pancreatic cancer"],"tldr":"Mismatch repair deficient pancreatic cancer is the rare pancreatic cancer whose cells cannot fix spelling errors in DNA and so carry thousands of mutations. That makes it one of the few pancreatic cancers that immunotherapy works against, and pembrolizumab is approved for it, though fewer of these tumours respond than in bowel cancer; testing every pancreatic cancer for the defect is the point.","summary":"Mismatch repair deficiency (loss of MLH1, MSH2, MSH6 or PMS2) produces microsatellite instability and a very high mutation burden with many frameshift neoantigens, which is why these tumours respond to PD-1 blockade despite the immunosuppressive stroma that defeats immunotherapy in the rest of pancreatic cancer. In the pancreas the defect is found in about 1 percent of ductal adenocarcinomas, more often in Lynch syndrome carriers, in KRAS wild-type tumours and in tumours with medullary or mucinous colloid histology, including some arising in intraductal papillary mucinous neoplasms. Testing is by immunohistochemistry for the four proteins or by sequencing-based microsatellite analysis, and a positive result should prompt germline testing for Lynch syndrome.\n\nThe tumour-agnostic approval of pembrolizumab in May 2017, based on KEYNOTE-016 and related studies, covered pancreatic cancer; the pancreatic cohort of KEYNOTE-158 showed responses in a minority of patients, lower than in colorectal or endometrial cancer, but some responses were durable. Dostarlimab received a tumour-agnostic approval in 2021 for mismatch repair deficient solid tumours after chemotherapy. Reasons for the lower response rate include misclassification by immunohistochemistry, the pancreatic stroma and lower neoantigen burden in some tumours, and chemotherapy remains the first-line standard with a checkpoint inhibitor used after progression or first line in patients unfit for chemotherapy.\n\nOpen questions are whether checkpoint inhibitors should be used first line, whether dual checkpoint blockade (as in colorectal cancer) or combination with chemotherapy improves responses, and whether frameshift neoantigen vaccines being tested in Lynch syndrome could prevent pancreatic cancer in carriers. Because the group is so small, evidence comes from baskets and case series rather than pancreatic-specific trials.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Microsatellite_instability","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Microsatellite_instability"},{"label":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}],"tags":["subtype-page","gastrointestinal"],"related":["metastatic-pdac","kras-wild-type-pdac","brca-palb2-pdac","locally-advanced-pdac","kras-g12c-pdac","msi-high-colorectal"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","cgp","germline-testing","cytotoxic-chemotherapy"],"targets":["pd1","pdl1","ctla4","kras"],"drugs":["pembrolizumab","dostarlimab","nivolumab","ipilimumab","folfirinox","gemcitabine-nab-paclitaxel"],"companies":["merck","bms"],"institutions":[],"pathways":["mismatch-repair-msi","pd1-checkpoint","cancer-immunity-cycle","immune-desert-exclusion"],"terms":["msi","mss-pmmr","lynch-syndrome","tmb","neoantigen","germline-vs-somatic"],"trials":["keynote-177"],"people":["dung-le","bert-vogelstein","elizabeth-jaffee","eileen-oreilly"],"bottlenecks":[],"keyPapers":["paper-keynote-158-pembrolizumab-msi-high-noncolorectal-jco-2020","paper-le-mmr-deficiency-science-2017","paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018","paper-lynch-frameshift-vaccine-ccr-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 1 percent of pancreatic ductal adenocarcinomas are mismatch repair deficient, a smaller share than in bowel or womb cancer; many arise in people with Lynch syndrome, and medullary and mucinous histology are clues.","subtypes":["Lynch syndrome-associated mismatch repair deficient PDAC (germline MLH1, MSH2, MSH6, PMS2 or EPCAM)","Sporadic mismatch repair deficient PDAC (MLH1 promoter methylation)","Medullary or mucinous colloid carcinoma of the pancreas (histology enriched for the defect)","Mismatch repair deficient PDAC arising in an IPMN","Mismatch repair deficient PDAC after progression on chemotherapy (pembrolizumab or dostarlimab)"],"biomarkers":["Mismatch repair protein immunohistochemistry (MLH1, MSH2, MSH6, PMS2) or sequencing-based microsatellite instability testing on every pancreatic cancer","Tumour mutational burden (high in most mismatch repair deficient tumours)","Germline Lynch syndrome testing when the tumour is deficient","KRAS status (wild-type more often) and medullary or colloid histology","CA 19-9 for response monitoring"],"standardOfCare":[{"setting":"Testing","approach":"Mismatch repair immunohistochemistry or microsatellite instability testing for every pancreatic adenocarcinoma at diagnosis, with germline testing for Lynch syndrome when deficient.","refs":["msi","lynch-syndrome","germline-testing","tmb"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Advanced, first line","approach":"Chemotherapy as for other pancreatic adenocarcinoma; pembrolizumab first line for patients unfit for chemotherapy or in trials.","refs":["folfirinox","gemcitabine-nab-paclitaxel","pembrolizumab"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Advanced, after chemotherapy","approach":"Pembrolizumab (tumour-agnostic approval, KEYNOTE-158 pancreatic cohort) or dostarlimab (tumour-agnostic approval for mismatch repair deficient solid tumours).","refs":["pembrolizumab","dostarlimab","checkpoint-inhibitor","pd1"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Resectable","approach":"Surgery and adjuvant chemotherapy as for other pancreatic adenocarcinoma; neoadjuvant immunotherapy only in trials.","refs":["whipple","folfirinox","prodige-24"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Pembrolizumab and dostarlimab are approved for mismatch repair deficient pancreatic cancer through tumour-agnostic labels.","Universal testing is guideline standard because the defect cannot be predicted from the clinic.","Responses are less frequent than in bowel cancer, and combinations are being tested.","Frameshift neoantigen vaccines in Lynch syndrome carriers aim at prevention."],"history":[{"year":1993,"title":"Microsatellite instability and mismatch repair genes discovered in Lynch syndrome colorectal cancer","refs":["msi","lynch-syndrome","bert-vogelstein"]},{"year":2015,"title":"Le and Diaz show PD-1 blockade works in mismatch repair deficient tumours of any site","refs":["pembrolizumab","dung-le"]},{"year":2017,"title":"Pembrolizumab receives the first tumour-agnostic approval, for mismatch repair deficient solid tumours","refs":["pembrolizumab","merck"]},{"year":2020,"title":"KEYNOTE-158 pancreatic cohort: responses in a minority, some durable","refs":["pembrolizumab"]},{"year":2021,"title":"Dostarlimab approved for mismatch repair deficient solid tumours after chemotherapy","refs":["dostarlimab"]}],"pipeline":["nivolumab","ipilimumab","dostarlimab","shared-antigen-vaccine","idea-prev-reflex-germline-testing"],"openProblems":["Response rates to PD-1 blockade are lower than in colorectal cancer and the reasons are not settled.","Whether checkpoint inhibitors should replace chemotherapy first line is untested in the pancreas.","Immunohistochemistry misses some deficient tumours and over-calls others; confirmatory sequencing is not universal.","Lynch syndrome carriers have no proven pancreatic surveillance strategy."],"parent":"pancreatic"},{"id":"msi-high-colorectal","kind":"cancer","name":"Mismatch-repair deficient (MSI-high) colorectal cancer","aka":["dMMR colorectal cancer","MSI-H colorectal cancer","Microsatellite unstable colorectal cancer","Lynch-associated colorectal cancer","Hypermutated colorectal cancer"],"tldr":"Mismatch-repair deficient bowel cancer has lost its DNA spell-checker, so it carries thousands of mutations that the immune system can recognise. Immunotherapy alone controls most metastatic cases for years and makes most localised tumours disappear before surgery, sometimes so completely that no surgery is needed.","summary":"Mismatch-repair deficiency arises when MLH1, MSH2, MSH6 or PMS2 is lost, either by sporadic MLH1 promoter methylation (typically right-sided, in older women, often with BRAF V600E) or by a germline mutation in Lynch syndrome, which is why every colorectal cancer is now tested by immunohistochemistry or microsatellite analysis at diagnosis. The tumours accumulate tens of thousands of frameshift mutations, produce abundant neoantigens and are infiltrated by T cells held in check by PD-1; they have a better prognosis when localised and do not benefit from fluorouracil alone as adjuvant therapy.\n\nIn metastatic disease KEYNOTE-177 (2020) showed that pembrolizumab alone doubled progression-free survival against chemotherapy (16.5 versus 8.2 months), with 54.8 percent of patients alive at five years and a median survival of 77.5 months; CheckMate 8HW (2024) showed that nivolumab plus ipilimumab cut progression by 79 percent against chemotherapy (median progression-free survival 54.1 versus 5.9 months) and beat nivolumab alone, and the combination was approved first line in April 2025. About a third of patients still progress early, often because of pMMR misclassification, JAK1 or B2M loss or immune-excluded biology.\n\nIn localised disease four weeks of neoadjuvant nivolumab and ipilimumab produced pathological complete response in 68 percent of colon cancers in NICHE-2 with no recurrence at three years; the ATOMIC phase 3 trial (2025) showed that adding atezolizumab to adjuvant FOLFOX improves disease-free survival in stage III disease; and in rectal cancer six months of dostarlimab produced a clinical complete response in every patient treated, allowing surgery and radiotherapy to be omitted. For Lynch carriers, colonoscopy every one to two years and daily aspirin (CAPP2) prevent cancers, and frameshift-neoantigen vaccines are in trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Microsatellite_instability","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Microsatellite_instability"},{"label":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}],"tags":["subtype-page"],"related":["braf-v600e-colorectal","early-onset-colorectal","her2-amplified-colorectal","kras-g12c-colorectal","rectal-cancer"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","histopathology-ihc","germline-testing","colorectal-screening"],"targets":["pd1","ctla4","wrn","braf"],"drugs":["pembrolizumab","nivolumab","ipilimumab","dostarlimab","atezolizumab","aspirin"],"companies":[],"institutions":[],"pathways":["colorectal-cancer-signalling"],"terms":["msi","lynch-syndrome","tmb","tumour-agnostic","clinical-complete-response","organ-preservation","cms-subtypes","mlh1-promoter-methylation"],"trials":["keynote-177","checkmate-8hw","niche-2","atomic","azur-1","nct05855200","nct07412613","nct06686576","nct06640049"],"people":["thierry-andre","luis-diaz","andrea-cercek","heinz-josef-lenz"],"bottlenecks":[],"keyPapers":["paper-keynote-177-nejm-2020","paper-niche-2-nejm-2024","paper-cercek-dostarlimab-rectal-nejm-2022","paper-checkmate-8hw-lancet-2025"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 15 percent of localised and 5 percent of metastatic colorectal cancers have lost DNA mismatch repair, most often through methylation of the MLH1 gene in right-sided tumours of older women and, in about a fifth, through inherited Lynch syndrome.","subtypes":["Sporadic mismatch-repair deficient (MLH1 promoter methylation, right-sided, often BRAF V600E)","Lynch syndrome (germline MLH1, MSH2, MSH6, PMS2 or EPCAM)","Localised dMMR colon cancer (neoadjuvant or adjuvant immunotherapy)","dMMR rectal cancer (non-operative management with a PD-1 antibody)","Metastatic MSI-high colorectal cancer (first-line checkpoint blockade)"],"biomarkers":["Mismatch repair immunohistochemistry (MLH1, MSH2, MSH6, PMS2)","Microsatellite instability by PCR or sequencing","MLH1 promoter methylation and BRAF V600E (sporadic versus Lynch)","Germline testing of mismatch repair genes","Tumour mutational burden","Circulating tumour DNA after curative treatment"],"standardOfCare":[{"setting":"Metastatic, first line","approach":"Pembrolizumab alone (KEYNOTE-177) or nivolumab plus ipilimumab (CheckMate 8HW); chemotherapy only if immunotherapy is contraindicated.","refs":["pembrolizumab","nivolumab","ipilimumab","keynote-177","checkmate-8hw","checkpoint-inhibitor"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Localised colon cancer","approach":"Neoadjuvant nivolumab plus ipilimumab for locally advanced tumours (NICHE-2) where available; surgery; adjuvant FOLFOX plus atezolizumab for stage III (ATOMIC); no fluoropyrimidine alone.","refs":["niche-2","atomic","nivolumab","ipilimumab","atezolizumab","folfox"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Rectal cancer","approach":"Six months of dostarlimab or another PD-1 antibody with non-operative management for complete responders (AZUR-1).","refs":["dostarlimab","azur-1","organ-preservation","clinical-complete-response"],"guideline":{"version":"NCCN Guidelines: Rectal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461"}},{"setting":"Lynch syndrome carriers","approach":"Colonoscopy every one to two years from age 25 (earlier for MLH1 and MSH2), daily aspirin (CAPP2), cascade germline testing of relatives, hysterectomy and oophorectomy after childbearing for women.","refs":["lynch-syndrome","aspirin","colorectal-screening","germline-testing","chemoprevention","capp2"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}}],"stateOfArt":["First-line immunotherapy without chemotherapy in metastatic disease, with more than half of patients alive at five years in KEYNOTE-177.","Neoadjuvant checkpoint blockade produces pathological complete response in most localised colon cancers (NICHE-2).","Rectal cancer can be cured with a PD-1 antibody alone, without surgery or radiotherapy.","Universal mismatch repair testing at diagnosis finds Lynch families."],"history":[{"year":1993,"title":"Microsatellite instability discovered in colorectal cancer and linked to hereditary non-polyposis colorectal cancer","refs":["msi","lynch-syndrome"]},{"year":2015,"title":"Le and Diaz: PD-1 blockade works in mismatch-repair deficient tumours (NEJM)","refs":["pembrolizumab","luis-diaz"]},{"year":2017,"title":"FDA approves pembrolizumab for any mismatch-repair deficient solid tumour, the first tissue-agnostic approval","refs":["pembrolizumab","tumour-agnostic"]},{"year":2020,"title":"KEYNOTE-177: pembrolizumab beats chemotherapy first line","refs":["keynote-177","thierry-andre"]},{"year":2022,"title":"NICHE-2 neoadjuvant nivolumab-ipilimumab and dostarlimab in rectal cancer","refs":["niche-2","dostarlimab","andrea-cercek"]},{"year":2024,"title":"CheckMate 8HW: nivolumab plus ipilimumab cuts progression by 79 percent","refs":["checkmate-8hw"]},{"year":2025,"title":"Nivolumab-ipilimumab approved first line; ATOMIC shows adjuvant atezolizumab helps stage III disease","refs":["nivolumab","ipilimumab","atomic"]}],"pipeline":["idea-bio1-wrn-msi-programme","eik1005","cadonilimab","nct07412613","nct06686576","nct05855200","idea-prev-lynch-frameshift-vaccine-rct","idea-prev-lynch-aspirin-implementation"],"openProblems":["A third of metastatic patients progress early on immunotherapy and the resistance mechanisms are only partly understood.","Whether surgery can be omitted after complete response in colon, as in rectal, cancer is untested.","WRN helicase inhibitors, a synthetic-lethal approach, are in early trials.","Lynch carriers still get cancers between colonoscopies; a preventive vaccine is in randomised testing."],"parent":"colorectal"},{"id":"endometrial-mmr-deficient","kind":"cancer","name":"Mismatch-repair-deficient endometrial cancer","aka":["dMMR endometrial cancer","MSI-high endometrial cancer","MMRd endometrial cancer","Lynch-associated endometrial cancer"],"tldr":"Mismatch-repair-deficient endometrial cancer has lost the machinery that corrects copying errors in DNA, so it accumulates thousands of mutations that make it visible to the immune system. Adding dostarlimab or pembrolizumab to chemotherapy in advanced disease cut the risk of progression by about seventy percent, and many patients remain in remission years later.","summary":"Loss of MLH1, PMS2, MSH2 or MSH6 on immunohistochemistry, or microsatellite instability on a molecular test, defines this class. In most tumours the cause is methylation of the MLH1 promoter; in a minority it is a germline mutation in a mismatch-repair gene, which is Lynch syndrome, so every deficient tumour without MLH1 methylation should prompt germline testing and family cascade testing. Mismatch-repair-deficient tumours are usually endometrioid, often high grade, with abundant tumour-infiltrating lymphocytes, and they carry an intermediate prognosis at early stage. The class has the same recurrence risk as no specific molecular profile after adjuvant radiotherapy, and PORTEC-3 found no benefit from adding chemotherapy in this group.\n\nThe mutational load makes these tumours the most immunotherapy-responsive solid cancers outside melanoma. Pembrolizumab's tumour-agnostic approval for mismatch-repair-deficient tumours in 2017 and dostarlimab's approval after the GARNET trial in 2021 established single-agent checkpoint inhibition after chemotherapy. RUBY then moved immunotherapy to the first line: dostarlimab with carboplatin-paclitaxel raised progression-free survival at two years from 15.7 to 61.4 percent in the deficient population, with a hazard ratio of 0.28. NRG-GY018 found the same with pembrolizumab, a hazard ratio of 0.30 for progression in deficient tumours, and DUO-E with durvalumab a hazard ratio of 0.42. Both dostarlimab and pembrolizumab gained approvals with chemotherapy in 2023 and 2024.\n\nThe next question is whether chemotherapy is needed at all. KEYNOTE-C93 compares pembrolizumab alone with platinum doublet chemotherapy as first-line treatment of deficient advanced disease. In the adjuvant setting KEYNOTE-B21 did not improve disease-free survival overall when pembrolizumab was added to chemotherapy after surgery, but the mismatch-repair-deficient subgroup appeared to benefit, and RAINBO's MMRd-GREEN trial randomises deficient stage II to III tumours to radiotherapy with or without durvalumab. Prevention in Lynch carriers rests on surveillance, aspirin and risk-reducing hysterectomy once childbearing is complete, and frameshift neoantigen vaccines are in early trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Endometrial_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Endometrial_cancer"}],"tags":["subtype-page"],"related":["advanced-recurrent-endometrial-cancer","endometrial-nsmp","endometrial-p53-abnormal","endometrial-pole-ultramutated","uterine-carcinosarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["garnet"],"people":[],"bottlenecks":[],"keyPapers":["paper-ruby-nejm-2023","paper-nrg-gy018-nejm-2023","paper-promise-talhouk-cancer-2017","paper-garnet-dostarlimab-oaknin-jama-oncol-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"About a quarter to three in ten endometrial cancers, the largest molecular class after no specific molecular profile; most are sporadic and caused by MLH1 promoter methylation, and about three percent of all endometrial cancers arise in Lynch syndrome carriers.","subtypes":["Sporadic MLH1 promoter hypermethylation (most cases)","Lynch syndrome germline MLH1, MSH2, MSH6 or PMS2 mutation","MSH6-deficient tumours (older age, lower MSI signal)","Dedifferentiated and undifferentiated carcinoma (often MMRd with SWI/SNF loss)","Stage II to III MMRd (RAINBO MMRd-GREEN, radiotherapy with or without durvalumab)","Advanced or recurrent MMRd (chemo-immunotherapy first line)"],"biomarkers":["MMR immunohistochemistry (MLH1, PMS2, MSH2, MSH6)","Microsatellite instability by PCR or sequencing","MLH1 promoter methylation (separates sporadic from Lynch)","Germline mismatch-repair gene testing","Tumour mutational burden","PD-L1 (not required for treatment)"],"standardOfCare":[{"setting":"Diagnosis and hereditary risk","approach":"Universal MMR immunohistochemistry on every endometrial cancer; MLH1 methylation testing on MLH1-deficient tumours; germline testing and cascade testing of relatives when methylation is absent.","refs":["msi","lynch-syndrome","germline-testing","histopathology-ihc","endometrial-molecular-classes"]},{"setting":"Early stage after surgery","approach":"Adjuvant therapy by stage and risk factors as for no specific molecular profile: vaginal brachytherapy for intermediate risk, pelvic radiotherapy for high-intermediate risk; chemotherapy adds little (PORTEC-3).","refs":["brachytherapy","imrt-igrt","portec-3"]},{"setting":"Advanced or recurrent, first line","approach":"Carboplatin-paclitaxel with dostarlimab (RUBY) or pembrolizumab (NRG-GY018), continued as maintenance; durvalumab (DUO-E) is an alternative.","refs":["dostarlimab","pembrolizumab","durvalumab","carboplatin","paclitaxel","ruby","nrg-gy018-keynote-868","duo-e","chemo-io-first-line-endometrial"]},{"setting":"Recurrent after chemotherapy without prior immunotherapy","approach":"Single-agent dostarlimab or pembrolizumab, with durable responses in a large minority.","refs":["dostarlimab","pembrolizumab","checkpoint-inhibitor","msi"]},{"setting":"Lynch carriers","approach":"Annual surveillance from the mid-thirties where offered, aspirin, and risk-reducing hysterectomy with salpingo-oophorectomy after childbearing.","refs":["lynch-syndrome","germline-testing","hysterectomy"]}],"stateOfArt":["RUBY and NRG-GY018 made chemo-immunotherapy the first-line standard, with about seventy percent fewer progressions in deficient tumours.","Universal MMR testing doubles as a Lynch syndrome screen.","KEYNOTE-C93 asks whether immunotherapy alone can replace chemotherapy."],"history":[{"year":2013,"title":"TCGA describes the hypermutated MSI class of endometrial cancer","refs":["endometrial-molecular-classes"]},{"year":2017,"title":"Pembrolizumab: first tumour-agnostic approval, for mismatch-repair-deficient tumours","refs":["pembrolizumab","msi"]},{"year":2021,"title":"Dostarlimab approved for recurrent dMMR endometrial cancer after GARNET","refs":["dostarlimab"]},{"year":2023,"title":"RUBY and NRG-GY018: chemo-immunotherapy first line, PFS hazard ratios 0.28 and 0.30 in dMMR tumours","refs":["ruby","nrg-gy018-keynote-868"]},{"year":2023,"title":"DUO-E: durvalumab with chemotherapy, PFS hazard ratio 0.42 in dMMR tumours","refs":["duo-e"]},{"year":2024,"title":"KEYNOTE-B21: adjuvant pembrolizumab misses its primary endpoint overall; dMMR subgroup appears to benefit","refs":["nct04634877"]}],"pipeline":["nct05173987","nct04634877","idea-moon-lynch-vaccine-phase3","idea-bio1-wrn-msi-programme","dostarlimab","pembrolizumab"],"openProblems":["Whether chemotherapy can be dropped in favour of immunotherapy alone.","Why a third of deficient tumours do not respond to checkpoint blockade.","Getting germline testing to every woman with an unmethylated deficient tumour."],"parent":"endometrial"},{"id":"mixed-phenotype-acute-leukaemia","kind":"cancer","name":"Mixed-phenotype acute leukaemia","aka":["MPAL","Mixed phenotype acute leukemia","Acute biphenotypic leukaemia","Acute biphenotypic leukemia","Bilineal acute leukaemia","Acute leukaemia of ambiguous lineage","Mixed-phenotype acute leukaemia"],"tldr":"Mixed-phenotype acute leukaemia is a rare acute leukaemia whose cells carry markers of both lymphoid and myeloid lines, so it fits neither acute lymphoblastic nor acute myeloid leukaemia. Pooled evidence favours starting with the drugs used for acute lymphoblastic leukaemia, adding a targeted drug when the Philadelphia chromosome is present, and a stem cell transplant in first remission.","summary":"WHO-HAEM5 keeps mixed-phenotype acute leukaemia under acute leukaemias of ambiguous lineage, defined by blasts co-expressing lineage-defining markers (B or T with myeloid) or by two blast populations, and subdivided by genetics, BCR::ABL1 and KMT2A-rearranged, then by phenotype (B/myeloid, T/myeloid, rare types) (Khoury 2022). The meta-analysis of 1,351 evaluable patients found that acute myeloid leukaemia-type induction was less likely to achieve complete remission than acute lymphoblastic leukaemia-type or hybrid induction, and analysed survival by treatment type and transplant (Maruffi 2018). In the Children's Oncology Group cohort, acute lymphoblastic leukaemia regimens achieved remission in 72 percent (28 of 39) and acute myeloid leukaemia regimens in 69 percent (9 of 13), and the task force set out a prospective trial strategy for paediatric disease (Orgel 2020).\n\nHow it differs from its parent: it sits between the two acute leukaemia pages; its diagnosis depends on strict flow cytometry criteria (myeloperoxidase or monocytic markers for myeloid lineage, cytoplasmic CD3 for T, CD19 with CD79a, CD22 or CD10 for B), and its treatment has no randomised evidence, only pooled case series.\n\nHow common: usually quoted as 2 to 5 percent of acute leukaemias, but no registry figure is in the sources read.\n\nTreatment: acute lymphoblastic leukaemia-type induction in most patients, with a tyrosine kinase inhibitor added for BCR::ABL1 disease and menin inhibitors under study for KMT2A-rearranged disease; allogeneic transplant in first remission for adults and high-risk children; measurable residual disease guides the choice, following the acute lymphoblastic and acute myeloid leukaemia pages (Maruffi 2018; Orgel 2020).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Mixed-phenotype_acute_leukemia","links":[{"label":"NCI PDQ: acute lymphoblastic leukaemia treatment","url":"https://www.cancer.gov/types/leukemia/patient/adult-all-treatment-pdq"},{"label":"Khoury 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, myeloid and histiocytic neoplasms","url":"https://doi.org/10.1038/s41375-022-01613-1"},{"label":"Maruffi 2018, Leukemia: therapy for mixed-phenotype acute leukaemia, systematic review and meta-analysis","url":"https://doi.org/10.1038/s41375-018-0058-4"},{"label":"Orgel 2020, Cancer: mixed-phenotype acute leukaemia, Children's Oncology Group cohort and research strategy","url":"https://doi.org/10.1002/cncr.32552"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["leukaemia","all-leukemia","aml","aml-npm1-kmt2a","burkitt-leukaemia"],"cancers":[],"sections":[],"technologies":["mrd-testing"],"targets":[],"drugs":["imatinib","dasatinib","cytarabine","blinatumomab"],"companies":[],"institutions":[],"pathways":[],"terms":["allogeneic-transplant"],"trials":["nct05433532"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare: a systematic review compiled 1,499 unique patients from 97 reports in 33 countries (Maruffi 2018); the Children's Oncology Group confirmed 54 of 70 banked cases as meeting WHO 2016 criteria (Orgel 2020). Usually quoted as 2 to 5 percent of acute leukaemias; no registry figure is in the sources read.","subtypes":["Mixed-phenotype acute leukaemia with BCR::ABL1 (add a tyrosine kinase inhibitor)","Mixed-phenotype acute leukaemia with KMT2A rearrangement (infants; menin inhibitors under study)","Mixed-phenotype acute leukaemia, B/myeloid, not otherwise specified","Mixed-phenotype acute leukaemia, T/myeloid, not otherwise specified","Acute undifferentiated leukaemia (related, no lineage markers)"],"biomarkers":["Flow cytometry: myeloperoxidase or monocytic markers with cytoplasmic CD3 or CD19 plus CD79a, CD22 or CD10","BCR::ABL1 and KMT2A rearrangement","Measurable residual disease after induction","Two distinct blast populations (bilineal)"],"standardOfCare":[{"setting":"Induction","approach":"Acute lymphoblastic leukaemia-type induction in most patients; tyrosine kinase inhibitor for BCR::ABL1 disease; allogeneic transplant in first remission for adults and high-risk children.","refs":["all-leukemia","aml","imatinib","dasatinib","allogeneic-transplant","mrd-testing"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"leukaemia"},{"id":"monomorphic-epitheliotropic-intestinal-t-cell-lymphoma","kind":"cancer","name":"Monomorphic epitheliotropic intestinal T-cell lymphoma","aka":["MEITL","Type II enteropathy-associated T-cell lymphoma","Type II EATL","Monomorphic CD56-positive intestinal T-cell lymphoma"],"tldr":"An aggressive T-cell lymphoma of the small bowel that looks and presents much like the lymphoma that complicates coeliac disease but has no connection with coeliac disease at all. It was separated out of that diagnosis in 2016, it is made of monotonous small to medium cells, and it often presents with perforation or obstruction of the bowel.","summary":"What it is. A lymphoma of the T cells between the cells lining the small bowel, like enteropathy-associated T-cell lymphoma, and otherwise a different disease. The name describes it: monomorphic, because the cells are monotonous small to medium-sized cells rather than the varied large ones of its neighbour; epitheliotropic, because the cells invade the lining itself; intestinal, because that is where it lives.\n\nHow it differs from the lymphoma it was carved out of. WHO-HAEM5 sets the differences out side by side. There is no association with coeliac disease. The cells are usually CD8-positive rather than negative for both CD4 and CD8. Necrosis is usually absent where it may be present in the other. The mutations differ: both carry gains of 9q34 and loss of 16q12, but this one carries mutations of SETD2 and of JAK3 and STAT5B, while the other carries JAK1 and STAT3. Neither carries Epstein-Barr virus, which separates both from extranodal NK/T-cell lymphoma when that disease involves the gut.\n\nHow it presents. As abdominal pain, weight loss and often perforation or obstruction of the small bowel, deep in the bowel wall. Patients commonly come to attention through emergency surgery, and the diagnosis is made on the resected bowel.\n\nWhat is known about treating it. Less than for its neighbour. The largest real-world cohort compared a modified version of the Newcastle regimen developed for enteropathy-associated T-cell lymphoma, giving cyclophosphamide, doxorubicin, vincristine and prednisone alternating with ifosfamide, etoposide and epirubicin but leaving out the methotrexate, against ordinary CHOP-based chemotherapy, in 50 patients who received systemic treatment. Median progression-free survival was 14.4 months against 6.6 and median overall survival 28.7 against 11.7 months, and the regimen remained an independent predictor of better progression-free survival after adjustment. The same study measured what the omitted methotrexate was meant to prevent: the two-year cumulative incidence of relapse in the central nervous system was 12.1 per cent. It is a retrospective comparison, not a trial.\n\nWhat a reader should take from this. This is a disease that was given its own name nine years ago, has no randomised evidence at all, and whose best available treatment comparison is a retrospective cohort of 50 treated patients. Entry into a trial is a reasonable first choice rather than a last resort, and the pages in this family say so where it is true.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Enteropathy-associated_T-cell_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"Modified Newcastle regimen in monomorphic epitheliotropic intestinal T-cell lymphoma, a real-world cohort of 56 patients (EJHaem 2026)","url":"https://doi.org/10.1002/jha2.70400"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["enteropathy-associated-t-cell-lymphoma","peripheral-t-cell-lymphoma","extranodal-nk-t-cell-lymphoma","small-bowel","non-hodgkin-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","fdg-pet"],"targets":[],"drugs":["ifosfamide","etoposide","cyclophosphamide"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-nodal-versus-extranodal","lymphoma-classification-2022","lymphoma-pit-score","lymphoma-tx-cns-prophylaxis","lymphoma-lugano-gastrointestinal"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare, and not reported separately in the United Kingdom population series, which predates the 2016 separation and counts it with enteropathy-associated T-cell lymphoma under the heading enteropathy type. The largest published real-world cohort assembled 56 patients diagnosed between 2002 and 2025 across several centres, and reports the median overall survival described in the literature as 7 to 15 months. The corpus does not quote a geographic distribution for it, because it could not verify one.","subtypes":[],"biomarkers":["Monotonous small to medium-sized cells invading the lining of the bowel, which is the name and the diagnosis","A CD8-positive, CD56-positive phenotype in most cases","SETD2 mutation, and mutations of JAK3 and STAT5B, which separate it from enteropathy-associated T-cell lymphoma","Gains of 9q34 and loss of 16q12, shared with enteropathy-associated T-cell lymphoma","Absence of coeliac disease, which is the main clinical difference","Absence of Epstein-Barr virus, which separates it from NK/T-cell lymphoma of the gut"],"standardOfCare":[{"setting":"Diagnosis, and telling it from its neighbour","approach":"Often made on small bowel resected as an emergency for perforation or obstruction. What separates it from enteropathy-associated T-cell lymphoma is the absence of coeliac disease, the monotonous small to medium cells rather than varied large ones, a CD8-positive and CD56-positive phenotype, and SETD2 mutation with JAK3 and STAT5B rather than JAK1 and STAT3. Neither carries Epstein-Barr virus, which separates both from NK/T-cell lymphoma of the gut.","refs":["histopathology-ihc","enteropathy-associated-t-cell-lymphoma","ebv-term","lymphoma-lugano-gastrointestinal"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Systemic treatment, and how thin the evidence is","approach":"There is no randomised evidence of any kind. The largest real-world comparison took 50 patients who received systemic chemotherapy and compared a modified version of the Newcastle regimen developed for enteropathy-associated T-cell lymphoma, giving cyclophosphamide, doxorubicin, vincristine and prednisone alternating with ifosfamide, etoposide and epirubicin but leaving out the methotrexate, against ordinary chemotherapy of the same backbone: median progression-free survival 14.4 against 6.6 months and overall survival 28.7 against 11.7 months, with the regimen remaining an independent predictor of better progression-free survival after adjustment. The two-year cumulative incidence of relapse in the central nervous system was 12.1 per cent, which is what the omitted methotrexate had been intended to prevent. Entry into a trial is a reasonable first choice rather than a last resort.","refs":["cyclophosphamide","doxorubicin","vincristine","prednisone","ifosfamide","etoposide","methotrexate","lymphoma-tx-cns-prophylaxis","lymphoma-tx-regimen-alphabet"],"guideline":{"version":"Real-world cohort of 56 patients (EJHaem 2026); NCCN T-Cell Lymphomas; NCI PDQ","url":"https://doi.org/10.1002/jha2.70400"}}],"stateOfArt":[],"history":[{"year":2016,"title":"Given its own name","note":"The revised fourth edition of the WHO classification separated what had been called type II enteropathy-associated T-cell lymphoma and named it monomorphic epitheliotropic intestinal T-cell lymphoma, because it has no association with coeliac disease and differs in appearance and genetics.","refs":[]},{"year":2022,"title":"Kept as an entity, with its differences tabulated","note":"WHO-HAEM5 retained the entity and set out the features that separate the five T-cell and NK-cell conditions of the gut from each other, including the mutations that differ between this and enteropathy-associated T-cell lymphoma.","refs":["lymphoma-classification-2022"]},{"year":2026,"title":"A real-world comparison of two regimens","note":"In 50 patients receiving systemic chemotherapy, a modified Newcastle regimen without methotrexate gave median progression-free survival of 14.4 months against 6.6 and overall survival of 28.7 against 11.7 months compared with CHOP-based chemotherapy; the two-year cumulative incidence of relapse in the central nervous system was 12.1 per cent.","refs":["ifosfamide","etoposide","cyclophosphamide"]}],"pipeline":[],"openProblems":["There is no randomised evidence of any kind in this disease, and the best comparison available is a retrospective cohort of 50 treated patients.","Whether methotrexate should be included to prevent relapse in the central nervous system is unresolved: the regimen that performed better left it out, and the two-year risk of relapse in the brain or spinal cord was still 12.1 per cent.","Because it is diagnosed on resected bowel after emergency surgery in many cases, the population that reaches systemic treatment is selected, and the published survival figures reflect that."],"parent":"peripheral-t-cell-lymphoma"},{"id":"colorectal-mucinous-adenocarcinoma","kind":"cancer","name":"Mucinous adenocarcinoma of the colon and rectum","aka":["Mucinous colorectal cancer","Colloid carcinoma of the colon","Mucinous adenocarcinoma of the colon","Mucinous carcinoma of the colorectum"],"tldr":"Mucinous adenocarcinoma is a form of bowel cancer, about one in ten cases, in which more than half the tumour is made of mucus produced by the cancer cells. It favours the right side of the colon, is often mismatch-repair deficient, tends to be found at a later stage and does somewhat worse than ordinary bowel cancer, but it is treated the same way.","summary":"The WHO classification defines mucinous adenocarcinoma by extracellular mucin making up more than 50 percent of the tumour, and grades it by its mismatch repair status rather than by gland formation (Nagtegaal 2020). In the Munich registry of 28,056 patients, mucinous adenocarcinoma made up 9.7 percent of colorectal cancers and was located in the proximal colon in 57 percent of cases against 34 percent of ordinary adenocarcinoma, was diagnosed at more advanced stages and had reduced survival (J Cancer Res Clin Oncol 2016). In 9,494 SEER patients with mucinous against 107,735 with non-mucinous adenocarcinoma, mucinous tumours occurred in older patients and were larger and more often of moderate grade, and surgery improved survival (Annals of Translational Medicine 2020). The meta-analysis of 1,087,055 patients found mucinous carcinoma more often right-sided than adenocarcinoma and with reduced five-year overall survival (Discover Oncology 2021).\n\nHow it differs from its parent: site, stage at diagnosis, frequent mismatch repair deficiency and a weaker response to some chemotherapy in older series; management nonetheless follows the colorectal page by stage and molecular status, with mismatch repair status deciding immunotherapy.\n\nHow common: about 10 percent (Discover Oncology 2021; J Cancer Res Clin Oncol 2016).\n\nTreatment: as the parent, by stage and mismatch repair status (surgery, FOLFOX or CAPOX, checkpoint inhibitors for MSI-high disease); the sources read are registry and pathology studies, not trials in the type.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Mucinous_carcinoma","links":[{"label":"Nagtegaal 2020, Histopathology: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"J Cancer Res Clin Oncol 2016: mucinous and signet ring cell colorectal cancer in 28,056 Munich registry patients","url":"https://doi.org/10.1007/s00432-016-2224-2"},{"label":"Discover Oncology 2021: signet ring cell and mucinous carcinoma versus adenocarcinoma, meta-analysis of 1,087,055 patients","url":"https://doi.org/10.1007/s12672-021-00398-6"},{"label":"Annals of Translational Medicine 2020: colorectal mucinous adenocarcinoma in SEER, 9,494 against 107,735 patients","url":"https://doi.org/10.21037/atm.2020.01.52"}],"tags":["subtype-page","wave4","colorectal"],"related":["colorectal","colon-cancer","colorectal-signet-ring-cell-carcinoma","msi-high-colorectal","appendiceal-adenocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["folfox","capox","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 10 percent of colorectal cancers: 110,179 of 1,087,055 patients (10.13 percent) in a meta-analysis of 30 studies (Discover Oncology 2021) and 2,724 of 28,056 (9.7 percent) in the Munich registry (J Cancer Res Clin Oncol 2016).","subtypes":["Mucinous adenocarcinoma, mismatch-repair deficient (MSI-high; often right-sided)","Mucinous adenocarcinoma, mismatch-repair proficient","Adenocarcinoma with a mucinous component under 50 percent (not classified as mucinous)"],"biomarkers":["Extracellular mucin over 50 percent of the tumour","Mismatch repair and microsatellite instability (decides grade and immunotherapy)","BRAF V600E and KRAS status","Primary tumour side and stage"],"standardOfCare":[{"setting":"All stages","approach":"Treated as the colorectal page by stage and mismatch repair status.","refs":["colorectal","colon-cancer","folfox","pembrolizumab"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"colorectal"},{"id":"mucinous-carcinoma-breast","kind":"cancer","name":"Mucinous carcinoma of the breast","aka":["Mucinous carcinoma of the breast","Colloid carcinoma of the breast","Mucinous breast cancer","Pure mucinous carcinoma"],"tldr":"Mucinous carcinoma is a rare type of breast cancer in which the cancer cells float in pools of mucus they have made. It is usually hormone-receptor positive, slow-growing and less likely to reach the lymph nodes than ordinary breast cancer, so its outlook is good and it is treated like other hormone-driven breast cancer.","summary":"The WHO classification defines pure mucinous carcinoma by clusters of low-grade cells in lakes of extracellular mucin making up over 90 percent of the tumour, and separates it from mixed mucinous carcinoma and from mucinous cystadenocarcinoma (Tan 2020). In a Taiwanese series of 93 pure mucinous carcinomas compared with 2,674 infiltrating ductal carcinomas, hormone receptor expression was higher and grade, hormone receptor status and node involvement were all more favourable, confirming its less aggressive behaviour (World J Surg Oncol 2013).\n\nHow it differs from its parent: mucin makes the tumour soft and well-circumscribed, so it can look benign on imaging; nodal spread is uncommon in the pure form; and the mixed form (mucinous with ordinary no special type carcinoma) behaves like the ordinary component and is treated as such.\n\nHow common: about 3.5 percent of breast cancers in the Taiwanese series (World J Surg Oncol 2013).\n\nTreatment: as HR-positive breast cancer, following the parent page, with endocrine therapy and usually no chemotherapy for the pure form; the sources read report treatment patterns, not trials in this type.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Mucinous_carcinoma","links":[{"label":"Tan 2020, Histopathology: the 2019 WHO classification of tumours of the breast","url":"https://doi.org/10.1111/his.14091"},{"label":"World J Surg Oncol 2013: pure mucinous carcinoma of the breast, 93 cases against 2,674 ductal carcinomas","url":"https://doi.org/10.1186/1477-7819-11-139"},{"label":"Cancer Research UK: types of breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/types"}],"tags":["subtype-page","wave4","breast"],"related":["breast-cancer","breast-hr-positive","tubular-carcinoma-breast","papillary-carcinoma-breast","invasive-micropapillary-carcinoma-breast"],"cancers":[],"sections":[],"technologies":["endocrine-therapy"],"targets":[],"drugs":["tamoxifen","letrozole"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"About 3.5 percent of newly diagnosed breast cancers in Taiwan (World J Surg Oncol 2013); typically a cancer of older women. No UK figure was found in the sources read.","subtypes":["Pure mucinous carcinoma (over 90 percent mucinous; luminal A)","Mixed mucinous carcinoma (treated as its no special type component)","Mucinous carcinoma with neuroendocrine differentiation (hypercellular type B)","Mucinous cystadenocarcinoma (very rare)"],"biomarkers":["Proportion of mucinous component (over 90 percent for pure)","Oestrogen and progesterone receptor (usually positive), HER2 (usually negative)","Node status"],"standardOfCare":[{"setting":"All stages","approach":"Treated as HR-positive breast cancer: surgery, radiotherapy after breast conservation, endocrine therapy; chemotherapy for the mixed form as for no special type disease.","refs":["breast-hr-positive","endocrine-therapy","tamoxifen","letrozole"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"breast-cancer"},{"id":"gallbladder-mucinous-carcinoma","kind":"cancer","name":"Mucinous carcinoma of the gallbladder","aka":["Mucinous adenocarcinoma of the gallbladder","Colloid carcinoma of the gallbladder"],"tldr":"Mucinous carcinoma is a rare gallbladder cancer in which the cancer cells sit in pools of mucus that make up more than half the tumour. It affects men almost as often as women, is larger than usual at diagnosis, and often presents like an acute gallbladder attack. It is staged and treated like other gallbladder adenocarcinomas.","summary":"The WHO defines mucinous carcinoma by extracellular (stromal) mucin forming more than 50 percent of the tumour. In the only sizeable series, 606 invasive gallbladder carcinomas were reviewed: 40 (6.6 percent) showed some mucinous differentiation and 15 (2.5 percent) met the definition. Mean age was 65; the female to male ratio was 1.1, against 3.9 for conventional pancreatobiliary-type adenocarcinoma; two thirds (8 of 12 with records) presented with a clinical picture and operative findings read as acute cholecystitis; and the tumours were larger (mean 4.8 cm and median 3.4 cm, against 2.9 and 2.5 cm) (Dursun 2012). Cancer Research UK describes the type simply as cancer cells often lying in pools of mucus. Mucin in Rokitansky-Aschoff sinuses can mimic mucinous carcinoma and is a recognised pathology pitfall (Albores-Saavedra 2009).\n\nWhat differs in treatment: nothing formally. There is no type-specific trial evidence, so mucinous carcinoma is staged by TNM 8th edition and treated as gallbladder adenocarcinoma: radical cholecystectomy where resectable, adjuvant capecitabine, and gemcitabine and cisplatin with immunotherapy for advanced disease. The practical differences are the larger size and inflammatory presentation, which raise the chance that the cancer is unsuspected at the first operation, and the pathology pitfall above.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Mucinous_carcinoma","links":[{"label":"Dursun, Arch Pathol Lab Med 2012: mucinous carcinomas of the gallbladder, 15 of 606 carcinomas","url":"https://doi.org/10.5858/arpa.2011-0447-oa"},{"label":"CRUK: types of gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/types"},{"label":"Albores-Saavedra, Am J Surg Pathol 2009: mucin-containing Rokitansky-Aschoff sinuses simulating mucinous carcinoma","url":"https://doi.org/10.1097/pas.0b013e3181b63d66"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"}],"tags":["gallbladder","biliary","subtype-page"],"related":["gallbladder","gallbladder-adenocarcinoma","gallbladder-papillary-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["rokitansky-aschoff-sinus"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 2.5 percent of gallbladder carcinomas by the WHO definition: 15 of 606 in the defining series, with some mucin production in 6.6 percent (Dursun 2012).","subtypes":["Mucinous (colloid) carcinoma of the gallbladder, more than 50 percent stromal mucin","Gallbladder adenocarcinoma with a minor mucinous component (not classified as mucinous carcinoma)"],"biomarkers":["Share of the tumour made up of extracellular mucin (over 50 percent defines the type)","T category and nodal status as for adenocarcinoma"],"standardOfCare":[{"setting":"All stages","approach":"As for gallbladder adenocarcinoma: radical cholecystectomy where resectable, capecitabine after resection, gemcitabine and cisplatin with immunotherapy when advanced.","refs":["gallbladder-adenocarcinoma","radical-cholecystectomy","capecitabine","gemcitabine-cisplatin"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"gallbladder"},{"id":"mcn-associated-carcinoma","kind":"cancer","name":"Mucinous cystic neoplasm of the pancreas with associated invasive carcinoma (MCN-associated carcinoma)","aka":["Mucinous cystic neoplasm with associated invasive carcinoma (women, body and tail; 4 to 12 percent of resected MCNs)","Invasive MCN","Mucinous cystadenocarcinoma of the pancreas","MCN with invasive carcinoma","Malignant mucinous cystic neoplasm"],"tldr":"MCN-associated carcinoma is pancreatic cancer that has developed inside a mucinous cystic neoplasm, a thick-walled cyst with ovary-like tissue in its wall that occurs almost only in women, usually in the tail of the pancreas. Most such cysts are benign when removed; the minority with invasive cancer are larger, carry nodules and occur in older women, and about six in ten survive five years.","summary":"What it is. A mucinous cystic neoplasm is defined by ovarian-type stroma in the cyst wall and by the absence of communication with the pancreatic duct; the 2019 WHO classification grades it as MCN with low- or high-grade dysplasia or MCN with associated invasive carcinoma (Nagtegaal 2020). The invasive component is usually a tubular ductal adenocarcinoma and occasionally colloid or undifferentiated with osteoclast-like giant cells (Adsay 2001; Muraki 2016).\n\nHow it differs from its parent. In 163 resected MCNs defined by ovarian stroma, 95 percent were in women and 97 percent in the distal pancreas; 72 percent were adenomas, 10.5 percent borderline, 5.5 percent carcinoma in situ and 12 percent invasive carcinoma; patients with invasive cancer were older (55 against 44 years); every cancer was 40 mm or larger or had nodules; five-year disease-specific survival was 100 percent for non-invasive and 57 percent for invasive MCNs, and only invasive tumours recurred (Crippa 2008). In 156 Japanese cases, 82.7 percent were adenomas, 13.4 percent non-invasive carcinomas and 3.9 percent invasive; 98.1 percent were women with a mean age of 48, mean size 65 mm, and five- and ten-year survival were 96.6 percent overall, with cyst diameter and mural nodules predicting malignancy (Yamao 2011).\n\nHow common it is. Not counted by registries; the shares above come from resected series and understate benign cysts that were never removed.\n\nHow it is treated. Because MCNs sit in the body and tail, the operation is usually a distal pancreatectomy with splenectomy, minimally invasive where the DIPLOMA trial has shown the oncological outcome is not inferior for pancreatic cancer (Korrel 2023). Non-invasive MCNs are cured by resection and need no follow-up in the European guidance cited on the parent cyst page; MCN with invasive carcinoma is staged and treated as pancreatic ductal adenocarcinoma with adjuvant chemotherapy. The Japanese series recommended resecting all MCNs, while European guidance allows observation of small MCNs without nodules; both positions are recorded on the parent cyst page.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Pancreatic_mucinous_cystic_neoplasm","links":[{"label":"Crippa, Ann Surg 2008: mucinous cystic neoplasm of the pancreas is not an aggressive entity, 163 resected patients","url":"https://doi.org/10.1097/sla.0b013e31811f4449"},{"label":"Yamao, Pancreas 2011: mucinous cystic neoplasm with ovarian-type stroma, Japan Pancreas Society multi-institutional study","url":"https://doi.org/10.1097/mpa.0b013e3181f749d3"},{"label":"Korrel, Lancet Reg Health Eur 2023: DIPLOMA, minimally invasive versus open distal pancreatectomy for resectable pancreatic cancer","url":"https://doi.org/10.1016/j.lanepe.2023.100673"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"Adsay, Am J Surg Pathol 2001: colloid (mucinous non-cystic) carcinoma of the pancreas","url":"https://doi.org/10.1097/00000478-200101000-00003"}],"tags":["gi","pancreatic","subtype-page"],"related":["pancreatic","ipmn-cystic-precursors","ipmn-associated-carcinoma","pancreatic-colloid-carcinoma","pancreatic-undifferentiated-carcinoma-ogc","mucinous-ovarian-cancer"],"cancers":[],"sections":[],"technologies":["robotic-surgery","cytotoxic-chemotherapy","histopathology-ihc","mri","endoscopic-ultrasound-systems"],"targets":["kras"],"drugs":["folfirinox","gemcitabine-nab-paclitaxel"],"companies":[],"institutions":[],"pathways":["ras-mapk","pancreatic-cancer-signalling"],"terms":["distal-pancreatectomy","pancreatic-cyst-high-risk-stigmata","resection-margins","tumour-grade"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Invasive carcinoma was present in 12 percent of 163 resected mucinous cystic neoplasms in two European and US centres and 3.9 percent of 156 in Japan; MCNs themselves are uncommon and 95 to 98 percent occur in women, almost all in the body or tail.","subtypes":["MCN with low-grade dysplasia (adenoma; cured by resection)","MCN with high-grade dysplasia (carcinoma in situ)","MCN with associated invasive tubular carcinoma (treated as ductal PDAC)","MCN with associated colloid or undifferentiated carcinoma with osteoclast-like giant cells"],"biomarkers":["Ovarian-type stroma (progesterone and oestrogen receptor and inhibin positive) in the cyst wall (definition)","Cyst diameter of 40 mm or more and mural nodules (predictors of malignancy)","Cyst-fluid CEA (mucinous) without GNAS mutation (unlike IPMN); KRAS in the invasive component","Age: invasive disease in older women (55 against 44 in the Crippa series)"],"standardOfCare":[{"setting":"Resectable","approach":"Distal pancreatectomy with splenectomy (minimally invasive where expertise exists, DIPLOMA), pancreatoduodenectomy for the rare head lesion; adjuvant chemotherapy as for ductal adenocarcinoma when invasive carcinoma is found.","refs":["distal-pancreatectomy","robotic-surgery","folfirinox","neoadjuvant-adjuvant"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Advanced","approach":"Treated as pancreatic ductal adenocarcinoma: resection with adjuvant chemotherapy when removable, the chemotherapy rows of the parent page when not; the parent record carries the trials.","refs":["folfirinox","gemcitabine-nab-paclitaxel"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["MCN is recognised as a less aggressive entity than once thought (17.5 percent malignant in the 2008 series) once separated from IPMN by ovarian stroma.","Minimally invasive distal pancreatectomy is non-inferior for margin status in pancreatic cancer (DIPLOMA 2023)."],"history":[{"year":2008,"title":"163 resected MCNs: cancer in 17.5 percent, all 40 mm or larger or with nodules","refs":["distal-pancreatectomy"]},{"year":2011,"title":"Japan Pancreas Society series of 156 MCNs with ovarian-type stroma","refs":["tumour-grade"]},{"year":2023,"title":"DIPLOMA: minimally invasive distal pancreatectomy non-inferior for R0 resection in pancreatic cancer","refs":["distal-pancreatectomy","robotic-surgery"]}],"pipeline":[],"openProblems":["Whether small MCNs without nodules can be safely observed rather than resected divides the Japanese and European guidance.","No trial addresses adjuvant treatment for MCN-associated carcinoma specifically."],"parent":"pancreatic"},{"id":"mucinous-ovarian-cancer","kind":"cancer","name":"Mucinous ovarian cancer","aka":["Mucinous ovarian carcinoma","MOC"],"tldr":"Mucinous ovarian cancer is rare, usually confined to one large ovary at diagnosis and cured by surgery. Its genetics resemble bowel cancer more than ovarian cancer, and pathologists must first rule out a spread from the gut before making the diagnosis.","summary":"Primary mucinous carcinoma of the ovary is uncommon and was historically over-diagnosed because metastases from the appendix, colon, stomach and pancreas mimic it. True primary tumours carry KRAS mutations in about two thirds and HER2 amplification in a fifth, share their biology with gastrointestinal cancers and often arise from a mucinous borderline tumour. Most are stage I and treated with surgery alone or with fertility-sparing unilateral oophorectomy; appendicectomy is performed if the appendix looks abnormal. Advanced disease responds poorly to carboplatin-paclitaxel, and gastrointestinal-type regimens such as capecitabine-oxaliplatin are used by extrapolation; HER2-directed therapy is an option in amplified tumours.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Ovarian_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Ovarian_cancer"}],"tags":["subtype-page"],"related":["clear-cell-ovarian-cancer","low-grade-serous-ovarian-cancer","granulosa-cell-tumour","high-grade-serous-ovarian-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-cheasley-mucinous-ovarian-genomics-nat-commun-2019","paper-morice-mucinous-ovarian-carcinoma-nejm-2019"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"About three percent of ovarian cancers once metastases from the bowel and appendix are excluded; most are large, unilateral stage I tumours that surgery cures, and the rare advanced cases respond poorly to standard ovarian regimens.","subtypes":["Expansile (confluent) pattern (better outlook)","Infiltrative pattern","HER2-amplified","Arising from mucinous borderline tumour or teratoma"],"biomarkers":["KRAS mutation","HER2 amplification (about 20 percent)","CK7 and CK20 pattern and SATB2 to exclude gastrointestinal origin","CEA and CA 19-9 rather than CA-125"],"standardOfCare":[{"setting":"Early stage","approach":"Unilateral salpingo-oophorectomy or hysterectomy with staging; appendicectomy if abnormal; chemotherapy usually omitted for stage IA and IB.","refs":["ovarian"]},{"setting":"Advanced or recurrent","approach":"Cytoreduction; carboplatin-paclitaxel or gastrointestinal-type capecitabine-oxaliplatin; trastuzumab for HER2-amplified tumours in trials.","refs":["capecitabine","oxaliplatin","trastuzumab","carboplatin"]},{"setting":"Young women with stage IA disease","approach":"Fertility-sparing unilateral salpingo-oophorectomy with staging and close follow-up.","refs":["ovarian"]}],"stateOfArt":["Strict pathology criteria have cut the diagnosis to its true rare frequency and improved apparent survival.","The GI-like biology is steering treatment toward bowel cancer regimens and HER2-directed therapy.","International rare-tumour trials (mEOC/GOG 241) showed how hard it is to recruit for this disease."],"history":[{"year":2003,"title":"Seidman shows most 'mucinous ovarian cancers' are metastases from the gut","refs":[]},{"year":2019,"title":"mEOC/GOG 241 randomised trial closes early for poor accrual","refs":[]},{"year":2020,"title":"WHO classification separates expansile from infiltrative mucinous carcinoma","refs":[]}],"pipeline":["trastuzumab-deruxtecan","her2"],"openProblems":["No proven chemotherapy for advanced disease.","Trials cannot recruit enough patients.","Distinguishing primary from metastatic disease still needs expert pathology."],"parent":"ovarian"},{"id":"mucinous-tubular-spindle-cell-carcinoma","kind":"cancer","name":"Mucinous tubular and spindle cell carcinoma of the kidney","aka":["MTSCC","Mucinous tubular and spindle cell renal cell carcinoma","Low-grade collecting duct carcinoma (historical)"],"tldr":"Mucinous tubular and spindle cell carcinoma is a rare, usually slow-growing kidney cancer, commoner in women, whose cells form small tubes and spindles in a mucus-rich background. It is driven by loss of the Hippo growth-control pathway rather than the faults of common kidney cancer, and surgery cures most cases.","summary":"Mucinous tubular and spindle cell carcinoma is a renal cell carcinoma type recognised since 2004 and kept in the 2022 WHO classification, with tightly packed tubules merging into spindle cells in a mucinous stroma, a female predominance and generally indolent behaviour (Moch 2022). Whole-exome and transcriptome sequencing of 22 tumours found biallelic loss or alteration of Hippo pathway tumour suppressors in 85 percent, PTPN14 (31 percent) and NF2 (22 percent) most often, with SAV1 and HIPK2 in a mutually exclusive pattern, recurrent chromosomal losses, and increased nuclear YAP1 in 90 percent (Cancer Discovery 2016). VSTM2A and IRX5 were then identified as lineage-specific markers, with all 33 tumours showing moderate to high VSTM2A expression by RNA in situ hybridisation against low or absent expression in papillary, clear cell and chromophobe carcinomas (Am J Surg Pathol 2018).\n\nHow it differs from its parent: it lacks VHL loss and the papillary trisomies, its main differential is papillary renal cell carcinoma (from which VSTM2A separates it), and it is indolent in the typical form while high-grade and sarcomatoid variants can metastasise.\n\nHow common: no registry share was found in the sources read.\n\nTreatment: partial or radical nephrectomy, which is curative for typical tumours; advanced disease is very rare and treated on the renal cell carcinoma page without a dedicated standard.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Renal_cell_carcinoma","links":[{"label":"Moch 2022, European Urology: the 2022 WHO classification of urinary and male genital tumours, part A (renal, penile, testicular)","url":"https://doi.org/10.1016/j.eururo.2022.06.016"},{"label":"Cancer Discovery 2016: biallelic Hippo pathway alteration in mucinous tubular and spindle cell carcinoma","url":"https://doi.org/10.1158/2159-8290.cd-16-0267"},{"label":"Am J Surg Pathol 2018: VSTM2A overexpression as a marker of mucinous tubular and spindle cell carcinoma","url":"https://doi.org/10.1097/pas.0000000000001150"}],"tags":["subtype-page","wave4","kidney","rare"],"related":["rcc","papillary-rcc","eosinophilic-solid-cystic-renal-cell-carcinoma","clear-cell-papillary-renal-cell-tumour"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["nephrectomy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Rare; the largest molecular series holds 22 tumours (Cancer Discovery 2016) and the marker study 33 (Am J Surg Pathol 2018). No registry share was found in the sources read.","subtypes":[],"biomarkers":["Hippo pathway alterations (PTPN14, NF2) and nuclear YAP1","VSTM2A and IRX5 expression (research markers)","Mucinous stroma with tubules and spindle cells","WHO/ISUP grade (usually low)"],"standardOfCare":[{"setting":"All stages","approach":"Partial or radical nephrectomy; advanced disease on the renal cell carcinoma page without a dedicated standard.","refs":["rcc","nephrectomy"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"rcc"},{"id":"mucoepidermoid-carcinoma","kind":"cancer","name":"Mucoepidermoid carcinoma","aka":["MEC","Mucoepidermoid carcinoma of the salivary glands"],"tldr":"Mucoepidermoid carcinoma is the most common salivary gland cancer and, for most people, one of the most curable: low-grade tumours are removed surgically and rarely return, while high-grade tumours need radiotherapy after surgery and are treated like other aggressive head and neck cancers if they spread.","summary":"Mucoepidermoid carcinoma is made of mucous, intermediate and squamous-like (epidermoid) cells in varying proportions, and most tumours carry a CRTC1-MAML2 or CRTC3-MAML2 fusion that drives CREB-regulated genes and marks a better outlook. It arises in the parotid, the minor salivary glands of the palate and lips, and the bronchi, and it is the commonest salivary cancer in children and after radiotherapy or chemotherapy for a childhood cancer. Grade, assigned by histological systems such as the AFIP and Brandwein scores, is the strongest predictor of behaviour: low-grade tumours are indolent, high-grade tumours spread to nodes and distant sites.\n\nTreatment is surgical. Low-grade tumours are cured by complete excision with a margin (superficial or total parotidectomy preserving the facial nerve, or excision of the palatal lesion), and do not need radiotherapy when margins are clear. High-grade and intermediate-grade tumours, and any with positive margins, perineural invasion or nodal spread, are treated with neck dissection and postoperative radiotherapy, with cisplatin chemoradiation considered for extranodal extension or positive margins by analogy with squamous cell carcinoma.\n\nThere is no targeted therapy: the MAML2 fusion is not directly druggable, though it drives amphiregulin and EGFR signalling that has been explored preclinically. Recurrent or metastatic high-grade disease is treated with platinum-based chemotherapy, with pembrolizumab for the uncommon PD-L1-positive or mutation-rich tumour, and patients are offered the pan-salivary trials of new agents. Indolent low-grade metastases, which are rare, may be observed.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Mucoepidermoid_carcinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Mucoepidermoid_carcinoma"}],"tags":["subtype-page","head-and-neck"],"related":["adenoid-cystic-carcinoma","salivary-duct-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bernier-eortc-22931-nejm-2004","paper-tonon-crtc1-maml2-nat-genet-2003","paper-laurie-licitra-salivary-systemic-jco-2006"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"The commonest salivary gland cancer in both adults and children, most often in the parotid or the minor glands of the palate; low-grade tumours are cured by surgery in nearly every case, while high-grade tumours behave like other aggressive head and neck cancers.","subtypes":["Low-grade mucoepidermoid carcinoma (mostly cured by surgery)","Intermediate-grade mucoepidermoid carcinoma","High-grade mucoepidermoid carcinoma","CRTC1-MAML2 or CRTC3-MAML2 fusion-positive disease (the majority, better outlook)","Mucoepidermoid carcinoma of the palate and other minor salivary glands","Paediatric mucoepidermoid carcinoma, including after radiotherapy or chemotherapy"],"biomarkers":["MAML2 rearrangement by FISH (confirms the diagnosis)","Histological grade (AFIP or Brandwein system)","Margin status and perineural invasion","Nodal spread and extranodal extension","Ki-67"],"standardOfCare":[{"setting":"Low-grade, localised","approach":"Complete excision with a margin (parotidectomy preserving the facial nerve, or excision of the minor gland lesion); postoperative radiotherapy only for positive margins that cannot be re-excised.","refs":["imrt-igrt"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Intermediate- and high-grade or node-positive","approach":"Resection with neck dissection and postoperative radiotherapy; cisplatin chemoradiation considered for extranodal extension or positive margins.","refs":["imrt-igrt","cisplatin","chemoradiation"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Recurrent or metastatic","approach":"Platinum-based chemotherapy (carboplatin-paclitaxel or cisplatin-based); pembrolizumab for PD-L1-positive or mutation-rich tumours; observation for indolent low-grade metastases.","refs":["cisplatin","carboplatin","paclitaxel","pembrolizumab","pd-l1-testing"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Trials","approach":"Pan-salivary and pan-tumour trials of new agents that accept mucoepidermoid carcinoma.","refs":["gotistobart","nct05377996"]}],"stateOfArt":["Grade and margins, not molecular markers, still decide treatment.","The MAML2 fusion confirms the diagnosis and predicts a better course but has no drug.","Facial-nerve-sparing parotidectomy cures most patients with low-grade disease with little morbidity."],"history":[{"year":1945,"title":"Stewart, Foote and Becker name mucoepidermoid tumours of the salivary glands","refs":[]},{"year":2003,"title":"CRTC1-MAML2 fusion identified as the defining genetic event","refs":[]},{"year":2017,"title":"WHO classification confirms MAML2 fusion as diagnostic and prognostic","refs":[]}],"pipeline":["gotistobart","nct05377996","pembrolizumab"],"openProblems":["No targeted drug for the MAML2 fusion.","Grading systems disagree, so treatment intensity varies between centres.","High-grade disease has outcomes as poor as squamous cell carcinoma.","Second cancers in children treated for the disease."],"parent":"salivary-gland"},{"id":"mucosal-melanoma","kind":"cancer","name":"Mucosal melanoma","aka":["Melanoma of mucous membranes","Sinonasal melanoma","Oral mucosal melanoma","Anorectal melanoma","Vulvovaginal melanoma"],"tldr":"Mucosal melanoma grows on the moist linings of the nose, mouth, anus or genital tract rather than on sun-exposed skin, so it is found late and carries fewer of the mutations that make skin melanoma visible to the immune system. Immunotherapy helps less often than in skin melanoma; a minority of tumours has a KIT mutation that the pill imatinib can target.","summary":"Mucosal melanoma arises from melanocytes in the sinonasal tract, oral cavity, anorectum, vulva, vagina and, rarely, the urinary tract, biliary tree and oesophagus. It is not caused by ultraviolet light and its genome differs from cutaneous melanoma: a low mutation burden, frequent structural rearrangements and amplifications, KIT mutations or amplifications in a substantial minority, SF3B1 mutations, and BRAF V600 mutations in only about one in twenty. Presentation is late because the sites are hidden, and most patients have thick, often ulcerated or multifocal primaries; five-year survival is well below that of cutaneous melanoma at any stage.\n\nSurgery is the mainstay for localised disease, but local recurrence is frequent and radical operations at head and neck or anorectal sites carry heavy morbidity, so postoperative radiotherapy is often added to improve local control even though it has not lengthened survival. In China, where the disease is common, a randomised trial found adjuvant temozolomide-cisplatin chemotherapy improved relapse-free and overall survival over high-dose interferon and observation, and it remains an option there. Sentinel node biopsy is less standardised than in cutaneous disease.\n\nImmunotherapy works less well than in cutaneous melanoma: in the pooled analysis of the nivolumab trials the response rate was 23 percent with nivolumab alone and 37 percent with nivolumab plus ipilimumab, and pembrolizumab produced responses in 19 percent in the pooled KEYNOTE analysis. Chinese investigators combined toripalimab with the VEGF receptor inhibitor axitinib and reported responses in nearly half of chemotherapy-naive patients in phase 1b, and the pairing is being tested in randomised trials. Imatinib produces responses in roughly one in four tumours with KIT exon 11 or 13 mutations, and the MEK inhibitor tunlametinib is approved in China for NRAS-mutant melanoma, a group that includes many mucosal tumours.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Mucosal_melanoma","links":[{"label":"Pooled nivolumab analysis in mucosal melanoma (JCO 2017)","url":"https://ascopubs.org/doi/10.1200/JCO.2016.67.9258"},{"label":"Toripalimab plus axitinib (JCO 2019)","url":"https://ascopubs.org/doi/10.1200/JCO.19.00210"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Mucosal_melanoma"}],"tags":["subtype-page"],"related":["acral-melanoma","advanced-melanoma","vulvar","uveal-melanoma","braf-v600-melanoma"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","kinase-inhibitors","imrt-igrt"],"targets":["kit","pd1","ctla4","mek"],"drugs":["nivolumab","ipilimumab","pembrolizumab","imatinib","toripalimab","axitinib","tunlametinib"],"companies":[],"institutions":[],"pathways":["ras-mapk"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-dangelo-mucosal-melanoma-pooled-jco-2017","paper-hodi-imatinib-kit-melanoma-jco-2013","paper-curtin-kit-melanoma-jco-2006","paper-lian-adjuvant-temozolomide-cisplatin-mucosal-melanoma-ccr-2013"],"journals":[],"dependsOn":[],"notes":[],"group":"skin","burden":"Mucosal melanoma is about one in a hundred melanomas in Europe and North America but roughly a fifth of melanomas in China, where it is the second commonest subtype; it arises in the nose and sinuses, mouth, anus and rectum, and vulva and vagina, and is usually found late.","subtypes":["Sinonasal and oral mucosal melanoma (head and neck)","Anorectal mucosal melanoma","Vulvar and vaginal mucosal melanoma","KIT-mutant mucosal melanoma (imatinib candidates)","NRAS-mutant mucosal melanoma (MEK inhibitor trials)","Mucosal melanoma in East Asian populations (toripalimab-axitinib approach)"],"biomarkers":["KIT mutation or amplification (exon 11 and 13 predict imatinib response)","NRAS mutation","BRAF V600 mutation (uncommon)","SF3B1 mutation","Low tumour mutational burden","PD-L1 expression (weakly predictive)"],"standardOfCare":[{"setting":"Localised disease","approach":"Wide surgical excision with the least morbid operation that clears margins; postoperative radiotherapy for head and neck and anorectal primaries to improve local control.","refs":["wide-local-excision","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Adjuvant","approach":"Anti-PD-1 antibody as for cutaneous stage III disease by extrapolation; temozolomide-cisplatin chemotherapy is an option in China on a randomised trial.","refs":["nivolumab","pembrolizumab","temozolomide","cisplatin"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Advanced, first line","approach":"Nivolumab plus ipilimumab (higher response than nivolumab alone in the pooled analysis) or anti-PD-1 monotherapy; toripalimab with axitinib in China.","refs":["nivolumab","ipilimumab","pembrolizumab","toripalimab","axitinib"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"KIT-mutant disease","approach":"Imatinib for exon 11 or 13 mutations after or alongside immunotherapy; nilotinib is an alternative.","refs":["imatinib","nilotinib","kit"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"NRAS-mutant disease","approach":"Tunlametinib (approved in China) or MEK inhibitor trials; naporafenib with trametinib in the SEACRAFT-2 trial.","refs":["tunlametinib","nct06008106","seacraft-2","naporafenib"]}],"stateOfArt":["Immunotherapy doublets produce responses in about a third of patients, roughly half the rate seen in cutaneous melanoma.","KIT is the one recurrent drug target and imatinib the one approved kinase inhibitor that works in a subset.","China, where the disease is common, leads the trials of immunotherapy combined with anti-angiogenic drugs."],"history":[{"year":2006,"title":"Curtin and Bastian: KIT alterations found in mucosal and acral melanoma","refs":["kit"]},{"year":2011,"title":"Imatinib phase 2 trials show responses in KIT-mutant melanoma","refs":["imatinib"]},{"year":2013,"title":"Chinese randomised trial: adjuvant temozolomide-cisplatin beats interferon","refs":["temozolomide","cisplatin","interferon-alfa"]},{"year":2017,"title":"Pooled nivolumab analysis: lower response rates in mucosal melanoma","refs":["nivolumab","ipilimumab"]},{"year":2019,"title":"Toripalimab plus axitinib phase 1b reports responses in nearly half","refs":["toripalimab","axitinib"]},{"year":2024,"title":"Tunlametinib approved in China for NRAS-mutant melanoma","refs":["tunlametinib"]}],"pipeline":["toripalimab","axitinib","tunlametinib","nct06008106","seacraft-2","imatinib","lifileucel"],"openProblems":["No phase 3 trial has been run specifically in mucosal melanoma outside China.","Local control at head and neck and anorectal sites is poor without mutilating surgery.","The low mutation burden limits immunotherapy and there is no approved drug for the common structural alterations."],"parent":"melanoma"},{"id":"multiple-endocrine-neoplasia","kind":"cancer","name":"Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)","aka":["MEN1","MEN2A","MEN2B","MEN4","Wermer syndrome","Sipple syndrome"],"tldr":"The MEN syndromes are inherited faults in a single gene that cause tumours in several hormone glands over a lifetime. Because the gene can be found in childhood, at-risk relatives can be tested, watched and in MEN2 have the thyroid removed before cancer develops; and for MEN2 thyroid cancer that does spread there is now a precise pill, selpercatinib, that blocks the faulty RET protein.","summary":"MEN1 is caused by germline loss-of-function mutations in MEN1, encoding the tumour suppressor menin, and produces parathyroid hyperplasia (nearly universal), duodenopancreatic neuroendocrine tumours (gastrinoma, insulinoma, non-functioning PanNETs, the main cause of death), anterior pituitary tumours, and adrenal, thymic and bronchial neuroendocrine tumours. MEN2 is caused by germline activating mutations in the RET receptor tyrosine kinase: MEN2A (codon 634 most often) causes medullary thyroid carcinoma (MTC), pheochromocytoma and parathyroid disease; MEN2B (M918T) causes early aggressive MTC, pheochromocytoma, mucosal neuromas and a marfanoid habitus. MEN4 (CDKN1B) is a rare MEN1 phenocopy. These syndromes are on the NCI list because their management is oncological: surveillance, prophylactic surgery and, when tumours spread, targeted therapy.\n\nManagement is genotype-driven. In MEN2, the American Thyroid Association (2015) assigns RET codons to risk levels that set the age of prophylactic thyroidectomy (within the first year for M918T, before age 5 for codon 634, later with calcitonin monitoring for moderate-risk codons), an intervention that prevents MTC in carriers identified early. Pheochromocytoma must be excluded before any surgery. Advanced RET-mutant MTC is treated with selpercatinib, which outperformed cabozantinib or vandetanib in the randomised LIBRETTO-531 trial (NEJM 2023), with pralsetinib as an alternative. In MEN1, surveillance (calcium and PTH, gastrin and fasting gut hormones, pituitary hormones, pancreatic MRI or endoscopic ultrasound) begins in childhood; parathyroidectomy, proton pump inhibitors for gastrinoma, and surgery for PanNETs above about 2 cm or functioning; advanced PanNETs are treated as sporadic NETs with somatostatin analogues, everolimus, sunitinib and 177Lu-DOTATATE.\n\nOpen problems are the timing of pancreatic surgery in MEN1, the lack of menin-directed therapy for MEN1 tumours (menin inhibitors developed for leukaemia work by a different mechanism), and equitable access to genetic testing and lifelong surveillance.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia","links":[{"label":"NCI PDQ: multiple endocrine neoplasia syndromes","url":"https://www.cancer.gov/types/multiple-endocrine-neoplasia"},{"label":"ATA medullary thyroid carcinoma guideline (2015)","url":"https://doi.org/10.1089/thy.2014.0335"},{"label":"MEN1 clinical practice guidelines (JCEM 2012)","url":"https://doi.org/10.1210/jc.2012-1230"},{"label":"LIBRETTO-531 (NEJM 2023)","url":"https://doi.org/10.1056/NEJMoa2309719"}],"tags":["nci-coverage","rare","endocrine","hereditary"],"related":["neuroendocrine","thyroid","pheochromocytoma-paraganglioma","pituitary-tumours","parathyroid-carcinoma"],"cancers":[],"sections":[],"technologies":["germline-testing","kinase-inhibitors","prrt","sstr-pet"],"targets":["ret","menin","sstr2"],"drugs":["selpercatinib","pralsetinib","cabozantinib","vandetanib","octreotide-lanreotide","everolimus","sunitinib","lutathera"],"companies":["eli-lilly"],"institutions":[],"pathways":["rtk-activation","ras-mapk","oncogene-activation-two-hit"],"terms":["men1-hereditary-net","hereditary-cancer-syndromes","germline-vs-somatic"],"trials":["libretto-531"],"people":[],"bottlenecks":["b-hereditary-risk","b-rare-cancers"],"keyPapers":["paper-thakker-j-clin-endocrinol-metab"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"MEN1 affects about 2 to 3 per 100,000 people and MEN2 about 1 in 30,000; both are inherited in an autosomal dominant pattern with near-complete penetrance.","subtypes":["MEN1 (menin; parathyroid, pancreatic NET, pituitary)","MEN2A (RET; medullary thyroid carcinoma, pheochromocytoma, parathyroid)","MEN2B (RET M918T; early MTC, pheochromocytoma, mucosal neuromas)","Familial medullary thyroid carcinoma (MEN2A variant)","MEN4 (CDKN1B)"],"biomarkers":["Germline MEN1, RET or CDKN1B mutation (diagnostic; codon defines MEN2 risk level)","Calcitonin and CEA (MTC surveillance)","Calcium and PTH, gastrin, fasting glucose and insulin, prolactin and IGF-1 (MEN1 surveillance)","Plasma metanephrines before any surgery (pheochromocytoma exclusion)","Pancreatic imaging (MRI, endoscopic ultrasound, 68Ga-DOTATATE PET)"],"standardOfCare":[{"setting":"MEN2 carriers (RET-positive)","approach":"Prophylactic total thyroidectomy timed by ATA risk level (highest risk within the first year, high risk before age 5, moderate risk guided by calcitonin); annual screening for pheochromocytoma and hyperparathyroidism.","refs":["thyroid","germline-testing","pheochromocytoma-paraganglioma"],"guideline":{"version":"American Thyroid Association medullary thyroid carcinoma guideline 2015","url":"https://doi.org/10.1089/thy.2014.0335"}},{"setting":"Advanced RET-mutant medullary thyroid carcinoma","approach":"Selpercatinib (LIBRETTO-531: superior to cabozantinib or vandetanib); pralsetinib, cabozantinib or vandetanib as alternatives.","refs":["selpercatinib","libretto-531","pralsetinib","cabozantinib","vandetanib"],"guideline":{"nccn":"Category 1 (selpercatinib)","version":"NCCN Thyroid Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1470"}},{"setting":"MEN1 carriers","approach":"Surveillance from childhood; subtotal or total parathyroidectomy with autotransplantation for hyperparathyroidism; proton pump inhibitors for gastrinoma; resection of functioning or larger PanNETs; sporadic NET pathways (somatostatin analogues, everolimus, sunitinib, PRRT) for advanced disease.","refs":["men1-hereditary-net","octreotide-lanreotide","everolimus","sunitinib","lutathera","prrt","neuroendocrine"],"guideline":{"version":"MEN1 clinical practice guidelines (Thakker, JCEM 2012)","url":"https://doi.org/10.1210/jc.2012-1230"}}],"stateOfArt":["MEN2 is the clearest example of genotype-directed prevention in oncology: a RET codon result sets the age of an operation that prevents a lethal cancer.","Selpercatinib converted RET-mutant MTC from multikinase-inhibitor territory into precision oncology, with better responses and fewer toxicities in a randomised comparison.","MEN1 surveillance protocols detect pancreatic NETs early, and 68Ga-DOTATATE PET and endoscopic ultrasound have replaced CT for pancreatic screening in many centres.","Cascade genetic testing of relatives, often in childhood, is standard and effective."],"history":[{"year":1954,"title":"Wermer describes familial adenomatosis of endocrine glands (MEN1)","refs":[]},{"year":1961,"title":"Sipple describes the association of pheochromocytoma and thyroid carcinoma (MEN2)","refs":[]},{"year":1993,"title":"RET mutations cause MEN2A","note":"Mulligan and colleagues, Nature; Donis-Keller and colleagues.","refs":["ret"]},{"year":1997,"title":"MEN1 gene cloned","note":"Chandrasekharappa and colleagues, Science; menin identified.","refs":["menin"]},{"year":2015,"title":"ATA guideline: codon-based timing of prophylactic thyroidectomy","refs":["thyroid"]},{"year":2020,"title":"Selpercatinib and pralsetinib approved for RET-mutant MTC","refs":["selpercatinib","pralsetinib"]},{"year":2023,"title":"LIBRETTO-531: selpercatinib beats multikinase inhibitors in RET-mutant MTC","note":"Hadoux and colleagues, NEJM.","refs":["selpercatinib","libretto-531"]}],"pipeline":["selpercatinib","libretto-531","lutathera","everolimus"],"openProblems":["MEN1 has no menin-restoring or pathway-directed therapy; PanNET progression remains the main cause of death, addressed by earlier detection and NET therapies.","Timing and extent of pancreatic surgery in MEN1: prospective registries are comparing strategies.","Resistance to selpercatinib (RET solvent-front mutations): next-generation RET inhibitors are in trials.","Lifelong surveillance costs and psychological burden in carriers identified as children."]},{"id":"men1-syndrome","kind":"cancer","name":"Multiple endocrine neoplasia type 1 (MEN1)","aka":["MEN1","Wermer syndrome","MEN1 (menin; parathyroid, pancreatic NET, pituitary)"],"tldr":"MEN1 is an inherited condition, one of the multiple endocrine neoplasia syndromes, in which a faulty MEN1 gene lets tumours grow in the parathyroid glands, the pancreas and the pituitary. Each tumour is treated much as it would be in anyone else, but because there are many of them and they come back, families are followed for life in specialist clinics.","summary":"MEN1 is an autosomal dominant disorder caused by germline mutations in the tumour suppressor gene MEN1, which encodes the 610-amino-acid protein menin. It is defined by tumours of the parathyroid glands, the pancreatic islets and the anterior pituitary; some patients also develop carcinoid (neuroendocrine) tumours of the thymus, lung and stomach, adrenocortical tumours, meningiomas, facial angiofibromas, collagenomas and lipomas (Thakker 2012). The WHO classification of endocrine and neuroendocrine tumours (5th edition) lists MEN1 among the genetic tumour syndromes rather than as a tumour, which is why it sits here as an entity under the syndromes page.\n\nHow it differs from its parent: MEN1 is the menin-driven syndrome; MEN2 is driven by RET and centres on the thyroid. Within MEN1 the pancreatic and thymic tumours carry the mortality: patients have a decreased life expectancy, and the outcomes of treatments that work in sporadic tumours are less good because the tumours are multiple, often larger and more aggressive, and metastases coincide (Thakker 2012). Thymic neuroendocrine tumour accounts for almost a fifth of MEN1-associated deaths; its pooled prevalence in 2,710 MEN1 patients was 3.7 percent, four fifths of them men (Ye 2017). Parathyroid carcinoma is rare in MEN1: one case in 348 patients (0.28 percent) in a Mayo cohort, with ten reported in the literature (Singh Ospina 2016).\n\nTreatment is by manifestation, as the parent page sets out: parathyroid surgery for hyperparathyroidism, resection of functioning or larger pancreatic neuroendocrine tumours, medical treatment of gastrinoma, and the sporadic pathways for pituitary and neuroendocrine tumours. The guideline recommends presymptomatic detection by MEN1 mutation testing of first-degree relatives and lifelong surveillance under a multidisciplinary team with experience of endocrine tumours (Thakker 2012). Menin inhibitors approved for leukaemia act on the same protein but have no trial in MEN1.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia_type_1","links":[{"label":"NCI: multiple endocrine neoplasia (MEN) syndromes","url":"https://www.cancer.gov/types/multiple-endocrine-neoplasia"},{"label":"Thakker 2012, JCEM: clinical practice guidelines for MEN1","url":"https://doi.org/10.1210/jc.2012-1230"},{"label":"Orphanet: multiple endocrine neoplasia type 1 (ORPHA:652)","url":"https://www.orpha.net/en/disease/detail/652"},{"label":"Ye 2017, Clin Endocrinol: thymic neuroendocrine tumours in MEN1, meta-analysis","url":"https://doi.org/10.1111/cen.13480"},{"label":"Singh Ospina 2016, Clin Endocrinol: parathyroid carcinoma in 348 patients with MEN1","url":"https://doi.org/10.1111/cen.12714"}],"tags":["subtype-page","wave4","rare"],"related":["multiple-endocrine-neoplasia","men2-syndrome","pancreatic-net","pituitary-tumours","lung-net","parathyroid-carcinoma"],"cancers":[],"sections":[],"technologies":["germline-testing"],"targets":["menin"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["men1-hereditary-net","hereditary-cancer-syndromes"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-thakker-j-clin-endocrinol-metab"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"Orphanet lists MEN1 as a rare disease (ORPHA:652). The 2012 international guideline gives no incidence figure in its abstract; first-degree relatives of a carrier have a 50 percent chance of inheriting the mutation (Thakker 2012). No GLOBOCAN estimate exists for a syndrome.","subtypes":["Classic MEN1 with parathyroid, pancreatic islet and pituitary tumours","MEN1 with thymic or bronchial neuroendocrine tumour","MEN1-associated parathyroid carcinoma (rare)","Phenocopies and MEN4 (CDKN1B) presenting like MEN1"],"biomarkers":["Germline MEN1 mutation (first-degree relatives have a 50 percent risk)","Calcium and parathyroid hormone","Gastrin, insulin and glucose, chromogranin A","Prolactin and insulin-like growth factor 1","Pancreatic and thymic imaging on the guideline surveillance schedule"],"standardOfCare":[{"setting":"All manifestations","approach":"Treated by manifestation as the parent page describes, with germline testing of relatives and lifelong multidisciplinary surveillance.","refs":["multiple-endocrine-neoplasia","germline-testing","men1-hereditary-net"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"multiple-endocrine-neoplasia"},{"id":"men2-syndrome","kind":"cancer","name":"Multiple endocrine neoplasia type 2 (MEN2A and MEN2B)","aka":["MEN2","MEN2A","MEN2B","MEN3","Sipple syndrome","Familial medullary thyroid carcinoma (MEN2A variant)","MEN2A (RET; medullary thyroid carcinoma, pheochromocytoma, parathyroid)","MEN2B (RET M918T; early MTC, pheochromocytoma, mucosal neuromas)"],"tldr":"MEN2 is an inherited condition, one of the multiple endocrine neoplasia syndromes, in which a faulty RET gene causes medullary thyroid cancer in almost every carrier, often with adrenal tumours and overactive parathyroids. Because the thyroid cancer is so predictable, children who inherit the gene have the thyroid removed at an age set by which RET mutation they carry.","summary":"MEN2 is caused by germline activating mutations in the RET proto-oncogene. The American Thyroid Association guideline divides it into MEN2A, with medullary thyroid carcinoma, phaeochromocytoma and primary hyperparathyroidism (and the variants with cutaneous lichen amyloidosis or Hirschsprung disease, and familial medullary thyroid carcinoma, now classed as an MEN2A variant), and MEN2B, with earlier and more aggressive medullary thyroid carcinoma, phaeochromocytoma, mucosal neuromas and a marfanoid habitus, almost always from the RET M918T mutation (Wells 2015). The WHO endocrine classification lists MEN2 among the genetic tumour syndromes.\n\nHow it differs from its parent: MEN1 is a menin syndrome centred on parathyroid, pancreas and pituitary; MEN2 is a RET syndrome whose defining cancer is medullary thyroid carcinoma, which the corpus covers on its own page. The guideline stratifies RET mutations into highest risk (M918T), high risk (codon 634 and A883F) and moderate risk, and times prophylactic thyroidectomy accordingly: in the first year of life for the highest-risk group, at or before age five for the high-risk group, and by calcitonin surveillance for the moderate group; phaeochromocytoma is excluded before any operation (Wells 2015).\n\nTreatment of established disease follows the medullary thyroid cancer page: total thyroidectomy with node dissection, and for advanced RET-driven disease the selective RET inhibitor selpercatinib, which beat cabozantinib or vandetanib in the LIBRETTO-531 trial linked from the parent page; phaeochromocytoma and hyperparathyroidism are treated as in sporadic disease. The genotype-phenotype rules hold in practice: a single-centre series of 158 MEN2 patients tested the guideline's predictions against observed ages of onset (Cancers 2024, PMID 38339246).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia_type_2","links":[{"label":"NCI: multiple endocrine neoplasia (MEN) syndromes","url":"https://www.cancer.gov/types/multiple-endocrine-neoplasia"},{"label":"Wells 2015, Thyroid: revised American Thyroid Association guidelines for medullary thyroid carcinoma","url":"https://doi.org/10.1089/thy.2014.0335"},{"label":"Orphanet: multiple endocrine neoplasia type 2 (ORPHA:653)","url":"https://www.orpha.net/en/disease/detail/653"},{"label":"Genotype-specific phenotype in MEN2 against the guideline predictions, Cancers 2024","url":"https://doi.org/10.3390/cancers16030494"}],"tags":["subtype-page","wave4","rare"],"related":["multiple-endocrine-neoplasia","men1-syndrome","medullary-thyroid-cancer","hereditary-ppgl","pheochromocytoma-paraganglioma"],"cancers":[],"sections":[],"technologies":["germline-testing"],"targets":["ret"],"drugs":["selpercatinib","vandetanib","cabozantinib"],"companies":[],"institutions":[],"pathways":[],"terms":["thyroidectomy","hereditary-cancer-syndromes"],"trials":["libretto-531"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"Orphanet lists MEN2 as a rare disease (ORPHA:653). The American Thyroid Association guideline is the source for its clinical figures; no population incidence is given in the sources read, and GLOBOCAN counts medullary thyroid cancer within thyroid cancer.","subtypes":["MEN2A, classical (medullary thyroid carcinoma, phaeochromocytoma, hyperparathyroidism)","MEN2A with cutaneous lichen amyloidosis or Hirschsprung disease","Familial medullary thyroid carcinoma (an MEN2A variant in the ATA classification)","MEN2B (RET M918T; mucosal neuromas, marfanoid habitus)"],"biomarkers":["Germline RET mutation and its ATA risk category (highest, high, moderate)","Serum calcitonin and carcinoembryonic antigen","Plasma or urine metanephrines before any surgery","Calcium and parathyroid hormone"],"standardOfCare":[{"setting":"Gene carriers","approach":"Prophylactic thyroidectomy timed by RET risk category, after excluding phaeochromocytoma (ATA 2015).","refs":["thyroidectomy","ret","medullary-thyroid-cancer"]},{"setting":"Established medullary thyroid carcinoma","approach":"Treated as the medullary thyroid cancer page describes; selpercatinib for advanced RET-driven disease (LIBRETTO-531).","refs":["medullary-thyroid-cancer","selpercatinib","libretto-531"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"multiple-endocrine-neoplasia"},{"id":"multiple-myeloma","kind":"cancer","name":"Multiple myeloma","aka":[],"tldr":"Multiple myeloma is a plasma-cell cancer with more new drug classes than any other: proteasome inhibitors, IMiDs, CD38 antibodies, BCMA CAR-T, bispecifics, and an ADC.","summary":"Multiple myeloma is a cancer of antibody-producing plasma cells in the bone marrow, causing anaemia, bone destruction, kidney failure and infections. It is preceded by MGUS and smouldering myeloma, which are common (MGUS in ~3% of people over 50) and mostly harmless; whether to treat high-risk smouldering disease (AQUILA, daratumumab) is a live debate, and Iceland is screening its whole adult population (iStopMM). Staging (R-ISS/R2-ISS) and cytogenetics (del17p, t(4;14), 1q gain) drive prognosis; MRD negativity at one in a million marrow cells has become both the best prognostic marker and, since 2024, an accepted regulatory endpoint.\n\nNo cancer has gained more drug classes: proteasome inhibitors (bortezomib 2003, carfilzomib), immunomodulatory cereblon modulators (thalidomide, lenalidomide, pomalidomide; next-generation CELMoDs iberdomide and mezigdomide), CD38 antibodies (daratumumab, isatuximab), BCMA-directed CAR-T (ide-cel, cilta-cel; anito-cel decision December 2026), BCMA and GPRC5D bispecific T-cell engagers (teclistamab, elranatamab, linvoseltamab, talquetamab), a BCMA ADC (belantamab, withdrawn 2022 and re-approved 2025), plus XPO1 and BCL-2 inhibitors for subsets. Newly diagnosed patients receive a quadruplet (Dara-VRd or Isa-VRd) whether or not they proceed to autologous transplant (PERSEUS, CEPHEUS, IMROZ), then lenalidomide maintenance; median survival in fit patients now exceeds ten years. At relapse, cilta-cel (CARTITUDE-4, OS HR 0.55) and teclistamab plus daratumumab (MajesTEC-3, approved March 2026) are second-line options, with sequencing by prior antigen exposure.\n\nThe frontier is replacing transplant and indefinite maintenance with a single CAR-T infusion (CARTITUDE-5/6), MRD-guided stopping of therapy, trispecifics and combinations that pre-empt antigen escape, and CELMoDs that restore sensitivity after lenalidomide. The hard problems are high-risk cytogenetics and extramedullary disease, which respond briefly to everything; infections and prolonged cytopenias from T-cell redirection; delayed neurotoxicity after BCMA CAR-T; cost and manufacturing slots; and the fact that the disease still relapses in almost everyone eventually, so 'functional cure' remains a claim to be proven.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Multiple_myeloma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Multiple_myeloma"}],"tags":["heme","spike"],"related":["cd38-plus-triplet","bcma-then-gprc5d","bispecific-infection-prophylaxis","mmrf"],"cancers":[],"sections":[],"technologies":["car-t","t-cell-engager","adc","protac-degrader","whole-body-mri","mrd-testing","autologous-stem-cell-transplant","monoclonal-antibody","fdg-pet"],"targets":["bcma","gprc5d","cd38","cd3","tp53"],"drugs":["elotuzumab","panobinostat","sipuleucel-t","fluciclovine-f18","aminolevulinic-acid-gleolan","pegulicianine","clonoseq","carmustine","palifermin"],"companies":["nanjing-leads-biolabs","celltrion","chongqing-precision-biotech","shanghai-abelzeta","johnson-johnson","legend-biotech","bms","pfizer","regeneron","gsk","sanofi","amgen","takeda","gilead","genmab"],"institutions":["mskcc","dana-farber","mayo-clinic","md-anderson","mount-sinai"],"pathways":[],"terms":["r-iss","high-risk-myeloma","mrd-negativity-myeloma","smoldering-myeloma","mrd","crs","icans"],"trials":["nct07555938","nct07258511","nct07518186","nct07452198","nct07138209","quintessential-2","nct07297329","nct07579234","nct06508983","nct06868654","nct05730036","nct06952478","nct06464991","nct03844048","nct06956170","nct05438043","nct05572515","nct05623020","nct05827016","nct06152575","nct03539744","nct05519085","nct06514508","nct04975997","nct04162210","nct06413498","nct06158841","nct05020236","nct07095452","nct03246529","nct06208150","nct06679101","nct06868667","nct05552976","nct05317416","nct05552222","nct06045806","nct05455320","nct07393282","nct04270409","nct06980480","nct07742215"],"people":["maria-victoria-mateos","meletios-dimopoulos"],"bottlenecks":[],"keyPapers":[],"journals":["blood-cancer-discovery","blood-cancer-journal","clinical-lymphoma-myeloma-and-leukemia","current-hematologic-malignancy-reports","haematologica","journal-of-hematology-and-oncology"],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Multiple myeloma causes ~190,000 new cases a year worldwide, ~36,000 in the US, at a median age of 69. More new drug classes than any other cancer have pushed median survival to more than 10 years in transplant-eligible patients and ~5-7 years in older patients; ~120,000 deaths a year worldwide.","subtypes":["Standard-risk vs high-risk cytogenetics (IMS 2024 definition)","Transplant-eligible vs transplant-ineligible (fitness, not age alone)","Extramedullary disease (soft-tissue plasmacytomas; harder to control, a focus of CAR-T and bispecific trials)","Plasma cell leukaemia (≥5% circulating plasma cells)","Light-chain only, IgA, IgG, non-secretory","Smouldering myeloma and MGUS (precursors)","Triple-class refractory / penta-refractory","BCMA-exposed vs BCMA-naive at relapse"],"biomarkers":["Cytogenetics (del17p, t(4;14), 1q gain)","R-ISS","MRD (NGS/flow)","BCMA/GPRC5D expression","Serum and urine M-protein, free light chains","R-ISS / R2-ISS (β2-microglobulin, albumin, LDH, FISH)","FISH: del(17p), t(4;14), t(14;16), t(14;20), 1q gain/amp, del(1p)","TP53 mutation","MRD by NGS (clonoSEQ) or next-generation flow at 10⁻⁵ to 10⁻⁶","PET-CT and whole-body MRI (IMWG imaging)","BCMA and GPRC5D expression / TNFRSF17 loss at relapse","Renal function, calcium, haemoglobin (CRAB criteria)","Soluble BCMA (research)"],"standardOfCare":[{"setting":"Newly diagnosed","approach":"Dara-VRd ± ASCT → lenalidomide maintenance.","refs":["whole-body-mri"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Relapsed","approach":"CAR-T or bispecific; belantamab combinations; sequencing by prior exposure.","refs":["ciltacabtagene-autoleucel","teclistamab","belantamab-mafodotin"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"MGUS / low-risk smouldering","approach":"Observation with periodic labs; no treatment outside trials.","refs":["smoldering-myeloma","istopmm"],"guideline":{"nccn":"Observation","version":"NCCN Multiple Myeloma 2026"}},{"setting":"High-risk smouldering myeloma","approach":"Consider daratumumab monotherapy (AQUILA) or lenalidomide (E3A06), or trial enrolment; shared decision given indolent course in many.","refs":["daratumumab","lenalidomide","smoldering-myeloma"],"guideline":{"nccn":"Category 2A (daratumumab or lenalidomide for high-risk SMM)","version":"NCCN 2026"}},{"setting":"Newly diagnosed, transplant-eligible","approach":"Dara-VRd (or Isa-VRd) induction × 4-6 → stem-cell collection → high-dose melphalan + autologous transplant → Dara-VRd consolidation → lenalidomide (± daratumumab) maintenance; MRD-guided de-escalation emerging (PERSEUS design). Tandem transplant or extended therapy for high risk.","refs":["perseus","daratumumab","bortezomib","lenalidomide","autologous-stem-cell-transplant","mrd-negativity-myeloma"],"guideline":{"nccn":"Category 1 (Dara-VRd)","esmoMcbs":"A","version":"NCCN 2026 / EHA-ESMO 2021 update"}},{"setting":"Newly diagnosed, transplant-ineligible","approach":"Dara-VRd (CEPHEUS) or Isa-VRd (IMROZ) with bortezomib de-escalation after induction; Dara-Rd (MAIA) for frailer patients; continuous therapy with dose adjustment for frailty.","refs":["cepheus","imroz","daratumumab","isatuximab","lenalidomide"],"guideline":{"nccn":"Category 1","version":"NCCN 2026"}},{"setting":"Maintenance","approach":"Lenalidomide until progression (CALGB 100104, Myeloma XI); daratumumab added for high-risk or per PERSEUS; MRD-guided discontinuation in trials (DRAMMATIC, MASTER); iberdomide maintenance (EXCALIBER) pending.","refs":["lenalidomide","daratumumab","iberdomide","idea-mrd-guided-stop-myeloma","drammatic"]},{"setting":"First relapse (1-3 prior lines)","approach":"Cilta-cel if lenalidomide-refractory (CARTITUDE-4); teclistamab + daratumumab (MajesTEC-3, 2026); ide-cel after ≥2 lines; belantamab-Vd or -Pd (DREAMM-7/8); CD38-based triplets (Dara-Kd, Isa-Kd, Dara-Pd) by prior exposure; carfilzomib or pomalidomide combinations.","refs":["ciltacabtagene-autoleucel","cartitude-4","teclistamab","majestec-3","idecabtagene-vicleucel","karmma-3","belantamab-mafodotin","dreamm-7","dreamm-8","carfilzomib"],"guideline":{"nccn":"Category 1 (cilta-cel ≥1 line; tec-dara ≥1 line)","version":"NCCN 2026"}},{"setting":"Triple-class refractory (≥3-4 prior lines)","approach":"BCMA CAR-T if not yet given; bispecifics (teclistamab, elranatamab, linvoseltamab; talquetamab after BCMA exposure); belantamab; selinexor-based; CELMoDs in trials; anito-cel (PDUFA Dec 2026).","refs":["teclistamab","elranatamab","linvoseltamab","talquetamab","belantamab-mafodotin","mezigdomide","anitocabtagene-autoleucel","bcma-then-gprc5d"]},{"setting":"Supportive care","approach":"Bisphosphonate or denosumab for bone disease; IVIG, antiviral, PJP prophylaxis and vaccination during T-cell redirection; thromboprophylaxis with IMiDs; renal protection; radiotherapy for painful lesions or cord compression.","refs":["bispecific-infection-prophylaxis","imrt-igrt"]}],"stateOfArt":["CAR-T in second line.","Bispecifics after one prior line (2026).","Functional cure discussions.","Quadruplet induction (CD38 antibody + PI + IMiD + dexamethasone) for all newly diagnosed patients, with MRD negativity in 60-75%.","CAR-T with a survival benefit as early as second line (CARTITUDE-4, OS HR 0.55) and a third of late-line patients progression-free at five years without maintenance (CARTITUDE-1).","Two antigens for T-cell redirection (BCMA, GPRC5D) with four approved bispecifics; teclistamab plus daratumumab approved at first relapse (March 2026).","MRD negativity accepted by FDA as an endpoint for accelerated approval (2024), enabling faster trials and MRD-guided therapy.","Belantamab returned after withdrawal on the strength of two positive phase 3s, a rare regulatory reversal.","Nationwide precursor screening (iStopMM) and precursor treatment (AQUILA) are redefining where 'myeloma care' begins."],"history":[{"year":1844,"title":"First described case (Solly); Bence Jones protein 1847","refs":[]},{"year":1958,"title":"Melphalan introduced; melphalan-prednisone standard for 40 years","refs":["cytotoxic-chemotherapy"]},{"year":1983,"title":"High-dose melphalan with autologous marrow rescue (McElwain)","refs":["autologous-stem-cell-transplant"]},{"year":1996,"title":"IFM 90: transplant improves survival over chemotherapy","refs":["autologous-stem-cell-transplant"]},{"year":1999,"title":"Thalidomide shown active in refractory myeloma (Singhal, NEJM)","refs":[]},{"year":2003,"title":"Bortezomib approved","refs":[]},{"year":2003,"title":"Bortezomib: first proteasome inhibitor approved","refs":["bortezomib"]},{"year":2006,"title":"Lenalidomide approved","refs":["lenalidomide"]},{"year":2012,"title":"Carfilzomib approved; International Staging refined","refs":["carfilzomib"]},{"year":2015,"title":"Daratumumab approved","refs":[]},{"year":2015,"title":"Daratumumab: first CD38 antibody; R-ISS published","refs":["daratumumab","r-iss"]},{"year":2019,"title":"MAIA: Dara-Rd improves survival in transplant-ineligible disease","refs":["daratumumab"]},{"year":2020,"title":"Belantamab mafodotin: first BCMA ADC (accelerated; withdrawn 2022)","refs":["belantamab-mafodotin"]},{"year":2021,"title":"Ide-cel: first myeloma CAR-T","refs":[]},{"year":2021,"title":"Ide-cel: first myeloma CAR-T; CARTITUDE-1 shows 98% response","refs":["idecabtagene-vicleucel","cartitude-1"]},{"year":2022,"title":"Teclistamab: first myeloma bispecific","refs":["teclistamab"]},{"year":2022,"title":"Teclistamab: first myeloma bispecific; cilta-cel approved","refs":["teclistamab","majestec-1","ciltacabtagene-autoleucel"]},{"year":2023,"title":"CARTITUDE-4 and KarMMa-3 move CAR-T earlier; elranatamab and talquetamab approved","refs":["cartitude-4","karmma-3","elranatamab","talquetamab"]},{"year":2024,"title":"PERSEUS quadruplet approved; FDA accepts MRD as an endpoint; DREAMM-7/8 positive; cilta-cel and ide-cel approved after 1-2 lines","refs":["perseus","mrd-negativity-myeloma","dreamm-7","dreamm-8"]},{"year":2025,"title":"Linvoseltamab approved; belantamab re-approved; IMROZ/CEPHEUS labels; iMMagine-1 reports 97% ORR","refs":["linvoseltamab","linker-mm1","belantamab-mafodotin","imroz","cepheus","immagine-1"]},{"year":2026,"title":"Teclistamab after ≥1 line; isatuximab SC","refs":[]},{"year":2026,"title":"Teclistamab + daratumumab approved after ≥1 line (MajesTEC-3); isatuximab subcutaneous; anito-cel BLA accepted (PDUFA December)","refs":["majestec-3","isatuximab","anitocabtagene-autoleucel"]}],"pipeline":["teclistamab","ciltacabtagene-autoleucel","cevostamab","jnj-79635322","purinostat","gr1803","qls32015","arlocabtagene-autoleucel","sctc21c","f182112","sg301","gc012f","azd4045","sti-6129","feladilimab","anitocabtagene-autoleucel","immagine-1","cartitude-5","iberdomide","mezigdomide","talquetamab","linvoseltamab","elranatamab","istopmm","idea-mrd-guided-stop-myeloma","idea-car-t-replaces-transplant","bcma-then-gprc5d","mrd-negativity-myeloma","belantamab-mafodotin"],"openProblems":["High-risk cytogenetics.","Infections with T-cell redirecting therapy.","Cost and access.","High-risk cytogenetics and extramedullary disease respond briefly to every class; no regimen closes the gap.","Infections are the main safety problem on bispecifics; hypogammaglobulinaemia and T-cell exhaustion need better mitigation than IVIG and dose de-intensification.","Delayed neurotoxicity (parkinsonism, cranial neuropathies) after BCMA CAR-T and second primary malignancies after cereblon modulators and CAR-T.","Sequencing after BCMA failure: antigen loss (TNFRSF17 deletion) versus T-cell fitness; how to combine or alternate BCMA and GPRC5D agents.","Is transplant still needed? CARTITUDE-6 will answer; until then most fit patients receive high-dose melphalan.","Whether MRD-guided stopping is safe; whether MRD negativity at 10⁻⁶ equals cure for anyone.","Precursor disease: treating high-risk smouldering myeloma prevents progression but may over-treat; population screening's mortality effect is unknown.","Cost and capacity: CAR-T slots, bispecific hospitalisation for step-up dosing, and lifelong therapy costs strain every health system."],"prognosis":{"text":"In the United States, 63.7% of people diagnosed with myeloma in 2016-2022 were alive five years later, relative to people of the same age without the disease. Myeloma is a cancer of the bone marrow and is almost always systemic at diagnosis (96% of cases are recorded as distant), so stage-by-stage tables say little; risk is set instead by the Revised ISS, cytogenetics and fitness for transplant. The figures predate CAR-T and bispecific antibodies and are improving with each new line of treatment.","sources":[{"label":"SEER Cancer Stat Facts: Myeloma","url":"https://seer.cancer.gov/statfacts/html/mulmy.html"}]}},{"id":"lch-multisystem","kind":"cancer","name":"Multisystem Langerhans cell histiocytosis (with or without risk-organ involvement)","aka":["Multisystem LCH","MS-LCH","Risk-organ-positive LCH","Letterer-Siwe disease (obsolete)","Hand-Schüller-Christian disease (obsolete)"],"tldr":"Multisystem Langerhans cell histiocytosis is the severe form of this rare histiocytosis, in which the abnormal cells involve several organs at once, most dangerously the liver, spleen and bone marrow of infants. It is treated with a year of vinblastine and prednisone, with stronger drugs or BRAF-targeted tablets for children who do not respond quickly; survival is now high but late effects remain.","summary":"Multisystem Langerhans cell histiocytosis involves two or more organ systems, typically skin, bone, lymph nodes, pituitary, lungs and, in the highest-risk children, the liver, spleen and haematopoietic system. Risk-organ involvement, defined by hepatomegaly with liver dysfunction, splenomegaly or cytopenias, and a poor response to the first six weeks of therapy are the two strongest predictors of death; the mortality of risk-organ-positive disease has fallen from more than half in the 1980s to a small minority in the era of standardised protocols and salvage therapy. BRAF V600E is present in most multisystem cases, and the mutant clone can be traced to haematopoietic progenitors in the marrow, which explains why high-risk disease behaves like a systemic myeloid neoplasm; circulating BRAF V600E DNA tracks disease burden and predicts relapse.\n\nThe Histiocyte Society trials built the standard. LCH-I and LCH-II established vinblastine and prednisone as the backbone; LCH-III (Blood 2013), which randomised 376 patients, showed that adding methotrexate did not help but that extending treatment from six to twelve months roughly halved reactivation, and that children who respond by week six do well. For children with risk-organ disease who do not respond, cytarabine and cladribine (LCH-S-2005) or, in the most refractory, the intensive cladribine-cytarabine regimen followed by reduced-intensity allogeneic transplantation are salvage options, and the ongoing LCH-IV trial tests longer and intensified therapy. BRAF inhibitors changed refractory disease: vemurafenib and dabrafenib produce rapid responses in BRAF V600E-mutant children, including infants with risk-organ disease, though the disease returns when they stop, and cobimetinib is approved for adults with histiocytic neoplasms; combining targeted agents with chemotherapy to achieve durable remissions is the current trial question. Survivors face diabetes insipidus and anterior pituitary deficiency in a substantial minority, neurodegenerative disease years later, sclerosing cholangitis, hearing loss and orthopaedic problems, so structured long-term follow-up is standard.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosis","links":[{"label":"LCH-III (Blood 2013)","url":"https://doi.org/10.1182/blood-2012-09-455774"},{"label":"NCI PDQ Langerhans cell histiocytosis","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosis"}],"tags":["subtype-page","paediatric"],"related":["lch-single-system","langerhans-cell-histiocytosis","erdheim-chester-disease"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","kinase-inhibitors","allogeneic-hsct","mri","ultrasound","liquid-biopsy","survivorship-care-plan"],"targets":["braf"],"drugs":["vinblastine","cladribine","vemurafenib","dabrafenib-trametinib","cobimetinib"],"companies":[],"institutions":[],"pathways":[],"terms":["late-effects","braf-v600-mutation","cytopenias"],"trials":["lch-iii"],"people":[],"bottlenecks":[],"keyPapers":["paper-lch-iii-therapy-prolongation-multisystem-lch-blood-2013","paper-donadieu-vemurafenib-refractory-multisystem-lch-jco-2019","paper-badalian-very-braf-mutations-lch-blood-2010"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About a third of childhood Langerhans cell histiocytosis, commonest in infants and toddlers; involvement of the liver, spleen or bone marrow (risk organs) once carried high mortality and still marks the group that needs intensive treatment.","subtypes":["Multisystem Langerhans cell histiocytosis without risk-organ involvement (vinblastine and prednisone)","Multisystem Langerhans cell histiocytosis with risk-organ involvement (liver, spleen, bone marrow)","Refractory or non-responding multisystem Langerhans cell histiocytosis (cytarabine, cladribine, BRAF inhibitors)","Central nervous system risk lesions and pituitary Langerhans cell histiocytosis (diabetes insipidus)","Neurodegenerative Langerhans cell histiocytosis (late complication)","Adult multisystem Langerhans cell histiocytosis (cytarabine or cladribine based)"],"biomarkers":["Risk-organ involvement at diagnosis (liver, spleen, cytopenias)","Response at week six (LCH-III)","BRAF V600E in tissue and cell-free DNA (burden, relapse)","MAP2K1 and other MAPK alterations","Pituitary MRI, water deprivation testing and anterior pituitary hormones","Brain MRI for neurodegenerative change; liver imaging for sclerosing cholangitis"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Biopsy with BRAF testing; blood count, liver tests, coagulation, abdominal ultrasound, skeletal survey or whole-body MRI, pituitary assessment.","refs":["braf-v600-mutation","mri","ultrasound","histopathology-ihc"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}},{"setting":"First line","approach":"Vinblastine and prednisone induction for six to twelve weeks, then continuation to twelve months in total (LCH-III); mercaptopurine added for risk-organ disease in some protocols.","refs":["vinblastine","lch-iii","cytotoxic-chemotherapy"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}},{"setting":"Non-response at week six or risk-organ progression","approach":"Switch to cytarabine or cladribine; intensive cladribine-cytarabine for refractory risk-organ disease; BRAF inhibitor (vemurafenib, dabrafenib) for BRAF V600E-mutant disease; reduced-intensity allogeneic transplantation in selected cases.","refs":["cladribine","vemurafenib","dabrafenib-trametinib","allogeneic-hsct"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}},{"setting":"Reactivation","approach":"Repeat vinblastine-prednisone or cytarabine; targeted therapy for repeated reactivation; enrolment in LCH-IV.","refs":["vinblastine","cladribine","vemurafenib"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}},{"setting":"Long-term follow-up","approach":"Endocrine, neurological, hearing, hepatic and orthopaedic surveillance for late effects through a survivorship programme.","refs":["late-effects","survivorship-care-plan","mri"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}}],"stateOfArt":["Standardised vinblastine-prednisone protocols and salvage therapy have made death rare even in risk-organ disease.","BRAF inhibitors rescue refractory infants but do not yet cure.","Circulating BRAF V600E DNA gives a marker of residual disease."],"history":[{"year":1924,"title":"Letterer describes the acute disseminated disease of infants","refs":[]},{"year":1991,"title":"LCH-I opens as the first international randomised trial in the disease","refs":["vinblastine"]},{"year":2010,"title":"BRAF V600E discovered in Langerhans cell histiocytosis","refs":["braf","ras-mapk"]},{"year":2013,"title":"LCH-III: twelve months of therapy halves reactivation; methotrexate adds nothing","refs":["lch-iii","vinblastine"]},{"year":2019,"title":"Vemurafenib reported to produce responses in refractory BRAF-mutant children","refs":["vemurafenib"]},{"year":2022,"title":"Cobimetinib approved for adults with histiocytic neoplasms including Langerhans cell histiocytosis","refs":["cobimetinib"]}],"pipeline":["dabrafenib-trametinib","vemurafenib","lch-iii","cobimetinib"],"openProblems":["Targeted therapy controls but does not cure; how to stop it safely is unknown.","Neurodegenerative disease appears years later and has no proven treatment.","Reactivation affects a third or more of children despite twelve months of therapy.","Adults are treated by extrapolation from paediatric protocols."],"parent":"langerhans-cell-histiocytosis"},{"id":"muscle-invasive-bladder-cancer","kind":"cancer","name":"Muscle-invasive and advanced bladder cancer","aka":["MIBC","Invasive urothelial carcinoma","Metastatic urothelial carcinoma"],"tldr":"Once bladder cancer has grown into the muscle it needs more than scraping out: chemotherapy then removal of the bladder, or chemoradiation to keep it. For cancer that has spread, the antibody-drug conjugate enfortumab vedotin with pembrolizumab has replaced platinum chemotherapy as the first treatment.","summary":"Muscle-invasive urothelial carcinoma is treated with cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy and urinary diversion, or by trimodality bladder preservation (maximal resection plus chemoradiation) in suitable patients. Perioperative immunotherapy has entered practice: adjuvant nivolumab after cystectomy (CheckMate 274) and durvalumab with neoadjuvant chemotherapy and after surgery (NIAGARA), which improved overall survival. For metastatic disease, enfortumab vedotin with pembrolizumab nearly doubled survival compared with platinum chemotherapy (EV-302) and became the standard first-line treatment in 2023; erdafitinib is used for FGFR3-altered tumours, and platinum chemotherapy followed by avelumab maintenance remains an option. Molecular subtypes (luminal, basal) and circulating tumour DNA are being used to select who needs adjuvant treatment.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Bladder_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Bladder_cancer"}],"tags":["subtype-page"],"related":["non-muscle-invasive-bladder-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-niagara-nejm-2024","paper-ev-302-nejm-2024","paper-swog-8710-neoadjuvant-mvac-nejm-2003","paper-javelin-bladder-100-nejm-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"About a quarter of bladder cancers at diagnosis plus those that progress from superficial disease; half of patients with muscle invasion die of it within five years despite surgery, and metastatic disease had a median survival near a year until antibody-drug conjugates and immunotherapy changed it.","subtypes":["Muscle-invasive, organ-confined (T2)","Locally advanced (T3 to T4, node-positive)","Metastatic urothelial carcinoma","FGFR3-altered urothelial carcinoma","Variant histologies (squamous, small cell, plasmacytoid, micropapillary)"],"biomarkers":["Cisplatin eligibility (kidney function, hearing, performance status)","PD-L1 expression (selects immunotherapy in some settings)","FGFR3 mutations and fusions (erdafitinib)","Nectin-4 expression (near universal; enfortumab vedotin target)","Circulating tumour DNA after cystectomy (adjuvant selection)"],"standardOfCare":[{"setting":"Muscle-invasive, cisplatin-eligible","approach":"Neoadjuvant cisplatin-based chemotherapy (dose-dense MVAC or gemcitabine-cisplatin) with durvalumab (NIAGARA), then radical cystectomy with lymph node dissection and adjuvant durvalumab; adjuvant nivolumab for high-risk residual disease (CheckMate 274).","refs":["cisplatin","gemcitabine","durvalumab","niagara","cystectomy","nivolumab","checkmate-274"]},{"setting":"Bladder preservation","approach":"Maximal transurethral resection followed by chemoradiation, with salvage cystectomy for recurrence, in patients with unifocal tumours and no carcinoma in situ or in those unfit for surgery.","refs":["imrt-igrt","radiosensitisers","cisplatin"]},{"setting":"Metastatic, first line","approach":"Enfortumab vedotin plus pembrolizumab (EV-302); gemcitabine-platinum followed by avelumab maintenance where the combination is unavailable.","refs":["enfortumab-vedotin","pembrolizumab","ev-302"]},{"setting":"Later lines","approach":"Erdafitinib for FGFR3 alterations; platinum chemotherapy or enfortumab vedotin if not given first line; clinical trials.","refs":["erdafitinib","fgfr3-receptor","enfortumab-vedotin"]}],"stateOfArt":["EV-302 was the first trial in forty years to beat platinum chemotherapy first line, and it did so by a wide margin.","Perioperative immunotherapy now improves survival around cystectomy, and circulating tumour DNA promises to select who needs it.","Bladder preservation with chemoradiation gives survival similar to cystectomy in selected patients and is under-used."],"history":[{"year":1985,"title":"MVAC chemotherapy established for advanced disease","refs":["cisplatin"]},{"year":2003,"title":"Neoadjuvant MVAC improves survival before cystectomy (SWOG 8710)","refs":["cisplatin"]},{"year":2016,"title":"Atezolizumab: first immunotherapy approval in bladder cancer","refs":[]},{"year":2019,"title":"Erdafitinib: first targeted drug for FGFR3-altered urothelial cancer","refs":["erdafitinib"]},{"year":2021,"title":"Adjuvant nivolumab (CheckMate 274)","refs":["checkmate-274"]},{"year":2023,"title":"EV-302: enfortumab vedotin plus pembrolizumab replaces platinum first line","refs":["ev-302"]},{"year":2024,"title":"NIAGARA: perioperative durvalumab improves survival","refs":["niagara"]}],"pipeline":["durvalumab","erdafitinib","enfortumab-vedotin"],"openProblems":["Cisplatin-ineligible patients still have fewer options.","Choosing between cystectomy and bladder preservation lacks randomised evidence.","Variant histologies are excluded from most trials.","Cost and access to antibody-drug conjugates."],"parent":"urothelial"},{"id":"mycosis-fungoides","kind":"cancer","name":"Mycosis fungoides","aka":["MF","Mycosis fungoides / Sezary syndrome (CTCL)","Alibert-Bazin syndrome","Granuloma fungoides","Folliculotropic mycosis fungoides","Pagetoid reticulosis","Granulomatous slack skin"],"tldr":"The commonest cutaneous T-cell lymphoma, and a disease that behaves like a long-term skin condition for most of the people who have it: flat scaly patches that have often been treated as eczema or psoriasis for years before anyone takes a biopsy. In its early stages life expectancy is close to normal, and the treatment is creams and light rather than chemotherapy.","summary":"What it is. A lymphoma of mature T cells that lives in the skin. It begins as flat, scaly, often itchy patches, classically on parts of the body the sun does not reach, and over years some people develop raised plaques and then tumours. A minority develop redness over most of the body, and a minority have lymphoma cells in the blood, at which point it overlaps with Sezary syndrome. It is the commonest of the cutaneous T-cell lymphomas.\n\nThe diagnosis is slow and that is normal. Early mycosis fungoides looks like eczema, psoriasis or a drug rash, and the biopsy is often not diagnostic until the disease is established. Several biopsies over several years, read by a dermatopathologist alongside photographs and the history, are the usual route to the diagnosis, and that is not a failure of care. WHO-HAEM5 states the principle for the whole group of skin lymphomas: because the appearances overlap, dermatological examination and clinical photographic documentation are indispensable.\n\nHow it is staged, and why the stage matters more than usual. The system in use is the revised ISCL and EORTC staging of 2007, which classifies the skin (patches or plaques covering under or over a tenth of the body surface, tumours, or redness over most of the body), the lymph nodes, the internal organs and the blood. The validation study in 1,502 patients confirmed that the resulting stages separate survival, and found something the earlier system had missed: among people with early skin disease, those with patches alone did significantly better than those with patches and plaques, which is why the stage now records the difference.\n\nThe things that predict the course. In that study, advanced skin stage, the presence of the tumour clone in the blood without full-blown Sezary cells, a raised lactate dehydrogenase and the folliculotropic form were each independently associated with worse survival. In the other direction, the pale form, the mottled form and mycosis fungoides occurring with lymphomatoid papulosis were associated with better survival and less risk of progression. Large-cell transformation, where the cells in a lesion become large and more aggressive, is a specific event that changes the treatment.\n\nThe variants. WHO-HAEM5 keeps the variants of mycosis fungoides as subtypes and makes one change: within the folliculotropic form, which involves the hair follicles and is harder to treat because creams and light do not reach deeply enough, early and advanced clinical patterns are now distinguished because they behave differently.\n\nWhat it means for a person. Early-stage mycosis fungoides, which is most of it, has a life expectancy close to that of the general population and is treated with creams, light and occasionally small doses of radiotherapy, over decades. Treating early disease with chemotherapy shortens neither the disease nor anything else and causes harm. Advanced disease, meaning tumours, widespread redness, or involvement of the nodes, organs or blood, needs systemic treatment and is a different situation: in a cohort of 168 people with advanced mycosis fungoides or Sezary syndrome, median survival was 2.47 years, and those started on biological treatments rather than combination chemotherapy lived longer. The treatment rows for every stage are on the cutaneous T-cell lymphoma page, which is the hub this record sits under.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Mycosis_fungoides","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"Survival outcomes and prognostic factors in mycosis fungoides and Sezary syndrome, validation of the revised ISCL/EORTC staging proposal in 1,502 patients (Agar, J Clin Oncol 2010)","url":"https://doi.org/10.1200/JCO.2009.27.7665"},{"label":"Advanced-stage mycosis fungoides and Sezary syndrome, survival and response to treatment in 168 patients (Clinical Lymphoma Myeloma and Leukemia 2015)","url":"https://doi.org/10.1016/j.clml.2015.02.027"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["cutaneous-t-cell-lymphoma","sezary-syndrome","primary-cutaneous-anaplastic-large-cell-lymphoma","lymphomatoid-papulosis","peripheral-t-cell-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","total-skin-electron-therapy","palliative-radiotherapy","allogeneic-hsct"],"targets":["cd30"],"drugs":["mechlorethamine","bexarotene","mogamulizumab","brentuximab-vedotin","methotrexate","interferon-alfa","romidepsin","vorinostat","denileukin-diftitox","methoxsalen-ecp","imiquimod","pegylated-liposomal-doxorubicin"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-tx-skin-directed-therapy","lymphoma-indolent-versus-aggressive","lymphoma-classification-2022","lymphoma-nodal-versus-extranodal","lymphoma-tx-radiotherapy","lymphoma-transformation","lymphoma-tx-uk-access"],"trials":["alcanza","mavoric"],"people":[],"bottlenecks":[],"keyPapers":["paper-olsen-mycosis-fungoides-staging-blood-2007"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"In the United Kingdom population series that reports lymphoma by subtype, 39 of 5,796 lymphomas were mycosis fungoides, a European age-standardised rate of 0.12 per 100,000 a year, with men affected about 2.7 times as often as women and a median age at diagnosis of 65.8 years; five-year relative survival in that series was 86.6 per cent. In the international cohort of 1,502 people with mycosis fungoides or Sezary syndrome that validated the current staging system, the mean age at diagnosis was 54 years, 71 per cent presented with early-stage disease, the disease progressed in 34 per cent and 26 per cent died of it.","subtypes":["Classic mycosis fungoides, with patches, plaques and sometimes tumours","Folliculotropic mycosis fungoides, which involves the hair follicles; WHO-HAEM5 distinguishes early from advanced clinical patterns within it","Pagetoid reticulosis, a localised form","Granulomatous slack skin","Hypopigmented, poikilodermatous and other clinical variants, several of which carry a better outlook","Large-cell transformation, which is an event rather than a variant and changes the treatment"],"biomarkers":["The revised ISCL and EORTC stage of 2007, covering skin, nodes, viscera and blood","Patches alone against patches and plaques within early skin stage, which separates survival","The folliculotropic variant, independently associated with worse survival","The tumour clone detectable in the blood without Sezary cells, which is independently associated with worse survival","Lactate dehydrogenase","Large-cell transformation on a repeat biopsy of a changing lesion","CD30 expression, which decides whether brentuximab vedotin is an option"],"standardOfCare":[{"setting":"Mycosis fungoides: staging first, because stage decides everything","approach":"Mycosis fungoides is staged by the ISCL/EORTC TNMB system, which classifies skin (patches or plaques covering under or over 10 per cent of the body surface, tumours, erythroderma), nodes, viscera and blood. The staging revision of 2007 remains the basis of treatment choice and trial eligibility, and a validation study in a large cohort confirmed that the resulting stages separate survival.\n\nWhy it matters more here than in most cancers: early-stage mycosis fungoides (stage IA to IIA, patches and plaques without tumours or blood involvement) has a life expectancy close to that of the general population and is treated with creams and light, while advanced disease (tumour stage, erythroderma, nodal or blood involvement) needs systemic treatment. Treating early disease with chemotherapy shortens neither the disease nor anything else and causes harm, which is the single most important thing to get right.\n\nThe diagnosis itself is often slow, because early mycosis fungoides looks like eczema or psoriasis for years and the biopsy is frequently non-diagnostic until the disease is established. Repeated biopsies over time, read by a dermatopathologist, are normal and are not a failure.","refs":["paper-olsen-mycosis-fungoides-staging-blood-2007","lymphoma-tx-skin-directed-therapy","lymphoma-type"],"guideline":{"version":"NCCN Primary Cutaneous Lymphomas; ESMO; ISCL/EORTC staging","url":"https://doi.org/10.1200/JCO.2009.27.7665"}},{"setting":"Early-stage mycosis fungoides (IA to IIA): skin-directed treatment only","approach":"The aim is control of the skin with the least treatment that achieves it, over decades.\n\nTopical corticosteroids, potent or very potent, are first line for patches and plaques and clear a large proportion. Topical mechlorethamine (chlormethine) gel, approved in the United States on 23 August 2013 for stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma after prior skin-directed therapy, cleared index lesions in its pivotal randomised trial in 58.5 per cent of patients against 47.7 per cent with the traditional compounded ointment, meeting the non-inferiority bar; contact dermatitis is the main problem and is managed by reducing frequency rather than stopping. Topical bexarotene gel and topical carmustine are alternatives. Imiquimod is used for a small number of resistant plaques.\n\nPhototherapy is the mainstay for widespread patch and plaque disease: narrowband UVB for patches and thin plaques, PUVA (psoralen with UVA) for thicker plaques and follicular disease, given two or three times a week at a dermatology unit and then tapered to a maintenance schedule. Cumulative UV dose carries its own long-term skin cancer risk, which is the reason for tapering.\n\nLocalised radiotherapy at low dose, often 8 Gy in two fractions, clears an individual tumour or a resistant plaque quickly and can be repeated. Total skin electron beam therapy treats the whole skin surface and is reserved for extensive disease; low-dose schedules of 10 to 12 Gy are now preferred to the historic 30 to 36 Gy because they can be repeated.","refs":["mechlorethamine","bexarotene","carmustine","imiquimod","total-skin-electron-therapy","palliative-radiotherapy","lymphoma-tx-skin-directed-therapy","lymphoma-tx-radiotherapy","paper-study-201-jama-dermatol-2013"],"guideline":{"version":"NCCN Primary Cutaneous Lymphomas; ESMO; BAD/BSH primary cutaneous lymphoma guideline","url":"https://www.cancer.gov/types/lymphoma/hp/mycosis-fungoides-treatment-pdq"}},{"setting":"Advanced mycosis fungoides (IIB to IVB): systemic treatment, and what to reach for first","approach":"Systemic treatment is indicated for tumour-stage disease, erythroderma, nodal or visceral involvement, blood involvement, or skin disease that has failed skin-directed therapy. Single agents are preferred to combination chemotherapy, which produces fast responses that do not last and damages the immune system in a patient already prone to skin infection and sepsis.\n\nRetinoids and interferon. Oral bexarotene and interferon alfa are long-standing options, often combined with phototherapy; both are slow-acting and require monitoring of lipids and thyroid function in the case of bexarotene.\n\nMethotrexate at low weekly oral dose, which is inexpensive, familiar and effective in a proportion.\n\nMogamulizumab, an anti-CCR4 antibody approved in the United States on 8 August 2018. MAVORIC randomised 372 patients with previously treated mycosis fungoides or Sezary syndrome to mogamulizumab or vorinostat: median progression-free survival 7.7 against 3.1 months (hazard ratio 0.53) and overall response 28 against 5 per cent, with a response in the blood compartment of 68 per cent. It is therefore the drug of choice where the blood is involved.\n\nBrentuximab vedotin for CD30-expressing disease. ALCANZA randomised patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large cell lymphoma to brentuximab vedotin or to physician's choice of methotrexate or bexarotene: objective response lasting four months or more was 56.3 against 12.5 per cent and median progression-free survival 16.7 against 3.5 months. Peripheral neuropathy is the limiting toxicity.\n\nOther options: romidepsin, denileukin diftitox, which returned in 2024 as Lymphir for relapsed or refractory stage I to III disease after at least one systemic therapy, gemcitabine, pegylated liposomal doxorubicin, and allogeneic transplant with reduced-intensity conditioning, which is the only treatment that produces long remissions in advanced disease and is offered to younger fit patients.","refs":["paper-mavoric-mogamulizumab-lancet-oncol-2018","paper-alcanza-brentuximab-vedotin-lancet-2017","mogamulizumab","brentuximab-vedotin","bexarotene","interferon-alfa","methotrexate","romidepsin","vorinostat","denileukin-diftitox","gemcitabine","pegylated-liposomal-doxorubicin","allogeneic-hsct","lymphoma-tx-skin-directed-therapy"],"guideline":{"version":"NCCN Primary Cutaneous Lymphomas; ESMO; MAVORIC, ALCANZA","url":"https://www.cancer.gov/types/lymphoma/hp/mycosis-fungoides-treatment-pdq"}},{"setting":"Living with mycosis fungoides: itch, infection and the things that make the difference day to day","approach":"Itch is the symptom patients rank as the worst and it is undertreated. Emollients applied several times a day, potent topical steroids, sedating antihistamines at night, gabapentin or pregabalin for neuropathic itch, and aprepitant or mirtazapine in resistant cases. Controlling the disease is the most effective anti-itch treatment, which is an argument for treating skin disease that is not otherwise dangerous.\n\nInfection. Staphylococcus aureus colonises broken skin and is a common cause of both flares and sepsis; swabs, topical antiseptics, bleach baths and prompt antibiotics for cellulitis are part of routine care, and a patient with advanced disease and a fever is treated as an emergency.\n\nSkin care. Soap substitutes, lukewarm baths, cotton clothing, and avoidance of overheating. Photoprotection after phototherapy or radiotherapy.\n\nThe long view. Early-stage mycosis fungoides is a chronic skin disease to be managed rather than an emergency, and most people with it die of something else. That is worth saying out loud at diagnosis, because the word lymphoma does not sound like that.","refs":["lymphoma-tx-skin-directed-therapy","palliative-care","mechlorethamine","bexarotene"],"guideline":{"version":"NCCN Primary Cutaneous Lymphomas; BAD/BSH primary cutaneous lymphoma guideline","url":"https://www.cancer.gov/types/lymphoma/hp/mycosis-fungoides-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":1806,"title":"Described by Alibert","note":"Jean-Louis Alibert described the mushroom-like tumours that gave the disease its misleading name; it has nothing to do with fungal infection.","refs":[]},{"year":2007,"title":"The ISCL and EORTC staging revision","note":"The staging system was revised to classify skin, node, visceral and blood involvement separately, which remains the basis of treatment choice and trial eligibility.","refs":["paper-olsen-mycosis-fungoides-staging-blood-2007"]},{"year":2010,"title":"The staging validated in 1,502 patients","note":"The revised stages were shown to separate survival, and patients with patches alone were shown to do significantly better than those with patches and plaques within the same early stage.","refs":[]},{"year":2022,"title":"The folliculotropic form split by clinical pattern","note":"WHO-HAEM5 kept the variants of mycosis fungoides as subtypes and distinguished early from advanced clinical patterns within the folliculotropic category, because their outcomes differ.","refs":["lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["Nothing has been shown to change the natural history of early-stage mycosis fungoides, so every treatment given in early disease is for symptoms, and over-treatment is the commonest harm.","The time from first rash to diagnosis is measured in years, and no test identifies early mycosis fungoides reliably on a single biopsy.","Itch is the symptom people with this disease rank as the worst and there is no randomised trial of any treatment for it in mycosis fungoides.","Allogeneic transplant is the only treatment that produces long remissions in advanced disease, and no trial defines who should have it or when.","Early-stage mycosis fungoides has a life expectancy close to that of the general population and no treatment has been shown to change it, so every intervention in early disease is for symptoms; over-treatment is the commonest harm in this disease.","Itch is the symptom patients rank worst and there is no randomised trial of any anti-itch treatment in mycosis fungoides.","Allogeneic transplant is the only treatment that produces long remissions in advanced cutaneous T-cell lymphoma, and there is no trial defining who should have it or when."],"parent":"cutaneous-t-cell-lymphoma"},{"id":"mds","kind":"cancer","name":"Myelodysplastic syndromes / neoplasms (MDS)","aka":[],"tldr":"Bone-marrow disorders where blood cells are made badly and too few reach the blood; a third progress to acute leukaemia. Treatment ranges from transfusions and growth factors to hypomethylating drugs and, for the fit, transplant.","summary":"MDS are clonal myeloid neoplasms with ineffective haematopoiesis, cytopenias, dysplasia and variable risk of transformation to AML. Risk is stratified by IPSS-R and, since 2022, the molecular IPSS-M, which incorporates mutations (TP53 multi-hit, ASXL1, RUNX1, SF3B1 among 31 genes). The WHO 2022 and ICC classifications define genetically specified entities (SF3B1-mutant, del(5q), biallelic TP53) and renamed the group 'myelodysplastic neoplasms'.\n\nLower-risk disease is treated for anaemia: erythropoiesis-stimulating agents, lenalidomide for del(5q), luspatercept (MEDALIST 2020, COMMANDS 2023 first line), and imetelstat (IMerge, 2024) after ESA failure. Higher-risk disease is treated with hypomethylating agents (azacitidine, decitabine, oral decitabine-cedazuridine) and, for the fit with a donor, allogeneic transplant, the only cure. Three large phase 3 additions to azacitidine failed in 2023-24 (magrolimab ENHANCE, sabatolimab STIMULUS-MDS2, venetoclax VERONA), leaving azacitidine alone as the higher-risk standard.\n\nOpen problems: TP53-mutant MDS, post-HMA failure (median survival under six months), and how to use IPSS-M to time transplant.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Myelodysplastic_syndrome","links":[{"label":"IPSS-M (NEJM Evidence 2022)","url":"https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200008"},{"label":"NCI PDQ: MDS","url":"https://www.cancer.gov/types/myeloproliferative/patient/myelodysplastic-treatment-pdq"}],"tags":["gap-fill","haematologic"],"related":["systemic-mastocytosis"],"cancers":[],"sections":[],"technologies":["epigenetic-drugs","allogeneic-hsct","ngs-mrd-clonoseq","flow-cytometry-mrd","cytogenetics-fish","transfusion-support"],"targets":["tp53","cd47","tim3","bcl2"],"drugs":["azacitidine","decitabine-cedazuridine","lenalidomide","luspatercept","imetelstat","venetoclax","magrolimab","decitabine","dorocubicel"],"companies":["bms","gilead","novartis","taiho"],"institutions":[],"pathways":["p53-cell-cycle","apoptosis-bcl2"],"terms":["eln-risk","mrd","differentiation-syndrome"],"trials":["nct05883956","nct04256317","nct04064060"],"people":["uwe-platzbecker","pierre-fenaux"],"bottlenecks":[],"keyPapers":[],"journals":["leukemia-research"],"dependsOn":[],"notes":[],"group":"haematologic","burden":"MDS affects around 4-5 per 100,000 people per year overall, rising steeply with age (median age ~70), according to SEER.","subtypes":["MDS with low blasts (MDS-LB)","MDS with SF3B1 mutation (ring sideroblasts)","MDS with del(5q)","MDS with biallelic TP53 inactivation","MDS with increased blasts (IB1, IB2)","Hypoplastic MDS","Therapy-related MDS"],"biomarkers":["IPSS-R and IPSS-M risk","Cytogenetics (del(5q), -7, complex karyotype)","NGS panel (SF3B1, TP53, ASXL1, RUNX1, TET2, DNMT3A, SRSF2, U2AF1)","Blast percentage","Serum EPO level (ESA response prediction)","Transfusion burden"],"standardOfCare":[{"setting":"Lower risk, anaemia","approach":"ESA if serum EPO <500; luspatercept first line (COMMANDS) or after ESA failure (MEDALIST); imetelstat after ESA failure (IMerge); lenalidomide for del(5q).","refs":["luspatercept","imetelstat","lenalidomide"],"guideline":{"nccn":"Category 1 (luspatercept), Category 2A (imetelstat)","version":"NCCN Guidelines: MDS","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}},{"setting":"Higher risk, transplant candidate","approach":"Allogeneic HSCT, usually after hypomethylating-agent cytoreduction; BMT CTN 1102 showed a survival benefit for transplant in 50-75-year-olds.","refs":["allogeneic-hsct","azacitidine","bmt-ctn-1102"],"guideline":{"version":"NCCN Guidelines: MDS","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1446"}},{"setting":"Higher risk, not transplant candidate","approach":"Azacitidine (AZA-001) or decitabine / oral decitabine-cedazuridine until progression; supportive care and trials.","refs":["azacitidine","decitabine-cedazuridine"],"guideline":{"nccn":"Category 1 (azacitidine)","version":"NCCN Guidelines: MDS"}},{"setting":"Supportive care, all risks","approach":"Transfusion, iron chelation for transfusional iron overload (TELESTO), infection management, G-CSF for neutropenic infection.","refs":["transfusion-support","g-csf-growth-factors","telesto"]}],"stateOfArt":["IPSS-M (2022) reclassifies about half of patients relative to IPSS-R and is now the recommended risk model.","Two new drugs for lower-risk anaemia in four years: luspatercept and imetelstat, both reducing transfusion dependence.","Higher-risk MDS has had no new drug since azacitidine: the 2023-24 failures of magrolimab, sabatolimab and venetoclax combinations were a field-wide setback.","Allogeneic transplant remains the only cure; reduced-intensity conditioning extends it to older patients."],"history":[{"year":1982,"title":"FAB classification of MDS","note":"Bennett and colleagues define refractory anaemia, RARS, RAEB, RAEB-T and CMML.","refs":[]},{"year":1997,"title":"IPSS risk score","note":"Greenberg's International Prognostic Scoring System combines blasts, cytogenetics and cytopenias.","refs":[]},{"year":2004,"title":"Azacitidine approved","note":"First drug approved for MDS (US); AZA-001 (2009) shows survival benefit in higher-risk disease.","refs":["azacitidine"]},{"year":2005,"title":"Lenalidomide for del(5q)","note":"Transfusion independence in two-thirds of del(5q) patients (List et al.).","refs":["lenalidomide"]},{"year":2012,"title":"IPSS-R","note":"Revised score with five cytogenetic groups and refined thresholds.","refs":[]},{"year":2020,"title":"Luspatercept approved","note":"MEDALIST in ring-sideroblast MDS after ESA failure; COMMANDS (2023) moves it to first line.","refs":["luspatercept"]},{"year":2022,"title":"IPSS-M and WHO5/ICC","note":"Molecular risk model with 31 genes; classification renamed myelodysplastic neoplasms with genetically defined entities.","refs":[]},{"year":2023,"title":"Higher-risk combinations fail","note":"Magrolimab (ENHANCE) and sabatolimab (STIMULUS-MDS2) add nothing to azacitidine; VERONA (venetoclax) negative in 2024.","refs":["magrolimab","venetoclax","azacitidine"]},{"year":2024,"title":"Imetelstat approved","note":"IMerge: telomerase inhibitor achieves durable transfusion independence after ESA failure.","refs":["imetelstat"]}],"pipeline":["imetelstat","luspatercept","allogeneic-hsct","tuspetinib","bexmarilimab","spartalizumab","sabatolimab","ard103"],"openProblems":["No drug has beaten azacitidine in higher-risk MDS.","TP53-mutant and complex-karyotype disease: median survival about a year even after transplant.","Clonal cytopenia of undetermined significance (CCUS): who to watch, who to treat.","Post-HMA failure has no standard."]},{"id":"myeloid-leukaemia-of-down-syndrome","kind":"cancer","name":"Myeloid leukaemia of Down syndrome","aka":["ML-DS","Myeloid leukemia of Down syndrome","Myeloid leukaemia associated with Down syndrome","Down syndrome acute megakaryoblastic leukaemia","DS-AMKL","Myeloid leukaemia of Down syndrome (GATA1-mutated; reduced-intensity chemotherapy)"],"tldr":"Myeloid leukaemia of Down syndrome is a form of acute myeloid leukaemia in young children with Down syndrome, driven by a GATA1 mutation on top of the extra chromosome 21 and often preceded by a transient leukaemia-like illness in the newborn. Its cells are unusually sensitive to chemotherapy, so children are cured about nine times in ten with gentler treatment than other childhood leukaemia.","summary":"WHO-HAEM5 keeps myeloid leukaemia associated with Down syndrome as a distinct entity, defined by trisomy 21, a GATA1 mutation and onset usually before age five, often after transient abnormal myelopoiesis in the newborn (Khoury 2022). Nearly half of the leukaemias of children with Down syndrome are acute megakaryoblastic, a rare subtype in other children; GATA1 mutations and trisomy 21 cooperate in leukaemogenesis (Critical Reviews in Oncogenesis 2011). The blasts are unusually sensitive to cytarabine and daunorubicin, so the Children's Oncology Group trial AAML0431 reduced anthracycline exposure and moved high-dose cytarabine into induction: for 204 eligible patients five-year event-free survival was 89.9 percent and overall survival 93.0 percent, while the 17 with refractory or relapsed disease had 34.3 percent overall survival; measurable residual disease by flow cytometry after the first induction cycle was highly predictive of outcome (Taub 2017).\n\nHow it differs from its parent: it is the paediatric acute myeloid leukaemia with the best outlook and the least treatment, because of drug sensitivity, but with heavy treatment-related toxicity in children with Down syndrome, so dose reduction rather than intensification is the direction; relapse, though rare, is hard to salvage.\n\nHow common: no population figure in the sources read; it accounts for a large share of leukaemia in children with Down syndrome.\n\nTreatment: reduced-intensity chemotherapy on the AAML0431 model (cytarabine and daunorubicin-based induction with high-dose cytarabine, fewer anthracycline courses, no transplant in first remission), with measurable residual disease guiding further reduction in current trials such as the response-based trial linked here; relapsed disease has no standard (Taub 2017).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Transient_myeloproliferative_disease","links":[{"label":"NCI PDQ: childhood acute myeloid leukaemia treatment","url":"https://www.cancer.gov/types/leukemia/patient/child-aml-treatment-pdq"},{"label":"Khoury 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, myeloid and histiocytic neoplasms","url":"https://doi.org/10.1038/s41375-022-01613-1"},{"label":"Taub 2017, Blood: improved outcomes for myeloid leukaemia of Down syndrome, COG AAML0431","url":"https://doi.org/10.1182/blood-2017-01-764324"},{"label":"Critical Reviews in Oncogenesis 2011: myeloid leukaemia in Down syndrome","url":"https://doi.org/10.1615/critrevoncog.v16.i1-2.40"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["aml-paediatric","aml","childhood-cancers","mixed-phenotype-acute-leukaemia"],"cancers":[],"sections":[],"technologies":["mrd-testing"],"targets":["gata1"],"drugs":["cytarabine","daunorubicin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["nct02521493"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Children with Down syndrome have a much higher risk of leukaemia than other children, and nearly half of their leukaemias are acute megakaryoblastic (Critical Reviews in Oncogenesis 2011); the COG AAML0431 trial enrolled 204 eligible patients (Taub 2017). No population figure is in the sources read.","subtypes":["Myeloid leukaemia of Down syndrome, megakaryoblastic (the usual form)","Myeloid leukaemia of Down syndrome with prior transient abnormal myelopoiesis","Myelodysplasia-related presentation of myeloid leukaemia of Down syndrome","Refractory or relapsed myeloid leukaemia of Down syndrome (shorter survival)"],"biomarkers":["Trisomy 21 with somatic GATA1 mutation","Megakaryoblastic morphology and markers (CD41, CD61)","Measurable residual disease by flow cytometry on day 28 of induction","History of transient abnormal myelopoiesis"],"standardOfCare":[{"setting":"Newly diagnosed","approach":"Reduced-intensity cytarabine and daunorubicin-based chemotherapy on the AAML0431 model, with measurable residual disease guiding further reduction; no transplant in first remission.","refs":["cytarabine","daunorubicin","mrd-testing","aml-paediatric","nct02521493"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"aml-paediatric"},{"id":"myeloproliferative-neoplasms","kind":"cancer","name":"Myeloproliferative neoplasms (PV, ET, myelofibrosis)","aka":["MPN","Polycythaemia vera","Essential thrombocythaemia","Primary myelofibrosis"],"tldr":"Myeloproliferative neoplasms are slow-growing blood cancers in which the marrow overproduces red cells (polycythaemia vera), platelets (essential thrombocythaemia) or scar tissue (myelofibrosis). Almost all carry a mutation in JAK2, CALR or MPL; treatment aims to prevent clots and control symptoms, and only transplant cures myelofibrosis.","summary":"The classical BCR-ABL1-negative MPNs (polycythaemia vera, essential thrombocythaemia, primary myelofibrosis) are clonal diseases driven by JAK-STAT activation: JAK2 V617F in ~95% of PV and ~60% of ET/PMF, CALR in ~25% of ET/PMF, MPL in ~5%. Risk in PV/ET is thrombosis (managed with aspirin, phlebotomy, hydroxyurea or interferon); in myelofibrosis it is cytopenias, splenomegaly, constitutional symptoms and leukaemic transformation (about 10-20%), risk-scored by DIPSS-plus, MIPSS70 and MIPSS70+ v2.0.\n\nRuxolitinib (COMFORT-I/II, 2011) was the first JAK inhibitor; fedratinib (2019), pacritinib (2022, for platelets <50) and momelotinib (2023, for anaemic patients) followed. None is disease-modifying: allogeneic transplant remains the only cure for myelofibrosis. Ropeginterferon alfa-2b (2021) is the first approved interferon for PV with evidence of molecular response, and rusfertide (2026), a hepcidin mimetic, is the first drug to control PV erythrocytosis without phlebotomy (VERIFY). CALR-directed antibodies and JAK2 V617F-selective inhibitors are the disease-modifying hope; pelabresib (BET inhibitor) plus ruxolitinib improved spleen response but not symptoms in MANIFEST-2.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Myeloproliferative_neoplasm","links":[{"label":"NCCN Guidelines: MPN","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1477"},{"label":"NCI PDQ: chronic MPN","url":"https://www.cancer.gov/types/myeloproliferative/patient/chronic-treatment-pdq"},{"label":"MPN Research Foundation","url":"https://www.mpnresearchfoundation.org/"}],"tags":["gap-fill","haematologic"],"related":[],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","allogeneic-hsct","cytokine-therapy","ngs-mrd-clonoseq"],"targets":["jak2","bcl2"],"drugs":["ruxolitinib","fedratinib","pacritinib","momelotinib","hydroxyurea","ropeginterferon-alfa-2b","rusfertide","luspatercept","anagrelide"],"companies":["novartis","bms","gsk","incyte"],"institutions":[],"pathways":["pi3k-akt-mtor"],"terms":["eln-risk"],"trials":["nct06093672","nct06351631","nct04468984","nct06468033","nct04717414","nct04562389","verify","nct07429266","nct05481151","nct06033586","nct04064060","impactmf","nct04285086","nct04655092"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Combined incidence around 2-3 per 100,000 per year; PV and ET are chronic diseases lived with for decades, myelofibrosis has a median survival of about six years.","subtypes":["Polycythaemia vera (PV)","Essential thrombocythaemia (ET)","Prefibrotic and overt primary myelofibrosis (PMF)","Post-PV / post-ET myelofibrosis","MPN in blast phase","Triple-negative MPN"],"biomarkers":["JAK2 V617F and exon 12","CALR type 1/2","MPL W515","High-molecular-risk mutations (ASXL1, EZH2, SRSF2, IDH1/2, U2AF1)","DIPSS-plus / MIPSS70+ v2.0","Haematocrit target <45% (CYTO-PV)","Platelet count (pacritinib eligibility)"],"standardOfCare":[{"setting":"PV","approach":"Low-dose aspirin, phlebotomy to haematocrit <45%; cytoreduction (hydroxyurea or ropeginterferon alfa-2b) for high-risk; ruxolitinib after hydroxyurea failure (RESPONSE); rusfertide to eliminate phlebotomy need (VERIFY, 2026).","refs":["hydroxyurea","ropeginterferon-alfa-2b","ruxolitinib","rusfertide"],"guideline":{"nccn":"Category 1 (ropeginterferon, hydroxyurea)","version":"NCCN Guidelines: MPN","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1477"}},{"setting":"ET","approach":"Risk-adapted (IPSET-thrombosis): observation or aspirin in low risk; hydroxyurea or interferon in high risk; anagrelide second line.","refs":["hydroxyurea","ropeginterferon-alfa-2b"],"guideline":{"version":"NCCN Guidelines: MPN"}},{"setting":"Myelofibrosis, intermediate-2/high risk","approach":"JAK inhibitor for spleen and symptoms: ruxolitinib (COMFORT), fedratinib, pacritinib if platelets <50×10⁹/L, momelotinib if anaemic (MOMENTUM); allogeneic HSCT for eligible patients (the only cure).","refs":["ruxolitinib","fedratinib","pacritinib","momelotinib","allogeneic-hsct","comfort-i","comfort-ii"],"guideline":{"nccn":"Category 1 (ruxolitinib, fedratinib); 2A (pacritinib, momelotinib)","version":"NCCN Guidelines: MPN"}},{"setting":"Anaemia of myelofibrosis","approach":"Momelotinib, luspatercept (INDEPENDENCE), ESA, danazol, transfusion.","refs":["momelotinib","luspatercept"]}],"stateOfArt":["Four approved JAK inhibitors cover spleen, symptoms, thrombocytopenia and anaemia, but none reverses fibrosis or clears the clone.","Interferon is the only drug with consistent molecular responses in PV/ET, and ropeginterferon made it practical.","Rusfertide (2026) is the first mechanistically new PV drug in a decade and removes the need for phlebotomy in most patients.","The next wave targets the clone itself: mutant-CALR antibodies (e.g. INCA033989), JAK2 V617F-selective inhibitors, and navitoclax/pelabresib combinations with mixed phase 3 results."],"history":[{"year":1951,"title":"Dameshek groups the MPNs","note":"Proposes that PV, ET, CML and myelofibrosis are related myeloproliferative disorders.","refs":[]},{"year":2005,"title":"JAK2 V617F discovered","note":"Four groups report the mutation in most PV and half of ET/PMF; the first molecular marker for BCR-ABL1-negative MPN.","refs":["jak2"]},{"year":2011,"title":"Ruxolitinib approved","note":"COMFORT-I/II: spleen and symptom benefit in myelofibrosis; the first JAK inhibitor.","refs":["ruxolitinib"]},{"year":2013,"title":"CALR mutations","note":"Klampfl and Nangalia find CALR exon 9 mutations in most JAK2-negative ET/PMF.","refs":[]},{"year":2013,"title":"Haematocrit target proven","note":"CYTO-PV: keeping haematocrit <45% cuts cardiovascular death and major thrombosis in PV.","refs":[]},{"year":2019,"title":"Fedratinib approved","note":"JAKARTA; the second JAK inhibitor after an eight-year gap.","refs":["fedratinib"]},{"year":2021,"title":"Ropeginterferon alfa-2b approved for PV","note":"PROUD/CONTINUATION-PV: superior long-term haematologic and molecular response versus hydroxyurea.","refs":["ropeginterferon-alfa-2b"]},{"year":2022,"title":"Pacritinib for severe thrombocytopenia","refs":["pacritinib"]},{"year":2023,"title":"Momelotinib for anaemic myelofibrosis","note":"MOMENTUM: symptom, spleen and transfusion-independence benefit versus danazol.","refs":["momelotinib"]},{"year":2026,"title":"Rusfertide approved for PV","note":"VERIFY: hepcidin mimetic controls erythrocytosis without phlebotomy; FDA approval August 2026.","refs":["rusfertide"]}],"pipeline":["rusfertide","momelotinib","luspatercept","allogeneic-hsct","givinostat","bomedemstat","navitoclax","krt-232","flonoltinib","jbi-802"],"openProblems":["No disease-modifying therapy in myelofibrosis short of transplant.","MPN in blast phase: outcomes as poor as secondary AML.","Whether interferon-induced molecular response prevents progression.","Sequencing and combining JAK inhibitors with BET, BCL-XL or CALR-directed agents."]},{"id":"myxofibrosarcoma","kind":"cancer","name":"Myxofibrosarcoma","aka":["MFS","Myxoid malignant fibrous histiocytoma (historic)"],"tldr":"Myxofibrosarcoma is a sarcoma of older people that grows just beneath the skin of the limbs and sends invisible tails along the tissue planes, so it comes back after surgery more often than any other sarcoma. Wide surgery guided by MRI, usually with radiotherapy, is the treatment; chemotherapy is reserved for spread disease.","summary":"Myxofibrosarcoma is a fibroblastic sarcoma of late adult life, usually presenting as a painless superficial or subcutaneous mass in the limbs, and is now the commonest sarcoma diagnosis in the elderly. Its defining behaviour is infiltrative growth along fascial planes and septa well beyond the palpable mass, seen on MRI as curvilinear tail-like enhancement, and this explains a local recurrence rate that exceeds every other soft tissue sarcoma. Grade rises with each recurrence, and metastasis, mainly to the lungs, follows grade: rare in low-grade tumours, common in high-grade ones.\n\nTreatment is wide surgical resection planned on contrast-enhanced MRI to encompass the tail sign, with radiotherapy for most intermediate- and high-grade tumours and for recurrent disease, given preoperatively or postoperatively as for other extremity sarcomas. Positive margins are common even in expert hands and re-excision is frequently needed. Systemic therapy for high-grade or metastatic disease follows the general soft tissue sarcoma approach with doxorubicin-based chemotherapy, and the tumour has no recurrent driver alteration to target.\n\nResearch has focused on the genomics of progression, with recurrent copy number gains and losses and TP53, CDKN2A and RB1 alterations shared with undifferentiated pleomorphic sarcoma, and on defining surgical margins by imaging so that the first operation is the last.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Myxofibrosarcoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Myxofibrosarcoma"}],"tags":["subtype-page"],"related":["undifferentiated-pleomorphic-sarcoma","extremity-soft-tissue-sarcoma","leiomyosarcoma","liposarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-eortc-62012-doxorubicin-ifosfamide-judson-lancet-oncol-2014","paper-esmo-sts-guideline-gronchi-ann-oncol-2021","paper-myxofibrosarcoma-mentzel-ajsp-1996"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"A common sarcoma of the elderly, typically a slow-growing lump just under the skin of the leg or arm; it recurs locally in a large minority of patients because of finger-like spread along tissue planes, and higher-grade tumours metastasise to the lungs.","subtypes":["Low-grade myxofibrosarcoma (mostly local recurrence)","Intermediate- and high-grade myxofibrosarcoma (metastatic risk)","Epithelioid myxofibrosarcoma (aggressive variant)","Superficial (subcutaneous) versus deep tumours"],"biomarkers":["FNCLCC grade and grade progression at recurrence","MRI tail sign (infiltrative margins)","TP53, CDKN2A and RB1 alterations","Absence of specific fusion or MDM2 amplification (excludes liposarcoma)"],"standardOfCare":[{"setting":"Localised","approach":"Wide resection planned on contrast-enhanced MRI to include tail-like extensions; preoperative or postoperative radiotherapy for intermediate- and high-grade and recurrent tumours.","refs":["limb-salvage-surgery","mri","imrt-igrt","fnclcc-grade"]},{"setting":"Recurrent local disease","approach":"Re-resection with radiotherapy if not previously given; amputation only for uncontrollable multiply recurrent disease.","refs":["limb-salvage-surgery","imrt-igrt"]},{"setting":"Metastatic","approach":"Doxorubicin-based chemotherapy as for other high-grade soft tissue sarcomas; metastasectomy for limited lung disease.","refs":["doxorubicin","ifosfamide","gemcitabine","docetaxel"]}],"stateOfArt":["MRI-defined surgical margins that encompass the tail sign lower local recurrence.","Radiotherapy is used for most tumours because margins are so often positive.","Genomic studies place myxofibrosarcoma on a spectrum with undifferentiated pleomorphic sarcoma."],"history":[{"year":1977,"title":"Angervall, Kindblom and Merck describe myxofibrosarcoma","refs":[]},{"year":2002,"title":"WHO recognises myxofibrosarcoma as a distinct entity","refs":[]},{"year":2014,"title":"MRI tail sign linked to local recurrence and used to plan margins","refs":["mri"]}],"pipeline":[],"openProblems":["Local recurrence remains the highest of any sarcoma.","No targetable driver has been found.","Elderly patients often cannot tolerate full-dose chemotherapy for metastatic disease."],"parent":"sarcoma"},{"id":"sinonasal","kind":"cancer","name":"Nasal cavity and paranasal sinus cancers (including esthesioneuroblastoma)","aka":["Sinonasal cancer","Esthesioneuroblastoma","Olfactory neuroblastoma","Sinonasal undifferentiated carcinoma","SNUC","Paranasal sinus cancer"],"tldr":"Cancers of the nose and sinuses are a mixed group, from squamous carcinoma to the nerve-derived esthesioneuroblastoma and the aggressive undifferentiated carcinoma SNUC. Surgery through the nose with an endoscope followed by precise radiotherapy has replaced disfiguring open operations, and giving chemotherapy first to see who responds now guides how SNUC is treated.","summary":"Sinonasal malignancies arise in the nasal cavity, maxillary and ethmoid sinuses and comprise squamous cell carcinoma (the majority, including HPV-related and inverted-papilloma-associated forms), intestinal-type adenocarcinoma (strongly linked to occupational wood and leather dust), esthesioneuroblastoma (olfactory neuroblastoma, graded by Hyams), sinonasal undifferentiated carcinoma (SNUC), neuroendocrine carcinoma, adenoid cystic carcinoma, mucosal melanoma, NUT carcinoma and SMARCB1- or SMARCA4-deficient carcinomas. Molecular reclassification has split SNUC: about half carry IDH2 R172 mutations, and others are SWI/SNF-deficient; DEK-AFF2 fusion defines a distinct carcinoma. Proximity to orbit, skull base and brain dictates both symptoms (late presentation with obstruction, epistaxis, proptosis) and treatment complexity.\n\nSurgery is the mainstay for resectable tumours, and endoscopic endonasal and combined cranioendoscopic approaches have replaced craniofacial resection for most, with equivalent control and less morbidity. Post-operative IMRT or proton therapy is standard for advanced stage, close margins, high grade and esthesioneuroblastoma; protons reduce dose to optic pathways and brain. SNUC is treated with induction platinum-etoposide chemotherapy, and the response-adapted approach from MD Anderson (JAMA Oncol 2019) directs responders to definitive chemoradiotherapy and non-responders to surgery, with better outcomes than surgery-first. Esthesioneuroblastoma is managed by resection and radiotherapy, with chemotherapy for high Hyams grade or advanced disease.\n\nFrontiers are IDH2 inhibitors for IDH2-mutant SNUC (case reports and early trials with enasidenib), SWI/SNF-directed therapy, HPV-based prognostication, and multi-institutional consortia to run trials in these rare histologies.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Esthesioneuroblastoma","links":[{"label":"NCI PDQ: paranasal sinus and nasal cavity cancer","url":"https://www.cancer.gov/types/head-and-neck/patient/adult/paranasal-sinus-treatment-pdq"},{"label":"NCCN Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"},{"label":"Response-adapted SNUC treatment (JAMA Oncol 2019)","url":"https://doi.org/10.1001/jamaoncol.2018.5526"}],"tags":["nci-coverage","rare","head-and-neck"],"related":[],"cancers":[],"sections":[],"technologies":["imrt-igrt","proton-therapy","robotic-surgery","cytotoxic-chemotherapy","checkpoint-inhibitor"],"targets":["idh","pd1"],"drugs":["cisplatin","etoposide","platinum-etoposide","pembrolizumab","nivolumab","enasidenib"],"companies":[],"institutions":[],"pathways":["idh-2hg","swi-snf-chromatin"],"terms":["head-neck-subsites","hpv-status","rare-cancers"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers"],"keyPapers":["paper-chen-jama-oncol"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"About 3 to 5 percent of head and neck cancers, or roughly one case per 100,000 per year; more common in men and in woodworkers, leather and nickel workers.","subtypes":["Sinonasal squamous cell carcinoma (keratinising, non-keratinising, HPV-related)","Intestinal-type adenocarcinoma (occupational)","Esthesioneuroblastoma (Hyams grade I to IV)","Sinonasal undifferentiated carcinoma (IDH2-mutant and other)","SMARCB1- and SMARCA4-deficient sinonasal carcinoma","Sinonasal mucosal melanoma","Adenoid cystic carcinoma of the sinonasal tract"],"biomarkers":["Histological subtype and Hyams grade (esthesioneuroblastoma)","IDH2 R172 mutation (SNUC)","SMARCB1/SMARCA4 loss","NUT immunohistochemistry to exclude NUT carcinoma","HPV status (non-keratinising squamous)","Occupational exposure history (wood dust)"],"standardOfCare":[{"setting":"Resectable squamous carcinoma, adenocarcinoma, esthesioneuroblastoma","approach":"Endoscopic or cranioendoscopic resection with negative margins followed by IMRT or proton therapy for advanced stage, high grade or close margins; concurrent cisplatin for positive margins or nodal disease.","refs":["imrt-igrt","proton-therapy","cisplatin","robotic-surgery"],"guideline":{"nccn":"Category 2A","version":"NCCN Head and Neck Cancers (ethmoid and maxillary sinus tumours)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Sinonasal undifferentiated carcinoma","approach":"Induction platinum-etoposide; responders proceed to definitive chemoradiotherapy, non-responders to surgery plus radiotherapy (response-adapted approach, JAMA Oncol 2019).","refs":["cisplatin","etoposide","platinum-etoposide","imrt-igrt"],"guideline":{"version":"Amit and colleagues, JAMA Oncol 2019","url":"https://doi.org/10.1001/jamaoncol.2018.5526"}},{"setting":"Unresectable or metastatic","approach":"Platinum-based chemotherapy, and pembrolizumab or nivolumab per head and neck squamous indications for squamous histology; trials for IDH2-mutant SNUC (enasidenib) and SWI/SNF-deficient carcinoma.","refs":["pembrolizumab","nivolumab","enasidenib"]}],"stateOfArt":["Endoscopic skull-base surgery has replaced open craniofacial resection for most tumours with equivalent oncological outcomes and far less morbidity.","Response to induction chemotherapy is now used as a biomarker in SNUC to decide between organ-preserving chemoradiotherapy and surgery.","Molecular splitting of SNUC into IDH2-mutant and SWI/SNF-deficient groups has given the first targetable alterations in a disease that had none.","Proton therapy reduces dose to optic nerves and brain in tumours that sit against both."],"history":[{"year":1924,"title":"Esthesioneuroblastoma first described (Berger and Luc)","refs":[]},{"year":1965,"title":"Wood dust linked to sinonasal adenocarcinoma","note":"Occupational epidemiology in the UK furniture industry (Acheson).","refs":[]},{"year":1986,"title":"Frierson describes sinonasal undifferentiated carcinoma","refs":[]},{"year":1988,"title":"Hyams grading of esthesioneuroblastoma","refs":[]},{"year":2000,"title":"Endoscopic endonasal resection of sinonasal cancer established","note":"Series from Pittsburgh and Europe show equivalence to open surgery.","refs":[]},{"year":2017,"title":"IDH2 mutations define a SNUC subset","note":"Dogan and colleagues; Jo and colleagues.","refs":[]},{"year":2019,"title":"Response-adapted treatment of SNUC","note":"Amit and colleagues, JAMA Oncol.","refs":["cisplatin","etoposide"]}],"pipeline":["proton-therapy","enasidenib","pembrolizumab"],"openProblems":["Late presentation: most tumours are locally advanced at diagnosis; awareness in ENT clinics and imaging AI are the response.","No randomised trials exist for any sinonasal histology; international consortia are pooling cases.","IDH2-mutant SNUC: prospective trials of IDH2 inhibitors.","Visual and neurocognitive toxicity of radiotherapy: protons and reduced-margin planning."]},{"id":"nasopharyngeal","kind":"cancer","name":"Nasopharyngeal carcinoma","aka":["NPC"],"tldr":"A cancer at the back of the nose caused largely by the Epstein-Barr virus and common in southern China and Southeast Asia. Radiation cures most early cases; adding chemotherapy and, recently, PD-1 immunotherapy has improved outcomes in advanced disease, and a blood test for viral DNA can detect it early.","summary":"Nasopharyngeal carcinoma (NPC) in endemic regions is EBV-associated non-keratinising carcinoma with distinct biology (NF-κB pathway alterations, immune-rich stroma, low TMB), while sporadic Western cases include keratinising HPV- or smoking-related tumours. Plasma EBV DNA is a diagnostic, prognostic and surveillance marker, and population screening with EBV DNA detected early-stage cancers in Hong Kong (Chan, NEJM 2017).\n\nIMRT is the backbone: radiotherapy alone for stage I, concurrent cisplatin-radiotherapy for stage II-IVA (Intergroup 0099), with induction gemcitabine-cisplatin improving survival in locoregionally advanced disease (Zhang, NEJM 2019) and adjuvant metronomic capecitabine adding benefit in high-risk patients (Chen, Lancet 2021). Recurrent or metastatic disease is treated with gemcitabine-cisplatin plus a PD-1 inhibitor: toripalimab (JUPITER-02; FDA approval 2023, the first US approval for NPC), camrelizumab (CAPTAIN-1st), tislelizumab (RATIONALE-309) and penpulimab (FDA 2025). Nasopharyngectomy (endoscopic) and re-irradiation are options for local recurrence. Late toxicities of radiotherapy (xerostomia, hearing loss, temporal-lobe necrosis, carotid stenosis) drive de-escalation trials guided by EBV DNA.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Nasopharyngeal_carcinoma","links":[{"label":"CSCO/ASCO NPC guideline (JCO 2021)","url":"https://doi.org/10.1200/JCO.20.03237"},{"label":"EBV DNA screening (NEJM 2017)","url":"https://doi.org/10.1056/NEJMoa1701717"},{"label":"NCI PDQ: nasopharyngeal cancer","url":"https://www.cancer.gov/types/head-and-neck/patient/adult/nasopharyngeal-treatment-pdq"}],"tags":["gap-fill","head-and-neck","viral"],"related":[],"cancers":[],"sections":[],"technologies":["imrt-igrt","proton-therapy","checkpoint-inhibitor","platinum","liquid-biopsy","tors","tcr-t","acupuncture-xerostomia"],"targets":["pd1","pdl1","egfr","vegf"],"drugs":["toripalimab","camrelizumab","tislelizumab","penpulimab","gemcitabine-cisplatin","cisplatin","nivolumab","pembrolizumab"],"companies":["akeso","hengrui","beone"],"institutions":["sysucc"],"pathways":["pd1-checkpoint"],"terms":["ctdna","re-irradiation"],"trials":["taishan-301","nct05294172","nct06976190","nct06118333","nct04974398"],"people":[],"bottlenecks":[],"keyPapers":["paper-chan-n-engl-j-med"],"journals":["tumour-virus-research"],"dependsOn":[],"notes":[],"group":"head and neck","burden":"About 120,000 cases per year worldwide, ~70% in East and Southeast Asia (Guangdong incidence 20-30 per 100,000 versus <1 in the West); strongly linked to Epstein-Barr virus.","subtypes":["Non-keratinising undifferentiated (EBV-associated, endemic; WHO type III)","Non-keratinising differentiated (type II)","Keratinising squamous (type I; sporadic, smoking)","HPV-associated NPC (non-endemic, oropharynx-like)"],"biomarkers":["Plasma EBV DNA (screening, staging, post-treatment risk)","EBER in situ hybridisation on biopsy","TNM (AJCC 8th) stage","PD-L1 (not required for PD-1 therapy)","Post-radiotherapy detectable EBV DNA (adjuvant therapy selection)","Family history / HLA (risk)"],"standardOfCare":[{"setting":"Stage I","approach":"IMRT alone (70 Gy) to nasopharynx and elective neck.","refs":["imrt-igrt"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck (Nasopharynx); CSCO/ASCO NPC guideline","url":"https://doi.org/10.1200/JCO.20.03237"}},{"setting":"Stage II-IVA","approach":"Induction gemcitabine-cisplatin ×3 then concurrent cisplatin-IMRT (for stage III-IVA); concurrent chemoradiation alone for stage II; adjuvant capecitabine for high-risk (detectable post-RT EBV DNA, N2-3).","refs":["gemcitabine-cisplatin","cisplatin","imrt-igrt"],"guideline":{"nccn":"Category 1 (induction GP)","esmoMcbs":"A","version":"CSCO/ASCO NPC guideline 2021"}},{"setting":"Recurrent/metastatic, first line","approach":"Gemcitabine-cisplatin + PD-1 inhibitor (toripalimab, camrelizumab, tislelizumab or penpulimab), then PD-1 maintenance.","refs":["toripalimab","camrelizumab","tislelizumab","penpulimab","gemcitabine-cisplatin"],"guideline":{"nccn":"Category 1 (toripalimab + GP)","esmoMcbs":"4","version":"NCCN Guidelines: Head and Neck"}},{"setting":"Local recurrence","approach":"Endoscopic or open nasopharyngectomy for resectable rT1-3 (better survival than re-irradiation, Liu Lancet Oncol 2021); hyperfractionated re-IMRT otherwise.","refs":["imrt-igrt","tors"]}],"stateOfArt":["Plasma EBV DNA is the most mature liquid biopsy in oncology: it screens, stages, guides adjuvant therapy and detects relapse.","PD-1 inhibitors with GP chemotherapy roughly doubled PFS in metastatic disease; toripalimab was the first FDA approval for NPC and among the first for a Chinese-developed PD-1 antibody.","Induction GP and adjuvant capecitabine are the standard for locoregionally advanced disease.","De-escalation (omitting concurrent cisplatin in low-risk stage II, reducing neck irradiation) is being validated in trials led from Guangzhou."],"history":[{"year":1921,"title":"Regaud and Schmincke describe lymphoepithelioma","refs":[]},{"year":1966,"title":"EBV antibodies linked to NPC (Old et al.)","refs":[]},{"year":1998,"title":"Intergroup 0099: concurrent cisplatin-RT improves survival (Al-Sarraf)","refs":["cisplatin"]},{"year":1999,"title":"Plasma EBV DNA quantified as a tumour marker (Lo, Cancer Res)","refs":[]},{"year":2017,"title":"EBV DNA screening detects early NPC in 20,000 men (Chan, NEJM)","refs":[]},{"year":2019,"title":"Induction gemcitabine-cisplatin improves survival (Zhang, NEJM)","refs":["gemcitabine-cisplatin"]},{"year":2021,"title":"JUPITER-02, CAPTAIN-1st, RATIONALE-309: PD-1 + GP first line","refs":["toripalimab","camrelizumab","tislelizumab"]},{"year":2023,"title":"Toripalimab: first FDA approval for NPC","refs":["toripalimab"]},{"year":2025,"title":"Penpulimab approved (FDA)","refs":["penpulimab"]}],"pipeline":["toripalimab","penpulimab","camrelizumab","tislelizumab","proton-therapy","yl201","kl-a167","mrg003","hmbd-001"],"openProblems":["Radiation late effects in a disease cured young.","Western access to PD-1 inhibitors studied in Asia; regulatory lag.","EBV-targeted therapy (vaccines, EBV-specific T cells) still investigational.","Distant metastasis is the main way treatment fails after chemoradiation; plasma EBV DNA now identifies who needs more."]},{"id":"neuroblastoma","kind":"cancer","name":"Neuroblastoma (paediatric)","aka":[],"tldr":"Neuroblastoma is a childhood nerve-cell cancer where anti-GD2 antibodies and, recently, GD2 CAR-T have improved survival in high-risk disease.","summary":"Neuroblastoma arises from developing sympathetic nerve cells, usually in the adrenal gland or along the spine, and is the most common cancer of infants and the most common extracranial solid tumour of childhood. It spans the widest clinical range in oncology: some infant tumours (stage MS) regress without treatment, while high-risk disease (about half of patients, defined by INRG stage, age over 18 months, MYCN amplification and other genomic features) is cured in only 50-60% despite the most intensive therapy given to children, which is where anti-GD2 antibodies and CAR-T have made their gains. ALK mutations (~10%) are the main druggable driver; MYCN, though not directly druggable, points to polyamine and ALK biology.\n\nHigh-risk therapy is a year-long sequence: five to six cycles of induction chemotherapy, surgery, myeloablative chemotherapy with autologous stem-cell rescue (tandem transplant in North America after ANBL0532; busulfan-melphalan single transplant in Europe after HR-NBL1), radiotherapy to the primary site, then anti-GD2 immunotherapy (dinutuximab or dinutuximab beta with GM-CSF; IL-2 abandoned after HR-NBL1) and isotretinoin. Anti-GD2 antibody raised survival by about 20 points (ANBL0032). Since December 2023, two years of oral eflornithine (DFMO) is approved as maintenance on the strength of an externally controlled study; naxitamab and irinotecan-temozolomide-dinutuximab treat relapse; lorlatinib is being added for ALK-aberrant tumours and 131I-MIBG tested in induction (ANBL1531).\n\nNeuroblastoma is also where CAR-T first produced lasting cures in a solid tumour: GD2-CART01 (Bambino Gesù, NEJM 2023) achieved 63% responses and 33% complete remissions in relapsed disease, with some remissions lasting more than a decade. The open questions are whether cell therapy can consolidate first-line remission, how to reduce the lifelong burden of hearing loss, infertility and second cancers in survivors, how to treat MYCN-amplified relapse, and how to bring anti-GD2 therapy to the majority of children in the world who cannot access it.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Neuroblastoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Neuroblastoma"}],"tags":["paediatric","spike"],"related":["paediatric-oncology-roadmap","wilms-tumor","hepatoblastoma","retinoblastoma","paediatric-germ-cell-tumours","anti-gd2-plus-chemo-relapse","il2-anti-gd2-caution"],"cancers":[],"sections":[],"technologies":["car-t","monoclonal-antibody","radioligand-therapy","proton-therapy","tandem-transplant","mibg-theranostics","autologous-stem-cell-transplant"],"targets":["alk","gd2"],"drugs":["isotretinoin"],"companies":["y-mabs","us-worldmeds","childrens-oncology-group"],"institutions":["mskcc","dana-farber","stanford","city-of-hope"],"pathways":[],"terms":["inrg-staging","mycn-amplification","efs","adcc","crs"],"trials":["ccss","nct04724369"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["journal-of-pediatric-hematology-oncology","pediatric-hematology-and-oncology"],"dependsOn":[],"notes":[],"group":"paediatric","burden":"~7-8% of childhood cancers; ~800 US cases a year; median age at diagnosis ~18 months; 5-year survival >90% for low/intermediate risk and ~50-60% for high risk.","subtypes":["Very-low and low risk (L1, MS in infants; often observation or surgery alone)","Intermediate risk (L2, M in infants; moderate chemotherapy)","High risk (stage M >18 months, or MYCN-amplified at any age)","ALK-mutated or amplified (~10%; lorlatinib-responsive)","MYCN-amplified (~20%)","Relapsed/refractory (MIBG-avid vs non-avid; marrow vs soft-tissue)","Ganglioneuroblastoma / ganglioneuroma (differentiated spectrum)","Opsoclonus-myoclonus-associated (paraneoplastic)"],"biomarkers":["MYCN amplification","ALK mutation","Age, stage, ploidy","Segmental chromosome aberrations","INRG stage and image-defined risk factors","Age (<18 months)","MYCN amplification (FISH)","ALK mutation/amplification","11q aberration, 1p deletion, ploidy, segmental chromosomal aberrations","INPC histology","Urinary catecholamines (VMA/HVA)","123I-MIBG Curie score / 18F-MFBG PET","Bone marrow minimal residual disease (PHOX2B, TH qPCR)","GD2 expression (near-universal)"],"standardOfCare":[{"setting":"High-risk","approach":"Induction chemo → surgery → tandem transplant → RT → anti-GD2 + isotretinoin; lorlatinib if ALK-mutant.","refs":["lorlatinib","monoclonal-antibody"],"guideline":{"version":"NCI PDQ: Neuroblastoma Treatment (COG risk groups)","url":"https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq"}},{"setting":"Very-low / low risk (L1, MS)","approach":"Observation with serial imaging for asymptomatic L1/MS (many regress); surgery alone for resectable L1; short chemotherapy only for symptoms or progression.","refs":["inrg-staging","ultrasound"],"guideline":{"nccn":"COG/SIOPEN low-risk protocols (observation or surgery)","version":"COG ANBL1232 / SIOPEN LINES"}},{"setting":"Intermediate risk","approach":"2-8 cycles of moderate chemotherapy (carboplatin, etoposide, cyclophosphamide, doxorubicin) guided by response and biology; surgery; isotretinoin in some protocols.","refs":["doxorubicin","cytotoxic-chemotherapy","inrg-staging"]},{"setting":"High risk: induction","approach":"5-6 cycles (COG: topotecan-cyclophosphamide × 2 then cisplatin-etoposide, cyclophosphamide-doxorubicin-vincristine; SIOPEN: rapid COJEC); stem-cell harvest; ANBL1531 adds 131I-MIBG (randomised) or lorlatinib (ALK); ANBL17P1 adds dinutuximab to induction.","refs":["anbl1531","i131-mibg","lorlatinib","dinutuximab","doxorubicin","anbl17p1"],"guideline":{"nccn":"COG ANBL1531 backbone","version":"COG 2026"}},{"setting":"High risk: local control","approach":"Surgical resection of primary after induction (gross total where safe); external-beam radiotherapy 21.6 Gy to primary site (boost to residual) and MIBG-avid metastatic sites; proton therapy where available.","refs":["imrt-igrt","proton-therapy"]},{"setting":"High risk: consolidation","approach":"Tandem autologous transplant (thiotepa-cyclophosphamide, then CEM) in North America (ANBL0532); single busulfan-melphalan transplant in Europe (HR-NBL1).","refs":["tandem-transplant","autologous-stem-cell-transplant","anbl0532","hr-nbl1"],"guideline":{"nccn":"COG standard (tandem); SIOPEN standard (BuMel)","version":"2026"}},{"setting":"High risk: post-consolidation","approach":"Anti-GD2 antibody (dinutuximab + GM-CSF + isotretinoin; dinutuximab beta in Europe, no IL-2) × 5-6 cycles; then eflornithine maintenance 2 years (US, 2023).","refs":["dinutuximab","anbl0032","eflornithine","nmtrc003","il2-anti-gd2-caution"],"guideline":{"nccn":"Dinutuximab: FDA-approved standard; eflornithine: FDA-approved maintenance","version":"2026"}},{"setting":"Relapsed / refractory","approach":"Irinotecan-temozolomide + dinutuximab or naxitamab (ANBL1221); naxitamab + GM-CSF for marrow/bone disease; 131I-MIBG for MIBG-avid disease; lorlatinib for ALK; GD2 CAR-T (Italy, trials); DFMO-based maintenance; palliative radiotherapy.","refs":["dinutuximab","naxitamab","naxitamab-201","i131-mibg","lorlatinib","gd2-cart01","anti-gd2-plus-chemo-relapse","anbl1221"]},{"setting":"Survivorship","approach":"Audiology (platinum, DFMO), endocrine and fertility follow-up, cardiac surveillance (anthracycline), second-malignancy screening, neurocognitive support; lifelong late-effects clinic.","refs":["cardio-oncology"]}],"stateOfArt":["Anti-GD2 raised high-risk survival to ~60%.","GD2 CAR-T responses.","Anti-GD2 immunotherapy after transplant is standard worldwide (ANBL0032), with IL-2 removed after HR-NBL1 showed no benefit.","Tandem transplant (North America) and busulfan-melphalan (Europe) are the two evidence-based consolidation standards.","Eflornithine is the first oral maintenance therapy approved (December 2023), on an externally controlled study.","GD2 CAR-T produced durable complete remissions in relapsed neuroblastoma, the first such result in a childhood solid tumour.","ALK inhibition with lorlatinib for ALK-aberrant tumours and 131I-MIBG during induction are being tested in ANBL1531.","Risk-adapted de-escalation: many infants and low-risk patients are observed or cured with surgery alone."],"history":[{"year":1910,"title":"James Homer Wright describes neuroblastoma and its rosettes","refs":[]},{"year":1971,"title":"Spontaneous regression of stage IV-S (now MS) disease recognised (Evans staging)","refs":["inrg-staging"]},{"year":1983,"title":"MYCN amplification linked to aggressive disease (Brodeur, Schwab)","refs":["mycn-amplification"]},{"year":1985,"title":"131I-MIBG therapy first used in relapsed neuroblastoma","refs":["mibg-theranostics"]},{"year":1999,"title":"CCG-3891: myeloablative therapy with autologous rescue and isotretinoin improve survival","refs":["autologous-stem-cell-transplant"]},{"year":2008,"title":"ALK mutations identified as a hereditary and somatic driver","refs":["alk"]},{"year":2009,"title":"INRG classification unifies international risk grouping","refs":["inrg-staging"]},{"year":2010,"title":"Anti-GD2 (ch14.18) improves EFS","refs":[]},{"year":2010,"title":"ANBL0032: anti-GD2 immunotherapy raises survival ~20 points (NEJM)","refs":["anbl0032","dinutuximab"]},{"year":2015,"title":"Dinutuximab approved (US); dinutuximab beta in EU 2017","refs":["dinutuximab"]},{"year":2017,"title":"HR-NBL1: busulfan-melphalan beats CEM; IL-2 adds no benefit (2018)","refs":["hr-nbl1"]},{"year":2019,"title":"ANBL0532: tandem transplant improves EFS (JAMA)","refs":["anbl0532","tandem-transplant"]},{"year":2020,"title":"Naxitamab approved for relapsed disease (accelerated)","refs":["naxitamab","naxitamab-201"]},{"year":2023,"title":"GD2 CAR-T phase 1/2 in NEJM","refs":[]},{"year":2023,"title":"GD2-CART01 in NEJM: durable CAR-T remissions in a solid tumour; eflornithine approved (13 Dec)","refs":["gd2-cart01","eflornithine","nmtrc003"]},{"year":2025,"title":"Long-term GD2 CAR-T follow-up (Nature Medicine); naxitamab primary-refractory phase 2 (75% CR); eflornithine EU filing","refs":["gd2-cart01","naxitamab","eflornithine"]},{"year":2026,"title":"ANBL1531 MIBG randomisation maturing; ALK arm reports","refs":["anbl1531"]}],"pipeline":["armored-car","anbl1531","i131-mibg","lorlatinib","gd2-cart01","idea-gd2-car-t-frontline-consolidation","idea-mfbg-pet-replaces-mibg","mibg-theranostics","eflornithine","naxitamab","anti-gd2-plus-chemo-relapse","tandem-transplant","y-mabs"],"openProblems":["Relapsed high-risk disease.","Long-term toxicity of intensive therapy.","Relapsed high-risk neuroblastoma is rarely curable; MYCN-amplified relapse worst of all.","Anti-GD2 therapy causes severe neuropathic pain; less painful antibody formats (e.g., humanised, Fc-engineered) and CAR-T are needed.","Long-term toxicity of tandem transplant, cisplatin (hearing loss), and radiation in children who will live 70 years.","Eflornithine's approval rests on an external control; a randomised trial is unlikely, so uncertainty persists.","Access: anti-GD2 antibodies are expensive and unavailable in most low- and middle-income countries where most children with cancer live.","MYCN remains undruggable directly; polyamine and Aurora/BET strategies are indirect.","GD2 CAR-T needs randomised evidence and manufacturing at scale; only a few centres can deliver it.","Imaging burden: repeated MIBG scans with sedation; MFBG PET adoption is slow."],"parent":"childhood-cancers"},{"id":"prostate-nepc","kind":"cancer","name":"Neuroendocrine and small-cell prostate cancer","aka":["NEPC","Treatment-emergent neuroendocrine prostate cancer","t-NEPC","Small-cell carcinoma of the prostate","Aggressive variant prostate cancer","Treatment-related neuroendocrine prostatic carcinoma","Small cell neuroendocrine carcinoma of the prostate","Small cell carcinoma of the prostate","Neuroendocrine prostatic carcinoma"],"tldr":"Neuroendocrine prostate cancer is a form that has stopped depending on the androgen receptor, either from the start or after years of hormone therapy. It no longer shows up on PSA, spreads to the liver and brain, and is treated with the platinum chemotherapy used for small-cell lung cancer.","summary":"Neuroendocrine prostate cancer includes rare de novo small-cell carcinoma and, far more often, treatment-emergent disease that arises when adenocarcinoma under prolonged androgen receptor blockade switches lineage, typically with combined loss of RB1 and TP53, PTEN loss, MYCN or AURKA amplification and loss of androgen receptor and PSA expression. It is suspected when disease progresses with a low or flat PSA, visceral or lytic bone metastases, raised chromogranin, neuron-specific enolase or lactate dehydrogenase, or FDG-avid but PSMA-negative lesions, and confirmed by biopsy showing small-cell morphology or synaptophysin and chromogranin staining. There is no approved therapy specific to it: platinum with etoposide, or carboplatin with docetaxel for mixed histology, is standard, with response rates of about half but brief duration, and androgen deprivation is usually continued. Immunotherapy adds little outside mismatch repair deficiency. DLL3 is expressed in most neuroendocrine prostate cancers, and the DLL3 T-cell engager tarlatamab, approved for small-cell lung cancer, is in trials here; EZH2 inhibitors and aurora kinase inhibitors are being tested against the lineage switch itself.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Prostate_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Prostate_cancer"},{"label":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"},{"label":"Kench et al., Histopathology 2022: WHO Classification of Tumours fifth edition, evolving issues in the classification, diagnosis and prognostication of prostate cancer","url":"https://doi.org/10.1111/his.14711"},{"label":"Royal College of Pathologists G084: dataset for histopathology reports for prostatic carcinoma, version 4, October 2024","url":"https://www.rcpath.org/static/8cc88604-2c8d-4df4-a99542df41c102af/G084-dataset-for-histopathology-reports-for-prostatic-carcinoma.pdf"},{"label":"WHO Classification of Tumours, 5th edition: tumours of the prostate (IARC, 2022)","url":"https://tumourclassification.iarc.who.int/chapters/36"}],"tags":["subtype-page"],"related":["prostate-mcrpc","prostate-mhspc","prostate-nmcrpc","prostate-ductal-adenocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["prostate-acinar-adenocarcinoma","tnm-prostate-cancer","castration-resistance","neuroendocrine-differentiation","radiographic-progression-free-survival"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-beltran-nepc-divergent-evolution-nat-med-2016","paper-aggarwal-t-sccpc-jco-2018","paper-aparicio-aggressive-variant-ccr-2013"],"journals":[],"dependsOn":[],"notes":["This page is a tumour type, not a disease state. The WHO fifth edition gives treatment-related neuroendocrine prostatic carcinoma its own section inside the prostate chapter, rather than folding it into the classification's consolidated neuroendocrine chapter, because of its distinctive clinical and biological behaviour. It is defined there as tumours demonstrating complete neuroendocrine differentiation, or partial neuroendocrine differentiation with adenocarcinoma, following androgen deprivation therapy, and the definition covers both the primary and its metastases (Kench 2022).","What a UK report will and will not do with it. Neuroendocrine carcinomas are not Gleason graded. The dataset in force does not ask for routine synaptophysin and chromogranin staining of ordinary prostate adenocarcinoma, because almost all of them show some neuroendocrine differentiation and there is not enough evidence that finding it changes treatment or prognosis; the stains are for tumours that already look neuroendocrine down the microscope. PSA and NKX3.1 are usually lost in these tumours, which is one of the reasons the PSA can stay low while the disease advances (RCPath G084).","How common it is in the setting where it matters. Treatment-related neuroendocrine prostatic carcinoma is found in 10.5 to 17 percent of people with metastatic castration-resistant prostate cancer after treatment with androgen receptor signalling inhibitors (Kench 2022). The evidence is that these carcinomas arise by transformation of an existing adenocarcinoma rather than from neuroendocrine cells, which is what lineage plasticity means here and why it is a route to resistance rather than a second cancer."],"group":"genitourinary","burden":"Pure small-cell prostate cancer is under 1 percent of new diagnoses, but neuroendocrine features emerge in 10 to 20 percent of men treated with potent androgen receptor inhibitors; median survival after diagnosis is about a year.","subtypes":["De novo small-cell carcinoma of the prostate","Treatment-emergent neuroendocrine prostate cancer (after androgen receptor pathway inhibitors)","Mixed adenocarcinoma and neuroendocrine carcinoma","Aggressive variant prostate cancer (clinical definition, low PSA, visceral spread)","Large-cell neuroendocrine carcinoma of the prostate"],"biomarkers":["Synaptophysin, chromogranin and INSM1 staining","Loss of androgen receptor and PSA expression","Combined RB1 and TP53 loss","MYCN and AURKA amplification","DLL3 expression","Serum chromogranin A, neuron-specific enolase and lactate dehydrogenase","FDG PET-avid, PSMA PET-negative lesions"],"standardOfCare":[{"setting":"Small-cell or predominantly neuroendocrine","approach":"Cisplatin or carboplatin with etoposide, as for small-cell lung cancer; continue androgen deprivation; brain imaging.","refs":["platinum-etoposide","cisplatin","carboplatin","etoposide","androgen-deprivation"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Mixed adenocarcinoma and neuroendocrine, or aggressive variant","approach":"Carboplatin plus docetaxel or cabazitaxel, then platinum with etoposide; clinical trial enrolment preferred.","refs":["carboplatin","docetaxel","cabazitaxel","cytotoxic-chemotherapy"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Recognition and biopsy","approach":"Biopsy any progression with low PSA, visceral metastases or PSMA-negative FDG-avid lesions; test for mismatch repair deficiency (pembrolizumab) and HRR genes.","refs":["psma-pet","pet","pembrolizumab"]},{"setting":"Trials","approach":"DLL3 T-cell engagers (tarlatamab), EZH2 inhibitors and aurora kinase inhibitors against the lineage switch; lurbinectedin borrowed from small-cell lung cancer.","refs":["tarlatamab","dll3","mevrometostat","ezh2","lurbinectedin"]}],"stateOfArt":["Sequencing has shown that neuroendocrine prostate cancer evolves from the same clone as the adenocarcinoma rather than arising anew.","DLL3 gives the disease its first surface target, borrowed from small-cell lung cancer.","Lineage plasticity is now studied as a drug target in its own right."],"history":[{"year":1977,"title":"Small-cell carcinoma of the prostate first described","refs":["sclc"]},{"year":2011,"title":"Beltran finds AURKA and MYCN amplification in neuroendocrine prostate cancer","refs":["myc"]},{"year":2016,"title":"Divergent clonal evolution from adenocarcinoma shown by sequencing","refs":[]},{"year":2017,"title":"RB1 and TP53 loss drive lineage plasticity in models","refs":["tp53"]},{"year":2018,"title":"Aggarwal: 17 percent of men on potent hormone therapy have neuroendocrine features at biopsy","refs":["castration-resistance"]},{"year":2024,"title":"Tarlatamab shows activity against DLL3-positive neuroendocrine prostate cancer","refs":["tarlatamab","dll3"]}],"pipeline":["tarlatamab","mevrometostat","lurbinectedin","ifinatamab-deruxtecan"],"openProblems":["No approved therapy specific to the disease; every regimen is borrowed from lung cancer.","No blood test reliably detects the lineage switch before it shows on scans.","Whether androgen receptor blockade should be de-escalated to slow the switch."],"parent":"prostate"},{"id":"gallbladder-neuroendocrine-carcinoma","kind":"cancer","name":"Neuroendocrine carcinoma of the gallbladder","aka":["Small cell carcinoma of the gallbladder","Oat cell carcinoma of the gallbladder","Large cell neuroendocrine carcinoma of the gallbladder","Mixed neuroendocrine non-neuroendocrine neoplasm of the gallbladder","MiNEN"],"tldr":"Neuroendocrine carcinoma is a rare, fast-growing form of gallbladder cancer made of small cell or large cell hormone-type cells, often mixed with ordinary adenocarcinoma. It is usually advanced when found and median survival in the largest series was six to seven months. It is treated like other high-grade neuroendocrine carcinomas rather than like gallbladder adenocarcinoma.","summary":"Gallbladder neuroendocrine carcinomas were characterised in 2026 from 31 cases among 636 gallbladder cancers: 7 pure small cell, 2 pure large cell and 22 mixed with an adenocarcinoma component (the neuroendocrine part averaging 80 percent of the tumour). The female to male ratio was 5.2 to 1 and median age 58, seven years younger than ordinary gallbladder cancer; high-grade glandular dysplasia was present in 15, six arising in intracholecystic papillary neoplasms. Median Ki-67 was 70 percent, lymphovascular invasion was seen in 74 percent and perineural invasion in 56 percent; 72 percent were pT3 or pT4 against 26 percent of ordinary cancers. Synaptophysin was positive in 95 percent, chromogranin in 75 percent and CD56 in 90 percent; the pRB/p16 pathway was inactivated in 83 percent and p53 was mutant-pattern in 89 percent. Median survival was 6.1 months, with a few unexpectedly long survivors (Reid 2026). In SEER (287 cases, 1975 to 2016) the incidence was 1.6 percent of gallbladder carcinomas, the male to female ratio 1 to 2, median survival 7 months, and one, two, three and five-year overall survival 36.6, 17.8, 13.2 and 7.3 percent; serum chromogranin A was proposed as a marker (Cai 2022). Cancer Research UK lists small cell (oat cell) carcinoma and neuroendocrine tumours among the rare types and notes they are not necessarily treated like adenocarcinoma.\n\nWhat differs in treatment: these are managed as poorly differentiated neuroendocrine carcinomas of the digestive tract, with platinum and etoposide chemotherapy rather than gemcitabine and cisplatin, and surgery for the minority with localised disease; a population-based analysis found surgery and adjuvant chemotherapy each associated with better survival (Khan 2023, J Pers Med, doi 10.3390/jpm13061009). Mixed tumours are treated according to the higher-grade neuroendocrine component. Well-differentiated neuroendocrine tumours of the gallbladder are a separate, far less aggressive group covered on the neuroendocrine pages.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor","links":[{"label":"Reid, Am J Surg Pathol 2026: neuroendocrine carcinoma of the gallbladder, 31 cases","url":"https://doi.org/10.1097/pas.0000000000002580"},{"label":"Cai and Wu, World J Clin Cases 2022: gallbladder neuroendocrine carcinoma in SEER","url":"https://doi.org/10.12998/wjcc.v10.i23.8212"},{"label":"Louis, Cancer Causes Control 2025: gallbladder adenocarcinoma and neuroendocrine carcinoma in the National Cancer Database","url":"https://doi.org/10.1007/s10552-025-01967-8"},{"label":"CRUK: types of gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/types"},{"label":"Khan, J Pers Med 2023: surgery and adjuvant chemotherapy in gallbladder neuroendocrine carcinoma","url":"https://doi.org/10.3390/jpm13061009"}],"tags":["gallbladder","biliary","subtype-page"],"related":["gallbladder","gallbladder-adenocarcinoma","extrapulmonary-nec","grade-3-net","neuroendocrine"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["tumour-grade","lymphovascular-invasion","perineural-invasion"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Under 5 percent of gallbladder cancers in a 636-case pathology cohort (Reid 2026), 1.6 percent of gallbladder carcinomas in SEER (Cai 2022) and 3.3 percent of gallbladder neoplasms in the US National Cancer Database 2011 to 2020 (Louis 2025).","subtypes":["Small cell neuroendocrine carcinoma of the gallbladder","Large cell neuroendocrine carcinoma of the gallbladder","Mixed neuroendocrine and non-neuroendocrine neoplasm of the gallbladder (adenocarcinoma plus neuroendocrine carcinoma)","Well-differentiated neuroendocrine tumour of the gallbladder (separate, low grade)"],"biomarkers":["Synaptophysin, chromogranin A and CD56 on immunohistochemistry","Ki-67 proliferation index (median 70 percent)","Loss of pRB or p16 and mutant-pattern p53","Serum chromogranin A (proposed)","Share of neuroendocrine versus adenocarcinoma component"],"standardOfCare":[{"setting":"Localised disease","approach":"Resection as for gallbladder cancer where feasible; surgery and adjuvant chemotherapy were each associated with better survival in population data.","refs":["radical-cholecystectomy","extrapulmonary-nec"]},{"setting":"Advanced disease","approach":"Platinum and etoposide chemotherapy as for other extrapulmonary neuroendocrine carcinomas, rather than the gemcitabine and cisplatin used for adenocarcinoma.","refs":["extrapulmonary-nec","cisplatin","grade-3-net"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"gallbladder"},{"id":"neuroendocrine-neoplasms-breast","kind":"cancer","name":"Neuroendocrine neoplasms of the breast","aka":["Neuroendocrine carcinoma of the breast","Neuroendocrine tumour of the breast","Primary small cell neuroendocrine carcinoma of the breast","Breast carcinoma with neuroendocrine differentiation"],"tldr":"Neuroendocrine neoplasms of the breast are rare breast cancers whose cells make hormone-like granules, ranging from slow-growing tumours to small cell carcinoma like that of the lung. They are easily mistaken for ordinary breast cancer or for spread from elsewhere; slow-growing forms are treated like hormone-driven breast cancer and small cell forms with the lung small cell regimens.","summary":"The 2019 WHO classification divides neuroendocrine neoplasms of the breast into well-differentiated neuroendocrine tumour, neuroendocrine carcinoma (small cell and large cell) and, separately, invasive carcinomas of other types with neuroendocrine differentiation such as solid papillary and hypercellular mucinous carcinoma (Tan 2020). The entity as first defined by the WHO in 2012 spans well-differentiated tumours to highly aggressive small cell carcinomas; correct diagnosis needs an interdisciplinary approach because the tumours are misclassified as carcinoma with neuroendocrine differentiation, no special type carcinoma or a metastasis to the breast, and in one specialised unit only five of 612 neuroendocrine patients had a breast primary (Cancers 2020). Primary small cell neuroendocrine carcinoma of the breast is histologically indistinguishable from the lung tumour, so a primary elsewhere must be excluded, and there is no standard approach to treatment because only a limited number of cases have been reported (Int J Surg Case Rep 2017).\n\nHow it differs from its parent: the well-differentiated tumours are usually hormone-receptor positive and behave like luminal breast cancer, whereas the small cell carcinomas are treated with the platinum-etoposide regimens of small cell lung cancer rather than the breast pathways; neither has a trial of its own.\n\nHow common: no incidence figure is given in the sources read.\n\nTreatment: well-differentiated tumours as HR-positive breast cancer on the parent page; small cell and large cell neuroendocrine carcinoma with surgery and the extrapulmonary neuroendocrine carcinoma pathway (platinum and etoposide, radiotherapy), as the case literature describes (Int J Surg Case Rep 2017).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Breast_cancer_classification","links":[{"label":"Tan 2020, Histopathology: the 2019 WHO classification of tumours of the breast","url":"https://doi.org/10.1111/his.14091"},{"label":"Cancers 2020: primary neuroendocrine neoplasms of the breast, case series and literature review","url":"https://doi.org/10.3390/cancers12030733"},{"label":"Int J Surg Case Rep 2017: primary small cell neuroendocrine carcinoma of the breast, case and review","url":"https://doi.org/10.1016/j.ijscr.2017.07.002"}],"tags":["subtype-page","wave4","breast"],"related":["breast-cancer","breast-hr-positive","extrapulmonary-nec","papillary-carcinoma-breast","mucinous-carcinoma-breast"],"cancers":[],"sections":[],"technologies":["endocrine-therapy"],"targets":[],"drugs":["cisplatin","etoposide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Rare and probably under-diagnosed: five patients among 612 seen over 2008 to 2019 in one specialised neuroendocrine unit (Cancers 2020). No population figure is given in the sources read.","subtypes":["Well-differentiated neuroendocrine tumour of the breast (luminal, HR-positive)","Small cell neuroendocrine carcinoma of the breast","Large cell neuroendocrine carcinoma of the breast","Invasive carcinoma with neuroendocrine differentiation (solid papillary, hypercellular mucinous)"],"biomarkers":["Synaptophysin, chromogranin A and INSM1","Ki-67 and grade","Oestrogen and progesterone receptor (positive in well-differentiated tumours)","Exclusion of a lung or gut primary by imaging"],"standardOfCare":[{"setting":"Well-differentiated tumour","approach":"Treated as HR-positive breast cancer.","refs":["breast-hr-positive","endocrine-therapy"]},{"setting":"Small cell or large cell neuroendocrine carcinoma","approach":"Surgery and the extrapulmonary neuroendocrine carcinoma pathway (platinum and etoposide, radiotherapy); no standard exists.","refs":["extrapulmonary-nec","cisplatin","etoposide"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"breast-cancer"},{"id":"neuroendocrine","kind":"cancer","name":"Neuroendocrine tumours","aka":["Gastrointestinal Neuroendocrine Tumors","Pancreatic Neuroendocrine Tumors (Islet Cell Tumors)"],"tldr":"A family of usually slow-growing tumours that start in hormone-producing cells of the gut, pancreas and lungs. They pioneered the idea of using the same molecule to see a tumour on a scan and then to treat it with radiation.","summary":"Neuroendocrine neoplasms range from indolent grade 1 tumours that patients live with for decades to poorly differentiated neuroendocrine carcinomas that behave like small-cell lung cancer. Most arise in the small bowel, pancreas, rectum or lung; many secrete hormones (serotonin, insulin, gastrin) that cause syndromes, and most well-differentiated tumours express somatostatin receptor 2 (SSTR2), which is the hinge of both diagnosis and therapy. Incidence has risen six-fold over 40 years, largely from incidental detection on imaging and endoscopy.\n\nTherapy is sequenced by grade, receptor status and tempo. Somatostatin analogues (octreotide, lanreotide) control symptoms and slow growth (PROMID, CLARINET). For progression, peptide receptor radionuclide therapy with 177Lu-DOTATATE (NETTER-1; NETTER-2 first line for grade 2-3) is standard, and 177Lu-edotreotide beat everolimus head-to-head in COMPETE (PFS 23.9 vs 14.1 months) with an FDA decision due August 2026. Targeted pills (everolimus, sunitinib, and since March 2025 cabozantinib after CABINET) and chemotherapy (CAPTEM for pancreatic NETs; platinum-etoposide for neuroendocrine carcinoma) fill in. Surgery and liver-directed therapy (resection, embolisation, ablation, transplant in rare cases) remain central because disease is often liver-dominant.\n\nThe frontier is alpha-emitting PRRT: 212Pb-DOTAMTATE (AlphaMedix) met all primary endpoints in phase 2 with a 54% response rate in PRRT-naive patients and Breakthrough designation, and 225Ac-DOTATATE (RYZ101) is in the phase 3 ACTION-1 trial after lutetium failure. SSTR antagonist ligands, dosimetry-personalised dosing, and combinations with CAPTEM or immunotherapy are being tested. Open problems include the lack of randomised evidence for sequencing, the absence of effective therapy for SSTR-negative and high-grade disease, a 2-3% risk of therapy-related leukaemia after PRRT, and isotope supply.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor"}],"tags":["endocrine","spike"],"related":["sstr-pet-to-prrt","prrt-then-alpha-net","radiopharma-roadmap","beta-then-alpha"],"cancers":[],"sections":[],"technologies":["radioligand-therapy","targeted-alpha-therapy","pet","sstr-pet","prrt","pet-ct","tace","radioembolisation-tare","thermal-ablation","kinase-inhibitors","germline-testing","histopathology-ihc"],"targets":["sstr2","vegf","met","akt","menin","hif2a","dll3"],"drugs":["i131-mibg","telotristat-ethyl"],"companies":["crinetics-pharmaceuticals","molecular-partners","sinotau-pharmaceutical","vyriad","novartis","ipsen","itm","orano-med","radiomedix","sanofi","rayzebio","bms","exelixis","pfizer","alliance-oncology","ecog-acrin"],"institutions":["mskcc","uke-hamburg","heidelberg-nct","royal-marsden"],"pathways":[],"terms":["net-grade-ki67","chromogranin-a","carcinoid-syndrome","men1-hereditary-net","theranostics","alpha-vs-beta","dosimetry"],"trials":["nct06943755","netter-1","nct05459844","nct06398444","nct07544654","nct07087054","nct04919226"],"people":["steve-jobs"],"bottlenecks":[],"keyPapers":[],"journals":["endocrine-related-cancer"],"dependsOn":[],"notes":[],"group":"endocrine","burden":"About 7 per 100,000 people per year in the US, rising six-fold since the 1970s; prevalence is high because many patients live for years (>170,000 living with NETs in the US).","subtypes":["Small-bowel (midgut) NET, often with carcinoid syndrome","Pancreatic NET (functioning: insulinoma, gastrinoma, glucagonoma; non-functioning)","Lung NET (typical and atypical carcinoid)","Rectal and appendiceal NET (often incidental, excellent prognosis)","Grade 3 well-differentiated NET","Neuroendocrine carcinoma (small- and large-cell), treated like SCLC","Hereditary: MEN1, VHL, NF1, TSC; paraganglioma/phaeochromocytoma (SDHx)"],"biomarkers":["Ki-67 grade","SSTR PET uptake","Chromogranin A","MEN1, DAXX/ATRX","Ki-67 index and mitotic count (WHO grade)","SSTR2 expression by 68Ga/64Cu-DOTATATE PET","FDG PET avidity (high-grade or dedifferentiated disease)","Chromogranin A (monitoring)","24-hour urinary 5-HIAA (carcinoid syndrome)","Germline MEN1, VHL, SDHx testing","MGMT status (CAPTEM response, investigational)"],"standardOfCare":[{"setting":"Localised","approach":"Resection.","refs":[],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Advanced","approach":"SSA → 177Lu-DOTATATE → everolimus/cabozantinib/chemotherapy; alpha therapy in trials.","refs":["lutathera","ryz101"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Diagnosis and staging","approach":"Histology with Ki-67 grading; 68Ga/64Cu-DOTATATE PET/CT ± FDG PET; triple-phase CT or MRI of the liver; chromogranin A and syndrome-specific hormones; germline testing for pancreatic NETs and paragangliomas.","refs":["sstr-pet","net-grade-ki67","chromogranin-a","germline-testing","men1-hereditary-net"],"guideline":{"nccn":"Neuroendocrine and Adrenal Tumors","version":"NCCN 2026 / ENETS 2023"}},{"setting":"Localised disease","approach":"Surgical resection (including primary tumour resection with liver metastases where feasible); endoscopic resection for small rectal/gastric NETs; surveillance for small incidental lesions.","refs":["robotic-surgery"],"guideline":{"nccn":"Category 2A"}},{"setting":"Advanced, grade 1-2, SSTR-positive, first line","approach":"Somatostatin analogue (octreotide LAR or lanreotide); 177Lu-DOTATATE first line for grade 2-3 (NETTER-2) with high burden.","refs":["octreotide-lanreotide","promid","clarinet","lutathera","prrt"],"guideline":{"nccn":"Category 1 (SSA); category 1 PRRT for grade 2-3 first line"}},{"setting":"Advanced, progression on SSA","approach":"PRRT with 177Lu-DOTATATE (or 177Lu-edotreotide if approved); everolimus; sunitinib (pancreatic); cabozantinib (CABINET, all sites).","refs":["lutathera","itm-11","compete","everolimus","radiant-3-4","sunitinib","cabozantinib","cabinet"],"guideline":{"nccn":"Category 1 for PRRT and cabozantinib; 2A sequencing"}},{"setting":"Advanced pancreatic NET needing tumour shrinkage","approach":"CAPTEM (E2211); PRRT; liver-directed therapy for hepatic-dominant disease.","refs":["capecitabine-temozolomide","tace","radioembolisation-tare","thermal-ablation"],"guideline":{"nccn":"Category 2A"}},{"setting":"Carcinoid syndrome","approach":"SSA dose escalation; telotristat ethyl for refractory diarrhoea; octreotide infusion peri-procedurally; echocardiographic screening for carcinoid heart disease.","refs":["octreotide-lanreotide","carcinoid-syndrome"],"guideline":{"nccn":"Category 2A"}},{"setting":"Neuroendocrine carcinoma (poorly differentiated)","approach":"Platinum-etoposide (as in SCLC) ± PD-L1 inhibitor by extrapolation; FOLFIRINOX or CAPTEM in later lines; DLL3-directed agents in trials.","refs":["carboplatin","tarlatamab","atezolizumab"],"guideline":{"nccn":"Category 2A"}},{"setting":"After PRRT failure","approach":"Everolimus or cabozantinib; alpha PRRT in trials (ACTION-1, AlphaMedix); PRRT retreatment in selected patients.","refs":["ryz101","action-1","alphamedix","prrt-then-alpha-net"],"guideline":{"nccn":"Trials preferred"}},{"setting":"VHL-associated pancreatic NET","approach":"Belzutifan (approved 2021) for non-metastatic tumours not requiring immediate surgery.","refs":["belzutifan","men1-hereditary-net"],"guideline":{"nccn":"Category 2A"}}],"stateOfArt":["Theranostic paradigm; first-line PRRT in higher-grade disease.","Theranostic paradigm is routine: SSTR PET selects, 177Lu-DOTATATE treats, including first line for grade 2-3 disease.","First head-to-head radioligand-versus-drug trial (COMPETE) won on PFS; FDA decision on 177Lu-edotreotide due 28 August 2026.","Cabozantinib approved (2025) across pancreatic and extra-pancreatic NETs after prior therapy, with an 81% reduction in progression risk in lung/thymic NETs.","Alpha PRRT (212Pb-DOTAMTATE) met all phase 2 endpoints with Breakthrough designation; 225Ac-DOTATATE in phase 3.","Germline testing and syndrome-directed care (belzutifan for VHL) are standard for pancreatic NETs."],"history":[{"year":1907,"title":"Oberndorfer coins 'Karzinoid' for small-bowel tumours","refs":[]},{"year":1954,"title":"Carcinoid syndrome described (Thorson)","refs":["carcinoid-syndrome"]},{"year":1987,"title":"Octreotide approved","refs":[]},{"year":1988,"title":"Octreotide approved for carcinoid syndrome","refs":["octreotide-lanreotide"]},{"year":1994,"title":"111In-octreotide scintigraphy (OctreoScan) approved","note":"First SSTR imaging; later replaced by PET.","refs":["sstr-pet"]},{"year":2000,"title":"First 90Y- and 177Lu-DOTATOC/DOTATATE PRRT series (Rotterdam, Basel)","refs":["prrt"]},{"year":2009,"title":"PROMID: octreotide slows tumour growth","refs":["promid"]},{"year":2011,"title":"Everolimus (RADIANT-3) and sunitinib approved for pancreatic NETs","refs":["radiant-3-4","everolimus","sunitinib"]},{"year":2014,"title":"CLARINET: lanreotide antiproliferative approval","refs":["clarinet"]},{"year":2016,"title":"68Ga-DOTATATE PET (Netspot) approved; RADIANT-4 extends everolimus to lung/GI NETs","refs":["sstr-pet","radiant-3-4"]},{"year":2018,"title":"Lutathera approved","refs":["lutathera"]},{"year":2018,"title":"Lutathera approved (NETTER-1): PRRT enters standard care","refs":["lutathera","prrt"]},{"year":2020,"title":"SANET trials positive in China (surufatinib)","refs":["sanet"]},{"year":2024,"title":"NETTER-2: first-line PRRT","refs":[]},{"year":2024,"title":"NETTER-2: PRRT first line in grade 2-3; CABINET published; AlphaMedix Breakthrough designation","refs":["lutathera","cabinet","alphamedix"]},{"year":2025,"title":"Cabozantinib approved (March); COMPETE positive (ENETS, Lancet); AlphaMedix phase 2 meets all endpoints (October)","refs":["cabozantinib","compete","alphamedix-02"]},{"year":2026,"title":"FDA accepts 177Lu-edotreotide NDA (PDUFA 28 August); ACTION-1 dosimetry published; pancreatic subgroup of COMPETE at ENETS","refs":["itm-11","action-1"]}],"pipeline":["ryz101","pm8002","zg006","zanzalintinib","peluntamig","itm-11","compete","alphamedix","alphamedix-02","action-1","prrt","sstr-pet","cabozantinib","idea-net-dosimetry-prrt","idea-net-antagonist-ligands","prrt-then-alpha-net","tarlatamab","dll3"],"openProblems":["Neuroendocrine carcinoma (high grade) behaves like SCLC.","Sequencing of PRRT vs targeted therapy.","Sequencing is unproven: no randomised trial orders SSA, PRRT, everolimus, cabozantinib and chemotherapy.","SSTR-negative, FDG-avid and high-grade disease has few options; neuroendocrine carcinoma outcomes remain poor.","Therapy-related MDS/AML (~2-3%) and renal toxicity after PRRT; long-term data on retreatment are thin.","Overall survival benefits are hard to demonstrate because patients live for years and cross over.","Isotope supply (177Lu, 212Pb, 225Ac) and nuclear-medicine capacity limit access outside major centres.","Chromogranin A is an unreliable marker; better blood tests (NETest, ctDNA) are not validated for decisions.","Rare syndromic and paediatric NETs lack trials; hereditary carriers need lifelong surveillance protocols."]},{"id":"myeloma-transplant-eligible","kind":"cancer","name":"Newly diagnosed multiple myeloma, transplant-eligible","aka":["Transplant-eligible myeloma","TE NDMM","Newly diagnosed myeloma, fit for autologous transplant"],"tldr":"Fit patients with newly diagnosed myeloma receive four drugs at once, then their own stem cells are collected, they are given high-dose chemotherapy, the cells are returned and they continue on maintenance. Adding the CD38 antibody daratumumab to the three-drug backbone, tested in PERSEUS and CASSIOPEIA, means most patients now reach a state where no myeloma can be detected.","summary":"Eligibility for autologous transplant rests on age, organ function and frailty rather than a fixed cut-off; most centres transplant to around 70 to 75. The sequence is three to six cycles of induction, stem cell mobilisation and collection, high-dose melphalan with autologous stem cell rescue, consolidation and then lenalidomide maintenance until progression. Two randomised trials settled the place of the transplant in the era of modern induction: IFM 2009 and DETERMINATION both showed a longer remission with early transplant after bortezomib-lenalidomide-dexamethasone (median progression-free survival 67.5 versus 46.2 months in DETERMINATION) but no survival difference, so delayed transplant at first relapse is an accepted choice.\n\nInduction moved from triplets to quadruplets on the strength of CD38 antibodies. CASSIOPEIA (2019) added daratumumab to bortezomib-thalidomide-dexamethasone and raised stringent complete responses after consolidation from 20 to 29 percent while cutting progression or death by about half. PERSEUS (2024) added daratumumab to bortezomib-lenalidomide-dexamethasone around transplant with daratumumab-lenalidomide maintenance: progression-free survival at four years 84.3 percent versus 67.7 percent (hazard ratio 0.42), with three in four patients reaching MRD negativity at 10^-5, and daratumumab-VRd became the standard induction with regulatory approval in 2024. Isatuximab quadruplets (IsKia, GMMG-HD7) show the same pattern.\n\nMaintenance with lenalidomide until progression lengthens life (Myeloma XI, CALGB 100104); whether to add a CD38 antibody, and whether MRD-negative patients can stop, are the questions of the MIDAS, DRAMMATIC and other MRD-adapted trials. The larger question is whether the transplant itself is still needed when quadruplets produce such deep responses, and CARTITUDE-6 is testing cilta-cel CAR-T in its place. High-risk cytogenetics (del(17p), t(4;14), t(14;16), gain or amplification of 1q) still predict early relapse and are treated with the deepest available regimens, sometimes with tandem transplant.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Multiple_myeloma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Multiple_myeloma"},{"label":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}],"tags":["subtype-page"],"related":["myeloma-transplant-ineligible","plasma-cell-leukaemia","myeloma-relapsed-refractory","smouldering-myeloma"],"cancers":[],"sections":[],"technologies":["autologous-stem-cell-transplant","ngs-mrd-clonoseq"],"targets":["cd38","proteasome","cereblon"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["vrd","autologous-transplant","mrd-negativity-myeloma","high-risk-myeloma","r-iss","maintenance-therapy","proteasome-inhibitor","imid","m-protein-free-light-chains"],"trials":["cartitude-6","cassiopeia","ifm-2009","determination"],"people":[],"bottlenecks":[],"keyPapers":["paper-perseus-dara-vrd-transplant-nejm-2024","paper-cassiopeia-lancet-2019","paper-ifm-2009-attal-nejm-2017","paper-r-iss-palumbo-jco-2015"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Roughly four in ten people with newly diagnosed myeloma are fit enough for high-dose melphalan with an autologous stem cell transplant, generally those under about 70 without major organ disease.","subtypes":["Standard-risk transplant-eligible myeloma (R-ISS I or II without high-risk cytogenetics)","High-risk transplant-eligible myeloma (del(17p), t(4;14), t(14;16), gain 1q or R2-ISS high)","Transplant-deferred myeloma (stem cells collected, transplant kept for first relapse)","Light chain myeloma and IgA myeloma in fit patients"],"biomarkers":["R-ISS and R2-ISS stage","FISH: del(17p), t(4;14), t(14;16), gain or amplification 1q","Lactate dehydrogenase","Serum free light chains and M-protein","MRD by next-generation sequencing or flow cytometry at 10^-5 and 10^-6","Frailty and organ function for transplant fitness"],"standardOfCare":[{"setting":"Induction","approach":"Daratumumab plus bortezomib, lenalidomide and dexamethasone (PERSEUS) for four to six cycles; isatuximab-VRd or daratumumab-VTd (CASSIOPEIA) are alternatives.","refs":["daratumumab","bortezomib","lenalidomide","dexamethasone","perseus","isatuximab","vrd","cd38-plus-triplet"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Consolidation","approach":"High-dose melphalan with autologous stem cell transplant, early or deferred to first relapse after stem cell collection; tandem transplant considered in high-risk disease.","refs":["melphalan","autologous-stem-cell-transplant","autologous-transplant"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Maintenance","approach":"Lenalidomide until progression; daratumumab added after daratumumab-based induction (PERSEUS); bortezomib-containing maintenance in high-risk disease; MRD-guided stopping in trials.","refs":["lenalidomide","daratumumab","bortezomib","perseus","maintenance-therapy","idea-mrd-guided-stop-myeloma"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Response assessment","approach":"M-protein and free light chains every cycle, MRD by sequencing or flow cytometry after transplant and during maintenance, imaging for residual focal lesions.","refs":["ngs-mrd-clonoseq","flow-cytometry-mrd","mrd-negativity-myeloma","whole-body-mri","pet-ct"]}],"stateOfArt":["A daratumumab quadruplet around autologous transplant is standard after PERSEUS; most patients reach MRD negativity and more than eight in ten are progression-free at four years.","Early transplant lengthens remission but not life compared with a deferred transplant, so both are offered.","CAR-T in place of transplant and MRD-guided stopping of maintenance are under randomised test."],"history":[{"year":1983,"title":"McElwain: high-dose melphalan produces remissions in myeloma","refs":["melphalan"]},{"year":1996,"title":"IFM 90: autologous transplant beats conventional chemotherapy","refs":["autologous-stem-cell-transplant"]},{"year":2003,"title":"Bortezomib approved; proteasome inhibition enters induction","refs":["bortezomib"]},{"year":2012,"title":"Lenalidomide maintenance after transplant lengthens remission (IFM 2005-02, CALGB 100104)","refs":["lenalidomide"]},{"year":2017,"title":"IFM 2009: early transplant lengthens remission but not life after VRd","refs":["vrd"]},{"year":2019,"title":"CASSIOPEIA: daratumumab quadruplet raises deep responses","refs":["daratumumab"]},{"year":2024,"title":"PERSEUS: daratumumab-VRd around transplant approved as standard induction","refs":["perseus","daratumumab"]}],"pipeline":["daratumumab","isatuximab","ciltacabtagene-autoleucel","cartitude-5","idea-car-t-replaces-transplant","idea-mrd-guided-stop-myeloma"],"openProblems":["Whether high-dose melphalan is still necessary after a quadruplet that produces MRD negativity.","Whether MRD-negative patients can stop maintenance safely.","High-risk cytogenetic disease still relapses early despite quadruplets."],"parent":"multiple-myeloma"},{"id":"myeloma-transplant-ineligible","kind":"cancer","name":"Newly diagnosed multiple myeloma, transplant-ineligible","aka":["Transplant-ineligible myeloma","TI NDMM","Myeloma in older or frail patients","Newly diagnosed myeloma not for transplant"],"tldr":"Most people with newly diagnosed myeloma are too old or frail for a stem cell transplant. Combining a CD38 antibody with lenalidomide and dexamethasone (MAIA) and, for the fitter, with bortezomib as well (IMROZ), now keeps the disease away for around five years in many and lengthens life.","summary":"Transplant ineligibility is decided on frailty, comorbidity and organ function using the IMWG frailty index rather than age alone, and treatment intensity is scaled to it: fit older patients receive quadruplets, frail patients doublets or attenuated triplets with dose reductions. Continuous therapy until progression is the rule, since SWOG S0777 and FIRST showed that stopping shortens remission. Supportive care carries as much weight as the anti-myeloma drugs: bone protection with zoledronic acid or denosumab, infection prophylaxis, thrombosis prophylaxis on lenalidomide and attention to neuropathy from bortezomib.\n\nMAIA (2019) randomised 737 patients, median age 73, to daratumumab-lenalidomide-dexamethasone or lenalidomide-dexamethasone until progression: progression or death fell by 44 percent (hazard ratio 0.56), median progression-free survival later reached about five years, and the antibody lengthened overall survival (hazard ratio 0.68 at five years), making daratumumab-Rd the standard for older patients. IMROZ (2024) tested a quadruplet in fitter transplant-ineligible patients up to 80: isatuximab with bortezomib-lenalidomide-dexamethasone against VRd gave five-year progression-free survival of 63.2 percent versus 45.2 percent (hazard ratio 0.60), and CEPHEUS did the same with daratumumab-VRd, raising MRD negativity from 39.4 to 60.9 percent (progression-free survival hazard ratio 0.57). Both quadruplets are approved.\n\nThe frail remain under-served: they were largely excluded from these trials, tolerate bortezomib poorly, and gain less from a fourth drug. The BENEFIT trial suggested that weekly bortezomib added to isatuximab-Rd improves MRD negativity in this group, and dose-attenuated regimens, fixed-duration therapy, and bispecific antibodies in the front line (MajesTEC-7, CEPHEUS-type designs) are the current trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Multiple_myeloma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Multiple_myeloma"},{"label":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}],"tags":["subtype-page"],"related":["myeloma-transplant-eligible","plasma-cell-leukaemia","myeloma-relapsed-refractory","smouldering-myeloma"],"cancers":[],"sections":[],"technologies":["geriatric-assessment","ngs-mrd-clonoseq"],"targets":["cd38","proteasome","cereblon"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["vrd","mrd-negativity-myeloma","r-iss","maintenance-therapy","proteasome-inhibitor","imid"],"trials":["maia"],"people":[],"bottlenecks":[],"keyPapers":["paper-maia-daratumumab-rd-nejm-2019","paper-cepheus-dara-vrd-natmed-2025"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"More than half of people diagnosed with myeloma, typically over 70 or with frailty or organ disease, are not candidates for high-dose chemotherapy; their outlook has improved more than any other group's in the past decade.","subtypes":["Fit transplant-ineligible myeloma (quadruplet candidates, up to about 80)","Intermediate-fitness myeloma (daratumumab-Rd)","Frail myeloma (attenuated doublets or triplets, dose-reduced)","High-risk cytogenetic myeloma in older patients","Myeloma with renal failure at diagnosis"],"biomarkers":["IMWG frailty index","R-ISS and R2-ISS stage","FISH cytogenetics: del(17p), t(4;14), t(14;16), gain 1q","Renal function and light chain burden","MRD by sequencing or flow cytometry","Peripheral neuropathy baseline"],"standardOfCare":[{"setting":"Fit, transplant-ineligible","approach":"Isatuximab or daratumumab with bortezomib, lenalidomide and dexamethasone (IMROZ, CEPHEUS), continuing the antibody and lenalidomide until progression.","refs":["isatuximab","daratumumab","bortezomib","lenalidomide","dexamethasone","imroz","cepheus","vrd"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Intermediate fitness","approach":"Daratumumab with lenalidomide and dexamethasone until progression (MAIA).","refs":["daratumumab","lenalidomide","dexamethasone"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Frail","approach":"Daratumumab-Rd with reduced lenalidomide and dexamethasone, or lenalidomide-dexamethasone alone, with early dose reduction and steroid tapering.","refs":["daratumumab","lenalidomide","dexamethasone","geriatric-assessment"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Supportive care, all patients","approach":"Bisphosphonate or denosumab bone protection, antiviral and thrombosis prophylaxis, vaccination, renal protection and early management of neuropathy.","refs":["transfusion-support","maintenance-therapy"]}],"stateOfArt":["A CD38 antibody with lenalidomide-dexamethasone (MAIA) is standard for older patients and lengthens life; the fitter now receive quadruplets after IMROZ and CEPHEUS.","Frailty assessment, not age, sets treatment intensity.","Median progression-free survival in trial populations has reached about five years without a transplant."],"history":[{"year":1969,"title":"Melphalan and prednisone become the first standard for myeloma","refs":["melphalan","prednisone"]},{"year":2006,"title":"Thalidomide with melphalan-prednisone improves survival in older patients","refs":["thalidomide"]},{"year":2014,"title":"FIRST: continuous lenalidomide-dexamethasone beats melphalan-prednisone-thalidomide","refs":["lenalidomide"]},{"year":2017,"title":"SWOG S0777: bortezomib added to Rd lengthens life without transplant","refs":["bortezomib","vrd"]},{"year":2019,"title":"MAIA: daratumumab-Rd approved for transplant-ineligible myeloma","refs":["daratumumab"]},{"year":2024,"title":"IMROZ and CEPHEUS: quadruplets for fit transplant-ineligible patients","refs":["imroz","cepheus","isatuximab"]}],"pipeline":["isatuximab","daratumumab","teclistamab","cartitude-5","cepheus"],"openProblems":["Frail patients were excluded from the quadruplet trials and gain least from them.","Whether treatment can be fixed in duration or MRD-guided rather than continued until progression.","The cost of continuous antibody therapy for years in the largest myeloma population."],"parent":"multiple-myeloma"},{"id":"nodal-marginal-zone-lymphoma","kind":"cancer","name":"Nodal marginal zone lymphoma","aka":["NMZL","Nodal marginal zone B cell lymphoma","Nodal marginal zone B-cell lymphoma","Monocytoid B-cell lymphoma","Paediatric nodal marginal zone lymphoma"],"tldr":"Nodal marginal zone lymphoma is a slow-growing lymphoma of the lymph nodes that looks like the MALT and splenic types under the microscope but has no organ or spleen involvement to explain it. It lacks a diagnostic marker, so it is diagnosed by excluding the other small B-cell lymphomas, and it is treated like follicular lymphoma with rituximab-based therapy.","summary":"WHO-HAEM5 keeps nodal marginal zone lymphoma as the nodal member of the family, distinguished from splenic marginal zone lymphoma by its pattern of dissemination and still lacking distinct markers (Alaggio 2022; Spina 2016). Exome, targeted and transcriptome sequencing of 35 cases found a distinctive pattern of lesions: KMT2D (MLL2) mutated in 34 percent, PTPRD in 20 percent, NOTCH2 in 20 percent and KLF2 in 17 percent, with PTPRD mutations enriched in this lymphoma among mature B-cell tumours and linked to loss of phosphatase activity and increased proliferation (Spina 2016). Gene expression profiling against follicular lymphoma identified enriched interleukin, integrin, CD40, PI3K and NF-kB pathways, high SYK and TACI expression, and higher CHIT1, TGFB1 and TACI than the BCL6, LMO2 and CD10 of follicular lymphoma (Blood 2012). A paediatric type with an indolent course is recognised.\n\nHow it differs from its parent: no infection to eradicate and no spleen to remove; it presents like other indolent nodal lymphomas and its main difficulty is telling it from follicular lymphoma and from nodal spread of an extranodal or splenic marginal zone lymphoma.\n\nHow common: no registry share in the sources read; rare.\n\nTreatment: as for follicular lymphoma of the same stage, following the ESMO marginal zone guideline: involved-site radiotherapy for localised disease, watch and wait or rituximab with or without chemotherapy for advanced disease, and lenalidomide-rituximab or BTK inhibitors on relapse (Zucca 2020).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Marginal_zone_B-cell_lymphoma","links":[{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq"},{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"Zucca 2020, Annals of Oncology: marginal zone lymphomas, ESMO clinical practice guidelines","url":"https://doi.org/10.1016/j.annonc.2019.10.010"},{"label":"Spina 2016, Blood: the genetics of nodal marginal zone lymphoma","url":"https://doi.org/10.1182/blood-2016-02-696757"},{"label":"Blood 2012: nodal marginal zone lymphoma gene expression and miRNA profiling","url":"https://doi.org/10.1182/blood-2011-02-339556"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["marginal-zone-lymphoma","malt-lymphoma","splenic-marginal-zone-lymphoma","follicular-lymphoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["rituximab","bendamustine","lenalidomide","zanubrutinib"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-tx-watch-and-wait","lymphoma-tx-radiotherapy"],"trials":["augment","fort"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare; the largest genetic study holds 35 patients (Spina 2016). The ESMO guideline gives it as the rarest or second rarest of the three marginal zone lymphomas; no registry share is in the sources read.","subtypes":["Nodal marginal zone lymphoma, adult type (KMT2D, PTPRD, NOTCH2 and KLF2 mutations)","Paediatric nodal marginal zone lymphoma (indolent, localised, young males)","Nodal marginal zone lymphoma with plasmacytic differentiation"],"biomarkers":["Exclusion immunophenotype: CD20 positive, CD5, CD10, cyclin D1 and BCL6 negative","KMT2D, PTPRD, NOTCH2 and KLF2 mutations","Absence of extranodal or splenic disease on staging"],"standardOfCare":[{"setting":"All stages","approach":"Treated as follicular lymphoma of the same stage: radiotherapy when localised, rituximab with or without chemotherapy when advanced, lenalidomide-rituximab or BTK inhibitors on relapse.","refs":["follicular-lymphoma","rituximab","bendamustine","lenalidomide","zanubrutinib"]},{"setting":"Nodal marginal zone lymphoma: treated like follicular lymphoma, with the same choices","approach":"Nodal marginal zone lymphoma has no site-specific treatment of its own and is managed on the follicular lymphoma pathway: watch and wait while asymptomatic, involved-site radiotherapy at 24 Gy for genuinely localised disease, and rituximab-based chemoimmunotherapy (bendamustine and rituximab, or R-CVP) when the disease causes symptoms, organ compromise or cytopenias. Lenalidomide with rituximab is supported by AUGMENT, which enrolled marginal zone as well as follicular lymphoma and gave median progression-free survival of 39.4 against 14.1 months for rituximab alone. Zanubrutinib is an option at relapse on the strength of MAGNOLIA. Hepatitis C should be tested for, as in the splenic form. Transformation to diffuse large B-cell lymphoma is treated as aggressive lymphoma.","refs":["rituximab","bendamustine","lenalidomide","zanubrutinib","augment","lymphoma-tx-watch-and-wait","lymphoma-tx-radiotherapy","paper-magnolia-zanubrutinib-mzl-ccr-2021"],"guideline":{"version":"ESMO marginal zone lymphomas; NCCN B-Cell Lymphomas; AUGMENT, MAGNOLIA","url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-haematological-malignancies"}}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"marginal-zone-lymphoma"},{"id":"angioimmunoblastic-t-cell-lymphoma","kind":"cancer","name":"Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma)","aka":["Angioimmunoblastic T-cell lymphoma","AITL","Nodal TFH lymphoma","Nodal TFH lymphoma (angioimmunoblastic type)","nTFHL-AI","Angioimmunoblastic lymphadenopathy with dysproteinaemia"],"tldr":"Angioimmunoblastic T-cell lymphoma, now called nodal T-follicular helper cell lymphoma of angioimmunoblastic type, is one of the commonest T-cell lymphomas and mostly affects people over 60. It presents with widespread swollen nodes, fever, rash and immune upsets such as anaemia; about four in ten people are alive five years after chemotherapy, more after a transplant in first remission.","summary":"WHO-HAEM5 groups angioimmunoblastic T-cell lymphoma with follicular and not-otherwise-specified T-follicular helper lymphomas as nodal T-follicular helper cell lymphoma, angioimmunoblastic type being the commonest, defined by TFH markers (PD1, CXCL13, ICOS, BCL6, CD10), a polymorphous infiltrate with arborising venules and expanded follicular dendritic cell meshworks, EBV-positive B cells, and recurrent TET2, DNMT3A, RHOA G17V and IDH2 R172 mutations (Alaggio 2022). In the International Project, 76 percent presented with generalised lymphadenopathy and 89 percent with stage III or IV disease; rash occurred in 21 percent, haemolytic anaemia in 13 percent and hypergammaglobulinaemia in 30 percent; five-year overall and failure-free survival were 33 and 18 percent (Federico 2013). In the prospective T-cell Project, 282 patients had a median age of 64, 81 percent received anthracycline-based regimens, 13 percent had autologous transplant in first complete remission with improved outcomes, five-year overall and progression-free survival were 44 and 32 percent, and age 60 or over, poor performance status, raised C-reactive protein and raised beta-2 microglobulin predicted worse outcome (Advani 2021).\n\nHow it differs from its parent: the peripheral T-cell lymphoma page covers the group; this type is defined by its TFH origin and epigenetic mutations, which make it the T-cell lymphoma most responsive to histone deacetylase inhibitors and hypomethylating agents, and by its immune manifestations (autoimmune haemolysis, polyclonal hypergammaglobulinaemia, rashes) that can precede the diagnosis.\n\nHow common: 18.5 percent of peripheral T-cell lymphomas (Federico 2013).\n\nTreatment: CHOP-based chemotherapy (with etoposide in younger patients) and autologous transplant in first remission for fit patients, as on the parent page; romidepsin, belinostat, pralatrexate, and azacitidine with or without romidepsin in relapsed disease, with the TFH-phenotype trial of duvelisib (TERZO) linked here; brentuximab vedotin when CD30 is expressed (Advani 2021 for the transplant data).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Angioimmunoblastic_T-cell_lymphoma","links":[{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq"},{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"Federico 2013, JCO: angioimmunoblastic T-cell lymphoma in the International Peripheral T-cell Lymphoma Project","url":"https://doi.org/10.1200/jco.2011.37.3647"},{"label":"Advani 2021, Blood: outcomes and prognostic factors in angioimmunoblastic T-cell lymphoma, the international T-cell Project","url":"https://doi.org/10.1182/blood.2020010387"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["peripheral-t-cell-lymphoma","hepatosplenic-t-cell-lymphoma","cutaneous-t-cell-lymphoma","dlbcl","rhoa-g17v","ig-tcr-clonality"],"cancers":[],"sections":[],"technologies":["cgp","clonality-testing","histopathology-ihc"],"targets":["rhoa","tet2","dnmt3a","fyn","b2m","cd58","cd30","cd52"],"drugs":["cyclophosphamide","romidepsin","belinostat","pralatrexate","azacitidine","brentuximab-vedotin"],"companies":[],"institutions":[],"pathways":["epigenetic-reprogramming","clonal-haematopoiesis","jak-stat"],"terms":["r-chop","lymphoma-tx-regimen-alphabet","lymphoma-tx-transplant-role","lymphoma-tx-pjp-and-infection-prophylaxis","lymphoma-bio-lineage-antigen-cost"],"trials":["nct06522737"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"18.5 percent of peripheral T-cell and NK-cell lymphomas: 243 of 1,314 patients in the International Peripheral T-cell Lymphoma Project, making it one of the two commonest types (Federico 2013).","subtypes":["Nodal TFH lymphoma, angioimmunoblastic type (the commonest)","Nodal TFH lymphoma, follicular type","Nodal TFH lymphoma, not otherwise specified","Angioimmunoblastic T-cell lymphoma with EBV-positive B-cell proliferation or secondary B-cell lymphoma"],"biomarkers":["TFH markers: PD1, CXCL13, ICOS, BCL6, CD10","TET2, DNMT3A, RHOA G17V and IDH2 R172 mutations","EBV-positive B immunoblasts","C-reactive protein and beta-2 microglobulin (AITL prognostic score)"],"standardOfCare":[{"setting":"First line","approach":"CHOP-based chemotherapy, with etoposide in younger patients, and autologous transplant in first complete remission for fit patients (T-cell Project data).","refs":["peripheral-t-cell-lymphoma","cyclophosphamide","r-chop"]},{"setting":"Relapsed","approach":"Romidepsin, belinostat or pralatrexate; azacitidine with romidepsin; duvelisib in the TFH-phenotype trial TERZO; brentuximab vedotin when CD30-positive.","refs":["romidepsin","belinostat","pralatrexate","azacitidine","brentuximab-vedotin","nct06522737"]},{"setting":"Angioimmunoblastic T-cell lymphoma: treated as a nodal peripheral T-cell lymphoma, with two differences","approach":"First line is CHOP or CHOEP, with brentuximab vedotin substituted for vincristine where the tumour expresses CD30, and autologous transplant consolidation of a first remission in patients fit for it, exactly as for other nodal T-cell lymphomas. Two things are specific.\n\nThe presentation is often autoimmune rather than oncological: rash, polyclonal hypergammaglobulinaemia, autoimmune haemolytic anaemia, arthritis and a positive Coombs test in a systemically unwell older person. Corticosteroids produce a rapid response that can be mistaken for a diagnosis, and the lymphoma returns as soon as they are reduced. Infection risk is high because the immune system is already disordered, so prophylaxis against Pneumocystis and herpes is given from the start.\n\nThe mutational profile, TET2, DNMT3A, IDH2 and RHOA G17V, is the same set that produces clonal haematopoiesis, and it is the reason hypomethylating agents such as azacitidine and histone deacetylase inhibitors have more activity here than in other T-cell lymphomas. They are not yet a standard first-line option and belong in a trial.","refs":["lymphoma-tx-regimen-alphabet","brentuximab-vedotin","cyclophosphamide","doxorubicin","vincristine","prednisone","etoposide","romidepsin","belinostat","autologous-stem-cell-transplant","lymphoma-tx-pjp-and-infection-prophylaxis","lymphoma-tx-transplant-role"],"guideline":{"version":"NCCN T-Cell Lymphomas; ESMO","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":["Angioimmunoblastic T-cell lymphoma grows out of clonal haematopoiesis. The TET2 and DNMT3A mutations it carries are present in non-tumour blood cells as well as in the lymphoma, which places them earlier, in the stem cell; the RHOA G17V substitution is found only in the tumour cells and is the later, lineage-defining event.","RHOA G17V was reported in 68% of cases, and every case carrying it also carried a TET2 mutation. An independent series found it in 67% of angioimmunoblastic cases and 18% of peripheral T-cell lymphoma not otherwise specified, alongside IDH2, FYN, ATM, B2M and CD58 lesions.","The mutated protein does not bind GTP and also blocks the normal copy, so it works against the wild-type protein rather than simply failing. The epigenetic lesions are the reason hypomethylating agents are used and studied here, although no test selects them."],"history":[],"pipeline":[],"openProblems":[],"parent":"peripheral-t-cell-lymphoma"},{"id":"node-positive-penile-cancer","kind":"cancer","name":"Node-positive and metastatic penile cancer","aka":["Advanced penile squamous cell carcinoma","Inguinal node-positive penile cancer","Locally advanced penile cancer","Metastatic penile cancer"],"tldr":"Node-positive penile cancer is squamous cell cancer of the penis that has reached the lymph nodes of the groin or pelvis, and it is where penile cancer becomes life-threatening. Treatment combines removal of the groin nodes with chemotherapy or chemoradiotherapy before or after surgery, the InPACT trial is testing the best order, and PD-1 antibodies are being added for advanced disease.","summary":"Penile squamous cell carcinoma spreads in an orderly way from the primary to the superficial and deep inguinal nodes, then to the pelvic nodes and only later to distant sites, which is why inguinal lymphadenectomy can still cure patients with limited node disease. The 2023 EAU-ASCO guideline recommends radical inguinal lymphadenectomy for a positive sentinel node or a palpable, biopsy-proven node, with pelvic lymphadenectomy when two or more inguinal nodes are involved or a node shows extranodal extension. Survival falls steeply with the number of nodes, bilateral disease, extranodal extension and pelvic involvement, and lymphadenectomy itself carries high rates of wound breakdown and lymphoedema, which minimally invasive and robotic techniques aim to reduce.\n\nSystemic therapy is borrowed from small trials. The TIP regimen (paclitaxel, ifosfamide and cisplatin) produced responses in half of 30 patients given it before lymphadenectomy in a phase 2 trial at MD Anderson (Journal of Clinical Oncology 2010) and became the guideline neoadjuvant regimen for bulky or fixed nodes; paclitaxel and cisplatin with or without fluorouracil are alternatives. Adjuvant chemotherapy or chemoradiotherapy is offered after lymphadenectomy for pelvic node disease or extranodal extension, but the order and value of these treatments has never been randomised, which is what the international InPACT trial (International Penile Advanced Cancer Trial) is designed to answer. For metastatic disease platinum chemotherapy gives short responses, and phase 2 trials of pembrolizumab or cemiplimab, alone or with chemotherapy (HERCULES, EPIC), have shown responses in a subset, especially HPV-positive or PD-L1-positive tumours; the TG4001 HPV 16 vaccine with avelumab is also being tested in HPV 16-positive recurrent cancers.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Penile_cancer","links":[{"label":"Neoadjuvant TIP phase 2 (JCO 2010)","url":"https://doi.org/10.1200/JCO.2010.29.5477"},{"label":"InPACT (ISRCTN)","url":"https://www.isrctn.com/ISRCTN36516280"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Penile_cancer"}],"tags":["subtype-page","genitourinary"],"related":["localised-penile-cancer","penile","metastatic-anal-cancer"],"cancers":[],"sections":[],"technologies":["sentinel-node","robotic-surgery","cytotoxic-chemotherapy","checkpoint-inhibitor","imrt-igrt"],"targets":["pd1"],"drugs":["cisplatin","paclitaxel","ifosfamide","fluorouracil","pembrolizumab","cemiplimab"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphadenectomy","hpv-p16","hpv-status"],"trials":["nct03260023"],"people":[],"bottlenecks":[],"keyPapers":["paper-pagliaro-neoadjuvant-tip-penile-cancer-jco-2010","paper-eau-asco-penile-cancer-guideline-eur-urol-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"A minority of patients in high-income countries but the group in which most deaths occur; groin node involvement is the strongest predictor of survival.","subtypes":["Single inguinal node metastasis without extranodal extension (pN1; lymphadenectomy alone)","Multiple or bilateral inguinal node metastases (pN2; lymphadenectomy with adjuvant therapy considered)","Pelvic node metastasis or extranodal extension (pN3; multimodal therapy)","Bulky or fixed inguinal nodes (neoadjuvant TIP then surgery)","Distant metastatic penile squamous cell carcinoma"],"biomarkers":["Number, laterality and extranodal extension of inguinal nodes","Pelvic node involvement on CT or PET-CT","p16 immunohistochemistry and HPV DNA (prognostic, trial stratification)","PD-L1 expression (investigational)","TP53 and CDKN2A alterations in HPV-independent tumours"],"standardOfCare":[{"setting":"Positive sentinel node or resectable palpable nodes","approach":"Radical inguinal lymphadenectomy; pelvic lymphadenectomy when two or more inguinal nodes are involved or extranodal extension is found.","refs":["lymphadenectomy","sentinel-node","robotic-surgery"],"guideline":{"version":"EAU-ASCO Collaborative Guideline on Penile Cancer 2023","url":"https://doi.org/10.1016/j.eururo.2023.02.027"}},{"setting":"Bulky or fixed inguinal nodes","approach":"Neoadjuvant TIP chemotherapy (paclitaxel, ifosfamide, cisplatin) followed by lymphadenectomy in responders; chemoradiotherapy as an alternative within InPACT.","refs":["paclitaxel","ifosfamide","cisplatin","cytotoxic-chemotherapy","inpact"],"guideline":{"version":"EAU-ASCO Collaborative Guideline on Penile Cancer 2023","url":"https://doi.org/10.1016/j.eururo.2023.02.027"}},{"setting":"After lymphadenectomy with pelvic nodes or extranodal extension","approach":"Adjuvant chemotherapy or chemoradiotherapy, ideally within InPACT because the benefit is unproven.","refs":["cisplatin","paclitaxel","imrt-igrt","inpact"],"guideline":{"version":"EAU-ASCO Collaborative Guideline on Penile Cancer 2023","url":"https://doi.org/10.1016/j.eururo.2023.02.027"}},{"setting":"Metastatic disease","approach":"Platinum-based chemotherapy (TIP, paclitaxel-cisplatin, or with fluorouracil); PD-1 antibodies in trials or later lines (pembrolizumab, cemiplimab).","refs":["cisplatin","paclitaxel","fluorouracil","pembrolizumab","cemiplimab","checkpoint-inhibitor"],"guideline":{"version":"EAU-ASCO Collaborative Guideline on Penile Cancer 2023","url":"https://doi.org/10.1016/j.eururo.2023.02.027"}},{"setting":"HPV 16-positive recurrent disease","approach":"Trials of HPV-directed vaccines with checkpoint inhibition (TG4001 with avelumab).","refs":["nct03260023"],"guideline":{"version":"EAU-ASCO Collaborative Guideline on Penile Cancer 2023","url":"https://doi.org/10.1016/j.eururo.2023.02.027"}}],"stateOfArt":["Inguinal and pelvic lymphadenectomy still cures many men with limited node disease.","TIP chemotherapy before surgery for bulky nodes is the accepted approach, on phase 2 evidence.","InPACT is the first randomised trial to test the order of surgery, chemotherapy and radiotherapy."],"history":[{"year":1948,"title":"Daseler describes the anatomy of inguinal lymphadenectomy for penile cancer","refs":["lymphadenectomy"]},{"year":2010,"title":"MD Anderson phase 2: neoadjuvant TIP produces responses in half of men with bulky nodes","refs":["paclitaxel","ifosfamide","cisplatin"]},{"year":2017,"title":"InPACT opens in the United Kingdom, United States and Canada","refs":[]},{"year":2023,"title":"EAU-ASCO guideline codifies node management; HERCULES reports responses to pembrolizumab with chemotherapy","refs":["lymphadenectomy","pembrolizumab"]}],"pipeline":["pembrolizumab","cemiplimab","nct03260023"],"openProblems":["No randomised trial has ever shown that chemotherapy improves survival in penile cancer.","Lymphadenectomy causes lymphoedema and wound complications in a large share of patients.","Distant metastatic disease is rarely controlled for long.","HPV-positive and HPV-independent tumours may need different systemic strategies but are treated alike."],"parent":"penile"},{"id":"nodular-lymphocyte-predominant-hodgkin-lymphoma","kind":"cancer","name":"Nodular lymphocyte-predominant Hodgkin lymphoma (nodular lymphocyte-predominant B-cell lymphoma)","aka":["NLPHL","NLPBL","Nodular lymphocyte-predominant B-cell lymphoma","Lymphocyte-predominant Hodgkin disease","Popcorn cell lymphoma"],"tldr":"Nodular lymphocyte-predominant Hodgkin lymphoma is the rare, slow-growing cousin of classical Hodgkin lymphoma, so different in its CD20-bearing cells that the WHO renamed it a B-cell lymphoma in 2022. Early disease is usually cured with radiotherapy alone or surgery in children, advanced disease with rituximab-based chemotherapy, and patients are followed for life because it can return late.","summary":"Nodular lymphocyte-predominant Hodgkin lymphoma was separated from classical Hodgkin lymphoma in 1994 because its tumour cells, the 'popcorn' or LP cells, are CD20-positive, CD30- and CD15-negative B cells that keep their B-cell programme, sit in nodules of small B lymphocytes and follicular T-helper cells, and lack EBV; the 2022 WHO classification took the logic to its end and renamed the disease nodular lymphocyte-predominant B-cell lymphoma, while the International Consensus Classification kept the older name. It presents with a single group of peripheral nodes (neck, axilla or groin) in a young man, rarely in the mediastinum, and stays indolent for years; but a proportion of cases show T-cell-rich or diffuse growth patterns (Fan patterns C to F) that behave more aggressively and blur into T-cell/histiocyte-rich large B-cell lymphoma, into which the disease transforms in a minority over the following decades.\n\nTreatment is gentler than for classical disease. Stage IA disease without risk factors is cured in most patients by involved-site radiotherapy alone (30 Gy), and children with a completely excised single node can be watched without further treatment, as Children's Oncology Group and EuroNet studies showed. Stage II to IV disease is treated with chemotherapy, usually ABVD or, because the cells are CD20-positive, R-CHOP or R-CVP with rituximab, which some centres prefer for its lower risk of transformation; single-agent rituximab produces responses in most patients but they are not durable. Relapse is common but slow, and relapsed disease is treated with rituximab alone or with chemotherapy, radiotherapy or, rarely, autologous transplantation; transformation is treated as diffuse large B-cell lymphoma. Survival is excellent and most deaths in older series were from treatment or second cancers, which is the reason to treat as little as possible. Because the disease is rare and heterogeneous, trials are small, and the current questions are whether rituximab-based regimens should replace ABVD in advanced disease and how to identify the variant patterns that need more.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Nodular_lymphocyte_predominant_Hodgkin_lymphoma","links":[{"label":"NCCN Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Nodular_lymphocyte_predominant_Hodgkin_lymphoma"}],"tags":["subtype-page","haematologic"],"related":["early-stage-classical-hodgkin-lymphoma","advanced-stage-classical-hodgkin-lymphoma","hodgkin-lymphoma","follicular-lymphoma"],"cancers":[],"sections":[],"technologies":["imrt-igrt","fdg-pet","histopathology-ihc","autologous-stem-cell-transplant","active-surveillance"],"targets":[],"drugs":["rituximab","doxorubicin","vinblastine","dacarbazine","cyclophosphamide","vincristine","bendamustine"],"companies":[],"institutions":[],"pathways":[],"terms":["r-chop","abvd-beacopp","lymphoma-type","lugano-classification","lymphoma-tx-radiotherapy","lymphoma-tx-hodgkin-late-effects","lymphoma-tx-watch-and-wait","lymphoma-tx-regimen-alphabet"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2022-lymphoid-alaggio-leukemia-2022","paper-eichenauer-nlphl-ghsg-hd7-hd15-long-term-jco-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About one in twenty Hodgkin lymphomas, mostly in men in their thirties and forties and in boys; it is indolent, rarely fatal, but relapses over decades and can transform into an aggressive B-cell lymphoma.","subtypes":["Stage IA nodular lymphocyte-predominant Hodgkin lymphoma (radiotherapy alone or excision and observation in children)","Stage II to IV nodular lymphocyte-predominant Hodgkin lymphoma (ABVD or R-CHOP)","Typical nodular growth pattern (Fan patterns A and B; indolent)","Variant growth patterns (Fan patterns C to F; T-cell-rich or diffuse, more aggressive)","Relapsed nodular lymphocyte-predominant Hodgkin lymphoma (rituximab-based)","Transformation to T-cell/histiocyte-rich large B-cell lymphoma"],"biomarkers":["CD20-positive, CD30- and CD15-negative LP cells with OCT2 and PAX5 expression","Fan growth pattern (A to F) on the biopsy","Absence of EBV","Stage and number of nodal sites","Lactate dehydrogenase and B symptoms (transformation suspicion)","FDG-PET (staging; avid)"],"standardOfCare":[{"setting":"Diagnosis","approach":"Excisional node biopsy with expert haematopathology review to distinguish from classical Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma; FDG-PET/CT staging.","refs":["histopathology-ihc","fdg-pet","lugano-classification","lymphoma-type"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Stage IA without risk factors","approach":"Involved-site radiotherapy alone (30 Gy); in children, complete excision followed by observation.","refs":["imrt-igrt","active-surveillance","childrens-oncology-group"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Stage IB to IV","approach":"ABVD or rituximab-containing chemotherapy (R-CHOP, R-CVP, R-ABVD) with or without involved-site radiotherapy; rituximab alone for frail patients.","refs":["rituximab","r-chop","abvd-beacopp","doxorubicin","cyclophosphamide","vincristine","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Relapse","approach":"Rebiopsy to exclude transformation; rituximab alone or with chemotherapy, radiotherapy for localised relapse; autologous transplantation only for early or repeated relapse.","refs":["rituximab","autologous-stem-cell-transplant","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Transformation","approach":"Treat as diffuse large B-cell lymphoma with R-CHOP.","refs":["r-chop","rituximab"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Nodular lymphocyte-predominant Hodgkin lymphoma: a different disease that keeps the name","approach":"The malignant cell expresses CD20 and not CD30 or CD15, which is the opposite of classical Hodgkin lymphoma and the reason rituximab works and brentuximab vedotin does not. The WHO fifth edition renames it nodular lymphocyte-predominant B-cell lymphoma, which is a better description. It is indolent, affects men more than women, and relapses late.\n\nStage IA disease without risk factors is treated with involved-site radiotherapy alone, typically 30 Gy, and a substantial proportion never relapse. Complete surgical excision of a single node followed by observation is used in children and in selected adults.\n\nMore advanced disease is treated with rituximab-containing systemic treatment: R-CHOP, R-ABVD or bendamustine with rituximab, with or without radiotherapy to a residual site. A retrospective population series of 23 patients treated with bendamustine and rituximab in Alberta reported a response rate of 100 per cent, complete response in 78 per cent, and four-year progression-free survival of 83 per cent and overall survival of 87 per cent, which is the kind of evidence this uncommon disease has.\n\nThe long-term data make the central point about how gently it should be treated. Across 471 patients in the German Hodgkin Study Group HD7 to HD15 trials, ten-year progression-free survival was 75.5 per cent and overall survival 92.1 per cent, but second malignancies occurred in 10.2 per cent, and of 43 deaths only 10 were from the lymphoma against 20 from second cancers and 13 from possibly treatment-related conditions. Over-treatment, not the lymphoma, is the main threat to life here.\n\nTransformation to a T-cell/histiocyte-rich large B-cell lymphoma occurs in a minority and is treated as aggressive lymphoma.","refs":["paper-eichenauer-nlphl-ghsg-hd7-hd15-long-term-jco-2020","rituximab","bendamustine","r-chop","doxorubicin","cyclophosphamide","vincristine","prednisone","imrt-igrt","lymphoma-tx-radiotherapy","lymphoma-tx-watch-and-wait","lymphoma-tx-hodgkin-late-effects","secondary-malignancy"],"guideline":{"version":"NCCN Hodgkin Lymphoma; ESMO; GHSG HD7 to HD15 long-term follow-up","url":"https://doi.org/10.1111/ejh.14443"}}],"stateOfArt":["Radiotherapy alone or excision cures most early-stage patients with minimal toxicity.","Rituximab, useless in classical Hodgkin lymphoma, is active here because the cells are CD20-positive.","The 2022 renaming reflects a disease now understood as an indolent B-cell lymphoma."],"history":[{"year":1944,"title":"Jackson and Parker describe the paragranuloma form of Hodgkin disease","refs":[]},{"year":1966,"title":"Lukes and Butler define lymphocyte-predominant Hodgkin disease","refs":[]},{"year":1994,"title":"REAL classification separates nodular lymphocyte-predominant from classical Hodgkin lymphoma","refs":["lymphoma-type"]},{"year":2003,"title":"Fan describes the six growth patterns that predict behaviour","refs":[]},{"year":2017,"title":"Children's Oncology Group shows excision alone is enough for completely resected stage IA disease in children","refs":["childrens-oncology-group"]},{"year":2022,"title":"WHO renames the disease nodular lymphocyte-predominant B-cell lymphoma","refs":["lymphoma-type"]}],"pipeline":["rituximab"],"openProblems":["No randomised trial has compared ABVD with rituximab-based chemotherapy.","Variant growth patterns are hard to reproduce between pathologists.","Late relapse and transformation over decades make lifelong follow-up necessary.","The rarity of the disease limits every study to retrospective series."],"parent":"hodgkin-lymphoma"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","aka":["Non-Hodgkin Lymphoma","NHL","Non-Hodgkin's lymphoma","Lymphoma (non-Hodgkin)","Lymphoma","Mature B-cell neoplasms","Mature T-cell and NK-cell neoplasms","B-cell lymphoma","T-cell lymphoma","NK-cell lymphoma","Lymphatic cancer","Cancer of the lymph glands","C82","C83","C84","C85","C86"],"tldr":"Non-Hodgkin lymphoma is not one disease but a family of more than sixty cancers of the lymphocytes, the white blood cells of the immune system. About 95 per cent come from B cells and the rest from T or NK cells; some grow over years and are watched, others grow over weeks and are treated to cure. The family is the map; the subtype is the disease, and the subtype is what decides the treatment.","summary":"What it is. Non-Hodgkin lymphoma is not a disease. It is the name given to every cancer of the lymphatic system that is not Hodgkin lymphoma, and it covers scores of separate diseases whose only shared feature is the cell they come from: the tables of the 2022 WHO classification list more than sixty mature B-cell, T-cell and NK-cell entities: a lymphocyte, one of the white blood cells that run the immune system. Two people both told they have non-Hodgkin lymphoma may have conditions that differ more from each other than breast cancer differs from bowel cancer. One may be watched for ten years without treatment; the other may start chemotherapy the week of diagnosis with the intention of cure. The single most useful thing to find out after the word lymphoma is the rest of the name on the report, because that is what decides everything.\n\nHow the classification is built, in plain words. The reference book is the fifth edition of the World Health Organization Classification of Haematolymphoid Tumours, published in 2022 and usually shortened to WHO-HAEM5. It does not use the phrase non-Hodgkin lymphoma at all. It sorts lymphomas on a tree: first by the class of cell, then into a family of related diseases, then into the entity that is the diagnosis. The first fork is B-cell on one side and T-cell and NK-cell on the other. B cells make antibodies; T cells and NK cells kill infected cells directly. In the United Kingdom the B-cell side is about 95 per cent of lymphoma diagnoses and the T-cell and NK-cell side about 5 per cent (Haematological Malignancy Research Network, 5,796 lymphomas in a population of nearly four million). That first fork matters because B cells carry a protein called CD20 on their surface and T cells do not, and the antibody that attaches to CD20, rituximab, is the drug that transformed B-cell lymphoma from 1997 onwards and has no equivalent on the T-cell side.\n\nThe second thing a reader is told is the pace, and it is the fork that decides what happens next week. Indolent lymphomas grow over years: follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, most cutaneous T-cell lymphoma. They are generally not curable with the treatments in use today, and they are also not usually urgent, so a person with no symptoms may reasonably be watched rather than treated, sometimes for a decade. Aggressive lymphomas grow over weeks: diffuse large B-cell lymphoma, high-grade B-cell lymphoma, Burkitt lymphoma, most of the T-cell lymphomas. They are treated immediately and they are treated to cure. The sentence that surprises people most is that the aggressive ones are the ones more often cured, and the slow ones the ones more often lived with. Waiting is not neglect in an indolent lymphoma; it is the treatment that has been shown not to shorten life, and the glossary entry on watching and waiting says what is being watched for.\n\nThe third fork is where the lymphoma is. Nodal lymphoma arises in lymph nodes, the bean-sized filters strung along the lymphatic vessels, and shows itself as a painless lump in the neck, armpit or groin. Extranodal lymphoma arises in an organ that has lymphoid tissue in it but is not a lymph node: the stomach, the eye socket, the skin, the brain, the testis, the small bowel, the thyroid, the salivary gland. A substantial minority of non-Hodgkin lymphomas start outside the lymph nodes, and the site changes the disease. A marginal zone lymphoma in the stomach is usually caused by a bacterial infection and is usually cured by a fortnight of antibiotics; the same cell type in a lymph node is not. A large B-cell lymphoma in the testis, the eye or the brain behaves as one disease across those three sites, which WHO-HAEM5 recognised in 2022 by grouping them as lymphomas of immune-privileged sites, places the immune system does not patrol.\n\nWho gets it. Lymphoma is mostly a disease of later life: the median age at diagnosis in the HMRN population was 67.2 years for all lymphomas together and 69.1 years for the non-Hodgkin group, with men diagnosed younger than women and at higher rates at almost every age. But the family spans every age, and different subtypes dominate different ages: Burkitt lymphoma and Hodgkin lymphoma are the common lymphomas of childhood and early adult life, while above 60 the diffuse large B-cell, marginal zone and follicular subtypes account for more than 80 per cent of diagnoses. Most people with lymphoma have no identifiable cause. The known causes account for a minority and are worth naming because several are preventable or treatable: Epstein-Barr virus, the virus of glandular fever, which is involved in Burkitt lymphoma, in some diffuse large B-cell lymphomas and in extranodal NK/T-cell lymphoma; Helicobacter pylori in the stomach; hepatitis C; HIV; HTLV-1, which causes adult T-cell leukaemia/lymphoma; Kaposi sarcoma herpesvirus, which causes primary effusion lymphoma; coeliac disease, which precedes enteropathy-associated T-cell lymphoma; immune suppression after an organ transplant; and autoimmune diseases such as Sjogren syndrome and Hashimoto thyroiditis, which produce the lymphoid tissue that marginal zone lymphomas grow in. Cancer Research UK estimates that about 3 per cent of UK cases are preventable, which is the honest counterpart to the fact that most people did nothing to cause this.\n\nHow it is staged, and why the old words survive. Lymphoma is not staged with the TNM system used for solid tumours, because it does not have a primary tumour and lymph nodes in the way a breast or bowel cancer does: in lymphoma, the lymph nodes are the disease. The system in use is the Lugano classification, agreed at the International Conference on Malignant Lymphoma in Lugano in 2011 and published in 2014. It counts how many regions of lymph nodes are involved and whether they sit on one side of the diaphragm or both: stage I is one region, stage II is two or more on the same side, stage III is both sides, stage IV is disease that has spread diffusely into an organ such as the bone marrow, liver or lung. Lugano kept the descriptive language of the Ann Arbor system that preceded it, agreed at a meeting in Ann Arbor, Michigan in 1971 for Hodgkin's disease, which is why a report in 2026 may still say Ann Arbor stage IIA and mean the same thing. What Lugano changed is how the stage is measured: PET-CT scanning became the standard staging test for the lymphomas that take up the tracer, the A and B suffixes for fever, night sweats and weight loss are now recorded only for Hodgkin lymphoma, and a routine bone marrow biopsy is no longer needed to stage Hodgkin lymphoma or, in most cases, diffuse large B-cell lymphoma.\n\nStage is not the main thing. This is the largest difference between lymphoma and the cancers most people have heard of. In breast or bowel cancer the stage is the dominant fact; in lymphoma the subtype matters more, and within a subtype the prognosis is read from a score that counts clinical features rather than anatomy. The International Prognostic Index, built in 1993 from 2,031 patients with aggressive lymphoma treated across 16 institutions, counts five: age over 60, stage III or IV, a raised lactate dehydrogenase, a performance status of 2 or worse, and more than one site outside the lymph nodes. Follicular lymphoma has its own version (FLIPI), mantle cell lymphoma has MIPI, and the nodal T-cell lymphomas have the Prognostic Index for T-cell lymphoma, built from 385 patients in 2004. Stage IV lymphoma is a routine curable diagnosis, which is the opposite of what the word means in most other cancers, and it is worth saying out loud at the point where somebody has just been handed the number.\n\nThe state of the art, in one paragraph. The B-cell side has had thirty years of advances that compound. Rituximab, approved in 1997, was the first antibody ever licensed for a cancer, and adding it to chemotherapy raised both the proportion of people whose diffuse large B-cell lymphoma went away and the proportion still alive years later; the trial and its figures are on that page. CAR-T cell therapy, in which a patient's own T cells are collected, engineered to recognise CD19 and given back, was approved for relapsed large B-cell lymphoma in 2017 and now cures a proportion of people whose disease had come back after chemotherapy. Bispecific antibodies, which grip a lymphoma cell with one arm and a T cell with the other, arrived in 2023 and do a related job without the manufacturing wait. Antibody-drug conjugates deliver chemotherapy to the cell that carries a particular marker. The T-cell and NK-cell side has had almost none of this: there is no CD20 to aim at, the entities are individually rare, and brentuximab vedotin added to chemotherapy for CD30-positive disease is the only randomised first-line advance in twenty years. The gap between the two sides of the first fork is the largest unsolved problem in this family, and it is a gap in research effort as much as in biology.\n\nA note on names. Because two classifications were published in 2022 and they do not agree about everything, a British report, an American report and a trial protocol may give the same disease three names. Where that happens the pages in this family give both and say which book each name comes from. The glossary entry on the two classifications lists the disagreements that change what a patient is called.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Non-Hodgkin_lymphoma","links":[{"label":"NCI: Lymphoma","url":"https://www.cancer.gov/types/lymphoma"},{"label":"GLOBOCAN 2020 (Sung 2021)","url":"https://doi.org/10.3322/caac.21660"},{"label":"Lymphoma Action: helpline services","url":"https://lymphoma-action.org.uk/information-and-support/support-you/helpline-services"},{"label":"Lymphoma Action: questions to ask your medical team about lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/questions-ask-your-medical-team-about-lymphoma"},{"label":"Lymphoma Action: follow-up after lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/follow-after-lymphoma-treatment"},{"label":"Lymphoma Action: infections, risk and prevention","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/infections-risk-and-prevention"},{"label":"Lymphoma Action: neutropenia (low neutrophils)","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/neutropenia-low-neutrophils"},{"label":"Lymphoma Action: cancer-related fatigue","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/cancer-related-fatigue"},{"label":"Lymphoma Action: lymphoma, work and you","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/day-day-living/lymphoma-work-and-you"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"NHS: non-Hodgkin lymphoma","url":"https://www.nhs.uk/conditions/non-hodgkin-lymphoma/"},{"label":"NHS: non-Hodgkin lymphoma, symptoms","url":"https://www.nhs.uk/conditions/non-hodgkin-lymphoma/symptoms/"},{"label":"NHS: non-Hodgkin lymphoma, treatment","url":"https://www.nhs.uk/conditions/non-hodgkin-lymphoma/treatment/"},{"label":"Macmillan: lymphoma","url":"https://www.macmillan.org.uk/cancer-information-and-support/lymphoma"},{"label":"Macmillan: non-Hodgkin lymphoma","url":"https://www.macmillan.org.uk/cancer-information-and-support/lymphoma/non-hodgkin-lymphoma"},{"label":"Cancer Research UK: living with non-Hodgkin lymphoma","url":"https://www.cancerresearchuk.org/about-cancer/non-hodgkin-lymphoma/living-with"},{"label":"Cancer Research UK: tests to diagnose non-Hodgkin lymphoma","url":"https://www.cancerresearchuk.org/about-cancer/non-hodgkin-lymphoma/getting-diagnosed/tests-diagnose"},{"label":"Cancer Research UK: follow-up for non-Hodgkin lymphoma","url":"https://www.cancerresearchuk.org/about-cancer/non-hodgkin-lymphoma/treatment/follow-up"},{"label":"NICE NG52: non-Hodgkin's lymphoma, diagnosis and management","url":"https://www.nice.org.uk/guidance/ng52"},{"label":"NICE NG47: haematological cancers, improving outcomes","url":"https://www.nice.org.uk/guidance/ng47"},{"label":"Lymphoma Action: lymphoma staging","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/lymphoma-staging"},{"label":"Lymphoma Action: biopsy","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/biopsy"},{"label":"Lymphoma Action: CT and PET/CT scans","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/ct-and-petct-scan"},{"label":"Lymphoma Action: waiting for test and scan results","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/waiting-test-and-scan-results"},{"label":"Lymphoma Action: your medical team","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/your-medical-team-mdt"},{"label":"Lymphoma Action: taking part in a clinical trial","url":"https://lymphoma-action.org.uk/information-and-support/lymphoma-treatment/clinical-trials-lymphoma-trialslink/taking-part-clinical"},{"label":"Lymphoma Action: caring for someone who has lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/relationships-family-friends/caring-someone-who-has-lymphoma"},{"label":"NHS: carer's assessments","url":"https://www.nhs.uk/social-care-and-support/support-and-benefits-for-carers/carer-assessments/"},{"label":"NHS: when to use 111","url":"https://www.nhs.uk/nhs-services/urgent-and-emergency-care-services/when-to-use-111/"},{"label":"NHS: when to call 999","url":"https://www.nhs.uk/nhs-services/urgent-and-emergency-care-services/when-to-call-999/"},{"label":"NHS: sepsis","url":"https://www.nhs.uk/conditions/sepsis/"},{"label":"Macmillan: metastatic spinal cord compression","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/metastatic-spinal-cord-compression"},{"label":"Macmillan: superior vena cava obstruction","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/superior-vena-cava-obstruction"},{"label":"NICE NG234: spinal metastases and metastatic spinal cord compression","url":"https://www.nice.org.uk/guidance/ng234"},{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"},{"label":"Lugano classification: recommendations for initial evaluation, staging and response assessment of Hodgkin and non-Hodgkin lymphoma (Cheson, J Clin Oncol 2014)","url":"https://doi.org/10.1200/JCO.2013.54.8800"},{"label":"SEER Cancer Stat Facts: non-Hodgkin lymphoma (United States incidence, mortality and relative survival)","url":"https://seer.cancer.gov/statfacts/html/nhl.html"},{"label":"Cancer Research UK: non-Hodgkin lymphoma statistics (incidence, mortality, survival)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/non-hodgkin-lymphoma"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (patient version)","url":"https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq"},{"label":"Lymphoma Action: types of lymphoma (UK patient charity)","url":"https://lymphoma-action.org.uk/types-lymphoma"},{"label":"Lymphoma Research Foundation: about lymphoma","url":"https://lymphoma.org/understanding-lymphoma/aboutlymphoma/"},{"label":"GLOBOCAN 2020 global cancer statistics (Sung, CA Cancer J Clin 2021)","url":"https://doi.org/10.3322/caac.21660"},{"label":"NICE NG12: suspected cancer, haematological cancers (1.10.1 to 1.10.9)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"},{"label":"Lymphoma Action: the UK lymphoma charity","url":"https://lymphoma-action.org.uk/"},{"label":"Cancer Research UK: non-Hodgkin lymphoma statistics","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/non-hodgkin-lymphoma"}],"tags":["heme","umbrella"],"related":["dlbcl","follicular-lymphoma","mantle-cell-lymphoma","cll","burkitt-lymphoma","waldenstrom","primary-cns-lymphoma","peripheral-t-cell-lymphoma","hiv-associated-lymphoma","hodgkin-lymphoma","bcl2-rearrangement","double-hit-rearrangement","myc-bcl2-double-expressor","cd79b-itam-mutation","ezh2-y646-mutation","btk-c481s","bcl2-g101v","rhoa-g17v","pd-ligand-9p24-alteration","ig-tcr-clonality","marginal-zone-lymphoma","primary-mediastinal-b-cell-lymphoma","high-grade-b-cell-lymphoma-myc-bcl2","t-cell-histiocyte-rich-large-b-cell-lymphoma","primary-testicular-lymphoma","mycosis-fungoides","extranodal-nk-t-cell-lymphoma","lymphoma-roadmap","lymphoma-ev-genetic-subtype-directed-first-line","lymphoma-ev-ctdna-instead-of-the-interim-scan","lymphoma-ev-radiotherapy-free-early-hodgkin","lymphoma-ev-fixed-duration-chemotherapy-free-first-line","lymphoma-ev-randomised-evidence-for-the-t-cell-lymphomas","lymphoma-ev-manufacturing-time-as-a-trial-endpoint","lymphoma-ev-the-drugs-that-cure-and-the-places-without-them","lymphoma-ev-late-effects-of-the-treatments-given-now"],"cancers":[],"sections":[],"technologies":["car-t","t-cell-engager","adc","palliative-care","psycho-oncology","peer-support-groups","survivorship-care-plan","fertility-preservation","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","multidisciplinary-tumour-board","oncology-nutrition","prehabilitation","bispecific-antibody","autologous-stem-cell-transplant","pet-ct","clonality-testing","histopathology-ihc","cytogenetics-fish","flow-cytometry-mrd","ngs-mrd-clonoseq","ctdna-lymphoma-monitoring","pet-adapted-therapy","fdg-pet","cgp","liquid-biopsy","checkpoint-inhibitor","monoclonal-antibody","wes-wgs","ngs"],"targets":["cd20","cd19","btk","bcl2","cd30","cd79b","cd22","cd38","cd3","cd47","ccr4","cd52","syk","plcg2","prkcb","card11","myd88","mcl1","bim","bcl6","myc-gene","ezh2","crebbp","ep300","kmt2d","tp53","cdkn2a","jak1","jak2","jak3","stat3","stat5","stat6","socs1","ciita","rhoa","tet2","dnmt3a","fyn","b2m","cd58","malt1","bcl10","birc3","tnfaip3","ccnd1","ccnd3","tcf3","id3","notch1","notch2","irf4","vav1","plcg1","atm","pdl1"],"drugs":["rituximab","polatuzumab-vedotin","ibrutinib","venetoclax","brentuximab-vedotin"],"companies":[],"institutions":["lymphoma-action","blood-cancer-uk","anthony-nolan"],"pathways":["germinal-centre-reaction","bcr-signalling","inflammation-nfkb","apoptosis-bcl2","myc","jak-stat","epigenetic-reprogramming","pd1-checkpoint","cd47-sirpa","oncogenic-viruses","antigen-presentation-immunoediting","tumor-microenvironment","resistance-routes-map","clonal-evolution","transcription-addiction"],"terms":["lymphoma-tx-regimen-alphabet","lymphoma-tx-watch-and-wait","lymphoma-tx-tumour-lysis","lymphoma-tx-hepatitis-b-reactivation","lymphoma-tx-pjp-and-infection-prophylaxis","lymphoma-tx-immunoglobulin-replacement","lymphoma-tx-crs-icans","lymphoma-tx-fertility-preservation","lymphoma-tx-uk-versus-us","lymphoma-tx-uk-access","lymphoma-tx-failed-and-negative","lymphoma-tx-pod24","lymphoma-tx-transplant-role","lymphoma-tx-car-t-pathway","lymphoma-tx-bispecific-step-up","lymphoma-tx-radiotherapy","lymphoma-tx-maintenance","lymphoma-tx-cns-prophylaxis","cancer-related-fatigue","late-effects","febrile-neutropenia","neutropenia","financial-toxicity","central-venous-access","hypogammaglobulinaemia","performance-status","quality-of-life","lymphoma-decision-watch-and-wait","lymphoma-decision-transplant-or-car-t","lymphoma-decision-beacopp-or-abvd","lymphoma-decision-fertility-timing","lymphoma-decision-trial","lymphoma-decision-local-or-car-t-centre","lymphoma-living-fatigue","lymphoma-living-hodgkin-survivorship-screening","lymphoma-living-infection-years-after","lymphoma-living-vaccinations","lymphoma-living-scanxiety-and-surveillance","lymphoma-living-returning-to-work","lymphoma-living-indolent-lymphoma","watchful-waiting","crs","icans","tumor-lysis-syndrome","secondary-malignancy","cardiotoxicity","deauville","lymphoma-bio-germinal-centre","lymphoma-bio-cell-of-origin-in-practice","lymphoma-bio-lymphgen","lymphoma-bio-antigen-escape","lymphoma-bio-lineage-antigen-cost","lymphoma-bio-ebv-latency","lymphoma-bio-htlv1","lymphoma-bio-hodgkin-microenvironment","lymphoma-bio-transformation","cell-of-origin","plasma-ebv-dna","flipi","fish","ihc","ngs","mrd","ctdna","cytogenetics","gene-fusion","gene-amplification","driver-mutation","resistance","cross-resistance","lymphoma-classification-2022","lymphoma-b-versus-t-cell","lymphoma-indolent-versus-aggressive","lymphoma-nodal-versus-extranodal","lymphoma-transformation","lymphoma-pit-score","lymphoma-htlv-1","lugano-classification","deauville-score","ipi-score","mipi","lymphoma-type","ebv-term","r-chop","double-hit-lymphoma","autologous-transplant","maintenance-therapy"],"trials":["nct03844048","nct04002297","nct06230224","nct05947851","nct06084936","nct05645107","nct07582432","nct06082102","nct06947967","nct06522737","flyer","calgb-50303","goya","remarc","polargo","juliet","transcend-nhl-001","prima-follicular","ielsg-19","trog-99-03","elara","rosewood","shine","enrich","lyma","jcog9801","smile-enktl","polar-bear","arched","prima-cns","fortplus","mosun-lbt-fl","mosun-len-mzl"],"people":[],"bottlenecks":["b-tumor-heterogeneity","b-biomarker-validation","b-manufacturing-cell-therapy","b-rare-cancers","b-global-access","b-trial-design","b-negative-results","b-dormancy-mrd"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Living with non-Hodgkin lymphoma, the decisions and the people who make them: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the 24-hour number they gave you come first, and no figure here is a prediction about you. The decision records, the question sets, the first 60 days checklist and the red cards on this page were written from the NHS, Lymphoma Action, Macmillan and Cancer Research UK patient pages, from NICE NG52, NG47, CG151 and NG234, from the NHS Breast Screening Programme protocols and the Green Book, and from the trial reports named beside each figure, all read on 1 October 2026.","The biology in detail, 1 of 5. The antigens. Ten surface targets carry the lymphoma medicines, and nine of the ten are normal proteins on normal cells. CD20 and CD19 are B-cell lineage antigens, so anti-CD20 and anti-CD19 treatments empty the B-cell compartment and leave hypogammaglobulinaemia, more infection, a blunted vaccine response and a risk of hepatitis B reactivation; after CAR-T the aplasia is deeper and can last years. CD79b and CD22 are also B-cell antigens, chosen for conjugates because they internalise. CD30 is the nearest to a restricted antigen, carried by activated lymphocytes and monocytes but not by resting ones, which is why brentuximab vedotin's limiting toxicity is the auristatin payload rather than the target. CD38 is mostly a myeloma antigen with no lymphoma approval and one laboratory consequence worth knowing, a positive indirect antiglobulin test that masks alloantibodies. CD47 is on every red cell, so blocking it causes anaemia by design and the dosing had to be redesigned around that. CCR4 is on regulatory T cells as well as on cutaneous and adult T-cell lymphoma, so depleting it causes rash and raises transplant risk. CD52 is on B cells, T cells, monocytes and dendritic cells at very high density, which makes alemtuzumab efficient and leaves CD4 counts low for a year. CD3 is the one target not on the tumour at all in B-cell disease: it is the handle a bispecific antibody grips, and cytokine release syndrome is that mechanism working.","The biology in detail, 2 of 5. The lesions. Chronic active B-cell receptor signalling defines the activated B-cell-like group and was shown by killing those cells, and only those cells, with knockdown of IgM, CD79A, CD79B or BTK; CD79B ITAM mutations were present in 18% of them and activating CARD11 mutations in about 10%. MYD88 L265P feeds the same NF-kB hub from the toll-like receptor side in 29% of activated B-cell-like cases, 9% of MALT lymphomas and 91% of lymphoplasmacytic lymphoma. BCL2 arrives by a recombinase error at the pre-B-cell stage, t(14;18), present in most follicular lymphomas and 13.5% of unselected large B-cell lymphomas. MYC arrives the same way in Burkitt lymphoma, where it needs a partner that supplies survival: TCF3 or ID3 mutation in 70% of sporadic cases and CCND3 mutation in 38%. BCL6 is rearranged in 28.7% of large B-cell lymphomas. EZH2 Tyr646 substitutions, 7.2% of follicular and 21.7% of germinal-centre large B-cell lymphoma, are gain-of-function and absent from the activated subtype. CREBBP or EP300 inactivation affects about 39% and 41%, and KMT2D 32% and 89%. TP53 loss is the commonest route out of chemotherapy sensitivity, 11% in mantle cell lymphoma with median overall survival of 1.8 years against 12.7, and 47.1% in Richter transformation.","The biology in detail, 3 of 5. The immune lesions and the viruses. Classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma amplify 9p24.1, which carries both PD-1 ligand genes and JAK2; 97% of 108 classical Hodgkin lymphomas had concordant alterations of the two ligand loci, and CIITA, the master regulator of MHC class II, is rearranged in 38% of mediastinal and 15% of Hodgkin cases. That is why PD-1 blockade produced responses in 20 of 23 heavily pre-treated Hodgkin patients and does very little elsewhere in B-cell lymphoma. The Hodgkin node is mostly not cancer: the Reed-Sternberg cells are a small minority, their clonal B-cell identity had to be proved by picking single cells off a slide with a micromanipulator, and the infiltrate carries prognostic information of its own, with more CD68-positive macrophages predicting worse outcome. Two viruses matter. Epstein-Barr virus persists in almost everyone and causes different lymphomas according to which latency programme the infected cell runs: EBNA1 alone in Burkitt lymphoma, LMP1 added in Hodgkin and NK/T-cell lymphoma, and the full set where T-cell surveillance has gone. HTLV-1 starts adult T-cell leukaemia/lymphoma with Tax and HBZ, and the 426-case genomic analysis showed the acquired mutations cluster in the pathways Tax itself touches.","The biology in detail, 4 of 5. Resistance. Anti-CD20 fails by transcriptional down-regulation of CD20, found in 5 of 19 rebiopsied relapses, and by trogocytosis, in which macrophages shave the antigen off a living cell. Covalent BTK inhibitors fail on-target through BTK C481S, found in five of six patients with acquired resistance, which is answered by a non-covalent inhibitor giving 73.3% responses after a covalent one; they also fail through gain-of-function PLCG2 mutations below the kinase, which no BTK inhibitor reaches. Non-covalent inhibitors are in turn defeated by L528W and T474I, and L528W is enriched after zanubrutinib specifically, 7 of 13 progressing patients against 1 of 24 after ibrutinib. Venetoclax fails through BCL2 G101V in its own binding groove, which lowers affinity about 180-fold, appeared in 7 of 15 paired patients and is detectable months before progression. CD19 CAR-T fails through antigen loss by deletion, exon 2 mutation or exon 2 skipping, through the fitness of the collected T cells, where memory signatures predict response and exhaustion signatures predict failure, and through the node itself. Checkpoint blockade in Hodgkin lymphoma fails with loss of MHC class II, not class I, which is what points at a CD4 T cell as the effector.","The biology in detail, 5 of 5. The tests. An excisional biopsy rather than a core where it is possible, because architecture decides several of these diagnoses and because in Hodgkin lymphoma the malignant cells are rare enough to be missed. An immunohistochemistry panel of 10 to 12 stains, from which the Hans algorithm reads cell of origin. FISH for MYC, with BCL2 and BCL6 where MYC is rearranged or MYC protein is high, for CCND1 in a suspected mantle cell lymphoma, for t(11;18) in a gastric MALT lymphoma before relying on Helicobacter eradication, and for 9p24.1 where a research question needs it. Flow cytometry where cells can be put in suspension, which is how Sezary cells are counted and marrow involvement measured. Immunoglobulin and T-cell receptor clonality where the morphology is equivocal, remembering that clonality is not malignancy. A sequencing panel where TP53, MYD88, CXCR4, EZH2, BTK, PLCG2, BCL2 or the T-follicular-helper genes would change the plan. And FDG-PET, scored 1 to 5 against the mediastinal blood pool and the liver, which is the measurement lymphoma treatment is actually adapted to, with the warning that a score of 3 means different things in different protocols."],"group":"haematologic","burden":"About 13,747 new cases and 5,100 deaths a year in the United Kingdom, where 64.6 per cent of people are alive ten years later (Cancer Research UK); an estimated 79,320 new cases and 19,970 deaths in the United States in 2026, 3.8 per cent of all new cancer diagnoses, with five-year relative survival of 74.3 per cent for 2016 to 2022 (SEER); and about 544,000 cases and 260,000 deaths worldwide in 2020 (GLOBOCAN). It is the commonest group of blood cancers.","subtypes":["Diffuse large B-cell lymphoma","Follicular lymphoma","Marginal zone lymphoma","Mantle cell lymphoma","Chronic lymphocytic leukaemia / small lymphocytic lymphoma","Burkitt lymphoma","Waldenström macroglobulinaemia (lymphoplasmacytic lymphoma)","Primary CNS lymphoma","Peripheral T-cell lymphomas","Cutaneous T-cell lymphomas","HIV-associated lymphomas","B-cell lymphomas, about 95 per cent of lymphoma in the United Kingdom (HMRN)","Diffuse large B-cell lymphoma, the commonest single subtype at about 41 per cent of lymphoma diagnoses","Follicular lymphoma and the other indolent germinal-centre lymphomas","Marginal zone lymphomas: extranodal (MALT), nodal and splenic","Burkitt lymphoma and the high-grade B-cell lymphomas, including those with MYC and BCL2 rearrangements","Lymphoplasmacytic lymphoma, of which Waldenstrom macroglobulinaemia is the IgM type","Large B-cell lymphomas of immune-privileged sites: the central nervous system, the vitreoretina and the testis","Virus-associated B-cell lymphomas: EBV-positive, KSHV/HHV8-associated (primary effusion lymphoma) and plasmablastic lymphoma","Lymphomas arising in immune deficiency and dysregulation, including after transplant and in HIV","T-cell and NK-cell lymphomas, about 5 per cent of lymphoma in the United Kingdom","Nodal T-follicular helper cell lymphomas, of which the angioimmunoblastic type is the commonest","The anaplastic large cell lymphomas: ALK-positive, ALK-negative, primary cutaneous and breast implant-associated","Primary cutaneous T-cell lymphomas, of which mycosis fungoides is the commonest","EBV-positive NK/T-cell lymphomas, including extranodal NK/T-cell lymphoma","Adult T-cell leukaemia/lymphoma, caused by HTLV-1","Intestinal T-cell lymphomas: enteropathy-associated and monomorphic epitheliotropic"],"biomarkers":["Immunophenotype (CD20, CD5, CD10, CD30 and others) that assigns the subtype","MYC, BCL2 and BCL6 rearrangements (high-grade B-cell lymphoma)","Ki-67 proliferation index","Interim and end-of-treatment PET (Deauville score)","Cell of origin (germinal centre versus activated B-cell) in DLBCL","Cell of origin in large B-cell lymphoma: germinal-centre-like or non-germinal-centre, by the Hans three-stain algorithm or by expression profiling","MYC, BCL2 and BCL6 rearrangement by FISH: 8.8%, 13.5% and 28.7% of 442 unselected diffuse large B-cell lymphomas","MYD88 L265P: 29% of activated B-cell-like diffuse large B-cell lymphoma, 91% of lymphoplasmacytic lymphoma","CD79B ITAM mutation: 18% of activated B-cell-like diffuse large B-cell lymphoma","EZH2 Tyr646 gain-of-function mutation: 7.2% of follicular lymphoma, 21.7% of germinal-centre diffuse large B-cell lymphoma","CREBBP or EP300 inactivation: about 39% of diffuse large B-cell lymphoma, 41% of follicular lymphoma","TP53 mutation in mantle cell lymphoma: 11%, with median overall survival of 1.8 years against 12.7 years","RHOA G17V: 67 to 68% of angioimmunoblastic T-cell lymphoma, 18% of peripheral T-cell lymphoma not otherwise specified","9p24.1 alteration of the PD-1 ligand loci: 97% of 108 classical Hodgkin lymphomas","CIITA rearrangement: 38% of primary mediastinal B-cell lymphoma, 15% of classical Hodgkin lymphoma","t(11;18) API2-MALT1 in gastric MALT lymphoma: predicts failure of Helicobacter eradication","Immunoglobulin and T-cell receptor clonality: clonal, polyclonal or oligoclonal, read with the morphology and never alone","Deauville five-point score on interim and end-of-treatment PET","The immunophenotype, read by immunohistochemistry or flow cytometry (CD20, CD3, CD5, CD10, CD23, CD30, CD138, cyclin D1, ALK, BCL2, BCL6, MUM1), which assigns the entity and is the diagnosis","MYC, BCL2 and BCL6 rearrangements by fluorescence in situ hybridisation in every aggressive B-cell lymphoma, because MYC with BCL2 defines a separate entity","The Ki-67 proliferation index, which is above 95 per cent in Burkitt lymphoma and is part of the mantle cell risk score","Cell of origin in diffuse large B-cell lymphoma: germinal centre B-cell against activated B-cell","Epstein-Barr virus by EBER in situ hybridisation, which defines several entities and changes none of the treatment","Interim and end-of-treatment PET-CT, scored on the Deauville five-point scale","MYD88 L265P, which supports lymphoplasmacytic lymphoma and the immune-privileged large B-cell lymphomas","HTLV-1 serology where the person or their family comes from Japan, the Caribbean, west or central Africa, Iran, Romania or parts of South America"],"standardOfCare":[{"setting":"Aggressive B-cell (DLBCL and related)","approach":"Curative immunochemotherapy (R-CHOP or Pola-R-CHP); CAR-T or bispecific antibodies at relapse. See the DLBCL page.","refs":["rituximab","polatuzumab-vedotin"]},{"setting":"Indolent B-cell (follicular, marginal zone)","approach":"Watch and wait when asymptomatic; rituximab alone or with bendamustine or CHOP when treatment is needed; bispecifics and CAR-T for later relapses. See the follicular lymphoma page.","refs":["rituximab","bendamustine"]},{"setting":"Mantle cell lymphoma and CLL","approach":"BTK inhibitors and venetoclax-based regimens have largely replaced chemotherapy. See the mantle cell and CLL pages.","refs":["ibrutinib","venetoclax"]},{"setting":"T-cell lymphomas","approach":"CHOP-based chemotherapy, brentuximab vedotin for CD30-positive disease, transplant in first remission for fit patients. See the peripheral T-cell lymphoma page.","refs":["brentuximab-vedotin"]},{"setting":"How the treatment of a non-Hodgkin lymphoma is decided","approach":"Three questions, in order. Is it aggressive or indolent? Aggressive lymphomas (diffuse large B-cell, high-grade B-cell, Burkitt, most T-cell lymphomas, blastoid mantle cell) are treated immediately, with combination chemotherapy, with the intention to cure. Indolent lymphomas (follicular, marginal zone, lymphoplasmacytic) may not need treatment at all for years, and when they do the aim is control rather than cure. Is it a B-cell or a T-cell lymphoma? B-cell lymphomas carry CD20 and almost all first-line regimens contain an anti-CD20 antibody; T-cell lymphomas do not, which is the main reason their outcomes lag. Where is it, and what does it threaten? A lymphoma in the stomach, the brain, the testis, the eye or the skin is treated by rules specific to that site, not by the rules for nodal disease.\n\nThe things that must be done before the first dose are the same across the family: a proper biopsy reported to the current WHO classification, PET-CT staging reported by the Lugano classification, hepatitis B and HIV testing, and a fertility conversation.","refs":["lymphoma-type","lugano-classification","fdg-pet","lymphoma-tx-regimen-alphabet","lymphoma-tx-watch-and-wait","lymphoma-tx-hepatitis-b-reactivation","lymphoma-tx-fertility-preservation"],"guideline":{"version":"NCCN B-Cell and T-Cell Lymphomas; ESMO; WHO fifth edition; NCI PDQ","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Supportive care that belongs to lymphoma specifically","approach":"Five things, each with its own entry. Tumour lysis syndrome: predictable from bulk, LDH and histology, prevented with fluids, allopurinol and, in high-risk patients, rasburicase; screen for glucose-6-phosphate dehydrogenase deficiency first. Hepatitis B reactivation: test surface antigen and core antibody before any anti-CD20 antibody and give entecavir or tenofovir prophylaxis, which in a randomised trial cut reactivation from 30 to 6.6 per cent against lamivudine. Pneumocystis and herpes prophylaxis with steroid-containing, purine-analogue, PI3K-inhibitor, CAR-T and bispecific regimens. Immunoglobulin replacement for those left with low IgG and recurrent infection after B-cell depletion. Cytokine release syndrome and ICANS after CAR-T and bispecific antibodies, graded by the ASTCT criteria and treated with tocilizumab and steroids. Fertility preservation before alkylating chemotherapy, arranged in days rather than weeks.","refs":["lymphoma-tx-tumour-lysis","lymphoma-tx-hepatitis-b-reactivation","lymphoma-tx-pjp-and-infection-prophylaxis","lymphoma-tx-immunoglobulin-replacement","lymphoma-tx-crs-icans","lymphoma-tx-fertility-preservation","rasburicase","tocilizumab","human-normal-immunoglobulin"],"guideline":{"version":"BSH guidelines; ASTCT consensus grading; NCCN supportive care","url":"https://doi.org/10.1016/j.bbmt.2018.12.758"}},{"setting":"Where British and American practice differ","approach":"In advanced Hodgkin lymphoma, the United States moved to nivolumab with AVD after SWOG S1826 while Germany moved to PET-guided BrECADD after HD21 and British practice sits between the two. In older mantle cell lymphoma, the British-led ENRICH trial made ibrutinib with rituximab a first-line option without chemotherapy, with the benefit concentrated against R-CHOP rather than against bendamustine-rituximab. In first-line diffuse large B-cell lymphoma, pola-R-CHP is the American default for IPI 2 and above while R-CHOP remains the commonest first treatment in England. Central nervous system prophylaxis has been dropped faster in the United Kingdom than in the United States. Access to bispecific antibodies and CAR-T exists in both countries by different routes: national commissioning and panel approval in England, insurance authorisation at an accredited centre in the United States.","refs":["lymphoma-tx-uk-versus-us","lymphoma-tx-uk-access","swog-s1826","hd21","polarix","triangle"],"guideline":{"version":"NICE; NCCN; ESMO; ENRICH, S1826, HD21","url":"https://doi.org/10.1016/S0140-6736(25)01432-1"}},{"setting":"Treatments that did not work, and are worth not being offered","approach":"DA-EPOCH-R as a general upgrade to R-CHOP failed in Alliance/CALGB 50303. Obinutuzumab in place of rituximab in diffuse large B-cell lymphoma failed in GOYA, although it works in follicular lymphoma in GALLIUM. Lenalidomide maintenance after R-CHOP lengthened progression-free survival but not life in REMARC. Tisagenlecleucel in second line failed in BELINDA while two other CAR-T products succeeded in the same setting. Four gray in two fractions is inferior to 24 gray for curative radiotherapy of indolent lymphoma in FoRT. Central nervous system prophylaxis did not lower central nervous system relapse below the rate predicted by CNS-IPI in the largest cohort that received it.","refs":["lymphoma-tx-failed-and-negative","belinda","gallium","lymphoma-tx-cns-prophylaxis","lymphoma-tx-maintenance","lymphoma-tx-radiotherapy"],"guideline":{"version":"The trials named","url":"https://doi.org/10.1200/JCO.18.01994"}}],"stateOfArt":["The antigens, and what they cost. Almost every surface target in lymphoma is a lineage antigen: a normal protein on a normal cell, present on the cancer because the cancer came from that cell. CD20 and CD19 are on every normal B cell, so the treatments that use them empty the B-cell compartment and leave low immunoglobulin and more infection behind; CD52 adds T cells and monocytes and produces the deepest lymphopenia of any antibody here; CCR4 is on regulatory T cells, which is why mogamulizumab causes rash and is associated with severe graft-versus-host disease if given shortly before an allogeneic transplant; CD47 is on red cells, so blocking it causes anaemia by design. CD30 is the exception, close to restricted to activated cells in an adult. CD3 is not on the tumour at all in B-cell disease: it is the handle a bispecific antibody uses to grip a T cell.","Which antigens can carry a payload. CD20 is not internalised, so it carries naked antibodies and T-cell engagers and no conjugate; CD79b, CD30 and CD22 are internalised, which is why the conjugates aim at them. This single property, not specificity, explains most of the format choices in lymphoma.","The B-cell receptor is the one pathway that picks a drug. Activated B-cell-like lymphoma signals continuously through CD79a and CD79b to SYK, BTK, PLC-gamma-2 and the CARD11-BCL10-MALT1 complex into NF-kB; the toll-like receptor arm feeds the same hub through MYD88 L265P. BTK inhibitors are standard in mantle cell lymphoma and Waldenstrom macroglobulinaemia and do little in germinal-centre disease.","The germinal centre explains the rest. To make a better antibody a B cell deliberately mutates its own DNA while dividing fast, with its damage response held down by BCL6 and its exit locked by polycomb. The translocations of BCL2 and MYC to an immunoglobulin locus are recombinase errors made during that programme, EZH2 gain-of-function mutations keep the exit locked, and CREBBP and EP300 loss leaves BCL6 active when it should be off.","Classification by molecule, honestly. Cell of origin is real, prognostic, and does not currently choose a treatment outside a trial. The genetic subtypes, MCD, BN2, N1, EZB and the rest, explain a great deal and change nothing today: no regulator licenses a drug on a LymphGen call and no randomised trial has assigned treatment by it. Two classifications apply only in practice: a MYC with BCL2 rearrangement, which moves most patients off R-CHOP, and an EZH2 mutation in relapsed follicular lymphoma, which opens tazemetostat.","Checkpoint blockade works in Hodgkin lymphoma for a genetic reason. The 9p24.1 amplicon carries both PD-1 ligand genes and JAK2, which induces them further, and 97% of 108 classical Hodgkin lymphomas carried concordant alterations of the two loci. PD-1 blockade gave an objective response in 20 of 23 heavily pre-treated patients; outside Hodgkin lymphoma and the mediastinal group, single-agent checkpoint blockade in B-cell lymphoma does very little.","Resistance, by class. Anti-CD20 is defeated by transcriptional loss of CD20, found in 5 of 19 rebiopsied relapses; covalent BTK inhibitors by BTK C481S, answered by a non-covalent inhibitor, and by PLCG2 gain of function, which no BTK inhibitor can reach; venetoclax by BCL2 G101V, which lowers drug affinity about 180-fold and appears months before progression; CD19 CAR-T by antigen loss, by the fitness of the collected T cells, and by the node the cells have to work in; and checkpoint blockade in Hodgkin lymphoma by loss of MHC class II rather than class I.","Tests, in practice. An excisional biopsy with an immunohistochemistry panel, FISH for MYC with BCL2 and BCL6, flow cytometry where cells can be put in suspension, immunoglobulin and T-cell receptor clonality where the morphology is equivocal, a gene panel where TP53, MYD88, EZH2 or a resistance mutation would change the plan, and FDG-PET scored on the Deauville five-point scale. Circulating tumour DNA can do all of genotyping, burden and residual disease, and no approval yet depends on it.","The B-cell side now has four ways of attacking the same cell surface and they stack: the naked antibody (rituximab, obinutuzumab), the antibody-drug conjugate (polatuzumab vedotin, brentuximab vedotin), the engineered T cell (CAR-T against CD19) and the bispecific antibody (glofitamab, epcoritamab, mosunetuzumab). A person whose large B-cell lymphoma relapses in 2026 has a realistic second and third chance of cure, which was not true in 2015.","The T-cell and NK-cell side has had one positive randomised first-line trial in twenty years, ECHELON-2, and it applies only to CD30-positive disease. Most of what is given in T-cell lymphoma is convention rather than demonstrated benefit, and the pages in this family say so where it is true.","The 2022 classifications moved several diseases from being a descriptive label to being a genetically defined entity: high-grade B-cell lymphoma with MYC and BCL2 rearrangements, the large B-cell lymphomas of immune-privileged sites, mediastinal grey zone lymphoma. Each of those moves exists because the genetics predicted the behaviour better than the appearance did.","PET-CT and the Deauville score made treatment adaptive. Scanning after two cycles and changing the plan on what the scan shows is now standard in Hodgkin lymphoma and is being tested across the aggressive B-cell lymphomas.","Infection remains the common cause of harm. Hepatitis B reactivation after anti-CD20 antibodies, Pneumocystis pneumonia on steroids, and low immunoglobulins for years after CAR-T or bispecific therapy each have a prevention that works and is sometimes forgotten."],"history":[{"year":1958,"title":"A jaw tumour in Ugandan children is described, and its geography points at a virus","note":"Burkitt's report in the British Journal of Surgery has no abstract indexed on Europe PMC; its importance is that mapping where the tumour occurred prompted the search for an infectious cause.","refs":["paper-burkitt-sarcoma-involving-jaws-african-children-br-j-surg-1958"]},{"year":1964,"title":"The first virus found in a human tumour","note":"Epstein, Achong and Barr saw virus particles in lymphoblasts cultured from one of Burkitt's biopsies, beginning the field that now includes human papillomavirus, hepatitis B and Helicobacter pylori.","refs":["paper-epstein-virus-particles-burkitt-lymphoblasts-lancet-1964"]},{"year":1971,"title":"Ann Arbor staging agreed","note":"A committee meeting in Ann Arbor, Michigan set out the four-stage anatomical system for Hodgkin's disease. Its descriptive language is still in use in 2026, inside the Lugano classification that replaced it.","refs":["lugano-classification"]},{"year":1980,"title":"The first human retrovirus, isolated from a T-cell lymphoma","note":"Poiesz and Gallo characterised type C particles with a reverse transcriptase unlike any known primate retrovirus; Hinuma's Japanese seroepidemiology the following year found antibodies in all 44 patients with adult T-cell leukaemia tested and in 26 per cent of healthy adults from endemic areas.","refs":["paper-poiesz-htlv-retrovirus-cutaneous-t-cell-lymphoma-pnas-1980","paper-hinuma-adult-t-cell-leukaemia-antigen-pnas-1981"]},{"year":1982,"title":"MYC is mapped to the Burkitt translocation","note":"The human c-myc gene is placed at 8q24, the region translocated to chromosome 2, 14 or 22 in Burkitt lymphoma cells, tying an oncogene to a specific chromosome swap for the first time in a human cancer.","refs":["myc-gene","double-hit-rearrangement"]},{"year":1985,"title":"t(14;18) is shown to be a recombinase error","note":"The breakpoint sequences carry N-region nucleotides and lie beside signal-like sequences, which places the founding lesion of follicular lymphoma at the pre-B-cell stage, years before the disease.","refs":["bcl2","bcl2-rearrangement"]},{"year":1993,"title":"The International Prognostic Index","note":"Built from 2,031 patients with aggressive lymphoma treated at 16 institutions across the United States, Europe and Canada. It counts age, stage, lactate dehydrogenase, performance status and extranodal sites, and it still decides treatment intensity in 2026.","refs":["ipi-score"]},{"year":1994,"title":"The Reed-Sternberg cell is proved to be a clonal B cell","note":"Single cells picked off a histological section with a micromanipulator each gave one clonal immunoglobulin rearrangement, settling the identity of a cell that had lost almost every B-cell marker.","refs":["lymphoma-bio-hodgkin-microenvironment"]},{"year":1997,"title":"Rituximab approved, the first antibody for a cancer","note":"Anti-CD20 rituximab for relapsed follicular lymphoma; added to CHOP it raised cure rates in diffuse large B-cell lymphoma.","refs":["rituximab"]},{"year":2000,"title":"Cell of origin","note":"Microarray profiling splits diffuse large B-cell lymphoma into germinal-centre B-cell-like and activated B-cell-like forms with different survival, the first molecular classification of a lymphoma.","refs":["cell-of-origin","lymphoma-bio-cell-of-origin-in-practice"]},{"year":2002,"title":"Gene expression turns one lymphoma into three","note":"Rosenwald profiled 240 biopsies, found germinal-centre, activated and type 3 subgroups and built a 17-gene survival predictor independent of the International Prognostic Index; Hans reproduced the split in 2004 with three ordinary stains, giving five-year survival of 76 against 34 per cent.","refs":["paper-rosenwald-molecular-profiling-dlbcl-nejm-2002","paper-hans-immunohistochemistry-cell-of-origin-dlbcl-blood-2004","paper-alizadeh-nature"]},{"year":2003,"title":"Clonality testing is standardised","note":"The BIOMED-2 collaboration reduces immunoglobulin and T-cell receptor clonality to 107 primers in 18 tubes, making the result comparable between laboratories.","refs":["clonality-testing","ig-tcr-clonality"]},{"year":2004,"title":"Cell of origin becomes three stains","note":"The Hans algorithm reproduces the microarray split with CD10, BCL6 and MUM1 on a tissue microarray, with five-year survival of 76% against 34%, which is why most laboratories report non-germinal-centre rather than activated.","refs":["cell-of-origin"]},{"year":2007,"title":"The only randomised trial ever run in adult T-cell leukaemia/lymphoma","note":"JCOG9801, 118 patients: complete response 40 against 25 per cent for VCAP-AMP-VECP over biweekly CHOP, three-year overall survival 24 against 13 per cent, grade 4 thrombocytopenia 74 against 17 per cent.","refs":["paper-jcog9801-vcap-amp-vecp-adult-t-cell-leukaemia-jco-2007","jcog9801"]},{"year":2010,"title":"Chronic active B-cell receptor signalling, and the 9p24.1 amplicon","note":"Two findings in one year: activated B-cell-like lymphoma depends on continuous B-cell receptor signalling through BTK, which is the rationale for every BTK inhibitor; and Hodgkin lymphoma and mediastinal large B-cell lymphoma amplify the locus carrying both PD-1 ligands and JAK2, which is the rationale for checkpoint blockade there.","refs":["btk","cd79b","jak2","pd-ligand-9p24-alteration"]},{"year":2010,"title":"EZH2 Tyr641 mutations","note":"Gain-of-function substitutions at a single tyrosine in the SET domain are found in 21.7% of germinal-centre large B-cell lymphomas and 7.2% of follicular lymphomas, and absent from the activated subtype; tazemetostat follows.","refs":["ezh2","ezh2-y646-mutation"]},{"year":2011,"title":"MYD88 L265P, and the chromatin genes","note":"An oncogenic MYD88 substitution is found in 29% of activated B-cell-like lymphomas; in the same period CREBBP and EP300 inactivation is found in about 39% of diffuse large B-cell and 41% of follicular lymphoma, and KMT2D in 32% and 89%, which makes lymphoma a disease of chromatin and not only of signalling.","refs":["myd88","crebbp","kmt2d","myd88-l265p"]},{"year":2011,"title":"Asparaginase makes NK/T-cell lymphoma treatable, and rituximab maintenance doubles remission in follicular lymphoma","note":"SMILE reached an overall response of 79 per cent in 38 patients with a disease that resists anthracyclines; PRIMA raised three-year progression-free survival from 57.6 to 74.9 per cent, and at nine years the medians were 10.5 against 4.1 years with no survival difference.","refs":["paper-smile-chemotherapy-nk-t-cell-lymphoma-jco-2011","paper-prima-rituximab-maintenance-follicular-lancet-2011","paper-prima-final-rituximab-maintenance-follicular-jco-2019","smile-enktl","prima-follicular"]},{"year":2012,"title":"MYD88 L265P defines Waldenstrom macroglobulinaemia","note":"Whole-genome sequencing finds the same substitution in all 10 paired cases and in 91% of lymphoplasmacytic lymphoma overall, absent from normal tissue, which turns a diagnosis of exclusion into a genotype.","refs":["myd88","myd88-l265p"]},{"year":2014,"title":"Resistance to a BTK inhibitor is read in the kinase","note":"BTK C481S in five of six patients with acquired ibrutinib resistance and PLCG2 gain-of-function mutations in two, which is why the non-covalent inhibitors exist.","refs":["btk","plcg2","btk-c481s"]},{"year":2014,"title":"RHOA G17V in angioimmunoblastic T-cell lymphoma","note":"A single substitution in 67 to 68% of cases, specific to the tumour cells, with the accompanying TET2 mutations also present in normal blood cells, which places this lymphoma as a growth out of clonal haematopoiesis.","refs":["rhoa","tet2","rhoa-g17v"]},{"year":2014,"title":"The Lugano classification","note":"Agreed at the International Conference on Malignant Lymphoma, it made PET-CT the standard staging test for lymphomas that take up the tracer, restricted the A and B symptom suffixes to Hodgkin lymphoma, and removed routine bone marrow biopsy from the staging of Hodgkin lymphoma.","refs":["lugano-classification","fdg-pet","deauville-score"]},{"year":2015,"title":"Antigen escape after CAR-T is explained","note":"Relapse without CD19 turns out to combine deletion, exon 2 mutation and selection for an alternatively spliced transcript that skips the epitope and still partly works, which is why a standard sequencing test can call the gene normal.","refs":["cd19","lymphoma-bio-antigen-escape"]},{"year":2015,"title":"Checkpoint blockade in Hodgkin lymphoma","note":"Nivolumab produces an objective response in 20 of 23 heavily pre-treated patients, most of whom had already failed autologous transplant and brentuximab vedotin.","refs":["pd-ligand-9p24-alteration","nivolumab"]},{"year":2015,"title":"Early progression splits follicular lymphoma in two","note":"Casulo: 19 per cent of 588 patients progressed within two years of first-line R-CHOP, with five-year overall survival of 50 against 90 per cent and an index-adjusted hazard ratio of 6.44.","refs":["paper-casulo-pod24-follicular-lymphoma-jco-2015","lymphoma-tx-pod24"]},{"year":2016,"title":"A blood test reads the lymphoma without a biopsy","note":"Scherer showed circulating tumour DNA predicts outcome at diagnosis, classifies cell of origin from plasma, beats imaging for residual disease and distinguishes follicular lymphomas that will transform from those that will not.","refs":["paper-scherer-ctdna-lymphoma-subtypes-genome-evolution-sci-transl-med-2016","paper-kurtz-j-clin-oncol","ctdna"]},{"year":2017,"title":"First CAR-T for lymphoma","note":"Axicabtagene ciloleucel approved for relapsed large B-cell lymphoma after two or more lines.","refs":["axicabtagene-ciloleucel"]},{"year":2018,"title":"The genetic subtypes","note":"Two large series read large B-cell lymphoma as four and five genetically defined groups, MCD, BN2, N1 and EZB among them, with different outcomes after immunochemotherapy.","refs":["lymphoma-bio-lymphgen"]},{"year":2018,"title":"Two genetic classifications of diffuse large B-cell lymphoma, three weeks apart","note":"Chapuy's five clusters from 304 tumours and Schmitz's four subtypes from 574; Wright's LymphGen tool in 2020 extended them to seven and made per-patient classification possible. None has yet changed a first-line treatment.","refs":["paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018","paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018","paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020","lymphoma-ev-genetic-subtype-directed-first-line"]},{"year":2019,"title":"Venetoclax resistance is a single amino acid","note":"BCL2 G101V, found at progression in 7 of 15 paired patients and in none at study entry, lowers drug affinity about 180-fold and is detectable months before clinical relapse.","refs":["bcl2","bcl2-g101v"]},{"year":2019,"title":"Four cycles instead of six, and a targeted tablet that helped the young and harmed the old","note":"FLYER: three-year progression-free survival 96 per cent with four cycles of R-CHOP in young favourable disease, non-inferior to six. PHOENIX: ibrutinib improved event-free survival under 60 (hazard ratio 0.579) and worsened it over 60, raising serious adverse events from 38.2 to 63.4 per cent.","refs":["paper-flyer-four-vs-six-cycles-r-chop-lancet-2019","paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019","flyer"]},{"year":2020,"title":"LymphGen makes the genetic subtypes usable on one patient","note":"A probabilistic classifier assigns a lymphoma to one of seven genetic subtypes and shows each shares a pathogenesis with a particular indolent or extranodal lymphoma. No randomised trial has yet assigned treatment by it.","refs":["lymphoma-bio-lymphgen"]},{"year":2020,"title":"The third CAR-T product, and the mantle cell question changes shape","note":"TRANSCEND NHL 001: objective response 73 per cent and complete response 53 per cent in 256 evaluable patients, with grade 3 or worse cytokine release syndrome in 2 per cent. SHINE then gained 28 months of progression-free survival in older mantle cell lymphoma with no survival benefit.","refs":["paper-transcend-nhl-001-liso-cel-lancet-2020","paper-shine-ibrutinib-bendamustine-rituximab-mantle-cell-nejm-2022","transcend-nhl-001","shine"]},{"year":2021,"title":"Residual disease at parts per million","note":"PhasED-seq uses several mutations carried on one DNA fragment, which lymphoma genomes supply because of somatic hypermutation, and finds residual disease in a further 25% of participants called negative by the previous method.","refs":["ctdna-lymphoma-monitoring","ctdna-mrd-positive"]},{"year":2022,"title":"The WHO fifth edition","note":"High-grade B-cell lymphoma with MYC and BCL2 rearrangements becomes an entity of its own and the T-follicular-helper lymphomas are grouped by origin rather than appearance. A second classification published the same year disagrees on several names.","refs":["double-hit-rearrangement"]},{"year":2022,"title":"Two classifications instead of one","note":"The fifth edition of the WHO classification and the International Consensus Classification were published within months of each other. They agree about most entities and differ about several names and boundaries, which is why a report may give a disease a name that a trial protocol does not recognise.","refs":["lymphoma-classification-2022"]},{"year":2022,"title":"The second-line CAR-T trial that failed, and why","note":"BELINDA: median event-free survival 3.0 months in both arms, with a 52-day median interval from leukapheresis to infusion and 25.9 per cent of the CAR-T group progressing by week 6 against 13.8 per cent of the comparator group.","refs":["paper-belinda-tisagenlecleucel-second-line-nejm-2022","belinda","lymphoma-ev-manufacturing-time-as-a-trial-endpoint"]},{"year":2023,"title":"Bispecific antibodies approved","note":"Glofitamab and epcoritamab, off-the-shelf CD20 x CD3 antibodies, approved for relapsed large B-cell lymphoma.","refs":["glofitamab","epcoritamab"]},{"year":2025,"title":"A chemotherapy-free first line beats immunochemotherapy in mantle cell lymphoma","note":"ENRICH, 397 patients: adjusted progression-free survival hazard ratio 0.69, driven by the comparison against R-CHOP (0.37) rather than against bendamustine-rituximab (0.91). ECHELON-3 and POLARGO gave transplant-ineligible relapsed diffuse large B-cell lymphoma two more options with a survival benefit.","refs":["paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025","paper-echelon-3-brentuximab-lenalidomide-rituximab-dlbcl-jco-2025","paper-polargo-polatuzumab-r-gemox-dlbcl-jco-2026","enrich","polargo"]},{"year":2032,"title":"The first-line bispecific question completes","note":"The National Cancer Institute trial of mosunetuzumab against rituximab in low tumour burden follicular lymphoma (NCT06337318, 600 estimated participants) has a primary completion date of 31 March 2032; RADAR, the radiotherapy-free Hodgkin trial, is listed for September 2030.","refs":["mosun-lbt-fl","radar-hodgkin","lymphoma-ev-fixed-duration-chemotherapy-free-first-line"]}],"pipeline":["glofitamab","epcoritamab","mosunetuzumab","obecabtagene-autoleucel","tqb3702","stp938","lymphoma-ev-genetic-subtype-directed-first-line","lymphoma-ev-ctdna-instead-of-the-interim-scan","lymphoma-ev-radiotherapy-free-early-hodgkin","lymphoma-ev-fixed-duration-chemotherapy-free-first-line","lymphoma-ev-randomised-evidence-for-the-t-cell-lymphomas","lymphoma-ev-manufacturing-time-as-a-trial-endpoint","lymphoma-ev-the-drugs-that-cure-and-the-places-without-them","lymphoma-ev-late-effects-of-the-treatments-given-now"],"openProblems":["Relapsed T-cell lymphomas still lack effective options.","Access to CAR-T and bispecifics outside high-income countries.","The genetic classifications of large B-cell lymphoma are the best-validated molecular taxonomy in haematology and no randomised trial has yet assigned treatment by one. Patients are genotyped, told which subtype they have, and then given the same regimen as everyone else.","Cell of origin has been known for a quarter of a century and every randomised attempt to act on it in first line has failed to change survival in the whole population. It is not clear whether the problem is the classification, the drugs chosen, or the fact that immunohistochemistry cannot separate the activated type from the unclassified one.","Nobody knows how often a large B-cell lymphoma relapses without CD19 after CAR-T. The published series are small and do not agree, and most relapses are not rebiopsied at all, so the field is choosing second treatments without the measurement that would decide between them.","The same is true of CD20: the only series that looked found 5 of 19 rebiopsied relapses had lost the antigen, which means the denominator for every other patient is unknown and a second anti-CD20 drug is often given without checking the target is still there.","MYC has been a known driver of Burkitt lymphoma since 1982 and there is still no drug that acts on it. The regimens that cure Burkitt lymphoma are the most toxic in lymphoma, which is why it remains hardest to treat in older patients and in the equatorial regions where the endemic form occurs.","Circulating tumour DNA in lymphoma can genotype, measure burden and find residual disease at parts per million, and no trial has yet shown that changing treatment on the result helps anyone.","BCL2 was the first apoptosis gene found in a human cancer and venetoclax has not repeated its chronic lymphocytic leukaemia result in follicular or large B-cell lymphoma, because those cells also lean on MCL1 and BCL-xL. MCL1 inhibitors have been held back by cardiac toxicity.","The T-cell and NK-cell lymphomas are about one lymphoma in twenty and have a small fraction of the trials, the drugs and the survival gains of the B-cell lymphomas. Five-year relative survival in the UK population series was 45.4 per cent across T-cell lymphomas against 68.8 per cent across B-cell lymphomas.","Several of these diseases are common where trials are not run. Extranodal NK/T-cell lymphoma is a disease of east Asia and Latin America; adult T-cell leukaemia/lymphoma is a disease of south-western Japan, the Caribbean and west Africa. The treatments with the best evidence were developed there, and are least available to people from those populations living elsewhere.","Two reference classifications were published in 2022 and they disagree about names and boundaries. A patient can be told they have three different diagnoses depending on which book the pathologist used and which trial they are being screened for.","CAR-T and bispecific antibodies are available in a small number of countries and in a small number of centres within them. The gap between what is possible and what is reachable is now the main determinant of outcome in relapsed large B-cell lymphoma.","There is no way to predict which indolent lymphoma will transform into an aggressive one, and transformation is the commonest cause of death in follicular lymphoma.","Three genetic classifications of diffuse large B-cell lymphoma exist and none of them decides anyone's first-line treatment outside a trial. The gap between Schmitz in 2018 and a randomised trial that assigns treatment by LymphGen subtype is the clearest unfinished business in the disease.","Circulating tumour DNA predicts outcome at diagnosis, detects residual disease better than imaging and flags transformation before it declares itself, and no randomised trial has yet shown that changing treatment on the strength of it helps anyone.","The T-cell lymphomas have almost no randomised evidence. Adult T-cell leukaemia/lymphoma has had exactly one controlled trial, opened in 1998 with 118 patients, and the regimen that makes extranodal NK/T-cell lymphoma treatable rests on a 38-patient single-arm study.","Rituximab is thirty years old and still unavailable or unaffordable in much of the world, asparaginase is subject to recurrent shortages, and CAR-T needs an apheresis service and a cryopreservation chain. Lymphoma is among the most curable common cancers in the places that have the drugs."],"basics":{"symptoms":["A painless, persistent swelling of a lymph node in the neck, armpit or groin, usually over weeks rather than days, that does not go down after an infection clears.","The B symptoms: drenching night sweats that soak nightclothes, unexplained fever, and weight loss of more than a tenth of body weight in six months. They are recorded formally in the stage for Hodgkin lymphoma and noted but not staged in non-Hodgkin lymphoma.","Itching without a rash, fatigue out of proportion to activity, and loss of appetite.","Symptoms of the organ involved where the lymphoma is extranodal: indigestion and anaemia in gastric lymphoma, a painless lump in the testis, a bulging or displaced eye, a skin patch that has been treated as eczema for years, abdominal pain or perforation in intestinal lymphoma, headache or confusion in lymphoma of the central nervous system.","Swelling of the face and arms with breathlessness, which is superior vena cava obstruction from a large chest mass, and is an emergency: it is the usual presentation of primary mediastinal B-cell lymphoma and of mediastinal grey zone lymphoma."],"diagnosis":["An excision biopsy of a whole lymph node where that is possible, because the architecture of the node is part of the diagnosis and a needle core may not show it. A fine-needle aspirate is not sufficient to diagnose lymphoma.","Immunohistochemistry and flow cytometry on the biopsy, which identify the lineage and the entity, followed by fluorescence in situ hybridisation for the rearrangements that define separate diseases.","Blood tests: full blood count, lactate dehydrogenase, kidney and liver function, calcium, and virology for hepatitis B, hepatitis C and HIV before any antibody treatment, because anti-CD20 antibodies can reactivate hepatitis B.","PET-CT from the skull base to mid-thigh for the lymphomas that take up the tracer; CT alone for those that do not.","A bone marrow biopsy where it will change the stage or the treatment. The Lugano classification removed it from routine staging of Hodgkin lymphoma and from most diffuse large B-cell lymphoma staged by PET.","A lumbar puncture, an MRI of the brain, or an eye examination where the subtype or the sites involved carry a risk to the central nervous system."],"staging":["The Lugano classification (2014), which modified the Ann Arbor system of 1971: stage I, one lymph node region; stage II, two or more on the same side of the diaphragm; stage III, both sides; stage IV, diffuse involvement of an organ outside the lymphatic system.","The suffix E marks a single extranodal site reached by direct extension, and the suffixes A and B for the absence or presence of fever, night sweats and weight loss are formally recorded only for Hodgkin lymphoma.","Bulk is recorded separately: a single mass of 10 cm or more, or more than a third of the width of the chest, which changes treatment in several subtypes.","Stage matters less in lymphoma than in solid cancers. The prognosis is read from a score: the International Prognostic Index for aggressive lymphoma, FLIPI for follicular, MIPI for mantle cell and the Prognostic Index for T-cell lymphoma for the nodal T-cell lymphomas.","Stage IV lymphoma is routinely treated with the intention to cure, which is not what stage IV means in most other cancers."],"sources":[{"label":"Lugano classification: recommendations for initial evaluation, staging and response assessment of Hodgkin and non-Hodgkin lymphoma (Cheson, J Clin Oncol 2014)","url":"https://doi.org/10.1200/JCO.2013.54.8800"},{"label":"Report of the Committee on Hodgkin's Disease Staging Classification (Carbone, Cancer Research 1971, 31:1860 to 1861)","url":"https://pubmed.ncbi.nlm.nih.gov/5121694/"},{"label":"A predictive model for aggressive non-Hodgkin's lymphoma: the International Prognostic Index (N Engl J Med 1993)","url":"https://doi.org/10.1056/NEJM199309303291402"},{"label":"Peripheral T-cell lymphoma unspecified: the Prognostic Index for T-cell lymphoma (Gallamini, Blood 2004)","url":"https://doi.org/10.1182/blood-2003-09-3080"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"},{"label":"Lymphoma Action: types of lymphoma (UK patient charity)","url":"https://lymphoma-action.org.uk/types-lymphoma"}]},"prognosis":{"text":"The figures for non-Hodgkin lymphoma as a whole are the average of more than sixty diseases and apply exactly to nobody, which is the reason to read the subtype page instead. With that said: in the United Kingdom, 64.6 per cent of people diagnosed with non-Hodgkin lymphoma are alive ten years later (Cancer Research UK), and in the United States five-year relative survival was 74.3 per cent for 2016 to 2022, up from about 47 per cent in the mid-1970s (SEER). The spread behind those averages is very wide. In the UK population series that reports survival by subtype, five-year relative survival ran from 86.5 per cent in follicular lymphoma and 87.9 per cent in extranodal marginal zone lymphoma, through 54.8 per cent in diffuse large B-cell lymphoma, to 31.4 per cent in mantle cell lymphoma and 45.4 per cent across the T-cell lymphomas as a group; those figures are for people diagnosed between 2004 and 2012 and followed to 2014, so they predate the bispecific antibodies, CAR-T and the newer mantle cell regimens, and they understate what is achieved today in several subtypes.","sources":[{"label":"Cancer Research UK: non-Hodgkin lymphoma statistics (incidence, mortality, survival)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/non-hodgkin-lymphoma"},{"label":"SEER Cancer Stat Facts: non-Hodgkin lymphoma (United States incidence, mortality and relative survival)","url":"https://seer.cancer.gov/statfacts/html/nhl.html"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"}]}},{"id":"prostate-nmcrpc","kind":"cancer","name":"Non-metastatic castration-resistant prostate cancer","aka":["nmCRPC","M0 CRPC","Non-metastatic CRPC","Rising PSA on hormone therapy without metastases","Non-metastatic hormone-relapsed prostate cancer"],"tldr":"Non-metastatic castration-resistant prostate cancer is a PSA that keeps rising on hormone therapy while scans still show nothing. Three androgen receptor blockers, apalutamide, enzalutamide and darolutamide, each delay metastasis by about two years and lengthen life, and darolutamide is the gentlest.","summary":"Non-metastatic castration-resistant prostate cancer is defined by a rising PSA with castrate testosterone (below 50 ng/dL) and no metastases on CT and bone scan. It is found in men on long-term androgen deprivation, and the risk is judged by PSA doubling time: under ten months marks high risk. Three trials in men with a doubling time of ten months or less changed care in 2018 and 2019: SPARTAN (apalutamide), PROSPER (enzalutamide) and ARAMIS (darolutamide) each roughly doubled metastasis-free survival, from about 16 to 18 months to 36 to 40 months, and each later showed longer overall survival, so all three are approved. Darolutamide crosses into the brain least and causes the fewest falls, fractures and cognitive effects. Men with a slow doubling time can be observed on hormone therapy. PSMA PET now finds metastases in most of these men, which moves them into metastatic castration-resistant disease on paper without changing their biology, so guidelines still treat by the conventional imaging that the trials used.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Castration-resistant_prostate_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Castration-resistant_prostate_cancer"},{"label":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"},{"label":"NICE NG131: prostate cancer, diagnosis and management (recommendations, including the Cambridge Prognostic Group table at 1.2.15)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"}],"tags":["subtype-page"],"related":["prostate-bcr","prostate-mhspc","prostate-mcrpc"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["psa-kinetics","disease-volume-chaarted","pten-loss","tnm-prostate-cancer","castration-resistance","metastasis-free-survival","other-cause-mortality","psa-doubling-time"],"trials":["aramis","nct01946204","prosper"],"people":[],"bottlenecks":[],"keyPapers":["paper-spartan-nejm-2018","paper-prosper-nejm-2018","paper-aramis-nejm-2019"],"journals":[],"dependsOn":[],"notes":["NICE calls this hormone-relapsed rather than castration-resistant. NG131's section is headed 'hormone-relapsed metastatic prostate cancer' and the phrase castration-resistant does not appear in its recommendations, while the trials, the drug labels and the American guidelines use castration-resistant throughout. They describe the same state."],"group":"genitourinary","burden":"A shrinking group, because PSMA PET reveals metastases in most men once called non-metastatic; about a third with a PSA doubling time under ten months developed visible metastases within two years on hormone therapy alone.","subtypes":["High-risk nmCRPC (PSA doubling time 10 months or less)","Low-risk nmCRPC (slow PSA doubling time, observation)","PSMA PET-positive, conventional imaging-negative castration-resistant disease"],"biomarkers":["Castrate testosterone (below 50 ng/dL)","PSA doubling time","Conventional imaging negative","PSMA PET (often positive)","AR alterations and AR-V7 (research)"],"standardOfCare":[{"setting":"High-risk nmCRPC (doubling time 10 months or less)","approach":"Continue androgen deprivation and add apalutamide (SPARTAN), enzalutamide (PROSPER) or darolutamide (ARAMIS); darolutamide preferred when falls or cognition are concerns.","refs":["apalutamide","enzalutamide","darolutamide","androgen-deprivation","castration-resistance"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Low-risk nmCRPC","approach":"Observation on androgen deprivation with PSA monitoring and imaging; first-generation antiandrogen or its withdrawal as older options.","refs":["androgen-deprivation","bicalutamide","psa"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Staging","approach":"PSMA PET locates disease in most men; conventional imaging still defines the setting the trials studied.","refs":["psma-pet","mcrpc-mhspc"]}],"stateOfArt":["Three androgen receptor inhibitors, each proven in its own trial, give men a choice weighted by side effects.","Metastasis-free survival was accepted by regulators as a surrogate endpoint on the strength of these trials.","PSMA PET is dissolving the category from the inside."],"history":[{"year":2012,"title":"Metastasis-free survival validated as a surrogate for survival in prostate cancer","refs":["castration-resistance"]},{"year":2018,"title":"SPARTAN and PROSPER: apalutamide and enzalutamide approved for nmCRPC","refs":["apalutamide","enzalutamide"]},{"year":2019,"title":"ARAMIS: darolutamide approved for nmCRPC","refs":["darolutamide"]},{"year":2020,"title":"All three trials report longer overall survival","refs":["apalutamide","enzalutamide","darolutamide"]}],"pipeline":["darolutamide","psma-pet","ar-v7"],"openProblems":["Whether PSMA PET-detected metastases should be treated locally or the man treated as metastatic.","Cost and side effects of years of androgen receptor inhibition in men without symptoms.","No trial compares the three drugs head to head."],"parent":"prostate"},{"id":"non-muscle-invasive-bladder-cancer","kind":"cancer","name":"Non-muscle-invasive bladder cancer","aka":["NMIBC","Superficial bladder cancer","Ta, T1 and carcinoma in situ of the bladder"],"tldr":"Most bladder cancers are found while still confined to the lining. They are scraped out through the urethra and, when higher risk, treated with BCG instilled into the bladder; the challenge is the frequent recurrences and the patients whose tumours stop responding to BCG.","summary":"Non-muscle-invasive bladder cancer includes papillary tumours confined to the mucosa (Ta) or lamina propria (T1) and flat carcinoma in situ. It is diagnosed by cystoscopy and removed by transurethral resection, with a single immediate dose of intravesical chemotherapy for low-risk tumours. Intermediate- and high-risk disease receives induction and maintenance intravesical BCG, the oldest cancer immunotherapy in use, which halves recurrence and reduces progression. Tumours that recur despite adequate BCG are called BCG-unresponsive; radical cystectomy is the standard, and bladder-sparing alternatives have arrived: pembrolizumab (KEYNOTE-057), nadofaragene firadenovec, nogapendekin alfa inbakicept with BCG, the gemcitabine-releasing device TAR-200 and the oncolytic virus cretostimogene. Worldwide BCG shortages have pushed dose-reduction and chemotherapy substitutes into practice. Blue-light cystoscopy improves detection of flat lesions.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Bladder_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Bladder_cancer"}],"tags":["subtype-page"],"related":["muscle-invasive-bladder-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-057"],"people":[],"bottlenecks":[],"keyPapers":["paper-keynote-057-lancet-oncol-2021","paper-nadofaragene-firadenovec-lancet-oncol-2021","paper-sylvester-eortc-risk-tables-eur-urol-2006","paper-eau-nmibc-guideline-eur-urol-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"About three quarters of new bladder cancers; rarely fatal at this stage but it recurs in half of patients and progresses to muscle invasion in a fifth of the high-risk group, so years of cystoscopic surveillance make it one of the most expensive cancers to manage.","subtypes":["Low-grade Ta papillary tumours (low risk)","High-grade Ta and T1 tumours (high risk)","Carcinoma in situ","BCG-unresponsive disease","Upper tract urothelial carcinoma of the renal pelvis and ureter (related)"],"biomarkers":["Grade and stage (EAU and AUA risk groups)","Carcinoma in situ and lymphovascular invasion","FGFR3 mutations (common in low-grade disease)","Urinary biomarkers and cytology for surveillance","Molecular subtypes under study"],"standardOfCare":[{"setting":"Diagnosis and resection","approach":"Cystoscopy, transurethral resection with muscle in the specimen, blue-light or enhanced imaging for carcinoma in situ; re-resection of T1 tumours.","refs":["urothelial"]},{"setting":"Low risk","approach":"Single immediate instillation of mitomycin or gemcitabine after resection; surveillance cystoscopy.","refs":["mitomycin","gemcitabine"]},{"setting":"Intermediate and high risk","approach":"Induction and one to three years of maintenance BCG; intravesical chemotherapy when BCG is unavailable; early cystectomy for the highest-risk T1 disease.","refs":["bcg-and-intravesical-therapy"]},{"setting":"BCG-unresponsive","approach":"Radical cystectomy, or bladder-sparing treatment: pembrolizumab, nadofaragene firadenovec, nogapendekin alfa inbakicept with BCG, TAR-200, cretostimogene in trials and early approvals.","refs":["cystectomy","pembrolizumab","nadofaragene-firadenovec","nogapendekin-alfa","tar-200","cretostimogene"]}],"stateOfArt":["BCG remains the standard forty years on, and shortages have shown how much depends on one biologic.","Four bladder-sparing options for BCG-unresponsive disease have been approved or reached late trials since 2020, an unprecedented pace for this stage.","Intravesical drug-releasing devices and gene therapies show that local delivery, not systemic drugs, is the frontier here."],"history":[{"year":1976,"title":"Morales reports intravesical BCG","refs":["bcg-and-intravesical-therapy"]},{"year":1990,"title":"BCG approved for carcinoma in situ of the bladder","refs":["bcg-and-intravesical-therapy"]},{"year":2020,"title":"Pembrolizumab approved for BCG-unresponsive carcinoma in situ","refs":["pembrolizumab"]},{"year":2022,"title":"Nadofaragene firadenovec: first gene therapy for bladder cancer","refs":["nadofaragene-firadenovec"]},{"year":2024,"title":"Nogapendekin alfa inbakicept with BCG approved","refs":["nogapendekin-alfa"]}],"pipeline":["tar-200","cretostimogene"],"openProblems":["Recurrent BCG shortages.","Predicting who will progress to muscle invasion.","The burden and cost of lifelong cystoscopy.","Comparing the new bladder-sparing options with each other and with cystectomy."],"parent":"urothelial"},{"id":"non-seminoma","kind":"cancer","name":"Non-seminomatous germ cell tumour","aka":["NSGCT","Non-seminoma","Embryonal carcinoma","Yolk sac tumour","Choriocarcinoma","Teratoma","Mixed germ cell tumour"],"tldr":"Non-seminoma is the faster-growing half of testicular cancer, marked by AFP and hCG in the blood. Surgery cures most early cases, cisplatin chemotherapy cures most of the rest, and surgeons remove what remains after chemotherapy because teratoma does not respond to drugs.","summary":"Non-seminomatous germ cell tumours include embryonal carcinoma, yolk sac tumour, choriocarcinoma and teratoma, usually mixed. AFP, hCG and LDH set the IGCCCG risk group and track response. After orchidectomy, stage I disease is watched, with about 30 percent relapsing (more with lymphovascular invasion) and almost all cured on relapse; one cycle of adjuvant BEP is offered to higher-risk men who prefer it. Metastatic disease receives three cycles of BEP for good risk and four for intermediate and poor risk; residual masses after chemotherapy are resected by retroperitoneal lymph node dissection because a third contain teratoma and a tenth viable cancer. Relapse is treated with conventional or high-dose salvage chemotherapy, compared head to head in the TIGER trial. Fertility preservation and long-term follow-up are routine.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Testicular_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Testicular_cancer"}],"tags":["subtype-page"],"related":["seminoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-igcccg-classification-jco-1997","paper-igcccg-update-gillessen-jco-2021","paper-getug-13-marker-guided-dose-dense-chemotherapy-fizazi-lancet-oncol-2014","paper-williams-bep-vs-pvb-nejm-1987"],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Just under half of testicular germ cell tumours, in men in their twenties and thirties; cure rates are above 95 percent for early disease and about half for the small poor-risk group, whose treatment is the hardest problem left in testicular cancer.","subtypes":["Embryonal carcinoma","Yolk sac tumour","Choriocarcinoma (very high hCG, haemorrhagic metastases)","Teratoma (chemoresistant; surgery)","Mixed germ cell tumour","Growing teratoma syndrome"],"biomarkers":["AFP, hCG and LDH (IGCCCG risk grouping)","Lymphovascular invasion (stage I relapse risk)","Marker decline during chemotherapy","Chromosome 12p gain (i12p) on pathology"],"standardOfCare":[{"setting":"Stage I","approach":"Orchidectomy then surveillance; one cycle of adjuvant BEP for men with lymphovascular invasion who choose it; nerve-sparing retroperitoneal dissection in selected cases.","refs":["bleomycin","etoposide","cisplatin","active-surveillance"]},{"setting":"Metastatic, good risk","approach":"Three cycles of BEP (or four of EP if bleomycin is contraindicated).","refs":["bleomycin","etoposide","cisplatin"]},{"setting":"Metastatic, intermediate and poor risk","approach":"Four cycles of BEP, or VIP; poor-risk patients with slow marker decline are switched to intensified therapy (GETUG 13); treatment in high-volume centres.","refs":["cisplatin","etoposide","getug-13"]},{"setting":"Residual masses after chemotherapy","approach":"Retroperitoneal lymph node dissection and resection of other residual masses when markers have normalised.","refs":["testicular"]},{"setting":"Relapse","approach":"Conventional (TIP) or high-dose chemotherapy with stem cell support, as compared in the TIGER trial; late relapse treated surgically where possible.","refs":["cisplatin","autologous-stem-cell-transplant"]}],"stateOfArt":["Testicular cancer was the first disseminated solid tumour to become curable with chemotherapy, and cure rates keep rising through risk adaptation.","Post-chemotherapy surgery is a defining feature: teratoma and residual cancer are cut out rather than treated with more drugs.","The remaining frontier is the poor-risk group and the balance between cure and late toxicity."],"history":[{"year":1977,"title":"Cisplatin combination chemotherapy cures metastatic disease (Einhorn)","refs":["cisplatin"]},{"year":1987,"title":"BEP becomes the standard (etoposide replaces vinblastine)","refs":["etoposide","bleomycin"]},{"year":1997,"title":"IGCCCG risk classification published","refs":[]},{"year":2014,"title":"GETUG 13: marker-guided intensification in poor-risk disease","refs":[]}],"pipeline":["tiger-trial","autologous-stem-cell-transplant"],"openProblems":["Poor-risk disease still kills about half of those affected.","Whether high-dose chemotherapy is better than conventional salvage (TIGER).","Cardiovascular disease, hearing loss and neuropathy in long-term survivors."],"parent":"testicular"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","aka":["LUAD","LUSC","LSCC","TCGA-LUAD","TCGA-LUSC","lung adenocarcinoma (TCGA LUAD cohort)","lung squamous cell carcinoma (TCGA LUSC and CPTAC LSCC cohorts)","Non-small-cell lung cancer (adenocarcinoma, squamous, large cell)","NSCLC","Non-small cell lung carcinoma","Non-small-cell carcinoma of the lung"],"tldr":"Non-small-cell lung cancer is the proving ground for precision medicine: a dozen targetable mutations each with a matched pill, immunotherapy for the rest, and ADCs and bispecifics arriving now. Because most cases are still found late, low-dose CT screening is the other half of the story.","summary":"Biomarker testing (EGFR, ALK, ROS1, BRAF, MET, RET, NTRK, KRAS G12C, HER2, PD-L1) is mandatory at diagnosis. Oncogene-addicted disease gets targeted therapy first (osimertinib, amivantamab-lazertinib, lorlatinib, selpercatinib, zongertinib, sotorasib/adagrasib); the rest get PD-(L)1 blockade ± chemotherapy. Perioperative immunotherapy (CheckMate 816, KEYNOTE-671) and adjuvant targeted therapy (ADAURA, ALINA) are standard. ADCs (Dato-DXd, T-DXd, telisotuzumab vedotin, iza-bren, HER3-DXd) and bispecifics (ivonescimab PD-1×VEGF) are the next layer. Low-dose CT screening cuts mortality by 20-24%.\n\nHow common it is. Non-small-cell disease is about 85 percent of lung cancer, so the world figures for the site are very close to the figures for this disease: 2,637,005 new lung cancers and 1,861,839 deaths a year, first in the world on both counts (GLOBOCAN 2024). GLOBOCAN does not split lung cancer by histology, so the split has to be read from registry series: of 1,572,045 lung cancers in men in 2022, 45.6 percent were adenocarcinoma, 29.4 percent squamous cell carcinoma and 6.5 percent large-cell carcinoma, and of 908,630 in women, 59.7, 17.1 and 6.5 percent, which is 81.5 percent of men's and 83.3 percent of women's lung cancers in the three non-small-cell types (Lancet Respiratory Medicine 2025). In the UK the site total is around 50,200 cases and 32,800 deaths a year (Cancer Research UK); in the United States 229,410 cases and 124,990 deaths are projected for 2026, with a five-year relative survival of 29.5 percent for the site (SEER).\n\nWhy the numbers are moving in opposite directions. In the United States lung cancer incidence is falling 1.9 percent a year and mortality 4.1 percent a year, the mortality falling faster than the incidence because more cancers are found early and because targeted drugs and immunotherapy work. In the UK incidence is down 11 percent since the early 1990s and mortality down 40 percent since the early 1970s, but the projection to 2038 to 2040 is for around 66,200 cases a year: rates fall while the population ages, so the count rises. What does not move is the share found late. In England 34 percent of staged cases in 2022 were stage I or II; in the United States 24 percent are localised at diagnosis, 21 percent regional and 51 percent already distant (Cancer Research UK; SEER).\n\nSmoking, and how much of the disease it explains. This is an account of why the UK has as many lung cancers as it does, not of why any one person has one, and it changes nothing about the treatment on this page. Cancer Research UK attributes 72 percent of UK lung cancer cases to tobacco, 71 percent to active smoking and 1 percent to second-hand smoke, and about 86 percent of UK lung cancer deaths to smoking. Seventy-nine percent of UK cases are judged preventable in total. Stopping works and works better the earlier it happens: of British men who smoke all their lives 15.9 percent die of lung cancer by age 75, against 9.9 percent of those who stop by 60, 6 percent by 50, 3 percent by 40 and 1.7 percent by 30; in women the figures are 9.5 percent for lifelong smokers, 5.3 percent for stopping by 60 and 2.2 percent by 50. Risk in people who stopped about 7 years ago is 43 percent lower than in current smokers, and 72 percent lower about 12 years after stopping. Starting younger is worse: lung cancer death risk is 37 percent higher per five years younger at starting (Cancer Research UK, quoting the studies behind each figure).\n\nThe other causes, with the share of UK cases each accounts for. Workplace exposures account for 13 percent of UK cases, and asbestos alone is linked to 6 to 8 percent of UK lung cancer deaths each year, with lung cancer mortality 77 percent higher in asbestos-exposed workers than in the general population. Outdoor air pollution accounts for 8 percent of UK cases; adenocarcinoma risk is 40 percent higher per 10 micrograms per cubic metre of fine particulate matter, and overall lung cancer risk 9 percent higher, with no significant association for the coarser PM10 fraction. Ionising radiation accounts for 5 percent, of which indoor radon is the largest part: an estimated 9 percent of European lung cancer deaths are linked to indoor radon, and risk rises 16 percent per 100 becquerels per cubic metre of usual home radon. Second-hand smoke accounts for 1 percent of all cases but an estimated 15 percent of cases in people who have never smoked, raising their risk by 31 percent. Family history matters independently of smoking: risk is 82 percent higher with an affected sibling and 25 to 37 percent higher with an affected parent. Previous lung disease matters too, with risk 43 to 57 percent higher after pneumonia and 104 to 144 percent higher after emphysema. The smaller occupational exposures each account for a fraction of a percent of British cases: silica 0.02 percent, diesel engine exhaust 0.02 percent, painting 0.01 percent, welding 0.001 percent (Cancer Research UK).\n\nLung cancer in people who have never smoked. Fifteen percent of lung cancers diagnosed in the UK arise in never-smokers, which would make it the 8th commonest cancer in the country if it were counted as a disease of its own (BJC Reports 2023); worldwide the figure is put at 15 to 25 percent depending on the region, and if counted separately it would be the 7th commonest cause of cancer death (OLIVE protocol, BMJ Open Respiratory Research 2026; Health Science Reports 2026). It is a different disease: overwhelmingly adenocarcinoma, commoner in women and in east Asian populations, and far more often driven by a targetable mutation. The UK's largest prospective look at it, the Million Women Study, followed 634,039 never-smoking women for 14 years and found 1,469 lung cancers, 0.2 percent of the cohort; of 34 candidate risk factors only three reached significance, non-white ethnicity (relative risk 2.34), asthma requiring treatment (1.32) and height of 165 cm or more (1.16), and restricting the analysis to adenocarcinoma did not change the result. The practical consequence is that the risk factors that select people for screening do not select these patients, and the assumption that a non-smoker's cough is not cancer delays their diagnosis.\n\nHow it presents, and when the NHS refers. The NHS lists a cough that is not going away, shortness of breath, coughing up blood, chest or shoulder pain, repeated chest infections or one that will not clear, losing weight without trying, loss of appetite and constant tiredness as the common symptoms, and swelling of the face or neck, difficulty swallowing, a hoarse voice that does not go away and finger clubbing as the less common ones; early lung cancer often causes nothing at all. NICE NG12 turns that into three rules for general practice. Refer on the suspected cancer pathway if the chest X-ray suggests lung cancer, or if the person is 40 or over with unexplained coughing of blood (1.1.1). Offer an urgent direct access chest X-ray at 40 and over for two or more of cough, fatigue, shortness of breath, chest pain, weight loss and appetite loss, or for one of them in anyone who has ever smoked (1.1.2). Consider an urgent chest X-ray at 40 and over for persistent or recurrent chest infection, finger clubbing, supraclavicular or persistent cervical lymphadenopathy, chest signs consistent with lung cancer, or a raised platelet count (1.1.3). Mesothelioma has its own rules in the same section, with asbestos exposure lowering the threshold. In England in 2019 about 26 percent of lung cancers were diagnosed after an urgent suspected cancer referral and 33 percent after an emergency presentation (Cancer Research UK).\n\nScreening: the evidence, the programme and the harms. The evidence is two randomised trials. The National Lung Screening Trial gave 53,454 Americans aged 55 to 74 with 30 or more pack-years three annual low-dose CT scans or chest radiographs and cut lung cancer mortality by 20.0 percent (95 percent confidence interval 6.8 to 26.7) and all-cause mortality by 6.7 percent. NELSON gave 13,195 men and 2,594 women aged 50 to 74 volume CT at baseline and years 1, 3 and 5.5, and found a lung cancer death rate ratio of 0.76 (0.61 to 0.94) in men at ten years, with only 2.1 percent of participants referred for a suspicious nodule. The number needed to screen to prevent one lung cancer death is 323 over 6.5 years in the National Lung Screening Trial and 130 over ten years in NELSON. The harms are real and are the reason screening is targeted rather than universal: 24.2 percent of low-dose CT screens in the National Lung Screening Trial were positive and 96.4 percent of those positives were false; false positives led to 17 invasive procedures per 1,000 people screened, with fewer than one major complication; incidental findings were reported in 4.4 to 40.7 percent of people screened; and estimates of overdiagnosis, the cancers found that would never have caused harm, ranged from 0 to 67 percent across studies (US Preventive Services Task Force evidence report, 2021). In the United States the Task Force recommends annual low-dose CT from 50 to 80 for people with a 20 pack-year history who smoke or stopped within the past 15 years (grade B, 2021), widened from the 55 to 80 and 30 pack-year criteria of 2013.\n\nScreening in the United Kingdom. The UK National Screening Committee recommended targeted screening in June 2022 for people aged 55 to 74 identified as being at high risk, with smoking cessation built into the service, and named England's Targeted Lung Health Check programme as the starting point. The national programme was announced on 26 June 2023, costs £270 million a year at full size and is expected to deliver almost one million scans and find as many as 9,000 cancers a year. Eligibility is not age alone: a person's GP record identifies ever-smokers aged 55 to 74, and a risk model decides who is scanned, using PLCOm2012 or the Liverpool Lung Project version 2 in England, at a PLCOm2012 threshold of 1.51 percent risk over six years. Scanning is every two years for those at high risk. The first phase invited about 900,000 people, made 375,000 risk assessments, carried out 200,000 scans and found more than 2,000 cancers, of which 76 percent were early stage against 29 percent outside the programme in 2019, and about 70 percent of the scanning was done in mobile units parked in places such as supermarket car parks, deliberately in more deprived areas where people are four times more likely to smoke. By March 2025 the programme had invited over two million people and diagnosed 7,193 lung cancers, 63.1 percent at stage 1 and 12.6 percent at stage 2, and the early-stage share of all lung cancer in England rose over the five years, most in the most deprived regions. Full national coverage is expected in 2030.\n\nDiagnosis and staging. NICE NG122 sets the order. Contrast-enhanced CT of the chest, including the liver, adrenals and lower neck, comes before any biopsy. Everyone who could have treatment with curative intent is offered PET-CT. Where the nodal stage would change treatment, nodes are sampled through the airway or oesophageal wall: endobronchial ultrasound-guided transbronchial needle aspiration, endoscopic ultrasound-guided fine-needle aspiration, or both, with surgical mediastinal staging kept for a negative result when suspicion remains high. Enlarged nodes (10 mm or more in short axis on CT) or other lesions are biopsied in preference to the primary when the nodal stage decides treatment. Brain imaging is staged to the stage: none for clinical stage 1 without neurological symptoms, where the prevalence of brain metastases is about 4 percent; contrast-enhanced brain CT for clinical stage 2; contrast-enhanced brain MRI for stage 3. Samples must be big enough for subtyping and molecular markers, and the panel to run is set by the National Genomics Test Directory rather than by the guideline. One caution a reader should know: NG122's recommendations were written against the 7th edition of the American Joint Committee on Cancer staging system, which NICE says on the page, while staging in the clinic has moved two editions on.\n\nThe ninth edition of TNM, in force since 1 January 2025. The International Association for the Study of Lung Cancer built a new database of 124,581 patients diagnosed between 2011 and 2019 and analysed 76,518 of them. The T descriptors were tested and left alone: they are identical to the eighth edition. The N descriptors changed, splitting N2 into N2a, a single ipsilateral mediastinal or subcarinal station, and N2b, multiple ipsilateral mediastinal stations with or without the subcarinal station. The M descriptors changed at the far end, splitting M1c into M1c1, multiple metastases in one extrathoracic organ system, and M1c2, multiple metastases in several organ systems; both stay in stage group IVB. The stage groups moved to follow: T1N1 to IIA, T1N2a to IIB, T3N2a to IIIA, and T2aN2b and T2bN2b to IIIB. The practical effect is finer prognostic separation at the borders of resectability rather than a change in who is operated on, and a discontinuity in every survival series that spans the change.\n\nPathology: how the histology is decided. The 2021 WHO classification keeps the same order of evidence: morphology first, immunohistochemistry to support it, molecular tests last. That matters because most lung cancers are diagnosed on a small biopsy or a cytology specimen rather than a resection, and the fifth edition added a section dedicated to classifying small samples for exactly that reason. In practice a poorly differentiated tumour is assigned by a two-stain panel: TTF-1 marks adenocarcinoma, p40 marks squamous cell carcinoma, and a tumour positive for one and negative for the other is called that type rather than left as non-small-cell carcinoma not otherwise specified, because the name decides whether the tumour is sequenced and whether pemetrexed and bevacizumab are safe. Other changes in the fifth edition bear on the corpus's pages: invasive non-mucinous adenocarcinomas are graded by the percentage of each growth pattern, only the invasive part counts towards the T size in part-lepidic tumours, spread through air spaces is recognised as a prognostic feature, lymphoepithelial carcinoma moved into the squamous cell carcinomas, and thoracic SMARCA4-deficient undifferentiated tumour was recognised as an entity.\n\nPrevention. Because tobacco causes about 72 percent of UK cases, prevention is tobacco control and stopping smoking, and nothing else comes close. NICE NG209 covers the whole of it, from preventing uptake in people aged 24 and under to treating dependence in everyone aged 12 and over, and was last updated on 4 February 2025 to add recommendations on cytisinicline. Lung cancer screening is also a prevention service and not only a detection service: the UK National Screening Committee's recommendation was explicitly for screening with integrated smoking cessation, and the screening appointment reaches people who smoke at a moment when they will act. The other preventable exposures are radon, which can be measured in a home and reduced by sealing and ventilation, and workplace exposures to asbestos, silica, diesel exhaust and the rest, which are regulated rather than chosen.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Non-small-cell_lung_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Non-small-cell_lung_cancer"},{"label":"GLOBOCAN trachea, bronchus and lung fact sheet (IARC Global Cancer Observatory, 2024 estimates)","url":"https://gco.iarc.who.int/media/globocan/factsheets/cancers/15-trachea-bronchus-and-lung-fact-sheet.pdf"},{"label":"SEER Cancer Stat Facts: lung and bronchus cancer (rates, stage distribution, survival by stage, age and race)","url":"https://seer.cancer.gov/statfacts/html/lungb.html"},{"label":"CRUK: lung cancer statistics (incidence, mortality, survival, early diagnosis, treatment)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer"},{"label":"CRUK: lung cancer incidence statistics","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/incidence"},{"label":"CRUK: lung cancer mortality statistics (including mortality by deprivation)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/mortality"},{"label":"CRUK: lung cancer survival statistics (by age, deprivation and over time)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/survival"},{"label":"CRUK: lung cancer risk factors (attributable fractions for the UK)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/risk-factors"},{"label":"NHS: lung cancer","url":"https://www.nhs.uk/conditions/lung-cancer/"},{"label":"NHS: symptoms of lung cancer (when to see a GP, when to call 111 and when to call 999)","url":"https://www.nhs.uk/conditions/lung-cancer/symptoms/"},{"label":"NHS: lung cancer screening (who is invited to a lung health check and what happens)","url":"https://www.nhs.uk/tests-and-treatments/lung-cancer-screening/"},{"label":"NICE NG12: suspected cancer, recommendations by site (lung and pleural cancers 1.1.1 to 1.1.6)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"},{"label":"NICE NG122: lung cancer, diagnosis and staging (published 28 March 2019, last updated 8 March 2024)","url":"https://www.nice.org.uk/guidance/ng122/chapter/Diagnosis-and-staging"},{"label":"NICE NG209: tobacco, preventing uptake, promoting quitting and treating dependence (published 30 November 2021, last updated 4 February 2025)","url":"https://www.nice.org.uk/guidance/ng209"},{"label":"UK National Screening Committee: lung cancer screening recommendation (June 2022 review)","url":"https://view-health-screening-recommendations.service.gov.uk/lung-cancer/"},{"label":"GOV.UK: new lung cancer screening roll out to detect cancer sooner (26 June 2023)","url":"https://www.gov.uk/government/news/new-lung-cancer-screening-roll-out-to-detect-cancer-sooner"},{"label":"National Lung Screening Trial Research Team, N Engl J Med 2011: reduced lung-cancer mortality with low-dose computed tomographic screening (53,454 people)","url":"https://doi.org/10.1056/nejmoa1102873"},{"label":"de Koning, N Engl J Med 2020: NELSON, reduced lung-cancer mortality with volume CT screening in a randomised trial (13,195 men and 2,594 women)","url":"https://doi.org/10.1056/nejmoa1911793"},{"label":"US Preventive Services Task Force, JAMA 2021: screening for lung cancer, recommendation statement (annual low-dose CT at 50 to 80 with 20 pack-years, grade B)","url":"https://doi.org/10.1001/jama.2021.1117"},{"label":"Jonas, JAMA 2021: screening for lung cancer with low-dose computed tomography, updated evidence report for the US Preventive Services Task Force (223 publications, 7 randomised trials, 86,486 people)","url":"https://doi.org/10.1001/jama.2021.0377"},{"label":"Nature Medicine 2026: implementation of the NHS England Lung Cancer Screening Programme over 5 years (over two million invited, 7,193 cancers to March 2025)","url":"https://doi.org/10.1038/s41591-026-04292-y"},{"label":"Br J Hosp Med 2026: how to translate quality standards into good lung cancer screening programmes, the UK experience","url":"https://doi.org/10.31083/bjhm53142"},{"label":"Br J Cancer 2021: comparative performance of lung cancer risk models to define lung screening eligibility in the United Kingdom (273,789 people in three cohorts)","url":"https://doi.org/10.1038/s41416-021-01278-0"},{"label":"Cancer Epidemiol 2023: the value of blood-based measures of liver function and urate in lung cancer risk prediction (388,199 UK Biobank participants; the 1.51 percent six-year threshold)","url":"https://doi.org/10.1016/j.canep.2023.102354"},{"label":"Br J Radiol 2025: something old something new, introduction to the ninth edition TNM classification of lung cancer (effective 1 January 2025)","url":"https://doi.org/10.1093/bjr/tqaf161"},{"label":"Rami-Porta, J Thorac Oncol 2024: IASLC lung cancer staging project, proposals for revision of the TNM stage groups in the forthcoming ninth edition (76,518 patients analysed of 124,581 registered)","url":"https://doi.org/10.1016/j.jtho.2024.02.011"},{"label":"J Thorac Oncol 2024: IASLC lung cancer staging project, proposals for the revisions of the T descriptors in the forthcoming ninth edition (no change recommended)","url":"https://doi.org/10.1016/j.jtho.2023.12.006"},{"label":"J Thorac Oncol 2024: IASLC staging project for lung cancer, proposals for the revision of the M descriptors in the forthcoming ninth edition (M1c split into M1c1 and M1c2)","url":"https://doi.org/10.1016/j.jtho.2024.01.019"},{"label":"J Thorac Oncol 2023: IASLC lung cancer staging project, the new database to inform revisions in the ninth edition of the TNM classification","url":"https://doi.org/10.1016/j.jtho.2023.01.088"},{"label":"Int J Cancer 2026: the 9th edition of the UICC TNM classification of malignant tumours, updates and rationale for change","url":"https://doi.org/10.1002/ijc.70561"},{"label":"Nicholson, J Thorac Oncol 2022: the 2021 WHO classification of lung tumours, impact of advances since 2015","url":"https://doi.org/10.1016/j.jtho.2021.11.003"},{"label":"Lancet Respir Med 2025: estimated worldwide variation and trends in incidence of lung cancer by histological subtype in 2022 and over time (GLOBOCAN 2022 with Cancer Incidence in Five Continents)","url":"https://doi.org/10.1016/s2213-2600(24)00428-4"},{"label":"BJC Reports 2023: lung cancer in never smokers, development of a UK national research strategy (127 surveys, 190 attendees)","url":"https://doi.org/10.1038/s44276-023-00006-w"},{"label":"BMJ Open Respir Res 2026: observational study of predictors and outcomes of lung cancer in never-smokers in the UK (OLIVE), study protocol","url":"https://doi.org/10.1136/bmjresp-2025-003966"},{"label":"Pirie, Int J Cancer 2016: lung cancer in never smokers in the UK Million Women Study (634,039 never smokers, 1,469 lung cancers over 14 years)","url":"https://doi.org/10.1002/ijc.30084"},{"label":"Health Sci Rep 2026: lung cancer in never smokers, an underappreciated public health burden","url":"https://doi.org/10.1002/hsr2.73080"},{"label":"NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"},{"label":"Ding et al., BMJ Open 2024: applying the ESMO Magnitude of Clinical Benefit Scale to antibody-drug conjugates in solid cancers, a systematic analysis of phase 3 and pivotal phase 2 trials","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11163648/"},{"label":"NHS: treatment for lung cancer","url":"https://www.nhs.uk/conditions/lung-cancer/treatment/"},{"label":"NICE NG122: lung cancer, palliative interventions and supportive and palliative care","url":"https://www.nice.org.uk/guidance/ng122/chapter/Palliative-interventions-and-supportive-and-palliative-care"},{"label":"NICE NG122: lung cancer, support from clinical nurse specialists","url":"https://www.nice.org.uk/guidance/ng122/chapter/Support-from-clinical-nurse-specialists"},{"label":"NICE NG122: lung cancer, follow-up and patient perspectives","url":"https://www.nice.org.uk/guidance/ng122/chapter/Follow-up-and-patient-perspectives"},{"label":"Roy Castle Lung Cancer Foundation: living with lung cancer","url":"https://roycastle.org/learn-about-lung-cancer/living-with-cancer/"},{"label":"Roy Castle Lung Cancer Foundation: the support available to you","url":"https://roycastle.org/our-support/"},{"label":"Macmillan: non-small cell lung cancer (NSCLC)","url":"https://www.macmillan.org.uk/cancer-information-and-support/lung-cancer/non-small-cell-lung-cancer"},{"label":"Macmillan: breathlessness","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/breathlessness"},{"label":"Macmillan: superior vena cava obstruction (SVCO)","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/superior-vena-cava-obstruction"},{"label":"Cancer Research UK: living with lung cancer","url":"https://www.cancerresearchuk.org/about-cancer/lung-cancer/living-with"},{"label":"Cancer Research UK: coping with breathlessness when you have lung cancer","url":"https://www.cancerresearchuk.org/about-cancer/lung-cancer/living-with/coping-with-breathlessness"},{"label":"Cancer Research UK: coping and support when you have lung cancer","url":"https://www.cancerresearchuk.org/about-cancer/lung-cancer/living-with/coping"},{"label":"Cancer Research UK: fluid on the lungs (pleural effusion)","url":"https://www.cancerresearchuk.org/about-cancer/coping/physically/breathing-problems/fluid-on-lungs-pleural-effusion"},{"label":"Asthma + Lung UK: breathlessness","url":"https://www.asthmaandlung.org.uk/symptoms-tests-treatments/symptoms/breathlessness"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Marie Curie: what is palliative care?","url":"https://www.mariecurie.org.uk/information/getting-care/palliative-care"},{"label":"Temel et al., early palliative care for patients with metastatic non-small-cell lung cancer (NEJM 2010)","url":"https://doi.org/10.1056/NEJMoa1000678"},{"label":"National Lung Cancer Audit: State of the Nation 2026","url":"https://www.natcan.org.uk/wp-content/uploads/2026/02/NLCA-State-of-the-Nation-Report-2026.pdf"},{"label":"NHS England: National Optimal Lung Cancer Pathway v4.0","url":"https://rmpartners.nhs.uk/wp-content/uploads/2024/09/national-optimal-lung-cancer-pathway_v4_01jan2024.pdf"},{"label":"Roy Castle Lung Cancer Foundation","url":"https://roycastle.org/"}],"tags":["lung","spike"],"related":["sclc","kras-roadmap","adc-generations","immunotherapy-roadmap","targeted-before-io-nsclc","amivantamab-plus-lazertinib","tki-then-adc-lung","lung-cancer","lung-lcnec","pd-l1-tps","pd-l1-tc-score","pd-l1-ic-score","egfr-exon-19-deletion","egfr-l858r","egfr-exon-20-insertion","egfr-t790m","egfr-c797s","alk-fusion","alk-resistance-mutation","ros1-fusion","ret-fusion","met-ex14","met-amplification-readout","met-overexpression","her2-mutation","kras-g12c","kras-g12d","braf-v600e","braf-class-ii-iii","ntrk-fusion","nrg1-fusion","stk11-keap1-loss","tmb-high","pik3ca-hotspot-mutation"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","checkpoint-inhibitor","adc","bispecific-antibody","sbrt","ct","liquid-biopsy","cgp","omega3-epa-cachexia","shark-cartilage","hydrazine-sulfate","nhs-targeted-lung-health-check","low-dose-ct-screening","robotic-bronchoscopy","mrd-testing","pet","histopathology-ihc","palliative-care","palliative-radiotherapy","psycho-oncology","peer-support-groups","oncology-nutrition","pain-management","prehabilitation","survivorship-care-plan","cbt-fatigue-distress","exercise-during-chemotherapy","tmb-testing","rna-seq","wes-wgs","cytogenetics-fish"],"targets":["egfr","alk","kras","met","ret","braf","ntrk","her2","her3","trop2","pd1","pdl1","vegf","ros1","ctla4","tp53","stk11","keap1","nrg1","smarca4","rbm10","nf1","cdkn2a","nkx2-1","pik3ca","nfe2l2","sox2","fgfr1"],"drugs":["guardant360-cdx","oncomine-dx-target-test","therascreen-cdx","ventana-pd-l1-sp142","caris-mi-cancer-seek","resolution-ctdx-first","necitumumab","talc-sclerosant","samarium-153-lexidronam"],"companies":["kanvas-biosciences","nanjing-leads-biolabs","avistone-biotechnology","catalym","shanghai-fosun-pharmaceutical-industrial-development","bioinvent-international","haihe-biopharma","multitude-therapeutics","orion-orion-pharma","epicentrx","shenzhen-ionova-life-sciences","ap-biosciences","celltrion","civatech-oncology","elpiscience-suzhou-biopharma","genprex","ionctura","krystal-biotech","mabxience-research-s-l","maia-biotechnology","mbrace-therapeutics","molecular-partners","stcube","vyriad","astrazeneca","johnson-johnson","pfizer","roche-genentech","eli-lilly","bms","amgen","merck","novartis","bayer","boehringer-ingelheim","nuvalent","akeso","summit-therapeutics","abbvie","daiichi-sankyo"],"institutions":["roy-castle-lung-cancer-foundation","royal-papworth","liverpool-heart-and-chest","leeds-cancer-centre","birmingham-cancer-centre","uclh","the-christie","royal-marsden","newcastle-cancer-centre","nottingham-cancer-centre"],"pathways":["ras-mapk","pi3k-akt-mtor","pd1-checkpoint","nsclc-signalling","sclc-signalling","rtk-activation","keap1-nrf2","p53-cell-cycle","fgfr-signalling","swi-snf-chromatin","notch","lineage-plasticity-neuroendocrine","t-cell-exhaustion","mutagenesis-signatures","chromosomal-instability","clonal-evolution","resistance-routes-map","drug-tolerant-persisters","myc","antigen-presentation-immunoediting","cancer-immunity-cycle","chemical-carcinogenesis-receptor-activation"],"terms":["tps","egfr-exon19-l858r","egfr-exon20-insertion","c797s","met-amplification","histologic-transformation","oligoprogression","histology","pack-year","never-smoker-lung-cancer","ebus-tbna","tnm-9-lung-cancer","resectability-lung-cancer","pneumonitis","pulmonary-nodule","lung-rads","radon","asbestos","smoking-cessation","haemoptysis","pancoast-tumour","spread-through-air-spaces","ttf1-p40","mediastinal-lymph-node-stations","targeted-lung-health-check","oligometastatic","performance-status","resectability","tnm-staging","bronchoscopy","malignant-pleural-effusion","superior-vena-cava-obstruction","sublobar-resection","lobectomy","segmentectomy","pneumonectomy","radiation-pneumonitis","irae","immune-colitis","pleural-effusion","pleurodesis","brain-metastases","bone-metastases","cancer-related-fatigue","anaemia","cachexia","curative-intent","late-effects","egfr-mutation-subtypes","kras-mutation-subtypes","met-exon-14-skipping","stk11-keap1","tmb","gene-fusion","gene-amplification","amplification","copy-number-variation-term","resistance","cross-resistance","driver-mutation","wild-type","tumour-agnostic","mutational-signature","cold-vs-hot","immune-exclusion","neoantigen","ihc","fish","ngs","ctdna","cfdna","biopsy","somatic-mutations-wxs-wgs","vus","germline-vs-somatic","cdkn2a-homozygous-deletion","braf-v600-mutation","tert-promoter"],"trials":["gefitinib-chemo-tmh","symbiotic-lung-04","symbiotic-lung-01","nct06980272","nct06612151","nct07739758","nct06616532","nct07174908","nct07155187","nct07005102","nct05211895","nct05502237","nct05020769","nct05221840","nct06498479","nct07189455","nct07554339","nct06345729","nct07431827","nct07190248","nct06954246","nsclc-2","nct05450692","sqnsclc","nct07416994","nct05132075","nct05487391","nct05690945","nct07063745","nct06247605","nct07459751","nct06927986","nct07365319","nct07668752","nct05973773","nct07128199","aurora","nct06754644","nct05671510","dllevate","nct06671379","nct07365241","fleteo","nsclc-3","nct06984588","nct06416410","nct06735391","nct06635824","nct04655976","nct07566052","nct07662395","nct07217301","nct06646276","nct07362459","nct06472245","nsclc-4","nct06417008","nct06080776","nct06123754","luminosity","jcog0403","chisel","nct06712316","nct05687266","nct02486718","nct06119581","nct03164616","nct05555732","nct06627647","nct06692738","nct02453282","nct03178552","nct06561386","nct02542293","nct05984277","nct07513376","nct04380636","nct06077760","nct06422143","nct07361497","nct06868277","nct03800134","nct06312137","nct06767514","nct04988295","nct06012435","nct06726265","nct05920356","nct07361510","nct06417814","nct05215340","nct06216301","nct06687369","nct03833154","nct06838273","nct06758401","nct06890598","nct06382129","nct06899126","nct06623422","nct06357533","nct03003962","nct03390686","nct06875310","nct04613596","nct04923906","nct05654454","nct05609968","nct06170788","nct05089734","nct05987956","nct06793215","nct06881784","nct06350097","nct07183189","nct06041776","nct06617416","ukls","ylst","summit-lung","lungsearch","chart-lung","big-lung-trial","violet","tracerx"],"people":["philip-crosbie","matthew-callister","john-field","david-baldwin","gary-middleton","sanjay-popat","alastair-greystoke"],"bottlenecks":[],"keyPapers":["paper-tcga-lung-adenocarcinoma-nature-2014","paper-tcga-lung-squamous-nature-2012","paper-campbell-pan-lung-somatic-alterations-nat-genet-2016","paper-jordan-prospective-lung-adenocarcinoma-msk-cancer-discov-2017","paper-chen-east-asian-lung-adenocarcinoma-nat-genet-2020","paper-kris-lung-cancer-mutation-consortium-jama-2014","paper-alexandrov-tobacco-smoking-mutational-signatures-science-2016","paper-soda-eml4-alk-fusion-nature-2007","paper-bergethon-ros1-rearrangements-lung-jco-2012","paper-awad-met-exon-14-mutations-lung-jco-2016","paper-weiss-fgfr1-amplification-squamous-lung-sci-transl-med-2010","paper-fernandez-cuesta-cd74-nrg1-fusion-lung-cancer-discov-2014","paper-jonna-nrg1-fusions-solid-tumours-ccr-2019","paper-schoenfeld-smarca4-alterations-lung-ccr-2020","paper-skoulidis-kras-co-mutation-subsets-cancer-discov-2015","paper-arbour-kras-co-mutation-outcomes-ccr-2018","paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022","paper-blueprint-phase-2-pd-l1-assays-jto-2018","paper-rimm-pd-l1-assay-comparison-jama-oncol-2017","paper-rizvi-targeted-ngs-immunotherapy-determinants-jco-2018","paper-checkmate-026-first-line-nivolumab-nejm-2017","paper-ricciuti-tmb-pd-l1-levels-jama-oncol-2022","paper-keynote-042-tmb-mutations-ann-oncol-2023","paper-keynote-189-407-tmb-jtocrr-2023","paper-gandara-blood-tmb-atezolizumab-nat-med-2018","paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005","paper-pao-egfr-t790m-acquired-resistance-plos-med-2005","paper-engelman-met-amplification-gefitinib-resistance-science-2007","paper-yu-acquired-resistance-rebiopsy-egfr-ccr-2013","paper-oxnard-osimertinib-resistance-mechanisms-jama-oncol-2018","paper-gainor-alk-resistance-mutations-cancer-discov-2016","paper-shaw-alk-resistance-mutations-lorlatinib-jco-2019","paper-shaw-alk-l1198f-resensitisation-nejm-2016","paper-lee-clonal-history-small-cell-transformation-jco-2017","paper-offin-rb1-tp53-transformation-risk-jto-2019","paper-marcoux-egfr-small-cell-transformation-outcomes-jco-2019","paper-lindeman-lung-molecular-testing-guideline-jto-2018","paper-leighl-nile-cfdna-tissue-genotyping-ccr-2019","paper-aggarwal-plasma-genotyping-personalised-therapy-jama-oncol-2019","paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","paper-gay-sclc-subtypes-inflamed-cancer-cell-2021","paper-baine-sclc-subtype-immunohistochemistry-jto-2020","paper-hirsch-j-thorac-oncol","paper-rizvi-mutational-landscape-pd1-science-2015","paper-checkmate-227-n-engl-j-med-2018","paper-keynote-024-nejm-2016","paper-keynote-010-lancet-2016","paper-thress-nat-med","paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","paper-frampton-met-exon-14-cancer-discov-2015","paper-kras-nsclc-cancer-discov-2018","paper-tracerx-100-nejm-2017","paper-george-sclc-genomic-profiles-nature-2015","paper-zhang-lung-cancer-never-smokers-nat-genet-2021","paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020"],"journals":["clinical-lung-cancer","lung-cancer-journal","thoracic-cancer","chinese-journal-of-lung-cancer"],"dependsOn":[],"notes":["What does non-small-cell lung cancer mean? It is not one tumour type but everything that is not small-cell lung cancer: adenocarcinoma, squamous cell carcinoma, large cell carcinoma and a handful of rarer types. The grouping exists because the first decision in treatment, whether surgery and driver-matched drugs are on the table at all, turns on that line. Together the three main types are about 85 percent of lung cancer.","How is the type decided from a small biopsy? By morphology first, immunohistochemistry second and molecular tests last, which is the order the 2021 WHO classification sets out. On a poorly differentiated tumour a two-stain panel usually settles it: TTF-1 positive and p40 negative points to adenocarcinoma, p40 positive and TTF-1 negative to squamous cell carcinoma. It matters beyond the label, because adenocarcinoma is sequenced for drivers and squamous cell carcinoma usually is not, and because pemetrexed and bevacizumab are used in one and avoided in the other.","What raises the risk, and how much of it can I change? In the UK, 79 percent of lung cancer cases are judged preventable. Tobacco accounts for 72 percent (71 percent active smoking, 1 percent second-hand smoke), workplace exposures 13 percent, outdoor air pollution 8 percent and ionising radiation including indoor radon 5 percent. Family history raises risk independently of smoking, by 82 percent if a sibling has had it and 25 to 37 percent if a parent has (Cancer Research UK).","Is radon really a risk in Britain? Yes, as the largest single part of the 5 percent of cases caused by ionising radiation. An estimated 9 percent of European lung cancer deaths are linked to indoor radon, and risk rises about 16 percent for every 100 becquerels per cubic metre of the usual level in a home. Radon comes out of the ground, varies by geology rather than by anything a householder has done, can be measured with a posted detector and reduced by sealing and ventilation (Cancer Research UK).","I have never smoked and I have been diagnosed. Why me? There is often no answer, and that is itself the finding. Fifteen percent of UK lung cancers are in never-smokers, and the largest British study of never-smoking women found only three significant factors out of 34 examined. Second-hand smoke explains an estimated 15 percent of never-smoker cases, radon and air pollution some more. What is known is that the tumour is far more likely to carry a targetable mutation, so the biopsy should be sequenced.","Why did my GP send me for a chest X-ray rather than a scan? It is what NICE asks for. NG12 puts an urgent chest X-ray at the front of the pathway for people aged 40 and over with the symptom combinations it lists, and sends people straight to the suspected cancer pathway only when the X-ray already suggests cancer or when there is unexplained coughing of blood. A normal X-ray does not close the question: if symptoms persist, ask again.","What is EBUS and why do I need it after a CT and a PET scan? Endobronchial ultrasound-guided transbronchial needle aspiration passes an ultrasound probe down the airway and puts a needle through the airway wall into the lymph nodes beside it. CT sees that a node is big and PET sees that it is active, but neither proves cancer, and a wrong nodal stage changes the whole plan. NICE asks for it, or for the oesophageal equivalent, or for both, whenever the nodal stage would change treatment, and keeps surgical staging for the cases where the needle comes back negative and the suspicion remains.","Will I have a brain scan? It depends on the stage. NICE does not offer dedicated brain imaging for clinical stage 1 disease with no neurological symptoms, because the chance of finding a brain metastasis is about 4 percent and finding one rarely changes the lung operation. Stage 2 gets a contrast-enhanced brain CT and stage 3 a contrast-enhanced brain MRI, both before treatment with curative intent, because at those stages a metastasis is likelier and does change the plan.","Why does my new report use different stage numbers from my old one? Because staging moved to the ninth edition of TNM on 1 January 2025. The T categories are the same, but N2 was split into N2a and N2b by how many mediastinal node stations are involved, M1c was split by how many organ systems carry metastases, and several combinations moved between stage groups: T1N1 is now IIA, T1N2a IIB, T3N2a IIIA, and T2aN2b and T2bN2b IIIB. Nothing about the tumour changed; the label did.","Am I eligible for the NHS lung health check? In England the invitation goes to people aged 55 to 74 whose GP record shows they smoke or used to. A risk model, PLCOm2012 or the Liverpool Lung Project version 2, then decides who is scanned, at a PLCOm2012 threshold of 1.51 percent risk over six years; those above it are offered a low-dose CT scan every two years. The programme is arriving area by area and full coverage is expected in 2030, so an eligible person in an area not yet reached will not have been invited yet. Make sure the GP record says you smoke or used to, because the invitation is drawn from it.","Is screening worth the radiation and the false alarms? On the balance the evidence supports, yes for people at high risk. Screening cuts lung cancer deaths by a fifth to a quarter and all-cause deaths by about 7 percent in the trial that measured it, at the cost of a false alarm rate that was 96.4 percent of positive scans in the American trial, 17 invasive procedures per 1,000 people screened, incidental findings in 4.4 to 40.7 percent, and an unresolved amount of overdiagnosis. The European protocol, which watches nodule volume and growth instead of diameter, referred only 2.1 percent of participants, so the harm figures differ by protocol as much as by population.","What is the outlook? In the United States 29.5 percent of people are alive at five years, 65.5 percent for cancers still confined to the lung and 10.5 percent once the cancer has spread. In the UK 11.1 percent survive ten years or more, against 3.3 percent in the 1970s. These are averages over everybody diagnosed, including people whose disease was never treatable, and they lag the targeted drugs, immunotherapy and screening now in use by years.","Living with non-small-cell lung cancer: This is orientation from public patient pages and guidelines, not advice for your case: your own team's instructions and 24-hour number come first. The decision pages, the appointment question sets and the first 60 days checklist are written once, on the parent lung cancer record, because most of them apply to both histologies; the red cards, the symptom and procedure records and the links above are attached here as well. Written from NICE NG122 and NG234 and the NHS, Roy Castle Lung Cancer Foundation, Macmillan, Cancer Research UK, Asthma + Lung UK, Maggie's and Marie Curie patient pages, all read on 25 September 2026.","The science in detail, 1 of 8, in full; the one-sentence version is on the overview. The adenocarcinoma landscape. TP53 46 to 54%, KRAS 27 to 33% (G12C 41 to 51% of those records, about 13% of all adenocarcinomas), EGFR 12 to 47% by ancestry (exon 19 deletion 13 to 19%, L858R 9 to 21%, exon 20 insertion 1 to 3%, G719X, L861Q and S768I together 3 to 5%), KEAP1 11 to 18%, STK11 13 to 18%, CDKN2A deleted 15 to 20%, NKX2-1 amplified 8 to 14%, NF1 8 to 12%, SMARCA4 6 to 10%, RBM10 7 to 11%, PIK3CA 5 to 7%, ALK fusion 3 to 6%, MET exon 14 skipping 2 to 4% and MET amplification 2 to 3%, ERBB2 mutation 2 to 4% and amplification 1 to 3%, ROS1 fusion 1 to 3%, RET fusion 1 to 2%, BRAF V600E 1 to 2% against non-V600 3 to 4%, NRG1 fusion about 0.3% and NTRK fusion about 0.2%. Every figure names its cohort in the molecular table; the cBioPortal rows were computed on the TCGA PanCancer Atlas and 2014 deposits, the pan-lung TCGA and Broad set, two MSK-IMPACT cohorts (915 and 2,653 samples), the metastatic MSK cohort of 2,621, the Singaporean East Asian cohort, the never-smoker whole genomes and the CPTAC proteogenomic sets.","The science in detail, 2 of 8, in full; the one-sentence version is on the overview. The squamous landscape, which shares an organ with the above and almost nothing else. TP53 83 to 94%; SOX2 amplified about 40% and TP63 about 30% on the 3q26 amplicon that also carries PIK3CA, amplified in 38% with mutation in 11 to 16%; CDKN2A deleted 26.3% with mutation in 15.1%, and CDKN2A with RB1 altered in 72% once methylation and exon skipping are counted; FGFR1 amplified 17 to 22%; NFE2L2 hotspot mutated 12 to 15% with KEAP1 10.1% and CUL3 4.5%, the pathway altered in 34%; PTEN lost in about 20%; KMT2D 22.9% and NOTCH1 7.9% as truncating tumour suppressor events. Against that, EGFR mutation is 2.9% and mostly non-canonical, KRAS 1.4%, and ALK, ROS1 and RET fusions are absent from the structural-variant profile. That is why guidelines recommend full molecular testing in squamous disease only for never smokers, small biopsies and mixed histology.","The science in detail, 3 of 8, in full; the one-sentence version is on the overview. Small-cell disease. Biallelic TP53 and RB1 inactivation in nearly all of 110 sequenced genomes, sometimes by complex rearrangement, so mutation calls read lower (85.8% and 72.5%) than the biology; the two RB1 wild-type cases reached the same end by chromothripsis and cyclin D1 overexpression. NOTCH family inactivation in 25%, oncogenic TP73 rearrangements, and chromatin regulators (KMT2D 18.3%, EP300 10.8%, CREBBP 9.2%, KMT2C 10.0%) make up the rest, with kinase mutations only in rare individual cases. The clinically useful classification is transcriptional rather than genomic: 69% ASCL1-dominant, 17% NEUROD1-dominant, 7% POU2F3-positive and the remainder double-negative, with 37% co-expressing ASCL1 and NEUROD1. The fourth class is defined by an inflamed signature and gains most from adding immunotherapy to chemotherapy; the others carry vulnerabilities to PARP, Aurora kinase and BCL-2 inhibition, and DLL3 expression follows the neuroendocrine-high subtypes rather than the whole disease.","The science in detail, 4 of 8, in full; the one-sentence version is on the overview. PD-L1, the one protein biomarker that changes treatment. Four scoring rules on five assays: the tumour proportion score (22C3, tumour cells only, at least 100 counted), the tumour-cell score (28-8, SP263, SP142), the immune-cell area score (SP142) and the combined positive score used outside the lung. The thresholds are trial artefacts: 50% or more by 22C3 for first-line pembrolizumab monotherapy, where progression-free survival was 10.3 against 6.0 months; 1% or more after platinum; the SP142 combination of tumour cells 50% or more or immune cells 10% or more for first-line atezolizumab, where overall survival was 20.2 against 13.1 months; and 5% or more by 28-8, at which first-line nivolumab failed outright. Analytically, 22C3, 28-8 and SP263 are interchangeable on tumour cells, SP142 stains fewer tumour cells (mean score 1.99 against 2.96) and 73-10 more, agreement between pathologists is 0.86 to 0.93 on tumour cells and 0.18 to 0.19 on immune cells, cytology cell blocks score reliably (0.78 to 0.85) and digital images agree with glass slides above 0.96.","The science in detail, 5 of 8, in full; the one-sentence version is on the overview. Tumour mutational burden and why it failed. It is a real biological correlate: whole-exome sequencing first tied non-synonymous burden to pembrolizumab response in lung cancer, panel-based estimates track exome estimates at rho 0.86, burden and PD-L1 are independent, and across 1,552 patients burden tracked response, progression-free survival and overall survival within every PD-L1 stratum, with response ranging from 57% where both were high to 8.7% where neither was. It failed as a selector for three reasons. The unit is not standardised (per megabase on a panel, per exome on sequencing, a plasma score), the best data-derived threshold in the largest cohort was more than 19 per megabase rather than the licensed 10, and the effect is confined to single-agent immunotherapy: in KEYNOTE-189 and KEYNOTE-407 continuous burden showed no association with survival for pembrolizumab plus chemotherapy in either histology, and neither did STK11, KEAP1 or KRAS status. CheckMate 227 reported a progression-free survival benefit in the high-burden group and then found its survival benefit did not depend on burden at all.","The science in detail, 6 of 8, in full; the one-sentence version is on the overview. The never-smoker disease. Whole genomes of 232 never-smoker lung cancers carry no strong tobacco signature even with recorded secondhand exposure, and split into three copy-number subtypes: piano, the dominant and slow one, with somatic UBA1 mutations, germline androgen receptor variants, low mutation burden, high intratumour heterogeneity, long telomeres, frequent KRAS and driver progenitor cells dating back many years; mezzo-forte, with specific amplifications and EGFR mutations; and forte, with whole-genome doubling. The driver spectrum in the same cohort is EGFR 28.4%, ALK fusion 5.6%, ERBB2 exon 20 insertion 3.4%, MET exon 14 2.2%, ROS1 2.2%, RET 1.3% and NRG1 0.9%, with KRAS at only 7.3% and led by G12D, and TP53 at 15.5%, STK11 at 2.2% and KEAP1 at 0.4%. Ancestry is a separate axis: East Asian adenocarcinomas have more stable genomes with fewer mutations and fewer copy-number changes, a difference that is larger in smokers, and EGFR at 47.4%.","The science in detail, 7 of 8, in full; the one-sentence version is on the overview. Resistance, in three categories. On-target mutation: EGFR T790M in 63% of rebiopsies after a first-generation inhibitor, then C797S in 22% of osimertinib resistance, where the allelic phase with T790M decides whether a first-plus-third-generation combination can cover it; in ALK-rearranged disease, a diverse spectrum after crizotinib and G1202R after second-generation inhibitors, with lorlatinib response 69% where an ALK mutation is present and 27% where it is not. Bypass activation: MET amplification in 5 to 22% and HER2 amplification in 13%, both answered by adding an inhibitor rather than swapping one. Lineage change: small-cell transformation in 3 to 14%, requiring RB1 and TP53 loss, predictable from the baseline genotype with a 43-fold risk, treated as small-cell disease with platinum and etoposide and unresponsive to checkpoint blockade. Losing T790M at osimertinib resistance, which happens in 68% of cases, signals a pre-existing competing clone and a much shorter time on treatment (6.1 against 15.2 months).","The science in detail, 8 of 8, in full; the one-sentence version is on the overview. Testing, in practice. Plasma and tissue together at diagnosis: cell-free DNA found a guideline biomarker in 27.3% of 282 patients against 21.3% by tissue, with 100% positive predictive value for the alterations that have approved drugs and a median turnaround of 9 against 15 days, and using both raised detection by 48%. A negative plasma result rules nothing out, since clinical sensitivity against tissue is 80% and the misses concentrate in low-volume, intrathoracic and brain-confined disease. What tissue alone can miss is different: fusions and MET exon 14 skipping need intron baiting or RNA, PD-L1 cannot be read from plasma at all, and histology has no liquid substitute. The practical rule is tissue stewardship, cutting unstained slides at diagnosis and avoiding reflex stains that consume the block, with cytology cell blocks used where they are the only material. The guideline requires ROS1 for every adenocarcinoma, 5% sensitivity for EGFR T790M in acquired resistance, immunohistochemistry as a screen for ALK and ROS1 but not for EGFR, and plasma to rule in rather than out.","Frequencies marked cBioPortal were computed from the public API on 25 September 2026 on the sequenced sample lists of luad_tcga_pan_can_atlas_2018 (566), lusc_tcga_pan_can_atlas_2018 (484 sequenced, 487 with copy number), luad_tcga_pub (230), lusc_tcga_pub (178), nsclc_tcga_broad_2016 (1,144), lung_msk_2017 (915), nsclc_ctdx_msk_2022 (2,621), luad_mskcc_2023_met_organotropism (2,653 sequenced, 2,422 with copy number and structural variants), luad_oncosg_2020 (302), lung_nci_2022 (232), sclc_ucologne_2015 (120), nsclc_pd1_msk_2018 (240), luad_cptac_2020 (110) and lusc_cptac_2021 (108), as sample-level counts of non-synonymous mutation, high-level amplification, deep deletion or structural variant. They are not the papers' own percentages, which are quoted alongside.","What the panels cannot see. Fusion counts here come from the structural-variant profile, which requires intron baiting or RNA, so every fusion rate is a floor: ALK reads 3 to 6% on panels against 8% by fluorescence in situ hybridisation in the Lung Cancer Mutation Consortium, and NRG1 reads 0.3% by RNA sequencing against near zero on most DNA panels. Point mutations in ALK, ROS1, RET and NTRK read 2 to 8% in exome cohorts and are almost all passengers in a tobacco-mutated genome. The Cologne small-cell deposit carries no copy-number profile, so MYC family amplification rates cannot be recomputed from it, and biallelic TP53 and RB1 inactivation by complex rearrangement is invisible to a mutation call, which is why the deposit reads 85.8% and 72.5% where the paper reports near-universal loss. The TRACERx cohort is multiregion, so its sample counts are regions rather than patients and no frequency is taken from it here.","EGFR class counts are sample-level and a tumour with both an exon 19 deletion and T790M is counted in both classes, which is deliberate: the point of reading the classes separately is that a treated patient carries both. KRAS, BRAF and NFE2L2 allele shares are counts of mutation records over all records for that gene in a study, so a tumour with two mutations in one gene counts twice. T790M and C797S rates in the MSK cohorts are inflated relative to the untreated population because those cohorts are largely treated patients resequenced at progression."],"group":"lung","burden":"About 85 percent of lung cancer, and lung cancer is first in the world for both new cases and deaths: 2,637,005 cases and 1,861,839 deaths a year (GLOBOCAN 2024). Around 50,200 UK lung cancers and 32,800 UK deaths a year (Cancer Research UK); 229,410 US cases and 124,990 deaths projected for 2026, with five-year relative survival of 29.5 percent for the site (SEER). Of lung cancers in men worldwide 45.6 percent are adenocarcinoma, 29.4 percent squamous and 6.5 percent large-cell; in women 59.7, 17.1 and 6.5 percent (Lancet Respiratory Medicine 2025).","subtypes":["Adenocarcinoma","Squamous","EGFR-mutant","ALK-rearranged","KRAS-mutant","PD-L1-high","Adenocarcinoma (~50%)","Squamous cell carcinoma (~25-30%)","Large-cell / NOS","EGFR-mutant (exon 19 del, L858R, exon 20 ins, uncommon)","ROS1-rearranged","KRAS G12C and non-G12C","BRAF V600E","MET exon 14 skipping / MET-amplified","RET-fusion","HER2-mutant","NTRK-fusion","Driver-negative PD-L1-high (TPS ≥50%)","Driver-negative PD-L1-low/negative","STK11/KEAP1 co-mutated (IO-resistant)"],"biomarkers":["EGFR","ALK","ROS1","BRAF V600E","MET ex14 / amplification / c-MET IHC","RET","NTRK","KRAS G12C","HER2 mutation","PD-L1 TPS","ctDNA","PD-L1 TPS (22C3)","EGFR (exon 19 del, L858R, exon 20 ins, T790M, C797S)","ALK fusion","ROS1 fusion","KRAS G12C (and G12D/V)","MET exon 14 skipping, MET amplification, c-Met IHC","RET fusion","HER2 (ERBB2) mutation","NTRK fusion","STK11 / KEAP1 (prognostic, IO resistance)","TP53 / RB1 (transformation risk)","ctDNA (genotyping, MRD, resistance tracking)","TMB (limited use)","TTF-1 and p40 immunohistochemistry to assign histology on a small biopsy before molecular testing","Spread through air spaces, recorded on resection specimens since the 2021 WHO classification","Pathological stage by TNM 9, including the N2a and N2b split","KRAS G12C: 41-51%","EGFR: 12-47%","EGFR exon 19 deletion: 13-19%","EGFR L858R: 9-21%","EGFR exon 20 insertion: 1-3%","STK11 (LKB1): 13-18%","KEAP1: 11-18%","MET exon 14 skipping: 2-4%","MET amplification: 2-3%","ERBB2 (HER2) mutation: 2-4%","BRAF V600E: 1-2%","ALK fusion: 3-6%","ROS1 fusion: 1-3%","RET fusion: 1-2%","NTRK fusion: 0.2%","NRG1 fusion: 0.3%"],"standardOfCare":[{"setting":"Screening (age 50-80, ≥20 pack-years)","approach":"Annual low-dose CT with Lung-RADS reporting; AI nodule scoring emerging; robotic bronchoscopy for peripheral nodule biopsy.","refs":["low-dose-ct-screening","nlst-nelson","robotic-bronchoscopy","radiology-ai-screening"]},{"setting":"Stage I-II resectable","approach":"Lobectomy or segmentectomy (small peripheral) with nodal staging; SBRT if inoperable. Stage IB-IIIA: neoadjuvant chemo-IO (CheckMate 816) or perioperative chemo-IO (KEYNOTE-671); adjuvant osimertinib if EGFR-mutant (ADAURA), alectinib if ALK-positive (ALINA); adjuvant chemotherapy otherwise for stage II+.","refs":["robotic-surgery","sbrt","checkmate-816","keynote-671","adaura","alina","osimertinib","alectinib"]},{"setting":"Stage III unresectable","approach":"Concurrent platinum chemoradiation → durvalumab 1 year (PACIFIC), or osimertinib until progression if EGFR-mutant (LAURA). Proton therapy in selected cases.","refs":["imrt-igrt","pacific","laura","durvalumab","osimertinib","proton-therapy"]},{"setting":"Metastatic, EGFR exon 19 del / L858R","approach":"First line: osimertinib ± platinum-pemetrexed (FLAURA2) or amivantamab + lazertinib (MARIPOSA, OS benefit). Progression: re-biopsy/ctDNA; amivantamab + chemotherapy (MARIPOSA-2), Dato-DXd (TROPION-Lung05), platinum doublet; MET TKI add-on if MET-amplified; platinum-etoposide if small-cell transformation.","refs":["osimertinib","flaura2","amivantamab","lazertinib","mariposa","amivantamab-plus-lazertinib","datopotamab-deruxtecan","tropion-lung05","egfr-exon19-l858r","c797s","met-amplification","histologic-transformation"]},{"setting":"Metastatic, EGFR exon 20 insertion","approach":"Amivantamab + platinum-pemetrexed (PAPILLON); sunvozertinib later line.","refs":["amivantamab","egfr-exon20-insertion"]},{"setting":"Metastatic, ALK-rearranged","approach":"Lorlatinib (CROWN; 5-year PFS 60%) or alectinib first line; on progression, neladalkib (under review) or lorlatinib if not used; local therapy for oligoprogression; chemotherapy.","refs":["lorlatinib","crown","alectinib","neladalkib","alkove-1","oligoprogression"]},{"setting":"Metastatic, ROS1-rearranged","approach":"Repotrectinib or zidesamtinib (2026) first line; entrectinib/crizotinib alternatives.","refs":["repotrectinib","zidesamtinib","ros1"]},{"setting":"Metastatic, KRAS G12C","approach":"First line: PD-(L)1 ± chemotherapy by PD-L1 (G12C inhibitor + IO combinations in phase 3: olomorasib SUNRAY-01, divarasib Krascendo 2). Second line: sotorasib or adagrasib (CodeBreaK 200, KRYSTAL-12); divarasib superior head-to-head (Krascendo 1, 2026).","refs":["sotorasib","adagrasib","divarasib","olomorasib","codebreak-200","krystal-12","krascendo-1","kras-inhibitors"]},{"setting":"Metastatic, BRAF V600E","approach":"Dabrafenib + trametinib or encorafenib + binimetinib first line; chemo-IO as alternative.","refs":["dabrafenib-trametinib","encorafenib","braf"]},{"setting":"Metastatic, MET exon 14 skipping","approach":"Capmatinib or tepotinib first line; telisotuzumab vedotin for c-Met-overexpressing EGFR-wild-type disease after chemotherapy (accelerated 2025).","refs":["capmatinib-tepotinib","telisotuzumab-vedotin","telimet-nsclc-01","met"]},{"setting":"Metastatic, RET-fusion","approach":"Selpercatinib first line (LIBRETTO-431); pralsetinib alternative.","refs":["selpercatinib","libretto-431","pralsetinib","ret"]},{"setting":"Metastatic, HER2-mutant","approach":"First line: zongertinib (2026) or chemo-IO; sevabertinib (Nov 2025) or T-DXd after prior therapy.","refs":["zongertinib","sevabertinib","soho-01","trastuzumab-deruxtecan","her2"]},{"setting":"Metastatic, NTRK-fusion","approach":"Larotrectinib, entrectinib, or repotrectinib (tumour-agnostic).","refs":["repotrectinib","ntrk","tumour-agnostic"]},{"setting":"Metastatic, driver-negative, PD-L1 TPS ≥50%","approach":"Pembrolizumab (KEYNOTE-024) or cemiplimab monotherapy; add chemotherapy for high burden or rapid progression. Ivonescimab beat pembrolizumab in China (HARMONi-2); not approved in the US.","refs":["pembrolizumab","cemiplimab","keynote-024-189","ivonescimab","harmoni-2","tps"]},{"setting":"Metastatic, driver-negative, PD-L1 TPS <50%","approach":"Pembrolizumab + platinum doublet (KEYNOTE-189 non-squamous; KEYNOTE-407 squamous); nivolumab + ipilimumab ± chemotherapy; tremelimumab + durvalumab + chemotherapy for PD-L1-negative or STK11/KEAP1-altered disease. Second line: docetaxel ± ramucirumab, TTFields, or trials of ADCs.","refs":["pembrolizumab","nivolumab","ipilimumab","tremelimumab","durvalumab","pd1-plus-chemo-pdl1-low","optune"]},{"setting":"Metastatic, squamous","approach":"Pembrolizumab + carboplatin + (nab-)paclitaxel (KEYNOTE-407); no ADC approved (TROPION-Lung01 showed no benefit in squamous); ivonescimab + chemotherapy under study (HARMONi-3).","refs":["pembrolizumab","paclitaxel","carboplatin","tropion-lung01","harmoni-3"]}],"stateOfArt":["5-year PFS 60% with lorlatinib in ALK+ disease.","Adjuvant osimertinib after surgery for EGFR-mutant disease roughly halves the risk of the cancer returning or of dying from it (ADAURA).","First regimen to beat osimertinib (MARIPOSA) and first to beat pembrolizumab (ivonescimab, China).","Lorlatinib: 5-year PFS 60% in ALK-positive disease, the longest for any targeted therapy in metastatic solid tumours.","Adjuvant osimertinib after surgery roughly halves the risk of dying from EGFR-mutant disease (ADAURA, OS HR 0.49); adjuvant alectinib cuts recurrence by 76% (ALINA).","Amivantamab + lazertinib is the first regimen to beat osimertinib, with median OS more than 12 months longer (MARIPOSA).","Perioperative chemo-immunotherapy improves survival in resectable disease (CheckMate 816, KEYNOTE-671).","Twelve targetable drivers each have an approved matched therapy; two oral HER2 TKIs (zongertinib, sevabertinib) arrived in 2025-26.","First-in-class bispecific ivonescimab beat pembrolizumab on PFS and OS in China; the US decision (PDUFA 14 Nov 2026) hinges on HARMONi.","5-year survival with pembrolizumab in PD-L1-high disease is 31.9% in the KEYNOTE-024 five-year analysis, against 16.3% with platinum chemotherapy in the same trial.","Two genomic landscapes, not one. Adenocarcinoma is oncogene-addicted: EGFR 12 to 47% by ancestry, KRAS 27 to 33%, ALK 3 to 6%, MET exon 14 skipping 2 to 4%, ERBB2 exon 20 insertion about 2%, ROS1 1 to 3%, RET 1 to 2%, BRAF V600E 1 to 2%, NTRK and NRG1 below 0.5%. Squamous carcinoma is copy-number driven: TP53 83 to 94%, SOX2 amplified about 40%, PIK3CA amplified 38%, TP63 about 30%, CDKN2A deleted 26%, FGFR1 17 to 22%, NFE2L2 12 to 15%, with targetable kinase alterations at 1 to 3%.","Ancestry and smoking move the numbers more than anything else. EGFR is mutated in 47.4% of East Asian lung adenocarcinomas and 12.4% of the resected, mostly-smoker TCGA series; KRAS runs the other way, 29.7% against 10.9%; TP53 falls from 52 to 54% in smoker cohorts to 15.5% in never-smoker whole genomes.","PD-L1 is the only measurement that changes first-line treatment, and it is not standardised: four scoring rules on five assays, with 22C3, 28-8 and SP263 agreeing on tumour cells, SP142 staining less and 73-10 more, and agreement between pathologists of 0.18 to 0.19 on immune cells against 0.86 to 0.93 on tumour cells.","Tumour mutational burden failed as a selector. It tracks benefit from single-agent checkpoint blockade within every PD-L1 stratum, but the best data-derived cut-off was more than 19 mutations per megabase rather than the licensed 10, and it predicted nothing for pembrolizumab with chemotherapy, the regimen most patients receive.","Resistance comes in three kinds with three different answers: a mutation in the target, a bypass receptor amplified, or a change of lineage into small-cell carcinoma. Which one it is cannot be guessed, so genotyping at progression is standard rather than optional.","Small-cell lung cancer has one genotype and four states: TP53 and RB1 are both inactivated in nearly every tumour, and the classification that matters is transcriptional, ASCL1-dominant 69%, NEUROD1-dominant 17%, POU2F3 7%, and an inflamed class that gains most from immunotherapy."],"history":[{"year":2002,"title":"Gefitinib approved; dramatic responses in a minority","refs":[]},{"year":2004,"title":"EGFR mutations explain gefitinib responses","note":"Lynch, Paez, and Pao identify activating EGFR mutations; the birth of lung cancer precision medicine.","refs":["egfr","egfr-exon19-l858r"]},{"year":2005,"title":"A second mutation in the same gene explains resistance","note":"EGFR T790M is found in a patient relapsing after two years on gefitinib, and independently in progressing tumours that had not carried it before treatment. It becomes the most studied resistance mutation in cancer.","refs":["paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005","paper-pao-egfr-t790m-acquired-resistance-plos-med-2005","egfr-t790m"]},{"year":2007,"title":"EML4-ALK fusion discovered","note":"Soda et al.; crizotinib approved 2011.","refs":["alk"]},{"year":2007,"title":"Resistance without touching the target","note":"MET amplification restores the growth signal through ERBB3 in 4 of 18 lung cancers resistant to an EGFR inhibitor, defining bypass resistance as a category.","refs":["paper-engelman-met-amplification-gefitinib-resistance-science-2007","met"]},{"year":2010,"title":"The first tractable target in squamous lung cancer","note":"Focal FGFR1 amplification in 22% of squamous cell lung cancers, with selective killing of amplified cell lines by FGFR inhibition.","refs":["paper-weiss-fgfr1-amplification-squamous-lung-sci-transl-med-2010","fgfr1"]},{"year":2011,"title":"NLST: low-dose CT screening reduces mortality 20%","refs":["nlst-nelson","low-dose-ct-screening"]},{"year":2012,"title":"The squamous genome read in full, and a second fusion class","note":"TP53 mutated in nearly all of 178 squamous tumours, with the NFE2L2 and KEAP1 pathway altered in 34%, squamous differentiation genes in 44% and CDKN2A with RB1 in 72%; ROS1 rearrangements are defined as a class in 1,073 screened patients.","refs":["paper-tcga-lung-squamous-nature-2012","paper-bergethon-ros1-rearrangements-lung-jco-2012","nfe2l2","ros1"]},{"year":2013,"title":"How EGFR-mutant lung cancer escapes, counted","note":"Rebiopsy of 155 patients: T790M in 63%, MET amplification in 5%, HER2 amplification in 13% and small-cell transformation in 3%, making rebiopsy at progression standard.","refs":["paper-yu-acquired-resistance-rebiopsy-egfr-ccr-2013","egfr","met"]},{"year":2014,"title":"The adenocarcinoma reference map, and the case for multiplex testing","note":"Two hundred and thirty adenocarcinomas profiled on every platform add RIT1 and MGA to the driver list and show that NF1, MET, ERBB2 and RIT1 drive the tumours with no other oncogene; the Lung Cancer Mutation Consortium finds a driver in 64% of 733 patients and longer survival where treatment matched it.","refs":["paper-tcga-lung-adenocarcinoma-nature-2014","paper-kris-lung-cancer-mutation-consortium-jama-2014","rit1","mga"]},{"year":2015,"title":"Nivolumab beats docetaxel: immunotherapy era","note":"CheckMate 017/057; pembrolizumab first line for PD-L1 ≥50% follows (KEYNOTE-024, 2016).","refs":["nivolumab","pembrolizumab","keynote-024-189"]},{"year":2015,"title":"The small-cell genome, and mutation load as a predictor","note":"Biallelic TP53 and RB1 loss in nearly all of 110 small-cell genomes, with NOTCH inactivation in 25%; in the same year, non-synonymous mutation burden is shown to predict response to PD-1 blockade in lung cancer, and KRAS-mutant disease is split into immune-poor and inflamed subsets by its co-mutations.","refs":["paper-george-sclc-genomic-profiles-nature-2015","paper-rizvi-mutational-landscape-pd1-science-2015","paper-skoulidis-kras-co-mutation-subsets-cancer-discov-2015","rb1","stk11"]},{"year":2016,"title":"A resistance map by inhibitor generation","note":"Across 103 repeat biopsies, each ALK inhibitor is shown to select its own spectrum of resistance mutations, with G1202R rising after second-generation treatment and the presence of a mutation predicting benefit from the third generation.","refs":["paper-gainor-alk-resistance-mutations-cancer-discov-2016","alk"]},{"year":2017,"title":"PACIFIC: durvalumab consolidation in stage III","refs":["pacific","durvalumab"]},{"year":2017,"title":"One protein, five stains, and prospective sequencing measured against what patients receive","note":"The Blueprint comparison shows three PD-L1 assays agree on tumour cells and SP142 does not. Of 860 patients with metastatic lung adenocarcinoma sequenced prospectively, 37.1% received a matched therapy, and the limiting factor was the evidence behind each alteration rather than detection; transformation to small-cell carcinoma is shown to branch from the adenocarcinoma clone before treatment begins.","refs":["paper-hirsch-j-thorac-oncol","paper-jordan-prospective-lung-adenocarcinoma-msk-cancer-discov-2017","paper-lee-clonal-history-small-cell-transformation-jco-2017","pdl1"]},{"year":2018,"title":"Osimertinib first line (FLAURA); first tumour-agnostic approval (larotrectinib)","refs":["osimertinib","ntrk"]},{"year":2018,"title":"Co-mutations, and the testing guideline that followed","note":"STK11 and KEAP1 are tied to poor immunotherapy outcomes in KRAS-mutant disease; the College of American Pathologists, the International Association for the Study of Lung Cancer and the Association for Molecular Pathology require ROS1 testing for all adenocarcinomas and allow plasma to rule a mutation in but not out.","refs":["paper-kras-nsclc-cancer-discov-2018","paper-arbour-kras-co-mutation-outcomes-ccr-2018","paper-lindeman-lung-molecular-testing-guideline-jto-2018","stk11","keap1"]},{"year":2019,"title":"Four kinds of small-cell lung cancer, and plasma as a first test","note":"Transcription factor expression splits small-cell disease into four subtypes; in parallel, cell-free DNA is shown to be non-inferior to tissue genotyping at diagnosis and six days faster.","refs":["paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","paper-leighl-nile-cfdna-tissue-genotyping-ccr-2019","paper-aggarwal-plasma-genotyping-personalised-therapy-jama-oncol-2019"]},{"year":2020,"title":"ADAURA: adjuvant osimertinib; MET and RET inhibitors approved","refs":["adaura","capmatinib-tepotinib","selpercatinib","pralsetinib"]},{"year":2021,"title":"Sotorasib: first KRAS inhibitor; amivantamab for exon 20 insertions","refs":["sotorasib","amivantamab","egfr-exon20-insertion"]},{"year":2021,"title":"Lung cancer in never smokers gets its own classification","note":"Whole genomes of 232 never-smoker lung cancers find no tobacco signature and three copy-number subtypes, one of them slow-growing with driver progenitor cells dating back many years.","refs":["paper-zhang-lung-cancer-never-smokers-nat-genet-2021"]},{"year":2022,"title":"CheckMate 816: neoadjuvant immunotherapy; tremelimumab-durvalumab (POSEIDON)","refs":["checkmate-816","tremelimumab"]},{"year":2023,"title":"MARIPOSA beats osimertinib; KEYNOTE-671 perioperative IO; ALINA adjuvant alectinib; repotrectinib approved","refs":["mariposa","keynote-671","alina","repotrectinib"]},{"year":2023,"title":"Tumour mutational burden fails where it matters","note":"In the trials of pembrolizumab with chemotherapy, continuous tissue mutational burden predicts nothing in either histology, and neither do STK11, KEAP1 or KRAS status.","refs":["paper-keynote-189-407-tmb-jtocrr-2023","paper-keynote-042-tmb-mutations-ann-oncol-2023"]},{"year":2024,"title":"LAURA (osimertinib after chemoradiation); HARMONi-2: ivonescimab beats pembrolizumab in China; lazertinib approved","refs":["laura","harmoni-2","lazertinib"]},{"year":2025,"title":"First MET ADC (telisotuzumab vedotin); Dato-DXd in EGFR-mutant disease; MARIPOSA OS benefit; HER3-DXd BLA withdrawn; zongertinib and sevabertinib approved","refs":["telisotuzumab-vedotin","datopotamab-deruxtecan","tropion-lung05","herthena-lung02","zongertinib","sevabertinib"]},{"year":2026,"title":"Zongertinib first line; zidesamtinib (ROS1) approved; divarasib beats first-generation KRAS inhibitors; neladalkib and ivonescimab under FDA review","refs":["zongertinib","zidesamtinib","krascendo-1","neladalkib","alkove-1","harmoni-3"]}],"pipeline":["ivonescimab","izalontamab-brengitecan","sacituzumab-tirumotecan","tilatamig-samrotecan","daraxonrasib","patritumab-deruxtecan","intismeran-autogene","zidesamtinib","pf-08634404","shr-8068","yl201","shr-a2102","tqb2102","pm8002","in10018","telisotuzumab-adizutecan","domvanalimab","si-b001","oleclumab","cetrelimab","hs-20093","zg006","calderasib","ak117","qlc5508","budigalimab","ceralasertib","rc148","yl202","livmoniplimab","jdq443","saruparib","ql1706","monalizumab","navlimetostat","al8326","hlx43","sys6010","kl-a167","quemliclustat","eik1001","gfh375","zipalertinib","aglatimagene-besadenovec","ql2107","gotistobart","tqb2450","zl-1310","shr-a2009","pf-07248144","abbv-706","ty-9591","tgrx-326","uliledlimab","sitneprotafib","jmt101","acasunlimab","bnt324","cobolimab","olvimulogene-nanivacirepvec","setidegrasib","sctb41","tak-928","atigotatug","sctb14","ose2101","pf-08046054","hs-20117","ibi363","vs-7375","t3011","tng462","mcla-129","tqb6411","anvumetostat","xnw27011","hmbd-001","ssgj-706","ep0031","absk061","rilvegostomig","mavrostobart","hb0036","jk08","tri-611","silevertinib","palacaparib","peluntamig","tng456","jyp0015","hlx26","ba3071","env-501","azd7789","vrn110755","dji136","js111","tng260","au-007","or502","jmt203","befotertinib","lp-184","upifitamab-rilsodotin","vibostolimab","boserolimab","neladalkib","alkove-1","divarasib","krascendo-1","olomorasib","harmoni-3","telimet-nsclc-01","sevabertinib","low-dose-ct-screening","mrd-testing","radiology-ai-screening","immuno-pet"],"openProblems":["Screening uptake is under 20% in the US and lower elsewhere; never-smoker adenocarcinoma has no screening pathway.","Resistance to every TKI is near-universal in metastatic disease; C797S has no approved fourth-generation EGFR inhibitor and small-cell transformation is undetectable by ctDNA.","Squamous cell carcinoma has almost no targeted options and no approved ADC.","KRAS G12C inhibitors add only ~1-2 months of PFS over docetaxel; non-G12C KRAS (G12D, G12V) remains undrugged outside trials.","STK11/KEAP1 co-mutated and PD-L1-negative tumours respond poorly to immunotherapy.","ADCs after TKI failure have not yet shown a survival benefit over platinum chemotherapy (HERTHENA-Lung02, TROPION-Lung01), and ILD limits combinations.","Brain metastases occur in 30-50% of driver-positive patients; CNS activity now drives TKI choice, but leptomeningeal disease remains very hard to treat.","Global access: most of the world's lung cancer patients never receive genomic profiling.","The disease is still found late, and that is where most of the lost survival is. Fifty-one percent of American cases are already distant at diagnosis and survive 10.5 percent at five years, against 65.5 percent for the quarter found while the cancer is confined to the lung (SEER). Screening changes this only where it is offered, and it is offered to a minority of the people at risk even in the countries that have programmes.","Screening cannot see never-smokers. Fifteen percent of UK cases and 15 to 25 percent worldwide arise in people who never smoked, and every eligibility rule starts from a smoking history, so the fastest-growing part of the disease is the part no programme is looking for.","Never-smoker disease has no measured risk factor set to build a rule from. The largest UK prospective study found only three significant factors of 34 examined in 634,039 never-smoking women, and two of them, height and ethnicity, are not actionable (Million Women Study 2016).","The staging change of January 2025 breaks every survival series that spans it. N2a and N2b patients were one group until 2024, several stage groups moved, and a cohort staged either side of the line cannot be pooled without restaging.","NICE's diagnostic guideline is anchored two staging editions behind the clinic. NG122 states that its recommendations were developed with the 7th edition of the AJCC system while the ninth edition of TNM has been in force since January 2025, and the thresholds in the guideline (for example which stage triggers brain imaging) were fixed against the older groupings.","More than half of KRAS-mutant lung adenocarcinoma has no approved inhibitor: G12C is 41 to 51% of KRAS records, and G12V, G12D, G12A, G13X and Q61X together are the rest.","Squamous cell lung cancer still has no targeted therapy. Its three commonest alterations are a transcription factor amplicon (SOX2 and TP63), a tumour suppressor deletion (CDKN2A) and an antioxidant switch (NFE2L2 and KEAP1), and the one tractable-looking target, FGFR1 amplification, has not predicted response on its own.","No biomarker selects patients for chemotherapy plus immunotherapy, the regimen most patients with driver-negative disease receive: tumour mutational burden, STK11, KEAP1 and KRAS status all failed to predict benefit from the combination in the randomised analyses.","Fusion detection depends on assay design rather than on biology. A coding-exon panel returns wild-type for ALK, ROS1, RET, NTRK and NRG1 rearrangements and for MET exon 14 skipping, together about 8 to 10% of lung adenocarcinoma, and the patients most likely to be under-tested are never smokers, who are the likeliest to have one.","The allelic phase of EGFR C797S with T790M decides whether a combination of inhibitors can work, and most reports do not state it.","The transcriptional subtypes of small-cell lung cancer have no approved assay, no prospective trial, and a moving target: 37% of tumours express two of the four markers at once and platinum shifts tumours towards the inflamed state.","PD-L1 thresholds are trial artefacts that cannot be transferred between assays, yet laboratories report a single percentage as though it were a property of the tumour."],"basics":{"symptoms":["A cough that is not going away, shortness of breath, coughing up blood, chest or shoulder pain, repeated chest infections or one that will not clear, losing weight without trying, loss of appetite, feeling tired all the time (NHS)","Less common: swelling of the face or neck, difficulty swallowing, a hoarse voice that does not go away, finger clubbing (NHS)","A tumour at the top of the lung can press on the nerves and vessels there and cause shoulder and arm pain with a drooping eyelid rather than any chest symptom at all (a Pancoast or superior sulcus tumour)","Early disease often causes nothing, which is why a third of English cases still reach the hospital as an emergency (Cancer Research UK)","GP referral rules (NICE NG12 1.1.1 to 1.1.3): suspected cancer pathway referral for chest X-ray findings suggesting lung cancer or unexplained haemoptysis at 40 and over; urgent direct access chest X-ray at 40 and over for two or more of cough, fatigue, shortness of breath, chest pain, weight loss and appetite loss, or one of them in anyone who has ever smoked; consider one for persistent or recurrent chest infection, finger clubbing, supraclavicular or persistent cervical lymphadenopathy, chest signs, or thrombocytosis","See a GP for a cough lasting more than 3 weeks; ask for an urgent appointment or call NHS 111 if you cough up blood; call 999 if you are struggling to breathe or have pain in the chest or upper back (NHS)"],"diagnosis":["Contrast-enhanced CT of the chest, liver, adrenals and lower neck before any biopsy; PET-CT for everyone who could have treatment with curative intent (NICE NG122 1.2.2, 1.2.4, 1.2.14)","Endobronchial ultrasound-guided transbronchial needle aspiration for paratracheal and peri-bronchial lesions and for mediastinal nodes; endoscopic ultrasound-guided fine-needle aspiration, or both together, where the nodal stage decides treatment; surgical mediastinal staging only when those are negative and suspicion stays high (NICE NG122 1.2.8, 1.2.20 to 1.2.22)","Image-guided biopsy for peripheral lesions when treatment can be planned from that alone; biopsy enlarged nodes (10 mm or more short axis on CT) in preference to the primary when the nodal stage matters (NICE NG122 1.2.16, 1.2.17)","Brain imaging by stage: none for clinical stage 1 without neurological symptoms (brain metastasis prevalence about 4 percent), contrast-enhanced CT for stage 2, contrast-enhanced MRI for stage 3 (NICE NG122 1.2.24 to 1.2.26)","The sample must be adequate for subtyping and molecular markers; the panel is set by the National Genomics Test Directory, not by the guideline (NICE NG122 1.2.11, 1.2.12)","Histology is assigned by morphology first, then immunohistochemistry (TTF-1 for adenocarcinoma, p40 for squamous cell carcinoma), then molecular tests; the 2021 WHO classification has a section on doing this on small samples (Nicholson 2022)"],"staging":["TNM 9th edition, in force since 1 January 2025 and built on 124,581 patients diagnosed 2011 to 2019 (British Journal of Radiology 2025; IASLC staging project)","T: unchanged from the eighth edition. The T subcommittee tested chest wall and parietal pleural involvement against the new database and proposed no reallocation","N: N0 no nodes; N1 ipsilateral hilar or intrapulmonary; N2a a single ipsilateral mediastinal or subcarinal station; N2b multiple ipsilateral mediastinal stations with or without the subcarinal station; N3 contralateral or supraclavicular","M: M1a within the chest (contralateral lung nodules, pleural or pericardial nodules or effusion); M1b a single extrathoracic metastasis; M1c1 several metastases in one extrathoracic organ system; M1c2 several metastases across organ systems. M1c1 and M1c2 both sit in stage IVB","Stage groups that moved in the ninth edition: T1N1 to IIA, T1N2a to IIB, T3N2a to IIIA, T2aN2b and T2bN2b to IIIB","NICE NG122's recommendations were written against the 7th edition of the AJCC staging system, which the guideline states on the page; the clinic is two editions ahead of it","In England 34 percent of staged lung cancers in 2022 were stage I or II; in the United States 24 percent are localised, 21 percent regional and 51 percent distant at diagnosis (Cancer Research UK; SEER)"],"sources":[]},"prognosis":{"text":"Population averages, not a personal prognosis, and they lag the treatments now in use. In the United States 29.5 percent of people diagnosed with lung and bronchus cancer in 2016 to 2022 were alive five years later relative to people of the same age without the disease; by stage that is 65.5 percent for localised disease (24 percent of cases), 38.2 percent for regional (21 percent), 10.5 percent for distant (51 percent) and 17.5 percent for unstaged (4 percent) (SEER). In the UK, 11.1 percent of people are predicted to survive ten years or more, up from 3.3 percent in the 1970s; 18.1 percent of people diagnosed in England survive five years, rising to 43.5 percent among those who have already survived one year. Survival is higher in women than men and falls steeply with age: 32.7 percent of women and 22.2 percent of men diagnosed at 15 to 44 survive ten years, against 9.2 percent of women and 5.2 percent of men diagnosed at 75 to 99. It also tracks deprivation: 20.1 percent five-year survival in the most deprived group in England against 27.6 percent in the least (Cancer Research UK).","sources":[{"label":"SEER Cancer Stat Facts: lung and bronchus cancer (rates, stage distribution, survival by stage, age and race)","url":"https://seer.cancer.gov/statfacts/html/lungb.html"},{"label":"CRUK: lung cancer survival statistics (by age, deprivation and over time)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/survival"}]},"parent":"lung-cancer"},{"id":"aml-npm1-kmt2a","kind":"cancer","name":"NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia","aka":["NPM1-mutated AML","KMT2A-rearranged AML","MLL-rearranged AML","Menin-dependent AML"],"tldr":"NPM1-mutated and KMT2A-rearranged leukaemias depend on a protein called menin to keep leukaemia genes switched on. Menin inhibitors, revumenib and ziftomenib, are the first drugs to exploit this, and they produce remissions in patients whose leukaemia had come back after everything else.","summary":"Both leukaemias run on the same circuit. A KMT2A fusion protein, or the mislocated mutant nucleophosmin, needs the chromatin adaptor menin to hold the HOXA9 and MEIS1 programme open; without it the blasts differentiate. NPM1-mutated AML without FLT3-ITD sits in the ELN favourable group and is cured by chemotherapy in about half of patients, with NPM1 transcript MRD after two cycles the strongest predictor of relapse. KMT2A-rearranged AML, whichever partner gene, is adverse or intermediate risk and is treated with intensive chemotherapy and transplant.\n\nAUGMENT-101 reported revumenib in heavily pretreated relapsed KMT2A-rearranged leukaemias in 2023 and 2024: complete remission with full or partial count recovery in 22.8 percent and an overall response rate of 63.2 percent, leading to approval in November 2024 for relapsed or refractory KMT2A-rearranged acute leukaemia from the age of one, the first menin inhibitor and the first drug approved for this genotype. KOMET-001 followed with ziftomenib in relapsed NPM1-mutated AML, complete remission in 23 percent, and 2025 brought approvals for both drugs in relapsed NPM1-mutated disease. Differentiation syndrome and QT prolongation are the class toxicities; MEN1 mutations that stop menin inhibitor binding were the first resistance mechanism described.\n\nThe next phase is combination: menin inhibitors with venetoclax and azacitidine in unfit patients, with 7+3 in fit patients, and as maintenance after transplant, together with bleximenib and other second-generation inhibitors. Whether adding a menin inhibitor to first-line therapy raises cure rates in NPM1-mutated AML, where chemotherapy already cures many, is the trial question of the decade.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Nucleophosmin","links":[{"label":"Wikipedia: Nucleophosmin","url":"https://en.wikipedia.org/wiki/Nucleophosmin"},{"label":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}],"tags":["subtype-page"],"related":["aml-flt3","aml-idh","aml-paediatric","aml-older-unfit"],"cancers":[],"sections":[],"technologies":["menin-inhibitors"],"targets":["menin","npm1","kmt2a"],"drugs":[],"companies":[],"institutions":[],"pathways":["menin-kmt2a"],"terms":["differentiation-syndrome","eln-risk","mrd"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-augment-101-revumenib-menin-nature-2023","paper-eln-2022-aml-dohner-blood-2022","paper-falini-npm1-nejm-2005","paper-ivey-npm1-mrd-nejm-2016"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"NPM1 is the commonest mutation in adult acute myeloid leukaemia, in about three in ten patients; KMT2A rearrangements are found in about one in twenty adults, in most infants with leukaemia, and in leukaemia that follows chemotherapy.","subtypes":["NPM1-mutated AML without FLT3-ITD (favourable risk)","NPM1-mutated AML with FLT3-ITD","KMT2A-rearranged AML (MLL fusion, any partner gene)","Therapy-related KMT2A-rearranged AML after topoisomerase II inhibitors","Infant KMT2A-rearranged leukaemia"],"biomarkers":["NPM1 mutation and NPM1 transcript MRD","KMT2A rearrangement by FISH or RNA sequencing","FLT3-ITD co-mutation","MEN1 mutations (menin inhibitor resistance)","ELN 2022 risk group","HOXA9 and MEIS1 expression"],"standardOfCare":[{"setting":"Newly diagnosed, fit for intensive chemotherapy","approach":"7+3 induction with consolidation; NPM1 MRD monitoring decides transplant in favourable-risk disease; transplant in first remission for KMT2A-rearranged and FLT3-ITD co-mutated disease.","refs":["cytarabine-7-3","allogeneic-hsct","ngs-mrd-clonoseq","eln-risk"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Newly diagnosed, unfit for intensive chemotherapy","approach":"Venetoclax plus azacitidine, with a menin inhibitor added in trials.","refs":["venetoclax","azacitidine","viale-a","menin-plus-venetoclax-hma"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Relapsed or refractory","approach":"Revumenib (KMT2A-rearranged or NPM1-mutated) or ziftomenib (NPM1-mutated) as a bridge to allogeneic transplant; menin inhibitor combinations in trials.","refs":["revumenib","ziftomenib","augment-101","komet-001","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}}],"stateOfArt":["Menin inhibitors are the first targeted therapy for KMT2A-rearranged leukaemia and for NPM1-mutated AML, approved in 2024 and 2025.","NPM1 transcript MRD after two chemotherapy cycles is the best guide to who needs a transplant in favourable-risk disease.","Menin inhibitors with venetoclax and azacitidine are producing high remission rates in early combination trials."],"history":[{"year":2005,"title":"NPM1 mutations described in a third of adult AML","refs":["npm1"]},{"year":2005,"title":"Menin shown to be required by KMT2A fusion leukaemia","refs":["menin","kmt2a"]},{"year":2016,"title":"NPM1 transcript MRD predicts relapse after chemotherapy","refs":["mrd"]},{"year":2024,"title":"AUGMENT-101: revumenib, the first menin inhibitor, approved for relapsed KMT2A-rearranged leukaemia","refs":["augment-101","revumenib"]},{"year":2025,"title":"Ziftomenib and revumenib approved for relapsed NPM1-mutated AML","refs":["komet-001","ziftomenib","revumenib"]}],"pipeline":["revumenib","ziftomenib","bleximenib","menin-inhibitors","myelomatch"],"openProblems":["Whether a menin inhibitor added to first-line therapy raises cure rates in NPM1-mutated AML.","MEN1 resistance mutations and how to sequence or combine inhibitors around them.","Dosing menin inhibitors safely with azoles and other QT-prolonging drugs."],"parent":"aml"},{"id":"ntrk-fusion-nsclc","kind":"cancer","name":"NTRK fusion-positive non-small-cell lung cancer","aka":["NTRK-rearranged lung cancer","TRK fusion lung cancer","NTRK1, NTRK2 or NTRK3 fusion NSCLC"],"tldr":"NTRK fusion lung cancer is very rare and is treated with the same TRK-blocking pills approved for any cancer with the fusion: larotrectinib, entrectinib or repotrectinib shrink most tumours, including in the brain, so the point is to test broadly enough to find it.","summary":"NTRK1, NTRK2 and NTRK3 fusions drive a small share of many cancers, common in a few rare tumours (infantile fibrosarcoma, secretory carcinoma) and rare in common ones such as lung cancer. Larotrectinib was approved in November 2018 for any solid tumour with an NTRK fusion, the second tumour-agnostic approval after pembrolizumab for mismatch-repair deficiency, on a pooled response rate of 75 percent across tumour types in its phase 1 and 2 studies (NAVIGATE among them); entrectinib followed in August 2019 with a 57 percent pooled response rate and intracranial activity, and repotrectinib received a tumour-agnostic accelerated approval in June 2024, with activity against the solvent-front mutations that arise on the first two drugs.\n\nIn lung cancer specifically the numbers are small: lung cohorts within the larotrectinib and entrectinib programmes reported response rates of about 70 percent with responses in brain metastases, and the drugs are recommended first line or after chemotherapy. Dizziness, weight gain and paraesthesia from on-target TRK inhibition in the nervous system are the characteristic side effects. Checkpoint inhibitors and chemotherapy are used as for driver-negative disease when TRK inhibitors are exhausted.\n\nBecause the fusions are so rare, the practical question is testing: DNA panels miss some NTRK fusions, especially those involving NTRK2 and NTRK3 with large introns, so RNA sequencing or a combined panel is needed when no other driver is found. Open questions are the sequence of TRK inhibitors after resistance and whether next-generation inhibitors can avoid the neurological side effects.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Trk_receptor","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Trk_receptor"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":["ros1-positive-nsclc","ret-fusion-nsclc","alk-positive-nsclc","met-altered-nsclc","braf-v600e-nsclc","her2-mutant-nsclc"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","cgp"],"targets":["ntrk","ros1"],"drugs":["larotrectinib","entrectinib","repotrectinib"],"companies":["bayer","roche-genentech","bms"],"institutions":[],"pathways":["nsclc-signalling","rtk-activation"],"terms":["gene-fusion","tumour-agnostic","oncogene-addiction","gatekeeper-mutation","brain-metastases"],"trials":["navigate","nct02568267","nct03093116"],"people":["alexander-drilon"],"bottlenecks":[],"keyPapers":["paper-drilon-larotrectinib-nejm-2018","paper-doebele-entrectinib-ntrk-lancet-oncol-2020","paper-trident-1-repotrectinib-nejm-2024"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"NTRK fusions occur in well under 1 percent of non-small-cell lung cancers, in adenocarcinoma regardless of smoking history; they are found mainly when broad RNA-based panels are used.","subtypes":["NTRK1 fusion adenocarcinoma","NTRK2 or NTRK3 fusion adenocarcinoma (often missed by DNA-only panels)","TRK inhibitor-resistant disease with solvent-front mutations (repotrectinib)"],"biomarkers":["NTRK1, NTRK2 and NTRK3 fusions by RNA sequencing (preferred) or DNA panel","Pan-TRK immunohistochemistry as a screen","NTRK resistance mutations (solvent front, gatekeeper) at progression","Brain MRI"],"standardOfCare":[{"setting":"Advanced, first line or after chemotherapy","approach":"Larotrectinib or entrectinib under their tumour-agnostic approvals; repotrectinib after resistance to either; chemoimmunotherapy as for driver-negative disease before or after.","refs":["larotrectinib","navigate","entrectinib","nct02568267","repotrectinib","tumour-agnostic","pembrolizumab","carboplatin","pemetrexed"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Three TRK inhibitors approved for any tumour with an NTRK fusion, with response rates of 57 to 75 percent across cancers and brain activity.","RNA-based testing recommended when no driver is found on a DNA panel."],"history":[{"year":2018,"title":"Larotrectinib: tumour-agnostic approval for NTRK fusion cancers","refs":["larotrectinib","navigate","tumour-agnostic","alexander-drilon"]},{"year":2019,"title":"Entrectinib approved for NTRK fusion tumours and ROS1 lung cancer","refs":["entrectinib","nct02568267"]},{"year":2024,"title":"Repotrectinib gains tumour-agnostic accelerated approval for NTRK fusions","refs":["repotrectinib","nct03093116"]}],"pipeline":["repotrectinib","nct03093116"],"openProblems":["Fusions are missed when only DNA panels are run.","Neurological side effects from TRK inhibition are class-wide.","Data specific to lung cancer come from small cohorts within basket trials."],"parent":"nsclc"},{"id":"nut-carcinoma","kind":"cancer","name":"NUT carcinoma (midline carcinoma with NUTM1 rearrangement)","aka":["NUT midline carcinoma","Midline tract carcinoma with NUT gene changes","NMC"],"tldr":"NUT carcinoma is a fast-growing cancer of the midline of the body driven by a single fused gene, BRD4-NUTM1, that locks cells in an immature state. Chemotherapy and surgery rarely control it for long, but drugs that block the BET proteins the fusion depends on have produced responses and are the focus of trials.","summary":"NUT carcinoma is a poorly differentiated squamous carcinoma defined by rearrangement of NUTM1 (nuclear protein in testis), most often fused to BRD4 (about 70 percent), otherwise BRD3, NSD3 or ZNF532. The fusion protein tethers NUT's histone acetyltransferase-recruiting domain to BET bromodomains, creating megadomains of hyperacetylated chromatin that drive MYC and SOX2 expression and block squamous differentiation. It was first recognised in the mediastinum of children and young adults but occurs at any age and in the sinonasal tract, lung, and other sites; diagnosis requires NUT immunohistochemistry (highly specific) or fusion testing, and many cases were historically misdiagnosed as undifferentiated carcinoma or sarcoma.\n\nThe disease is among the most aggressive human cancers. Multimodality treatment (surgery, radiotherapy and ifosfamide- or platinum-based chemotherapy, Ewing-type regimens) achieves control in a minority, mostly those with localised disease amenable to complete resection and radiotherapy. The International NUT Carcinoma Registry (Brigham and Women's Hospital) has pooled outcomes and shown that initial resection or radiotherapy is associated with longer survival, and that non-BRD4 fusions have a somewhat better course.\n\nMechanistically the disease is an ideal test of BET inhibition: BRD4-NUTM1 requires bromodomain binding to chromatin. BET inhibitors (molibresib/GSK525762, birabresib/OTX015, ZEN-3694, NUV-868) have produced objective responses and disease stabilisation in NUT carcinoma cohorts of phase 1 and 2 trials, with thrombocytopenia as the dose-limiting toxicity; combination with chemotherapy, CDK9 or HDAC inhibitors, and next-generation BET degraders are the main directions. Rapid, accurate diagnosis is the first intervention that changes outcome.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/NUT_midline_carcinoma","links":[{"label":"NCI PDQ: childhood midline tract carcinoma with NUT gene changes","url":"https://www.cancer.gov/types/midline/patient-child-midline-tract-carcinoma-treatment-pdq"},{"label":"Filippakopoulos 2010: BET inhibition in NUT carcinoma (Nature)","url":"https://doi.org/10.1038/nature09504"}],"tags":["nci-coverage","rare","head-and-neck","paediatric"],"related":[],"cancers":[],"sections":[],"technologies":["epigenetic-drugs","cytotoxic-chemotherapy","imrt-igrt"],"targets":[],"drugs":["ifosfamide","cisplatin","etoposide"],"companies":[],"institutions":["dana-farber"],"pathways":["transcription-addiction","epigenetic-reprogramming","myc"],"terms":["gene-fusion","rare-cancers"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers","b-undruggable-targets"],"keyPapers":["paper-filippakopoulos-nature"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"Very rare and under-recognised; arises at any age with a median in the twenties, most often in the head, neck and thorax.","subtypes":["BRD4-NUTM1 (most common)","BRD3-NUTM1","NSD3-NUTM1","Other NUTM1 partners (ZNF532, ZNF592)"],"biomarkers":["NUT immunohistochemistry (C52 antibody, nuclear speckled)","NUTM1 fusion by FISH or RNA sequencing","Fusion partner (non-BRD4 partners associated with longer survival in the registry)","Site (thoracic vs non-thoracic)"],"standardOfCare":[{"setting":"Localised","approach":"Multimodality: complete resection where feasible, radiotherapy, and intensive chemotherapy (ifosfamide-based or platinum-based, often Ewing-type regimens); early referral to a centre with NUT carcinoma experience.","refs":["ifosfamide","cisplatin","imrt-igrt"],"guideline":{"version":"NCI PDQ: childhood midline tract carcinoma with NUT gene changes; International NUT Carcinoma Registry","url":"https://www.cancer.gov/types/midline/patient-child-midline-tract-carcinoma-treatment-pdq"}},{"setting":"Advanced or relapsed","approach":"Clinical trial of a BET inhibitor (ZEN-3694, NUV-868, molibresib) alone or with chemotherapy; palliative chemotherapy and radiotherapy.","refs":["epigenetic-drugs"]}],"stateOfArt":["A single oncogenic fusion with a druggable domain: NUT carcinoma is the founding indication for BET bromodomain inhibitors.","NUT immunohistochemistry has made diagnosis fast and cheap, and is now recommended for any poorly differentiated midline carcinoma, particularly in young patients.","Registry data show that complete resection and radiotherapy of localised disease produce long-term survivors, so long-term survival is achievable.","BET inhibitors have shown objective responses, but durability is limited; degraders and combinations are the next step."],"history":[{"year":1991,"title":"First reports of aggressive midline carcinoma with t(15;19) in children","refs":[]},{"year":2003,"title":"BRD4-NUT fusion cloned","note":"French and colleagues identify the fusion gene.","refs":[]},{"year":2009,"title":"NUT immunohistochemistry validated","note":"Haack and colleagues: highly specific antibody enables diagnosis.","refs":[]},{"year":2010,"title":"BET inhibitor JQ1 induces differentiation of NUT carcinoma cells","note":"Filippakopoulos and colleagues, Nature: proof of concept for BET inhibition.","refs":[]},{"year":2016,"title":"First BET inhibitor responses in patients","note":"Birabresib (OTX015) and molibresib phase 1 cohorts.","refs":["epigenetic-drugs"]},{"year":2021,"title":"International NUT Carcinoma Registry outcomes","note":"Chau and colleagues, JCO: fusion partner and initial treatment predict survival.","refs":[]}],"pipeline":["zen-3694","zen-3694-platinum-nut","zen-3694-abemaciclib-nut","cemiplimab-nut","epigenetic-drugs","checkpoint-inhibitor"],"openProblems":["Misdiagnosis and delay: NUT immunohistochemistry should be routine in poorly differentiated midline tumours.","BET inhibitor responses are short: degraders, CDK9 and HDAC combinations, and chemotherapy combinations are in trials.","Thrombocytopenia limits BET inhibitor dosing.","No randomised trials exist; the registry is the evidence base."]},{"id":"ocular-adnexal-malt-lymphoma","kind":"cancer","name":"Ocular adnexal MALT lymphoma","aka":["Ocular adnexal marginal zone lymphoma","OAMZL","Orbital lymphoma","Conjunctival lymphoma","Lacrimal gland lymphoma","Ocular adnexal lymphoma","Eyelid lymphoma","Salmon patch lymphoma"],"tldr":"A slow-growing MALT lymphoma of the tissues around the eye: the conjunctiva, the eye socket, the tear gland or the eyelid. It usually shows itself as a painless salmon-pink patch on the white of the eye or as an eye that has begun to bulge, and it is controlled in almost everybody, often by a short course of radiotherapy.","summary":"What it is. The tissues around the eye, the conjunctiva that lines the eyelids and covers the white of the eye, the orbit the eye sits in, the tear gland and the eyelids, are collectively the ocular adnexa. A marginal zone lymphoma arising there grows slowly and causes trouble by taking up space rather than by destroying anything. Three-quarters of lymphomas in this location are MALT lymphomas; the rest are follicular lymphoma, diffuse large B-cell lymphoma or others, which is why a biopsy is needed before anything is decided.\n\nHow it shows itself. A flat, salmon-pink patch under the conjunctiva that has been there for months; a painless swelling of the eyelid; an eye that has begun to bulge forward or to sit slightly out of line; double vision; a lump at the outer corner where the tear gland is. Pain, rapid growth and loss of vision are unusual and suggest a different, more aggressive lymphoma. Both sides are involved in a substantial minority, so the other eye is always examined.\n\nHow it differs from its parent and from its sibling in the stomach. WHO-HAEM5 sets out that marginal zone lymphomas differ genetically by the site they arise in, and that ocular adnexal disease has its own profile: mutation or deletion of TNFAIP3 is common, and gain of chromosome 6p with loss of 6q is recurrent here and not at other extranodal sites. The translocation that governs treatment in the stomach, t(11;18), is rare here.\n\nThe bacterium, and the honest version of the story. In Italian studies, the ocular adnexal lymphomas were associated with Chlamydia psittaci, the bacterium of psittacosis, and a course of doxycycline produced lymphoma regression in about two-thirds of patients in prospective trials. That association does not hold everywhere. A United States study tested 28 ocular adnexal lymphoma specimens with two different polymerase chain reaction assays and found no Chlamydia psittaci DNA in any of them, and noted that the association has been reported internationally with great variability. So whether an antibiotic is worth trying depends on where the patient lives and what the local series show, and a reader told that this lymphoma is caused by an infection should ask which population that finding came from.\n\nHow it is treated. For disease confined to the orbit, low-dose radiotherapy is the usual treatment and it is effective. In a series of 28 patients who were given doxycycline first and whose lymphoma relapsed or progressed, salvage radiotherapy at 30 to 36 Gy in 15 to 18 fractions produced a response in every patient and a complete response in 89 per cent, with 4-year progression-free survival of 74 per cent; the recorded toxicity was three cases of grade 2 cataract and three of grade 1 blepharitis, and all but one patient was alive at a median follow-up of 96 months from diagnosis. That paper also answers the question it was written to answer: delaying radiotherapy while an antibiotic is tried did not cost those patients their chance of cure. Very low doses of radiotherapy, around 4 Gy in two fractions, are used in some centres to spare the lens and the tear gland, with retreatment if needed. Disease that has spread beyond the orbit is treated systemically, like any other marginal zone lymphoma.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/MALT_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"Salvage irradiation for ocular adnexal MALT lymphoma refractory to Chlamydia psittaci eradication, 28 patients (Advances in Radiation Oncology 2025)","url":"https://doi.org/10.1016/j.adro.2025.101822"},{"label":"Lack of an association between Chlamydia psittaci and ocular adnexal lymphoma, 28 United States specimens tested by two assays (Leukemia and Lymphoma 2007)","url":"https://doi.org/10.1080/10428190601132105"},{"label":"Orbital and ocular adnexal lymphoma, epidemiology and prognostic factors in 112 patients in Taiwan (Eye 2021)","url":"https://doi.org/10.1038/s41433-020-01198-y"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"}],"tags":["heme","lymphoma","subtype-page"],"related":["malt-lymphoma","marginal-zone-lymphoma","gastric-malt-lymphoma","non-hodgkin-lymphoma","primary-cutaneous-marginal-zone-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","imrt-igrt"],"targets":[],"drugs":["rituximab"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-nodal-versus-extranodal","lymphoma-indolent-versus-aggressive","lymphoma-tx-radiotherapy","lymphoma-tx-watch-and-wait","lugano-classification"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-esmo-marginal-zone-lymphoma-zucca-ann-oncol-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"No separate incidence figure for the ocular adnexa is published in the United Kingdom population series, which counts all extranodal marginal zone lymphomas together: 211 of 5,796 lymphomas, a European age-standardised rate of 0.60 per 100,000 a year and five-year relative survival of 87.9 per cent across all extranodal sites. In a Taiwanese series of 112 patients with lymphoma of the orbit and ocular adnexa, 67.9 per cent were MALT lymphomas, the mean age was 59 years, and disease-specific survival was 93.1 per cent at five years and 87.7 per cent at ten.","subtypes":["Conjunctival, the salmon-pink patch on the white of the eye","Orbital, an extranodal site behind the eye","Lacrimal gland","Eyelid","Bilateral, which occurs in a substantial minority"],"biomarkers":["A marginal zone phenotype: CD20 positive, CD5 negative, CD10 negative, often with plasmacytic differentiation","TNFAIP3 mutation or deletion, commoner here than at other marginal zone sites","Gain of chromosome 6p and loss of 6q, recurrent in ocular adnexal disease and not at other extranodal sites","Chlamydia psittaci, found in Italian series and absent from several United States series; the association varies by region","Staging of the orbit by magnetic resonance imaging, and of the rest of the body to exclude disease elsewhere"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"A biopsy of the lesion is needed, because about a third of lymphomas at this site are not marginal zone lymphomas and the treatment differs. Imaging of the orbit, usually by magnetic resonance, maps the extent and the relationship to the optic nerve and the muscles. Staging of the rest of the body follows, because apparently localised ocular disease is sometimes part of a systemic marginal zone lymphoma. Both orbits are examined; bilateral disease is common and does not by itself mean the lymphoma has spread.","refs":["histopathology-ihc","lugano-classification","fdg-pet","lymphoma-nodal-versus-extranodal"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Localised disease: radiotherapy, and an antibiotic where the evidence supports it","approach":"Radiotherapy to the orbit is the standard treatment for disease confined to the ocular adnexa and it controls it in almost everybody. In a series of 28 patients irradiated after a trial of doxycycline, 30 to 36 Gy in 15 to 18 fractions produced a response in all of them and a complete response in 89 per cent, with four-year progression-free survival of 74 per cent and little toxicity beyond three cases of grade 2 cataract and three of grade 1 blepharitis. Very low-dose schedules of about 4 Gy in two fractions are used to spare the lens and the tear gland, with retreatment if the lymphoma returns. Where local series have shown an association with Chlamydia psittaci, a course of doxycycline is a reasonable first step, and the same series shows that trying it first did not cost patients their response to radiotherapy afterwards.","refs":["imrt-igrt","lymphoma-tx-radiotherapy","palliative-radiotherapy"],"guideline":{"version":"Advances in Radiation Oncology 2025, salvage irradiation after Chlamydia psittaci eradication; NCI PDQ","url":"https://doi.org/10.1016/j.adro.2025.101822"}},{"setting":"Disease beyond the orbit","approach":"Treated as any other marginal zone lymphoma: watched where it is causing no trouble, and treated with an anti-CD20 antibody alone or with chemotherapy when it is. The regimens, the thresholds for starting and the evidence are on the marginal zone and MALT lymphoma pages and in the treatment layer of this family.","refs":["marginal-zone-lymphoma","malt-lymphoma","rituximab","bendamustine","lymphoma-tx-watch-and-wait","paper-esmo-marginal-zone-lymphoma-zucca-ann-oncol-2020"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":2004,"title":"Chlamydia psittaci reported in Italian series","note":"Italian investigators reported the bacterium of psittacosis in ocular adnexal marginal zone lymphomas and showed that doxycycline produced regression in a proportion of patients.","refs":[]},{"year":2007,"title":"The association not found in the United States","note":"A United States study tested 28 ocular adnexal lymphoma specimens with two polymerase chain reaction assays and found no Chlamydia psittaci DNA, and noted that the association has been reported internationally with great variability.","refs":[]},{"year":2025,"title":"Trying the antibiotic first does not cost the radiotherapy","note":"In 28 patients whose lymphoma relapsed or progressed after doxycycline, salvage radiotherapy produced a response in every one and a complete response in 89 per cent, with four-year progression-free survival of 74 per cent.","refs":["lymphoma-tx-radiotherapy"]}],"pipeline":[],"openProblems":["Whether Chlamydia psittaci causes this lymphoma depends on where the series was collected, and the question has not been settled in twenty years. A patient in Britain cannot be told with confidence whether an antibiotic is worth trying.","The right radiotherapy dose is unresolved: the conventional 24 to 36 Gy controls the lymphoma and causes cataract and dry eye, while very low doses of about 4 Gy spare both and have not been compared head to head here.","Bilateral disease is common and is sometimes counted as stage IV and sometimes as two localised sites, which changes the treatment a patient is offered."],"parent":"malt-lymphoma"},{"id":"oesophageal-adenocarcinoma","kind":"cancer","name":"Oesophageal and junctional adenocarcinoma","aka":["Esophageal adenocarcinoma","EAC","Gastro-oesophageal junction adenocarcinoma","Barrett's cancer"],"tldr":"Adenocarcinoma of the lower oesophagus and junction grows out of Barrett's oesophagus, the change in the lining caused by long-standing acid reflux. Chemotherapy or chemoradiation before surgery is standard, and HER2, PD-L1 and claudin 18.2 now guide drugs for advanced disease as they do in stomach cancer.","summary":"Oesophageal adenocarcinoma arises in the lower oesophagus and gastro-oesophageal junction from Barrett's oesophagus, driven by reflux, obesity and smoking; TP53 mutation, chromosomal instability and amplification of HER2, EGFR, MET or KRAS are typical. Barrett's surveillance and endoscopic ablation or resection of dysplasia prevent progression. Locally advanced disease is treated with perioperative FLOT chemotherapy, which the ESOPEC trial showed gives better survival than CROSS chemoradiation, followed by oesophagectomy. Advanced disease is managed with stomach cancer regimens: nivolumab or pembrolizumab with chemotherapy for PD-L1-positive tumours, trastuzumab with chemotherapy for HER2-positive tumours, zolbetuximab for claudin 18.2-positive tumours, and trastuzumab deruxtecan after HER2-directed therapy.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Esophageal_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Esophageal_cancer"}],"tags":["subtype-page"],"related":["oesophageal-squamous-cell-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["esopec","flot4"],"people":[],"bottlenecks":[],"keyPapers":["paper-checkmate-649-lancet-2021","paper-flot4-lancet-2019","paper-cross-nejm-2012","paper-keynote-590-lancet-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"The dominant oesophageal cancer in Western countries, where its incidence has risen several-fold since the 1970s with reflux and obesity; it affects men six times more than women, and five-year survival is about 20 percent overall.","subtypes":["Barrett's-associated adenocarcinoma of the lower oesophagus","Gastro-oesophageal junction adenocarcinoma (Siewert types I to III)","HER2-positive (about 15 to 20 percent)","Claudin 18.2-positive","Mismatch repair-deficient (a minority)"],"biomarkers":["HER2 amplification","PD-L1 combined positive score","Claudin 18.2 expression","Mismatch repair and microsatellite instability","Barrett's dysplasia grade on surveillance"],"standardOfCare":[{"setting":"Barrett's oesophagus","approach":"Endoscopic surveillance; radiofrequency ablation or endoscopic resection for dysplasia and early cancer.","refs":["endoscopic-resection"]},{"setting":"Locally advanced","approach":"Perioperative FLOT (docetaxel, oxaliplatin, fluorouracil, leucovorin) and oesophagectomy, preferred over CROSS after ESOPEC; chemoradiation where chemotherapy is not tolerated.","refs":["flot","docetaxel","oxaliplatin","fluorouracil","cross"]},{"setting":"Advanced, first line","approach":"Nivolumab or pembrolizumab with platinum-fluoropyrimidine chemotherapy for PD-L1-positive tumours; trastuzumab with chemotherapy (and pembrolizumab) for HER2-positive tumours; zolbetuximab with chemotherapy for claudin 18.2-positive tumours.","refs":["nivolumab","pembrolizumab","trastuzumab","zolbetuximab","her2","pdl1","cldn18-2"]},{"setting":"Later lines","approach":"Trastuzumab deruxtecan for HER2-positive disease; ramucirumab with paclitaxel; trifluridine-tipiracil.","refs":["trastuzumab-deruxtecan","ramucirumab","paclitaxel"]}],"stateOfArt":["ESOPEC settled a decade-long argument in favour of perioperative chemotherapy over chemoradiation for adenocarcinoma.","Three biomarkers, HER2, PD-L1 and claudin 18.2, now decide first-line treatment of advanced disease.","Endoscopic therapy of Barrett's dysplasia prevents cancer and has replaced surgery for early disease."],"history":[{"year":1950,"title":"Norman Barrett describes the columnar-lined oesophagus","refs":[]},{"year":2010,"title":"ToGA: trastuzumab for HER2-positive gastro-oesophageal cancer","refs":["trastuzumab"]},{"year":2012,"title":"CROSS chemoradiation before surgery","refs":["cross"]},{"year":2019,"title":"FLOT4: perioperative FLOT beats ECF","refs":["flot"]},{"year":2024,"title":"ESOPEC: FLOT better than CROSS in adenocarcinoma","refs":["flot"]},{"year":2024,"title":"Zolbetuximab approved for claudin 18.2-positive disease","refs":["zolbetuximab"]}],"pipeline":["zolbetuximab","trastuzumab-deruxtecan"],"openProblems":["Barrett's surveillance finds few of the cancers that occur.","Rising incidence with obesity.","Oesophagectomy remains a major operation with lasting effects on eating."],"parent":"esophageal"},{"id":"esophageal","kind":"cancer","name":"Oesophageal cancer","aka":["ESCA","TCGA-ESCA","oesophageal carcinoma (TCGA ESCA cohort)"],"tldr":"Oesophageal cancer is really two diseases sharing one organ: squamous cell carcinoma, which dominates in Asia, and adenocarcinoma, which dominates in the West and is treated like gastric cancer. Immunotherapy is now standard, and the bispecific ADC iza-bren posted a positive phase 3 in the squamous type in 2026.","summary":"Oesophageal cancer is two diseases: squamous cell carcinoma (ESCC, ~85% globally, driven by tobacco, alcohol, hot beverages, and nutritional factors along a belt from Iran through Central Asia to China) and adenocarcinoma (EAC, dominant in the West, arising from Barrett's oesophagus through reflux and obesity). Japan and parts of China screen high-risk populations endoscopically and cure early squamous cancers with endoscopic resection; elsewhere most patients present with dysphagia and locally advanced or metastatic disease. It causes about 510,000 new cases a year (the seventh most common cancer) and, because of late presentation, 445,000 deaths (sixth among cancers); five-year survival is about 20% overall.\n\nLocalised disease is treated with multimodality therapy. CROSS chemoradiation followed by oesophagectomy gives 10-year survival of 38% versus 25% for surgery alone; perioperative FLOT is the alternative for adenocarcinoma (ESOPEC favoured it). Definitive chemoradiation is used for cervical tumours and unfit patients. CheckMate 577 added a year of adjuvant nivolumab for residual disease after chemoradiation (DFS 22.4 vs 11.0 months), and SANO showed that patients with a clinical complete response can be watched rather than operated on with non-inferior survival. Advanced disease is treated with chemotherapy plus PD-1 blockade: pembrolizumab (KEYNOTE-590, both histologies), nivolumab ± ipilimumab (CheckMate 648, squamous), tislelizumab (RATIONALE-306, squamous PD-L1 ≥1%), and camrelizumab or sintilimab in China. HER2-positive adenocarcinoma follows the gastric pathway (trastuzumab, zanidatamab after HERIZON-GEA-01, T-DXd second line). In 2026 the EGFR×HER3 bispecific ADC izalontamab brengitecan became the first agent to improve overall survival in second-line ESCC after immunotherapy (PANKU-Esophagus01).\n\nOpen fronts: whether PD-1 blockade added to definitive chemoradiation raises cure rates (KEYNOTE-975, SKYSCRAPER-07 and Chinese trials), how far organ preservation can be pushed, non-endoscopic screening for Barrett's (BEST4), the absence of targets in squamous disease beyond PD-1 and now EGFR/HER3, and the persistent gap between Asian and Western outcomes that early detection explains.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Esophageal_cancer","links":[{"label":"NCCN Esophageal and EGJ Cancers guideline","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433"},{"label":"ESMO oesophageal cancer guideline","url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-gastrointestinal-cancers/"},{"label":"NCI PDQ esophageal cancer treatment","url":"https://www.cancer.gov/types/esophageal/hp/esophageal-treatment-pdq"}],"tags":["gi","spike"],"related":[],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","bispecific-adc","imrt-igrt","gastric-endoscopic-screening","endoscopic-resection","active-surveillance","brachytherapy","robotic-surgery","adc"],"targets":["pd1","egfr","her3","her2","pdl1","ctla4","cldn18-2","vegf"],"drugs":[],"companies":["nanjing-leads-biolabs","neonc-technologies","ap-biosciences","merck","bms","beone","systimmune","astrazeneca","daiichi-sankyo","jazz"],"institutions":["jiangsu-cancer-hospital","nki","sysucc","ncc-japan","cams-cancer-hospital"],"pathways":["pd1-checkpoint","ras-mapk"],"terms":["escc-vs-eac","barretts-esophagus","siewert-classification","clinical-complete-response","cps","neoadjuvant-adjuvant","pcr","endoscopic-resection-term","flot-term"],"trials":["rationale-302","symbiotic-gi-16","nct07463573","nct06194734","nct04415853","nct06356311","nct06022861","nct07217704","nct07431281","nct06644781","nct07554456","nct04550260"],"people":[],"bottlenecks":[],"keyPapers":["paper-spotlight-lancet-2023","paper-alcohol-cancer-burden-lancet-oncol-2021"],"journals":["esophagus-journal"],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"~510,000 cases per year; ~85% squamous cell carcinoma globally, adenocarcinoma dominant in North America, Western Europe, and Australia. Endoscopic screening, where it exists, cures most early disease. 5-year survival is >80% for endoscopically treated early cancers and ~20% overall; ~445,000 deaths per year.","subtypes":["Squamous cell carcinoma (upper/mid oesophagus; tobacco, alcohol; Asia and Africa)","Adenocarcinoma (distal oesophagus/GEJ; Barrett's, reflux, obesity; the West)","GEJ tumours by Siewert type (I treated as oesophageal, III as gastric)","HER2-positive adenocarcinoma (~15-20%)","PD-L1-high (CPS ≥10 or TAP ≥10%) tumours with greater immunotherapy benefit","Cervical oesophageal cancer (definitive chemoradiation, no surgery)","Early (T1a) disease amenable to endoscopic resection"],"biomarkers":["PD-L1","HER2 (adenocarcinoma)","EGFR (squamous)","Histology (squamous vs adenocarcinoma) determines the pathway","PD-L1 (CPS for adenocarcinoma/pembrolizumab; TAP score for tislelizumab in ESCC)","HER2 IHC/ISH in adenocarcinoma","MSI/dMMR","CLDN18.2 in GEJ adenocarcinoma (gastric trials)","Pathologic response after neoadjuvant therapy (residual disease → adjuvant nivolumab)","Clinical complete response assessment (endoscopy, biopsy, PET-CT) for surveillance","EGFR and HER3 expression (not required for iza-bren)"],"standardOfCare":[{"setting":"Localised","approach":"Neoadjuvant chemoradiation (CROSS) or perioperative FLOT → surgery → nivolumab if residual disease.","refs":["nivolumab","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Esophageal and Esophagogastric Junction Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433"}},{"setting":"Advanced","approach":"Chemotherapy + pembrolizumab/nivolumab; iza-bren in trials.","refs":["pembrolizumab","izalontamab-brengitecan"],"guideline":{"version":"NCCN Guidelines: Esophageal and Esophagogastric Junction Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433"}},{"setting":"Prevention and screening","approach":"Tobacco and alcohol control; endoscopic screening of high-risk populations in China and Japan (Lugol chromoendoscopy); surveillance of Barrett's oesophagus with ablation or resection of dysplasia; non-endoscopic capsule-sponge screening in trials (BEST4).","refs":["endoscopic-resection","barretts-esophagus","idea-non-endoscopic-barretts-screening"],"guideline":{"url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433"}},{"setting":"Early (T1a, high-grade dysplasia)","approach":"Endoscopic resection (EMR/ESD) with radiofrequency ablation of residual Barrett's; oesophagectomy for T1b with high-risk features.","refs":["endoscopic-resection"],"guideline":{"nccn":"Category 1 (endoscopic therapy for Tis/T1a)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433"}},{"setting":"Resectable locally advanced (cT2-4a or N+)","approach":"CROSS chemoradiation (carboplatin/paclitaxel + 41.4 Gy) then oesophagectomy for squamous and adenocarcinoma; perioperative FLOT for adenocarcinoma/GEJ (ESOPEC). Adjuvant nivolumab for residual disease after chemoradiation (CheckMate 577).","refs":["cross","checkmate-577","flot","nivolumab","cross-then-nivolumab"],"guideline":{"nccn":"Category 1 (preoperative chemoradiation; adjuvant nivolumab)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433"}},{"setting":"Clinical complete response after chemoradiation","approach":"Active surveillance with surgery on regrowth is a non-inferior option (SANO); requires intensive endoscopic and PET surveillance.","refs":["sano","active-surveillance","clinical-complete-response"],"guideline":{"url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-gastrointestinal-cancers/"}},{"setting":"Unresectable locally advanced or cervical","approach":"Definitive chemoradiation (50-50.4 Gy with cisplatin/5-FU or carboplatin/paclitaxel); PD-1 blockade added in trials.","refs":["imrt-igrt","platinum"],"guideline":{"nccn":"Category 1 (definitive chemoradiation)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433"}},{"setting":"Advanced squamous cell carcinoma, first line","approach":"Chemotherapy + pembrolizumab (KEYNOTE-590), nivolumab (CheckMate 648), or tislelizumab (RATIONALE-306, PD-L1 ≥1%); nivolumab + ipilimumab chemotherapy-free option; camrelizumab/sintilimab/toripalimab in China.","refs":["keynote-590","checkmate-648","rationale-306","escort-1st","pembrolizumab","nivolumab","ipilimumab","tislelizumab","camrelizumab"],"guideline":{"nccn":"Category 1 (PD-L1-positive)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433"}},{"setting":"Advanced adenocarcinoma, first line","approach":"As for gastric cancer: chemotherapy + pembrolizumab or nivolumab (PD-L1 CPS ≥5 or ≥1); trastuzumab-based therapy if HER2-positive; zolbetuximab if CLDN18.2-positive (GEJ eligible in SPOTLIGHT/GLOW).","refs":["keynote-590","checkmate-649","trastuzumab","zanidatamab","zolbetuximab"],"guideline":{"url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433"}},{"setting":"Second line, squamous cell carcinoma","approach":"Izalontamab brengitecan after PD-(L)1 + platinum (PANKU-Esophagus01, OS and PFS benefit, 2026; approval pending); otherwise taxane or irinotecan; nivolumab/pembrolizumab if IO-naive.","refs":["panku-esophagus01","izalontamab-brengitecan"],"guideline":{"url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-gastrointestinal-cancers/"}},{"setting":"Second line, adenocarcinoma","approach":"T-DXd if HER2-positive (DESTINY-Gastric04); ramucirumab + paclitaxel; CLDN18.2 ADC after CLARITY-Gastric 01.","refs":["destiny-gastric04","trastuzumab-deruxtecan","ramucirumab","clarity-gastric01"],"guideline":{"url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1433"}},{"setting":"Palliation of dysphagia","approach":"Self-expanding metal stent, brachytherapy, or external beam radiation; nutritional support; early palliative care.","refs":["brachytherapy","imrt-igrt"],"guideline":{"url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-gastrointestinal-cancers/"}}],"stateOfArt":["Immunotherapy in first line and adjuvant.","First bispecific ADC phase 3 success in ESCC.","Chemoradiation before surgery (CROSS) has a durable 13-point 10-year survival gain; organ preservation after complete response is non-inferior (SANO).","Adjuvant nivolumab doubles disease-free survival after incomplete response to chemoradiation (CheckMate 577), though OS was not significantly improved.","Chemo-immunotherapy is first-line standard in both histologies, replicated in five phase 3 trials; PD-L1 defines the size of benefit.","A chemotherapy-free immunotherapy doublet (nivolumab + ipilimumab) is an option in squamous disease.","The first bispecific ADC with an OS benefit in second-line ESCC (iza-bren, 2026) gives post-immunotherapy squamous cancer its first targeted option.","Endoscopic screening and resection in East Asia cure most early squamous cancers; Barrett's surveillance and ablation prevent adenocarcinoma in the West."],"history":[{"year":1913,"title":"Torek performs the first successful oesophagectomy for cancer","refs":[]},{"year":1980,"title":"Cisplatin/5-FU chemoradiation defined (RTOG 85-01 reported 1992)","note":"Definitive chemoradiation shown superior to radiation alone; 5-year OS 26% vs 0%.","refs":["imrt-igrt","platinum"]},{"year":1990,"title":"Endoscopic mucosal resection for early oesophageal cancer (Japan)","refs":["endoscopic-resection"]},{"year":2006,"title":"MAGIC: perioperative chemotherapy for GEJ adenocarcinoma","refs":["cytotoxic-chemotherapy"]},{"year":2010,"title":"ToGA includes GEJ adenocarcinoma: trastuzumab for HER2-positive disease","refs":["toga","trastuzumab"]},{"year":2012,"title":"CROSS: neoadjuvant chemoradiation","refs":[]},{"year":2012,"title":"CROSS: neoadjuvant chemoradiation becomes standard","refs":["cross"]},{"year":2019,"title":"PD-1 blockade second line: pembrolizumab (KEYNOTE-181) and nivolumab (ATTRACTION-3)","refs":["pembrolizumab","nivolumab"]},{"year":2021,"title":"Checkpoint inhibitors first line","refs":[]},{"year":2021,"title":"CROSS 10-year data; CheckMate 577 adjuvant nivolumab; KEYNOTE-590 and ESCORT-1st first-line chemo-IO","refs":["cross","checkmate-577","keynote-590","escort-1st"]},{"year":2022,"title":"CheckMate 648: nivolumab + chemotherapy and nivolumab + ipilimumab approved; RATIONALE-306 reported","refs":["checkmate-648","rationale-306"]},{"year":2023,"title":"SANO: active surveillance non-inferior after complete response","refs":["sano"]},{"year":2024,"title":"Tislelizumab approved in the US (second-line ESCC, first-line gastric); ESOPEC favours FLOT over CROSS in adenocarcinoma","refs":["tislelizumab","flot"]},{"year":2025,"title":"Tislelizumab first-line ESCC approval; CheckMate 577 final OS not significant; DESTINY-Gastric04 for HER2+ GEJ","refs":["tislelizumab","checkmate-577","destiny-gastric04"]},{"year":2026,"title":"Iza-bren phase 3 positive","refs":["bl-b01d1-307"]},{"year":2026,"title":"PANKU-Esophagus01: iza-bren improves OS in second-line ESCC; HERIZON-GEA-01 for HER2+ GEJ; CheckMate 648 five-year data","refs":["panku-esophagus01","herizon-gea-01","checkmate-648"]}],"pipeline":["izalontamab-brengitecan","pf-08634404","hs-20093","qlc5508","kc1036","hlx43","gotistobart","lerotinib","mcla-129","tqb6411","hmbd-001","azd5863","panku-esophagus01","sano","idea-organ-preservation-esophageal","idea-non-endoscopic-barretts-screening","herizon-gea-01","zanidatamab","tislelizumab","clarity-gastric01","mrd-testing","fapi-pet","cross-then-nivolumab","checkmate-648"],"openProblems":["Late presentation.","Squamous cell carcinoma lacks targets beyond EGFR/HER3.","Most patients present with advanced disease; no Western screening for squamous cancer and only trial-stage non-endoscopic screening for Barrett's.","Adjuvant nivolumab improves DFS but not significantly OS; who truly needs it (PD-L1, ctDNA) is unknown.","Squamous cell carcinoma has no validated molecular targets beyond PD-1 and, since 2026, EGFR/HER3 antigen delivery.","PD-L1-negative tumours derive little from chemo-immunotherapy; alternatives are lacking.","Whether adding PD-1 blockade to definitive chemoradiation improves cure remains unproven pending KEYNOTE-975 and SKYSCRAPER-07.","Organ preservation requires intensive surveillance and salvage surgery capacity that many centres lack.","Oesophagectomy carries high morbidity; centralisation and minimally invasive approaches are unevenly adopted."]},{"id":"oesophageal-squamous-cell-carcinoma","kind":"cancer","name":"Oesophageal squamous cell carcinoma","aka":["Esophageal squamous cell carcinoma","ESCC","Oesophageal SCC"],"tldr":"Squamous cell carcinoma of the oesophagus, the world's commonest form, is linked to smoking, alcohol and very hot drinks and sits in the upper and middle gullet. It is treated with chemoradiation, with or without surgery, and immunotherapy has recently joined chemotherapy for advanced disease.","summary":"Oesophageal squamous cell carcinoma arises from the squamous lining of the upper and middle oesophagus; tobacco, alcohol, scalding drinks, nutritional deficiency and achalasia are its causes, and TP53 and NOTCH1 mutations its genetics. Early lesions found by endoscopy, common in Japanese and Chinese screening programmes, are removed endoscopically. Locally advanced disease is treated either with neoadjuvant chemoradiation followed by surgery (CROSS) or with definitive chemoradiation alone, which cures a similar share in this histology; adjuvant nivolumab after chemoradiation and surgery lowers recurrence when residual disease remains (CheckMate 577). Advanced disease is treated with nivolumab plus chemotherapy or nivolumab plus ipilimumab (CheckMate 648) or pembrolizumab plus chemotherapy (KEYNOTE-590); Chinese trials with camrelizumab, tislelizumab, toripalimab and sintilimab have produced the same result.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Esophageal_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Esophageal_cancer"}],"tags":["subtype-page"],"related":["oesophageal-adenocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-cross-nejm-2012","paper-checkmate-648-nejm-2022","paper-keynote-590-lancet-2021","paper-checkmate-577-nejm-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 85 percent of oesophageal cancers worldwide and the dominant type across the Asian oesophageal cancer belt, East Africa and South America; in high-income countries it is now outnumbered by adenocarcinoma, and five-year survival is around 20 percent overall.","subtypes":["Upper and middle third squamous cell carcinoma","Early (T1a) squamous cell carcinoma (endoscopic resection)","Locally advanced (chemoradiation with or without surgery)","Metastatic (immunotherapy plus chemotherapy)"],"biomarkers":["PD-L1 combined positive score or tumour proportion score","TP53 and NOTCH1 mutations","Endoscopic Lugol staining for early lesions","Pathological response after chemoradiation"],"standardOfCare":[{"setting":"Early (T1a)","approach":"Endoscopic submucosal dissection; oesophagectomy or chemoradiation if deeper invasion is found.","refs":["endoscopic-resection"]},{"setting":"Locally advanced","approach":"Neoadjuvant carboplatin-paclitaxel chemoradiation and surgery (CROSS), or definitive cisplatin-fluorouracil chemoradiation with surgery reserved for persistent disease; adjuvant nivolumab after incomplete response (CheckMate 577).","refs":["cross","carboplatin","paclitaxel","cisplatin","fluorouracil","nivolumab","checkmate-577"]},{"setting":"Metastatic, first line","approach":"Nivolumab plus chemotherapy or nivolumab plus ipilimumab (CheckMate 648), or pembrolizumab plus chemotherapy (KEYNOTE-590).","refs":["nivolumab","ipilimumab","pembrolizumab","checkmate-648","keynote-590"]},{"setting":"Prevention and screening","approach":"Smoking cessation, alcohol reduction, avoiding very hot drinks; endoscopic screening in high-incidence regions of China.","refs":["smoking-cessation-after-diagnosis","alcohol-reduction-labelling"]}],"stateOfArt":["Immunotherapy added to chemotherapy improved survival in every first-line trial, including several run entirely in China.","Organ preservation with definitive chemoradiation and surveillance is an accepted alternative to surgery in this histology.","Endoscopic screening in China detects a large share of cancers at a curable stage."],"history":[{"year":1992,"title":"RTOG 85-01: chemoradiation beats radiotherapy alone","refs":[]},{"year":2012,"title":"CROSS: chemoradiation before surgery doubles survival","refs":["cross"]},{"year":2021,"title":"CheckMate 577 and KEYNOTE-590 bring immunotherapy to oesophageal cancer","refs":["checkmate-577","keynote-590"]},{"year":2022,"title":"CheckMate 648: nivolumab combinations first line","refs":["checkmate-648"]}],"pipeline":["nivolumab","tislelizumab"],"openProblems":["Whether surgery can be omitted after a complete response to chemoradiation.","Most cases worldwide present late without access to endoscopy.","Nutrition, swallowing and quality of life during and after treatment."],"parent":"esophageal"},{"id":"oligodendroglioma","kind":"cancer","name":"Oligodendroglioma, IDH-mutant and 1p/19q-codeleted","aka":["Oligodendroglioma","Anaplastic oligodendroglioma","1p/19q codeleted glioma"],"tldr":"Oligodendroglioma is the adult brain tumour most responsive to chemotherapy. It is recognised by an IDH mutation together with loss of parts of chromosomes 1 and 19, and after surgery it is treated with radiotherapy plus the PCV drug combination, or, for small grade 2 tumours, with vorasidenib or watchful waiting.","summary":"Oligodendroglioma, IDH-mutant and 1p/19q-codeleted is defined in WHO 2021 by the combination of an IDH1 or IDH2 mutation with whole-arm codeletion of 1p and 19q; TERT promoter mutations are near universal and CIC and FUBP1 mutations common. It is graded 2 or 3 by mitotic activity, microvascular proliferation and necrosis; there is no grade 4. Calcification, frontal location and seizures are typical, and the tumour infiltrates cortex widely, so complete resection is often impossible.\n\nThe codeletion was first linked to chemosensitivity by Cairncross in 1998, and two trials that opened in the 1990s proved it: RTOG 9402 (radiotherapy with or without PCV before it) and EORTC 26951 (radiotherapy with or without PCV after it). In codeleted tumours the long-term reports in 2013 showed survival roughly doubled, with a median of 14.7 years against 7.3 years in RTOG 9402 and median survival not reached against 112 months in EORTC 26951, so radiotherapy followed by PCV became the standard for grade 3 disease and, after RTOG 9802, for high-risk grade 2 disease. CODEL is testing whether temozolomide can replace PCV, which is harder to tolerate; CATNON did not include codeleted tumours.\n\nFor grade 2 tumours with residual or recurrent disease and no pressing need for radiotherapy, INDIGO included oligodendroglioma alongside astrocytoma and vorasidenib is now an approved alternative to observation. Because patients live for many years, the cumulative cognitive effects of radiotherapy, the timing of treatment after surgery and the sequencing of vorasidenib, chemotherapy and radiotherapy are the live questions. Recurrent disease is treated with re-resection, temozolomide, lomustine or re-irradiation.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Oligodendroglioma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Oligodendroglioma"},{"label":"RTOG 9402 long-term results (JCO 2013)","url":"https://doi.org/10.1200/JCO.2012.43.2674"},{"label":"EORTC 26951 long-term results (JCO 2013)","url":"https://doi.org/10.1200/JCO.2012.43.2229"}],"tags":["subtype-page","cns"],"related":["glioblastoma","idh-mutant-astrocytoma","brain-tumours","dipg-dmg","paediatric-high-grade-glioma","paediatric-low-grade-glioma"],"cancers":[],"sections":[],"technologies":["methylation-profiling","imrt-igrt","extent-of-resection"],"targets":["idh"],"drugs":["procarbazine","lomustine","vincristine","vorasidenib","temozolomide"],"companies":[],"institutions":[],"pathways":["glioma-signalling"],"terms":["re-irradiation","1p19q-codeletion","cdkn2a-homozygous-deletion"],"trials":["rtog-9402","eortc-26951","indigo","codel"],"people":[],"bottlenecks":[],"keyPapers":["paper-indigo-nejm-2023","paper-who-2021-cns-louis-neuro-oncology-2021","paper-rtog-9402-cairncross-jco-2013","paper-eortc-26951-van-den-bent-jco-2013"],"journals":[],"dependsOn":[],"notes":[],"group":"central nervous system","burden":"A small share of adult gliomas, typically found in the frontal lobes of people in their thirties and forties; it has the best outlook of any diffuse adult glioma, with survival often measured in decades.","subtypes":["Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, grade 2","Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, grade 3 (formerly anaplastic)","Oligodendroglioma with minigemistocytes or gliofibrillary oligodendrocytes (morphological variants)"],"biomarkers":["IDH1 or IDH2 mutation","Whole-arm 1p/19q codeletion (FISH, array or methylation-based copy number)","TERT promoter mutation","CIC and FUBP1 mutations","CDKN2A/B homozygous deletion (shorter survival, rare)","DNA methylation class"],"standardOfCare":[{"setting":"Newly diagnosed","approach":"Maximal safe resection and molecular diagnosis with 1p/19q testing; observation is reasonable after gross total resection of a grade 2 tumour in a younger patient.","refs":["extent-of-resection","methylation-profiling","active-surveillance"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Grade 2, residual or recurrent, not needing radiotherapy","approach":"Vorasidenib (INDIGO) or continued observation.","refs":["vorasidenib","indigo"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Grade 2, high risk, and grade 3","approach":"Radiotherapy followed by PCV (procarbazine, lomustine, vincristine), the regimen validated in RTOG 9402, EORTC 26951 and RTOG 9802; radiotherapy with temozolomide is an alternative being compared in CODEL.","refs":["imrt-igrt","procarbazine","lomustine","vincristine","rtog-9402","eortc-26951","temozolomide"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Recurrence","approach":"Re-resection, temozolomide or lomustine, re-irradiation; bevacizumab for symptoms.","refs":["temozolomide","lomustine","re-irradiation","bevacizumab-glioma"]}],"stateOfArt":["Oligodendroglioma was the first brain tumour in which a chromosomal marker predicted benefit from chemotherapy, fifteen years before the trials confirmed it.","Radiotherapy plus PCV roughly doubled survival in codeleted tumours and is still the standard for grade 3 disease.","Vorasidenib gives grade 2 patients a drug option before radiotherapy for the first time."],"history":[{"year":1926,"title":"Bailey and Cushing describe oligodendroglioma as a distinct tumour","refs":[]},{"year":1998,"title":"Cairncross links 1p/19q loss to chemosensitivity","note":"Journal of the National Cancer Institute report that codeleted anaplastic oligodendrogliomas respond to PCV and live longer.","refs":["procarbazine","lomustine","vincristine"]},{"year":2006,"title":"RTOG 9402 and EORTC 26951 report: PCV lengthens progression-free but not yet overall survival","refs":["rtog-9402","eortc-26951"]},{"year":2013,"title":"Long-term results: radiotherapy plus PCV doubles survival in codeleted tumours","note":"RTOG 9402 median 14.7 versus 7.3 years; EORTC 26951 median not reached versus 112 months (both JCO).","refs":["rtog-9402","eortc-26951"]},{"year":2016,"title":"WHO 2016 defines oligodendroglioma by IDH mutation and 1p/19q codeletion","refs":[]},{"year":2016,"title":"RTOG 9802: radiotherapy plus PCV for high-risk grade 2 glioma, including oligodendroglioma","refs":["procarbazine","lomustine","vincristine"]},{"year":2023,"title":"INDIGO: vorasidenib in grade 2 astrocytoma and oligodendroglioma","refs":["vorasidenib","indigo"]},{"year":2024,"title":"FDA approves vorasidenib","refs":["vorasidenib"]}],"pipeline":["vorasidenib","safusidenib","methylation-profiling"],"openProblems":["Whether temozolomide can replace PCV without losing survival (CODEL).","How to sequence vorasidenib, chemotherapy and radiotherapy over a disease course of decades.","Late cognitive effects of radiotherapy in long survivors.","No effective treatment for the rare tumours that acquire CDKN2A/B loss or hypermutation."],"parent":"glioblastoma"},{"id":"optic-pathway-glioma","kind":"cancer","name":"Optic pathway glioma","aka":["Optic nerve glioma","Optic glioma","NF1-associated optic pathway glioma","Hypothalamic-chiasmatic glioma","NF1-associated optic pathway glioma (paediatric low-grade glioma)"],"tldr":"Optic pathway glioma is a slow-growing childhood brain tumour of the nerves that carry sight, often in children with neurofibromatosis type 1. It rarely kills but can take away vision, so treatment aims to preserve sight: watching if stable, chemotherapy such as carboplatin and vincristine if vision is threatened, or the MEK-blocking tablet selumetinib, with radiotherapy avoided in young children.","summary":"Optic pathway gliomas are pilocytic or other low-grade astrocytomas of the optic nerves, chiasm and hypothalamus, sporadic or associated with neurofibromatosis type 1, and treated within the paediatric low-grade glioma pathway (NCI PDQ). Because visual acuity rather than tumour size is what matters, the Response Evaluation in Neurofibromatosis and Schwannomatosis committee recommended quantitative visual acuity (Teller cards, then HOTV) as the main functional outcome for trials (Neurology 2013). In a single-institution series of 43 children treated with chemotherapy or radiotherapy, about 14 percent improved their vision during therapy and site and age strongly predicted long-term visual outcome (Cancer 2015). The MEK inhibitor selumetinib produced responses in recurrent or progressive NF1-associated and BRAF-aberrant paediatric low-grade glioma in the Pediatric Brain Tumor Consortium phase 2 trial (Fangusaro 2019), and MEK and RAF inhibitors are now first-line options on the parent page.\n\nHow it differs from its parent: the goal is sight, not tumour shrinkage; NF1-associated tumours are usually not biopsied and follow a gentler course; radiotherapy is avoided because of vascular and second-tumour risks in NF1 and cognitive harm in young children.\n\nHow common: no registry figure in the sources read.\n\nTreatment: observation with ophthalmology follow-up when stable; carboplatin and vincristine chemotherapy or a MEK inhibitor (selumetinib) or RAF inhibitor (tovorafenib, dabrafenib with trametinib for BRAF V600E) when vision is threatened or the tumour progresses; surgery only for a blind, painful proptotic eye or hydrocephalus; radiotherapy deferred as long as possible.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Optic_nerve_glioma","links":[{"label":"NCI PDQ: childhood glioma (including astrocytoma)","url":"https://www.cancer.gov/types/brain/patient/childhood-glioma-astrocytoma"},{"label":"Neurology 2013: functional outcome measures for NF1-associated optic pathway glioma trials (REiNS)","url":"https://doi.org/10.1212/01.wnl.0000435745.95155.b8"},{"label":"Cancer 2015: long-term visual outcome after chemotherapy for optic pathway glioma in children","url":"https://doi.org/10.1002/cncr.29649"},{"label":"Fangusaro 2019, Lancet Oncology: selumetinib in paediatric BRAF-aberrant or NF1-associated low-grade glioma, phase 2","url":"https://doi.org/10.1016/s1470-2045(19)30277-3"}],"tags":["subtype-page","wave4","rare"],"related":["paediatric-low-grade-glioma","brain-tumours","childhood-cancers","vestibular-schwannoma"],"cancers":[],"sections":[],"technologies":[],"targets":["nf1"],"drugs":["carboplatin","vincristine","selumetinib","tovorafenib","dabrafenib","trametinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"A common form of paediatric low-grade glioma and the commonest brain tumour of neurofibromatosis type 1, in which it arises in about 15 to 20 percent of children by the estimates the trial literature uses; no registry figure is in the sources read.","subtypes":["NF1-associated optic nerve glioma (usually not biopsied; gentler course)","Sporadic optic pathway glioma (often KIAA1549-BRAF fusion)","Hypothalamic-chiasmatic glioma of infancy (diencephalic syndrome)","Optic nerve glioma confined to one nerve"],"biomarkers":["Quantitative visual acuity (Teller cards, HOTV)","NF1 germline status","KIAA1549-BRAF fusion or BRAF V600E in sporadic tumours","MRI of the optic pathway and hypothalamus"],"standardOfCare":[{"setting":"Stable vision","approach":"Observation with ophthalmology and MRI follow-up.","refs":["paediatric-low-grade-glioma"]},{"setting":"Threatened vision or progression","approach":"Carboplatin and vincristine, or selumetinib (phase 2, Fangusaro 2019), tovorafenib, or dabrafenib with trametinib for BRAF V600E; radiotherapy deferred.","refs":["carboplatin","vincristine","selumetinib","tovorafenib","dabrafenib","trametinib"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"paediatric-low-grade-glioma"},{"id":"oral-cavity-cancer","kind":"cancer","name":"Oral cavity cancer (mouth and tongue)","aka":["Oral cancer","Mouth cancer","Tongue cancer","Oral squamous cell carcinoma"],"tldr":"Cancer of the mouth and tongue, a head and neck cancer, is caused mainly by tobacco, alcohol and betel quid and is usually visible or feelable early, yet often diagnosed late. Surgery is the mainstay, with radiotherapy or chemoradiation after operation for higher-risk disease, and reconstruction to restore speech and swallowing.","summary":"Oral cavity squamous cell carcinoma arises on the tongue, floor of mouth, gums, buccal mucosa, palate and lips, often from a white or red patch (leukoplakia or erythroplakia). Unlike oropharyngeal cancer it is rarely HPV-driven; tobacco, alcohol and, in South and South-East Asia, betel quid with areca nut are the causes, and a screening trial in Kerala showed that visual inspection by trained health workers reduces mouth cancer deaths in high-risk people. Treatment is surgical resection with neck dissection and free-flap reconstruction, with postoperative radiotherapy or cisplatin chemoradiation for advanced stage, positive margins or nodal spread with extranodal extension. Depth of invasion now determines stage and the need to treat the neck. Recurrent or metastatic disease is treated as for other head and neck cancers with pembrolizumab-based therapy, and metronomic methotrexate-celecoxib from Tata Memorial Hospital offers a low-cost option.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Oral_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Oral_cancer"}],"tags":["subtype-page"],"related":["hpv-negative-head-and-neck-cancer","laryngeal-cancer","oropharyngeal-cancer","recurrent-metastatic-hnscc"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["celecoxib"],"companies":[],"institutions":[],"pathways":[],"terms":["extranodal-extension","depth-of-invasion"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-dcruz-elective-neck-dissection-nejm-2015","paper-sankaranarayanan-oral-screening-lancet-2005","paper-keynote-048-lancet-2019","paper-bernier-eortc-22931-nejm-2004"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"About 390,000 new cases a year worldwide, with the highest rates in South Asia from betel quid and tobacco chewing; it is the commonest cancer among men in India, and five-year survival is around 60 percent overall but far lower for late-stage disease.","subtypes":["Oral tongue","Floor of mouth","Buccal mucosa and gingiva (betel-quid related)","Lip (sun-related)","Hard palate and retromolar trigone"],"biomarkers":["Depth of invasion (staging and elective neck dissection)","Extranodal extension and margin status","TP53 mutation","PD-L1 combined positive score (recurrent disease)"],"standardOfCare":[{"setting":"Screening in high-risk populations","approach":"Visual oral examination by trained workers reduced mouth cancer deaths in the Kerala trial; opportunistic examination by dentists elsewhere.","refs":["head-and-neck"]},{"setting":"Early disease","approach":"Wide excision with elective neck dissection when depth of invasion exceeds about 3 to 4 mm; sentinel node biopsy in selected cases.","refs":["head-and-neck"]},{"setting":"Locally advanced disease","approach":"Resection with neck dissection and free-flap reconstruction, then postoperative radiotherapy, or cisplatin chemoradiation for positive margins or extranodal extension.","refs":["cisplatin","imrt-igrt"]},{"setting":"Recurrent or metastatic","approach":"Pembrolizumab with or without chemotherapy (KEYNOTE-048); low-cost metronomic methotrexate and celecoxib where access is limited.","refs":["pembrolizumab","keynote-048","methotrexate","metronomic-vs-cisplatin-tmh"]},{"setting":"Prevention","approach":"Tobacco and betel quid cessation, alcohol reduction, treatment of premalignant patches.","refs":["smoking-cessation-after-diagnosis"]}],"stateOfArt":["Elective neck dissection improves survival even in early tongue cancer (D'Cruz, Tata Memorial, 2015).","Free-flap reconstruction has made function-preserving resection routine.","India's low-cost trials have set standards for resource-limited care, from metronomic chemotherapy to screening."],"history":[{"year":1906,"title":"Crile describes radical neck dissection","refs":[]},{"year":2005,"title":"Kerala screening trial shows visual inspection cuts oral cancer deaths in high-risk people","refs":[]},{"year":2015,"title":"Elective neck dissection improves survival in early oral cancer (Tata Memorial)","refs":[]},{"year":2017,"title":"Depth of invasion enters staging (AJCC 8th edition)","refs":[]}],"pipeline":["pembrolizumab","nivolumab"],"openProblems":["Late presentation remains the norm in the highest-incidence countries.","Betel quid use is still rising in parts of Asia.","Field cancerisation causes second primaries in a fifth of survivors.","Speech and swallowing after large resections."],"parent":"head-and-neck"},{"id":"oral-tongue-cancer","kind":"cancer","name":"Oral tongue and floor of mouth cancer","aka":["Tongue cancer","Anterior two-thirds of tongue cancer","Floor of mouth cancer","Oral tongue squamous cell carcinoma"],"tldr":"Cancer of the front of the tongue or the floor of the mouth is treated first with surgery, and a Tata Memorial trial settled that the neck lymph nodes should be removed at the same operation even when scans look clear. How deep the tumour has grown is now the number that decides staging and the need to treat the neck.","summary":"Squamous cell carcinoma of the oral tongue (the mobile anterior two-thirds) and floor of mouth usually presents as a persistent ulcer or lump, often painful, sometimes with ear pain or a neck node. Tobacco, alcohol and betel quid are the causes in most patients, but tongue cancer in young adults without these exposures is increasing in several countries and is not HPV-related. The tongue's rich lymphatic drainage means that a substantial minority of patients with a clinically clear neck already harbour nodal metastases, and depth of invasion, which entered the staging system in 2017, is the best predictor of that risk.\n\nTreatment is surgical: partial glossectomy or floor-of-mouth resection with margins of at least 5 mm, and treatment of the neck. The Tata Memorial trial of elective versus therapeutic neck dissection in 596 patients with early node-negative oral cancer, reported by D'Cruz in 2015, showed three-year overall survival of 80.0 percent with elective neck dissection against 67.5 percent with watchful waiting, ending a fifty-year debate; sentinel node biopsy, validated in the European SENT study, is an alternative for small tumours. Larger defects are reconstructed with free radial forearm or anterolateral thigh flaps to preserve speech and swallowing, and brachytherapy, once common for small tongue cancers, has largely given way to surgery.\n\nPostoperative radiotherapy is given for stage III to IV disease, perineural invasion, close margins or multiple nodes, and cisplatin chemoradiation for extranodal extension or positive margins. Recurrent or metastatic disease is treated as for other head and neck squamous cell carcinoma with pembrolizumab-based therapy, or with oral metronomic methotrexate-celecoxib where resources are limited. Second primaries in the mouth, pharynx, oesophagus and lung are common in smokers, so cessation and surveillance matter.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Oral_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Oral_cancer"}],"tags":["subtype-page","head-and-neck"],"related":["buccal-mucosa-cancer","lip-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["celecoxib"],"companies":[],"institutions":[],"pathways":[],"terms":["extranodal-extension","depth-of-invasion","cdkn2a-homozygous-deletion"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-dcruz-elective-neck-dissection-nejm-2015","paper-keynote-048-lancet-2019","paper-bernier-eortc-22931-nejm-2004"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"The tongue is the commonest oral cavity site in Western countries, and tongue cancer is rising in young adults who neither smoke nor drink for reasons still unknown; the floor of mouth is the classic tobacco and alcohol site.","subtypes":["Oral tongue (anterior two-thirds) squamous cell carcinoma","Floor of mouth squamous cell carcinoma","Tongue cancer in young non-smokers","Thin (depth of invasion 5 mm or less) versus thick tumours","Verrucous carcinoma of the tongue and floor of mouth"],"biomarkers":["Depth of invasion (staging and elective neck dissection)","Worst pattern of invasion and perineural invasion","Margin status","Extranodal extension","TP53 mutation","PD-L1 combined positive score (recurrent disease)"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Biopsy, MRI or CT of the tongue and neck to measure depth of invasion and nodes, chest imaging or PET-CT for advanced stage, and dental assessment before radiotherapy.","refs":["pet-ct"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Primary treatment (T1 to T2, clinically node-negative)","approach":"Partial glossectomy or floor-of-mouth resection with at least 5 mm margins and elective neck dissection (Tata Memorial trial); sentinel node biopsy as an alternative in small tumours.","refs":["elective-neck-dissection-tmh","sentinel-node"],"guideline":{"nccn":"Category 1 (elective neck dissection)","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Locally advanced (T3 to T4 or node-positive)","approach":"Resection with neck dissection and free-flap reconstruction, then postoperative radiotherapy, or cisplatin chemoradiation for extranodal extension or positive margins.","refs":["imrt-igrt","cisplatin","chemoradiation"],"guideline":{"nccn":"Category 1 (chemoradiation for extranodal extension or positive margins)","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Recurrent or metastatic","approach":"Pembrolizumab alone or with platinum-fluorouracil (KEYNOTE-048); oral metronomic methotrexate-celecoxib where resources are limited.","refs":["pembrolizumab","keynote-048","methotrexate","metronomic-vs-cisplatin-tmh","recurrent-metastatic-hnscc"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Prevention","approach":"Tobacco, alcohol and betel quid cessation; treatment of leukoplakia and erythroplakia; oral examination in high-risk people.","refs":["smoking-cessation-after-diagnosis","alcohol-reduction-labelling","oral-visual-screening"]}],"stateOfArt":["Elective neck dissection for early tongue cancer is a category 1 recommendation on the strength of one Indian randomised trial.","Depth of invasion has replaced tumour thickness and diameter as the driver of staging.","Free-flap reconstruction preserves intelligible speech and oral swallowing after large resections."],"history":[{"year":1906,"title":"Crile describes radical neck dissection","refs":[]},{"year":2015,"title":"Tata Memorial: elective neck dissection improves survival in early oral cancer","refs":["elective-neck-dissection-tmh"]},{"year":2017,"title":"Depth of invasion enters staging (AJCC 8th edition)","refs":[]},{"year":2019,"title":"KEYNOTE-048: pembrolizumab first line in recurrent disease","refs":["keynote-048"]}],"pipeline":["pembrolizumab","keynote-689","sentinel-node","nivopostop"],"openProblems":["Why tongue cancer is rising in young non-smokers.","Whether sentinel node biopsy can replace elective neck dissection safely.","Speech and swallowing after resection of more than half the tongue.","Second primaries in the treated field."],"parent":"oral-cavity-cancer"},{"id":"oropharyngeal-cancer","kind":"cancer","name":"Oropharyngeal cancer (tonsil and base of tongue)","aka":["Oropharynx cancer","Tonsil cancer","Base of tongue cancer","HPV-positive head and neck cancer"],"tldr":"Cancer of the tonsils and back of the tongue, a head and neck cancer, now comes mostly from HPV infection rather than smoking, and behaves like a different disease: it responds well to chemoradiation, most patients are cured, and the research question is how much treatment can safely be removed.","summary":"Oropharyngeal squamous cell carcinoma arises in the tonsils, base of tongue, soft palate and pharyngeal wall. In North America and Europe most cases are now caused by HPV type 16 and are staged separately because they carry a far better outlook than tobacco-related, HPV-negative tumours, which are more often p53-mutant and resistant. Standard treatment is cisplatin chemoradiation, or transoral robotic surgery with neck dissection and adjuvant treatment for smaller tumours; cetuximab proved inferior to cisplatin in HPV-positive disease in RTOG 1016 and De-ESCALaTE. Trials are testing lower radiotherapy doses, fewer drugs and circulating HPV DNA to guide de-escalation in HPV-positive patients, while HPV vaccination is expected to prevent most future cases. Recurrent or metastatic disease is treated with pembrolizumab, alone or with chemotherapy, on KEYNOTE-048.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Oropharyngeal_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Oropharyngeal_cancer"}],"tags":["subtype-page"],"related":["hpv-negative-head-and-neck-cancer","laryngeal-cancer","oral-cavity-cancer","recurrent-metastatic-hnscc"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["de-escalate","orator"],"people":[],"bottlenecks":[],"keyPapers":["paper-keynote-048-lancet-2019","paper-ang-hpv-oropharyngeal-nejm-2010","paper-rtog-1016-lancet-2019","paper-checkmate-141-ferris-nejm-2016"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"The fastest-rising head and neck cancer in high-income countries, now driven mainly by human papillomavirus in men in their fifties and sixties; HPV-positive disease is cured in most cases, HPV-negative disease in far fewer.","subtypes":["HPV-positive (p16-positive) oropharyngeal cancer","HPV-negative (tobacco and alcohol related) oropharyngeal cancer","Tonsil","Base of tongue","Soft palate and pharyngeal wall"],"biomarkers":["p16 immunohistochemistry and HPV DNA or RNA","Smoking history (worsens HPV-positive outlook)","Circulating HPV DNA (surveillance and de-escalation trials)","PD-L1 combined positive score (recurrent disease)","TP53 mutation (HPV-negative)"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Examination and biopsy with p16 and HPV testing, PET-CT, and separate staging for HPV-positive disease.","refs":["hpv-testing"]},{"setting":"Early disease","approach":"Transoral robotic or laser surgery with neck dissection, or radiotherapy alone, chosen by expected function.","refs":["tors","imrt-igrt"]},{"setting":"Locally advanced disease","approach":"Cisplatin chemoradiation (70 Gy); cetuximab only for patients who cannot have cisplatin, since RTOG 1016 and De-ESCALaTE showed it inferior in HPV-positive disease.","refs":["cisplatin","cetuximab","rtog-1016","de-escalate","bonner-cetuximab-rt"]},{"setting":"Recurrent or metastatic","approach":"Pembrolizumab alone for PD-L1-positive disease or with platinum-fluorouracil (KEYNOTE-048); nivolumab after platinum (CheckMate 141).","refs":["pembrolizumab","nivolumab","keynote-048","checkmate-141"]},{"setting":"Prevention","approach":"HPV vaccination of girls and boys; smoking cessation.","refs":["hpv-vaccine","smoking-cessation-after-diagnosis"]}],"stateOfArt":["HPV-positive oropharyngeal cancer has an eighth-edition staging system of its own because its survival is so much better.","De-escalation is the frontier: reduced-dose radiotherapy after induction or surgery, and circulating HPV DNA to pick who can have less, are in phase 2 and 3 trials.","Immunotherapy is standard in recurrent disease and is being tested with chemoradiation in the curative setting."],"history":[{"year":2000,"title":"HPV linked to oropharyngeal cancer","note":"Gillison and colleagues show HPV16 in a distinct subset of tumours.","refs":[]},{"year":2010,"title":"Ang shows HPV status is the dominant prognostic factor","note":"RTOG 0129 analysis: three-year survival 82 versus 57 percent.","refs":[]},{"year":2017,"title":"Separate staging for HPV-positive disease (AJCC 8th edition)","refs":[]},{"year":2019,"title":"RTOG 1016 and De-ESCALaTE: cetuximab inferior to cisplatin","refs":["rtog-1016","de-escalate"]},{"year":2019,"title":"Pembrolizumab first line in recurrent disease (KEYNOTE-048)","refs":["keynote-048"]}],"pipeline":["de-escalate","adaptive-radiotherapy","hpv-vaccine"],"openProblems":["How far treatment can be reduced in HPV-positive disease without losing cures.","HPV-negative oropharyngeal cancer still has poor outcomes.","Long-term swallowing and dry mouth after chemoradiation.","HPV vaccination uptake in boys and in low-income countries."],"parent":"head-and-neck"},{"id":"osteosarcoma","kind":"cancer","name":"Osteosarcoma","aka":[],"tldr":"Osteosarcoma is the most common bone cancer, mostly in teenagers. Chemotherapy plus surgery cures about two-thirds when it has not spread; because no new drug has beaten that chemotherapy in a large trial in 30 years, the next gains are being sought in cellular therapy against GD2, HER2 and B7-H3.","summary":"Osteosarcoma is a high-grade bone sarcoma with chaotic genomes (TP53 and RB1 loss, chromothripsis, no recurrent targetable driver), arising in the metaphyses of long bones during growth spurts and in older adults after Paget disease or radiation. Germline predisposition (Li-Fraumeni, hereditary retinoblastoma, Rothmund-Thomson) accounts for a meaningful fraction.\n\nStandard therapy since the 1980s is neoadjuvant MAP (high-dose methotrexate, doxorubicin, cisplatin), limb-salvage surgery, and adjuvant MAP; histologic response (≥90% necrosis) is prognostic but intensifying therapy for poor responders (EURAMOS-1: adding ifosfamide-etoposide) did not help, nor did interferon maintenance. Mifamurtide (liposomal MTP-PE) is approved in the EU (INT-0133) but not in the US. Lung metastases are resected whenever possible. Relapsed disease has ~20% survival; multikinase inhibitors (regorafenib in SARC024/REGOBONE, cabozantinib in CABONE, sorafenib) give short PFS gains. Novel approaches: GD2- and HER2-directed CAR-T, B7-H3 ADCs, radiopharmaceuticals (Ra-223, Sm-153), and biology from canine osteosarcoma.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Osteosarcoma","links":[{"label":"NCCN Guidelines: Bone Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1418"},{"label":"EURAMOS-1 (Lancet Oncol 2016)","url":"https://doi.org/10.1016/S1470-2045(16)30214-5"},{"label":"NCI PDQ: osteosarcoma","url":"https://www.cancer.gov/types/bone/patient/osteosarcoma-treatment-pdq"}],"tags":["gap-fill","paediatric","sarcoma","aya"],"related":["ewing-sarcoma","chondrosarcoma","chordoma","rhabdomyosarcoma","undifferentiated-pleomorphic-sarcoma"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","limb-salvage-surgery","kinase-inhibitors","carbon-ion","proton-therapy","car-t","radioligand-therapy"],"targets":["gd2","her2","b7h3","tp53","vegf"],"drugs":["methotrexate","doxorubicin","cisplatin","ifosfamide","etoposide","mifamurtide","regorafenib","cabozantinib","docetaxel","radium-223"],"companies":["bayer","exelixis","takeda","childrens-oncology-group"],"institutions":[],"pathways":["p53-cell-cycle","vegf-angiogenesis"],"terms":["fnclcc-grade","limb-salvage-term","histological-response-induction"],"trials":["euramos-1","ccss","nct06935409","cabone","regobone","sarc028"],"people":["stefan-bielack"],"bottlenecks":[],"keyPapers":["paper-marina-lancet-oncol"],"journals":["journal-of-adolescent-and-young-adult-oncology"],"dependsOn":[],"notes":[],"group":"paediatric","burden":"The most common primary bone cancer; ~1,000 cases per year in the US with peaks in adolescence and over 60 (Paget disease, radiation); 5-year survival ~70% localised, ~25% metastatic.","subtypes":["Conventional high-grade (osteoblastic, chondroblastic, fibroblastic)","Telangiectatic","Small cell","Low-grade central and parosteal (surgery alone)","Periosteal (intermediate grade)","Secondary (Paget, post-radiation)"],"biomarkers":["Histologic necrosis after neoadjuvant chemotherapy (≥90% good response)","Alkaline phosphatase and LDH","Metastases at diagnosis (lung, bone)","Germline TP53 / RB1 / RECQL4","GD2, HER2, B7-H3 expression (trial eligibility)","ctDNA copy-number burden (prognostic, emerging)"],"standardOfCare":[{"setting":"Localised high-grade","approach":"Neoadjuvant MAP (methotrexate, doxorubicin, cisplatin) ×2 cycles, limb-salvage resection with wide margins (amputation if required), adjuvant MAP to ~29 weeks; mifamurtide added in EU.","refs":["methotrexate","doxorubicin","cisplatin","mifamurtide","limb-salvage-surgery"],"guideline":{"nccn":"Category 1 (MAP)","version":"NCCN Guidelines: Bone Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1418"}},{"setting":"Metastatic at diagnosis","approach":"Same chemotherapy with resection of all metastases (thoracotomy) when feasible; survival ~25-30%.","refs":["methotrexate","doxorubicin","cisplatin","ifosfamide","etoposide"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Bone Cancer"}},{"setting":"Relapsed","approach":"Surgical resection of recurrence; ifosfamide ± etoposide, gemcitabine-docetaxel; regorafenib or cabozantinib; clinical trials (CAR-T, ADCs).","refs":["ifosfamide","etoposide","regorafenib","cabozantinib","docetaxel"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Bone Cancer"}},{"setting":"Unresectable / axial","approach":"Carbon-ion or proton radiotherapy for craniofacial and pelvic tumours; Sm-153 or Ra-223 for bone-forming metastases (investigational).","refs":["carbon-ion","proton-therapy","radium-223"]}],"stateOfArt":["MAP chemotherapy, unchanged since the 1980s, remains the standard; EURAMOS-1 (2,260 patients) closed the door on intensification.","Limb salvage is possible in >90% with expandable prostheses for growing children.","Multikinase inhibitors are the only agents with randomised evidence at relapse, and the gain is months.","Immunotherapy has largely failed (checkpoint inhibitors inactive); cellular therapy against GD2/HER2/B7-H3 is the active frontier."],"history":[{"year":1970,"title":"Amputation alone cures <20%; lung metastases the rule","refs":[]},{"year":1972,"title":"High-dose methotrexate with leucovorin rescue (Jaffe) and adriamycin (Cortes) show activity","refs":["methotrexate","doxorubicin"]},{"year":1979,"title":"Rosen's T-10: neoadjuvant chemotherapy and limb salvage","refs":["limb-salvage-surgery"]},{"year":1986,"title":"Randomised proof that adjuvant chemotherapy cures (Link, NEJM; MIOS)","refs":[]},{"year":2008,"title":"INT-0133: mifamurtide improves overall survival; EU approval 2009","refs":["mifamurtide"]},{"year":2016,"title":"EURAMOS-1: no benefit from intensifying for poor responders or interferon for good responders","refs":[]},{"year":2019,"title":"Regorafenib (SARC024, REGOBONE) and cabozantinib (CABONE) show activity at relapse","refs":["regorafenib","cabozantinib"]}],"pipeline":["regorafenib","cabozantinib","car-t","radium-223","b7h3","hs-20093","cobolimab","vactosertib"],"openProblems":["No survival improvement since the 1980s; metastatic and relapsed disease ~20-30% survival.","No recurrent druggable driver; genomic chaos.","Chemotherapy toxicity: cardiotoxicity, hearing loss, infertility, second cancers.","Rarity fragments trials; international cooperation (EURAMOS) needed for every question."],"parent":"sarcoma"},{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","aka":["OV","TCGA-OV","ovarian serous cystadenocarcinoma (TCGA OV cohort)","Fallopian Tube Cancer","Primary Peritoneal Cancer"],"tldr":"Usually found late. PARP inhibitors transformed maintenance therapy, and ADCs against folate receptor and CDH6 are arriving for platinum-resistant disease.","summary":"Ovarian cancer is a group of diseases (~320,000 new cases a year) dominated by high-grade serous carcinoma, which arises in the fallopian tube, is almost always TP53-mutant, and is diagnosed at stage III-IV in three-quarters of women because there is no symptom or screening test that catches it early. Roughly half of high-grade serous tumours have homologous recombination deficiency, including ~20% with germline or somatic BRCA1/2 mutations. Low-grade serous, endometrioid, clear-cell, and mucinous carcinomas are biologically distinct and respond differently to treatment.\n\nThe standard of care is maximal cytoreductive surgery (primary or interval, after neoadjuvant carboplatin-paclitaxel), sometimes with HIPEC, followed by maintenance therapy chosen by biomarker: olaparib for BRCA-mutated disease (SOLO-1, 7-year OS 67% vs 47%), olaparib plus bevacizumab for HRD-positive disease (PAOLA-1), niraparib for the rest with declining enthusiasm after PRIMA showed no survival gain. Platinum-sensitive relapse is treated with platinum doublets and secondary surgery in selected patients (DESKTOP III); PARP inhibitors are re-used less since later-line safety signals. Platinum-resistant disease, historically the hardest setting, now has three new options with survival benefit: mirvetuximab soravtansine for FRα-high tumours (MIRASOL), relacorilant plus nab-paclitaxel (ROSELLA, approved 2026), and pembrolizumab plus weekly paclitaxel for PD-L1-positive tumours (KEYNOTE-B96, approved February 2026, the first immunotherapy in ovarian cancer). Low-grade serous carcinoma gained its first dedicated therapy in avutometinib plus defactinib (2025).\n\nWhat comes next: folate-receptor ADCs that work regardless of expression level (rinatabart sesutecan, luveltamab tazevibulin), a CDH6 ADC (raludotatug deruxtecan) in phase 3, ATR and WEE1 inhibitors for PARP-resistant disease, and prevention by opportunistic salpingectomy now that the tubal origin is accepted. Screening remains unsolved after UKCTOCS; multi-cancer blood tests are the only live hope.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Ovarian_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Ovarian_cancer"}],"tags":["gyn","spike"],"related":["parp-plus-bevacizumab","hipec-at-interval-surgery","caution-pd1-first-line-ovarian","adc-generations","ovarian-cancer-research-alliance","paediatric-germ-cell-tumours","idea-targeting-aneuploidy"],"cancers":[],"sections":[],"technologies":["parp-inhibitor","adc","hipec","hrd-testing","synthetic-lethality-approaches","mced","risk-reducing-salpingectomy","germline-testing","ultrasound","robotic-surgery"],"targets":["brca","parp","folr1","cdh6","wee1","atr","tp53","mesothelin","cldn6","kras","vegf","pdl1","pd1"],"drugs":["thiotepa","amifostine","talc-sclerosant","catumaxomab"],"companies":["nanjing-leads-biolabs","bioinvent-international","haihe-biopharma","shenzhen-ionova-life-sciences","scancell","astrazeneca","merck","gsk","abbvie","corcept","verastem","genmab","sutro-biopharma","daiichi-sankyo","roche-genentech"],"institutions":[],"pathways":["ddr","p53-cell-cycle"],"terms":["ca-125","lgsoc","hgsoc","cps"],"trials":["nct04498117","nct06394492","nct06834672","nct06855069","nct07214779","nct07546500","nct05281471","nct04169997","nct07218809","nct07213804","nct04921527","nct03949283","nct07109414","nct06828354","nct05445778","nct04884360","nct07219238","nct07318558","nct06994195","nct06824467","nct06072781","nct05804370","nct07604766","nct06819007","nct04421963","nct06619236","nct07225270","nct06915025","nct07564141","nct01874353","nct03602859","nct07286266"],"people":["robert-coleman"],"bottlenecks":[],"keyPapers":["paper-brca-risk-reducing-surgery-jama-2010"],"journals":["international-journal-of-gynecological-cancer","journal-of-gynecologic-oncology"],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"Ovarian cancer accounts for ~320,000 cases per year worldwide. PARP-inhibitor maintenance has turned BRCA-mutated disease into one where two-thirds of women are alive at seven years, and three new treatments that extend life arrived for platinum-resistant disease in three years. Because most cases are found at stage III-IV, it remains the gynaecologic cancer with the lowest survival: 5-year survival ~50% overall and under 30% for stage IV; ~200,000 deaths per year.","subtypes":["High-grade serous carcinoma (~70%; TP53-mutant, tubal origin)","Low-grade serous carcinoma (~5%; KRAS/BRAF, ER+, chemoresistant)","Endometrioid carcinoma (~10%; often with endometriosis; CTNNB1, PTEN, MMR)","Clear-cell carcinoma (~10%; ARID1A, PIK3CA; platinum-resistant; higher in East Asia)","Mucinous carcinoma (~3%; KRAS, HER2 amplification; often gastrointestinal-like)","Carcinosarcoma and other rare types","Germ-cell and sex-cord stromal tumours (young women; highly curable)"],"biomarkers":["BRCA1/2 (germline and somatic)","HRD (myChoice)","FRα IHC","CDH6","CA-125","PD-L1","Germline and somatic BRCA1/2","HRD genomic instability score (myChoice CDx, FoundationOne)","Folate receptor alpha IHC (≥75% of cells at 2+ for mirvetuximab)","PD-L1 CPS ≥1 (pembrolizumab, KEYNOTE-B96)","KRAS/BRAF/NRAS (low-grade serous)","CA-125 and HE4 (monitoring, ROMA index)","Platinum-free interval (defines sensitive vs resistant)","MMR/MSI (endometrioid, clear-cell)","HER2 (mucinous, some clear-cell)"],"standardOfCare":[{"setting":"Newly diagnosed","approach":"Surgery + platinum-taxane ± bevacizumab ± HIPEC; PARP maintenance by HRD status.","refs":["carboplatin","paclitaxel","hipec","olaparib","niraparib"],"guideline":{"version":"NCCN Guidelines: Ovarian Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1453"}},{"setting":"Platinum-sensitive relapse","approach":"Platinum doublet + PARP maintenance; secondary cytoreduction in selected cases.","refs":[],"guideline":{"version":"NCCN Guidelines: Ovarian Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1453"}},{"setting":"Platinum-resistant","approach":"Mirvetuximab (FRα-high), relacorilant + nab-paclitaxel, pembrolizumab (PD-L1+), single-agent chemotherapy.","refs":["mirvetuximab-soravtansine","relacorilant","pembrolizumab"],"guideline":{"esmoMcbs":"2 (SORAYA mirvetuximab, single-arm)","version":"NCCN Guidelines: Ovarian Cancer","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11163648/"}},{"setting":"Prevention and risk","approach":"Germline testing for all patients; risk-reducing salpingo-oophorectomy for BRCA carriers (age 35-45); opportunistic salpingectomy at pelvic surgery for average-risk women; oral contraceptives reduce risk. No population screening (UKCTOCS negative).","refs":["germline-testing","risk-reducing-salpingectomy","chemoprevention","ukctocs"],"guideline":{"nccn":"Genetic/Familial High-Risk Assessment v2.2026","url":"https://www.nccn.org/guidelines/category_2"}},{"setting":"Newly diagnosed stage I-II","approach":"Complete surgical staging; adjuvant carboplatin-paclitaxel for high-grade or stage IC-II disease; observation for low-risk stage IA-IB grade 1-2.","refs":["carboplatin","paclitaxel","robotic-surgery"],"guideline":{"nccn":"1"}},{"setting":"Newly diagnosed stage III-IV: surgery and chemotherapy","approach":"Primary debulking if complete resection is feasible, else 3 cycles neoadjuvant carboplatin-paclitaxel then interval debulking (with HIPEC in stage III, OVHIPEC-1) and 3 more cycles; add bevacizumab for high-risk or residual disease.","refs":["carboplatin","paclitaxel","hipec","ovhipec-1","bevacizumab","gog-0218-icon7"],"guideline":{"nccn":"1 (chemotherapy); 2A (HIPEC)"}},{"setting":"First-line maintenance, BRCA-mutated","approach":"Olaparib 2 years (SOLO-1) or olaparib + bevacizumab (PAOLA-1) or niraparib 3 years (PRIMA).","refs":["olaparib","solo-1","paola-1","niraparib","prima"],"guideline":{"nccn":"1","esmoMcbs":"A","url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-gynaecological-cancers/"}},{"setting":"First-line maintenance, HRD-positive BRCA-wild-type","approach":"Olaparib + bevacizumab (PAOLA-1, OS benefit) or niraparib (PRIMA, PFS only).","refs":["olaparib","bevacizumab","paola-1","niraparib","hrd-testing","parp-plus-bevacizumab"],"guideline":{"nccn":"1"}},{"setting":"First-line maintenance, HRD-negative","approach":"Bevacizumab continuation if started; niraparib is an option with small PFS benefit and no OS benefit (PRIMA); observation is reasonable.","refs":["bevacizumab","niraparib","prima"],"guideline":{"nccn":"2A"}},{"setting":"Platinum-sensitive relapse (interval >6 months)","approach":"Secondary cytoreduction if AGO-score positive (DESKTOP III); platinum doublet (carboplatin with PLD, paclitaxel, or gemcitabine) ± bevacizumab; PARP maintenance if PARP-naive and BRCA/HRD-positive.","refs":["desktop-iii","carboplatin","pegylated-liposomal-doxorubicin","bevacizumab","olaparib","niraparib","rucaparib"],"guideline":{"nccn":"1 (surgery in selected); 2A"}},{"setting":"Platinum-resistant relapse, FRα-high","approach":"Mirvetuximab soravtansine (MIRASOL, OS benefit) with ophthalmic prophylaxis.","refs":["mirvetuximab-soravtansine","mirasol","folr1"],"guideline":{"nccn":"1","esmoMcbs":"4"}},{"setting":"Platinum-resistant relapse, PD-L1 CPS ≥1","approach":"Pembrolizumab + weekly paclitaxel ± bevacizumab (KEYNOTE-B96, approved Feb 2026).","refs":["pembrolizumab","paclitaxel","bevacizumab","keynote-b96"],"guideline":{"nccn":"1 (2026 update)"}},{"setting":"Platinum-resistant relapse, other","approach":"Relacorilant + nab-paclitaxel (ROSELLA, approved 2026); single-agent weekly paclitaxel, PLD, or topotecan ± bevacizumab (AURELIA); clinical trials of FRα and CDH6 ADCs.","refs":["relacorilant","rosella","pegylated-liposomal-doxorubicin","bevacizumab","rinatabart-sesutecan","raludotatug-deruxtecan","aurelia"],"guideline":{"nccn":"2A"}},{"setting":"Low-grade serous carcinoma","approach":"Surgery; endocrine maintenance (letrozole) after chemotherapy or instead of it; at recurrence, avutometinib + defactinib if KRAS-mutated (2025), trametinib, or endocrine therapy.","refs":["letrozole","avutometinib-defactinib","ramp-201","lgsoc"],"guideline":{"nccn":"2A"}},{"setting":"Rare histologies","approach":"Clear-cell: platinum-based therapy, trials of immunotherapy and ARID1A-directed agents; mucinous: consider GI regimens and HER2 testing; germ-cell: BEP chemotherapy with >90% cure.","refs":["platinum","checkpoint-inhibitor"]}],"stateOfArt":["PARP maintenance with 7-year OS benefit in BRCA (SOLO-1).","First ADC (mirvetuximab) with OS benefit.","Biomarker-directed maintenance after first-line chemotherapy: olaparib for BRCA (7-year OS 67% vs 47%), olaparib + bevacizumab for HRD-positive disease.","Three new options with overall survival benefit in platinum-resistant disease within three years: mirvetuximab (FRα-high), relacorilant + nab-paclitaxel, and pembrolizumab + paclitaxel (PD-L1-positive, first immunotherapy approval in ovarian cancer, February 2026).","First treatment designed for low-grade serous carcinoma (avutometinib + defactinib, May 2025).","Surgery is evidence-based at both ends: HIPEC at interval debulking adds ~12 months of survival; selected secondary cytoreduction at relapse adds ~8 months.","Prevention by opportunistic salpingectomy is now routine policy in several countries because the tubal origin of high-grade serous cancer is accepted.","Germline and HRD testing at diagnosis is standard and changes treatment for roughly half of patients."],"history":[{"year":1976,"title":"Cisplatin transforms ovarian cancer chemotherapy","note":"First platinum responses in refractory disease; carboplatin follows in the 1980s.","refs":[]},{"year":1994,"title":"BRCA1 cloned; hereditary ovarian cancer explained","note":"BRCA2 in 1995; germline testing enters clinical practice over the next decade.","refs":["brca"]},{"year":1996,"title":"Paclitaxel-cisplatin standard","refs":[]},{"year":1996,"title":"Paclitaxel-cisplatin becomes standard (GOG-111)","refs":["paclitaxel","platinum"]},{"year":2005,"title":"Synthetic lethality of PARP inhibition in BRCA-deficient cells","note":"Farmer and Bryant papers in Nature set up the PARP inhibitor era.","refs":["parp","synthetic-lethality"]},{"year":2007,"title":"Fallopian tube identified as origin of high-grade serous cancer","note":"Serous tubal intraepithelial carcinoma described in BRCA carriers' prophylactic specimens; leads to salpingectomy-based prevention.","refs":["hgsoc","risk-reducing-salpingectomy"]},{"year":2011,"title":"Bevacizumab improves PFS (GOG-0218, ICON7)","refs":["gog-0218-icon7","bevacizumab"]},{"year":2014,"title":"Olaparib: first PARP inhibitor","refs":["olaparib"]},{"year":2014,"title":"Olaparib: first PARP inhibitor approved","note":"For germline BRCA-mutated ovarian cancer after three lines.","refs":["olaparib"]},{"year":2018,"title":"SOLO-1 and OVHIPEC-1","note":"Two years of first-line olaparib maintenance (PFS HR 0.30) and HIPEC at interval surgery (OS +12 months) both reported.","refs":["solo-1","ovhipec-1"]},{"year":2019,"title":"PARP maintenance extends beyond BRCA","note":"PRIMA (niraparib, all comers) and PAOLA-1 (olaparib + bevacizumab, HRD-positive).","refs":["prima","paola-1"]},{"year":2021,"title":"UKCTOCS: screening does not save lives; DESKTOP III: selected surgery at relapse does","refs":["ukctocs","desktop-iii"]},{"year":2022,"title":"Mirvetuximab: first ovarian ADC","refs":["mirvetuximab-soravtansine"]},{"year":2022,"title":"Mirvetuximab soravtansine: first ovarian ADC","note":"Accelerated approval; full approval after MIRASOL OS benefit in 2024.","refs":["mirvetuximab-soravtansine","mirasol"]},{"year":2023,"title":"SOLO-1 7-year OS benefit; PARP later-line labels narrowed","note":"First-line maintenance benefit confirmed while later-line PARP use retreats after OS imbalances (ARIEL4, SOLO3).","refs":["solo-1","rucaparib"]},{"year":2025,"title":"First LGSOC therapy (avutometinib + defactinib); ROSELLA and KEYNOTE-B96 positive","refs":["avutometinib-defactinib","ramp-201","rosella","keynote-b96"]},{"year":2026,"title":"Relacorilant and pembrolizumab approved in platinum-resistant disease","refs":["relacorilant"]},{"year":2026,"title":"Relacorilant and pembrolizumab approved in platinum-resistant disease","note":"First immunotherapy approval in ovarian cancer (February 2026).","refs":["relacorilant","pembrolizumab","keynote-b96"]}],"pipeline":["raludotatug-deruxtecan","puxitatug-samrotecan","parp-pet","galleri","pf-08634404","in10018","ipatasertib","saruparib","oregovomab","hlx43","shr-a1921","ibi354","gotistobart","hs-20089","incb123667","azenosertib","olvimulogene-nanivacirepvec","imp4927","azd5335","sofetabart-mipitecan","chiauranib","avzo-021","xnw27011","jk08","palacaparib","lorigerlimab","utomilumab","azd8421","tilt-123","pamiparib","cyh33","vudalimab","upifitamab-rilsodotin","theo-260","vb15010","nuv-1511","rinatabart-sesutecan","rainfol-01","luveltamab-tazevibulin","rejoice-ovarian01","avutometinib-defactinib","wee1","atr","risk-reducing-salpingectomy","idea-fra-adc-sequencing-ovarian","idea-ctdna-guided-parp-duration"],"openProblems":["No effective screening.","PARP resistance via BRCA reversion.","Platinum-resistant disease is the hardest setting; three drugs with survival benefit arrived in 2023-26 and each adds months, so combining and sequencing them is the next step.","Screening is unsolved: the UKCTOCS trial found no mortality reduction, so three-quarters of patients are still diagnosed at stage III-IV; opportunistic salpingectomy and multi-cancer blood tests are the live routes.","Platinum resistance is eventually near-universal in high-grade serous disease, and each new drug adds months, not years.","PARP inhibitor resistance (BRCA reversion, restored fork protection) has no approved counter; later-line PARP use has been curtailed by OS signals.","Immunotherapy fails in first-line disease; benefit is confined to PD-L1-positive platinum-resistant tumours.","Clear-cell, mucinous, and carcinosarcoma have no subtype-specific approved therapy.","FRα-low patients are excluded from mirvetuximab; next-generation ADCs are not yet approved.","Access to HRD testing, PARP inhibitors, and ADCs is limited outside high-income countries.","Optimal duration of maintenance and ctDNA-guided de-escalation are untested."],"prognosis":{"text":"In the United States, 52% of women diagnosed with ovarian cancer in 2016-2022 were alive five years later, relative to women of the same age without the disease. The problem is late diagnosis: 54% of cases are found after distant spread, with five-year relative survival of 31.5%, against 91.9% for the 22% found while confined to the ovary and 70.1% for regional disease (18% of cases). The figures cover the years PARP inhibitor maintenance was being adopted and only partly reflect it.","sources":[{"label":"SEER Cancer Stat Facts: Ovarian Cancer","url":"https://seer.cancer.gov/statfacts/html/ovary.html"}]}},{"id":"endometrial-p53-abnormal","kind":"cancer","name":"p53-abnormal endometrial cancer, including uterine serous carcinoma","aka":["p53abn endometrial cancer","Copy-number-high endometrial cancer","Uterine serous carcinoma","Uterine papillary serous carcinoma","Serous-like endometrial cancer"],"tldr":"p53-abnormal endometrial cancer is the aggressive class, dominated by serous carcinoma, whose cells have lost the p53 guardian gene and carry scrambled chromosomes. It is the one group that clearly gains from adding chemotherapy to radiotherapy after surgery, and about a quarter of serous tumours overexpress HER2, which trastuzumab and trastuzumab deruxtecan can target.","summary":"Abnormal p53 immunohistochemistry, either strong diffuse nuclear staining or complete absence, marks a TP53 mutation and defines the copy-number-high class of the TCGA. Uterine serous carcinoma is its archetype: a tumour of older, often thinner women that arises from atrophic endometrium through serous endometrial intraepithelial carcinoma, spreads through the peritoneum like ovarian cancer and is p53-abnormal in almost every case. Carcinosarcoma, clear cell carcinoma and a fifth of grade 3 endometrioid tumours also fall into the class. HER2 is amplified or overexpressed in about a quarter to a third of serous carcinomas, PIK3CA and PPP2R1A mutations are common, and there are no POLE or mismatch-repair defects. Even stage IA disease confined to a polyp can recur at a distance, so full staging with omental sampling is standard.\n\nPORTEC-3 randomised women with high-risk endometrial cancer to pelvic radiotherapy alone or chemoradiation followed by four cycles of carboplatin-paclitaxel; overall survival at five years was 81.4 percent against 76.1 percent, with a hazard ratio of 0.70, and the molecular analysis showed the benefit was concentrated in p53-abnormal tumours, which had the worst outcome of the four classes and the largest absolute gain from chemotherapy. The ESGO/ESTRO/ESP guideline therefore recommends chemotherapy with or without radiotherapy for p53-abnormal disease from stage I with myometrial invasion onwards. For HER2-positive serous carcinoma a randomised phase 2 trial added trastuzumab to carboplatin-paclitaxel and improved progression-free and overall survival, which the NCCN adopted for advanced and recurrent disease. In DESTINY-PanTumor02 trastuzumab deruxtecan produced responses in 57.5 percent of HER2-expressing endometrial cancers and 84.6 percent of those with 3+ staining, earning a tumour-agnostic approval for HER2 3+ tumours in 2024.\n\nThe RAINBO p53abn-RED trial is testing adjuvant chemoradiation with or without the PARP inhibitor olaparib, on the grounds that p53-abnormal tumours share homologous recombination defects with high-grade serous ovarian cancer. DESTINY-Endometrial01 is testing trastuzumab deruxtecan with pembrolizumab or rilvegostomig in the first line for HER2-expressing disease, and WEE1 and ATR inhibitors are in earlier trials because p53-null cells depend on the remaining cell-cycle checkpoints. Checkpoint inhibitors have modest activity in the class, and these are the tumours that most need new drugs.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Uterine_serous_carcinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Uterine_serous_carcinoma"}],"tags":["subtype-page"],"related":["advanced-recurrent-endometrial-cancer","endometrial-nsmp","endometrial-mmr-deficient","endometrial-pole-ultramutated","uterine-carcinosarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-promise-talhouk-cancer-2017","paper-tcga-endometrial-nature-2013","paper-portec-3-lancet-oncol-2018","paper-fader-trastuzumab-uterine-serous-jco-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"About fifteen percent of endometrial cancers but more than half of the deaths; the class includes most serous carcinomas, most carcinosarcomas and a share of grade 3 endometrioid and clear cell tumours, and it recurs distantly even when caught at an early stage.","subtypes":["Uterine serous carcinoma (p53-abnormal in nearly all cases)","HER2-positive serous carcinoma (about a quarter to a third)","Serous endometrial intraepithelial carcinoma (precursor)","p53-abnormal grade 3 endometrioid carcinoma","p53-abnormal clear cell carcinoma","Carcinosarcoma (biphasic, usually p53-abnormal)","Stage I to III p53abn (RAINBO p53abn-RED, chemoradiation with or without olaparib)"],"biomarkers":["p53 immunohistochemistry (mutant-pattern staining or null)","TP53 sequencing where staining is equivocal","HER2 immunohistochemistry and in situ hybridisation (serous and carcinosarcoma)","Copy-number burden and homologous recombination deficiency","CA-125 for monitoring","PIK3CA, PPP2R1A and FBXW7 mutations"],"standardOfCare":[{"setting":"Surgery and staging","approach":"Hysterectomy with bilateral salpingo-oophorectomy, sentinel node mapping and omental sampling, with peritoneal assessment because serous tumours spread like ovarian cancer.","refs":["hysterectomy","sentinel-node","robotic-surgery","histopathology-ihc"]},{"setting":"Adjuvant, stage I to III","approach":"Carboplatin-paclitaxel chemotherapy, with pelvic radiotherapy and vaginal brachytherapy as in PORTEC-3; chemotherapy is recommended for all p53-abnormal tumours with myometrial invasion.","refs":["portec-3","carboplatin","paclitaxel","imrt-igrt","brachytherapy","tp53"]},{"setting":"Advanced or recurrent HER2-positive serous","approach":"Trastuzumab added to carboplatin-paclitaxel and continued as maintenance; trastuzumab deruxtecan for HER2-expressing disease after chemotherapy (DESTINY-PanTumor02).","refs":["trastuzumab","trastuzumab-deruxtecan","destiny-pantumor02","her2"]},{"setting":"Advanced or recurrent HER2-negative","approach":"Carboplatin-paclitaxel with dostarlimab or pembrolizumab as for other endometrial cancers, though the immunotherapy gain is smaller in mismatch-repair-proficient disease; lenvatinib-pembrolizumab after platinum.","refs":["carboplatin","paclitaxel","dostarlimab","pembrolizumab","ruby","keynote-775"]}],"stateOfArt":["PORTEC-3 molecular analysis showed chemotherapy's benefit is concentrated in p53-abnormal tumours, which drives current adjuvant guidelines.","HER2 is the first targetable driver in serous carcinoma, with trastuzumab in the first line and trastuzumab deruxtecan afterwards.","RAINBO p53abn-RED is testing olaparib on the ovarian-cancer analogy."],"history":[{"year":1982,"title":"Hendrickson describes uterine papillary serous carcinoma as a distinct aggressive type","refs":[]},{"year":2013,"title":"TCGA defines the copy-number-high, serous-like class","refs":["endometrial-molecular-classes","tp53"]},{"year":2018,"title":"PORTEC-3: chemoradiation plus chemotherapy improves survival in high-risk disease","refs":["portec-3"]},{"year":2018,"title":"Randomised phase 2: trastuzumab with carboplatin-paclitaxel improves survival in HER2-positive serous carcinoma","refs":["trastuzumab","her2"]},{"year":2020,"title":"PORTEC-3 molecular analysis: chemotherapy benefit concentrated in p53-abnormal tumours","refs":["portec-3"]},{"year":2024,"title":"Trastuzumab deruxtecan approved for HER2 3+ solid tumours after DESTINY-PanTumor02","refs":["trastuzumab-deruxtecan","destiny-pantumor02"]}],"pipeline":["nct06989112","trastuzumab-deruxtecan","olaparib","idea-her2-adc-serous-endometrial","wee1","atr","sacituzumab-tirumotecan"],"openProblems":["Distant relapse after early-stage disease despite chemotherapy.","Whether PARP inhibition helps p53-abnormal tumours as it does ovarian cancer.","Low response to immunotherapy in a class that accounts for most deaths."],"parent":"endometrial"},{"id":"paediatric-high-grade-glioma","kind":"cancer","name":"Paediatric high-grade glioma (excluding diffuse midline glioma)","aka":["pHGG","Childhood high-grade glioma","Paediatric glioblastoma","Diffuse hemispheric glioma, H3 G34-mutant","Infant-type hemispheric glioma"],"tldr":"High-grade gliomas in children look like adult glioblastoma under the microscope but are driven by different genes, so they are now classified separately. Surgery and radiotherapy remain the mainstay and chemotherapy adds little; the real gains are in small subsets with a targetable gene change, such as BRAF V600E tumours and the fusion-driven tumours of infants.","summary":"WHO 2021 separates paediatric-type diffuse high-grade gliomas from adult glioblastoma into four types: diffuse midline glioma, H3 K27-altered (covered on its own page); diffuse hemispheric glioma, H3 G34-mutant, of adolescents and young adults with TP53 and ATRX mutations; diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, with PDGFRA amplification, MYCN amplification or EGFR alteration defining methylation subgroups; and infant-type hemispheric glioma, defined by NTRK, ALK, ROS1 or MET fusions in children under about three. Hypermutant tumours arising in constitutional mismatch repair deficiency and radiation-induced gliomas after treatment of another childhood cancer are distinct further groups. Methylation profiling is essential because morphology cannot separate these entities and some low-grade-appearing tumours prove high grade molecularly.\n\nTreatment is maximal safe resection followed by focal radiotherapy, with temozolomide during and after radiotherapy adopted from adult practice although the ACNS0126 study did not show it clearly improved on historical outcomes; the HERBY trial (2018) showed adding bevacizumab did not help. Radiotherapy is deferred or avoided in infants, whose tumours are chemosensitive and in whom fusion-directed drugs work: larotrectinib and entrectinib for NTRK fusions, alectinib or lorlatinib for ALK and ROS1 fusions, with responses that can allow less surgery. In BRAF V600E-mutant high-grade glioma dabrafenib plus trametinib produced durable responses in the paediatric cohort reported in 2023, and the combination has a tumour-agnostic approval for BRAF V600E solid tumours from the age of six. Constitutional mismatch repair deficiency tumours respond to PD-1 blockade.\n\nThe outlook for H3 G34-mutant and H3- and IDH-wildtype tumours has changed little; the pipeline includes CDK4/6 inhibition with temozolomide after radiotherapy, IDH inhibitors for the rare IDH-mutant adolescent tumours, CAR-T cells directed at GD2 and B7-H3 delivered into the ventricles, oncolytic viruses and focused-ultrasound opening of the blood-brain barrier. Late effects of radiotherapy on the developing brain weigh on every decision.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Glioma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Glioma"},{"label":"NCI PDQ: childhood astrocytomas, other gliomas and glioneuronal tumours","url":"https://www.cancer.gov/types/brain/hp/child-astrocytoma-treament-pdq"}],"tags":["subtype-page","cns","paediatric"],"related":["dipg-dmg","paediatric-low-grade-glioma","glioblastoma","brain-tumours","childhood-cancers","idh-mutant-astrocytoma","oligodendroglioma"],"cancers":[],"sections":[],"technologies":["methylation-profiling","imrt-igrt","proton-therapy","glioma-car-t"],"targets":["braf","mek","ntrk","alk","ros1","tp53"],"drugs":["dabrafenib-trametinib","dabrafenib","trametinib","temozolomide","larotrectinib","entrectinib","alectinib","lorlatinib"],"companies":["childrens-oncology-group"],"institutions":["siop-europe"],"pathways":["ras-mapk","glioma-signalling"],"terms":["h3k27m","late-effects","re-irradiation"],"trials":["herby"],"people":[],"bottlenecks":["b-rare-cancers"],"keyPapers":["paper-who-2021-cns-louis-neuro-oncology-2021","paper-mackay-paediatric-hgg-cancer-cell-2017","paper-hargrave-dabrafenib-trametinib-paediatric-hgg-jco-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"A minority of childhood brain tumours but a leading cause of death among them; most children with hemispheric high-grade glioma die within a few years of diagnosis, while infants with fusion-driven tumours can do far better.","subtypes":["Diffuse hemispheric glioma, H3 G34-mutant (adolescents; TP53 and ATRX)","Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (grade 4; PDGFRA, MYCN or EGFR subgroups)","Infant-type hemispheric glioma (NTRK, ALK, ROS1 or MET fusion)","BRAF V600E-mutant high-grade glioma (including transformed pleomorphic xanthoastrocytoma)","Hypermutant glioma in constitutional mismatch repair deficiency","Radiation-induced glioma after treatment of an earlier childhood cancer"],"biomarkers":["H3 G34 mutation (H3F3A) and, to exclude diffuse midline glioma, H3 K27 status","IDH1/IDH2 (wildtype in most; mutant in some adolescents)","NTRK, ALK, ROS1 and MET fusions in infants","BRAF V600E with CDKN2A deletion","PDGFRA, MYCN and EGFR amplification","Mismatch repair protein loss and tumour mutation burden (constitutional mismatch repair deficiency)","DNA methylation class"],"standardOfCare":[{"setting":"Newly diagnosed, child over about three years","approach":"Maximal safe resection, focal radiotherapy and temozolomide during and after radiotherapy by extrapolation from adult practice; molecular profiling of every tumour.","refs":["imrt-igrt","proton-therapy","temozolomide","methylation-profiling"],"guideline":{"version":"NCI PDQ: childhood astrocytomas, other gliomas and glioneuronal tumours","url":"https://www.cancer.gov/types/brain/hp/child-astrocytoma-treament-pdq"}},{"setting":"Infant-type hemispheric glioma with a fusion","approach":"Surgery and fusion-directed therapy: larotrectinib or entrectinib for NTRK fusions, alectinib or lorlatinib for ALK or ROS1 fusions; chemotherapy to defer radiotherapy.","refs":["larotrectinib","entrectinib","alectinib","lorlatinib"],"guideline":{"version":"NCI PDQ: childhood astrocytomas, other gliomas and glioneuronal tumours","url":"https://www.cancer.gov/types/brain/hp/child-astrocytoma-treament-pdq"}},{"setting":"BRAF V600E-mutant","approach":"Dabrafenib plus trametinib (paediatric high-grade glioma cohort 2023; tumour-agnostic approval for BRAF V600E solid tumours from age six).","refs":["dabrafenib-trametinib","dabrafenib","trametinib"],"guideline":{"version":"FDA label 2022 to 2023; NCI PDQ"}},{"setting":"Constitutional mismatch repair deficiency","approach":"PD-1 blockade (nivolumab or pembrolizumab) for hypermutant tumours; germline counselling for the family.","refs":["nivolumab","pembrolizumab","germline-testing"]},{"setting":"Recurrence","approach":"No standard; re-resection, re-irradiation, clinical trials including CAR-T and oncolytic virus studies.","refs":["re-irradiation","glioma-car-t"]}],"stateOfArt":["Molecular classification has split paediatric high-grade glioma into biologically distinct types, each with a different outlook and, for two of them, a targeted drug.","Fusion-driven infant gliomas are now among the most treatable high-grade brain tumours.","For the common H3- and IDH-wildtype and H3 G34-mutant tumours, surgery and radiotherapy remain the only treatments with proven benefit."],"history":[{"year":1989,"title":"CCG-943: chemotherapy adds to radiotherapy in childhood high-grade glioma","note":"Sposto and colleagues, the first randomised evidence for adjuvant chemotherapy in children.","refs":[]},{"year":2012,"title":"Histone H3 mutations discovered in paediatric glioma","note":"Schwartzentruber and colleagues (Nature) and Wu and colleagues (Nature Genetics) find H3.3 K27M and G34 mutations.","refs":[]},{"year":2018,"title":"HERBY: bevacizumab adds nothing to radiotherapy and temozolomide","note":"Grill and colleagues (JCO).","refs":["bevacizumab-glioma","temozolomide"]},{"year":2021,"title":"WHO 2021 defines four paediatric-type diffuse high-grade gliomas","refs":[]},{"year":2022,"title":"Tumour-agnostic approval of dabrafenib plus trametinib for BRAF V600E solid tumours, including high-grade glioma","refs":["dabrafenib-trametinib"]},{"year":2023,"title":"Dabrafenib plus trametinib in BRAF V600E paediatric high-grade glioma","note":"Hargrave and colleagues (JCO) report durable responses in the paediatric cohort.","refs":["dabrafenib-trametinib","dabrafenib","trametinib"]}],"pipeline":["dabrafenib-trametinib","larotrectinib","entrectinib","glioma-car-t","bbb-focused-ultrasound","methylation-profiling"],"openProblems":["No systemic therapy has improved survival in H3 G34-mutant or H3- and IDH-wildtype tumours.","How long to continue fusion or BRAF inhibitors in children who respond, and what happens on stopping.","Radiotherapy to the developing brain costs cognition and growth; avoiding it in infants depends on drugs that reach the brain.","Small numbers make randomised trials slow; international platform trials are the answer being tried."],"parent":"glioblastoma"},{"id":"paediatric-low-grade-glioma","kind":"cancer","name":"Paediatric low-grade glioma","aka":["Childhood astrocytoma","pLGG","Pilocytic astrocytoma","Optic pathway glioma","Childhood glioma (low grade)"],"tldr":"Paediatric low-grade gliomas are slow-growing brain tumours driven almost always by a single overactive signal, the MAPK pathway, most often through a BRAF gene change. Because the switch is known, pills that block it (dabrafenib with trametinib, and tovorafenib) now shrink tumours far more often than chemotherapy, and children are increasingly spared radiation to the developing brain.","summary":"Paediatric low-grade glioma (pLGG) is a family of WHO grade 1 and 2 tumours (pilocytic astrocytoma, ganglioglioma, diffuse astrocytoma, pleomorphic xanthoastrocytoma and others) that is biologically distinct from adult glioma: it is a single-pathway disease. The KIAA1549-BRAF fusion is the most common driver, BRAF V600E the second, with NF1 loss, FGFR1 alterations and other RAS-MAPK lesions accounting for most of the rest. Tumours rarely transform, but they sit in places (optic pathway, hypothalamus, brainstem, thalamus) where surgery cannot remove them and where growth costs vision, hormones and cognition. Children with neurofibromatosis type 1 make up a large minority of optic pathway gliomas.\n\nComplete resection is curative where it is possible. For unresectable or progressive disease the historical standard was carboplatin and vincristine (or vinblastine monotherapy), chosen so that radiotherapy could be deferred or avoided in young children. The field has now moved to pathway inhibition. In the phase 2 TADPOLE trial (NEJM 2023) dabrafenib plus trametinib produced far more responses and longer progression-free survival than carboplatin-vincristine in BRAF V600E tumours, leading to the first FDA approval of a targeted first-line therapy for a childhood glioma in March 2023. The type II RAF inhibitor tovorafenib, which works on BRAF fusions as well as V600E, produced durable responses in relapsed disease in FIREFLY-1 (Nature Medicine 2024) and received FDA accelerated approval in April 2024; FIREFLY-2/LOGGIC is testing it first line against chemotherapy. The MEK inhibitor selumetinib showed activity in the PBTC-029 studies and is being compared with carboplatin-vincristine in the COG trials ACNS1831 (NF1) and ACNS1833 (non-NF1).\n\nThe reframing is from a cancer to be eradicated to a chronic condition to be controlled while the brain matures: the open questions are how long to treat, whether tumours regrow when inhibitors stop, the long-term effects of MAPK inhibition on growth and bone, and how to protect vision in optic pathway tumours. Molecular diagnosis at presentation (fusion and point-mutation testing, methylation profiling) is now the standard entry point to care.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Pilocytic_astrocytoma","links":[{"label":"NCI PDQ: childhood astrocytomas, other gliomas and glioneuronal tumours","url":"https://www.cancer.gov/types/brain/hp/child-astrocytoma-treament-pdq"},{"label":"TADPOLE: dabrafenib plus trametinib in BRAF V600E pLGG (NEJM 2023)","url":"https://doi.org/10.1056/NEJMoa2303815"},{"label":"FIREFLY-1: tovorafenib in relapsed BRAF-altered pLGG (Nature Medicine 2024)","url":"https://doi.org/10.1038/s41591-023-02668-y"}],"tags":["nci-coverage","paediatric","cns"],"related":["dipg-dmg","glioblastoma","race-for-children-act","ependymoma","craniopharyngioma","idh-mutant-astrocytoma","oligodendroglioma","paediatric-high-grade-glioma"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","methylation-profiling","proton-therapy","mri","survivorship-care-plan"],"targets":["braf"],"drugs":["dabrafenib-trametinib","tovorafenib","carboplatin","vincristine","vinblastine"],"companies":["day-one-biopharmaceuticals","novartis","childrens-oncology-group","cclg"],"institutions":["siop-europe"],"pathways":["ras-mapk","glioma-signalling"],"terms":["late-effects","germline-testing"],"trials":["tadpole","firefly-1","pediatric-match"],"people":[],"bottlenecks":["b-rare-cancers","b-survivorship"],"keyPapers":["paper-kilburn-nat-med","paper-bouffet-n-engl-j-med"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"The most common brain tumour of childhood, roughly a third of all paediatric central nervous system tumours (NCI PDQ); many children live for decades with the disease.","subtypes":["Pilocytic astrocytoma (KIAA1549-BRAF fusion in most)","Ganglioglioma and pleomorphic xanthoastrocytoma (often BRAF V600E)","NF1-associated optic pathway glioma","Diffuse astrocytoma, MYB or MYBL1-altered","FGFR1-altered glioma (dysembryoplastic neuroepithelial tumour, rosette-forming glioneuronal tumour)","Subependymal giant cell astrocytoma (tuberous sclerosis; mTOR inhibitors)"],"biomarkers":["KIAA1549-BRAF fusion","BRAF V600E (worse response to chemotherapy, target of BRAF/MEK inhibitors)","NF1 germline status","FGFR1 mutation or fusion","CDKN2A deletion (with V600E, marks higher risk)","Methylation-based classification","Visual acuity and visual fields in optic pathway glioma"],"standardOfCare":[{"setting":"Resectable tumour","approach":"Maximal safe resection; gross total resection is curative in most and no adjuvant therapy is given. Observation for stable residual disease.","refs":["mri"],"guideline":{"version":"NCI PDQ: childhood astrocytomas, other gliomas and glioneuronal tumours","url":"https://www.cancer.gov/types/brain/hp/child-astrocytoma-treament-pdq"}},{"setting":"Unresectable or progressive, BRAF V600E","approach":"Dabrafenib plus trametinib first line (TADPOLE: higher response rate and longer progression-free survival than carboplatin-vincristine; FDA approval March 2023 for patients aged one year and over).","refs":["dabrafenib-trametinib","tadpole"],"guideline":{"version":"FDA label 2023; NCI PDQ"}},{"setting":"Relapsed or refractory, BRAF fusion or V600E","approach":"Tovorafenib (FIREFLY-1; FDA accelerated approval April 2024 for patients aged six months and over), or a MEK inhibitor such as selumetinib in trials.","refs":["tovorafenib","firefly-1"],"guideline":{"version":"FDA accelerated approval 2024"}},{"setting":"Unresectable, no targetable alteration or targeted drug unavailable","approach":"Carboplatin and vincristine, or weekly vinblastine, to defer radiotherapy; focal conformal or proton radiotherapy is reserved for older children and for progression after systemic options.","refs":["carboplatin","vincristine","vinblastine","proton-therapy"],"guideline":{"version":"NCI PDQ; SIOPE LGG guidance"}}],"stateOfArt":["pLGG is a single-pathway (RAS-MAPK) disease in almost every case; molecular testing at diagnosis now decides therapy.","Targeted therapy has displaced chemotherapy for BRAF V600E tumours (dabrafenib plus trametinib) and gives a second option for fusion-driven tumours (tovorafenib); FIREFLY-2/LOGGIC tests tovorafenib first line.","Radiotherapy is deferred or avoided in young children because of its cost to cognition, vision and endocrine function; proton therapy is used when radiation cannot be avoided.","The disease is increasingly managed as a chronic condition: the aim is to preserve vision, hormones and learning through childhood, not only to shrink the tumour."],"history":[{"year":1993,"title":"Carboplatin-vincristine established for progressive childhood low-grade glioma","note":"Packer and colleagues show chemotherapy can defer radiotherapy in young children.","refs":["carboplatin","vincristine"]},{"year":2008,"title":"KIAA1549-BRAF fusion discovered","note":"Tandem duplication at 7q34 found in most pilocytic astrocytomas (Jones and colleagues), defining pLGG as a MAPK-pathway disease.","refs":["braf","ras-mapk"]},{"year":2019,"title":"Selumetinib active in recurrent pLGG","note":"PBTC-029 phase 2 (Fangusaro, Lancet Oncology) reports responses in BRAF-altered and NF1-associated tumours.","refs":[]},{"year":2023,"title":"TADPOLE: dabrafenib plus trametinib beats chemotherapy first line","note":"Higher response rate and longer progression-free survival than carboplatin-vincristine in BRAF V600E pLGG (NEJM); FDA approval in March 2023.","refs":["dabrafenib-trametinib","tadpole"]},{"year":2024,"title":"Tovorafenib approved for relapsed BRAF-altered pLGG","note":"FIREFLY-1 (Nature Medicine 2024) shows durable responses across fusions and V600E; FDA accelerated approval April 2024.","refs":["tovorafenib","firefly-1"]}],"pipeline":["tovorafenib","dabrafenib-trametinib","firefly-1","methylation-profiling","proton-therapy"],"openProblems":["How long to continue MAPK inhibitors and whether tumours regrow on stopping; intermittent dosing and stop rules are being studied in FIREFLY-2 and the COG selumetinib trials.","Long-term effects of RAF and MEK inhibition on growth plates, skin and heart in children who may take them for years; registries and trial follow-up are collecting these data.","Preserving vision in optic pathway glioma, where imaging response and visual outcome do not always agree; visual endpoints are now built into trials.","Access to molecular testing and to the new drugs outside high-income countries."],"parent":"glioblastoma"},{"id":"paget-disease-of-the-nipple","kind":"cancer","name":"Paget disease of the nipple","aka":["Mammary Paget disease","Paget's disease of the breast","Paget disease of the nipple-areola complex"],"tldr":"Paget disease of the nipple looks like eczema: a scaly, red, itchy or weeping patch on the nipple that creams do not heal. Cancer cells have spread along the milk ducts into the nipple skin, and in most cases a ductal carcinoma in situ or invasive cancer lies underneath. Surgery removes the nipple and areola with the disease beneath, by mastectomy or central breast conservation with radiotherapy.","summary":"Paget disease presents as a unilateral eczema-like change of the nipple that spreads to the areola: scaling, redness, itching, crusting, discharge or nipple retraction, often treated as dermatitis for months before biopsy. Under the microscope the epidermis contains Paget cells, large pale cells with abundant cytoplasm that stain for cytokeratin 7 and, in most cases, overexpress HER2; they are thought to migrate from an underlying ductal carcinoma along the lactiferous ducts into the nipple skin. A full-thickness punch or wedge biopsy of the nipple makes the diagnosis, and bilateral mammography with breast MRI then looks for the disease behind it, which is present in the large majority of cases as ductal carcinoma in situ, invasive ductal carcinoma or both; a palpable mass makes invasion and node involvement more likely. Paget disease confined to the nipple without an underlying carcinoma is the exception, and extramammary Paget disease of the vulva or perianal skin is a different condition.\n\nMastectomy was the standard for a century because the underlying disease is often extensive or multicentric. The EORTC 10873 study of 61 women treated with excision of the nipple-areola complex and underlying tumour followed by whole-breast radiotherapy reported a five-year local recurrence rate of about five percent, and population analyses show survival matched by stage is the same after breast conservation with radiotherapy as after mastectomy, so central lumpectomy with radiotherapy is now offered when the underlying disease is limited and the margins are clear. Sentinel node biopsy is performed when invasive disease is present or when mastectomy is planned, because the nipple cannot be re-sampled afterwards. Systemic treatment, endocrine, chemotherapy and HER2-directed, follows the stage and receptors of the underlying carcinoma, not the nipple.\n\nPrognosis is set by what lies beneath. Paget disease with in situ disease alone is cured in almost all cases, and Paget disease with an invasive tumour behaves like that tumour, with node status the strongest factor. The frequent HER2 overexpression of Paget cells has made the disease a model for HER2 biology in the skin and an occasional candidate for topical or HER2-directed approaches, but there are no randomised trials of anything in a condition this rare, and delay in diagnosis remains the main avoidable harm.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Paget%27s_disease_of_the_breast","links":[{"label":"NCI: Paget disease of the breast","url":"https://www.cancer.gov/types/breast/paget-breast-fact-sheet"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Paget%27s_disease_of_the_breast"}],"tags":["subtype-page"],"related":["ductal-carcinoma-in-situ","inflammatory-breast-cancer","phyllodes-tumour"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-kothari-paget-disease-nipple-multifocal-cancer-2002"],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Rare, about one to three percent of breast cancers, mostly in women in their fifties and sixties; in the large majority an underlying ductal carcinoma in situ or invasive cancer sits behind the nipple change.","subtypes":["Paget disease with underlying ductal carcinoma in situ","Paget disease with underlying invasive ductal carcinoma (prognosis set by the invasive tumour)","Paget disease confined to the nipple epidermis (no underlying carcinoma found)","Paget disease with a palpable mass (higher chance of invasion and node involvement)","Pigmented Paget disease (melanoma mimic)"],"biomarkers":["Full-thickness nipple biopsy showing Paget cells (cytokeratin 7-positive, HER2 often overexpressed)","Mammography and breast MRI for the underlying tumour","Oestrogen receptor, progesterone receptor and HER2 of the underlying carcinoma","Nodal status by sentinel node biopsy when invasive disease is present","Margins of the nipple-areola excision"],"standardOfCare":[{"setting":"Diagnosis","approach":"Punch or wedge biopsy of the nipple for any eczema-like change not settling within a few weeks, with bilateral mammography and breast MRI to map the disease behind it.","refs":["core-needle-biopsy","histopathology-ihc","mammography","mri"]},{"setting":"Localised disease","approach":"Central breast-conserving surgery removing the nipple-areola complex and underlying tumour with clear margins followed by whole-breast radiotherapy, or mastectomy for extensive or multicentric disease.","refs":["lumpectomy","mastectomy","hypofractionated-radiotherapy"]},{"setting":"Axilla","approach":"Sentinel node biopsy when invasive carcinoma is present or when mastectomy is planned; not needed for Paget disease with in situ disease treated by breast conservation.","refs":["sentinel-node"]},{"setting":"Systemic therapy","approach":"Determined by the underlying carcinoma: endocrine therapy, chemotherapy and HER2-directed treatment on the same criteria as other breast cancers.","refs":["tamoxifen","trastuzumab","breast-her2-positive","breast-hr-positive","ductal-carcinoma-in-situ"]}],"stateOfArt":["Breast conservation with radiotherapy has replaced routine mastectomy for limited disease.","Breast MRI finds the underlying tumour that mammography misses in a substantial share of cases.","Nipple reconstruction restores appearance after central excision."],"history":[{"year":1874,"title":"James Paget describes eczema of the nipple preceding breast cancer","refs":[]},{"year":2001,"title":"EORTC 10873: breast conservation with radiotherapy for Paget disease","refs":["lumpectomy"]},{"year":2006,"title":"Population analysis shows survival matched by stage is equal after breast conservation and mastectomy","refs":["mastectomy"]}],"pipeline":["mri"],"openProblems":["Months of delay while the nipple is treated as eczema.","No randomised evidence exists for any treatment choice.","Whether Paget disease without an underlying carcinoma needs radiotherapy at all."],"parent":"breast-cancer"},{"id":"pancreatic-acinar-cell-carcinoma","kind":"cancer","name":"Pancreatic acinar cell carcinoma","aka":["Acinar cell carcinoma","ACC of the pancreas","Acinar carcinoma","Mixed acinar-neuroendocrine carcinoma"],"tldr":"Pancreatic acinar cell carcinoma is a rare pancreatic cancer that grows from the enzyme-making cells rather than the ducts. It forms large soft masses, can pour lipase into the blood and cause fat lumps under the skin and joint pain, usually lacks the KRAS mutation, often carries DNA repair faults or BRAF fusions, and responds better to bowel-cancer-style chemotherapy than to gemcitabine.","summary":"Acinar cell carcinoma arises from the exocrine cells that make digestive enzymes. Tumours are typically large, well circumscribed and soft, more often in the head, and are diagnosed by biopsy with immunohistochemistry for trypsin, chymotrypsin and BCL10; a minority are mixed acinar-neuroendocrine carcinomas. About one in ten patients has the lipase hypersecretion syndrome of subcutaneous fat necrosis, polyarthralgia and eosinophilia, and serum lipase and alpha-fetoprotein can serve as tumour markers. Metastases at diagnosis are common, most often to the liver.\n\nThe genetics differ sharply from ductal adenocarcinoma: KRAS mutations are rare, and instead sequencing finds recurrent BRAF or RAF1 fusions (SND1-BRAF and others) in roughly a fifth to a quarter of cases, alterations in homologous recombination genes including germline BRCA2 and PALB2 in a substantial minority, mismatch repair deficiency in a few, and APC or CTNNB1 changes in the Wnt pathway. Every patient should therefore have germline and tumour sequencing, and germline testing has consequences for relatives.\n\nSurgery is the only curative treatment and is offered even for large tumours and selected metastatic disease, because outcomes after resection are better than for ductal adenocarcinoma. There is no randomised evidence for systemic treatment; retrospective series show that fluoropyrimidine and oxaliplatin regimens (FOLFOX, FOLFIRINOX) produce more responses than gemcitabine-based treatment, which is why guidelines favour them. Tumours with BRAF fusions respond to MEK inhibitors in case reports, homologous recombination-deficient tumours to platinum and PARP inhibitors, and mismatch repair deficient tumours to pembrolizumab. Mixed acinar-neuroendocrine tumours are treated as acinar cell carcinoma.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Acinar_cell_carcinoma_of_the_pancreas","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Acinar_cell_carcinoma_of_the_pancreas"},{"label":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}],"tags":["subtype-page","gastrointestinal"],"related":["kras-wild-type-pdac","resectable-pdac","metastatic-pdac","brca-palb2-pdac","pancreatoblastoma","pancreatic-net"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","cgp","germline-testing","robotic-surgery","parp-inhibitor","checkpoint-inhibitor"],"targets":["braf","brca","kras"],"drugs":["folfox","folfirinox","oxaliplatin","fluorouracil","gemcitabine","olaparib","dabrafenib-trametinib","pembrolizumab"],"companies":[],"institutions":[],"pathways":["ras-mapk","homologous-recombination-repair","wnt","pancreatic-cancer-signalling"],"terms":["gene-fusion","hrd","gbrca-mutation","whipple","msi","tumour-grade","oligometastatic"],"trials":[],"people":["eileen-oreilly","anirban-maitra","richard-schulick"],"bottlenecks":[],"keyPapers":["paper-klimstra-acinar-cell-carcinoma-pancreas-28-cases-ajsp-1992","paper-la-rosa-acinar-cell-carcinoma-62-cases-ajsp-2012","paper-chmielecki-acinar-cell-carcinoma-raf-fusions-dna-repair-cancer-discov-2014","paper-wisnoski-acinar-cell-carcinoma-672-patients-seer-surgery-2008"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 1 to 2 percent of pancreatic cancers in adults, and the commonest pancreatic cancer in children after pancreatoblastoma; it affects men more often than women and presents at a median age around 60.","subtypes":["Pure acinar cell carcinoma (trypsin and BCL10 positive; usually KRAS wild-type rather than ductal PDAC)","Mixed acinar-neuroendocrine carcinoma (treated as acinar cell carcinoma)","Acinar cell carcinoma with a BRAF or RAF1 fusion (MEK inhibitor candidates)","Acinar cell carcinoma with germline BRCA2 or PALB2 or other homologous recombination defects (platinum, PARP inhibitors)","Acinar cell carcinoma with lipase hypersecretion syndrome","Paediatric acinar cell carcinoma (rare; distinguished from pancreatoblastoma)"],"biomarkers":["Trypsin, chymotrypsin and BCL10 immunohistochemistry (diagnosis)","Serum lipase and alpha-fetoprotein (markers in a subset)","BRAF or RAF1 fusions (SND1-BRAF and others)","Germline and somatic BRCA2, PALB2, ATM and other homologous recombination genes","Mismatch repair status","APC or CTNNB1 alterations; KRAS usually wild-type"],"standardOfCare":[{"setting":"Diagnosis","approach":"Biopsy with acinar markers; CT staging; germline testing and comprehensive tumour sequencing with fusion detection for every patient.","refs":["endoscopic-ultrasound-systems","ct","germline-testing","cgp"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Resectable","approach":"Pancreatoduodenectomy or distal pancreatectomy even for large tumours, with adjuvant chemotherapy by extrapolation from ductal adenocarcinoma, usually a fluoropyrimidine and oxaliplatin regimen.","refs":["whipple","folfox","folfirinox","neoadjuvant-adjuvant"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Advanced","approach":"FOLFOX or FOLFIRINOX preferred over gemcitabine-based regimens on retrospective evidence; resection of the primary and limited metastases considered after response.","refs":["folfox","folfirinox","oxaliplatin","fluorouracil","oligometastatic"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Molecularly selected","approach":"MEK inhibition for BRAF fusions on case-series evidence; platinum and PARP inhibitors for homologous recombination defects; pembrolizumab for mismatch repair deficiency.","refs":["dabrafenib-trametinib","olaparib","pembrolizumab","gene-fusion","hrd"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Recognition that acinar cell carcinoma is molecularly distinct from ductal adenocarcinoma, with BRAF fusions and DNA repair defects rather than KRAS.","Fluoropyrimidine and oxaliplatin regimens have replaced gemcitabine as the usual chemotherapy.","Surgery is offered more liberally than in ductal adenocarcinoma because resected patients do better.","Molecular tumour boards match fusions and repair defects to drugs approved in other cancers."],"history":[{"year":1908,"title":"Berner describes acinar cell carcinoma of the pancreas as a distinct tumour","refs":["whipple"]},{"year":1992,"title":"Klimstra and colleagues define the clinicopathological features of acinar cell carcinoma","refs":["tumour-grade"]},{"year":2014,"title":"Sequencing shows BRAF and RAF1 fusions and DNA repair gene defects, and rare KRAS mutation","refs":["gene-fusion","braf","brca"]},{"year":2018,"title":"Retrospective series favour fluoropyrimidine and oxaliplatin regimens over gemcitabine","refs":["folfox","folfirinox"]}],"pipeline":["pdac-organoid-pharmacotyping","cgp"],"openProblems":["No prospective trial has ever been completed in acinar cell carcinoma; all systemic therapy evidence is retrospective.","BRAF fusions have no approved drug and MEK inhibitor evidence is case reports.","The tumour is often misdiagnosed as neuroendocrine or ductal cancer on small biopsies.","Registries are small and international collaboration is needed for any trial."],"parent":"pancreatic"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","aka":["Pancreatic cancer","PDAC","Cancer of the pancreas","Exocrine pancreatic cancer","Pancreatic adenocarcinoma"],"tldr":"Almost every pancreatic tumour carries a KRAS mutation, and for the first time drugs against it work: daraxonrasib nearly doubled survival in previously treated disease in 2026. Pancreatic cancer has been the hardest common cancer to treat once advanced; that is what is starting to change.","summary":"Pancreatic ductal adenocarcinoma is defined by late presentation, a near-universal KRAS mutation (G12D about 40%, G12V about 32%, G12R about 16%, G12C 1 to 2%; 6 to 12% KRAS-wild-type with actionable fusions in NRG1, NTRK, ALK, or BRAF), a desmoplastic stroma that occupies most of the tumour, and an immunologically cold microenvironment. Surgery is the only cure and only ~20% of patients present resectable; five-year survival remains ~13% overall but exceeds 40% for resected patients who complete adjuvant mFOLFIRINOX.\n\nFor thirty years the story was chemotherapy: gemcitabine (1997), FOLFIRINOX (2011), gemcitabine/nab-paclitaxel (2013), adjuvant mFOLFIRINOX (PRODIGE 24, 2018), NALIRIFOX (2024), with olaparib maintenance for germline BRCA carriers (POLO, 2019) and zenocutuzumab for NRG1 fusions (2024) as the only biomarker-directed drugs. 2026 changed the trajectory. Optune Pax tumour treating fields were approved for locally advanced disease (PANOVA-3). Daraxonrasib, a pan-RAS(ON) inhibitor, nearly doubled overall survival in previously treated metastatic disease in RASolute 302 (13.2 vs 6.7 months, HR 0.40), presented in the ASCO 2026 plenary with simultaneous NEJM publication, and the FDA approved it on 26 August 2026 for metastatic disease after at least one systemic therapy or when multi-agent chemotherapy is unsuitable; no European or UK decision had been made by 24 September 2026. The G12D-selective zoldonrasib, combined with daraxonrasib or with chemotherapy, produced response rates never before seen in this disease.\n\nWhat remains unsolved: detection (no screening outside high-risk surveillance; MCED tests and new-onset-diabetes enrichment are the leading ideas), the stroma and immune exclusion that have defeated every checkpoint inhibitor trial, resistance to RAS inhibitors (already emerging), and the fact that half of patients are too frail for the most effective regimens. The most promising directions are RAS inhibitors moving into first line and neoadjuvant settings, personalised (autogene cevumeran) and shared-antigen (ELI-002 7P) vaccines in the adjuvant setting despite AMPLIFY-7P's miss, CLDN18.2 and FAP-directed delivery, and blood-based early detection.\n\nHow common it is, world and United States. The IARC pancreas fact sheet, served with the GLOBOCAN 2024 estimates, counts 531,318 new pancreatic cancers a year (the 11th commonest cancer, age-standardised rate 4.7 per 100,000) and 490,786 deaths (the 6th commonest cause of cancer death, 4.2 per 100,000). Asia has 45.9 percent of cases, Europe 27.7 percent, Northern America 13.6 percent, Latin America and the Caribbean 7.8 percent, Africa 3.9 percent and Oceania 1.1 percent, and the highest rates are in Western Europe and Northern America, the lowest in South Central Asia. Countries with very high human development had the highest incidence and mortality (age-standardised rates 7.7 and 4.9 in 2018), incidence rose in 14 of 48 countries with registry data for men and 17 for women over the decade to 2017, and higher national rates travel with smoking, alcohol, inactivity, obesity, hypertension and high cholesterol (Huang 2021). In the United States the SEER programme projects 67,530 new cases (3.2 percent of cancers) and 52,740 deaths (8.4 percent of cancer deaths) for 2026; the rate of new cases is 13.9 per 100,000 a year (2019 to 2023) and the death rate 11.3 (2020 to 2024); it is the third leading cause of cancer death; 113,931 people were living with it in 2023. Applying current rates to population growth, pancreatic cancer is projected to become the second leading cause of cancer death in the United States by 2040 (46,000 deaths, behind lung cancer's 63,000), overtaking colorectal cancer (Rahib 2021; the 2014 Rahib projection is in the key papers).\n\nUnited Kingdom (Cancer Research UK, drawing on the four national registries). Pancreatic cancer is the 10th commonest cancer with 11,479 new cases a year (2019 and 2021 to 2022), 31 a day and 3 percent of all cancers, about 5,600 in females and 5,800 in males; almost half (48 percent) are diagnosed at 75 or over and rates are highest at 90 and over. Incidence rates have risen by about a fifth (21 percent) since the early 1990s and by 7 percent in the last decade, and are projected to rise a further 4 percent by 2038 to 2040 with the count reaching about 16,000 a year; rates are lower in the Asian and mixed ethnic groups and higher in the Black ethnic group than in the White group in England (2013 to 2017). It is the 5th commonest cause of cancer death with about 10,200 deaths a year (2022 to 2024), 28 a day, more than half (54 percent) at 75 or over; mortality rates have stayed flat since the early 1970s, and although rates are projected to fall 4 percent, deaths are projected to reach about 12,600 a year by 2038 to 2040 as the population ages. Mortality is 20 percent higher for men and 25 percent higher for women in the most deprived areas of England than the least deprived (2007 to 2011). The lifetime risk of a diagnosis is 1 in 59 for females and 1 in 55 for males born in 1961. Cancer Research UK's summary page says 37 percent of cases are preventable and its risk page 31 percent; both figures are recorded here. In England in 2022, 26 percent of cases with a known stage (around 1,600) were stage I or II; Northern Ireland reports 30 percent, Scotland 19 percent (2023) and Wales 19 percent. In 2024 there were around 310 curative and 370 palliative radiotherapy episodes for pancreatic cancer in England.\n\nWho gets it. Age is the main risk factor: the US median age at diagnosis is 71, 32.7 percent of cases are diagnosed at 65 to 74 and only 3 percent under 45 (SEER 21, 2019 to 2023); the US rate is slightly higher in men (15.7 against 12.4 per 100,000) and highest in non-Hispanic Black men and women (18.0 and 15.4) against 16.3 and 12.3 in non-Hispanic White, 13.6 and 12.1 in Hispanic and 11.5 and 9.8 in Asian and Pacific Islander people. Smoking: current smokers have 2.2 times the risk of never smokers, former smokers 1.2 times, rising to 3.4 times at 35 or more cigarettes a day, and the risk returns to that of never smokers about 20 years after quitting (Bosetti 2012, 6,507 cases in the PanC4 consortium); 22 percent of UK cases are caused by smoking (Cancer Research UK). Body size: obesity (body mass index 30 or more) carries 1.47 times the risk of a normal weight, being overweight in early adulthood and obese later 1.54 times, and a high waist-to-hip ratio 1.35 times, in 846,340 people across 14 cohorts (Genkinger 2011); Cancer Research UK puts 12 percent of UK cases down to overweight and obesity, with a 10 percent rise in risk per 5 units of body mass index. Diabetes: type 2 diabetes carries about 1.8 to 1.9 times the risk (odds ratio 1.82 in 36 studies, Huxley 2005; relative risk 1.94 in 35 cohorts, Ben 2011), and the association is strongest when the diabetes is recent, which is where cause and consequence blur: 47 percent of 512 newly diagnosed patients had diabetes against 7 percent of controls, much of it new-onset and resolving after resection, so the tumour itself is diabetogenic (Pannala 2008). Chronic pancreatitis: about 16 times the risk within two years of the pancreatitis diagnosis, falling to about 8 times at five years and 3.5 times at nine years or more, part of the early excess being cancers first misread as pancreatitis (Kirkegard 2017); hereditary pancreatitis with a PRSS1 mutation raises risk more than 50-fold (Cancer Research UK). Alcohol at 3 or more units a day raises risk by 15 to 19 percent; gallstones by 25 percent, mostly soon after diagnosis; metabolic syndrome by 58 percent in women; red meat by 21 percent in men (Cancer Research UK risk page). The same factors, with alcohol most strongly, apply to cancers diagnosed before 60 (McWilliams 2016).\n\nFamily history and inherited genes. A first-degree relative with pancreatic cancer raises risk by 62 to 76 percent (Cancer Research UK); in the Johns Hopkins registry, members of familial kindreds (at least one pair of affected first-degree relatives) had 9.0 times the expected incidence, rising to 6.4 times with two and 32 times with three affected first-degree relatives, while spouses and unrelated relatives had no excess (Klein 2004). Germline testing of 3,030 unselected patients found a pathogenic variant in one of six genes in 5.5 percent (7.9 percent with a family history of pancreatic cancer, 5.2 percent without): ATM 2.3 percent of cases (odds ratio 5.71), BRCA2 1.9 percent (6.20), BRCA1 0.6 percent (2.58), CDKN2A 0.3 percent (12.33), TP53 0.2 percent (6.70) and MLH1 0.13 percent (6.66) (Hu 2018); 3.9 percent of 854 apparently sporadic resected cancers carried a deleterious germline mutation, and only 3 of those 33 patients had reported a family history (Shindo 2017), which is why guidelines now offer germline testing to every patient. Syndromes: Peutz-Jeghers more than 100 times the risk, familial atypical multiple mole melanoma (CDKN2A) 13 to 38 times, Lynch syndrome up to about 9 times, BRCA2 3.5 times and BRCA1 up to 2.3 times (Cancer Research UK). Pancreatic cysts: intraductal papillary mucinous and mucinous cystic neoplasms are precursors, and cysts of 2 mm or more were found on MRCP in 49.1 percent of 1,077 adults in a German population study, though only about 6 percent of cysts were over 1 cm and no cancer arose in five years of follow-up (Kromrey 2018); the cyst pages of this record carry the surveillance rules.\n\nHow it presents, and why late. The pancreas sits deep behind the stomach and the early tumour is silent; roughly 75 percent of cancers start in the head (Cancer Research UK types page), where they block the bile duct and cause painless jaundice, dark urine, pale stools and itching, while body and tail tumours present later with pain in the upper abdomen or back that is worse after eating or lying down and eased by leaning forward, weight loss, loss of appetite, fatty stools (steatorrhoea), nausea, indigestion, new diabetes, fever and blood clots (Cancer Research UK symptoms page; NHS). In the SYMPTOM pancreatic study of 391 people referred with suspected pancreatic cancer, 119 (30 percent) had it and 34 percent of those were already metastatic; no first symptom separated cancer from no cancer, but jaundice as a later symptom did (49 percent against 12 percent), and the authors asked clinicians to stay alert to evolving gut and systemic symptoms, particularly in people with diabetes or mental health conditions (Walter 2016). NICE NG12 (1.2.4) sends anyone aged 40 or over with jaundice on the suspected cancer pathway and (1.2.5) asks for an urgent direct-access CT, or ultrasound if CT is unavailable, for anyone 60 or over with weight loss and any of diarrhoea, back pain, abdominal pain, nausea, vomiting, constipation or new-onset diabetes; the NHS page asks for an urgent GP appointment or NHS 111 for yellowing of the eyes or skin, vomiting for more than two days or diarrhoea for more than seven. Even so, in England in 2019 only 22 percent of cases were diagnosed through an urgent suspected cancer referral and 45 percent through an emergency presentation (Cancer Research UK), the route that carries substantially lower one-year survival across cancers (Elliss-Brookes 2012); a 2026 US Veterans Affairs measure found 60.9 percent of 4,415 patients presenting as emergencies, with 1.38 times the odds of advanced stage and 1.64 times the mortality, and missed diagnostic opportunities in nearly one in five (Br J Cancer 2026). In the United States 51 percent of cases are distant at diagnosis, 28 percent regional and 15 percent localised (SEER). Weight loss is part of the presentation, not only a complication: 85 percent of patients meet the definition of cancer cachexia (Hendifar 2019) and 40.5 percent of 227 patients scheduled for surgery were already cachectic, which halved their chance of a resection (48.9 against 77.8 percent) because metastases were found more often (Bachmann 2008).\n\nHow it is diagnosed. NICE NG85 (1.1) sets the UK sequence: for obstructive jaundice with suspected pancreatic cancer, a pancreatic protocol CT before the bile duct is drained (1.1.1); if the diagnosis is still unclear, FDG PET-CT and or endoscopic ultrasound with EUS-guided tissue sampling (1.1.2), and a biliary brushing for cytology if ERCP is used to relieve the obstruction without a tissue diagnosis (1.1.3); for pancreatic abnormalities without jaundice, the same CT then PET-CT or EUS (1.1.4 to 1.1.6); for cysts, CT or MRI with MRCP, the other test if more is needed, EUS with fine-needle aspiration and CEA on the fluid when malignancy is in question (1.1.7 to 1.1.13). The pancreas protocol CT is a thin-slice, dual-phase scan read against a standard template that names each artery and vein the tumour touches and by how many degrees (Al-Hawary 2014); Cancer Research UK adds that a biopsy is often not taken when the tumour looks removable, the diagnosis then resting on imaging until the specimen is examined, and that EUS, ERCP, ultrasound- or CT-guided biopsy or laparoscopy are the routes when tissue is needed. Blood tests include liver function and the tumour markers CA 19-9 and CEA. CA 19-9 has a sensitivity of 79 to 81 percent and specificity of 82 to 90 percent in symptomatic patients but a positive predictive value of 0.5 to 0.9 percent as a screening test, is falsely negative in the 5 to 10 percent of people who are Lewis antigen-negative, and levels above 100 U/mL suggest unresectable or metastatic disease (Ballehaninna 2012); in 1,482 Chinese patients 8.4 percent were Lewis-negative and, contrary to the textbook, 27.4 percent of them still had a raised CA 19-9, while Lewis-negative status itself predicted shorter survival (hazard ratio 1.30, Luo 2018). Germline testing and tumour sequencing (KRAS status, fusions when KRAS is wild-type, mismatch repair) are offered at diagnosis (NCCN; the subtype pages carry the detail). The specialist pancreatic multidisciplinary team makes the shared decision (NG85 1.2.1) and partners with local units to deliver it.\n\nHow it is staged. Two systems run side by side. The TNM 8th edition (2017) sizes the tumour: T1 is 2 cm or less (T1a to 0.5 cm, T1b over 0.5 to 1 cm, T1c 1 to 2 cm), T2 over 2 to 4 cm, T3 over 4 cm, T4 growing into the coeliac axis, superior mesenteric artery or common hepatic artery; N1 is one to three regional nodes, N2 four or more; M1 is spread to the liver, lungs, peritoneum or distant nodes (Cancer Research UK TNM page). Stage 1 is T1 or T2 without nodes (1A and 1B by size), stage 2 is T3 without nodes (2A) or T1 to T3 with one to three nodes (2B), stage 3 is four or more nodes or a T4 tumour, and stage 4 is any metastasis (Cancer Research UK stages page). The 8th edition's size-based T and count-based N categories were validated in 2,318 margin-negative resections from three US centres (Allen 2017) and in 8,960 SEER resections, where they discriminated survival about as well as the 7th edition (c-index 0.60 against 0.59) while stratifying resected patients more finely by nodal burden (Kamarajah 2017). The second system is resectability, which is what decides treatment: the NCCN classes of resectable, borderline resectable and locally advanced (unresectable) are defined by the tumour's contact with the superior mesenteric artery, coeliac axis and common hepatic artery (arterial contact of less than 180 degrees without stenosis is borderline; more, or encasement, is locally advanced) and with the superior mesenteric and portal veins (contact with narrowing or occlusion that can be reconstructed is borderline; unreconstructable occlusion is locally advanced), and the 2017 international consensus added a biological dimension (suspected but unproven metastases or nodes on PET-CT or biopsy, or a CA 19-9 above 500 U/mL) and a conditional one (performance status 2 or worse) (Isaji 2018; Tempero 2021). Staging tests in the UK are a pancreatic protocol CT of chest, abdomen and pelvis for every new diagnosis (NG85 1.3.1), FDG PET-CT for everyone with localised disease on CT who will have treatment (1.3.2), and, when the decision still turns on it, MRI for suspected liver metastases, EUS for tumour and node staging, or laparoscopy with laparoscopic ultrasound for small-volume peritoneal or liver disease before an attempted resection (1.3.3).\n\nWhat the pathologist sees. About 80 percent of pancreatic cancers are ductal adenocarcinomas (Cancer Research UK types page), the entity this record describes: gland-forming tumours in a dense desmoplastic stroma, with the KRAS, CDKN2A, TP53 and SMAD4 alterations set out in the biomarkers list. The 2019 WHO classification of digestive tumours (5th edition, Nagtegaal 2020) lists its variants, each with a page linked from this record: adenosquamous carcinoma, colloid (mucinous non-cystic) carcinoma, undifferentiated carcinoma with or without osteoclast-like giant cells, and the carcinomas arising in intraductal papillary mucinous and mucinous cystic neoplasms; acinar cell carcinoma, solid pseudopapillary neoplasm and pancreatoblastoma are separate non-ductal tumours, and the neuroendocrine tumours of the islets are a different disease with their own record. Precursors: pancreatic intraepithelial neoplasia (PanIN), the microscopic duct lesion named and graded in 2001 (Hruban 2001) and reduced to two tiers, low grade and high grade, by the 2015 Baltimore consensus, which also set 0.5 to 1 cm as the boundary between a large PanIN and a small (incipient) IPMN (Basturk 2015); high-grade PanIN was present in 4 percent of 173 autopsy pancreata without cancer, always multifocal and more often in the body and tail, in people with diabetes and in the old (Matsuda 2017). Margins are reported by the 1 mm rule: the Royal College of Pathologists calls tumour within 1 mm of a margin R1, a definition that, applied with inked margins and axial slicing, raised the reported R1 rate to 76 to 85 percent of head resections (Verbeke 2006; Esposito 2008; Campbell 2009), and in the ESPAC-3 trial 43.9 percent of 1,151 patients were R1, with direct margin involvement carrying the worst survival and more local recurrence (Ghaneh 2019).\n\nScreening and surveillance. There is no population screening: the UK National Screening Committee does not recommend it and Cancer Research UK explains why (the cancer is relatively uncommon, so many people would have unnecessary tests, and the benefits do not outweigh the costs), and the US Preventive Services Task Force reaffirmed a grade D recommendation against screening asymptomatic adults in 2019 (Owens 2019). Surveillance of high-risk people is different. NICE NG85 offers it (1.1.15) to people with hereditary pancreatitis and a PRSS1 mutation, to carriers of BRCA1, BRCA2, PALB2 or CDKN2A with one or more first-degree relatives with pancreatic cancer, and to Peutz-Jeghers syndrome, and asks clinicians to consider it (1.1.16) for two or more first-degree relatives across two generations and for Lynch syndrome with an affected first-degree relative, by MRI with MRCP or EUS (1.1.17), or by pancreatic protocol CT in hereditary pancreatitis where EUS is not used (1.1.18, 1.1.19). The International CAPS consortium (2020) sets the goal as high-grade dysplasia and T1N0M0 cancer, starts familial surveillance at 50 or 55 or ten years before the youngest affected relative, uses EUS and MRI/MRCP yearly, and added ATM carriers with one affected relative (Goggins 2020). The programmes: in CAPS, 7 percent of 354 high-risk people progressed over 16 years, 1.6 percent a year, and 93 percent had worrisome features first (Canto 2018); in CAPS5, 1,461 people were enrolled, 7 of 9 cancers found under surveillance were stage I (77.8 percent), and across CAPS1 to 5 (1,731 people) 57.9 percent of the 19 surveillance-detected cancers were stage I against 85.7 percent stage IV for the seven found outside surveillance, with five-year survival of 73.3 percent and a median of 9.8 years for screen-detected disease (Dbouk 2022); in the Netherlands the cumulative incidence was 9.3 percent in mutation carriers and 0 percent in mutation-negative familial kindreds over an average of 63 months, with EUS outperforming MRI and four of ten cancers presenting between visits (Overbeek 2022); in 347 CDKN2A carriers 8.9 percent developed cancer (20.7 percent by age 70), 83.3 percent resectable at imaging and 33.3 percent stage I, with five-year survival of 32.4 percent (Klatte 2022). EUROPAC, the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer based in Liverpool, screened 321 people from 258 kindreds and found one cancer, two low-grade neuroendocrine tumours and 41 cystic lesions, the branch-duct IPMNs being unrelated to inherited risk (Sheel 2019). PRECEDE (Pancreatic Cancer Early Detection consortium) published its recommendations for an organised approach in 2021 (Gonda 2021) and its 20,000-person registry study has a trial record on this site. New-onset diabetes after 50 is the other route: about 1 percent are diagnosed with pancreatic cancer within three years (Chari 2005), the ENDPAC score (weight change, glucose change, age) picks out a group with 3.6 percent prevalence (Sharma 2018), and in over a fifth of cancers the diabetes began while the cancer was still asymptomatic, a median of 6.5 months before diagnosis (Aggarwal 2012); the glossary term and the ideas linked from this record carry the detail.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Pancreatic_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Pancreatic_cancer"},{"label":"GLOBOCAN pancreas fact sheet (IARC Global Cancer Observatory, 2024 estimates)","url":"https://gco.iarc.who.int/media/globocan/factsheets/cancers/13-pancreas-fact-sheet.pdf"},{"label":"SEER Cancer Stat Facts: pancreatic cancer (rates, stage distribution, survival by stage, age and race)","url":"https://seer.cancer.gov/statfacts/html/pancreas.html"},{"label":"CRUK: pancreatic cancer statistics (incidence, mortality, survival, early diagnosis and routes to diagnosis)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer"},{"label":"CRUK: pancreatic cancer incidence statistics","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer/incidence"},{"label":"CRUK: pancreatic cancer mortality statistics","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer/mortality"},{"label":"CRUK: pancreatic cancer survival statistics (professional)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer/survival"},{"label":"CRUK: pancreatic cancer risk factors (professional)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer/risk-factors"},{"label":"CRUK: types of pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/stages-types-grades/types"},{"label":"CRUK: symptoms of pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/symptoms"},{"label":"CRUK: TNM staging for pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/stages-types-grades/tnm-staging"},{"label":"CRUK: stages, types and grades of pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/stages-types-grades"},{"label":"CRUK: tests for pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/getting-diagnosed/tests"},{"label":"CRUK: screening for pancreatic cancer (no national programme; high-risk surveillance)","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/getting-diagnosed/screening"},{"label":"CRUK: survival for pancreatic cancer (ICBP SURVMARK-2 by stage; England and Wales index)","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/survival"},{"label":"CRUK: risks and causes of pancreatic cancer (patient page)","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/risks-causes"},{"label":"NHS: pancreatic cancer","url":"https://www.nhs.uk/conditions/pancreatic-cancer/"},{"label":"NHS: causes of pancreatic cancer","url":"https://www.nhs.uk/conditions/pancreatic-cancer/causes/"},{"label":"NICE NG12: suspected cancer, recommendations by site (pancreatic cancer 1.2.4 and 1.2.5)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"},{"label":"NCCN Guidelines: Pancreatic Adenocarcinoma (resectability criteria)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"},{"label":"Rahib, JAMA Netw Open 2021: estimated projection of US cancer incidence and death to 2040","url":"https://doi.org/10.1001/jamanetworkopen.2021.4708"},{"label":"Huang, Gastroenterology 2021: worldwide burden of, risk factors for, and trends in pancreatic cancer","url":"https://doi.org/10.1053/j.gastro.2020.10.007"},{"label":"Klein, Nat Rev Gastroenterol Hepatol 2021: pancreatic cancer epidemiology, lifestyle and inherited risk","url":"https://doi.org/10.1038/s41575-021-00457-x"},{"label":"McWilliams, Pancreas 2016: risk factors for early-onset and very-early-onset pancreatic adenocarcinoma (PanC4)","url":"https://doi.org/10.1097/mpa.0000000000000392"},{"label":"Bosetti, Ann Oncol 2012: cigarette smoking and pancreatic cancer, PanC4 pooled analysis of 6,507 cases","url":"https://doi.org/10.1093/annonc/mdr541"},{"label":"Genkinger, Int J Cancer 2011: pooled analysis of 14 cohorts, body size and pancreatic cancer risk","url":"https://doi.org/10.1002/ijc.25794"},{"label":"Huxley, Br J Cancer 2005: type 2 diabetes and pancreatic cancer, meta-analysis of 36 studies","url":"https://doi.org/10.1038/sj.bjc.6602619"},{"label":"Ben, Eur J Cancer 2011: diabetes mellitus and pancreatic cancer risk, meta-analysis of 35 cohorts","url":"https://doi.org/10.1016/j.ejca.2011.03.003"},{"label":"Kirkegard, Am J Gastroenterol 2017: chronic pancreatitis and pancreatic cancer risk, meta-analysis","url":"https://doi.org/10.1038/ajg.2017.218"},{"label":"Klein, Cancer Res 2004: prospective risk of pancreatic cancer in familial pancreatic cancer kindreds","url":"https://doi.org/10.1158/0008-5472.can-03-3823"},{"label":"Hu, JAMA 2018: inherited germline mutations in cancer predisposition genes and pancreatic cancer risk (3,030 patients)","url":"https://doi.org/10.1001/jama.2018.6228"},{"label":"Shindo, J Clin Oncol 2017: deleterious germline mutations in apparently sporadic pancreatic adenocarcinoma","url":"https://doi.org/10.1200/jco.2017.72.3502"},{"label":"Chari, Gastroenterology 2005: probability of pancreatic cancer following diabetes, Rochester population","url":"https://doi.org/10.1053/j.gastro.2005.05.007"},{"label":"Pannala, Gastroenterology 2008: prevalence and profile of pancreatic cancer-associated diabetes","url":"https://doi.org/10.1053/j.gastro.2008.01.039"},{"label":"Aggarwal, Pancreatology 2012: new-onset diabetes in pancreatic cancer in primary care","url":"https://doi.org/10.1016/j.pan.2012.02.003"},{"label":"Sharma, Gastroenterology 2018: the ENDPAC model for pancreatic cancer risk in new-onset diabetes","url":"https://doi.org/10.1053/j.gastro.2018.05.023"},{"label":"Walter, Lancet Gastroenterol Hepatol 2016: symptoms and diagnostic intervals for pancreatic cancer (SYMPTOM pancreatic study)","url":"https://doi.org/10.1016/s2468-1253(16)30079-6"},{"label":"Elliss-Brookes, Br J Cancer 2012: routes to diagnosis for cancer in England","url":"https://doi.org/10.1038/bjc.2012.408"},{"label":"Br J Cancer 2026: a digital quality measure for emergency presentation of pancreatic cancer (US Veterans Affairs)","url":"https://doi.org/10.1038/s41416-026-03343-y"},{"label":"Al-Hawary, Radiology 2014: pancreatic ductal adenocarcinoma radiology reporting template (SAR and APA consensus)","url":"https://doi.org/10.1148/radiol.13131184"},{"label":"Isaji, Pancreatology 2018: international consensus on the definition and criteria of borderline resectable pancreatic cancer","url":"https://doi.org/10.1016/j.pan.2017.11.011"},{"label":"Tempero, JNCCN 2021: NCCN pancreatic adenocarcinoma guidelines, version 2.2021","url":"https://doi.org/10.6004/jnccn.2021.0017"},{"label":"Allen, Ann Surg 2017: multi-institutional validation of the AJCC 8th edition T and N staging for pancreatic adenocarcinoma","url":"https://doi.org/10.1097/sla.0000000000001763"},{"label":"Kamarajah, Ann Surg Oncol 2017: validation of the AJCC 8th edition for pancreatic adenocarcinoma in SEER","url":"https://doi.org/10.1245/s10434-017-5810-x"},{"label":"Ballehaninna and Chamberlain, J Gastrointest Oncol 2012: clinical utility of serum CA 19-9 in pancreatic adenocarcinoma","url":"https://doi.org/10.3978/j.issn.2078-6891.2011.021"},{"label":"Luo, Pancreatology 2018: CA19-9 in Lewis-negative patients with pancreatic cancer (1,482 patients)","url":"https://doi.org/10.1016/j.pan.2018.08.003"},{"label":"Verbeke, Br J Surg 2006: redefining the R1 resection in pancreatic cancer","url":"https://doi.org/10.1002/bjs.5397"},{"label":"Esposito, Ann Surg Oncol 2008: most pancreatic cancer resections are R1 resections","url":"https://doi.org/10.1245/s10434-008-9839-8"},{"label":"Campbell, Histopathology 2009: classification of R1 resections, tumour within 1 mm of a margin","url":"https://doi.org/10.1111/j.1365-2559.2009.03376.x"},{"label":"Strobel, Ann Surg 2017: pancreatic cancer surgery, the new R-status counts (561 patients)","url":"https://doi.org/10.1097/sla.0000000000001731"},{"label":"Ghaneh, Ann Surg 2019: positive resection margins, survival and recurrence in ESPAC-3 (1,151 patients)","url":"https://doi.org/10.1097/sla.0000000000002557"},{"label":"Hruban, Am J Surg Pathol 2001: pancreatic intraepithelial neoplasia, a new nomenclature (PanIN)","url":"https://doi.org/10.1097/00000478-200105000-00003"},{"label":"Basturk, Am J Surg Pathol 2015: Baltimore consensus, revised classification of pancreatic precursor lesions","url":"https://doi.org/10.1097/pas.0000000000000533"},{"label":"Matsuda, Pancreas 2017: prevalence of high-grade PanIN in 173 autopsy pancreata","url":"https://doi.org/10.1097/mpa.0000000000000786"},{"label":"Kromrey, Gut 2018: prevalence, incidence and 5-year outcome of pancreatic cysts in a population MRCP study (SHIP)","url":"https://doi.org/10.1136/gutjnl-2016-313127"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"Goggins, Gut 2020: CAPS consortium updated recommendations for individuals at increased risk of familial pancreatic cancer","url":"https://doi.org/10.1136/gutjnl-2019-319352"},{"label":"Canto, Gastroenterology 2018: neoplastic progression in 354 high-risk individuals under long-term CAPS surveillance","url":"https://doi.org/10.1053/j.gastro.2018.05.035"},{"label":"Dbouk, J Clin Oncol 2022: the multicenter CAPS5 study, impact of surveillance on stage and survival","url":"https://doi.org/10.1200/jco.22.00298"},{"label":"Overbeek, Gut 2022: long-term yield of pancreatic cancer surveillance in 366 Dutch high-risk individuals","url":"https://doi.org/10.1136/gutjnl-2020-323611"},{"label":"Klatte, J Clin Oncol 2022: 20 years of surveillance in 347 germline CDKN2A carriers","url":"https://doi.org/10.1200/jco.22.00194"},{"label":"Sheel, Am J Gastroenterol 2019: cystic lesions found by EUROPAC secondary screening of familial pancreatic cancer kindreds","url":"https://doi.org/10.1038/s41395-018-0395-y"},{"label":"Gonda, Gastroenterology 2021: PRECEDE consortium recommendations for a more organised approach to early detection","url":"https://doi.org/10.1053/j.gastro.2021.08.036"},{"label":"US Preventive Services Task Force, JAMA 2019: screening for pancreatic cancer, reaffirmation (recommendation against, grade D)","url":"https://doi.org/10.1001/jama.2019.10232"},{"label":"Pereira, Lancet Gastroenterol Hepatol 2020: early detection of pancreatic cancer, a review","url":"https://doi.org/10.1016/s2468-1253(19)30416-9"},{"label":"Hendifar, Oncologist 2019: pancreas cancer-associated weight loss","url":"https://doi.org/10.1634/theoncologist.2018-0266"},{"label":"Bachmann, J Gastrointest Surg 2008: cachexia worsens prognosis in resectable pancreatic cancer (227 patients)","url":"https://doi.org/10.1007/s11605-008-0505-z"},{"label":"NICE NG85: pancreatic cancer in adults","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"},{"label":"National Pancreatic Cancer Audit: State of the Nation 2026","url":"https://www.natcan.org.uk/reports/npaca-state-of-the-nation-report-2026/"},{"label":"Pancreatic Cancer UK","url":"https://www.pancreaticcancer.org.uk/"},{"label":"NHS: pancreatic cancer, symptoms","url":"https://www.nhs.uk/conditions/pancreatic-cancer/symptoms/"},{"label":"NHS: pancreatic cancer, tests and next steps","url":"https://www.nhs.uk/conditions/pancreatic-cancer/tests-and-next-steps/"},{"label":"NHS: pancreatic cancer, treatment","url":"https://www.nhs.uk/conditions/pancreatic-cancer/treatment/"},{"label":"NHS: pancreatic cancer, help and support","url":"https://www.nhs.uk/conditions/pancreatic-cancer/help-and-support/"},{"label":"NICE TA476: nab-paclitaxel with gemcitabine for untreated metastatic pancreatic cancer","url":"https://www.nice.org.uk/guidance/ta476/chapter/1-Recommendations"},{"label":"NICE TA440: pegylated liposomal irinotecan for pancreatic cancer after gemcitabine","url":"https://www.nice.org.uk/guidance/ta440/chapter/1-Recommendations"},{"label":"NICE TA750: olaparib maintenance for BRCA mutation-positive metastatic pancreatic cancer (terminated appraisal, December 2021)","url":"https://www.nice.org.uk/guidance/terminated/ta750"},{"label":"Pancreatic Cancer UK: just diagnosed with pancreatic cancer?","url":"https://www.pancreaticcancer.org.uk/information-and-support/just-diagnosed-with-pancreatic-cancer/"},{"label":"Pancreatic Cancer UK: if you can't have surgery (inoperable cancer)","url":"https://www.pancreaticcancer.org.uk/information-and-support/just-diagnosed-with-pancreatic-cancer/if-you-cant-have-surgery-inoperable-cancer/"},{"label":"Pancreatic Cancer UK: surgery to remove pancreatic cancer","url":"https://www.pancreaticcancer.org.uk/information-and-support/treatments-for-pancreatic-cancer/surgery-for-pancreatic-cancer/"},{"label":"Pancreatic Cancer UK: how is chemotherapy used for pancreatic cancer?","url":"https://www.pancreaticcancer.org.uk/information-and-support/treatments-for-pancreatic-cancer/chemotherapy/how-is-chemotherapy-used-for-pancreatic-cancer/"},{"label":"Pancreatic Cancer UK: diet and pancreatic cancer","url":"https://www.pancreaticcancer.org.uk/information-and-support/managing-symptoms-and-side-effects/diet-and-pancreatic-cancer/"},{"label":"Pancreatic Cancer UK: how do I take pancreatic enzyme replacement therapy?","url":"https://www.pancreaticcancer.org.uk/information-and-support/managing-symptoms-and-side-effects/diet-and-pancreatic-cancer/pancreatic-enzyme-replacement-therapy-pert/how-do-i-take-pancreatic-enzyme-replacement-therapy-if-i-have-pancreatic-cancer/"},{"label":"Pancreatic Cancer UK: managing diabetes if you have pancreatic cancer (type 3c diabetes)","url":"https://www.pancreaticcancer.org.uk/information-and-support/managing-symptoms-and-side-effects/diabetes-with-pancreatic-cancer/"},{"label":"Pancreatic Cancer UK: managing pancreatic cancer pain","url":"https://www.pancreaticcancer.org.uk/information-and-support/managing-symptoms-and-side-effects/managing-pancreatic-cancer-pain/"},{"label":"Pancreatic Cancer UK: treating jaundice if you have pancreatic cancer","url":"https://www.pancreaticcancer.org.uk/information-and-support/managing-symptoms-and-side-effects/managing-jaundice-if-you-have-pancreatic-cancer/"},{"label":"Pancreatic Cancer UK: dealing with the emotional impact of pancreatic cancer","url":"https://www.pancreaticcancer.org.uk/information-and-support/dealing-with-pancreatic-cancer/dealing-with-the-emotional-impact-of-pancreatic-cancer/"},{"label":"Pancreatic Cancer UK: work and money","url":"https://www.pancreaticcancer.org.uk/information-and-support/dealing-with-pancreatic-cancer/daily-life-with-pancreatic-cancer/work-and-money/"},{"label":"Pancreatic Cancer UK: information for families and friends","url":"https://www.pancreaticcancer.org.uk/information-and-support/support-for-you/information-for-family-members/"},{"label":"Pancreatic Cancer UK: family history of pancreatic cancer","url":"https://www.pancreaticcancer.org.uk/information-and-support/family-history-of-pancreatic-cancer/"},{"label":"Pancreatic Cancer UK: current developments in pancreatic cancer treatment","url":"https://www.pancreaticcancer.org.uk/information-and-support/treatments-for-pancreatic-cancer/current-developments-in-pancreatic-cancer-treatment/"},{"label":"Macmillan: managing symptoms of pancreatic cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/pancreatic-cancer/controlling-symptoms-of-pancreatic-cancer"},{"label":"Macmillan: chemotherapy for pancreatic cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/chemotherapy-for-pancreatic-cancer"},{"label":"Macmillan: types of surgery for pancreatic cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/pancreatic-cancer/types-of-surgery-for-pancreatic-cancer"},{"label":"Macmillan: questions to ask your healthcare team","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatment/your-treatment-options/questions-to-ask-your-healthcare-team"},{"label":"Macmillan: advanced cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatment/if-you-have-an-advanced-cancer"},{"label":"Macmillan: olaparib","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/olaparib"},{"label":"Macmillan: BRCA1 and BRCA2 genes","url":"https://www.macmillan.org.uk/cancer-information-and-support/worried-about-cancer/causes-and-risk-factors/brca-gene"},{"label":"Cancer Research UK: treatment options for pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/treatment/treatment-decisions"},{"label":"Cancer Research UK: surgery for pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/treatment/surgery"},{"label":"Cancer Research UK: chemotherapy for pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/treatment/chemotherapy"},{"label":"Cancer Research UK: radiotherapy for pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/treatment/about-radiotherapy"},{"label":"Cancer Research UK: controlling symptoms of advanced pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/treatment/controlling-symptoms"},{"label":"Cancer Research UK: follow up after treatment for pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/treatment/follow-up-appointment"},{"label":"Cancer Research UK: your diet and pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/living-with/diet"},{"label":"Cancer Research UK: coping and support when you have pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/living-with/coping"},{"label":"ESMO: pancreatic cancer, a guide for patients","url":"https://www.esmo.org/for-patients/patient-guides/pancreatic-cancer"},{"label":"Marie Curie: what are palliative care and end of life care?","url":"https://www.mariecurie.org.uk/information/getting-care/palliative-care"},{"label":"Conroy et al., FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer, PRODIGE 4/ACCORD 11 (NEJM 2011)","url":"https://doi.org/10.1056/NEJMoa1011923"},{"label":"Von Hoff et al., increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine, MPACT (NEJM 2013)","url":"https://doi.org/10.1056/NEJMoa1304369"},{"label":"Wainberg et al., NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive metastatic pancreatic cancer, NAPOLI 3 (Lancet 2023)","url":"https://doi.org/10.1016/S0140-6736(23)01366-1"},{"label":"Conroy et al., FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer, PRODIGE 24/CCTG PA6 (NEJM 2018)","url":"https://doi.org/10.1056/NEJMoa1809775"},{"label":"Neoptolemos et al., adjuvant gemcitabine and capecitabine versus gemcitabine alone, ESPAC-4 (Lancet 2017)","url":"https://doi.org/10.1016/S0140-6736(16)32409-6"},{"label":"Golan et al., maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer, POLO (NEJM 2019)","url":"https://doi.org/10.1056/NEJMoa1903387"},{"label":"Versteijne et al., neoadjuvant chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer, PREOPANC long-term results (JCO 2022)","url":"https://doi.org/10.1200/JCO.21.02233"},{"label":"Wyse et al., randomised double-blind trial of early EUS-guided coeliac plexus neurolysis to prevent pain progression in pancreatic cancer (JCO 2011)","url":"https://doi.org/10.1200/JCO.2010.32.2750"},{"label":"Roberts et al., enzyme replacement improves survival among patients with pancreatic cancer, population-based study (Pancreatology 2019)","url":"https://doi.org/10.1016/j.pan.2018.10.010"},{"label":"Phillips et al., consensus for the management of pancreatic exocrine insufficiency: UK practical guidelines (BMJ Open Gastroenterology 2021)","url":"https://doi.org/10.1136/bmjgast-2021-000643"},{"label":"Scholten et al., new-onset diabetes after pancreatoduodenectomy, systematic review and meta-analysis (Surgery 2018)","url":"https://doi.org/10.1016/j.surg.2018.01.024"},{"label":"Roeland et al., management of cancer cachexia, ASCO guideline (JCO 2020)","url":"https://doi.org/10.1200/JCO.20.00611"},{"label":"NHS: clinical trials","url":"https://www.nhs.uk/tests-and-treatments/clinical-trials/"},{"label":"NHS: genetic and genomic testing","url":"https://www.nhs.uk/tests-and-treatments/genetic-and-genomic-testing/"},{"label":"Macmillan: sepsis","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/sepsis"},{"label":"Macmillan: looking after someone with cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/supporting-someone/looking-after-someone-with-cancer"}],"tags":["gi","spike"],"related":["kras-roadmap","early-detection-roadmap","pancan","idea-drugging-myc","idea-nerve-tumour-blockade","pancreatic-adenosquamous-carcinoma","pancreatic-colloid-carcinoma","pancreatic-undifferentiated-carcinoma-ogc","ipmn-associated-carcinoma","mcn-associated-carcinoma","solid-pseudopapillary-neoplasm","pancreatic-acinar-cell-carcinoma","ipmn-cystic-precursors","pancreatoblastoma","pancreatic-net","ampullary","cholangiocarcinoma","pancreatic-roadmap","idea-pdac-new-onset-diabetes-risk-score-pathway","idea-pdac-surveillance-for-every-germline-carrier","idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease","idea-pdac-stromal-reprogramming-not-depletion","idea-pdac-ras-inhibitor-combinations-and-sequencing","idea-pdac-cachexia-trials-embedded-in-chemotherapy-trials","idea-pdac-enzyme-replacement-prescribing-by-default","idea-pdac-uk-active-treatment-rate-audit-and-target","idea-pdac-uk-fast-track-diagnosis-to-treatment-pathway","kras-g12d","kras-g12c","msi-high","dmmr-ihc","tmb-high","brca-germline","brca-somatic","hrd-positive","ctdna-mrd-positive","alk-fusion","ntrk-fusion"],"cancers":[],"sections":[],"technologies":["kras-inhibitors","neoantigen-mrna-vaccine","ttfields","fapi-pet","mced","car-t","irreversible-electroporation","omega3-epa-cachexia","mistletoe-extracts","gerson-therapy-detox-regimens","cytotoxic-chemotherapy","sbrt","mr-linac","shared-antigen-vaccine","germline-testing","pancreatic-surveillance","pdac-organoid-pharmacotyping","liquid-biopsy","ct","mri","pet-ct","endoscopic-ultrasound-systems","histopathology-ihc","staging-laparoscopy","oncology-nutrition","biliary-stenting-drainage","palliative-care","pain-management","enteral-parenteral-nutrition","prehabilitation","cancer-associated-thrombosis","multidisciplinary-tumour-board","psycho-oncology","peer-support-groups","cbt-fatigue-distress","exercise-during-chemotherapy","palliative-radiotherapy","parp-inhibitor","checkpoint-inhibitor","bispecific-antibody","chemoradiation","hypofractionated-radiotherapy","wes-wgs","rna-seq","mrd-testing","msi-mmr-testing","tmb-testing","hrd-testing","single-cell-spatial","spatial-transcriptomics","organoids","proteomics","methylation-profiling","cfdna-methylation-testing"],"targets":["kras","brca","cldn18-2","fap","mesothelin","her3","ntrk","parp","nrg1","braf","alk","fgfr2","tp53","cdkn2a","smad4","palb2","atm","mmr","gnas","rnf43","kdm6a","myc-gene","arid1a","her2"],"drugs":["catumaxomab","tegafur-gimeracil-oteracil","pancrelipase","pegvorhyaluronidase-alfa","pegilodecakin","napabucasin","gemcitabine","capecitabine","nab-paclitaxel","liposomal-irinotecan","irinotecan","oxaliplatin","fluorouracil","leucovorin","folfox","erlotinib","olaparib","pembrolizumab","dostarlimab","zenocutuzumab","larotrectinib","entrectinib","repotrectinib","sotorasib","adagrasib","daraxonrasib","optune","autogene-cevumeran","elraglusib","ibrutinib","ponsegromab","dabrafenib-trametinib","foundationone-cdx","caris-mi-cancer-seek","guardant360-cdx","trusight-oncology-comprehensive","tempus-xt-cdx","bracanalysis-cdx","ventana-mmr-rxdx","signatera","galleri","rucaparib","crizotinib"],"companies":["marker-therapeutics","orion-orion-pharma","crinetics-pharmaceuticals","oncolytics-biotech","shenzhen-ionova-life-sciences","ascentawits-pharmaceuticals","cebiotex","civatech-oncology","mbrace-therapeutics","molecular-partners","revolution-medicines","ipsen","novocure","biontech","elicio-therapeutics","astrazeneca","carsgen","bms"],"institutions":["pancreatic-cancer-uk","pancreatic-cancer-action","wolfson-wohl-cancer-research-centre","liverpool-hpb-centre","glasgow-royal-infirmary","hull-castle-hill","royal-stoke-uhnm","uhcw-coventry","royal-surrey-guildford","royal-blackburn-elht","ninewells-dundee","aberdeen-royal-infirmary","raigmore-inverness"],"pathways":["ras-mapk","ddr","pancreatic-cancer-signalling","emt","p53-cell-cycle","tgf-beta","wnt","swi-snf-chromatin","homologous-recombination-repair","mismatch-repair-msi","mutagenesis-signatures","myc","chromosomal-instability","clonal-evolution","caf-activation-desmoplasia","immune-desert-exclusion","antigen-presentation-immunoediting","pd1-checkpoint","tumor-microenvironment","hedgehog","autophagy","rtk-activation","epigenetic-reprogramming"],"terms":["ca19-9","desmoplasia","cold-vs-hot","mrd","hazard-ratio","nccn-resectability-criteria-pancreatic","pancreas-protocol-ct","distal-pancreatectomy","vascular-resection-pancreatic","pancreatic-enzyme-replacement","lewis-negative","panin","pancreatic-cyst-high-risk-stigmata","new-onset-diabetes-pancreatic-cancer","r0-r1-margin-pancreatic","neoadjuvant-versus-upfront-surgery-pancreatic","emergency-presentation","familial-pancreatic-cancer","classical-vs-basal-like","clinical-benefit-response","type-3c-diabetes-pancreatic-cancer","coeliac-plexus-block","eating-after-whipple","chemotherapy-side-effects-pancreatic","urgent-help-pancreatic-cancer","work-and-money-pancreatic-cancer-uk","carers-pancreatic-cancer-uk","whipple","resectability","resection-margins","locally-advanced","neoadjuvant-adjuvant","cachexia","obstructive-jaundice","tnm-staging","tumour-grade","germline-vs-somatic","stage-shift","sarcopenia","stent-or-bypass-for-jaundice","biliary-stent-problems","acute-cholangitis","jaundice-and-itch-biliary","duodenal-stenting-gastric-outlet","nutrition-impact-symptoms","peripheral-neuropathy","neutropenia","febrile-neutropenia","hand-foot-syndrome","mucositis","cancer-related-fatigue","vte","central-venous-access","performance-status","financial-toxicity","emotional-support-cancer-uk","malnutrition-screening","total-neoadjuvant-therapy","tumour-markers","gbrca-mutation","kras-mutation-subtypes","neoantigen","biliary-stent","ppv","pancreatic-trials-open-today","pancreatic-palliation-obstruction-pain-nutrition","pancreatic-cancer-uk-drug-access","pancreatic-failed-programmes","chemoradiation","cancer-drugs-fund","gata6-classical-basal-marker","kras-allelic-imbalance","caf-subtypes-pancreatic","compass-study-pancreatic","caps-consortium-pancreatic-screening","detect-a-study","ccga-study","ctdna","cfdna","ngs","msi","tmb","hrd","ihc","fish","wild-type","mutational-signature","immune-exclusion","tumour-agnostic","synthetic-lethality","driver-mutation","whole-genome-doubling","copy-number-variation-term","hereditary-cancer-syndromes","lynch-syndrome","founder-mutation","somatic-mutations-wxs-wgs","tumour-informed-assay","vus"],"trials":["mountaintap-30","nct06608927","nct07262567","nct07409272","nct07522073","nct06079346","nct07079228","nct05254171","nct07562152","g-hope-002","nct01954992","notable-trial","nct07491445","nct07219238","nct07805954","nct07252232","nct07621718","nct04969731","nct06361888","nct03257033","nct06953999","nct07165886","nct06784752","nct05653453","nct03972488","nct06861088","nct07232875","nct06752811","nct07087054","nct07823049","nct05884255","nct07238283","nct03899636","rasolute-302","napoli-3","prodige-24","preopanc","polo","panova-3","amplify-7p","europac","precede","precision-panc","espac-4","espac-5","conko-001","lap07","nct05968326","espac-1","jaspac-01","apact","swog-s1505","neonax","preopanc-2","alliance-a021806","preopanc-3","alliance-a021501","conko-005","autogene-cevumeran-phase-1","starpac2","primus-001","prodige-4-accord-11","mpact","napoli-1","conko-003","panoptimox-prodige-35","conko-007","neolap","scalop","scalop-2","crossfire","panfire-2","halo-301","sequoia","canstem111p","resolve","codebreak-100","eclipse","espac-3","norpact-1","nct03785249","nct02912949","nct05379985","keynote-158","precision-promise","actuate-1801","avenger-500","lapis-trial","trybeca-1","impress-trial","nct05737706","nct06989437"],"people":["randy-pausch","daniel-von-hoff","andrew-biankin","paula-ghaneh","daniel-palmer","chris-halloran","bill-greenhalf"],"bottlenecks":[],"keyPapers":["paper-burris-gemcitabine-pancreatic-jco-1997","paper-rahib-projecting-cancer-deaths-2030-cancerres-2014","paper-jones-pancreatic-core-pathways-science-2008","paper-biankin-pancreatic-exomes-axon-guidance-nature-2012","paper-witkiewicz-pancreatic-exomes-utsw-nat-commun-2015","paper-tcga-pancreatic-integrated-characterisation-cancer-cell-2017","paper-collisson-pancreatic-subtypes-nat-med-2011","paper-aung-compass-early-results-ccr-2018","paper-okane-gata6-basal-like-compass-ccr-2020","paper-chan-seng-yue-pancreatic-transcription-phenotypes-nat-genet-2020","paper-rashid-purist-pancreatic-subtype-classifier-ccr-2020","paper-puleo-pancreatic-tumour-microenvironment-subtypes-gastroenterology-2018","paper-topham-subtype-discordant-pancreatic-ccr-2021","paper-hayashi-squamous-basal-like-pancreatic-nat-cancer-2020","paper-andricovich-kdm6a-squamous-pancreatic-cancer-cell-2018","paper-aguirre-real-time-genomic-characterisation-pancreatic-cancer-discov-2018","paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019","paper-philip-kras-wild-type-pancreatic-ccr-2022","paper-singhi-alk-rearrangements-pancreatic-jnccn-2017","paper-oreilly-hechtman-ntrk-fusion-pancreatic-larotrectinib-ann-oncol-2019","paper-luchini-msi-dmmr-pancreatic-systematic-review-gut-2021","paper-shindo-germline-sporadic-pancreatic-jco-2017","paper-yurgelun-germline-second-hits-resected-pancreatic-genet-med-2019","paper-lowery-prospective-germline-exocrine-pancreatic-jnci-2018","paper-roberts-familial-pancreatic-whole-genome-cancer-discov-2016","paper-golan-brca-pancreatic-platinum-survival-bjc-2014","paper-park-hrd-pancreatic-platinum-ccr-2020","paper-reiss-rucaparib-maintenance-brca-palb2-pancreatic-jco-2021","paper-connor-mutational-signatures-immune-pancreatic-jama-oncol-2017","paper-qian-driver-genes-outcomes-resected-pancreatic-jama-oncol-2018","paper-bournet-kras-g12d-prognosis-pancreatic-ctg-2016","paper-iacobuzio-donahue-dpc4-failure-pattern-autopsy-jco-2009","paper-crane-smad4-progression-pattern-locally-advanced-jco-2011","paper-yachida-metastasis-late-genetic-evolution-pancreatic-nature-2010","paper-notta-punctuated-evolution-pancreatic-nature-2016","paper-makohon-moore-metastases-driver-homogeneity-nat-genet-2017","paper-makohon-moore-precursor-cells-ductal-system-nature-2018","paper-hruban-panin-nomenclature-ajsp-2001","paper-basturk-baltimore-consensus-precursor-lesions-ajsp-2015","paper-kanda-panin-1-somatic-mutations-gastroenterology-2012","paper-wu-gnas-ipmn-sci-transl-med-2011","paper-wu-pancreatic-cyst-exomes-rnf43-pnas-2011","paper-springer-pancreatic-cyst-molecular-classification-gastroenterology-2015","paper-omori-ipmn-progression-pathways-gastroenterology-2019","paper-felsenstein-ipmn-cooccurring-cancer-relatedness-gut-2018","paper-noe-cyst-malignant-progression-genomics-nat-commun-2020","paper-olive-hedgehog-stroma-gemcitabine-delivery-science-2009","paper-rhim-stroma-restrains-pancreatic-cancer-cell-2014","paper-ohlund-caf-subtypes-mycaf-icaf-jem-2017","paper-elyada-antigen-presenting-cafs-single-cell-cancer-discov-2019","paper-feig-cxcl12-fap-cafs-t-cell-exclusion-pnas-2013","paper-grunwald-subtme-pancreatic-cell-2021","paper-royal-ipilimumab-pancreatic-j-immunother-2010","paper-brahmer-anti-pd-l1-phase-1-nejm-2012","paper-oreilly-durvalumab-tremelimumab-pancreatic-jama-oncol-2019","paper-balachandran-neoantigen-quality-long-term-survivors-nature-2017","paper-bear-pancreatic-immunotherapy-review-cancer-cell-2020","paper-ho-pancreatic-tumour-microenvironment-review-nrco-2020","paper-goonetilleke-ca19-9-systematic-review-ejso-2007","paper-hess-ca19-9-response-chemotherapy-lancet-oncol-2008","paper-yeh-ca19-9-lewis-negative-fut3-cutoff-ccr-2026","paper-sausen-ctdna-pancreatic-resection-nat-commun-2015","paper-pietrasz-ctdna-prognostic-pancreatic-ccr-2017","paper-bernard-ctdna-exodna-pancreatic-gastroenterology-2019","paper-groot-kras-ctdna-clinical-test-resected-pancreatic-ccr-2019","paper-lee-ctdna-adjuvant-benefit-localized-pancreatic-ann-oncol-2019","paper-cohen-ctdna-protein-liquid-biopsy-pancreatic-pnas-2017","paper-cohen-cancerseek-multi-analyte-blood-test-science-2018","paper-klein-ccga3-mced-validation-ann-oncol-2021","paper-gonda-precede-consortium-recommendations-gastroenterology-2021","paper-worthington-precede-early-detection-biomarkers-ijc-2026","paper-heining-nrg1-fusions-kras-wild-type-pancreatic-cancer-discov-2018","paper-jones-nrg1-fusions-recurrent-actionable-kras-wild-type-pdac-ccr-2019","paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018","paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023","paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023","paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019","paper-polo-overall-survival-olaparib-gbrca-pancreatic-jco-2022","paper-pishvaian-lancet-oncol","paper-enrgy-zenocutuzumab-nrg1-fusion-positive-cancer-nejm-2025","paper-daraxonrasib-pancreatic-n-engl-j-med-2026","paper-halo-301-pegvorhyaluronidase-jco-2020","paper-yamamoto-nature","paper-waddell-whole-genomes-pancreatic-nature-2015","paper-bailey-molecular-subtypes-pancreatic-nature-2016","paper-moffitt-virtual-microdissection-subtypes-nat-genet-2015","paper-keynote-158-pembrolizumab-msi-high-noncolorectal-jco-2020","paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018","paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014","paper-tempero-ca19-9-lewis-antigens-cancer-res-1987","paper-fahrmann-ca19-9-lead-time-gastroenterology-2021","paper-detect-a-science-2020","paper-canto-caps-long-term-surveillance-gastroenterology-2018","paper-caps-consortium-surveillance-recommendations-gut-2020","paper-dbouk-caps5-stage-survival-jco-2022","paper-sharma-endpac-model-new-onset-diabetes-gastroenterology-2018"],"journals":["journal-of-gastrointestinal-cancer"],"dependsOn":[],"notes":["Is pancreatic cancer the same as pancreatic ductal adenocarcinoma? Almost always: about 80 percent of pancreatic cancers are ductal adenocarcinomas (Cancer Research UK types page), and this record describes that disease. The rarer types (acinar cell carcinoma, the cystic tumours and the carcinomas that arise in them, solid pseudopapillary neoplasm, pancreatoblastoma) and the neuroendocrine tumours of the islets each have a page linked from this one and behave differently.","How common is it? 531,318 new cases and 490,786 deaths a year worldwide (GLOBOCAN 2024), 11,479 cases and about 10,200 deaths a year in the UK, where it is the 10th commonest cancer but the 5th commonest cause of cancer death (Cancer Research UK), and 67,530 cases and 52,740 deaths projected in the United States for 2026, where it is the third leading cause of cancer death (SEER). The UK lifetime risk is about 1 in 55 to 1 in 59.","Is it getting more common? Yes. UK incidence rates are up 21 percent since the early 1990s and 7 percent in the last decade, and the count is projected to reach about 16,000 a year by 2038 to 2040 (Cancer Research UK); incidence rose in 14 of 48 countries for men and 17 for women over a decade (Huang 2021); and in the United States it is projected to be the second leading cause of cancer death by 2040 (Rahib 2021). Ageing populations, obesity and diabetes are the usual explanations; mortality rates have not fallen because treatment gains have been small until recently.","What raises the risk? Age above all (median 71 in the United States). Smoking doubles the risk (2.2 times for current smokers, back to normal 20 years after quitting) and causes 22 percent of UK cases; obesity carries about 1.5 times the risk and causes 12 percent; type 2 diabetes about 1.8 to 1.9 times; chronic pancreatitis about 8 times at five years; a first-degree relative with the disease 1.6 to 1.8 times; alcohol at 3 or more units a day 15 to 19 percent more (Bosetti 2012; Genkinger 2011; Huxley 2005; Ben 2011; Kirkegard 2017; Cancer Research UK). About 5.5 percent of patients carry an inherited variant in ATM, BRCA2, BRCA1, CDKN2A, TP53 or MLH1, most without a family history (Hu 2018; Shindo 2017).","I have just been told I have diabetes. Should I worry? For most people, no: about 1 in 100 adults who develop diabetes after 50 is diagnosed with pancreatic cancer within three years (Chari 2005). But new diabetes with weight loss rather than weight gain, or diabetes that suddenly becomes hard to control, is a recognised warning sign: NICE NG12 lists new-onset diabetes with weight loss at 60 or over as a reason for an urgent CT, and research scores such as ENDPAC use weight change, glucose change and age to pick out the small group who need a scan (Sharma 2018).","Why is it found so late? The early tumour causes no symptoms; when symptoms come they are vague (back pain, indigestion, weight loss) unless the tumour blocks the bile duct and causes jaundice, which is why head tumours are found earlier than body and tail tumours. In England in 2019, 45 percent of cases were diagnosed after an emergency presentation and only 22 percent through an urgent suspected cancer referral; only about a quarter are stage I or II at diagnosis (Cancer Research UK). In the SYMPTOM study no first symptom distinguished people who turned out to have cancer from those who did not (Walter 2016).","Which tests will I have? A pancreatic protocol CT first (before any stent if you are jaundiced), then PET-CT and or endoscopic ultrasound with a needle sample if the diagnosis is unclear, blood tests including CA 19-9, and, if surgery is possible, sometimes MRI of the liver or a keyhole look inside the abdomen (NICE NG85 1.1 and 1.3). A biopsy is often not needed before surgery when the scan is clear (Cancer Research UK). Everyone should be offered a genetic (germline) test.","What do resectable, borderline resectable and locally advanced mean? They describe how the tumour sits against the arteries and veins behind the pancreas on the CT scan, and they decide whether surgery comes first, after chemotherapy, or not at all: resectable means no arterial contact and limited venous contact; borderline resectable means arterial contact of less than 180 degrees or venous involvement the surgeon can reconstruct (or a very high CA 19-9, or uncertain spread, or poor fitness); locally advanced means the tumour encases an artery or blocks a vein beyond repair (Isaji 2018; NCCN). The stage number (1 to 4) is a separate description of size, nodes and spread.","What does an R1 margin on my pathology report mean? In the UK, cancer cells within 1 mm of the cut edge of the removed tissue, even if not touching it (Royal College of Pathologists; Campbell 2009). Reported this way, most head-of-pancreas resections are R1 (76 to 85 percent in the studies that introduced the rule) because the tumour spreads along nerves and vessels behind the gland; it does not mean the operation failed, and adjuvant chemotherapy is given whatever the margin. Direct involvement of a margin carries a worse outlook than involvement within 1 mm (Ghaneh 2019).","Should my relatives be screened? There is no NHS screening programme for the general population and none is recommended (UK National Screening Committee; the US task force advises against it). Surveillance with yearly MRI/MRCP or endoscopic ultrasound is offered to people with hereditary pancreatitis and a PRSS1 mutation, to carriers of BRCA1, BRCA2, PALB2 or CDKN2A who have an affected first-degree relative, and to Peutz-Jeghers syndrome, and considered for two or more affected first-degree relatives across two generations or Lynch syndrome with an affected relative (NICE NG85 1.1.15 to 1.1.17). In the CAPS programmes 77.8 percent of cancers found under surveillance were stage I and five-year survival was 73.3 percent (Dbouk 2022). Ask the team for a referral to genetics; the trial record for PRECEDE and the EUROPAC registry are linked from this page.","Why have I been given enzyme capsules? Most pancreatic cancers block the duct that carries digestive enzymes, so fat is not absorbed and weight falls. NICE offers enteric-coated pancreatin to everyone with unresectable disease and considers it before and after surgery (NG85 1.6); in UK primary care records only 21.7 percent of patients received it, and those who did lived longer in a matched comparison (Roberts 2019). Fish oils are not recommended for weight loss (NG85 1.6.3).","What is the outlook? Averages hide a wide range. Across everyone in the United States 13.7 percent are alive at five years; for the 15 percent found while confined to the pancreas it is 43.6 percent, and resected patients who complete modern adjuvant chemotherapy do better still (the treatment rows carry those trial figures); for distant disease it is 3.4 percent (SEER). In the UK about 25 percent survive one year and about 5 percent ten years (Cancer Research UK). These figures predate the 2026 RAS inhibitor results and are population averages, not a personal prognosis.","The science in detail, 1 of 7 (the molecular layer; the headline is on the overview). Genomic landscape. KRAS mutation in 88 to 94% (G12D about 40%, G12V about 32%, G12R about 16%, Q61 about 7%, G12C 1 to 2%), TP53 66 to 76%, CDKN2A loss 37 to 48% with CDKN2B and often MTAP, SMAD4 loss 17 to 33%, RNF43 5 to 8%, ARID1A 5 to 9%, KDM6A 3 to 4%, GNAS R201 2 to 4%, MYC amplification 4 to 13%. The 6 to 12% of KRAS wild-type tumours carry the fusions and alternative drivers instead: BRAF mutation 13% and fusion 6.6% of them, FGFR2 5.2%, ALK 2.6%, NRG1 1.3%, RET 1.3%, with MSI-high 4.7% against 0.7%. Germline: BRCA2 1.4 to 2%, ATM 1.2 to 2.3%, BRCA1 0.4 to 1%, PALB2 0.2 to 0.6%, any susceptibility gene 4 to 10% and no family history in most carriers. Homologous recombination deficiency by gene mutation 11 to 19%; mismatch repair deficiency 1 to 2%; TMB 10 or more, 1 to 2%. Every figure and cohort is in the molecular table; the cBioPortal rows were computed on TCGA, QCMG, ICGC, UTSW, CPTAC and the two 2024 MSK cohorts.","The science in detail, 2 of 7 (the molecular layer; the headline is on the overview). Transcriptional subtypes. Two survive every re-analysis: classical (GATA6-high) and basal-like or squamous (GATA6-low). In COMPASS, basal-like was 20% of 195 advanced patients, with response to first-line chemotherapy 10% against 33%, progression on modified FOLFIRINOX 60% against 15% and median overall survival 5.9 against 9.3 months; a GATA6 in situ hybridisation stain calls the subtype with sensitivity 89% and specificity 83%. Collisson's three, Bailey's four (squamous, progenitor, immunogenic, ADEX) and Puleo's five map onto the same axis; the exocrine-like and ADEX classes were acinar contamination. Subtype is a continuum set by mutant KRAS and GATA6 copy number, about 12% of tumours are hybrids with intermediate survival, and squamous histology is the tissue form of the basal-like signature, often as a subclone.","The science in detail, 3 of 7 (the molecular layer; the headline is on the overview). Precursors. More than 99% of the smallest PanIN-1 lesions already carry KRAS, CDKN2A, GNAS or BRAF mutations; grading is now two-tier (Baltimore consensus 2015). IPMNs carry GNAS R201 in 66% and RNF43 in most, mucinous cystic neoplasms RNF43 without GNAS, and both are direct precursors, with SMAD4 and TGFBR2 loss marking the invasive step and about three years between high-grade dysplasia and cancer. A cancer beside a cyst is related in 51% of cases and independent in 18%. The classical KRAS-CDKN2A-TP53-SMAD4 ladder is only part of the story: two-thirds of genomes show punctuated, mitotic-error rearrangements that can knock out several drivers at once, and precursor cells travel along the ducts.","The science in detail, 4 of 7 (the molecular layer; the headline is on the overview). Stroma and immunity. The desmoplastic stroma limits perfusion, but removing it is harmful: depleting myofibroblasts or hedgehog signalling gave more aggressive tumours in mice, and hyaluronidase raised the response rate without changing survival in phase 3. Fibroblasts exist as myofibroblastic, inflammatory and antigen-presenting states, and tissue organises into reactive (immune-hot) and deserted (chemoprotective) neighbourhoods. T cells are excluded by CXCL12 from FAP-positive fibroblasts, and MHC class I is degraded by autophagy. Every checkpoint trial outside mismatch repair deficiency has failed: ipilimumab 0 of 27, anti-PD-L1 0 of 14, durvalumab with or without tremelimumab 3.1% and 0% of 65. The exceptions point the way: long-term survivors have both many high-quality neoantigens and abundant CD8 T cells, and those clones are edited out at metastasis.","The science in detail, 5 of 7 (the molecular layer; the headline is on the overview). Monitoring. CA 19-9 has pooled sensitivity 79% and specificity 82%, rises with cholestasis, and cannot be made at all by the roughly 10% of patients who are Lewis-negative (FUT3-null), whose median level is 2.4 against 496 U/mL and whose survival matches the worst marker group; a value of 7 U/mL or below identifies them with 95% positive predictive value. Baseline level is prognostic but a 50% fall on treatment is not a valid surrogate for survival. ctDNA is found in 43 to 62% of localised disease before surgery and 37 to 49% after it, predicts recurrence with 90% sensitivity about three months before imaging, and grades risk by allele fraction; most assays read only KRAS codons 12, 13 and 61, and no approval uses it.","The science in detail, 6 of 7 (the molecular layer; the headline is on the overview). Early detection, research only. CAPS surveillance of high-risk individuals shifted 57.9% of detected cancers to stage I with median overall survival 9.8 against 1.5 years; the consensus starts at 50 or ten years before the youngest affected relative with annual endoscopic ultrasound and MRI. PRECEDE is building the international cohort and biomarker validation under a PROBE design. Blood tests are not ready: CA 19-9 turns up about two years before diagnosis, multi-analyte panels reach 64% sensitivity in resectable disease at 99.5% specificity, and the methylation test reads 16.8% sensitivity at stage I. New-onset diabetes is the strongest clinical enrichment, with about 1% of people over 50 diagnosed within three years and the ENDPAC score giving a 4.4-fold enrichment.","The science in detail, 7 of 7 (the molecular layer; the headline is on the overview). Testing, in practice. Germline panel testing at diagnosis for every patient (BRCA1, BRCA2, PALB2, ATM, CDKN2A, TP53 and the mismatch repair genes), tumour sequencing with RNA for fusions where KRAS reads wild-type, mismatch repair immunohistochemistry especially for medullary and colloid tumours, allele-level KRAS reporting because the alleles differ in prognosis and in which inhibitor applies, and GATA6 or a subtype classifier where a trial requires it. Homologous recombination scores, ctDNA and TROP2-style expression readouts have no pancreatic label.","Frequencies marked cBioPortal were computed from the public API on 24 September 2026 on the sequenced sample lists of paad_tcga_pan_can_atlas_2018 (184 samples), paad_qcmg_uq_2016 (383 sequenced), paad_icgc (99), paad_utsw_2015 (109), paad_cptac_2021 (140), pdac_msk_2024 (2,336) and pancreas_msk_2024 (395), as sample-level counts of non-synonymous mutation, high-level amplification, deep deletion or structural variant; they are not the papers' own percentages, which are quoted alongside.","KRAS allele shares are counts of mutation records over all KRAS mutation records in a study, so a tumour with two KRAS mutations counts twice; the MSK study's own KRAS_VARIANT attribute gives the same ordering. The TCGA deposit reads KRAS in 65% because it keeps the low-cellularity and non-ductal samples the 2017 paper excluded; purified or microdissected cohorts read 92 to 96%.","Panel and exome figures are not interchangeable: copy-number amplification calls run lower on the MSK panel than on TCGA or UTSW arrays and exomes, and the panel TMB median (about 3 per megabase) is three times the exome median."],"group":"gastrointestinal","burden":"531,318 new cases and 490,786 deaths a year worldwide (GLOBOCAN 2024; 11th commonest cancer, 6th commonest cause of cancer death). 11,479 UK cases and about 10,200 UK deaths a year (Cancer Research UK); 67,530 US cases and 52,740 deaths projected for 2026 (SEER). Incidence is rising (21 percent in the UK since the early 1990s) and 45 percent of English cases arrive as emergencies.","subtypes":["Classical (GATA6-high, better prognosis, more chemosensitive)","Basal-like / squamous (GATA6-low, chemotherapy-resistant)","KRAS-wild-type (~10%; NRG1, NTRK, ALK, BRAF fusions; MSI-H)","Germline-driven (BRCA2, PALB2, ATM, CDKN2A, STK11)","Pancreatic neuroendocrine tumours (a different disease with its own record, linked from this page)","Adenosquamous carcinoma of the pancreas (squamous component of at least 30 percent; about 1 percent of cases; body and tail; worse after resection)","Colloid (mucinous non-cystic) carcinoma of the pancreas (mucin pools; usually the invasive part of an intestinal-type IPMN; better outlook)","Undifferentiated carcinoma with osteoclast-like giant cells (1.4 percent of resected pancreatic cancers; five-year survival 59 percent)","Undifferentiated (anaplastic) carcinoma without giant cells (aggressive; treated as ductal PDAC)","Invasive carcinoma arising in an IPMN (tubular or colloid type; 10 percent of resections; staged and treated as ductal adenocarcinoma)","Mucinous cystic neoplasm with associated invasive carcinoma (women, body and tail; 4 to 12 percent of resected MCNs)","Solid pseudopapillary neoplasm (young women; CTNNB1; low-grade malignant; cured by resection in about 95 percent)"],"biomarkers":["CA 19-9 (prognosis and monitoring)","KRAS mutation subtype (G12D about 40%, G12V about 32%, G12R about 16%, Q61 about 7%, G12C 1 to 2%; cohort ranges in the molecular table; wild-type triggers fusion testing)","Germline panel (BRCA1/2, PALB2, ATM, CDKN2A, STK11, Lynch)","HRD / platinum sensitivity","GATA6 (classical vs basal-like)","ctDNA (KRAS-mutant cfDNA) for MRD and response","FAPI PET avidity (investigational)","CLDN18.2 IHC (trials)","CA 19-9 with Lewis status: falsely low in the 5 to 10 percent who are Lewis-negative; above 500 U/mL counts as biological borderline resectability","Resectability class on pancreas protocol CT (degrees of arterial contact; venous contact and reconstructability), reported on a standard template","Resection margin by the 1 mm rule (R0 more than 1 mm; R1 within 1 mm; R1 direct), the strongest surgeon- and pathologist-controlled prognostic factor","KRAS activating mutation (any allele): 88-94%","KRAS G12D g12d allele (share of kras mutation records): 39-41%","KRAS G12V g12v allele (share of kras mutation records): 28-37%","KRAS G12R g12r allele (share of kras mutation records): 12-21%","KRAS Q61 q61h, q61r, q61l or q61k allele (share of kras mutation records): 5-8%","KRAS G12C g12c allele (share of kras mutation records): 1-2%","KRAS wild-type no kras mutation (fusion and alternative-driver search): 6-12%","NRG1 gene fusion (atp1b1-nrg1, cd44-nrg1 and others): 0.3-1%","BRAF mutation (v600e, in-frame deletion) or fusion: 1-3%","ALK gene fusion (eml4-alk, strn-alk): 0.2%","NTRK1 / NTRK3 gene fusion (etv6-ntrk3, ctrc-ntrk1): 0.4%","FGFR2 gene fusion: 0.2%","TP53 mutation: 66-76%","CDKN2A mutation or deep deletion (with cdkn2b and mtap co-deletion): 37-48%","SMAD4 (DPC4) mutation or deep deletion: 17-33%","BRCA2 germline pathogenic variant: 1.4-2%","BRCA1 germline pathogenic variant: 0.4-1%","PALB2 germline or somatic pathogenic variant: 0.2-0.6%","ATM germline pathogenic variant (somatic in a further 3 to 4%): 1.2-2.3%","Any germline susceptibility gene pathogenic germline variant (multigene panel): 4-10%","Homologous recombination deficiency hrd (core or biallelic hr gene mutation, unstable genome or signature 3): 11-19%","MLH1 / MSH2 / MSH6 / PMS2 mismatch repair deficiency or microsatellite instability: 0.5-2%","Tumour mutational burden tmb 10 or more mutations per megabase: 1-2%","GNAS r201 hotspot mutation (ipmn-derived tumours): 2-4%","RNF43 inactivating mutation: 5-8%","KDM6A inactivating mutation or structural disruption: 3-4%","MYC amplification: 4-13%","ARID1A inactivating mutation (swi/snf and chromatin genes): 5-9%","GATA6 amplification (classical lineage marker): 15-17%","ERBB2 (HER2) amplification (mutation in a further 1%): 1-5%"],"standardOfCare":[{"setting":"High-risk surveillance","approach":"Annual MRI/MRCP or EUS for germline carriers and familial kindreds (CAPS/PRECEDE); germline testing for every diagnosed patient and first-degree relatives.","refs":["pancreatic-surveillance","germline-testing","mri","precede"]},{"setting":"Resectable / borderline","approach":"Neoadjuvant mFOLFIRINOX (borderline; increasingly resectable), surgery, then adjuvant mFOLFIRINOX to complete ~6 months (PRODIGE 24); gemcitabine/capecitabine if unfit. Chemoradiation selectively (PREOPANC).","refs":["folfirinox","prodige-24","preopanc","robotic-surgery"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Locally advanced unresectable","approach":"FOLFIRINOX or gem/nab-paclitaxel; TTFields with gem/nab-paclitaxel (Optune Pax, 2026); SBRT or MR-guided ablative radiotherapy; IRE in selected centres; reassess for conversion surgery.","refs":["panova-3","optune","gemcitabine-nab-paclitaxel","sbrt"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Metastatic, first line","approach":"mFOLFIRINOX or NALIRIFOX (fit) or gemcitabine/nab-paclitaxel; olaparib maintenance if gBRCA after ≥16 weeks platinum; zenocutuzumab if NRG1 fusion; pembrolizumab if MSI-H; trials of RAS inhibitors + chemotherapy.","refs":["nalirifox","napoli-3","polo","zoldonrasib"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Metastatic, second line","approach":"Daraxonrasib after one prior line (FDA approval 26 August 2026; RASolute 302: OS 13.2 vs 6.7 months, HR 0.40); otherwise switch backbone (gem/nab-pac after FOLFIRINOX, or liposomal irinotecan/5-FU after gemcitabine). No European or UK decision on daraxonrasib by 24 September 2026.","refs":["rasolute-302","daraxonrasib"]},{"setting":"Diagnosis and staging (UK pathway)","approach":"Pancreatic protocol CT of chest, abdomen and pelvis before any biliary drainage; FDG PET-CT for localised disease before treatment; EUS with tissue sampling when a diagnosis or node staging is needed; MRI for suspected liver metastases and laparoscopy with laparoscopic ultrasound before an attempted resection when small-volume spread is suspected; CA 19-9 at baseline; germline testing for every patient; decision by a specialist pancreatic multidisciplinary team.","refs":["ct","pet-ct","endoscopic-ultrasound-systems","mri","staging-laparoscopy","ca19-9","germline-testing","pancreas-protocol-ct","nccn-resectability-criteria-pancreatic"],"guideline":{"version":"NICE NG85: pancreatic cancer in adults, diagnosis and management (2018)","url":"https://www.nice.org.uk/guidance/ng85"}},{"setting":"Nutrition and pancreatic enzyme replacement","approach":"Enteric-coated pancreatin for everyone with unresectable disease and consideration before and after resection; early enteral rather than parenteral nutrition after pancreatoduodenectomy; no fish oils for weight loss in unresectable disease; dietitian assessment for the weight loss, malabsorption and cachexia that affect most patients.","refs":["pancreatic-enzyme-replacement","oncology-nutrition","nutrition-screening-mnt","cachexia"],"guideline":{"version":"NICE NG85: pancreatic cancer in adults, diagnosis and management (2018)","url":"https://www.nice.org.uk/guidance/ng85"}},{"setting":"Resectable or borderline: surgery first or chemotherapy first","approach":"About one in five pancreatic cancers can be removed at diagnosis (the OnCo record; Pancreatic Cancer UK says only a small number of people can have surgery), and the word the multidisciplinary team gives you decides the order. Resectable (no contact with the main arteries, no more than abutment of the veins, no spread): NICE NG85 says surgery first, and only consider chemotherapy before surgery within a clinical trial; the operation is usually a Whipple procedure for the head of the pancreas or a distal pancreatectomy for the body and tail, followed by six months of chemotherapy. Borderline resectable (the tumour touches a main vein or artery, so an operation straight away would probably leave cancer behind): chemotherapy first for two to four months, usually modified FOLFIRINOX, then restaging, with surgery about 6 to 8 weeks after chemotherapy if the disease has not spread; NICE NG85 also places this within a trial, and Cancer Research UK says your doctor may offer one because the best treatment is uncertain. In the Dutch PREOPANC trial, chemoradiotherapy before surgery improved five-year survival over surgery first (20.5% against 6.5%), most clearly for borderline disease; the record's open problems note the question is unresolved for resectable disease after PREOPANC-2, NORPACT-1 and Alliance A021806. Fitness matters as much as anatomy: only people well enough for a major operation are offered one, prehabilitation (exercise, nutrition, stopping smoking) is offered in some hospitals, and if jaundice needs relieving first a metal stent is placed. A second opinion from a specialist pancreatic centre is reasonable when the scan is read differently by different teams.","refs":["resectability","whipple","folfirinox","preopanc","espac-5","prehabilitation","resectable-pdac","borderline-resectable-pdac","multidisciplinary-tumour-board"],"guideline":{"version":"NICE NG85 (2018, updated): pancreatic cancer in adults, 1.7 and 1.8","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Which chemotherapy: FOLFIRINOX, gemcitabine with nab-paclitaxel or NALIRIFOX, by fitness","approach":"Three combinations are used for cancer that cannot be removed, chosen by how well you are (performance status), your liver tests, any nerve damage and what you prefer. FOLFIRINOX (fluorouracil, folinic acid, irinotecan and oxaliplatin, every two weeks with a 46-hour pump): NICE NG85 offers it to people with metastatic disease and a performance status of 0 to 1; in the 2011 trial median survival was 11.1 months against 6.8 with gemcitabine, with more diarrhoea, neuropathy and low blood counts, so most UK units give the modified doses. Gemcitabine with nab-paclitaxel (weekly drips for three weeks in four): improved survival over gemcitabine alone in MPACT (8.5 against 6.7 months) and causes hair loss, neuropathy and low counts; NICE TA476 funds it on the NHS only when other combinations are unsuitable and gemcitabine alone would otherwise be given. NALIRIFOX (liposomal irinotecan, oxaliplatin, fluorouracil): in NAPOLI 3 median survival was 11.1 months against 9.2 with gemcitabine and nab-paclitaxel; it is on the OnCo record beside modified FOLFIRINOX for fit patients but NHS funding follows NICE appraisals, so ask what applies where you are treated. Gemcitabine alone, or GemCap, for people not well enough for these; best supportive care when chemotherapy would do harm. Everyone has a DPD blood test before fluorouracil or capecitabine, blood counts before each dose, scans about every three months, and the same temperature rule for the 24-hour line. Second line follows NICE NG85: an oxaliplatin-based regimen if you have not had oxaliplatin, a gemcitabine-based one after FOLFIRINOX; liposomal irinotecan with fluorouracil after gemcitabine is not NICE-recommended (TA440). Daraxonrasib after first-line chemotherapy is on the record's second-line row.","refs":["folfirinox","gemcitabine-nab-paclitaxel","nalirifox","gemcitabine","napoli-3","peripheral-neuropathy","performance-status","metastatic-pdac","locally-advanced-pdac"],"guideline":{"version":"NICE NG85, 1.9; NICE TA476; NICE TA440","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Chemotherapy after a Whipple operation","approach":"Chemotherapy after the operation is what turns surgery into a real chance of cure. NICE NG85 says start once you have had time to recover and as soon as you are well enough to tolerate all six cycles, offers gemcitabine plus capecitabine (GemCap, from ESPAC-4: median survival 28.0 months against 25.5 with gemcitabine alone) and considers gemcitabine alone for those not well enough for a combination; since PRODIGE 24 (2018), modified FOLFIRINOX has become the standard for fit patients, with a median survival of 54.4 months against 35.0 with gemcitabine in the 2018 report (53.5 against 35.5 months at the five-year update in 2022), at the cost of more diarrhoea, neuropathy and tiredness, and Pancreatic Cancer UK lists all three as the options, chosen by how well you are. Cancer Research UK and Pancreatic Cancer UK say it should start within 12 weeks (3 months) of surgery and lasts up to 6 months, so sorting out eating, weight, enzyme doses and blood sugar in the weeks after the operation matters: they are the usual reasons for a delay. Ask what the pathology showed about the resection margin (R0 or R1) and the lymph nodes. Follow-up after chemotherapy is usually a CT scan every 6 months for 5 years with blood tests and sometimes CA 19-9; contact the team about any new symptom between visits.","refs":["folfirinox","prodige-24","gemcitabine","capecitabine","whipple","ca19-9","resectable-pdac"],"guideline":{"version":"NICE NG85, 1.8.5 to 1.8.9","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Germline testing: what a BRCA result means for olaparib and for your family","approach":"About one in ten pancreatic cancers runs in families (Pancreatic Cancer UK), and the OnCo record asks for a germline panel (BRCA1, BRCA2, PALB2, ATM, CDKN2A, STK11 and the Lynch genes) for everyone diagnosed. Three things follow from a BRCA1 or BRCA2 (or PALB2) result. Treatment: platinum chemotherapy (FOLFIRINOX or NALIRIFOX, which contain oxaliplatin) is favoured, and in the POLO trial maintenance olaparib after at least 16 weeks of platinum without progression lengthened the time before the cancer grew (7.4 against 3.8 months) without lengthening survival overall; NICE could not make a recommendation on olaparib in pancreatic cancer (TA750, terminated December 2021) because the company made no submission, so ask what is funded where you are treated. Family: Macmillan says each child of a carrier has a 1 in 2 chance of inheriting the variant; the genetics team can offer relatives predictive testing, and NICE NG85 says offer pancreatic surveillance (MRI/MRCP or EUS) to people with BRCA1, BRCA2, PALB2 or CDKN2A variants who have a first-degree relative with pancreatic cancer, and to those with Peutz-Jeghers syndrome or hereditary pancreatitis. Time: results usually take weeks to a few months; a variant of uncertain significance means the effect on risk is not yet known and the genetics team will explain it. Tumour testing (KRAS subtype, NRG1 and other fusions, mismatch repair) is separate and decides trial eligibility and the rare targeted drugs on the record.","refs":["germline-testing","brca","olaparib","polo","brca-palb2-pdac","folfirinox"],"guideline":{"version":"NICE NG85, 1.1.14 to 1.1.19; NICE TA750 (terminated)","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Jaundice: a stent or surgery","approach":"Jaundice (yellow eyes or skin, dark urine, pale stools, itch) means the tumour is blocking the bile duct, and how it is relieved depends on the plan for the cancer. NICE NG85 says: if the cancer is resectable and you are well enough, offer the operation rather than draining the duct first (unless a trial requires drainage); if you are not yet fit for surgery, or will have chemotherapy first, offer a self-expanding metal stent placed by endoscopy (ERCP), a fully covered one where it may need removing later; if the cancer cannot be removed, offer a metal stent rather than a surgical bypass; and consider a surgical bypass (and a prophylactic gastrojejunostomy) only when the cancer turns out to be unresectable during an attempted resection. Pancreatic Cancer UK says most people feel better within a couple of days of a stent, the jaundice takes two to three weeks to clear completely, and that relieving it may be what allows chemotherapy to start; the problems are blockage (symptoms return), infection (antibiotics), the stent moving, and pancreatitis from the procedure. If ERCP fails the stent is placed through the skin (PTC). Macmillan says plastic stents may need replacing and metal ones usually do not. A blocked duodenum (vomiting large amounts, feeling full) is treated with a duodenal stent, or a gastrojejunostomy for people expected to live longer.","refs":["biliary-stenting-drainage","stent-or-bypass-for-jaundice","biliary-stent-problems","acute-cholangitis","obstructive-jaundice","duodenal-stenting-gastric-outlet"],"guideline":{"version":"NICE NG85, 1.7 relieving biliary and duodenal obstruction","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Pain, including a coeliac plexus block","approach":"Many people with pancreatic cancer have pain in the upper tummy or back, often because the tumour presses on the coeliac plexus, the bundle of nerves behind the pancreas; Pancreatic Cancer UK says asking for help early makes it easier to control. The steps Cancer Research UK describes: paracetamol and anti-inflammatories, then weak and strong opioids (morphine-based medicines as tablets, liquids, patches or injections) with regular laxatives because opioids constipate, and anti-sickness medicine for the first week; amitriptyline or gabapentin for burning, tingling or shooting nerve pain; radiotherapy or chemotherapy to shrink what is pressing on the nerves, which takes weeks to work; and relaxation, TENS, acupuncture and distraction alongside. NICE NG85 says consider an EUS-guided or image-guided coeliac plexus block for uncontrolled pain, unacceptable opioid side effects or escalating doses, and not to offer thoracic splanchnicectomy; Macmillan describes the injection through the back or from inside the stomach during an endoscopic ultrasound, and a randomised trial (Wyse 2011) found early EUS-guided neurolysis reduced pain at three months. Pain after a Whipple operation is normal for weeks and eases; sudden worse pain with a temperature means A&E. Palliative care and pain teams can be involved at any stage, alongside treatment.","refs":["pain-management","palliative-care","palliative-radiotherapy","endoscopic-ultrasound-systems"],"guideline":{"version":"NICE NG85, 1.5 pain management","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Pancreatic enzymes and diabetes, after surgery or with the tumour","approach":"The pancreas digests food and controls blood sugar, and the cancer, the operation or both can take away either job. Enzymes: Pancreatic Cancer UK says most people with pancreatic cancer will need pancreatic enzyme replacement therapy (PERT: Creon, Nutrizym, Pancrex) for life, and that the signs of needing it are weight loss, bloating, wind, tummy pain after eating and pale, oily, floating stools. NICE NG85 says offer enteric-coated pancreatin in unresectable disease and consider it before and after resection. How to take it: with all meals, snacks and milky drinks, half with the first mouthfuls and half spread through the meal, swallowed with a cool drink, starting at about 50,000 to 75,000 units for a main meal and 25,000 to 50,000 for a snack, more for larger or fattier meals, reviewed by the dietitian and increased until symptoms settle; if it is not working, a proton pump inhibitor, another brand, or another cause (bile acid diarrhoea, bacterial overgrowth, medicines) is looked for. Supplies have been disrupted since 2024; NICE points prescribers to the Specialist Pharmacy Service tool for equivalents. Diabetes: pancreatic cancer or surgery can cause type 3c diabetes, which differs from type 1 and 2, usually needs tablets or insulin, and is managed by a diabetes nurse and specialist dietitian who know you have pancreatic cancer; a systematic review found new diabetes in about 16 in 100 people after a Whipple operation, and removing the whole pancreas means insulin for life. If you take insulin, tell the DVLA before driving. Ask both questions at the first appointment: they are the most fixable causes of feeling terrible.","refs":["cachexia","oncology-nutrition","whipple","enzyme","nutrition-impact-symptoms"],"guideline":{"version":"NICE NG85, 1.6 nutritional management","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Feeding and weight","approach":"Most people with pancreatic cancer lose appetite and weight (Cancer Research UK), and the loss has two parts: undigested food, which enzymes fix, and the cancer's own effect on appetite and muscle (cachexia), which needs a dietitian early. Cancer Research UK says most pancreatic teams include a dietitian, and its advice is small frequent meals, high-calorie and high-protein snacks and full-fat versions, prescribed supplement drinks sipped through the day (with enzymes, and checked against diabetes), and eating what you feel like rather than what you think you should. Pancreatic Cancer UK says there is no special diet and no foods to avoid, and not to cut fat but to take more PERT with it. Medicines for appetite: Macmillan says steroids or an appetite stimulant may help for a time; the ASCO cachexia guideline recommends dietary counselling and says no drug is established. NICE NG85 says do not offer fish oils to manage weight loss in unresectable disease, and after a Whipple operation to offer early feeding by mouth or tube rather than into a vein when the gut works. With a duodenal stent: soft, moist, lower-fibre foods, little and often, chewed well, upright after eating. Weight and muscle are also what decide whether chemotherapy can be given on time and in full, so ask for the referral in the first weeks, not when the weight has gone.","refs":["cachexia","oncology-nutrition","enteral-parenteral-nutrition","malnutrition-screening","duodenal-stenting-gastric-outlet"],"guideline":{"version":"NICE NG85, 1.6; ASCO cachexia guideline 2020","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"A clinical trial or standard treatment","approach":"At every stage a trial can be a reasonable choice beside standard treatment, and in pancreatic cancer it is where the next answers are coming from: NICE NG85 itself places chemotherapy before surgery for resectable or borderline disease within trials, Cancer Research UK says your doctor may offer a trial for borderline disease because the best treatment is uncertain, and the record's pipeline is led by RAS inhibitors (daraxonrasib after first-line chemotherapy in RASolute 302, G12D-selective drugs, vaccines) that Pancreatic Cancer UK describes as a promising group of treatments. Ask what the comparison arm is, whether a placebo is used (the NHS says only where no proven treatment exists), whether a biopsy or tumour gene test is needed to qualify and whether tissue already taken can be used, what extra visits, scans and travel are involved and whether costs are paid, and what happens to your standard treatment if you leave; the NHS says you can leave at any time without giving a reason and without it affecting your care. Pancreatic Cancer UK has a trial finder and its nurses can talk through what a trial would mean for you.","refs":["daraxonrasib","rasolute-302","precede","pancan"],"guideline":{"version":"NICE NG85, 1.8.1 and 1.8.2","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Palliative care early, alongside treatment","approach":"Palliative care is symptom control and support, not a stage; Pancreatic Cancer UK says these services are not just for the end of life and are available at any point for cancer that cannot be cured, and a randomised trial (Temel 2010) found early palliative care alongside cancer treatment improved quality of life and mood. In pancreatic cancer the reasons to involve the team early are concrete: pain that may need a nerve block, sickness from a slow or blocked stomach, itch from jaundice, poor appetite and weight loss, fatigue, low mood, sleep, and the practical side (a written plan with numbers to ring at night, help at home, district nurses, a hospice's day services, money and work). The NHS says people whose cancer cannot be cured are referred to the palliative care or symptom control team, which works with you, your GP and the clinical nurse specialist, and that this team can help your loved ones too. NICE NG85 asks teams to assess the psychological impact of fatigue, pain, gut symptoms, nutrition, anxiety and depression throughout care. It is also the place to talk about what matters most to you and to record your wishes (advance care planning) while you are well enough to do it in your own words; Pancreatic Cancer UK's end of life pages, Marie Curie and Maggie's cover the conversations, and Pancreatic Cancer UK's nurses can be reached by phone, email or WhatsApp.","refs":["palliative-care","pain-management","psycho-oncology","emotional-support-cancer-uk","cbt-fatigue-distress"],"guideline":{"version":"NICE NG85, 1.4 psychological support","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Resectable disease: upfront surgery or neoadjuvant treatment","approach":"Upfront pancreatoduodenectomy or distal pancreatectomy followed by six months of adjuvant chemotherapy remains the reference for clearly resectable tumours: NORPACT-1 found 18-month survival 60 percent with neoadjuvant FOLFIRINOX against 73 percent with surgery first, SWOG S1505 found two-year survival of 47 to 48 percent with either perioperative regimen (no better than adjuvant history), and NEONAX missed its 18-month disease-free target in both arms. In favour of treating first: PREOPANC-1's neoadjuvant gemcitabine chemoradiotherapy gave five-year survival 20.5 against 6.5 percent (hazard ratio 0.73) across resectable and borderline patients, and PREOPANC-2 found neoadjuvant FOLFIRINOX and neoadjuvant chemoradiotherapy equivalent (21.9 against 21.3 months). Alliance A021806 (358 patients, perioperative against adjuvant modified FOLFIRINOX, primary completion December 2028) and PREOPANC-3 (378 patients) will settle the question; NICE NG85 restricts neoadjuvant therapy to trials (1.8.1, 1.8.2).","refs":["whipple","folfirinox","prodige-24","norpact-1","swog-s1505","neonax","preopanc","preopanc-2","alliance-a021806","preopanc-3","resectability","neoadjuvant-adjuvant","robotic-surgery"],"guideline":{"nccn":"Category 1 (adjuvant chemotherapy); Category 2A (neoadjuvant for high-risk features)","version":"NCCN Pancreatic Adenocarcinoma; NICE NG85 1.8.1 to 1.8.4; ESMO 2023","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Adjuvant chemotherapy after resection","approach":"Modified FOLFIRINOX for six months in fit patients (PRODIGE 24: median overall survival 53.5 against 35.5 months with gemcitabine, hazard ratio 0.68, five-year survival 43.2 against 31.4 percent). Gemcitabine plus capecitabine for those not eligible (ESPAC-4: 28.0 against 25.5 months, hazard ratio 0.82; long-term 31.6 against 28.4 months, and 49.9 against 32.2 months after R0 resection); this is the NICE NG85 recommendation for England (1.8.6, off-label). Gemcitabine alone for the frail (CONKO-001: five-year survival 20.7 against 10.4 percent with observation; NG85 1.8.7). S-1 for six months in Japan (JASPAC 01: five-year survival 44.1 against 24.4 percent with gemcitabine, hazard ratio 0.57), not licensed for this use in Europe. Nab-paclitaxel with gemcitabine missed its primary endpoint (APACT) and is not a standard. Start within 12 weeks of surgery once recovered.","refs":["folfirinox","prodige-24","gemcitabine","capecitabine","espac-4","conko-001","tegafur-gimeracil-oteracil","jaspac-01","gemcitabine-nab-paclitaxel","apact"],"guideline":{"nccn":"Category 1, preferred (mFOLFIRINOX); Category 1 (gemcitabine plus capecitabine, gemcitabine)","esmoMcbs":"A (PRODIGE 24)","version":"NICE NG85 1.8.5 to 1.8.7; NCCN Pancreatic Adenocarcinoma; ESMO 2023","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Borderline resectable disease","approach":"Neoadjuvant chemotherapy for two to four months, then restaging and surgery: ESPAC-5 (90 patients, UK and Germany) found one-year survival 39 percent with immediate surgery against 78 percent after gemcitabine plus capecitabine, 84 percent after FOLFIRINOX and 60 percent after chemoradiotherapy. Alliance A021501 established modified FOLFIRINOX alone as the reference regimen (18-month survival 66.7 percent, median 29.8 months) after its stereotactic radiotherapy arm closed at interim analysis for fewer R0 resections (10 against 17 of the first 30). PREOPANC-1 and PREOPANC-2 included borderline patients with the same conclusions as above. NICE NG85 still asks for neoadjuvant therapy to be given within a trial (1.8.1).","refs":["espac-5","alliance-a021501","preopanc","preopanc-2","folfirinox","gemcitabine-nab-paclitaxel","sbrt","resectability","ca19-9"],"guideline":{"nccn":"Category 2A (neoadjuvant therapy preferred)","version":"NCCN Pancreatic Adenocarcinoma; NICE NG85 1.8.1; ESMO 2023","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Locally advanced unresectable disease: chemotherapy, chemoradiation, stereotactic radiotherapy and ablation","approach":"Four to six months of modified FOLFIRINOX or gemcitabine plus nab-paclitaxel (NEOLAP: conversion to resection in 36 to 44 percent of randomised patients with either sequence, median survival 18.5 to 20.7 months). Chemoradiotherapy after induction improves local control but not survival: LAP07 (15.2 against 16.5 months; local progression 32 against 46 percent), CONKO-007 (R0 resection 25 against 18 percent overall, not significant; 69 against 50 percent among those operated; survival hazard ratio 0.94). When it is used, capecitabine is the radiosensitiser (SCALOP: median survival 15.2 against 13.4 months with gemcitabine; NG85 1.9.3). Stereotactic radiotherapy and irreversible electroporation are options in centres with experience: CROSSFIRE (68 patients after FOLFIRINOX) found MRI-guided stereotactic radiotherapy and electroporation equivalent (16.1 against 12.5 months, hazard ratio 1.39, stopped for futility), and PANFIRE-2 (50 patients) reported median survival 17 months from diagnosis with major complications in 42 percent. Tumour treating fields added to gemcitabine plus nab-paclitaxel are approved in the United States (PANOVA-3).","refs":["folfirinox","gemcitabine-nab-paclitaxel","neolap","lap07","conko-007","scalop","capecitabine","chemoradiation","sbrt","mr-linac","irreversible-electroporation","crossfire","panfire-2","panova-3","optune"],"guideline":{"nccn":"Category 2A (induction chemotherapy; chemoradiation or SBRT in selected patients)","version":"NICE NG85 1.9.1 to 1.9.3; NCCN Pancreatic Adenocarcinoma; ESMO 2023","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Metastatic disease, first line","approach":"FOLFIRINOX for performance status 0 to 1 (PRODIGE 4/ACCORD 11: median overall survival 11.1 against 6.8 months with gemcitabine, hazard ratio 0.57; febrile neutropenia 5.4 percent) or NALIRIFOX (NAPOLI 3: 11.1 against 9.2 months with nab-paclitaxel and gemcitabine, hazard ratio 0.83 in the Lancet report and 0.84 on the Onivyde label; FDA approval 13 February 2024, EU indication listed; NICE appraisal TA1052 terminated on 2 April 2025 without a company submission). Gemcitabine plus nab-paclitaxel for those less fit or with biliary stents (MPACT: 8.5 against 6.7 months, hazard ratio 0.72; grade 3 or worse neuropathy 17 percent); in England only when other combinations are unsuitable (NICE TA476). Gemcitabine alone for the frail. Four months of FOLFIRINOX then fluorouracil and leucovorin maintenance is an alternative to six months (PANOPTIMOX-PRODIGE 35: six-month progression-free survival 42.9 against 47.1 percent, survival without quality-of-life deterioration 11.4 against 7.2 months). Germline and tumour testing at diagnosis (BRCA, PALB2, mismatch repair, KRAS subtype, NRG1 and NTRK fusions) steers maintenance and later lines.","refs":["folfirinox","prodige-4-accord-11","nalirifox","napoli-3","gemcitabine-nab-paclitaxel","mpact","gemcitabine","panoptimox-prodige-35","germline-testing","performance-status"],"guideline":{"nccn":"Category 1, preferred (FOLFIRINOX, NALIRIFOX, gemcitabine plus nab-paclitaxel)","esmoMcbs":"5 (PRODIGE 4); 3 (MPACT); 3 (NAPOLI 3)","version":"NICE NG85 1.9.4 to 1.9.6, TA476; NCCN Pancreatic Adenocarcinoma; ESMO 2023","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Metastatic disease, second line","approach":"Daraxonrasib after one prior line (RASolute 302: median overall survival 13.2 against 6.7 months with chemotherapy, hazard ratio 0.40; progression-free 7.2 against 3.6 months; FDA approval 26 August 2026 for metastatic pancreatic adenocarcinoma after one systemic therapy or for people not fit for multi-agent chemotherapy; no EU or UK decision). Otherwise switch backbone: after gemcitabine, liposomal irinotecan with fluorouracil and leucovorin (NAPOLI-1: 6.1 against 4.2 months, hazard ratio 0.67; FDA 2015, EU 2016, not recommended by NICE TA440) or OFF (CONKO-003: 5.9 against 3.3 months, hazard ratio 0.66), noting that PANCREOX found modified FOLFOX6 worse than fluorouracil alone; after FOLFIRINOX, gemcitabine plus nab-paclitaxel. NG85 recommends oxaliplatin-based or gemcitabine-based second line (1.9.7, 1.9.8). Pegilodecakin (SEQUOIA) and eryaspase (TRYbeCA-1) failed here.","refs":["daraxonrasib","rasolute-302","liposomal-irinotecan","napoli-1","folfox","conko-003","gemcitabine-nab-paclitaxel","oxaliplatin","fluorouracil","sequoia","trybeca-1"],"guideline":{"nccn":"Category 1 (daraxonrasib; liposomal irinotecan with fluorouracil after gemcitabine); Category 2A (OFF, FOLFOX)","esmoMcbs":"2 (NAPOLI-1)","version":"NICE NG85 1.9.7 to 1.9.9, TA440; NCCN Pancreatic Adenocarcinoma; ASCO metastatic pancreatic cancer guideline 2020","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Maintenance after first-line platinum: germline BRCA carriers","approach":"Olaparib 300 mg twice daily for people with a germline BRCA1 or BRCA2 mutation whose metastatic disease has not progressed after at least 16 weeks of platinum chemotherapy (POLO: progression-free survival 7.4 against 3.8 months, hazard ratio 0.53; overall survival 19.0 against 19.2 months, hazard ratio 0.83, not significant; three-year survival 33.9 against 17.8 percent; FDA approval 2019, EU indication listed; NICE appraisal TA750 terminated on 8 December 2021 without a company submission). Continued chemotherapy, or fluorouracil and leucovorin maintenance after FOLFIRINOX (PANOPTIMOX), are the alternatives for everyone else. About 2 to 3 percent of unselected patients carry a germline BRCA1 or BRCA2 variant (Hu 2018, 3,030 patients: BRCA2 1.9 percent, BRCA1 0.6 percent), more in familial disease; 7.5 percent of the 3,315 screened for POLO carried one and 154 were randomised.","refs":["olaparib","polo","gbrca-mutation","germline-testing","parp-inhibitor","panoptimox-prodige-35","platinum-sensitivity"],"guideline":{"nccn":"Category 1 (olaparib, germline BRCA)","esmoMcbs":"3 (POLO)","version":"NCCN Pancreatic Adenocarcinoma; ASCO metastatic pancreatic cancer guideline 2020; ESMO 2023","url":"https://doi.org/10.1200/JCO.20.01364"}},{"setting":"Targeted and biomarker-directed therapy","approach":"RAS: daraxonrasib works across RAS G12 mutations (91.8 percent of RASolute 302) and is approved regardless of subtype; KRAS G12C (1 to 2 percent of tumours) responds to sotorasib (CodeBreaK 100 pancreatic cohort, 38 patients: response 21 percent, median survival 6.9 months) and adagrasib (KRYSTAL-1: 7 of 21 responses), which NCCN lists but no regulator has approved for pancreatic cancer; KRAS G12D (about 40 percent) has zoldonrasib in phase 3 first line (RASolute 305 with chemotherapy, RASolute 309 with daraxonrasib) after MRTX1133 was stopped. NRG1 fusions (KRAS wild-type tumours): zenocutuzumab (eNRGy: response 42 percent in 36 pancreatic patients; FDA accelerated approval 4 December 2024; not authorised in the EU). Mismatch repair deficiency (about 1 percent): pembrolizumab (KEYNOTE-158 pancreatic cohort: 4 of 22 responses, 18 percent) or dostarlimab under tumour-agnostic US approvals; NICE TA914 does not cover pancreatic cancer. NTRK fusions: larotrectinib (NICE TA630, Cancer Drugs Fund) or entrectinib (TA644 replaced by the terminated TA1118); repotrectinib after resistance. BRAF V600E: dabrafenib plus trametinib. Erlotinib with gemcitabine is licensed for metastatic disease in the US and EU but added under two weeks in its pivotal trial and nothing in later trials, and is not used.","refs":["daraxonrasib","sotorasib","codebreak-100","adagrasib","nct03785249","zoldonrasib","nct07621718","nct07805954","mrtx1133","zenocutuzumab","nct02912949","pembrolizumab","keynote-158","dostarlimab","larotrectinib","entrectinib","repotrectinib","dabrafenib-trametinib","erlotinib","kras-mutation-subtypes","gene-fusion","msi"],"guideline":{"nccn":"Category 2A (sotorasib, adagrasib for G12C; zenocutuzumab for NRG1; pembrolizumab or dostarlimab for dMMR; larotrectinib or entrectinib for NTRK)","version":"NCCN Pancreatic Adenocarcinoma; ASCO metastatic pancreatic cancer guideline 2020; NICE TA630, TA1118, TA914","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Tumour treating fields for locally advanced disease","approach":"Alternating electric fields at 150 kHz worn for at least 18 hours a day through skin arrays, with gemcitabine plus nab-paclitaxel (PANOVA-3, 571 patients: median overall survival 16.2 against 14.2 months, hazard ratio 0.82; pain-free survival 15.2 against 9.1 months; progression-free survival, local control and response not improved; device-related skin events in 76.3 percent, grade 3 in 7.7 percent). FDA approval of Optune Pax in 2026; no NICE appraisal. Open-label design and the modest effect are debated, and the device is not yet part of European guidelines.","refs":["optune","ttfields","panova-3","gemcitabine-nab-paclitaxel"],"guideline":{"nccn":"Category 2B","version":"NCCN Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Vaccines and cellular therapy: trials only","approach":"Personalised mRNA neoantigen vaccine: in the 16-patient phase 1, autogene cevumeran after surgery with atezolizumab and modified FOLFIRINOX induced T cells in 8, whose recurrence-free survival was not reached against 13.4 months in non-responders at 3.2 years, with vaccine-induced T cell clones estimated to live 7.7 years; the randomised phase 2 IMCODE003 (260 patients, eight UK sites) is closed to recruitment with disease-free survival due in 2031. Shared KRAS peptide vaccine ELI-002 7P missed its primary endpoint in AMPLIFY-7P (2026). GVAX with CRS-207 failed in ECLIPSE. Claudin 18.2 CAR-T (satricabtagene autoleucel) and mesothelin-directed cells are in early trials. Checkpoint inhibitors alone do not work outside mismatch repair deficient disease.","refs":["autogene-cevumeran","autogene-cevumeran-phase-1","nct05968326","eli-002-7p","amplify-7p","eclipse","car-t","neoantigen-mrna-vaccine","shared-antigen-vaccine","cold-vs-hot"],"guideline":{"version":"No guideline recommendation; NCCN lists clinical trial enrolment","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"The failed or stopped programmes","approach":"Added to chemotherapy without survival benefit in phase 3: pegvorhyaluronidase alfa (HALO-301), pegilodecakin (SEQUOIA), napabucasin (CanStem111P), ibrutinib (RESOLVE), devimistat (AVENGER 500), pamrevlumab (LAPIS), eryaspase (TRYbeCA-1), algenpantucel-L (IMPRESS), erlotinib as adjuvant (CONKO-005, RTOG 0848) and in locally advanced disease (LAP07). Chemoradiotherapy after induction improved local control or R0 rates but not survival (LAP07, CONKO-007), and adjuvant chemoradiotherapy was harmful in ESPAC-1. MRTX1133 (KRAS G12D) was terminated in 2025 and the ELI-002 7P vaccine missed in 2026. Neoadjuvant FOLFIRINOX for clearly resectable disease was not better than surgery first (NORPACT-1) or than chemoradiotherapy (PREOPANC-2), and adjuvant nab-paclitaxel with gemcitabine missed its primary endpoint (APACT).","refs":["pancreatic-failed-programmes","espac-1","halo-301","sequoia","canstem111p","resolve","avenger-500","lapis-trial","trybeca-1","impress-trial","conko-005","lap07","conko-007","nct05737706","amplify-7p","norpact-1","preopanc-2","apact"],"guideline":{"version":"Primary publications cited on the term page","url":"https://doi.org/10.1200/JCO.20.00590"}},{"setting":"UK access to treatments (NICE, September 2026)","approach":"Commissioned in England: FOLFIRINOX first line for performance status 0 to 1 and gemcitabine combinations or gemcitabine alone otherwise (NG85 1.9.4 to 1.9.6, several off-label); nab-paclitaxel with gemcitabine only when other combinations are unsuitable (TA476); adjuvant gemcitabine plus capecitabine or gemcitabine (NG85 1.8.6, 1.8.7); oxaliplatin-based or gemcitabine-based second line (1.9.7, 1.9.8); larotrectinib for NTRK fusions through the Cancer Drugs Fund (TA630). Not recommended: liposomal irinotecan with fluorouracil after gemcitabine (TA440). Ended: entrectinib (TA1118 terminated, January 2026). Terminated without a recommendation because the company made no submission: olaparib maintenance for germline BRCA carriers (TA750, December 2021) and NALIRIFOX (TA1052, April 2025). Not appraised: daraxonrasib, zenocutuzumab, tumour treating fields, sotorasib and adagrasib for pancreatic cancer; pembrolizumab for mismatch repair deficient tumours (TA914) does not include pancreatic cancer. Neoadjuvant therapy is trial-only under NG85.","refs":["pancreatic-cancer-uk-drug-access","folfirinox","gemcitabine-nab-paclitaxel","capecitabine","liposomal-irinotecan","larotrectinib","entrectinib","nalirifox","olaparib","daraxonrasib","cancer-drugs-fund","nice"],"guideline":{"version":"NICE NG85; technology appraisals TA476, TA440, TA630, TA750, TA1052, TA1118, TA914","url":"https://www.nice.org.uk/guidance/ta476"}},{"setting":"Palliation: biliary and duodenal obstruction","approach":"Self-expanding metal stent by ERCP for jaundice in unresectable disease and, when drainage is needed before surgery, in resectable disease (NG85 1.7.3 to 1.7.5); metal stents stay open 4.45 months longer than plastic with fewer cholangitis episodes and re-interventions (Almadi 2017, 20 trials). Endoscopic ultrasound-guided drainage when ERCP fails or is expected to be difficult (Paik 2018; DRA-MBO 2023). Surgery first rather than preoperative drainage in fit resectable patients (1.7.1). For duodenal obstruction, an enteral stent relieves symptoms within days and gastrojejunostomy lasts longer (SUSTENT); choose bypass for people with a better prognosis (1.7.8) and consider prophylactic gastrojejunostomy when a tumour is found unresectable at operation (1.7.6).","refs":["pancreatic-palliation-obstruction-pain-nutrition","biliary-stenting-drainage","biliary-stent","obstructive-jaundice","stent-or-bypass-for-jaundice","biliary-stent-problems","acute-cholangitis","endoscopic-ultrasound-systems"],"guideline":{"version":"NICE NG85 1.7; ESMO 2023","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}},{"setting":"Palliation: pain, digestion, weight loss and thrombosis","approach":"Opioid analgesia with endoscopic ultrasound-guided or percutaneous coeliac plexus block for uncontrolled pain, opioid side effects or escalating doses (NG85 1.5.1; Wyse 2011 randomised trial: pain scores lower at three months, no survival effect); no thoracic splanchnicectomy (1.5.2). Enteric-coated pancreatin with every meal for everyone with unresectable disease and around surgery (1.6.1, 1.6.2); no fish oils for weight loss (1.6.3); early enteral rather than parenteral nutrition after pancreatoduodenectomy (1.6.4). Dietetic review and early palliative care from diagnosis. Cachexia drugs are in trials (ponsegromab, seven UK sites). Thromboprophylaxis is decided by risk score under the NICE venous thromboembolism guideline; in CASSINI's pancreatic subgroup rivaroxaban cut clots during treatment (3.7 against 10.1 percent) but not over 180 days.","refs":["pancreatic-palliation-obstruction-pain-nutrition","pancrelipase","cachexia","palliative-care","oncology-nutrition","cancer-associated-thrombosis","ponsegromab","nct06989437","malnutrition-screening"],"guideline":{"version":"NICE NG85 1.5 and 1.6; ESMO 2023","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"}}],"stateOfArt":["First TTFields approval (2026).","RASolute 302 (2026): first targeted therapy to nearly double survival in pancreatic cancer; daraxonrasib approved by the FDA on 26 August 2026 for previously treated metastatic disease.","G12D-selective zoldonrasib combinations with 50% response rates in previously treated disease.","Adjuvant mFOLFIRINOX gives median OS beyond 4 years in resected fit patients.","High-risk surveillance shifts ~3 in 4 detected cancers to stage I in carriers.","Personalised mRNA vaccine responders remain recurrence-free for years (autogene cevumeran phase 1).","Genomic landscape. KRAS mutation in 88 to 94% (G12D about 40%, G12V about 32%, G12R about 16%, Q61 about 7%, G12C 1 to 2%), TP53 66 to 76%, CDKN2A loss 37 to 48%, SMAD4 loss 17 to 33%; the 6 to 12% of KRAS wild-type tumours carry the fusions and alternative drivers instead, and 4 to 10% of patients carry a germline susceptibility variant. Every figure and its cohort is in the molecular table; the full account is in the notes on the Data page.","Transcriptional subtypes. Two survive every re-analysis, classical (GATA6-high) and basal-like or squamous (GATA6-low); in COMPASS basal-like tumours responded to first-line chemotherapy in 10% against 33% and lived 5.9 against 9.3 months, and a GATA6 in situ hybridisation stain calls the subtype with sensitivity 89% and specificity 83%.","Precursors. More than 99% of the smallest PanIN-1 lesions already carry KRAS, CDKN2A, GNAS or BRAF mutations, IPMNs carry GNAS R201 in 66%, and the classical KRAS-CDKN2A-TP53-SMAD4 ladder is only part of the story: two-thirds of genomes show punctuated rearrangements that knock out several drivers at once.","Stroma and immunity. The desmoplastic stroma limits perfusion but removing it is harmful (depletion made tumours more aggressive in mice; hyaluronidase failed in phase 3), T cells are excluded by CXCL12 from FAP-positive fibroblasts, and every checkpoint trial outside mismatch repair deficiency has failed.","Monitoring. CA 19-9 has pooled sensitivity 79% and specificity 82%, rises with cholestasis and cannot be made by the roughly 10% of patients who are Lewis-negative; ctDNA predicts recurrence about three months before imaging, but most assays read only KRAS codons 12, 13 and 61 and no approval uses it.","Early detection, research only. CAPS surveillance of high-risk individuals shifted 57.9% of detected cancers to stage I (median survival 9.8 against 1.5 years); blood tests are not ready (the methylation test reads 16.8% sensitivity at stage I) and new-onset diabetes is the strongest clinical enrichment.","Testing, in practice. Germline panel testing at diagnosis for every patient, tumour sequencing with RNA for fusions where KRAS reads wild-type, mismatch repair immunohistochemistry, allele-level KRAS reporting because the alleles differ in prognosis and in which inhibitor applies, and GATA6 or a subtype classifier where a trial requires it."],"history":[{"year":1935,"title":"Whipple describes pancreaticoduodenectomy","note":"Surgery becomes the only curative option, a status it still holds.","refs":[]},{"year":1978,"title":"Pylorus-preserving Whipple operation described","note":"Traverso and Longmire, two patients; their 1980 follow-up of 18 found every patient had exocrine insufficiency and needed enzyme replacement.","refs":["paper-traverso-longmire-pylorus-preservation-pancreaticoduodenectomy-sgo-1978","whipple"]},{"year":1982,"title":"KRAS identified as a human oncogene","note":"Within a decade shown to be mutated in ~90% of pancreatic cancers.","refs":["kras"]},{"year":1987,"title":"Lewis-negative patients shown unable to make CA 19-9","note":"Tempero and colleagues, 20 patients: a normal marker never rules the cancer out.","refs":["paper-tempero-ca19-9-lewis-antigens-cancer-res-1987","ca19-9"]},{"year":1988,"title":"KRAS codon 12 mutations in 21 of 22 pancreatic cancers","note":"Almoguera and Perucho, by polymerase chain reaction; the most uniform driver in any common cancer.","refs":["paper-almoguera-kras-codon-12-pancreatic-cell-1988","kras"]},{"year":1997,"title":"Gemcitabine approved","note":"Clinical benefit response over 5-FU; the standard for 14 years.","refs":["gemcitabine-nab-paclitaxel"]},{"year":2001,"title":"PanIN nomenclature agreed for the microscopic precursor lesions","note":"Eight pathologists had used more than 70 terms for 35 duct lesions; the working group adopted pancreatic intraepithelial neoplasia grades 1 to 3, and precursor research became comparable.","refs":["panin","paper-hruban-panin-nomenclature-ajsp-2001"]},{"year":2004,"title":"ESPAC-1: adjuvant chemotherapy helps, chemoradiotherapy harms","note":"289 patients; five-year survival 21 versus 8 percent with chemotherapy, 10 versus 20 percent with chemoradiotherapy.","refs":["paper-espac-1-chemoradiotherapy-chemotherapy-resected-pancreatic-nejm-2004"]},{"year":2005,"title":"New-onset diabetes after 50 carries a 1 percent three-year risk of pancreatic cancer","note":"Chari's Minnesota cohort of 2,122; observed-to-expected ratio 7.94.","refs":["paper-chari-pancreatic-cancer-following-diabetes-gastroenterology-2005","idea-pdac-new-onset-diabetes-risk-score-pathway"]},{"year":2006,"title":"NCCN adopts a definition of borderline resectable pancreatic cancer","note":"Vessel contact on CT starts to decide who has surgery first and who has treatment first; the definition was revised yearly until the 2017 international consensus.","refs":["nccn-resectability-criteria-pancreatic","resectability"]},{"year":2007,"title":"CONKO-001: adjuvant gemcitabine doubles disease-free survival","note":"368 patients; 13.4 versus 6.9 months.","refs":["paper-conko-001-adjuvant-gemcitabine-observation-jama-2007","conko-001"]},{"year":2008,"title":"Core signalling pathways from the first pancreatic exomes","note":"Twenty-four cancers carried an average of 63 alterations hitting twelve pathways in 67 to 100% of tumours.","refs":["paper-jones-pancreatic-core-pathways-science-2008","kras"]},{"year":2009,"title":"The 1 mm margin rule in UK pathology reporting","note":"Tumour within 1 mm of a margin is R1 (Royal College of Pathologists); standardised protocols raised the reported R1 rate to 76 to 85 percent of head resections.","refs":["r0-r1-margin-pancreatic","resection-margins"]},{"year":2010,"title":"Metastasis shown to occur late","note":"A decade from the initiating mutation to the founder clone and five more years to metastatic ability: the quantitative case for early detection.","refs":["paper-yachida-metastasis-late-genetic-evolution-pancreatic-nature-2010"]},{"year":2011,"title":"FOLFIRINOX: OS 11.1 vs 6.8 months","note":"PRODIGE 4 / ACCORD 11 establishes combination chemotherapy for fit patients.","refs":["folfirinox"]},{"year":2011,"title":"GNAS mutations define the IPMN pathway; the first expression subtypes","note":"GNAS R201 in 66% of IPMNs and carried into the invasive cancer; Collisson's classical, quasi-mesenchymal and exocrine-like classes.","refs":["paper-wu-gnas-ipmn-sci-transl-med-2011","paper-wu-pancreatic-cyst-exomes-rnf43-pnas-2011","paper-collisson-pancreatic-subtypes-nat-med-2011","gnas"]},{"year":2013,"title":"Gemcitabine + nab-paclitaxel (MPACT)","refs":["gemcitabine-nab-paclitaxel"]},{"year":2015,"title":"Baltimore consensus: precursor lesions graded low or high","note":"PanIN, IPMN and MCN move to a two-tier grading; 0.5 to 1 cm separates a large PanIN from an incipient IPMN.","refs":["panin","pancreatic-cyst-high-risk-stigmata"]},{"year":2015,"title":"Whole genomes and the classical versus basal-like split","note":"Waddell's 100 genomes tie unstable genomes to BRCA-type defects and platinum response; Moffitt separates tumour from stroma and finds two tumour and two stromal subtypes; Witkiewicz's 109 microdissected exomes give the purified driver frequencies.","refs":["paper-waddell-whole-genomes-pancreatic-nature-2015","paper-moffitt-virtual-microdissection-subtypes-nat-genet-2015","paper-witkiewicz-pancreatic-exomes-utsw-nat-commun-2015"]},{"year":2016,"title":"Bailey's four subtypes; NAPOLI-1 gives a second line","note":"456 tumours, 32 genes, 10 pathways, squamous subtype worst. Liposomal irinotecan with fluorouracil: 6.1 versus 4.2 months after gemcitabine.","refs":["paper-bailey-molecular-subtypes-pancreatic-nature-2016","paper-napoli-1-nanoliposomal-irinotecan-lancet-2016","liposomal-irinotecan"]},{"year":2016,"title":"Punctuated evolution: two-thirds of pancreatic cancer genomes shaped by mitotic catastrophe","note":"Notta's whole genomes show chromothripsis and polyploidy, not stepwise mutation, in two-thirds of tumours, knocking out several drivers at once; Bailey's four expression subtypes from the same year are on the evidence entry.","refs":["paper-notta-punctuated-evolution-pancreatic-nature-2016","kdm6a"]},{"year":2017,"title":"TNM 8th edition: size-based T categories and node counts","note":"T1 to T3 by size (2 and 4 cm), N1 and N2 by one to three and four or more nodes; validated in 2,318 resections from three US centres and 8,960 SEER cases.","refs":["tnm-staging"]},{"year":2017,"title":"Neoantigen quality in long-term survivors; the integrated TCGA portrait","note":"Survivors have both many high-quality neoantigens and abundant CD8 T cells, and lose those clones at metastasis; TCGA fixes the driver list and shows KRAS wild-type tumours carry other RAS-pathway drivers.","refs":["paper-balachandran-neoantigen-quality-long-term-survivors-nature-2017","paper-tcga-pancreatic-integrated-characterisation-cancer-cell-2017","paper-connor-mutational-signatures-immune-pancreatic-jama-oncol-2017"]},{"year":2018,"title":"Adjuvant mFOLFIRINOX (PRODIGE 24)","note":"Median OS 54 months after resection.","refs":["prodige-24"]},{"year":2018,"title":"NICE NG85: pancreatic cancer in adults","note":"Pancreatic protocol CT before biliary drainage, PET-CT for localised disease, enzyme replacement for unresectable disease, surveillance criteria for inherited risk.","refs":["pancreas-protocol-ct","pancreatic-enzyme-replacement","pancreatic-surveillance"]},{"year":2018,"title":"Germline faults in 5.5 percent regardless of family history; CAPS surveillance finds operable cancers","note":"Hu, 3,030 patients. Canto, 354 high-risk individuals over 16 years: 9 of 10 surveillance-detected cancers resectable. Sharma's ENDPAC score for new-onset diabetes.","refs":["paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018","paper-canto-caps-long-term-surveillance-gastroenterology-2018","paper-sharma-endpac-model-new-onset-diabetes-gastroenterology-2018","idea-pdac-surveillance-for-every-germline-carrier"]},{"year":2018,"title":"NRG1 fusions in KRAS wild-type disease; germline carriers mostly lack a family history","note":"NRG1 fusions found in every KRAS wild-type tumour of a young-adult series (Heining), later put at about 1% of all pancreatic cancers (Philip 2022); only 3 of 33 Johns Hopkins germline carriers had a family history (Shindo). The 5.5% carrier rate of Hu 2018 is on the evidence entry for the same year.","refs":["paper-shindo-germline-sporadic-pancreatic-jco-2017","paper-heining-nrg1-fusions-kras-wild-type-pancreatic-cancer-discov-2018","paper-philip-kras-wild-type-pancreatic-ccr-2022","brca-germline"]},{"year":2019,"title":"POLO: olaparib maintenance in gBRCA","note":"First biomarker-directed approval.","refs":["polo","olaparib"]},{"year":2019,"title":"WHO classification of digestive tumours, 5th edition","note":"Adenosquamous, colloid and undifferentiated carcinomas and the IPMN- and MCN-associated carcinomas listed as variants of ductal adenocarcinoma; solid pseudopapillary neoplasm and acinar cell carcinoma stand apart.","refs":["pancreatic-adenosquamous-carcinoma","pancreatic-colloid-carcinoma","pancreatic-undifferentiated-carcinoma-ogc","solid-pseudopapillary-neoplasm"]},{"year":2019,"title":"COMPASS, targeted profiling at scale and ctDNA as a clinical test","note":"Classical tumours respond to chemotherapy three times as often as basal-like; 3,594 profiled tumours give KRAS 88% and MSI or TMB-high 0.5%; a CLIA KRAS ctDNA assay predicts recurrence 84 days before imaging.","refs":["paper-okane-gata6-basal-like-compass-ccr-2020","paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019","paper-groot-kras-ctdna-clinical-test-resected-pancreatic-ccr-2019","ctdna-mrd-positive"]},{"year":2020,"title":"CAPS consortium surveillance recommendations updated","note":"Goal: high-grade dysplasia and T1N0M0 cancer; EUS and MRI/MRCP yearly; ATM carriers with an affected relative now eligible.","refs":["pancreatic-surveillance","familial-pancreatic-cancer"]},{"year":2020,"title":"PREOPANC primary report; HALO-301 negative; ASCO makes biomarker testing routine","note":"Preoperative chemoradiotherapy: 16.0 versus 14.3 months, R0 71 versus 40 percent. Pegvorhyaluronidase: 11.2 versus 11.5 months. Germline and tumour testing for every treatment-eligible patient.","refs":["paper-preopanc-preoperative-chemoradiotherapy-jco-2020","paper-halo-301-pegvorhyaluronidase-jco-2020","paper-asco-metastatic-pancreatic-cancer-guideline-update-jco-2020","preopanc","idea-pdac-stromal-reprogramming-not-depletion"]},{"year":2020,"title":"Homologous recombination deficiency defined for platinum selection; fibroblast atlas","note":"Core and biallelic repair-gene mutations predict first-line platinum benefit (hazard ratio 0.44); single-cell sequencing adds antigen-presenting fibroblasts to the myofibroblastic and inflammatory states.","refs":["paper-park-hrd-pancreatic-platinum-ccr-2020","paper-elyada-antigen-presenting-cafs-single-cell-cancer-discov-2019","hrd-positive"]},{"year":2021,"title":"Sotorasib proves KRAS is druggable (G12C)","note":"Only 1-2% of pancreatic cancers carry G12C, but the door is open.","refs":["sotorasib"]},{"year":2021,"title":"Sub-tumour microenvironments and the CA 19-9 lead time","note":"Reactive and deserted tissue states track immunity and chemoprotection; CA 19-9 rises two years before diagnosis, reaching 60% sensitivity only in the last six months.","refs":["paper-grunwald-subtme-pancreatic-cell-2021","paper-fahrmann-ca19-9-lead-time-gastroenterology-2021","paper-gonda-precede-consortium-recommendations-gastroenterology-2021"]},{"year":2022,"title":"CAPS5: 77.8 percent of surveillance-detected cancers are stage I","note":"1,461 high-risk people enrolled; across CAPS1 to 5 (1,731 people) 57.9 percent of the 19 surveillance-detected cancers were stage I, with five-year survival 73.3 percent and median overall survival 9.8 years against 1.5 years for cancers found outside surveillance.","refs":["pancreatic-surveillance","paper-dbouk-caps5-stage-survival-jco-2022"]},{"year":2022,"title":"PRODIGE 24 at five years: median survival 53.5 months","note":"Adjuvant modified FOLFIRINOX against gemcitabine: median overall survival 53.5 versus 35.5 months, five-year survival 43.2 versus 31.4 percent, hazard ratio 0.68.","refs":["paper-prodige-24-five-year-outcomes-jama-oncol-2022","prodige-24"]},{"year":2023,"title":"MRTX1133 regressions in G12D models; autogene cevumeran phase 1 in Nature","refs":["mrtx1133","autogene-cevumeran"]},{"year":2024,"title":"NALIRIFOX approved; zenocutuzumab for NRG1 fusions","refs":["nalirifox","zenocutuzumab"]},{"year":2025,"title":"PANOVA-3 positive; daraxonrasib phase 1/2 OS ~14.5 months","note":"Tumour treating fields with gemcitabine and nab-paclitaxel: 16.2 against 14.2 months in 571 patients with locally advanced disease.","refs":["panova-3","daraxonrasib","paper-panova-3-ttfields-locally-advanced-pancreatic-jco-2025"]},{"year":2025,"title":"PREOPANC-2 leaves the resectable question open; vaccine T cells last years","note":"Neoadjuvant FOLFIRINOX 21.9 versus 21.3 months against gemcitabine chemoradiotherapy. Sethna: responders' recurrence-free survival not reached at 3.2 years.","refs":["paper-preopanc-2-neoadjuvant-folfirinox-vs-chemoradiotherapy-lancet-oncol-2025","paper-sethna-rna-neoantigen-vaccine-long-lived-t-cells-nature-2025","idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease"]},{"year":2026,"title":"RASolute 302: daraxonrasib OS 13.2 vs 6.7 months (HR 0.40)","note":"ASCO plenary and NEJM; FDA approval of daraxonrasib on 26 August 2026; Optune Pax approved; zoldonrasib combinations reported; AMPLIFY-7P vaccine misses.","refs":["rasolute-302","optune","zoldonrasib","amplify-7p"]},{"year":2026,"title":"A CA 19-9 cut-off for the Lewis-negative tenth","note":"FUT3-null patients, about 10%, have median CA 19-9 of 2.4 U/mL and the same short survival as patients above 200; a value of 7 or below identifies them without genotyping.","refs":["paper-yeh-ca19-9-lewis-negative-fut3-cutoff-ccr-2026","paper-worthington-precede-early-detection-biomarkers-ijc-2026","paper-daraxonrasib-pancreatic-n-engl-j-med-2026"]}],"pipeline":["daraxonrasib","autogene-cevumeran","cmg901","fap-2286","fapi-pet","galleri","satricabtagene-autoleucel","in10018","lm-108","navlimetostat","quemliclustat","gfh375","gotistobart","sitneprotafib","setidegrasib","incb161734","trabedersen","qls31905","ivospemin","atebimetinib","ibi343","vs-7375","tng462","xnw27011","e-edv-d682","azd4360","mavrostobart","jk08","jyp0015","spevatamig","azd5863","ct3001","ponsegromab","jmt203","lp-184","pbp1510","mitazalimab","vb15010","tqb2868","nuv-1511","zoldonrasib","elironrasib","mrtx1133","eli-002-7p","rasolute-302","g12d-plus-pan-ras","pancreatic-surveillance","pdac-organoid-pharmacotyping","idea-ras-inhibitor-neoadjuvant-pdac","idea-mced-new-onset-diabetes","idea-shared-kras-vaccine-adjuvant","idea-fap-theranostics-pancancer","mrd-testing","idea-pdac-new-onset-diabetes-risk-score-pathway","idea-pdac-surveillance-for-every-germline-carrier","idea-pdac-neoadjuvant-chemotherapy-for-all-resectable-disease","idea-pdac-stromal-reprogramming-not-depletion","idea-pdac-ras-inhibitor-combinations-and-sequencing","idea-pdac-cachexia-trials-embedded-in-chemotherapy-trials","idea-pdac-enzyme-replacement-prescribing-by-default","idea-pdac-uk-active-treatment-rate-audit-and-target","idea-pdac-uk-fast-track-diagnosis-to-treatment-pathway","nct07491445","nct07252232","nct07621718","nct07805954","alliance-a021806","preopanc-3","nct05968326","elraglusib","actuate-1801","starpac2","nct06608927","nct07522073"],"openProblems":["Resistance to RAS(ON) inhibitors: secondary RAS mutations, RTK bypass, and adaptive feedback are already described; combination strategies are unproven in phase 3.","Half of patients are too frail for FOLFIRINOX-class regimens; RAS inhibitors may change this but toxicity (rash, stomatitis) is not trivial.","No population screening; MCED sensitivity for stage I PDAC is low and PPV in average-risk adults is poor.","Immune exclusion: every checkpoint inhibitor trial has failed outside MSI-H disease; vaccines must overcome a cold microenvironment.","The dense stroma blocks drug delivery, yet stripping it out made tumours more aggressive in mice and hyaluronidase failed in phase 3 (HALO-301); reprogramming rather than depleting the stroma is unproven in patients.","Access: RAS inhibitors and TTFields will be expensive; global disparities will widen.","Emergency presentation: 45 percent of English cases (2019) and 60.9 percent of US Veterans Affairs cases (2026) are diagnosed as emergencies, with more advanced stage and higher mortality; the symptom-based referral rules (NG12) catch a minority.","Enzyme replacement reaches a minority: only 21.7 percent of 4,554 UK patients in primary care records received pancreatic enzyme replacement therapy, and supplies were disrupted in 2024 (NG85 note), although it is a NICE recommendation for every unresectable patient.","The 1 mm margin rule is not used everywhere, so R0 and R1 rates and their survival differences are not comparable between series or trials (Strobel 2017).","Surveillance of mutation-negative familial kindreds found no cancers in the Dutch programme and few in EUROPAC, while carriers of CDKN2A and other genes have substantial yields; who to watch, and when to stop, is unresolved.","Neither the new-onset diabetes score (3.6 percent prevalence among high scorers) nor carrier surveillance (7 of 9 CAPS5 cancers at stage I) has been tested prospectively at population scale, and CA 19-9 cannot be read in the Lewis-negative tenth of patients; four in five patients still present with disease that cannot be removed.","Two perioperative trials (PREOPANC-3, Alliance A021806) are the only ones comparing chemotherapy before and after surgery with the current adjuvant standard; until they read out, neoadjuvant treatment for clearly resectable disease rests on secondary endpoints.","Enzyme replacement reached 21.7 percent of UK patients in primary care data and cachexia has a mechanism-based drug in phase 2 but no phase 3; both determine whether combination chemotherapy is delivered, and both sit outside the trials that set the standards.","Whether chemotherapy should be given before surgery for clearly resectable tumours is still unanswered after NORPACT-1, PREOPANC-2, SWOG S1505 and NEONAX; Alliance A021806 (primary completion December 2028) and PREOPANC-3 are the only trials comparing perioperative chemotherapy with the current adjuvant standard, and until they read out neoadjuvant treatment for clearly resectable disease rests on secondary endpoints.","Radiotherapy has improved local control (LAP07) and R0 rates (CONKO-007) without lengthening life, and stereotactic radiotherapy and irreversible electroporation were equivalent in CROSSFIRE; no trial has shown that local ablation after chemotherapy extends survival in locally advanced disease.","Daraxonrasib is approved in the United States only after first-line chemotherapy; RASolute 303 (first line, six UK sites) and RASolute 304 (adjuvant, six UK sites) will show whether it belongs earlier, and no European regulator or NICE decision existed on 24 September 2026.","In England the newest options (NALIRIFOX, olaparib maintenance, daraxonrasib, zenocutuzumab, tumour treating fields) have no NICE recommendation (the olaparib and NALIRIFOX appraisals, TA750 and TA1052, were terminated when the companies made no submission; the rest have not been appraised) and liposomal irinotecan after gemcitabine is not recommended, so the funded pathway is FOLFIRINOX, gemcitabine combinations and gemcitabine plus capecitabine after surgery.","Supportive treatments that most patients need, enzyme replacement, coeliac plexus block, stents and cachexia drugs, rest on small or observational studies; the one randomised trial of enzyme replacement was negative on its primary endpoint, cachexia has a mechanism-based drug (ponsegromab) in phase 2 but no phase 3, and both sit outside the trials that set the standards even though they decide whether combination chemotherapy is delivered.","Homologous recombination deficiency in pancreatic cancer is wider than germline BRCA (somatic, PALB2 and signature-defined cases all respond to platinum) yet the only PARP inhibitor label is germline BRCA after platinum, and no genomic instability score has a pancreatic threshold.","Transcriptional subtype predicts chemotherapy response retrospectively and a GATA6 stain can call it, but no prospective subtype-directed trial has changed a guideline and basal-like patients still receive the regimen they resist.","Mutant KRAS allele and copy number change prognosis and drug choice, but routine reporting is often 'KRAS mutant' without the allele, and plasma assays that read only codons 12, 13 and 61 miss the wild-type minority in which the actionable fusions live.","CA 19-9 cannot be produced by about a tenth of patients, whose outlook is as poor as the highest-marker group, so a normal marker is a false reassurance that no guideline yet corrects with Lewis genotyping."],"basics":{"symptoms":["Painless jaundice (yellow eyes or skin, dark urine, pale stools, itching) when a head-of-pancreas tumour blocks the bile duct; about 75 percent of cancers start in the head (Cancer Research UK)","Pain in the upper abdomen or back, worse after eating or lying down and eased by leaning forward, commoner with body and tail tumours; unexplained weight loss and loss of appetite; fatty, pale, floating stools (steatorrhoea); nausea, bloating and indigestion that does not settle; new diabetes or diabetes that suddenly worsens; fever or shivering; blood clots (Cancer Research UK; NHS)","Jaundice is easier to see in the whites of the eyes than in brown or black skin (Cancer Research UK)","Get an urgent GP appointment or call NHS 111 for yellowing of the eyes or skin, vomiting for more than two days or diarrhoea for more than seven; see a GP for noticeable weight loss or symptoms that persist beyond two weeks (NHS)","GP referral rules: jaundice at 40 or over goes on the suspected cancer pathway (NICE NG12 1.2.4); weight loss at 60 or over with diarrhoea, back pain, abdominal pain, nausea, vomiting, constipation or new-onset diabetes calls for an urgent direct-access CT (1.2.5)","Late diagnosis is the rule: 45 percent of English cases in 2019 were diagnosed after an emergency presentation and only 26 percent of staged cases in 2022 were stage I or II (Cancer Research UK); in the United States 51 percent are distant at diagnosis (SEER)"],"diagnosis":["Pancreatic protocol CT first, before any bile duct drainage when there is jaundice (NICE NG85 1.1.1); it is a thin-slice dual-phase scan reported on a template that names every vessel the tumour touches (Al-Hawary 2014)","If the diagnosis is unclear: FDG PET-CT and or endoscopic ultrasound with EUS-guided tissue sampling; a biliary brushing if ERCP is used to place a stent (NG85 1.1.2 to 1.1.6)","A biopsy is often not taken when the tumour looks removable; the diagnosis rests on imaging and is confirmed on the resected specimen (Cancer Research UK tests page)","Blood tests: liver function, CA 19-9 and CEA; CA 19-9 is 79 to 81 percent sensitive and 82 to 90 percent specific in symptomatic patients, falsely negative in Lewis-negative people (5 to 10 percent) and raised by biliary obstruction and pancreatitis (Ballehaninna 2012)","Cysts: CT or MRI with MRCP, then the other if needed; EUS with fine-needle aspiration and cyst-fluid CEA when malignancy is in question; refer for resection with jaundice from a head cyst, an enhancing solid component or a main duct of 10 mm or more (NG85 1.1.7 to 1.1.13)","Germline testing is offered to every patient and tumour sequencing looks for KRAS status, fusions in KRAS-wild-type disease and mismatch repair deficiency (NCCN); a specialist pancreatic multidisciplinary team makes the shared decision (NG85 1.2.1)"],"staging":["TNM 8th edition: T1 2 cm or less (T1a to 0.5 cm, T1b to 1 cm, T1c to 2 cm), T2 over 2 to 4 cm, T3 over 4 cm, T4 into the coeliac axis, superior mesenteric artery or common hepatic artery; N1 one to three nodes, N2 four or more; M1 distant spread (Cancer Research UK TNM page)","Stage 1: T1 or T2, no nodes (1A, 1B). Stage 2: T3 without nodes (2A) or T1 to T3 with one to three nodes (2B). Stage 3: four or more nodes or a T4 tumour. Stage 4: metastases, most often liver, peritoneum or lung (Cancer Research UK stages page)","Resectability decides treatment: resectable (no arterial contact, venous contact of 180 degrees or less without contour irregularity), borderline resectable (arterial contact under 180 degrees or reconstructable venous involvement; or a CA 19-9 above 500 U/mL, or suspected but unproven spread; or performance status 2 or worse) and locally advanced (arterial encasement or unreconstructable venous occlusion) (Isaji 2018; NCCN)","UK staging tests: pancreatic protocol CT of chest, abdomen and pelvis for every new diagnosis (NG85 1.3.1); FDG PET-CT for localised disease before treatment (1.3.2); MRI for suspected liver metastases, EUS for tumour and node staging, laparoscopy with laparoscopic ultrasound before an attempted resection when small-volume peritoneal or liver disease is suspected (1.3.3)","In the United States 15 percent of cases are localised, 28 percent regional, 51 percent distant and 5 percent unstaged at diagnosis (SEER 21, 2016 to 2022)"],"sources":[{"label":"CRUK: symptoms of pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/symptoms"},{"label":"NHS: symptoms of pancreatic cancer (when to get urgent help)","url":"https://www.nhs.uk/conditions/pancreatic-cancer/symptoms/"},{"label":"NICE NG12: suspected cancer, recommendations by site (pancreatic cancer 1.2.4 and 1.2.5)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"},{"label":"NICE NG85: pancreatic cancer in adults (diagnosis 1.1, staging 1.3, nutrition 1.6, biliary obstruction 1.7, resectable disease 1.8)","url":"https://www.nice.org.uk/guidance/ng85/chapter/Recommendations"},{"label":"CRUK: tests for pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/getting-diagnosed/tests"},{"label":"NHS: tests and next steps for pancreatic cancer","url":"https://www.nhs.uk/conditions/pancreatic-cancer/tests-and-next-steps/"},{"label":"CRUK: TNM staging for pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/stages-types-grades/tnm-staging"},{"label":"CRUK: stages, types and grades of pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/stages-types-grades"},{"label":"SEER Cancer Stat Facts: pancreatic cancer (rates, stage distribution, survival by stage, age and race)","url":"https://seer.cancer.gov/statfacts/html/pancreas.html"},{"label":"CRUK: pancreatic cancer statistics (incidence, mortality, survival, early diagnosis and routes to diagnosis)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer"},{"label":"Al-Hawary, Radiology 2014: pancreatic ductal adenocarcinoma radiology reporting template (SAR and APA consensus)","url":"https://doi.org/10.1148/radiol.13131184"},{"label":"Isaji, Pancreatology 2018: international consensus on the definition and criteria of borderline resectable pancreatic cancer","url":"https://doi.org/10.1016/j.pan.2017.11.011"},{"label":"Ballehaninna and Chamberlain, J Gastrointest Oncol 2012: clinical utility of serum CA 19-9 in pancreatic adenocarcinoma","url":"https://doi.org/10.3978/j.issn.2078-6891.2011.021"}]},"prognosis":{"text":"Population averages, not a personal prognosis. In the United States, 13.7 percent of people diagnosed with pancreatic cancer in 2016 to 2022 were alive five years later relative to people of the same age without the disease (SEER). Stage at diagnosis is the biggest lever: five-year relative survival is 43.6 percent for the 15 percent found while confined to the pancreas, 17.0 percent for regional disease (28 percent of cases) and 3.4 percent for distant disease (51 percent). In the UK, 4.3 percent of people diagnosed in 2018 are predicted to survive ten years or more, against 2.4 percent in the 1970s; ten-year survival is 29.3 percent for women and 17.6 percent for men diagnosed at 15 to 44 but under 2 percent at 75 to 99; five-year survival is 7.6 percent in the most deprived fifth of England and 10.3 percent in the least deprived (2018 to 2022); UK five-year survival is generally below the European average (Cancer Research UK). By stage in England, Wales and Northern Ireland (ICBP SURVMARK-2, diagnoses 2012 to 2014): localised disease, almost 55 percent alive at one year and more than 25 percent at three; regional, around 50 and 15 percent; distant, around 10 and 1 percent (Cancer Research UK patient page). Screen-detected cancers in high-risk surveillance behave differently: 73.3 percent five-year survival and a median of 9.8 years in the CAPS cohorts (Dbouk 2022). These figures describe people diagnosed before the RAS inhibitors reported in 2026 and do not reflect them; the resected patients who complete adjuvant chemotherapy in the treatment rows do far better than the averages.","sources":[{"label":"SEER Cancer Stat Facts: pancreatic cancer (rates, stage distribution, survival by stage, age and race)","url":"https://seer.cancer.gov/statfacts/html/pancreas.html"},{"label":"CRUK: pancreatic cancer survival statistics (professional)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer/survival"},{"label":"CRUK: survival for pancreatic cancer (ICBP SURVMARK-2 by stage; England and Wales index)","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/survival"},{"label":"Dbouk, J Clin Oncol 2022: the multicenter CAPS5 study, impact of surveillance on stage and survival","url":"https://doi.org/10.1200/jco.22.00298"}]}},{"id":"pancreatic-net","kind":"cancer","name":"Pancreatic neuroendocrine tumours","aka":["pNET","Islet cell tumour","Pancreatic NET","Insulinoma","Gastrinoma","Non-functioning pancreatic neuroendocrine tumour"],"tldr":"Pancreatic neuroendocrine tumours arise from the hormone-producing islet cells of the pancreas and behave very differently from ordinary pancreatic cancer, often growing for years. Surgery cures localised tumours; advanced disease is treated in sequence with somatostatin analogues, lutetium-177 dotatate, targeted tablets and oral chemotherapy, and a minority secrete insulin or gastrin.","summary":"Pancreatic neuroendocrine tumours arise from islet cells and are graded by Ki-67 like other neuroendocrine tumours, but their genetics are their own: MEN1 is the most commonly mutated gene in sporadic tumours, with DAXX or ATRX loss and mutations in the mTOR pathway following, while KRAS and TP53, the drivers of ductal adenocarcinoma, are absent. Most are non-functioning and present as a mass or as liver metastases; the functioning minority cause syndromes, insulinoma with fasting hypoglycaemia (usually benign and cured by enucleation), gastrinoma with the ulcer disease of Zollinger-Ellison syndrome (controlled with proton-pump inhibitors, often malignant and often part of MEN1), and rarer glucagonomas and VIPomas. Germline testing is offered because MEN1, VHL, neurofibromatosis type 1 and tuberous sclerosis all predispose, and small non-functioning tumours under about two centimetres are often watched rather than removed.\n\nSurgery is curative for localised disease: enucleation or distal pancreatectomy for small tumours and a Whipple procedure for those in the head. For advanced disease, 2011 brought two tablets at once. RADIANT-3 (New England Journal of Medicine 2011) randomised 410 patients with progressive tumours to everolimus or placebo and lengthened progression-free survival from 4.6 to 11.0 months; the sunitinib phase 3 (New England Journal of Medicine 2011) was stopped early after 171 patients with 11.4 against 5.5 months. CLARINET (2014), in which almost half the patients had pancreatic tumours, established lanreotide as antiproliferative first-line therapy, and the E2211 trial (Journal of Clinical Oncology 2023) showed that adding capecitabine to temozolomide lengthened progression-free survival from 14.4 to 22.7 months with a higher response rate, making CAPTEM the chemotherapy of choice when shrinkage is needed. Streptozocin, approved in 1982, remains a guideline option.\n\nRadioligand therapy and cabozantinib have since reordered the sequence. Lutathera's 2018 approval covered all gastroenteropancreatic tumours on the strength of NETTER-1 in midgut disease, and NETTER-2 (Lancet 2024), in which more than half the patients had pancreatic tumours, showed first-line lutetium-177 dotatate lengthened progression-free survival from 8.5 to 22.8 months in grade 2 and 3 disease. CABINET (New England Journal of Medicine 2024) randomised a separate pancreatic cohort to cabozantinib or placebo after prior therapy and lengthened progression-free survival from 4.4 to 13.8 months, leading to approval in March 2025. Belzutifan was approved in 2021 for VHL-associated pancreatic tumours not needing immediate surgery, and its LITESPARK-015 trial has a sporadic pancreatic NET cohort. COMPETE (Lancet 2025) and COMPOSE test 177Lu-edotreotide against everolimus and against chemotherapy, and hepatic-dominant disease is still treated with embolisation, ablation and resection.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Pancreatic_neuroendocrine_tumor","links":[{"label":"RADIANT-3 (NEJM 2011)","url":"https://doi.org/10.1056/NEJMoa1009290"},{"label":"Sunitinib in pancreatic NET (NEJM 2011)","url":"https://doi.org/10.1056/NEJMoa1003825"},{"label":"CABINET (NEJM 2024)","url":"https://doi.org/10.1056/NEJMoa2403991"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Pancreatic_neuroendocrine_tumor"}],"tags":["subtype-page","endocrine"],"related":["extrapulmonary-nec","grade-3-net","lung-net","small-intestinal-net"],"cancers":[],"sections":[],"technologies":["sstr-pet","prrt","radioligand-therapy","germline-testing","tace","radioembolisation-tare","thermal-ablation"],"targets":["sstr2","mtor","menin","hif2a","vegf"],"drugs":["octreotide-lanreotide","lutathera","everolimus","sunitinib","cabozantinib","capecitabine-temozolomide","streptozocin","belzutifan","ga68-dotatate","itm-11","diazoxide"],"companies":[],"institutions":[],"pathways":[],"terms":["men1-hereditary-net","net-grade-ki67","chromogranin-a","whipple","prrt-term"],"trials":["clarinet","radiant-3-4","cabinet","nct03972488","netter-1","compete","nct04919226","nct04924075"],"people":[],"bottlenecks":[],"keyPapers":["paper-netter-2-lancet-2024","paper-cabinet-cabozantinib-nejm-2024","paper-radiant-3-everolimus-pnet-yao-nejm-2011","paper-raymond-sunitinib-pnet-nejm-2011"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"A small minority of pancreatic cancers but the site with the most approved drugs of any neuroendocrine tumour; most are non-functioning and found on imaging, while insulinomas and gastrinomas announce themselves through their hormones.","subtypes":["Non-functioning pancreatic NET (the majority, found as a mass or liver metastases)","Insulinoma (fasting hypoglycaemia, usually benign, cured by enucleation)","Gastrinoma and Zollinger-Ellison syndrome (often duodenal or pancreatic head, often MEN1)","Glucagonoma, VIPoma and somatostatinoma (rare functioning tumours)","MEN1- and VHL-associated pancreatic NET (multiple, young onset)","Grade 1 to 2 pancreatic NET (somatostatin analogue, radioligand, everolimus, sunitinib, cabozantinib)","Grade 3 well-differentiated pancreatic NET (see the grade 3 record)"],"biomarkers":["Ki-67 index and mitotic count (WHO grade)","Chromogranin A (monitoring)","Somatostatin receptor PET (staging and radioligand eligibility)","Fasting glucose, insulin, C-peptide and proinsulin (insulinoma)","Fasting gastrin and gastric pH (gastrinoma)","Germline MEN1, VHL, NF1 and TSC testing","MEN1, DAXX and ATRX status in the tumour (prognostic, research)","MGMT status (CAPTEM response, investigational)"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Contrast CT or MRI, somatostatin receptor PET, biopsy with Ki-67 grading, chromogranin A, hormone assays where a syndrome is suspected, and germline testing.","refs":["sstr-pet","ga68-dotatate","net-grade-ki67","chromogranin-a","germline-testing","men1-hereditary-net"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Localised, resectable","approach":"Enucleation or distal pancreatectomy for small tumours, Whipple procedure for tumours in the head, lymphadenectomy for tumours over two centimetres; surveillance for small non-functioning tumours.","refs":["whipple","robotic-surgery"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Functioning syndromes","approach":"Surgery for insulinoma with diazoxide or everolimus to control hypoglycaemia beforehand; high-dose proton-pump inhibitors and resection for gastrinoma; somatostatin analogues for glucagonoma and VIPoma.","refs":["octreotide-lanreotide","everolimus","men1-hereditary-net"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Advanced, first line","approach":"Lanreotide or octreotide (CLARINET); lutetium-177 dotatate first line for grade 2 to 3 tumours with a Ki-67 of 10 percent or more (NETTER-2); CAPTEM when shrinkage is needed.","refs":["octreotide-lanreotide","clarinet","lutathera","nct03972488","prrt","capecitabine-temozolomide"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Progression on a somatostatin analogue","approach":"Lutetium-177 dotatate; everolimus (RADIANT-3); sunitinib; cabozantinib (CABINET); CAPTEM or streptozocin-based chemotherapy.","refs":["lutathera","everolimus","radiant-3-4","sunitinib","cabozantinib","cabinet","capecitabine-temozolomide","streptozocin"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Liver-dominant disease","approach":"Resection, thermal ablation, chemoembolisation or radioembolisation, alongside systemic therapy.","refs":["hepatectomy","thermal-ablation","tace","radioembolisation-tare","liver-directed-therapy"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"VHL-associated pancreatic NET","approach":"Belzutifan for tumours not requiring immediate surgery (approved 2021).","refs":["belzutifan","nct04924075","men1-hereditary-net"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}}],"stateOfArt":["Five approved systemic drug classes (somatostatin analogues, radioligand therapy, mTOR inhibition, anti-angiogenic kinase inhibitors and oral chemotherapy) give years of sequential control.","NETTER-2 put lutetium-177 dotatate in first line for grade 2 to 3 disease and CABINET added cabozantinib after prior therapy.","Belzutifan was the first drug approved for a hereditary neuroendocrine syndrome, in VHL disease."],"history":[{"year":1927,"title":"Wilder describes hyperinsulinism from an islet cell tumour; first successful insulinoma resection follows in 1929","refs":[]},{"year":1955,"title":"Zollinger and Ellison describe the gastrinoma syndrome","refs":[]},{"year":1982,"title":"Streptozocin approved for metastatic islet cell carcinoma","refs":["streptozocin"]},{"year":2011,"title":"RADIANT-3 and the sunitinib phase 3 published; everolimus and sunitinib approved; MEN1, DAXX and ATRX mutations mapped by exome sequencing","refs":["radiant-3-4","everolimus","sunitinib","menin"]},{"year":2014,"title":"CLARINET: lanreotide approved as antiproliferative therapy","refs":["clarinet","octreotide-lanreotide"]},{"year":2018,"title":"Lutathera approved for gastroenteropancreatic tumours","refs":["lutathera","prrt"]},{"year":2021,"title":"Belzutifan approved for VHL-associated pancreatic NET","refs":["belzutifan","hif2a"]},{"year":2023,"title":"E2211 final analysis: CAPTEM beats temozolomide alone","refs":["capecitabine-temozolomide"]},{"year":2024,"title":"NETTER-2: first-line lutetium-177 dotatate in grade 2 to 3 disease; CABINET pancreatic cohort published","refs":["nct03972488","lutathera","cabinet"]},{"year":2025,"title":"Cabozantinib approved; COMPETE published","refs":["cabozantinib","compete"]}],"pipeline":["itm-11","compete","nct04919226","nct04924075","belzutifan","ryz101","action-1","alphamedix","nct06943755","nct05884255","idea-net-dosimetry-prrt"],"openProblems":["The best order of radioligand therapy, everolimus, sunitinib, cabozantinib and CAPTEM is unknown.","Which small non-functioning tumours can safely be watched rather than resected.","MGMT and other predictors of CAPTEM response are not validated for decisions.","Grade 3 well-differentiated tumours sit between the tumour and carcinoma paradigms and need their own trials."],"parent":"neuroendocrine"},{"id":"pancreatoblastoma","kind":"cancer","name":"Pancreatoblastoma","aka":["Infantile pancreatic carcinoma","Childhood pancreatic cancer","Paediatric pancreatoblastoma"],"tldr":"Pancreatoblastoma is the pancreatic cancer of young children, a tumour of immature pancreatic cells that behaves quite unlike adult pancreatic cancer. It grows as a large abdominal mass, often raises the blood marker alpha-fetoprotein, and is treated like the childhood liver cancer hepatoblastoma: chemotherapy to shrink it, then surgery, which cures most children whose tumour has not spread.","summary":"Pancreatoblastoma is an embryonal tumour that recapitulates fetal pancreatic development, with acinar, ductal and neuroendocrine differentiation and the squamoid nests that define it under the microscope. It presents in preschool children as a large, painless abdominal mass, sometimes with weight loss, vomiting or jaundice, and serum alpha-fetoprotein is raised in most. Alterations in the Wnt pathway (CTNNB1 mutations or APC loss) and loss of heterozygosity at 11p, the Beckwith-Wiedemann locus, are the recurrent genetic findings, and the tumour occurs in children with Beckwith-Wiedemann syndrome and in families with familial adenomatous polyposis. Adult cases occur and behave more aggressively.\n\nBecause the disease is so rare, treatment follows consensus from the European Cooperative Study Group for Paediatric Rare Tumours (EXPeRT) and national rare-tumour registries rather than trials. Complete surgical resection is the cornerstone, usually a pancreatoduodenectomy or distal pancreatectomy; for the large tumours that cannot be removed at diagnosis, neoadjuvant chemotherapy with cisplatin and doxorubicin (the PLADO regimen used in hepatoblastoma) shrinks the tumour and makes surgery possible, and alpha-fetoprotein is followed as a response marker. Adjuvant chemotherapy is given after incomplete resection or for metastatic disease, and radiotherapy is reserved for residual disease. Metastases, most often to the liver, occur in a minority at diagnosis and are treated with chemotherapy and resection where possible.\n\nChildren with localised, completely resected disease usually do well; outcomes are worse with metastases at diagnosis and in adults. Late effects of platinum and anthracycline chemotherapy and of pancreatic surgery, including diabetes and exocrine insufficiency, need lifelong follow-up. International registries are pooling cases to learn about relapse treatment and the role of Wnt-directed therapy.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Pancreatoblastoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Pancreatoblastoma"},{"label":"EXPeRT consensus on pancreatoblastoma (2021)","url":"https://doi.org/10.1002/pbc.29112"}],"tags":["subtype-page","gastrointestinal"],"related":["pancreatic-acinar-cell-carcinoma","resectable-pdac","pancreatic-net","hepatoblastoma","rare-childhood-cancers","childhood-cancers"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","ct","mri","germline-testing","fertility-preservation"],"targets":["kras"],"drugs":["cisplatin","doxorubicin","vincristine"],"companies":[],"institutions":[],"pathways":["wnt","pancreatic-cancer-signalling"],"terms":["whipple","resection-margins","neoadjuvant-adjuvant","metastasis","tumour-grade"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-klimstra-pancreatoblastoma-clinicopathologic-study-ajsp-1995","paper-bien-pancreatoblastoma-expert-european-cooperative-ejc-2011","paper-dhebri-pancreatoblastoma-diagnosis-treatment-outcome-pancreatology-2004","paper-bien-pediatr-blood-cancer"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"The commonest pancreatic cancer of early childhood yet extremely rare, with a few cases a year in most countries, a median age around four years, and occasional cases in adults; it is associated with Beckwith-Wiedemann syndrome and familial adenomatous polyposis.","subtypes":["Localised pancreatoblastoma, resected at diagnosis","Locally advanced pancreatoblastoma requiring neoadjuvant chemotherapy before resection","Metastatic pancreatoblastoma (liver most often)","Syndromic pancreatoblastoma (Beckwith-Wiedemann syndrome, familial adenomatous polyposis)","Adult pancreatoblastoma (more aggressive; distinguished from acinar cell carcinoma and ductal PDAC)"],"biomarkers":["Serum alpha-fetoprotein (raised in most; response and relapse marker)","Squamoid nests and acinar differentiation on histology; trypsin and BCL10 immunohistochemistry","CTNNB1 mutation or APC loss (Wnt pathway); nuclear beta-catenin staining","11p loss of heterozygosity (Beckwith-Wiedemann locus)","Germline APC testing where familial adenomatous polyposis is suspected","CT or MRI of abdomen and chest for staging"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Imaging of abdomen and chest, serum alpha-fetoprotein and biopsy; genetic review for Beckwith-Wiedemann syndrome and familial adenomatous polyposis.","refs":["ct","mri","germline-testing"],"guideline":{"version":"EXPeRT consensus on pancreatoblastoma (Pediatric Blood and Cancer 2021)","url":"https://doi.org/10.1002/pbc.29112"}},{"setting":"Resectable at diagnosis","approach":"Complete resection (pancreatoduodenectomy or distal pancreatectomy); adjuvant chemotherapy after incomplete resection.","refs":["whipple","resection-margins"],"guideline":{"version":"EXPeRT consensus on pancreatoblastoma (Pediatric Blood and Cancer 2021)","url":"https://doi.org/10.1002/pbc.29112"}},{"setting":"Unresectable at diagnosis","approach":"Neoadjuvant cisplatin and doxorubicin (PLADO, as in hepatoblastoma) followed by delayed resection when the tumour shrinks.","refs":["cisplatin","doxorubicin","neoadjuvant-adjuvant"],"guideline":{"version":"EXPeRT consensus on pancreatoblastoma (Pediatric Blood and Cancer 2021)","url":"https://doi.org/10.1002/pbc.29112"}},{"setting":"Metastatic or relapsed","approach":"Cisplatin and doxorubicin-based chemotherapy with resection of residual disease where possible; radiotherapy for unresectable residual tumour; international registry enrolment.","refs":["cisplatin","doxorubicin","metastasis"],"guideline":{"version":"EXPeRT consensus on pancreatoblastoma (Pediatric Blood and Cancer 2021)","url":"https://doi.org/10.1002/pbc.29112"}},{"setting":"Survivorship","approach":"Lifelong follow-up for pancreatic insufficiency, diabetes and the late effects of platinum and anthracycline chemotherapy.","refs":["fertility-preservation","cachexia"],"guideline":{"version":"EXPeRT consensus on pancreatoblastoma (Pediatric Blood and Cancer 2021)","url":"https://doi.org/10.1002/pbc.29112"}}],"stateOfArt":["EXPeRT consensus recommendations (2021) give a shared treatment pathway across Europe for a tumour no single country sees often.","Hepatoblastoma-style neoadjuvant chemotherapy makes most large tumours resectable.","Recognition of the Wnt pathway and Beckwith-Wiedemann link explains the biology and guides genetic counselling.","International rare-tumour registries are pooling cases to study relapse and late effects."],"history":[{"year":1957,"title":"Becker describes an infantile pancreatic carcinoma later named pancreatoblastoma","refs":["whipple"]},{"year":1977,"title":"Horie coins the term pancreatoblastoma for the childhood tumour with squamoid nests","refs":["tumour-grade"]},{"year":2001,"title":"Beta-catenin and APC alterations link pancreatoblastoma to the Wnt pathway and to familial adenomatous polyposis","refs":["wnt"]},{"year":2011,"title":"EXPeRT pooled analysis defines outcomes and the role of neoadjuvant chemotherapy and complete resection","refs":["cisplatin","doxorubicin"]},{"year":2021,"title":"EXPeRT consensus recommendations for diagnosis and treatment","refs":["whipple","cisplatin"]}],"pipeline":[],"openProblems":["No prospective trial exists or is likely; treatment is extrapolated from hepatoblastoma and pooled registries.","Relapsed and metastatic disease has no established second-line therapy.","Adult pancreatoblastoma is often misdiagnosed and behaves worse than the childhood form.","Survivors face pancreatic insufficiency and diabetes after major pancreatic surgery in early life."],"parent":"pancreatic"},{"id":"gallbladder-papillary-carcinoma","kind":"cancer","name":"Papillary carcinoma of the gallbladder","aka":["Papillary adenocarcinoma of the gallbladder","Intracholecystic papillary neoplasm with invasive carcinoma","ICPN"],"tldr":"Papillary carcinoma is a gallbladder cancer that grows as finger-like fronds into the cavity rather than burrowing into the wall. Cancer Research UK notes it is less likely to spread to the liver and lymph nodes and tends to have a better outlook. Its polypoid precursor, the intracholecystic papillary neoplasm, is often removed before it invades.","summary":"Papillary (exophytic) growth in the gallbladder covers two related entities that the WHO classification (5th edition, 2019) separates. The intracholecystic papillary (or papillary-tubular) neoplasm, ICPN, is a mass-forming preinvasive neoplasm of 1 cm or more: in the defining series of 123 cases patients were mostly women (2 to 1), mean age 61, median size 2.2 cm, half presenting with pain and half found incidentally, and gallstones were present in only 20 percent, far below their frequency in ordinary gallbladder cancer (Adsay 2012). Papillary gallbladder carcinoma proper is an invasive adenocarcinoma with complex papillary architecture. Akita and colleagues, applying strict criteria to 75 cancers, found that ICPNs (7) showed gross mucin hypersecretion in 43 percent, had no lymphovascular invasion or nodal metastasis, and were less advanced than either papillary (24) or non-papillary (44) carcinomas, in which those features occurred in 13 to 59 percent; exome sequencing also separated the groups (Akita 2019). Cancer Research UK describes papillary adenocarcinoma as less likely to spread to the liver and nearby nodes and as having a better outlook than most other types.\n\nWhat differs in treatment: the polypoid growth means these lesions are often visible on ultrasound and removed as polyps of 10 mm or more under the European polyp guideline, sometimes while still preinvasive; once invasive they are staged and treated as adenocarcinoma. A papillary lesion can be difficult to tell from adenomyomatosis or a cholesterol polyp on imaging, and the pathology report should say whether invasion is present and how deep (Adsay 2012; Foley 2022).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Gallbladder_cancer","links":[{"label":"CRUK: types of gallbladder cancer","url":"https://www.cancerresearchuk.org/about-cancer/gallbladder-cancer/types"},{"label":"Adsay, Am J Surg Pathol 2012: intracholecystic papillary-tubular neoplasms, 123 cases","url":"https://doi.org/10.1097/pas.0b013e318262787c"},{"label":"Akita, Am J Surg Pathol 2019: intracholecystic papillary neoplasms are distinct from papillary gallbladder cancers","url":"https://doi.org/10.1097/pas.0000000000001237"},{"label":"ESGAR, EAES, EFISDS and ESGE joint guideline on gallbladder polyps (Foley, Eur Radiol 2022)","url":"https://doi.org/10.1007/s00330-021-08384-w"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"}],"tags":["gallbladder","biliary","subtype-page"],"related":["gallbladder","gallbladder-adenocarcinoma","gallbladder-carcinoma-in-situ-and-dysplasia","gallbladder-mucinous-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["gallbladder-polyp","carcinoma-in-situ"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"A minority of gallbladder adenocarcinomas; in one Japanese pathology series 24 of 75 gallbladder cancers were papillary by strict criteria and 7 were intracholecystic papillary neoplasms (Akita 2019).","subtypes":["Intracholecystic papillary neoplasm of the gallbladder without invasion (preinvasive)","Intracholecystic papillary neoplasm with associated invasive carcinoma","Papillary adenocarcinoma of the gallbladder (invasive, complex papillary architecture)"],"biomarkers":["Presence and depth of invasion in a papillary lesion","Gross mucin hypersecretion (a feature of ICPN)","Lymphovascular invasion and nodal status","Polyp size on ultrasound (10 mm threshold for cholecystectomy)"],"standardOfCare":[{"setting":"Polypoid lesion of 10 mm or more on ultrasound","approach":"Cholecystectomy under the joint European polyp guideline; pathology decides whether invasion is present.","refs":["gallbladder-polyp","simple-cholecystectomy"]},{"setting":"Invasive papillary carcinoma","approach":"Staged and treated as gallbladder adenocarcinoma by T category.","refs":["gallbladder-adenocarcinoma","radical-cholecystectomy"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"gallbladder"},{"id":"papillary-carcinoma-breast","kind":"cancer","name":"Papillary carcinomas of the breast (encapsulated, solid and invasive papillary)","aka":["Papillary carcinomas of the breast","Papillary carcinoma of the breast","Encapsulated papillary carcinoma","Intracystic papillary carcinoma","Solid papillary carcinoma","Invasive papillary carcinoma","Tall cell carcinoma with reversed polarity"],"tldr":"Papillary carcinomas are rare breast cancers, about one in a hundred, that grow as finger-like fronds on stalks, often inside a cyst, mostly in older women. The encapsulated and solid forms behave almost like non-invasive disease and have an excellent outlook; the truly invasive papillary form is treated like ordinary hormone-driven breast cancer.","summary":"The 2019 WHO classification groups four entities under papillary neoplasms: encapsulated papillary carcinoma (a papillary carcinoma within a cystic space surrounded by a fibrous capsule, with no myoepithelial layer), solid papillary carcinoma (in situ and invasive forms, often with neuroendocrine differentiation), invasive papillary carcinoma, and the new tall cell carcinoma with reversed polarity (Tan 2020). Papillary carcinoma makes up 0.5 to 1 percent of breast cancer; in 302 cases, solid papillary carcinoma was more often accompanied by conventional invasive carcinoma than the intracystic form, and lesions lacking a myoepithelial layer are regarded as a special low-grade form of invasion whose behaviour is nonetheless indolent (Rakha 2011). Tall cell carcinoma with reversed polarity (solid papillary carcinoma with reverse polarity) has cuboid or tall cells with eosinophilic cytoplasm at the basal pole, grooved nuclei, Ki-67 under 5 percent in seven of nine cases, CK5/6 and calretinin expression, and a favourable prognosis (Modern Pathology 2018).\n\nHow it differs from its parent: papillary carcinomas are cancers of older women, hormone-receptor positive and HER2-negative in the encapsulated and solid forms, with an outlook close to that of ductal carcinoma in situ; the pathology question (in situ or invasive) decides the treatment more than the stage.\n\nHow common: 0.5 to 1 percent of breast cancer (Rakha 2011).\n\nTreatment: encapsulated and solid papillary carcinoma without conventional invasion are managed like ductal carcinoma in situ with excision and consideration of radiotherapy and endocrine therapy; a conventional invasive component is staged and treated as HR-positive breast cancer on the parent page (Rakha 2011).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Breast_cancer_classification","links":[{"label":"Tan 2020, Histopathology: the 2019 WHO classification of tumours of the breast","url":"https://doi.org/10.1111/his.14091"},{"label":"Rakha 2011, Am J Surg Pathol: encapsulated papillary carcinoma of the breast, 302 papillary carcinomas","url":"https://doi.org/10.1097/pas.0b013e31821b3f65"},{"label":"Modern Pathology 2018: solid papillary carcinoma with reverse polarity, nine cases","url":"https://doi.org/10.1038/s41379-018-0047-1"}],"tags":["subtype-page","wave4","breast"],"related":["breast-cancer","ductal-carcinoma-in-situ","breast-hr-positive","mucinous-carcinoma-breast","invasive-micropapillary-carcinoma-breast"],"cancers":[],"sections":[],"technologies":["endocrine-therapy"],"targets":[],"drugs":["tamoxifen"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Papillary carcinoma accounts for 0.5 to 1 percent of breast cancer; in a review of 302 papillary carcinomas from three institutions, 208 (84 percent) were intracystic (encapsulated), 30 (12 percent) solid papillary and 9 papillary ductal carcinoma in situ (Rakha 2011).","subtypes":["Encapsulated (intracystic) papillary carcinoma, 84 percent of papillary carcinomas","Solid papillary carcinoma, in situ or invasive, often neuroendocrine","Invasive papillary carcinoma (luminal, HR-positive)","Tall cell carcinoma with reversed polarity (IDH2-mutated, favourable)"],"biomarkers":["Absence of a myoepithelial layer (encapsulated and solid forms)","Oestrogen and progesterone receptor positive, HER2 negative","Ki-67 (low)","Neuroendocrine markers in solid papillary carcinoma"],"standardOfCare":[{"setting":"Encapsulated or solid, no conventional invasion","approach":"Managed as ductal carcinoma in situ: excision, with radiotherapy and endocrine therapy considered.","refs":["ductal-carcinoma-in-situ","tamoxifen"]},{"setting":"With conventional invasive carcinoma","approach":"Treated as HR-positive breast cancer.","refs":["breast-hr-positive","endocrine-therapy"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"breast-cancer"},{"id":"papillary-rcc","kind":"cancer","name":"Papillary renal cell carcinoma","aka":["KIRP","TCGA-KIRP","kidney renal papillary cell carcinoma (TCGA KIRP cohort)","pRCC","Papillary RCC"],"tldr":"Papillary kidney cancer is the second commonest type and does not share the VHL biology of clear cell cancer, so the drugs work differently: the MET-targeting drug cabozantinib beat sunitinib in the first trial run just for this disease, and two hereditary syndromes account for some cases.","summary":"Papillary renal cell carcinoma is a heterogeneous group defined by papillary architecture; the older split into type 1 and type 2 has given way to molecular groups in the WHO 2022 classification. MET alterations (mutation, amplification, chromosome 7 gain) are frequent, especially in the former type 1, and are inherited in hereditary papillary renal carcinoma. Fumarate hydratase-deficient renal cancer, from the hereditary leiomyomatosis and renal cell cancer syndrome, is an aggressive form once labelled type 2. Localised tumours are treated like other kidney cancers with surgery or ablation. For metastatic disease the PAPMET trial showed cabozantinib gave longer progression-free survival and more responses than sunitinib, making it the preferred first-line option; savolitinib is active in MET-driven tumours (SAVOIR), and immunotherapy combinations have shown activity in single-arm studies.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Papillary_renal_cell_carcinomas","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Papillary_renal_cell_carcinomas"}],"tags":["subtype-page"],"related":["chromophobe-rcc","clear-cell-rcc"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["papmet"],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2022-gu-moch-eur-urol-2022","paper-aspen-armstrong-lancet-oncol-2016","paper-papmet-pal-lancet-2021","paper-tcga-papillary-rcc-nejm-2016"],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Ten to fifteen percent of kidney cancers, commoner in men, in Black patients and in end-stage kidney disease; localised tumours do well after surgery, while metastatic disease has fared worse than clear cell cancer on the same drugs.","subtypes":["MET-altered papillary renal cell carcinoma (former type 1)","Hereditary papillary renal carcinoma (germline MET)","Fumarate hydratase-deficient renal cell carcinoma (HLRCC syndrome)","Papillary renal neoplasm with reverse polarity (indolent)"],"biomarkers":["MET mutation, amplification or chromosome 7 gain","Fumarate hydratase loss (2SC immunohistochemistry) with germline FH testing","CDKN2A loss (shorter survival)","Germline MET testing in young or multifocal disease"],"standardOfCare":[{"setting":"Localised","approach":"Partial or radical nephrectomy, ablation or surveillance as for other kidney cancers; adjuvant therapy evidence is thin.","refs":["thermal-ablation","active-surveillance"]},{"setting":"Metastatic","approach":"Cabozantinib first line (PAPMET); savolitinib for MET-driven tumours; immunotherapy combinations on single-arm data; clinical trials preferred.","refs":["cabozantinib","savolitinib","met","sunitinib","pembrolizumab"]},{"setting":"Hereditary syndromes","approach":"Early surgery for FH-deficient tumours because they spread early; surveillance in MET carriers; genetic counselling of relatives.","refs":["met"]}],"stateOfArt":["PAPMET was the first randomised trial in papillary kidney cancer and ended the practice of borrowing clear cell regimens unchanged.","The molecular reclassification is replacing the type 1 and type 2 labels with actionable groups.","FH-deficient cancer is now recognised as a distinct aggressive entity needing early treatment."],"history":[{"year":1997,"title":"Delahunt and Eble separate type 1 and type 2 papillary carcinoma","refs":[]},{"year":2002,"title":"Fumarate hydratase mutations found in HLRCC","refs":[]},{"year":2021,"title":"PAPMET: cabozantinib beats sunitinib","refs":["cabozantinib"]},{"year":2022,"title":"WHO drops type 1 and 2 in favour of molecular groups","refs":[]}],"pipeline":["savolitinib","cabozantinib"],"openProblems":["Small trials; most evidence is extrapolated from clear cell disease.","No approved therapy specific to FH-deficient cancer.","Which patients benefit from immunotherapy."],"parent":"rcc"},{"id":"papillary-thyroid-cancer","kind":"cancer","name":"Papillary thyroid cancer","aka":["Papillary thyroid carcinoma","PTC","Papillary microcarcinoma (under 1 cm)"],"tldr":"Papillary thyroid cancer is the commonest and most curable thyroid cancer. Most people are treated with surgery, some with radioactive iodine afterwards, and many small tumours can simply be watched. Only the rare tumours that stop taking up iodine need targeted drugs.","summary":"Papillary thyroid cancer arises from the follicular cells and often spreads to neck lymph nodes but rarely kills. About 60 percent carry a BRAF V600E mutation and others RET or NTRK fusions or RAS mutations. Treatment is lobectomy or total thyroidectomy, with radioactive iodine reserved for intermediate- and high-risk disease after the ESTIMABL2 and IoN trials showed low-risk patients do as well without it; TSH suppression with levothyroxine and thyroglobulin monitoring follow. Japanese studies established that papillary microcarcinomas under a centimetre can be kept under active surveillance, and guidelines now allow it. The minority whose recurrent or metastatic disease no longer takes up iodine are treated with lenvatinib or sorafenib, or with selpercatinib, larotrectinib or dabrafenib-trametinib when the matching alteration is found.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Papillary_thyroid_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Papillary_thyroid_cancer"},{"label":"American Thyroid Association guidelines","url":"https://www.thyroid.org/professionals/ata-professional-guidelines/"}],"tags":["subtype-page"],"related":["anaplastic-thyroid-cancer","follicular-thyroid-cancer","medullary-thyroid-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-ata-2015-thyroid-nodules-dtc-haugen-thyroid-2016","paper-select-lenvatinib-nejm-2015","paper-estimabl2-leboulleux-nejm-2022","paper-ito-kuma-active-surveillance-microcarcinoma-thyroid-2014"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"About four in five thyroid cancers; incidence tripled over three decades in many countries mainly through ultrasound detection of small tumours, while deaths barely changed; more than nine in ten patients are alive at ten years.","subtypes":["Classic papillary","Follicular variant","Tall cell, columnar and hobnail variants (more aggressive)","Papillary microcarcinoma (under 1 cm)","Diffuse sclerosing variant"],"biomarkers":["BRAF V600E (about 60 percent)","RET and NTRK fusions","TERT promoter mutation (worse outlook, especially with BRAF)","Thyroglobulin after surgery","ATA risk category (low, intermediate, high)"],"standardOfCare":[{"setting":"Papillary microcarcinoma","approach":"Active surveillance with ultrasound or lobectomy; surveillance is safe in most adults after the Kuma Hospital and Memorial Sloan Kettering series.","refs":["active-surveillance"]},{"setting":"Low risk","approach":"Lobectomy or total thyroidectomy without radioactive iodine (ESTIMABL2, IoN); levothyroxine and thyroglobulin follow-up.","refs":["thyroid"]},{"setting":"Intermediate and high risk","approach":"Total thyroidectomy with neck dissection where nodes are involved, radioactive iodine ablation, TSH suppression.","refs":["radioiodine-therapy","tshr"]},{"setting":"Iodine-refractory advanced disease","approach":"Lenvatinib (SELECT) or sorafenib (DECISION); selpercatinib for RET fusions, larotrectinib or entrectinib for NTRK fusions, dabrafenib plus trametinib for BRAF V600E.","refs":["lenvatinib","sorafenib","selpercatinib","larotrectinib","entrectinib","dabrafenib","trametinib","rai-refractory"]}],"stateOfArt":["Two randomised trials showed that low-risk patients can skip radioactive iodine without harm, ending decades of routine ablation.","Active surveillance of microcarcinomas is accepted practice and is reducing overtreatment.","Fusion-directed drugs give deep, durable responses in the few iodine-refractory patients who carry RET or NTRK fusions.","Redifferentiation with BRAF or MEK inhibitors can restore iodine uptake in some refractory tumours."],"history":[{"year":1946,"title":"Radioactive iodine first treats thyroid cancer","refs":["radioiodine-therapy"]},{"year":2003,"title":"BRAF V600E found in papillary thyroid cancer","refs":["braf"]},{"year":2010,"title":"Kuma Hospital reports safe observation of microcarcinomas","note":"Ito and Miyauchi's series of over a thousand patients.","refs":[]},{"year":2014,"title":"Sorafenib approved for iodine-refractory disease (DECISION)","refs":["sorafenib"]},{"year":2015,"title":"Lenvatinib approved (SELECT)","refs":["lenvatinib"]},{"year":2022,"title":"ESTIMABL2 and IoN: no radioactive iodine for low-risk disease","note":"Both trials found equivalent outcomes without ablation.","refs":["radioiodine-therapy"]}],"pipeline":["dabrafenib","selpercatinib","larotrectinib"],"openProblems":["Overdiagnosis and overtreatment of small tumours found by imaging.","Which intermediate-risk patients truly benefit from radioactive iodine.","Resistance to kinase inhibitors in refractory disease."],"parent":"thyroid"},{"id":"papillary-tumour-pineal-region","kind":"cancer","name":"Papillary tumour of the pineal region","aka":["PTPR","Papillary tumor of the pineal region"],"tldr":"Papillary tumour of the pineal region is a rare brain tumour of young adults arising near the pineal gland from cells of the embryonic subcommissural organ. It usually presents with raised pressure from blocked spinal fluid, is removed surgically at a centre that does pineal surgery and often given radiotherapy, and it recurs locally more often than it seeds the spine.","summary":"The WHO central nervous system classification lists papillary tumour of the pineal region as a neuroepithelial tumour of the pineal region, grade 2 or 3, thought to derive from the subcommissural organ; molecular studies of 24 cases found loss of chromosome 10 in all 13 examined, losses of chromosomes 3 and 22q and gains of 8p and 12 commonly, a methylation profile that separates it from ependymoma and pineal parenchymal tumours, two methylation subgroups with the more methylated one tending to shorter progression-free survival, and overexpression of SPDEF, a subcommissural organ gene (Brain Pathology 2016). In the review of 177 patients, intracranial hypertension and hydrocephalus dominated the presentation, 82 percent had surgery, and gross total resection was among the factors associated with survival at 36 months (Neurosurgery 2019).\n\nHow it differs from its parent: a distinct entity of the pineal region that mimics ependymoma and pineal parenchymal tumours histologically, diagnosed reliably only by methylation profiling, and marked by frequent local recurrence rather than spinal seeding.\n\nHow common: no incidence figure; 177 published cases in 14 years (Neurosurgery 2019).\n\nTreatment: gross total resection where possible, with adjuvant radiotherapy commonly given because of the recurrence rate; with only 177 published cases there is no randomised evidence to set a best strategy, and chemotherapy has no established role, so management is agreed by a neuro-oncology multidisciplinary team (Neurosurgery 2019).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Papillary_tumor_of_the_pineal_region","links":[{"label":"Brain Pathology 2016: papillary tumour of the pineal region, a distinct molecular entity (24 cases)","url":"https://doi.org/10.1111/bpa.12282"},{"label":"Neurosurgery 2019: papillary tumour of the pineal region, systematic review of 177 patients","url":"https://doi.org/10.1093/neuros/nyz062"}],"tags":["subtype-page","wave4","rare"],"related":["brain-tumours","pineal-parenchymal-tumours","pineoblastoma","ependymoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"central nervous system","burden":"Rare: a systematic review found 177 published patients between 2003 and 2017, mean age 33 and 53 percent male (Neurosurgery 2019).","subtypes":["Papillary tumour of the pineal region, methylation group 1 (less methylated)","Papillary tumour of the pineal region, methylation group 2 (more methylated; shorter progression-free survival)","Recurrent papillary tumour of the pineal region (local; repeat surgery or radiotherapy)"],"biomarkers":["Loss of chromosome 10 (all cases examined)","DNA methylation class distinguishing it from ependymoma and pineal parenchymal tumours","SPDEF and cytokeratin expression","Extent of resection"],"standardOfCare":[{"setting":"All cases","approach":"Gross total resection where possible, with adjuvant radiotherapy commonly given for the recurrence risk; chemotherapy has no established role.","refs":["brain-tumours","ependymoma"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"brain-tumours"},{"id":"parathyroid-carcinoma","kind":"cancer","name":"Parathyroid carcinoma","aka":[],"tldr":"Parathyroid carcinoma is a cancer of the glands that control blood calcium, seen in a few people per ten million a year; most of its harm comes from dangerously high calcium rather than spread. Removing the tumour intact at the first operation gives the best chance of cure, and cinacalcet and bone-protecting drugs control calcium when it cannot be removed.","summary":"Parathyroid carcinoma is a malignant neoplasm of parathyroid chief cells that presents with severe primary hyperparathyroidism: calcium and parathyroid hormone far above adenoma levels, bone disease, kidney stones and renal impairment, and often a palpable neck mass, in contrast to the mild disease of parathyroid adenoma. About a quarter of sporadic cases and nearly all cases in the hyperparathyroidism-jaw tumour syndrome carry inactivating mutations in CDC73 (HRPT2), whose product parafibromin is lost on immunohistochemistry; germline testing is recommended for all patients because of the syndromic association. Preoperative distinction from adenoma is unreliable, so the diagnosis is often made at surgery or pathology.\n\nThe only curative treatment is en bloc resection of the tumour with the ipsilateral thyroid lobe and any adherent tissue, avoiding capsular rupture; incomplete initial surgery is the main cause of recurrence, which is usually loco-regional and can be re-resected repeatedly. Radiotherapy and chemotherapy have little proven activity. Because morbidity and death come from hypercalcaemia rather than tumour mass, medical control matters: cinacalcet (a calcimimetic, approved for hypercalcaemia of parathyroid carcinoma), denosumab or bisphosphonates for bone resorption, hydration and, in crisis, dialysis. Rare durable responses to PD-1 inhibitors have been reported in tumours with high mutation burden, and case series describe activity of multikinase inhibitors, but there is no approved systemic anticancer therapy.\n\nOpen problems are pre-operative recognition (parafibromin and PGP9.5 staining, calcium and PTH thresholds), the lack of trials, and effective therapy for metastatic disease beyond calcium control.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Parathyroid_carcinoma","links":[{"label":"NCI PDQ: parathyroid cancer","url":"https://www.cancer.gov/types/parathyroid"},{"label":"NCCN Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"},{"label":"CDC73 in parathyroid carcinoma (NEJM 2003)","url":"https://doi.org/10.1056/NEJMoa031237"}],"tags":["nci-coverage","rare","endocrine"],"related":[],"cancers":[],"sections":[],"technologies":["bone-modifying-agents","germline-testing"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["hereditary-cancer-syndromes","rare-cancers"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers"],"keyPapers":["paper-shattuck-n-engl-j-med"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"Under one percent of primary hyperparathyroidism; a few cases per ten million people per year, with equal sex distribution and a median age around 50.","subtypes":["Sporadic parathyroid carcinoma","Hyperparathyroidism-jaw tumour syndrome associated (germline CDC73)","Non-functioning parathyroid carcinoma (rare)"],"biomarkers":["Serum calcium and PTH (typically far above adenoma levels)","CDC73 (HRPT2) mutation and parafibromin loss","PGP9.5 and galectin-3 immunostaining","Ki-67 and capsular or vascular invasion (WHO 2022 criteria)"],"standardOfCare":[{"setting":"Suspected or confirmed carcinoma, resectable","approach":"En bloc resection with ipsilateral thyroid lobectomy and removal of adherent tissue, avoiding capsule rupture; re-resection for loco-regional recurrence.","refs":["thyroid"],"guideline":{"nccn":"Category 2A","version":"NCCN Neuroendocrine and Adrenal Tumors (parathyroid carcinoma); American Association of Endocrine Surgeons guideline 2016","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Hypercalcaemia, unresectable or metastatic disease","approach":"Cinacalcet titrated to calcium, denosumab or intravenous bisphosphonate, hydration; palliative resection or ablation of metastases to reduce PTH burden.","refs":["bone-modifying-agents","cinacalcet"],"guideline":{"version":"NCCN Neuroendocrine and Adrenal Tumors"}},{"setting":"All patients","approach":"Germline CDC73 testing and family counselling; surveillance for jaw and renal tumours in carriers.","refs":["germline-testing","hereditary-cancer-syndromes"]}],"stateOfArt":["Cinacalcet and denosumab have turned uncontrollable hypercalcaemia, historically the cause of death, into a manageable problem for most patients.","CDC73 testing identifies the hereditary syndrome and allows surveillance of relatives.","Reports of checkpoint inhibitor response in high-mutation-burden tumours and of multikinase inhibitor activity point towards genomically guided treatment, no drug is approved for the carcinoma itself, so tumour sequencing and a tumour-agnostic or basket trial are the route to one.","The WHO 2022 classification tightened histological criteria, separating carcinoma from atypical parathyroid tumours."],"history":[{"year":1933,"title":"First clear description of parathyroid carcinoma (Sainton and Millot)","refs":[]},{"year":2002,"title":"HRPT2 (CDC73) identified as the hyperparathyroidism-jaw tumour syndrome gene","note":"Carpten and colleagues, Nat Genet.","refs":[]},{"year":2003,"title":"Somatic and germline CDC73 mutations in sporadic parathyroid carcinoma","note":"Shattuck and colleagues, NEJM.","refs":[]},{"year":2004,"title":"Cinacalcet approved","note":"Including hypercalcaemia of parathyroid carcinoma (FDA).","refs":[]},{"year":2022,"title":"WHO classification refines carcinoma criteria","note":"Fifth edition endocrine tumours.","refs":[]}],"pipeline":["bone-modifying-agents","checkpoint-inhibitor"],"openProblems":["Preoperative diagnosis: no reliable imaging or biochemical threshold, so many patients have inadequate first surgery.","No effective systemic anticancer therapy for metastatic disease; genomic profiling for actionable alterations and immunotherapy case series are the current approach.","Rarity precludes randomised trials; international registries are the evidence base."]},{"id":"gastric-pdl1-high","kind":"cancer","name":"PD-L1-high gastric cancer","aka":["PD-L1 CPS 5 or above gastric cancer","PD-L1-positive gastro-oesophageal adenocarcinoma","EBV-positive gastric cancer (PD-L1 high)"],"tldr":"PD-L1-high gastric cancer expresses the immune checkpoint protein PD-L1 on tumour and immune cells, and this is the group in which nivolumab or pembrolizumab added to chemotherapy clearly extends life. The benefit shrinks as the score falls, so regulators now restrict the antibodies to tumours with at least some PD-L1 expression.","summary":"PD-L1 in stomach cancer is scored with the combined positive score, the number of PD-L1-staining tumour cells, lymphocytes and macrophages divided by the number of viable tumour cells, using the 28-8 or 22C3 antibody. Epstein-Barr virus-positive tumours, about one in eleven, express PD-L1 heavily and respond best of all; microsatellite-unstable tumours do too. Scores of 5 or above with the 28-8 assay and 1 or above with 22C3 have become the practical thresholds, and the two assays are not perfectly interchangeable.\n\nCheckMate 649 (Lancet 2021) randomised HER2-negative advanced gastric, junctional and oesophageal adenocarcinoma to nivolumab plus oxaliplatin-fluoropyrimidine chemotherapy or chemotherapy alone; in the combined positive score 5 or above group median overall survival rose from 11.1 to 14.4 months, and in all randomised patients from 11.6 to 13.8 months, with the gain concentrated in tumours with higher scores and persisting at five years. KEYNOTE-859 (Lancet Oncology 2023) did the same with pembrolizumab, improving median survival from 11.5 to 12.9 months overall, from 11.4 to 13.0 months in score 1 or above and from 11.8 to 15.7 months in score 10 or above. Chinese trials with tislelizumab and sintilimab followed the same pattern.\n\nRegulators drew different lines. The FDA first approved nivolumab in 2021 regardless of PD-L1 and pembrolizumab in 2023, then in 2025 narrowed both to tumours with a combined positive score of 1 or above after its advisory committee found no benefit below that score; the European label requires a score of 5 for nivolumab. In resectable disease MATTERHORN added durvalumab to perioperative FLOT and improved event-free survival in all patients, PD-L1 status notwithstanding, so the biomarker matters most in the metastatic setting.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Stomach_cancer","links":[{"label":"CheckMate 649 (Lancet 2021)","url":"https://pubmed.ncbi.nlm.nih.gov/34102137/"},{"label":"KEYNOTE-859 (Lancet Oncology 2023)","url":"https://pubmed.ncbi.nlm.nih.gov/37875143/"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Stomach_cancer"}],"tags":["subtype-page"],"related":["gastric-cldn18-2-positive","early-gastric-cancer","gastric-her2-positive","gastric-msi-high"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["keynote-062","attraction-2"],"people":[],"bottlenecks":[],"keyPapers":["paper-checkmate-649-lancet-2021","paper-flot4-lancet-2019","paper-keynote-859-lancet-oncol-2023","paper-matterhorn-nejm-2025"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Roughly six in ten advanced gastric adenocarcinomas have a PD-L1 combined positive score of 1 or above and about half score 5 or above; the higher the score, the larger the survival gain from adding a PD-1 antibody to chemotherapy.","subtypes":["PD-L1 CPS 10 or above (largest benefit)","PD-L1 CPS 5 or above (nivolumab label in Europe)","PD-L1 CPS 1 to 4 (smaller benefit)","EBV-positive gastric cancer (PD-L1 high, immunotherapy-responsive)","PD-L1-negative (chemotherapy alone unless another target is present)"],"biomarkers":["PD-L1 combined positive score (28-8 or 22C3 assay)","Epstein-Barr virus in situ hybridisation","Microsatellite instability and mismatch repair (overlapping responders)","HER2 (must be negative for this pathway)","Claudin 18.2 (competing first-line target)"],"standardOfCare":[{"setting":"Advanced, first line, CPS 5 or above","approach":"Nivolumab with FOLFOX or CAPOX (CheckMate 649) or pembrolizumab with platinum-fluoropyrimidine chemotherapy (KEYNOTE-859).","refs":["checkmate-649","keynote-859","nivolumab","pembrolizumab","folfox","capox","pdl1","cps"]},{"setting":"Advanced, first line, CPS 1 to 4","approach":"PD-1 antibody with chemotherapy is permitted in the United States and offered with a smaller expected gain; chemotherapy alone or zolbetuximab where claudin 18.2 is positive.","refs":["nivolumab","pembrolizumab","zolbetuximab","cps"]},{"setting":"Resectable stage II to III","approach":"Perioperative FLOT with durvalumab (MATTERHORN), given irrespective of PD-L1 score.","refs":["matterhorn","durvalumab","flot"]},{"setting":"Second line","approach":"Ramucirumab with paclitaxel (RAINBOW); no established role for continued PD-1 blockade.","refs":["rainbow","ramucirumab","paclitaxel"]}],"stateOfArt":["Nivolumab and pembrolizumab with chemotherapy are the first-line standard for PD-L1-expressing HER2-negative disease, with five-year survivors in CheckMate 649.","The combined positive score is one of the few checkpoint biomarkers with a clear dose-response across trials.","Durvalumab with FLOT brought immunotherapy into curative-intent treatment without needing the biomarker."],"history":[{"year":2017,"title":"KEYNOTE-059 and ATTRACTION-2: PD-1 antibodies active in late-line gastric cancer","refs":["pembrolizumab","nivolumab"]},{"year":2021,"title":"CheckMate 649: nivolumab plus chemotherapy extends survival; FDA approval","refs":["checkmate-649","nivolumab"]},{"year":2023,"title":"KEYNOTE-859: pembrolizumab plus chemotherapy extends survival","refs":["keynote-859","pembrolizumab"]},{"year":2025,"title":"FDA restricts first-line PD-1 antibodies to PD-L1 CPS 1 or above; MATTERHORN positive with durvalumab and FLOT","refs":["matterhorn","durvalumab"]}],"pipeline":["matterhorn","tislelizumab","idea-biomarker-quadruplet-gastric","gotistobart","azd7789"],"openProblems":["Two assays with different thresholds leave patients near the cut-off in an uncertain position.","Most patients still progress within a year on chemo-immunotherapy.","How to combine PD-1 blockade with claudin 18.2 or HER2 therapy when targets overlap."],"parent":"gastric"},{"id":"pdl1-high-nsclc","kind":"cancer","name":"PD-L1-high non-small-cell lung cancer without a driver mutation","aka":["PD-L1 50 percent or more NSCLC","PD-L1-high lung cancer","Driver-negative PD-L1-high non-small-cell lung cancer","Immunotherapy-eligible lung cancer"],"tldr":"Lung cancers that carry a lot of PD-L1 and no targetable mutation can be treated with an immunotherapy antibody alone instead of chemotherapy. Pembrolizumab keeps about a third of patients alive at five years, roughly double what chemotherapy achieved, and adding chemotherapy is reserved for those who need a fast response.","summary":"PD-L1 on tumour cells switches off the T cells that would attack them, and the level of expression, measured by immunohistochemistry as the tumour proportion score, was the first biomarker for checkpoint inhibitors in lung cancer. KEYNOTE-024 (2016) randomised 305 patients with untreated advanced non-small-cell lung cancer, PD-L1 of 50 percent or more and no EGFR or ALK alteration to pembrolizumab or platinum chemotherapy: progression-free survival was 10.3 versus 6.0 months, median overall survival 26.3 versus 13.4 months, and 31.9 percent of pembrolizumab patients were alive at five years against 16.3 percent, despite most of the chemotherapy arm crossing over. The FDA approved first-line pembrolizumab monotherapy in October 2016, the first time a checkpoint inhibitor replaced chemotherapy first line in a common cancer.\n\nKEYNOTE-042 (2019) extended monotherapy to PD-L1 of 1 percent or more but showed the gain came from the high expressers; IMpower110 (atezolizumab, 2020) and EMPOWER-Lung 1 (cemiplimab, 2021) reproduced the result with other PD-1 and PD-L1 antibodies, and nivolumab plus ipilimumab (CheckMate 227) offered a chemotherapy-free doublet. For patients with bulky or symptomatic disease pembrolizumab plus platinum doublet (KEYNOTE-189 for non-squamous, KEYNOTE-407 for squamous) gives higher response rates and is the alternative, with no randomised evidence that it prolongs survival over monotherapy in this group. Squamous and non-squamous tumours are treated alike when PD-L1 is high, apart from the chemotherapy partner.\n\nThe next generation is trying to beat pembrolizumab directly. Ivonescimab, a PD-1 and VEGF bispecific antibody, beat pembrolizumab on progression-free survival in PD-L1-positive patients in the Chinese HARMONi-2 trial (11.1 versus 5.8 months, hazard ratio 0.51), and HARMONi-3 is the global confirmation with chemotherapy; TROP2 antibody-drug conjugates with pembrolizumab (TROPION-Lung08) and TIGIT antibodies have been tested with mixed results. Open questions are who can stop immunotherapy after two years, how to treat the half of patients who progress within a year, and whether PD-L1 will be replaced by better predictors.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/PD-L1","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/PD-L1"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":["kras-g12c-nsclc","egfr-mutant-nsclc","alk-positive-nsclc","stage-iii-unresectable-nsclc","resectable-nsclc","braf-v600e-nsclc"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","bispecific-antibody","adc","companion-diagnostic"],"targets":["pd1","pdl1","ctla4","vegf","trop2"],"drugs":["pembrolizumab","cemiplimab","atezolizumab","nivolumab","ipilimumab","ivonescimab","carboplatin","pemetrexed","paclitaxel","docetaxel","ramucirumab","ventana-pd-l1-sp142"],"companies":["merck","regeneron","sanofi","roche-genentech","bms","akeso","summit-therapeutics"],"institutions":[],"pathways":["pd1-checkpoint","nsclc-signalling"],"terms":["tps","pd-l1-testing","immuno-oncology","immune-checkpoint","maintenance-therapy"],"trials":["keynote-024-189","keynote-042","empower-lung-1","harmoni-2","harmoni-3","nct05215340","tropion-lung01","nct05502237","lung-map-s1800a","checkmate-227","keynote-407"],"people":["martin-reck","roy-herbst","tony-mok","julie-brahmer","solange-peters"],"bottlenecks":[],"keyPapers":["paper-keynote-024-nejm-2016","paper-keynote-189-nejm-2018","paper-keynote-001-pembrolizumab-nsclc-nejm-2015","paper-harmoni-2-lancet-2025"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"About a quarter to a third of advanced non-small-cell lung cancers express PD-L1 on 50 percent or more of tumour cells, and most of these lack an EGFR, ALK or other targetable driver; they occur mainly in current or former smokers with adenocarcinoma or squamous histology.","subtypes":["PD-L1-high adenocarcinoma without a driver (pembrolizumab, cemiplimab or atezolizumab alone, or with platinum-pemetrexed)","PD-L1-high squamous cell carcinoma (monotherapy or with carboplatin-paclitaxel)","PD-L1-high disease with STK11 or KEAP1 co-mutation (poorer immunotherapy response)","PD-L1-high disease with bulky or symptomatic tumour (chemoimmunotherapy for a faster response)"],"biomarkers":["PD-L1 tumour proportion score by immunohistochemistry (22C3, SP263, SP142) on tissue","Absence of EGFR, ALK, ROS1, RET, BRAF, MET, HER2, KRAS G12C and NTRK alterations on a broad panel","STK11 and KEAP1 co-mutations (prognostic)","Tumour mutational burden (of limited use)","Thyroid function, liver enzymes, cortisol and glucose for immune-related adverse events"],"standardOfCare":[{"setting":"Advanced, first line, PD-L1 50 percent or more","approach":"Pembrolizumab alone (KEYNOTE-024, KEYNOTE-042), cemiplimab alone (EMPOWER-Lung 1) or atezolizumab alone; pembrolizumab plus platinum doublet for bulky or symptomatic disease; nivolumab plus ipilimumab as a chemotherapy-free alternative.","refs":["pembrolizumab","keynote-024-189","keynote-042","cemiplimab","empower-lung-1","atezolizumab","nivolumab","ipilimumab","tps","pd-l1-testing"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, first line, PD-L1 1 to 49 percent","approach":"Pembrolizumab plus platinum doublet (KEYNOTE-189, KEYNOTE-407); monotherapy is not recommended below 50 percent.","refs":["pembrolizumab","keynote-024-189","carboplatin","pemetrexed","paclitaxel","pd1-plus-chemo-pdl1-low"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, after progression on immunotherapy","approach":"Platinum doublet if not yet given; docetaxel with or without ramucirumab; clinical trials of antibody-drug conjugates and bispecifics.","refs":["docetaxel","ramucirumab","carboplatin","pemetrexed","tropion-lung01"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Duration and stopping","approach":"Two years of immunotherapy for patients in response, with retreatment at relapse; management of immune-related adverse events by organ.","refs":["pembrolizumab","checkpoint-inhibitor","immuno-oncology"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Pembrolizumab alone: five-year survival 31.9 percent versus 16.3 percent with chemotherapy in KEYNOTE-024.","Three antibodies (pembrolizumab, cemiplimab, atezolizumab) approved as monotherapy in PD-L1-high disease.","Ivonescimab beat pembrolizumab on progression-free survival in HARMONi-2; global confirmation awaited.","Two-year fixed duration with retreatment at relapse."],"history":[{"year":2015,"title":"KEYNOTE-001: PD-L1 expression predicts pembrolizumab response in lung cancer","refs":["pembrolizumab","paper-keynote-001-pembrolizumab-nsclc-nejm-2015","tps"]},{"year":2016,"title":"KEYNOTE-024: pembrolizumab alone beats chemotherapy in PD-L1-high disease; first-line approval","refs":["keynote-024-189","pembrolizumab","martin-reck","paper-keynote-024-nejm-2016"]},{"year":2018,"title":"KEYNOTE-189 and KEYNOTE-407: pembrolizumab plus chemotherapy for all PD-L1 levels","refs":["keynote-024-189","pembrolizumab","paper-keynote-189-nejm-2018"]},{"year":2019,"title":"KEYNOTE-042: monotherapy label widened to PD-L1 of 1 percent or more, benefit concentrated at 50 percent or more","refs":["keynote-042","pembrolizumab","tony-mok"]},{"year":2021,"title":"EMPOWER-Lung 1: cemiplimab approved in PD-L1-high disease","refs":["empower-lung-1","cemiplimab"]},{"year":2024,"title":"HARMONi-2: ivonescimab beats pembrolizumab on progression-free survival in China","refs":["harmoni-2","ivonescimab","paper-harmoni-2-lancet-2025","akeso"]}],"pipeline":["harmoni-3","ivonescimab","nct05215340","tropion-lung01","datopotamab-deruxtecan","nct05502237","sacituzumab-tirumotecan","idea-bio2-ctdna-six-week-io-switch"],"openProblems":["Half of PD-L1-high patients progress within a year and have no predictor to identify them in advance.","Whether adding chemotherapy to a checkpoint inhibitor prolongs survival in PD-L1-high disease has never been tested in a randomised trial.","The two-year stopping rule rests on trial design rather than evidence, and the safe minimum duration is unknown.","Ivonescimab's advantage over pembrolizumab has been shown only in China and only on progression-free survival so far."],"parent":"nsclc"},{"id":"gist-pdgfra-d842v","kind":"cancer","name":"PDGFRA D842V-mutant GIST","aka":["PDGFRA exon 18-mutant GIST","Imatinib-resistant PDGFRA GIST","Epithelioid gastric GIST"],"tldr":"PDGFRA D842V GIST is driven by a mutation in the PDGFRA receptor rather than KIT, and it does not respond to imatinib at all. Avapritinib, designed to fit the mutant activation loop, shrinks nearly nine in ten of these tumours and is the standard treatment for advanced disease; localised tumours are cured by surgery alone.","summary":"About 10 to 15 percent of GISTs carry mutations in PDGFRA, the platelet-derived growth factor receptor alpha, discovered by Heinrich in 2003; the commonest, the D842V substitution in the activation loop encoded by exon 18, accounts for around two thirds of them and about 5 percent of GISTs overall. These tumours are almost always gastric, have epithelioid or mixed histology, may stain weakly or not at all for KIT, and often behave indolently, with a lower rate of metastasis than KIT-mutant tumours of the same size. Mutation testing is essential because D842V confers complete primary resistance to imatinib, sunitinib and regorafenib: the mutation stabilises the active conformation that these type II inhibitors cannot bind.\n\nLocalised tumours are removed surgically, and because imatinib is ineffective, adjuvant therapy is not given whatever the risk score. In advanced disease, avapritinib, a type I inhibitor built to bind the active conformation of KIT and PDGFRA, produced responses in 88 percent of D842V patients in the NAVIGATOR trial (Lancet Oncology 2020) with responses lasting years, and was approved by the FDA in January 2020 for PDGFRA exon 18 mutations including D842V and by the EMA for D842V; it was the first drug to work in this group. Cognitive effects, memory impairment and, rarely, intracranial haemorrhage are its distinctive toxicities and require dose adjustment and monitoring.\n\nVOYAGER, which compared avapritinib with regorafenib in unselected third-line GIST, was negative, a lesson in patient selection: the drug's benefit is confined to the mutation it was designed for. Other PDGFRA exon 18 mutations and exon 12 and 14 mutations remain imatinib-sensitive and are managed like KIT-mutant disease. Resistance to avapritinib eventually arises through secondary PDGFRA mutations, and the sequence after it is undefined.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Avapritinib","links":[{"label":"NAVIGATOR (Lancet Oncology 2020)","url":"https://pubmed.ncbi.nlm.nih.gov/32615108/"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Avapritinib"}],"tags":["subtype-page"],"related":["gist-imatinib-resistant","gist-kit-exon-11"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["gist-risk-stratification"],"trials":["navigator"],"people":[],"bottlenecks":[],"keyPapers":["paper-navigator-avapritinib-heinrich-lancet-oncol-2020","paper-heinrich-pdgfra-gist-science-2003"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About one in twenty gastrointestinal stromal tumours, almost always in the stomach, with epithelioid histology and often indolent behaviour; the D842V substitution in the activation loop makes the receptor untouchable by imatinib but exquisitely sensitive to avapritinib.","subtypes":["PDGFRA D842V-mutant gastric GIST, epithelioid (imatinib-resistant, avapritinib)","Other PDGFRA exon 18 mutations (avapritinib; some imatinib-sensitive)","PDGFRA exon 12 and 14-mutant GIST (imatinib-sensitive)","Localised PDGFRA D842V GIST (surgery alone, no adjuvant therapy)","Advanced PDGFRA D842V GIST after avapritinib"],"biomarkers":["PDGFRA exon 18 D842V mutation (defines the subtype and excludes imatinib)","Weak or absent KIT (CD117) staining with positive DOG1","Epithelioid histology","Mitotic count and size (risk, though behaviour is often indolent)","Secondary PDGFRA mutations at progression on avapritinib"],"standardOfCare":[{"setting":"Localised, resectable","approach":"Surgical resection; no adjuvant imatinib because the mutation is resistant to it.","refs":["robotic-surgery","pdgfra"]},{"setting":"Advanced, first line","approach":"Avapritinib 300 mg daily (NAVIGATOR), with monitoring for cognitive effects and bleeding.","refs":["avapritinib","pdgfra","kit"]},{"setting":"Progression on avapritinib","approach":"No established therapy; clinical trials, surgery or embolisation for isolated progression; regorafenib and other kinase inhibitors have low activity.","refs":["regorafenib","voyager","liquid-biopsy"]}],"stateOfArt":["Avapritinib is the first effective drug for a mutation that had defeated every earlier kinase inhibitor.","The failure of VOYAGER in unselected patients alongside NAVIGATOR's success is the clearest example of genotype-driven treatment in sarcoma.","Mutation testing before any imatinib is now mandatory in GIST guidelines, largely because of this subtype."],"history":[{"year":2003,"title":"Heinrich identifies PDGFRA mutations in KIT wild-type GIST","refs":["pdgfra"]},{"year":2005,"title":"D842V shown to confer primary imatinib resistance","refs":["imatinib"]},{"year":2020,"title":"NAVIGATOR: avapritinib responses in 88 percent; FDA approval","refs":["avapritinib"]},{"year":2021,"title":"VOYAGER: avapritinib no better than regorafenib in unselected GIST","refs":["voyager","avapritinib","regorafenib"]}],"pipeline":["avapritinib","liquid-biopsy","idrx-42"],"openProblems":["No proven therapy after progression on avapritinib.","Cognitive side effects limit dose and quality of life for some patients.","Whether indolent D842V tumours can be watched rather than resected."],"parent":"gist"},{"id":"penile","kind":"cancer","name":"Penile cancer","aka":["Penile squamous cell carcinoma","Carcinoma of the penis"],"tldr":"Penile cancer is a squamous skin-type cancer, about half of it caused by HPV. Caught early it is usually cured with organ-sparing surgery that has replaced amputation, and HPV vaccination and circumcision prevent it; the hard cases are those with lymph-node spread, where cisplatin-based chemotherapy plus surgery and now immunotherapy are being tested in the InPACT trial.","summary":"Penile squamous cell carcinoma arises on the glans or foreskin and follows two pathways: HPV-related (HPV16 predominant, p16-positive, basaloid or warty histology) and HPV-independent (differentiated PeIN linked to lichen sclerosus and chronic inflammation, TP53 and CDKN2A alterations). The disease spreads predictably to inguinal then pelvic nodes, and nodal stage is the dominant prognostic factor. Management has shifted from amputation to organ-sparing surgery for most primary tumours (glansectomy, glans resurfacing, laser, Mohs, or brachytherapy), which preserves function without compromising cure when margins are clear.\n\nThe inguinal nodes decide outcome. Dynamic sentinel node biopsy stages clinically node-negative patients with intermediate- or high-risk primaries, sparing most of them a morbid lymphadenectomy; palpable or proven nodal disease is treated with radical inguinal (and, when indicated, pelvic) lymphadenectomy, with adjuvant chemotherapy or chemoradiation for extensive nodal disease. Cisplatin-based combinations (TIP: paclitaxel, ifosfamide, cisplatin) are the standard neoadjuvant and first-line regimens; the international InPACT trial (NCT02305654) is the first randomised study to define the sequence of surgery, chemotherapy and radiotherapy in node-positive disease. Immune checkpoint inhibitors (pembrolizumab, cemiplimab) have produced responses in small series and are being combined with chemotherapy and radiotherapy in trials, and HPV-directed vaccines and cell therapies are being explored.\n\nThe EAU-ASCO 2023 collaborative guideline is the current reference. Prevention is straightforward in principle: HPV vaccination of boys, neonatal or childhood circumcision where culturally appropriate, phimosis treatment and smoking cessation.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Penile_cancer","links":[{"label":"NCI PDQ: penile cancer","url":"https://www.cancer.gov/types/penile"},{"label":"EAU-ASCO collaborative guideline (Eur Urol 2023)","url":"https://doi.org/10.1016/j.eururo.2023.02.027"},{"label":"InPACT (NCT02305654)","url":"https://clinicaltrials.gov/study/NCT02305654"},{"label":"NCCN: Penile Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1456"}],"tags":["nci-coverage","rare","genitourinary","hpv"],"related":["cervical","vulvar","anal","head-and-neck","cutaneous-scc"],"cancers":[],"sections":[],"technologies":["sentinel-node","brachytherapy","cytotoxic-chemotherapy","checkpoint-inhibitor","hpv-vaccine","robotic-surgery"],"targets":["pd1","egfr","tp53"],"drugs":["cisplatin","paclitaxel","ifosfamide","pembrolizumab","cemiplimab","gardasil-9","fluorouracil"],"companies":[],"institutions":[],"pathways":["oncogenic-viruses","p53-cell-cycle"],"terms":["hpv-p16","hpv-status","lymphadenectomy","mohs-surgery"],"trials":["nct06465914"],"people":[],"bottlenecks":["b-rare-cancers","b-prevention-adoption"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Rare in high-income countries (well under one per 100,000 men per year) and several times more common in parts of South America, sub-Saharan Africa and South Asia, tracking HPV prevalence, phimosis and low circumcision rates.","subtypes":["HPV-associated squamous cell carcinoma (basaloid, warty)","HPV-independent squamous cell carcinoma (usual type, verrucous, sarcomatoid)","Penile intraepithelial neoplasia (PeIN; precursor)","Rare: melanoma, basal cell carcinoma, sarcoma, urethral carcinoma of the penis"],"biomarkers":["p16 IHC / HPV DNA status","Grade and lymphovascular invasion of the primary (decides sentinel node biopsy)","Inguinal and pelvic nodal stage (extranodal extension, number of nodes)","PD-L1 expression (investigational)","TP53 and CDKN2A status (HPV-independent tumours)"],"standardOfCare":[{"setting":"Primary tumour","approach":"Organ-sparing treatment where feasible (glansectomy, glans resurfacing, wide local excision, laser or brachytherapy); partial or total penectomy reserved for extensive tumours.","refs":["brachytherapy","mohs-surgery"],"guideline":{"version":"EAU-ASCO Collaborative Guideline on Penile Cancer 2023","url":"https://doi.org/10.1016/j.eururo.2023.02.027"}},{"setting":"Clinically node-negative, intermediate or high-risk primary","approach":"Dynamic sentinel node biopsy (or modified inguinal lymphadenectomy where unavailable); observation only for low-risk primaries.","refs":["sentinel-node"],"guideline":{"version":"EAU-ASCO 2023; NCCN Guidelines: Penile Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1456"}},{"setting":"Node-positive","approach":"Radical inguinal lymphadenectomy; pelvic lymphadenectomy and adjuvant chemotherapy or chemoradiation for extensive disease; neoadjuvant TIP for bulky or fixed nodes (InPACT is testing the sequence).","refs":["lymphadenectomy","paclitaxel","cisplatin","ifosfamide","inpact"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Penile Cancer"}},{"setting":"Metastatic or recurrent","approach":"Cisplatin-based chemotherapy (TIP); checkpoint inhibitors in trials or where approved for tumour-agnostic indications; palliative radiotherapy.","refs":["cisplatin","paclitaxel","pembrolizumab","cemiplimab"]}],"stateOfArt":["Organ-sparing surgery has replaced amputation for most primary tumours without loss of cure, a quiet revolution in quality of life.","Dynamic sentinel node biopsy spares most node-negative men a lymphadenectomy and its lifelong lymphoedema risk.","InPACT, a UK-US-led academic trial, is the first randomised study in node-positive penile cancer, testing neoadjuvant chemotherapy and chemoradiation before surgery.","HPV vaccination of boys and men is the prevention lever; several countries adopted gender-neutral vaccination in the 2010s and 2020s."],"history":[{"year":1932,"title":"Squamous origin and HPV precursors described","note":"Bowen's disease and erythroplasia of Queyrat recognised as penile carcinoma in situ.","refs":[]},{"year":1994,"title":"Dynamic sentinel node biopsy for penile cancer","note":"Horenblas and colleagues (Netherlands Cancer Institute) introduce lymphatic mapping.","refs":["sentinel-node"]},{"year":2010,"title":"TIP neoadjuvant chemotherapy","note":"Pagliaro and colleagues (JCO 2010) report responses and resectability in bulky nodal disease.","refs":["paclitaxel","cisplatin","ifosfamide"]},{"year":2017,"title":"InPACT opens","note":"International phase 3 platform for node-positive penile cancer (NCT02305654).","refs":[]},{"year":2023,"title":"EAU-ASCO collaborative guideline","note":"First joint European and American guideline for penile cancer.","refs":[]}],"pipeline":["pembrolizumab","cemiplimab","hpv-vaccine"],"openProblems":["Node-positive disease: the best sequence of chemotherapy, radiotherapy and surgery is unknown; InPACT is designed to answer it.","No approved systemic therapy beyond cisplatin combinations; checkpoint inhibitor trials (often HPV-stratified) are recruiting.","Late presentation from stigma and delayed referral; awareness campaigns and rapid-access clinics are the response.","Lymphoedema and sexual function after treatment; sentinel node biopsy and organ preservation reduce the toll."]},{"id":"peripheral-t-cell-lymphoma","kind":"cancer","name":"Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma)","aka":["PTCL","CTCL","Mycosis fungoides","Anaplastic large-cell lymphoma","Mature T-cell and NK-cell neoplasms","T-cell lymphoma","NK-cell lymphoma","Peripheral T-cell lymphoma, not otherwise specified","PTCL-NOS"],"tldr":"Peripheral T-cell lymphomas are lymphomas of T cells rather than B cells. They are rarer, more varied and, apart from a few subtypes, harder to treat than B-cell lymphomas; several new drugs help only defined subtypes.","summary":"PTCLs are a heterogeneous group: PTCL-NOS, nodal T-follicular-helper lymphomas (angioimmunoblastic), ALK-positive and ALK-negative anaplastic large-cell lymphoma (ALCL), adult T-cell leukaemia/lymphoma (HTLV-1), extranodal NK/T-cell lymphoma (EBV), enteropathy-associated and hepatosplenic T-cell lymphoma, and the cutaneous T-cell lymphomas (mycosis fungoides, Sézary syndrome). Except ALK-positive ALCL, five-year survival with CHOP is 30-40%.\n\nCHOP or CHOEP remains the backbone; brentuximab vedotin-CHP replaced CHOP for CD30-positive PTCL after ECHELON-2 (2018) and is the standard for ALCL. Autologous transplant consolidation in first remission is common practice without randomised proof. Relapsed disease is treated with pralatrexate (2009), the HDAC inhibitors romidepsin (2009, US PTCL indication withdrawn 2021) and belinostat (2014), brentuximab, or allogeneic transplant. NK/T-cell lymphoma uses asparaginase-based regimens (SMILE, P-GemOx) and radiotherapy; PD-1 blockade is active. Cutaneous T-cell lymphoma is managed by skin-directed therapy, then mogamulizumab (anti-CCR4, MAVORIC 2018), brentuximab (ALCANZA), bexarotene, extracorporeal photopheresis, and allogeneic transplant.\n\nOpen: TFH-lymphoma-directed epigenetic combinations (azacitidine-CHOP, ORACLE), CD30/CD7/CD5 CAR-T with fratricide engineering, and JAK/STAT inhibitors.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Peripheral_T-cell_lymphoma","links":[{"label":"NCCN Guidelines: T-Cell Lymphomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1483"},{"label":"ECHELON-2 (Lancet 2019)","url":"https://doi.org/10.1016/S0140-6736(18)32984-2"},{"label":"NCI PDQ: mycosis fungoides","url":"https://www.cancer.gov/types/lymphoma/patient/mycosis-fungoides-treatment-pdq"},{"label":"Lymphoma Action: helpline services","url":"https://lymphoma-action.org.uk/information-and-support/support-you/helpline-services"},{"label":"Lymphoma Action: questions to ask your medical team about lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/questions-ask-your-medical-team-about-lymphoma"},{"label":"Lymphoma Action: follow-up after lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/follow-after-lymphoma-treatment"},{"label":"Lymphoma Action: infections, risk and prevention","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/infections-risk-and-prevention"},{"label":"Lymphoma Action: neutropenia (low neutrophils)","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/neutropenia-low-neutrophils"},{"label":"Lymphoma Action: cancer-related fatigue","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/cancer-related-fatigue"},{"label":"Lymphoma Action: lymphoma, work and you","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/day-day-living/lymphoma-work-and-you"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Lymphoma Action: taking part in a clinical trial","url":"https://lymphoma-action.org.uk/information-and-support/lymphoma-treatment/clinical-trials-lymphoma-trialslink/taking-part-clinical"},{"label":"Lymphoma Action: autologous (your own) stem cell transplant","url":"https://lymphoma-action.org.uk/information-and-support/lymphoma-treatment/stem-cell-transplants/self-autologous-stem-cell"},{"label":"Macmillan: non-Hodgkin lymphoma","url":"https://www.macmillan.org.uk/cancer-information-and-support/lymphoma/non-hodgkin-lymphoma"},{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"}],"tags":["gap-fill","haematologic"],"related":["dlbcl","mantle-cell-lymphoma","follicular-lymphoma","rhoa-g17v","ig-tcr-clonality","lymphoma-roadmap","lymphoma-ev-randomised-evidence-for-the-t-cell-lymphomas","lymphoma-ev-the-drugs-that-cure-and-the-places-without-them"],"cancers":[],"sections":[],"technologies":["adc","monoclonal-antibody","epigenetic-drugs","autologous-stem-cell-transplant","allogeneic-hsct","car-t","palliative-care","psycho-oncology","peer-support-groups","survivorship-care-plan","fertility-preservation","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","multidisciplinary-tumour-board","oncology-nutrition","prehabilitation","clonality-testing","cgp","histopathology-ihc","flow-cytometry-mrd"],"targets":["cd30","ccr4","alk","pd1","cd52","cd38","stat3","stat5","jak1","jak3","rhoa","tet2","dnmt3a","vav1","irf4","plcg1","card11","fyn"],"drugs":["brentuximab-vedotin","pralatrexate","romidepsin","belinostat","mogamulizumab","azacitidine","crizotinib","pembrolizumab","doxorubicin","cyclophosphamide","vincristine","asparaginase","alemtuzumab","interferon-alfa"],"companies":["pfizer","takeda","bms","bioinvent-international","haihe-biopharma","immuneoncia-therapeutics"],"institutions":[],"pathways":["jak-stat","oncogenic-viruses","epigenetic-reprogramming","inflammation-nfkb"],"terms":["lugano-classification","histologic-transformation","lymphoma-tx-regimen-alphabet","lymphoma-tx-transplant-role","lymphoma-tx-pjp-and-infection-prophylaxis","lymphoma-tx-radiotherapy","lymphoma-tx-failed-and-negative","lymphoma-tx-uk-access","plasma-ebv-dna","cancer-related-fatigue","late-effects","febrile-neutropenia","neutropenia","financial-toxicity","central-venous-access","hypogammaglobulinaemia","performance-status","quality-of-life","lymphoma-decision-trial","lymphoma-decision-fertility-timing","lymphoma-living-fatigue","lymphoma-living-scanxiety-and-surveillance","lymphoma-living-returning-to-work","lymphoma-bio-htlv1","lymphoma-bio-lineage-antigen-cost","lymphoma-bio-ebv-latency","lymphoma-pit-score","lymphoma-htlv-1","lymphoma-classification-2022","lymphoma-b-versus-t-cell","lymphoma-indolent-versus-aggressive"],"trials":["nct06561048","nct06776952","nct06072131","nct04668690","alcanza","echelon-2","jcog9801","smile-enktl"],"people":[],"bottlenecks":[],"keyPapers":["paper-horwitz-lancet"],"journals":[],"dependsOn":[],"notes":["Living with a peripheral T-cell lymphoma, where a trial is more often the right first question: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the 24-hour number they gave you come first, and no figure here is a prediction about you. The decision records, the question sets, the first 60 days checklist and the red cards on this page were written from the NHS, Lymphoma Action, Macmillan and Cancer Research UK patient pages, from NICE NG52, NG47, CG151 and NG234, from the NHS Breast Screening Programme protocols and the Green Book, and from the trial reports named beside each figure, all read on 1 October 2026.","Taxonomy. This page is used as the hub for the mature T-cell and NK-cell lymphomas, which is wider than its name. WHO-HAEM5 reserves \"peripheral T-cell lymphoma, not otherwise specified\" for a single entity within the family it calls other peripheral T-cell lymphomas, and files the anaplastic large cell lymphomas, the nodal T-follicular helper cell lymphomas, the EBV-positive NK/T-cell lymphomas, the intestinal T-cell lymphomas and the primary cutaneous T-cell lymphomas as separate families. The corpus keeps this page as the entry point because it is where a reader arrives, and the entities now have pages of their own, listed above."],"group":"haematologic","burden":"Peripheral T-cell lymphomas make up about 10-15% of non-Hodgkin lymphomas in the West, more in Asia; there are over 30 WHO subtypes, most individually rare.","subtypes":["PTCL, not otherwise specified","Nodal TFH lymphoma (angioimmunoblastic type)","ALK-positive ALCL","ALK-negative ALCL (DUSP22, TP63 subsets)","Adult T-cell leukaemia/lymphoma (HTLV-1)","Extranodal NK/T-cell lymphoma (EBV)","Mycosis fungoides / Sézary syndrome (CTCL)","Enteropathy-associated and hepatosplenic T-cell lymphoma"],"biomarkers":["CD30 expression (brentuximab)","ALK rearrangement","TFH markers (PD-1, CXCL13, ICOS) and RHOA G17V / TET2 / IDH2 R172","EBV DNA (NK/T-cell)","HTLV-1 serology","CCR4 (mogamulizumab)","TCR clonality"],"standardOfCare":[{"setting":"First line, CD30+ PTCL / ALCL","approach":"Brentuximab vedotin + CHP ×6 (ECHELON-2, OS benefit) ± consolidative autologous transplant.","refs":["brentuximab-vedotin","autologous-stem-cell-transplant"],"guideline":{"nccn":"Category 1 (ALCL)","esmoMcbs":"4","version":"NCCN Guidelines: T-Cell Lymphomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1483"}},{"setting":"First line, other nodal PTCL","approach":"CHOP or CHOEP (≤60 years) ×6, autologous transplant consolidation in responders; clinical trial preferred.","refs":["doxorubicin","cyclophosphamide","vincristine","autologous-stem-cell-transplant"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: T-Cell Lymphomas"}},{"setting":"Relapsed/refractory PTCL","approach":"Pralatrexate, belinostat, romidepsin (ex-US), brentuximab (CD30+), gemcitabine-based regimens, allogeneic HSCT for fit responders.","refs":["pralatrexate","belinostat","romidepsin","brentuximab-vedotin","allogeneic-hsct"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: T-Cell Lymphomas"}},{"setting":"Mycosis fungoides / Sézary","approach":"Skin-directed therapy (topical steroids, phototherapy, radiotherapy, total-skin electron beam), then mogamulizumab (MAVORIC), brentuximab (ALCANZA, CD30+), bexarotene, interferon, photopheresis; allogeneic HSCT for advanced disease.","refs":["mogamulizumab","brentuximab-vedotin","allogeneic-hsct"],"guideline":{"nccn":"Category 1 (mogamulizumab, brentuximab)","version":"NCCN Guidelines: Primary Cutaneous Lymphomas"}},{"setting":"Extranodal NK/T-cell","approach":"Asparaginase-based chemotherapy (P-GemOx, SMILE) with involved-site radiotherapy for localised disease; PD-1 inhibitors at relapse.","refs":["pembrolizumab","imrt-igrt"]},{"setting":"Peripheral T-cell lymphoma: the questions that decide the regimen","approach":"Four things to establish before treatment. Which entity: ALK-positive anaplastic large cell lymphoma does much better than every other nodal T-cell lymphoma and is curable with chemotherapy alone in most patients; ALK-negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified and the enteropathy-associated forms do considerably worse. CD30 expression by immunohistochemistry, because it decides whether brentuximab vedotin is added to first-line chemotherapy. Whether the disease is nodal, extranodal (nasal NK/T-cell), leukaemic (adult T-cell leukaemia/lymphoma, T-cell prolymphocytic leukaemia) or cutaneous, because those four groups have entirely different treatments. HTLV-1 serology where the patient comes from or has family from Japan, the Caribbean, west Africa, Iran or parts of South America, because adult T-cell leukaemia/lymphoma is treated differently from everything else.\n\nA breast implant-associated anaplastic large cell lymphoma presenting as a late seroma around an implant is treated primarily by complete surgical removal of the implant and capsule, and most patients need nothing else. That is a different disease from systemic anaplastic large cell lymphoma despite the shared name.","refs":["lymphoma-type","lymphoma-tx-regimen-alphabet","brentuximab-vedotin","fdg-pet","lugano-classification"],"guideline":{"version":"NCCN T-Cell Lymphomas; ESMO; WHO fifth edition","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"First-line nodal peripheral T-cell lymphoma, CD30-positive: brentuximab vedotin with CHP","approach":"ECHELON-2 randomised 452 patients with untreated CD30-positive peripheral T-cell lymphoma to brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone (A+CHP) or to CHOP. Median progression-free survival by blinded independent review was 48.2 against 20.8 months (hazard ratio 0.71), with improved overall survival, and toxicity was comparable: febrile neutropenia 18 against 15 per cent and peripheral neuropathy 52 against 55 per cent. It is the only positive randomised first-line trial in this family in twenty years and it changed the standard.\n\nThree-quarters of the trial population had systemic anaplastic large cell lymphoma, so the benefit is best established there and is extrapolated to other CD30-positive entities. Six cycles are given, with G-CSF support. Vincristine is omitted because brentuximab vedotin is itself a tubulin-directed agent and giving both causes unacceptable neuropathy.","refs":["echelon-2","brentuximab-vedotin","cyclophosphamide","doxorubicin","prednisone","g-csf-growth-factors","lymphoma-tx-regimen-alphabet","paper-horwitz-lancet"],"guideline":{"nccn":"Category 1 (A+CHP, CD30-positive)","version":"NCCN T-Cell Lymphomas; ESMO; ECHELON-2","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"First-line nodal peripheral T-cell lymphoma, CD30-negative: CHOP, CHOEP and an honest account of the evidence","approach":"CHOP for six cycles is the default, and it is a default rather than a demonstrated best. No randomised trial has shown any regimen superior to CHOP in CD30-negative nodal peripheral T-cell lymphoma, and roughly half of patients are not cured by it.\n\nAdding etoposide (CHOEP) is standard in much of Europe for patients under 60 with a normal LDH, on the basis of a retrospective analysis of the German High-Grade Non-Hodgkin Lymphoma Study Group trials in which that subgroup had better event-free survival; the analysis was not randomised and not confined to T-cell lymphoma, so the practice rests on an observation rather than a trial. Adding romidepsin to CHOP was tested properly in the Ro-CHOP trial and failed, which is why the United States withdrew romidepsin's peripheral T-cell lymphoma indication.\n\nAngioimmunoblastic T-cell lymphoma is the entity in which the epigenetic drugs look most promising, because it is driven by mutations in TET2, DNMT3A, IDH2 and RHOA; azacitidine-containing combinations and histone deacetylase inhibitors are being tested and are not yet standard. Enteropathy-associated T-cell lymphoma is treated with intensive regimens and early nutritional support, because it presents with perforation or obstruction in a malnourished patient with coeliac disease.\n\nEntering a trial is a reasonable first choice rather than a last resort in this group.","refs":["r-chop","cyclophosphamide","doxorubicin","vincristine","prednisone","etoposide","romidepsin","lymphoma-tx-regimen-alphabet","lymphoma-tx-failed-and-negative"],"guideline":{"version":"NCCN T-Cell Lymphomas; ESMO; no randomised evidence for CHOEP over CHOP","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Autologous transplant consolidation in first remission","approach":"Consolidating a first complete or partial remission with high-dose therapy and an autologous stem cell transplant is standard practice in Europe and common in the United States for nodal peripheral T-cell lymphomas other than ALK-positive anaplastic large cell lymphoma, which does well enough without it. The evidence is a prospective single-arm Nordic study and a series of registry comparisons; there has never been a randomised trial, and the registry comparisons are subject to the obvious bias that only patients who respond well enough and stay fit enough reach transplant.\n\nSo the row is written as it is: this is the convention, it is reasonable, and a patient is entitled to be told that its benefit has not been demonstrated against continuing observation. Stem cells are collected after two to four cycles, before the marrow is exhausted. Allogeneic transplant is reserved for relapsed disease and for hepatosplenic T-cell lymphoma, where it is the only treatment that produces long remissions.","refs":["autologous-stem-cell-transplant","allogeneic-hsct","lymphoma-tx-transplant-role","carmustine","etoposide","cytarabine","melphalan"],"guideline":{"version":"NCCN T-Cell Lymphomas; ESMO; no randomised evidence","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Relapsed and refractory peripheral T-cell lymphoma","approach":"Response rates to every available single agent sit between about 25 and 35 per cent, and remissions are usually short, so the question at relapse is whether the patient can be taken to an allogeneic transplant or a trial.\n\nApproved single agents in the United States: pralatrexate, an antifolate, approved in 2009 on a response rate of about 29 per cent; belinostat, a histone deacetylase inhibitor, approved in 2014 on about 26 per cent, usable when platelets are low; romidepsin, approved in 2011 and withdrawn from this indication after the confirmatory Ro-CHOP trial failed. Brentuximab vedotin is highly active in relapsed systemic anaplastic large cell lymphoma, where response rates are far higher than in other entities; its first-line United States approval with cyclophosphamide, doxorubicin and prednisone for untreated systemic anaplastic large cell lymphoma and other CD30-expressing peripheral T-cell lymphomas came on 16 November 2018. Availability differs sharply between countries: pralatrexate and belinostat are not routinely commissioned in England.\n\nOther options are gemcitabine-based chemotherapy (GemOx, GDP), which is widely used in the United Kingdom and has no randomised support, bendamustine, alemtuzumab in selected cases, and a clinical trial. Allogeneic transplant is the only treatment with curative potential at this point and is offered to fit patients who achieve a response. Valemetostat, an EZH1/EZH2 inhibitor, is approved in Japan for relapsed adult T-cell leukaemia/lymphoma and peripheral T-cell lymphoma and is in trials elsewhere; the corpus does not yet hold a record for it and this page does not quote a figure for it.","refs":["pralatrexate","belinostat","romidepsin","brentuximab-vedotin","gemcitabine","oxaliplatin","bendamustine","alemtuzumab","allogeneic-hsct","lymphoma-tx-transplant-role"],"guideline":{"version":"NCCN T-Cell Lymphomas; ESMO","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":["Brentuximab-CHP is the only regimen ever to improve survival over CHOP in PTCL, and only for CD30-positive disease.","Molecular subtyping (TFH, DUSP22, TP63) now guides prognosis and trial design, though not yet routine therapy.","Mogamulizumab and brentuximab give durable disease control in advanced cutaneous T-cell lymphoma.","Epigenetic therapy (azacitidine, HDAC inhibitors) is most active in TFH lymphomas with TET2/DNMT3A mutations.","The T-cell lymphomas are where the antigen problem is hardest, because the tumour and the effector are the same kind of cell. CD52 is on B cells, T cells, monocytes and dendritic cells, so alemtuzumab leaves CD4 counts low for a year; CCR4 is on regulatory T cells as well as on the tumour; and a CD3-engaging bispecific cannot be used the way it is in B-cell disease.","JAK-STAT is the recurring signalling lesion. Activating STAT3 and STAT5B mutations were found across 51 NK/T-cell lymphomas and 43 gamma-delta T-cell lymphomas, with STAT5B N642H particularly frequent in the gamma-delta group; the substitution raises the affinity of the phosphotyrosine for the mutant histidine so the active form persists.","HTLV-1 defines adult T-cell leukaemia/lymphoma, and the genomics show it is not simply a viral disease: across 426 cases, the acquired alterations overlapped significantly with the proteins the viral Tax protein binds, concentrating in T-cell receptor and NF-kB signalling, trafficking and immune surveillance, with activating CCR4 mutations among them."],"history":[{"year":1975,"title":"Mycosis fungoides staging (TNMB)","refs":[]},{"year":1994,"title":"ALK fusion in anaplastic large-cell lymphoma","note":"NPM-ALK identified by Morris et al.; ALK-positive ALCL becomes the good-prognosis PTCL.","refs":["alk"]},{"year":2009,"title":"Pralatrexate and romidepsin approved","note":"First drugs specifically for relapsed PTCL.","refs":["pralatrexate","romidepsin"]},{"year":2011,"title":"Brentuximab vedotin approved for ALCL","refs":["brentuximab-vedotin"]},{"year":2014,"title":"Belinostat approved","refs":["belinostat"]},{"year":2017,"title":"ALCANZA: brentuximab in CD30+ CTCL","refs":["brentuximab-vedotin"]},{"year":2018,"title":"ECHELON-2 and mogamulizumab","note":"Brentuximab-CHP improves OS over CHOP; mogamulizumab approved for MF/Sézary (MAVORIC).","refs":["brentuximab-vedotin","mogamulizumab"]},{"year":2021,"title":"Romidepsin US PTCL indication withdrawn","note":"Confirmatory Ro-CHOP trial negative.","refs":["romidepsin"]}],"pipeline":["brentuximab-vedotin","azacitidine","allogeneic-hsct","soquelitinib","azd3470","dr-01"],"openProblems":["Five-year survival under 40% for PTCL-NOS with no new first-line regimen for non-CD30 disease.","Randomised evidence for transplant consolidation is lacking.","T-cell CAR-T faces fratricide and T-cell aplasia.","Most subtypes too rare for conventional phase 3 trials.","Almost nothing given in peripheral T-cell lymphoma rests on a randomised trial. CHOP is the default without ever having been shown superior to anything; CHOEP rests on a retrospective subgroup; autologous transplant consolidation in first remission rests on a single-arm study and registry comparisons that select for the patients who were going to do well.","Adding romidepsin to CHOP failed in Ro-CHOP and the indication was withdrawn, leaving the CD30-negative nodal T-cell lymphomas with no advance since CHOP itself.","Extranodal NK/T-cell lymphoma and adult T-cell leukaemia/lymphoma are common in east Asia, the Caribbean and west Africa and rare in the countries that run most trials, so their evidence base is thin in exactly the places where patients are treated outside those regions.","Valemetostat is approved in Japan for relapsed adult T-cell leukaemia/lymphoma and peripheral T-cell lymphoma and has no record in this corpus and no approval in the United Kingdom or the United States at the time of writing, which is a gap rather than a judgement."],"parent":"non-hodgkin-lymphoma"},{"id":"peritoneal-mesothelioma","kind":"cancer","name":"Peritoneal mesothelioma","aka":["Malignant peritoneal mesothelioma","MPeM","Diffuse malignant peritoneal mesothelioma"],"tldr":"Peritoneal mesothelioma grows in the lining of the abdomen, causing swelling, pain and fluid. Unlike its pleural cousin it is often treated with major surgery to strip the lining followed by heated chemotherapy washed through the abdomen, which can give long survival in fit patients with epithelioid disease.","summary":"Peritoneal mesothelioma presents with abdominal distension from ascites, pain, weight loss or a mass found at surgery, and is diagnosed by laparoscopic biopsy with the same immunohistochemistry as pleural disease. Asbestos exposure is found in only a minority; BAP1 germline mutations account for some cases, and the disease is commoner in women than pleural mesothelioma. For fit patients with epithelioid histology and disease that can be removed, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) is the standard in specialist centres and gives median survival of five years or more in series, though no randomised trial exists. Patients who are not candidates receive platinum-pemetrexed chemotherapy, with immunotherapy increasingly used on the basis of small trials and the pleural data. Well-differentiated papillary and multicystic forms behave almost benignly and are managed separately.","asOf":"2026-09-16","wikipedia":"https://en.wikipedia.org/wiki/Peritoneal_mesothelioma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Peritoneal_mesothelioma"}],"tags":["subtype-page"],"related":["pleural-mesothelioma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["bap1-loss"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-yan-peritoneal-mesothelioma-crs-hipec-jco-2009","paper-raghav-atezolizumab-bevacizumab-peritoneal-mesothelioma-cancer-discov-2021","paper-checkmate-743-lancet-2021","paper-vogelzang-pemetrexed-mesothelioma-jco-2003"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About one in ten mesotheliomas; a few hundred cases a year in the US. The asbestos link is weaker than in the pleura, it affects more women and younger people, and selected patients live many years after surgery.","subtypes":["Epithelioid (most cases)","Biphasic and sarcomatoid (rare, shorter survival)","Well-differentiated papillary mesothelial tumour (indolent)","Multicystic mesothelioma (indolent)"],"biomarkers":["Histology and peritoneal cancer index at laparoscopy","BAP1 loss (somatic and germline)","Ki-67 (prognostic after surgery)","Completeness of cytoreduction score"],"standardOfCare":[{"setting":"Diagnosis","approach":"CT, laparoscopy with biopsy and scoring of disease extent; germline BAP1 testing when young or with a family history.","refs":["mesothelioma"]},{"setting":"Resectable epithelioid disease, fit patient","approach":"Cytoreductive surgery with HIPEC in an experienced centre; long-term survival in a substantial fraction.","refs":["hipec"]},{"setting":"Unresectable or unfit","approach":"Platinum-pemetrexed chemotherapy; nivolumab plus ipilimumab or pembrolizumab combinations extrapolated from pleural trials and small peritoneal series.","refs":["pemetrexed","nivolumab","ipilimumab","pembrolizumab"]},{"setting":"Indolent variants","approach":"Well-differentiated papillary and multicystic tumours: surgical removal and surveillance; systemic therapy rarely needed.","refs":["active-surveillance"]}],"stateOfArt":["Cytoreduction with HIPEC, pioneered by Sugarbaker, turned a disease with a median survival under a year into one where a substantial fraction of selected patients live five years or more.","Immunotherapy is being adopted from pleural mesothelioma with encouraging early results, and peritoneal patients are now included in mesothelin-directed trials.","Registries and consortia have replaced case series as the evidence base because randomised trials are so hard to run in a disease this rare."],"history":[{"year":1908,"title":"Miller and Wynn describe peritoneal mesothelioma","note":"Among the earliest descriptions of a primary tumour of the peritoneum.","refs":[]},{"year":1995,"title":"Sugarbaker develops cytoreduction with HIPEC","note":"Peritonectomy procedures and heated intraperitoneal chemotherapy applied to peritoneal surface malignancy.","refs":["hipec"]},{"year":2009,"title":"Multi-institutional registry of 405 patients","note":"Yan and colleagues report median survival of 53 months after cytoreduction and HIPEC.","refs":[]},{"year":2021,"title":"Immunotherapy series in peritoneal disease","note":"Early phase 2 and retrospective data for nivolumab plus ipilimumab and for atezolizumab plus bevacizumab.","refs":[]}],"pipeline":["idea-adc-for-mesothelioma"],"openProblems":["No randomised trial has compared surgery plus HIPEC with systemic therapy.","Selection for surgery relies on centre experience rather than validated criteria.","Peritoneal patients were excluded from the pleural immunotherapy trials, so their benefit is inferred."],"parent":"mesothelioma"},{"id":"pecoma","kind":"cancer","name":"Perivascular epithelioid cell tumour (PEComa)","aka":["PEComa","Malignant PEComa","Angiomyolipoma and lymphangioleiomyomatosis (PEComa family)"],"tldr":"PEComa is a rare tumour, grouped with the sarcomas, of cells that sit around blood vessels and share features of muscle and pigment cells. Most are benign, but malignant ones spread and resist chemotherapy. They usually have lost the TSC1 or TSC2 brake on the growth signal mTOR, and in 2021 the mTOR blocker nab-sirolimus became the first approved treatment.","summary":"Perivascular epithelioid cell tumours express both smooth muscle and melanocytic markers (HMB-45, Melan-A) and include renal angiomyolipoma, pulmonary lymphangioleiomyomatosis and clear cell sugar tumour of the lung as well as PEComa not otherwise specified of the uterus, retroperitoneum, gastrointestinal tract and soft tissue. Most carry biallelic loss of TSC1 or TSC2, with or without tuberous sclerosis complex, which unleashes mTOR signalling; a minority instead carry TFE3 fusions and do not respond to mTOR inhibition. Malignancy is predicted by size over five centimetres, infiltrative growth, high grade, necrosis, mitotic count and vascular invasion.\n\nComplete surgical resection is the treatment for localised tumours, with no established role for adjuvant therapy, and surveillance for those with high-risk features. Conventional chemotherapy has little activity in malignant PEComa. Case series of sirolimus, everolimus and temsirolimus showed responses in TSC-altered tumours, establishing mTOR inhibition as the rational systemic therapy.\n\nThe single-arm phase 2 AMPECT trial tested albumin-bound sirolimus (nab-sirolimus) in advanced malignant PEComa and reported objective responses in around four in ten patients, with responses lasting years in some and higher response rates in TSC2-mutant tumours, leading to FDA approval in November 2021, the first drug approved for PEComa. The PRECISION 1 basket trial extends nab-sirolimus to any solid tumour with inactivating TSC1 or TSC2 alterations.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Perivascular_epithelioid_cell_tumour","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Perivascular_epithelioid_cell_tumour"}],"tags":["subtype-page"],"related":["uterine-sarcoma","retroperitoneal-sarcoma","alveolar-soft-part-sarcoma","epithelioid-sarcoma","inflammatory-myofibroblastic-tumour","tenosynovial-giant-cell-tumour"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-esmo-sts-guideline-gronchi-ann-oncol-2021","paper-ampect-nab-sirolimus-pecoma-wagner-jco-2021","paper-wagner-sirolimus-pecoma-jco-2010"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"A very rare family of tumours, a few hundred malignant cases reported worldwide, arising in the uterus, retroperitoneum, gut and soft tissue of adults, more often women; most are benign, and malignant PEComa did not respond to chemotherapy until mTOR inhibitors.","subtypes":["Uterine PEComa (commonest site of malignant PEComa)","Retroperitoneal and abdominopelvic PEComa","Gastrointestinal PEComa","Soft tissue and cutaneous PEComa","TFE3-rearranged PEComa (younger patients; not TSC-driven)","Angiomyolipoma and lymphangioleiomyomatosis (related, mostly benign)"],"biomarkers":["TSC1 or TSC2 inactivation (mTOR inhibitor response)","TFE3 fusion (excludes TSC pathway; poor mTOR response)","HMB-45, Melan-A and smooth muscle actin co-expression","Size over 5 cm, mitoses, necrosis and infiltration (malignancy criteria)"],"standardOfCare":[{"setting":"Localised","approach":"Complete resection; surveillance for tumours with malignant features; no proven adjuvant therapy.","refs":["limb-salvage-surgery","active-surveillance"]},{"setting":"Advanced malignant PEComa","approach":"Nab-sirolimus (AMPECT; FDA approved 2021); oral sirolimus, everolimus or temsirolimus as alternatives; check TSC status.","refs":["sirolimus-albumin-bound","ampect","everolimus","temsirolimus","mtor"]},{"setting":"After mTOR inhibitor","approach":"Anthracycline- or gemcitabine-based chemotherapy has modest activity; trials of mTOR-based combinations; PRECISION 1 for TSC-altered tumours.","refs":["doxorubicin","gemcitabine","nct05103358"]}],"stateOfArt":["Nab-sirolimus is the first approved drug for PEComa, with durable responses in TSC2-mutant tumours.","TSC1/TSC2 loss defines a targetable pathway across the PEComa family and beyond.","TFE3-rearranged tumours form a distinct group that needs different treatment."],"history":[{"year":1992,"title":"Bonetti and colleagues propose the perivascular epithelioid cell concept","refs":[]},{"year":2002,"title":"WHO recognises PEComa as a tumour family","refs":[]},{"year":2010,"title":"Sirolimus responses reported in malignant PEComa with TSC loss","refs":["mtor"]},{"year":2021,"title":"AMPECT: nab-sirolimus approved for advanced malignant PEComa","refs":["ampect","sirolimus-albumin-bound"]}],"pipeline":["sirolimus-albumin-bound","nct05103358","ampect"],"openProblems":["Malignancy cannot always be predicted from histology.","Resistance to mTOR inhibition eventually develops.","TFE3-rearranged PEComa lacks an effective drug."],"parent":"sarcoma"},{"id":"pheochromocytoma-paraganglioma","kind":"cancer","name":"Pheochromocytoma and paraganglioma (PPGL)","aka":["Pheochromocytoma","Paraganglioma","PPGL","Phaeochromocytoma"],"tldr":"Pheochromocytomas and paragangliomas are tumours of adrenaline-producing tissue that cause dangerous blood pressure surges. Surgery after careful blood-pressure blockade cures most, genetic testing finds an inherited cause in nearly half, and for the minority that spread there are now radioactive drugs that home to the tumour and, since 2025, the first oral targeted pill, belzutifan.","summary":"PPGL are catecholamine-secreting tumours of the adrenal medulla (pheochromocytoma) or extra-adrenal sympathetic and parasympathetic paraganglia. They have the highest heritability of any human tumour: about 40 percent carry germline mutations in one of more than 15 genes, grouped into cluster 1 (pseudohypoxia: SDHA/B/C/D, VHL, FH, EPAS1) and cluster 2 (kinase signalling: RET, NF1, TMEM127, MAX). SDHB carriers have the highest metastatic risk. Diagnosis rests on plasma free or urinary fractionated metanephrines, then anatomical imaging and functional imaging with 68Ga-DOTATATE PET (most sensitive for SDHx and metastatic disease) or 18F-FDOPA. Endocrine Society guidance recommends germline testing for every patient.\n\nSurgery after 7 to 14 days of alpha-adrenergic blockade is curative for localised disease, with cortical-sparing adrenalectomy in hereditary bilateral cases. Metastatic disease is treated to control catecholamine excess and tumour burden: 177Lu-DOTATATE for SSTR-positive tumours (NCCN-listed; prospective trials ongoing), high-specific-activity 131I-MIBG (iobenguane I-131, Azedra; FDA 2018, though the manufacturer later announced its commercial discontinuation), cyclophosphamide-vincristine-dacarbazine or temozolomide chemotherapy (particularly SDHB-mutant), and sunitinib, which improved progression-free survival versus placebo in the randomised FIRSTMAPPP trial (Lancet 2024). Belzutifan, the HIF-2alpha inhibitor first approved for VHL-associated tumours, received FDA approval on 14 May 2025 for locally advanced, unresectable or metastatic PPGL in patients aged 12 and older on the basis of the LITESPARK-015 cohort (objective response rate 26 percent), the first oral therapy approved for the disease and a direct hit on the pseudohypoxia biology of cluster 1 tumours.\n\nOpen problems are predicting metastasis (no histological criterion is reliable), lifelong surveillance of gene carriers, and sequencing radioligand, HIF-2alpha and kinase therapy.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Pheochromocytoma","links":[{"label":"NCI PDQ: pheochromocytoma and paraganglioma","url":"https://www.cancer.gov/types/pheochromocytoma"},{"label":"FDA approval of belzutifan for PPGL (May 2025)","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pheochromocytoma-or-paraganglioma"},{"label":"Endocrine Society guideline 2014","url":"https://doi.org/10.1210/jc.2014-1498"},{"label":"FIRSTMAPPP (Lancet 2024)","url":"https://doi.org/10.1016/S0140-6736(23)02554-0"}],"tags":["nci-coverage","rare","endocrine"],"related":[],"cancers":[],"sections":[],"technologies":["radioligand-therapy","prrt","mibg-theranostics","sstr-pet","germline-testing","kinase-inhibitors","cytotoxic-chemotherapy"],"targets":["hif2a","sstr2","vegf","ret"],"drugs":["belzutifan","lutathera","i131-mibg","sunitinib","temozolomide","cyclophosphamide","vincristine","cabozantinib"],"companies":["merck","novartis","pfizer"],"institutions":[],"pathways":["hif-vhl","cancer-metabolism","rtk-activation"],"terms":["hereditary-cancer-syndromes","adrenalectomy","rare-cancers"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers","b-hereditary-risk"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"About 2 to 8 cases per million people per year; roughly one in ten pheochromocytomas and a higher share of paragangliomas are metastatic, and about 40 percent of all cases are hereditary.","subtypes":["Adrenal pheochromocytoma","Sympathetic paraganglioma (abdominal, thoracic)","Head and neck (parasympathetic) paraganglioma, usually non-secreting","Hereditary PPGL (SDHx, VHL, RET/MEN2, NF1, MAX, TMEM127)","Metastatic PPGL"],"biomarkers":["Plasma free or urinary fractionated metanephrines","Germline panel testing (SDHA/B/C/D, SDHAF2, VHL, RET, NF1, MAX, TMEM127, FH, EPAS1)","SDHB immunohistochemistry (loss indicates SDHx)","68Ga-DOTATATE PET (SSTR2 expression; selects for PRRT)","123I-MIBG scintigraphy (selects for 131I-MIBG)","Tumour size, extra-adrenal location and SDHB status as metastatic risk factors"],"standardOfCare":[{"setting":"Localised, secreting","approach":"Alpha-blockade (phenoxybenzamine or doxazosin) for 7 to 14 days, volume expansion, then laparoscopic or open adrenalectomy; cortical-sparing surgery in hereditary bilateral disease.","refs":["adrenalectomy","germline-testing"],"guideline":{"version":"Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors","url":"https://doi.org/10.1210/jc.2014-1498"}},{"setting":"All patients","approach":"Germline genetic testing and, for carriers, lifelong biochemical and imaging surveillance; cascade testing of relatives.","refs":["germline-testing","hereditary-cancer-syndromes"],"guideline":{"version":"Endocrine Society 2014","url":"https://doi.org/10.1210/jc.2014-1498"}},{"setting":"Metastatic or unresectable","approach":"Belzutifan (FDA May 2025, LITESPARK-015); 177Lu-DOTATATE for SSTR-positive disease; 131I-MIBG where available; sunitinib (FIRSTMAPPP); CVD or temozolomide chemotherapy for rapidly progressive or SDHB-mutant disease; alpha-blockade throughout.","refs":["belzutifan","lutathera","prrt","i131-mibg","mibg-theranostics","sunitinib","temozolomide","cyclophosphamide","vincristine","firstmappp"],"guideline":{"nccn":"Category 2A","version":"NCCN Neuroendocrine and Adrenal Tumors"}}],"stateOfArt":["Belzutifan is the first drug to target the pseudohypoxia biology (HIF-2alpha) shared by SDHx- and VHL-driven tumours, and the first oral therapy approved for PPGL (2025).","Theranostics matured here early: 123I-MIBG and 68Ga-DOTATATE imaging select patients for 131I-MIBG or 177Lu-DOTATATE treatment of the same target.","FIRSTMAPPP was the first randomised phase 2 in metastatic PPGL, showing that trials are possible in a disease this rare and that sunitinib delays progression.","Universal germline testing has turned PPGL into a model for hereditary cancer surveillance, with SDHB carriers identified before tumours form."],"history":[{"year":1886,"title":"Fränkel describes bilateral adrenal tumours in an 18-year-old","note":"Later shown by genetic analysis to be a case of MEN2.","refs":[]},{"year":1926,"title":"First successful resection (Roux in Lausanne, Mayo in Rochester)","refs":[]},{"year":2000,"title":"SDHD mutations in hereditary paraganglioma","note":"Baysal and colleagues, Science: metabolic enzyme genes as tumour suppressors.","refs":[]},{"year":2014,"title":"Endocrine Society guideline recommends germline testing for all","refs":["germline-testing"]},{"year":2018,"title":"High-specific-activity 131I-MIBG (Azedra) approved","note":"FDA, July 2018, for unresectable MIBG-positive PPGL; later discontinued commercially.","refs":["i131-mibg"]},{"year":2024,"title":"FIRSTMAPPP: sunitinib delays progression","note":"Baudin and colleagues, Lancet: first randomised trial in metastatic PPGL.","refs":["sunitinib"]},{"year":2025,"title":"Belzutifan approved for PPGL","note":"FDA, 14 May 2025, LITESPARK-015 cohort A1; first oral therapy for the disease.","refs":["belzutifan"]}],"pipeline":["belzutifan","lutathera","prrt","sunitinib","cabozantinib"],"openProblems":["No reliable predictor of metastasis at diagnosis: molecular classifiers and SDHB status are being validated.","Withdrawal of 131I-MIBG from the market left a gap that 177Lu-DOTATATE and alpha-emitters are filling.","Sequencing belzutifan, radioligand therapy and kinase inhibitors: no comparative data.","Lifelong surveillance burden for gene carriers, with children of SDHB carriers screened from early childhood."]},{"id":"all-ph-like","kind":"cancer","name":"Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL)","aka":["Ph-like ALL","BCR::ABL1-like ALL","B-ALL with BCR::ABL1-like features"],"tldr":"Ph-like leukaemia behaves like Philadelphia chromosome-positive leukaemia, with the same kind of overactive growth signalling, but lacks the BCR::ABL1 gene itself. It is caused by a scattered set of gene fusions and mutations, many of them blockable by existing kinase pills such as dasatinib or ruxolitinib, and it is now screened for at diagnosis so those drugs can be tried.","summary":"Two groups reported in 2009 that a subset of B-ALL without BCR::ABL1 shared its gene-expression profile and its high risk of relapse: 'BCR-ABL1-like' from the Dutch Childhood Oncology Group and 'Ph-like' from St Jude and the Children's Oncology Group. Whole-genome and transcriptome sequencing, reported in the New England Journal of Medicine in 2014, showed that nearly all of these leukaemias carried a kinase-activating lesion: rearrangements of CRLF2 in about half, with JAK1 or JAK2 mutations in roughly half of those; ABL-class fusions of ABL1, ABL2, CSF1R or PDGFRB in about one in eight; JAK2 or EPOR rearrangements; and mutations in IL7R, SH2B3, FLT3 and the RAS pathway. IKZF1 deletions accompany most. In cell lines and patient samples, ABL-class fusions responded to imatinib and dasatinib and JAK-STAT lesions to ruxolitinib.\n\nPh-like ALL is now a WHO 2022 entity, B-ALL with BCR::ABL1-like features, and cooperative groups screen for it at diagnosis by a low-density gene expression array or RNA sequencing followed by FISH or PCR for the specific lesion. Its outcome on chemotherapy is poor because induction leaves high residual disease, so most patients are treated as high risk with intensified therapy and, when residual disease persists, allogeneic transplant. The Children's Oncology Group added dasatinib to chemotherapy for ABL-class fusions in AALL1131 and tested ruxolitinib with chemotherapy for CRLF2 and JAK-pathway disease in AALL1521, and the same lesions are treated with kinase inhibitors in adults on trial. Because the CD19 antigen is unaffected, blinatumomab and CD19 CAR T-cells work as in other B-ALL and are the standard rescue when residual disease does not clear.\n\nWhether a kinase inhibitor added to chemotherapy improves cure, rather than just early response, is not settled: the Ph-positive experience with imatinib is the model, but Ph-like disease is heterogeneous, and CRLF2-rearranged leukaemia, which also carries JAK and RAS mutations, is less kinase-dependent than ABL-class disease. Screening is still uneven outside trial centres and in lower-income countries, so many patients are never identified. Down syndrome-associated ALL, CRLF2-rearranged in over half of cases, sits at the boundary and has its own toxicity constraints. Ph-like ALL is also over-represented among Hispanic and Latino children, linked to inherited GATA3 variants, one of the clearest examples of an inherited contribution to a childhood cancer subtype.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia","links":[{"label":"Wikipedia: Acute lymphoblastic leukaemia","url":"https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia"},{"label":"NCI PDQ: Childhood ALL Treatment","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}],"tags":["subtype-page","paediatric"],"related":["all-paediatric-ph-positive","all-paediatric-high-risk","aya-cancers","all-infant","all-paediatric-relapsed","all-paediatric-standard-risk"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","flow-cytometry-mrd"],"targets":["jak2","epor","pdgfrb","bcr-abl","cd19"],"drugs":[],"companies":["childrens-oncology-group"],"institutions":["st-jude"],"pathways":[],"terms":["philadelphia-chromosome","mrd","ph-like-all","b-all-cytogenetic-risk"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-hunger-mullighan-all-children-nejm-2015","paper-roberts-ph-like-all-nejm-2014","paper-den-boer-bcr-abl1-like-all-lancet-oncol-2009","paper-mullighan-ikzf1-nejm-2009"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About one in ten children with standard-risk B-cell ALL, one in seven with high-risk disease and around a quarter of adolescents and young adults with B-ALL have a Ph-like signature, making it one of the commonest high-risk subtypes.","subtypes":["Ph-like ALL with CRLF2 rearrangement (P2RY8::CRLF2 or IGH::CRLF2, often with JAK2 or JAK1 mutation)","Ph-like ALL with ABL-class fusions (ABL1, ABL2, CSF1R, PDGFRB; dasatinib- and imatinib-sensitive)","Ph-like ALL with JAK2 or EPOR rearrangements (ruxolitinib-sensitive in vitro)","Ph-like ALL with other JAK-STAT or RAS-pathway mutations (IL7R, SH2B3, FLT3, NRAS, KRAS)","Down syndrome-associated B-ALL with CRLF2 rearrangement"],"biomarkers":["Ph-like gene expression signature (low-density array or RNA sequencing)","CRLF2 overexpression by flow cytometry and CRLF2 rearrangement by FISH","ABL-class, JAK2 and EPOR fusions by FISH or RNA sequencing","JAK1, JAK2, IL7R and SH2B3 mutations","IKZF1 deletion","Flow cytometry MRD at end of induction and consolidation"],"standardOfCare":[{"setting":"Diagnosis","approach":"Screen every B-ALL without BCR::ABL1 for the Ph-like signature and identify the kinase lesion; treat as high risk with MRD monitoring.","refs":["cgp","flow-cytometry-mrd","ngs-mrd-clonoseq"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"ABL-class fusions","approach":"Dasatinib or imatinib added to high-risk chemotherapy from induction, as for Ph-positive ALL.","refs":["dasatinib","imatinib","pdgfrb"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"CRLF2, JAK2 or EPOR lesions","approach":"High-risk chemotherapy; ruxolitinib added in trials (AALL1521).","refs":["ruxolitinib","jak2","epor","aall1521"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Persistent residual disease","approach":"Blinatumomab or CD19 CAR T-cells to clear residual disease, then allogeneic transplant.","refs":["blinatumomab","tisagenlecleucel","allogeneic-hsct"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}}],"stateOfArt":["Ph-like ALL is a WHO entity screened for at diagnosis in cooperative group trials, with the kinase lesion determining which inhibitor is tried.","ABL-class fusions are treated with dasatinib on the Ph-positive model; the benefit of ruxolitinib for JAK-pathway disease is still being tested.","CD19 immunotherapy works irrespective of the kinase lesion and is the rescue for persistent residual disease."],"history":[{"year":2009,"title":"Ph-like (BCR-ABL1-like) ALL described by Dutch and US groups as a poor-prognosis subgroup","refs":[]},{"year":2014,"title":"Sequencing shows kinase-activating lesions in nearly all Ph-like ALL, many drug-sensitive","refs":["bcr-abl","jak2"]},{"year":2016,"title":"AALL1521 opens: ruxolitinib with chemotherapy for CRLF2 and JAK-pathway Ph-like ALL","refs":["ruxolitinib"]},{"year":2022,"title":"WHO classifies B-ALL with BCR::ABL1-like features as an entity","refs":[]}],"pipeline":["ruxolitinib","dasatinib","blinatumomab","tisagenlecleucel","ngs-mrd-clonoseq","cgp"],"openProblems":["Whether kinase inhibitors improve cure rather than early response in Ph-like ALL.","Screening is unavailable in most of the world, so most Ph-like patients are never identified.","CRLF2-rearranged disease carries RAS and JAK mutations together and is less dependent on a single kinase."],"parent":"all-leukemia"},{"id":"all-paediatric-ph-positive","kind":"cancer","name":"Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL)","aka":["Ph+ ALL in children","BCR::ABL1-positive childhood ALL","Paediatric Ph-positive ALL"],"tldr":"Philadelphia chromosome-positive leukaemia carries the same faulty BCR::ABL1 gene as chronic myeloid leukaemia. Until 2000 most children with it needed a bone marrow transplant; adding the targeted pill imatinib to chemotherapy, and then dasatinib, means most are now cured without one.","summary":"The t(9;22) translocation fuses BCR to ABL1 and makes a constitutively active tyrosine kinase; in ALL the fusion is usually the p190 form. Before kinase inhibitors, Ph-positive childhood ALL had the worst outcome of any subtype, with event-free survival around a quarter to a third on chemotherapy alone, and allogeneic transplant from a matched sibling in first remission was standard. Imatinib, approved for chronic myeloid leukaemia in 2001, was taken into childhood ALL by the Children's Oncology Group in AALL0031: given continuously with intensive chemotherapy, it produced a three-year event-free survival of 80 percent in the highest-exposure cohort against about 35 percent in historical controls, and no advantage for transplant over chemotherapy plus imatinib. The European EsPhALL trials confirmed that continuous imatinib beat intermittent dosing, and imatinib was approved for children with newly diagnosed Ph-positive ALL in 2013.\n\nDasatinib is more potent and crosses into the cerebrospinal fluid. AALL0622 combined it with the AALL0031 backbone and dropped cranial irradiation without excess central nervous system relapse; CA180-372, the registration trial, gave three-year event-free survival of 65.5 percent and overall survival of 91.5 percent with dasatinib and EsPhALL chemotherapy, and dasatinib was approved for children with Ph-positive ALL in December 2018. The Chinese Children's Cancer Group randomised 189 children directly between imatinib and dasatinib on the CCCG-ALL-2015 backbone: four-year event-free survival 71.0 percent with dasatinib against 48.9 percent with imatinib, overall survival 88.4 percent against 69.2 percent, and fewer central nervous system relapses. Transplant is now reserved for children with a poor residual disease response or persistent disease after consolidation.\n\nThe adult field has moved to ponatinib, a third-generation inhibitor that covers the T315I gatekeeper mutation, to chemotherapy-free induction with a kinase inhibitor plus blinatumomab (D-ALBA, PhALLCON), and to transplant-free treatment guided by molecular residual disease. Whether the same applies in children is the question for EsPhALL2017/COG AALL1631, which stratifies by residual disease and tests reduced-intensity chemotherapy with imatinib for good responders, and for trials adding blinatumomab. Resistance through ABL1 kinase domain mutations, kinase inhibitor effects on growing bones and the heart, and how long to continue the inhibitor after chemotherapy ends are unsettled.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Philadelphia_chromosome","links":[{"label":"Wikipedia: Philadelphia chromosome","url":"https://en.wikipedia.org/wiki/Philadelphia_chromosome"},{"label":"NCI PDQ: Childhood ALL Treatment","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}],"tags":["subtype-page","paediatric"],"related":["all-ph-like","cml-chronic-phase","all-paediatric-high-risk","all-infant","all-paediatric-relapsed","all-paediatric-standard-risk"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","allogeneic-hsct"],"targets":["bcr-abl","cd19"],"drugs":[],"companies":["childrens-oncology-group"],"institutions":[],"pathways":["bcr-abl1-signalling"],"terms":["philadelphia-chromosome","ph-positive-all","mrd","abl1-kinase-domain-mutations"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-aall0031-imatinib-ph-positive-all-schultz-jco-2009","paper-esphall-imatinib-biondi-lancet-oncol-2012","paper-dasatinib-vs-imatinib-ph-positive-all-shen-jama-oncol-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About 3 to 5 percent of childhood acute lymphoblastic leukaemia carries the Philadelphia chromosome, a proportion that rises with age to a quarter of adult cases.","subtypes":["Ph-positive B-ALL with good residual disease response (standard risk; chemotherapy plus kinase inhibitor, no transplant)","Ph-positive B-ALL with poor residual disease response (high risk; transplant considered)","Ph-positive ALL with ABL1 kinase domain mutations (T315I and others; ponatinib in adults)","Ph-positive ALL in adolescents and young adults (adult-style ponatinib and blinatumomab regimens)"],"biomarkers":["BCR::ABL1 by FISH or PCR (p190 and p210 transcripts)","BCR::ABL1 transcript quantification during therapy","Flow cytometry MRD at end of induction and consolidation","ABL1 kinase domain mutation testing at relapse","IKZF1 deletion (adverse co-lesion)"],"standardOfCare":[{"setting":"Newly diagnosed","approach":"Imatinib or dasatinib started in induction and continued throughout intensive BFM or EsPhALL-type chemotherapy; intrathecal therapy without cranial irradiation.","refs":["dasatinib","imatinib","vincristine","dexamethasone","asparaginase","methotrexate","flow-cytometry-mrd","ph-positive-all","bcr-abl","esphall"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Poor residual disease response","approach":"Blinatumomab to clear residual disease, then allogeneic transplant in first remission with a kinase inhibitor continued afterwards.","refs":["allogeneic-hsct","dasatinib","imatinib","blinatumomab","ngs-mrd-clonoseq"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Relapsed or refractory","approach":"Switch kinase inhibitor by mutation (ponatinib for T315I, used off label in children), blinatumomab or CD19 CAR T-cells, inotuzumab ozogamicin, then transplant.","refs":["ponatinib","blinatumomab","tisagenlecleucel","inotuzumab-ozogamicin","allogeneic-hsct","tki-plus-blinatumomab-ph-all"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}}],"stateOfArt":["Continuous imatinib or dasatinib with chemotherapy cures most children without transplant, reversing the pre-2000 standard.","Dasatinib beat imatinib head to head in the Chinese CCCG-ALL-2015 trial and is approved for children.","Adult regimens have moved to ponatinib and blinatumomab without chemotherapy; paediatric trials are following."],"history":[{"year":1960,"title":"Nowell and Hungerford describe the Philadelphia chromosome","refs":["philadelphia-chromosome"]},{"year":2001,"title":"Imatinib approved for chronic myeloid leukaemia","refs":["imatinib"]},{"year":2009,"title":"AALL0031: continuous imatinib with chemotherapy gives 80 percent three-year event-free survival","refs":["imatinib"]},{"year":2013,"title":"Imatinib approved for children with newly diagnosed Ph-positive ALL","refs":["imatinib"]},{"year":2018,"title":"Dasatinib approved for children with Ph-positive ALL after CA180-372","refs":["dasatinib"]},{"year":2020,"title":"CCCG-ALL-2015: dasatinib beats imatinib in a randomised paediatric trial","refs":["dasatinib","imatinib"]},{"year":2024,"title":"PhALLCON: ponatinib beats imatinib in adults with Ph-positive ALL","refs":["phallcon","ponatinib"]}],"pipeline":["ponatinib","blinatumomab","tki-plus-blinatumomab-ph-all","idea-transplant-free-ph-all","d-alba","phallcon","asciminib","ngs-mrd-clonoseq"],"openProblems":["Whether chemotherapy-free kinase inhibitor plus blinatumomab regimens can replace intensive chemotherapy in children.","Kinase domain resistance mutations and the lack of paediatric approval for ponatinib.","Long-term effects of kinase inhibitors on growth, bone and heart."],"parent":"all-leukemia"},{"id":"phyllodes-tumour","kind":"cancer","name":"Phyllodes tumour of the breast","aka":["Cystosarcoma phyllodes (historical)","Fibroepithelial tumour of the breast","Malignant phyllodes tumour"],"tldr":"A phyllodes tumour is a fast-growing, usually painless breast lump of gland and connective tissue that forms leaf-like fronds. Most are benign, some borderline and a few malignant, behaving like a sarcoma and spreading through the blood. Treatment is surgery with a rim of normal tissue; radiotherapy is considered for higher grades, and chemotherapy has little proven role.","summary":"Phyllodes tumours are fibroepithelial tumours in which the stroma, not the epithelium, is the neoplastic component; the epithelium is stretched into the leaf-like clefts that give the name. The World Health Organization grades them benign, borderline or malignant on stromal cellularity, nuclear atypia, mitotic count, stromal overgrowth and the character of the border, and most are benign. They present as a smooth, mobile, often large lump that has grown quickly over months, in women a decade older than those with fibroadenoma. Imaging cannot reliably separate the two, and a core biopsy often returns only a fibroepithelial lesion, so any rapidly growing or large fibroepithelial lesion is excised for diagnosis. Benign phyllodes tumours and fibroadenomas share MED12 mutations, and TERT promoter mutations accumulate in borderline and malignant tumours.\n\nSurgery is the treatment for every grade. Wide local excision with clear margins is the aim, and mastectomy is reserved for tumours too large for the breast; the traditional demand for a 1 cm margin has softened, and guidelines now accept any negative margin for benign tumours while recommending re-excision for positive margins in borderline and malignant disease. Lymph node metastases are rare, so sentinel node biopsy and axillary dissection are not performed. Adjuvant radiotherapy has no randomised evidence: a single-arm phase 2 study of 46 borderline and malignant tumours treated with margin-negative breast-conserving surgery and radiotherapy reported no local recurrences, and guidelines list radiotherapy as a consideration after breast conservation for these grades. Adjuvant chemotherapy has no proven benefit and hormone receptors, though often present in the epithelium, do not guide treatment.\n\nBenign tumours are cured by excision and recur locally in a minority, often at a higher grade than the original. Malignant tumours recur locally more often and a substantial minority metastasise, most often to the lungs and bone within the first few years, at which point they are treated like soft-tissue sarcomas with doxorubicin-based chemotherapy, and survival after recurrence is short. Follow-up with examination and imaging for the first few years catches most recurrences. The rarity of the disease means margin width, the role of radiotherapy and the value of molecular grading rest on retrospective series and registries rather than trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Phyllodes_tumor","links":[{"label":"NCCN Guidelines: Breast Cancer (phyllodes tumour section)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Phyllodes_tumor"}],"tags":["subtype-page"],"related":["sarcoma","ductal-carcinoma-in-situ","paget-disease-of-the-nipple","male-breast-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-rare-cancers"],"keyPapers":["paper-tan-phyllodes-consensus-histopathology-2016","paper-barth-phyllodes-adjuvant-radiotherapy-ann-surg-oncol-2009"],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Under one percent of breast tumours, typically in women in their forties, a decade later than fibroadenoma; most are benign, and only the malignant minority behave as sarcomas and spread.","subtypes":["Benign phyllodes tumour (most; excision alone)","Borderline phyllodes tumour (wide excision, radiotherapy considered)","Malignant phyllodes tumour (sarcoma-like; wide excision or mastectomy, radiotherapy, sarcoma chemotherapy if metastatic)","Phyllodes tumour with heterologous sarcomatous elements (liposarcoma, osteosarcoma)","Recurrent phyllodes tumour (often a higher grade than the original)"],"biomarkers":["WHO grade from stromal cellularity, atypia, mitotic count, stromal overgrowth and border (benign, borderline, malignant)","Margin status after excision","Tumour size relative to the breast","MED12 mutation (shared with fibroadenoma) and TERT promoter mutation (borderline and malignant)","No routine hormone receptor or HER2 testing (stroma-driven tumour)","Chest CT for metastases in malignant tumours"],"standardOfCare":[{"setting":"Diagnosis","approach":"Ultrasound and mammography, core needle biopsy, and excision of any rapidly growing or large fibroepithelial lesion because biopsy cannot reliably separate phyllodes tumour from fibroadenoma.","refs":["ultrasound","mammography","core-needle-biopsy","histopathology-ihc"]},{"setting":"Benign phyllodes tumour","approach":"Complete excision with clear margins; observation if margins are close after a benign diagnosis.","refs":["lumpectomy"]},{"setting":"Borderline and malignant phyllodes tumour","approach":"Wide excision aiming for clear margins or mastectomy for large tumours, no axillary staging, and adjuvant radiotherapy considered after breast conservation.","refs":["lumpectomy","mastectomy","imrt-igrt"]},{"setting":"Metastatic malignant phyllodes tumour","approach":"Treated as a soft-tissue sarcoma with doxorubicin-based chemotherapy; no proven benefit from adjuvant chemotherapy.","refs":["doxorubicin","sarcoma"]}],"stateOfArt":["Margin requirements have relaxed for benign tumours, sparing breast tissue.","Molecular grading with TERT promoter and other mutations is being tested against histology.","Radiotherapy after breast conservation is accepted as an option for borderline and malignant tumours on single-arm evidence."],"history":[{"year":1838,"title":"Johannes Müller names cystosarcoma phyllodes","refs":[]},{"year":1981,"title":"World Health Organization adopts phyllodes tumour with benign, borderline and malignant grades","refs":[]},{"year":2009,"title":"Single-arm phase 2: no local recurrences after breast conservation with radiotherapy for borderline and malignant tumours","refs":["imrt-igrt"]},{"year":2015,"title":"MED12 and TERT promoter mutations mapped across fibroepithelial tumours","refs":[]}],"pipeline":["imrt-igrt"],"openProblems":["No randomised trial has tested margin width or radiotherapy.","Core biopsy cannot reliably distinguish phyllodes tumour from fibroadenoma.","Metastatic malignant phyllodes tumour has no effective systemic therapy.","Grading is subjective at the benign-borderline and borderline-malignant boundaries."],"parent":"breast-cancer"},{"id":"pineoblastoma","kind":"cancer","name":"Pineoblastoma","aka":["Pineal embryonal tumour","Pineoblastoma (WHO grade 4)","Trilateral retinoblastoma (pineoblastoma with bilateral retinoblastoma)"],"tldr":"Pineoblastoma is a rare, aggressive brain tumour of the pineal gland, mostly in children, made of primitive cells like those of medulloblastoma. It is treated with surgery, radiotherapy to the whole brain and spine in children old enough, and chemotherapy; survival is lowest in infants, in whom radiotherapy is limited by age, and the subgroups found in 2020 now guide treatment.","summary":"Pineoblastoma is the grade 4 embryonal tumour of the pineal gland in the WHO central nervous system classification (NCI PDQ). DNA methylation profiling of 72 core cases from the Rare Brain Tumor Consortium defined five molecular subgroups: groups 1 and 2 almost exclusively carried homozygous loss-of-function alterations in the microRNA biogenesis genes DICER1, DROSHA and DGCR8, and the subgroups differed in age, metastasis and survival (Acta Neuropathologica 2020). The pooled cohort of 178 cases from the Children's Oncology Group and institutional series found age the strongest determinant of outcome, with sex-specific differences, and noted that no pineoblastoma-specific trial has ever been run (Neuro-Oncology Advances 2022). Pineoblastoma with bilateral retinoblastoma is the trilateral retinoblastoma of RB1 carriers.\n\nHow it differs from its parent: it is treated on the medulloblastoma and CNS embryonal tumour protocols (craniospinal irradiation and chemotherapy) rather than as a glioma, it seeds the spinal fluid, and it is one of the DICER1 syndrome tumours, so germline testing and family screening follow the diagnosis.\n\nHow common: no incidence figure; 178 cases in 30 years across the pooled series (Neuro-Oncology Advances 2022).\n\nTreatment: maximal safe resection, craniospinal irradiation with a boost in children over about three years, and platinum-based chemotherapy, with high-dose chemotherapy and stem cell rescue used to defer or replace radiotherapy in infants, as the PDQ embryonal tumour summary describes; molecular subgroup and DICER1 status are being built into current protocols.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Pineoblastoma","links":[{"label":"NCI PDQ: childhood medulloblastoma and other CNS embryonal tumours treatment","url":"https://www.cancer.gov/types/brain/patient/child-cns-embryonal-treatment-pdq"},{"label":"Acta Neuropathologica 2020: pineoblastoma molecular subgroups, Rare Brain Tumor Consortium registry","url":"https://doi.org/10.1007/s00401-019-02111-y"},{"label":"Neuro-Oncology Advances 2022: paediatric pineoblastoma, pooled outcomes of 178 North American and Australian cases","url":"https://doi.org/10.1093/noajnl/vdac056"}],"tags":["subtype-page","wave4","rare"],"related":["brain-tumours","medulloblastoma","pineal-parenchymal-tumours","papillary-tumour-pineal-region","retinoblastoma","pleuropulmonary-blastoma-dicer1"],"cancers":[],"sections":[],"technologies":[],"targets":["dicer1"],"drugs":["cisplatin","carboplatin","vincristine","cyclophosphamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Rare: the Rare Brain Tumor Consortium registry gathered 91 patients from 29 centres (Acta Neuropathologica 2020) and a pooled North American and Australian cohort held 178 cases over 30 years (Neuro-Oncology Advances 2022).","subtypes":["Pineal pineoblastoma, DICER1- or DROSHA-altered (molecular groups 1 and 2; DICER1 syndrome)","Pineoblastoma, MYC or FOXR2-activated group","Pineoblastoma, RB1-altered (trilateral retinoblastoma)","Pineoblastoma in infants (worst outcome; radiotherapy-sparing protocols)"],"biomarkers":["DNA methylation subgroup","DICER1, DROSHA and DGCR8 alterations; germline DICER1 testing","RB1 status","Spinal MRI and cerebrospinal fluid cytology"],"standardOfCare":[{"setting":"All cases","approach":"Maximal safe resection, craniospinal irradiation with boost in older children, platinum-based chemotherapy; high-dose chemotherapy with stem cell rescue to spare radiotherapy in infants, as on the CNS embryonal tumour summary.","refs":["brain-tumours","medulloblastoma","cisplatin","carboplatin","vincristine"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"brain-tumours"},{"id":"pineal-parenchymal-tumours","kind":"cancer","name":"Pineocytoma and pineal parenchymal tumour of intermediate differentiation","aka":["Pineocytoma","Pineal parenchymal tumour of intermediate differentiation","PPTID","Pineal parenchymal tumours"],"tldr":"Pineocytoma and pineal parenchymal tumour of intermediate differentiation are rare brain tumours of the pineal gland in adults, sitting between the benign end and the aggressive pineoblastoma. Pineocytoma is cured by surgery; the intermediate tumour recurs and spreads through the spinal fluid more often, so radiotherapy is usually added after surgery.","summary":"The WHO classification of central nervous system tumours grades the pineal parenchymal tumours from pineocytoma (grade 1) through pineal parenchymal tumour of intermediate differentiation (grade 2 or 3) to pineoblastoma (grade 4); the intermediate tumour is defined molecularly by recurrent small in-frame insertions in KBTBD4 and the absence of the DROSHA deletions or DICER1 mutations of pineoblastoma (Acta Neuropathologica 2019). In the pooled analysis of 127 patients with the intermediate tumour, median age was 33 (range 4.5 to 75), the MIB-1 labelling index a median of 7 percent (range 1 to 30), and adjuvant radiotherapy was widely used with surgery (Radiotherapy and Oncology 2016).\n\nHow it differs from its parent: the brain tumours page groups all central nervous system tumours; these are adult tumours of one small midline gland, presenting with hydrocephalus and eye movement disorders, staged with spinal imaging and cerebrospinal fluid because of the risk of seeding, and diagnosed now by methylation profiling and KBTBD4 testing.\n\nHow common: under 1 percent of central nervous system tumours (Radiotherapy and Oncology 2016).\n\nTreatment: pineocytoma by complete resection alone; the intermediate tumour by resection followed by radiotherapy, focal for grade 2 and craniospinal where the grade or spinal fluid findings warrant, with chemotherapy reserved for recurrence; the papillary tumour of the pineal region and pineoblastoma have their own pages.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Pineocytoma","links":[{"label":"Radiotherapy and Oncology 2016: pineal parenchymal tumour of intermediate differentiation, individual patient data of 127 cases","url":"https://doi.org/10.1016/j.radonc.2016.10.025"},{"label":"Acta Neuropathologica 2019: KBTBD4 insertions differentiate PPTID from pineoblastoma","url":"https://doi.org/10.1007/s00401-019-01990-5"}],"tags":["subtype-page","wave4","rare"],"related":["brain-tumours","pineoblastoma","papillary-tumour-pineal-region","cns-germ-cell-tumours","choroid-plexus-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"central nervous system","burden":"Pineal parenchymal tumours are under 1 percent of central nervous system tumours; the pooled analysis of the intermediate type found 127 published patients, median age 33, with 1.6 women to each man (Radiotherapy and Oncology 2016).","subtypes":["Pineocytoma (WHO grade 1; pineal, cured by resection)","Pineal parenchymal tumour of intermediate differentiation, low grade (grade 2; KBTBD4-mutated)","Pineal parenchymal tumour of intermediate differentiation, high grade (grade 3; higher MIB-1 index, spinal seeding)"],"biomarkers":["KBTBD4 in-frame insertion","MIB-1 (Ki-67) labelling index","DNA methylation class","Spinal MRI and cerebrospinal fluid cytology for seeding"],"standardOfCare":[{"setting":"Pineocytoma","approach":"Complete resection alone.","refs":["brain-tumours"]},{"setting":"Intermediate differentiation","approach":"Resection followed by radiotherapy, focal or craniospinal by grade and staging; chemotherapy for recurrence.","refs":["brain-tumours","pineoblastoma"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"brain-tumours"},{"id":"pituitary-tumours","kind":"cancer","name":"Pituitary tumours (pituitary neuroendocrine tumours) and pituitary carcinoma","aka":["Pituitary adenoma","PitNET","Prolactinoma","Acromegaly","Cushing disease","Pituitary carcinoma"],"tldr":"Pituitary tumours are usually benign growths of the hormone gland at the base of the brain that cause trouble by overproducing hormones or pressing on the optic nerves. Prolactin-producing tumours melt away with a tablet, most others are cured by surgery through the nose, and the rare aggressive ones respond to the chemotherapy drug temozolomide.","summary":"Pituitary neuroendocrine tumours (PitNETs, the WHO 2022 term for pituitary adenomas) are classified by cell lineage using transcription factors (PIT1, TPIT, SF1) and hormone expression: lactotroph (prolactinoma), somatotroph (acromegaly), corticotroph (Cushing disease), gonadotroph (usually non-functioning) and rarer types. Most are sporadic; germline AIP, MEN1, CDKN1B and other mutations account for young-onset and familial cases. Aggressive PitNETs invade the cavernous sinus and recur despite surgery and radiotherapy; pituitary carcinoma is defined by cerebrospinal or systemic metastasis and is very rare. Because the NCI lists pituitary tumours among cancer types and their management sits between endocrinology, neurosurgery and oncology, they belong in a complete corpus.\n\nTreatment is lineage-specific. Prolactinomas respond to dopamine agonists (cabergoline) in most cases, with surgery reserved for resistance or intolerance. Other functioning and symptomatic non-functioning tumours are treated by transsphenoidal endoscopic surgery; acromegaly not cured by surgery is controlled with first-generation somatostatin analogues (octreotide, lanreotide), pasireotide or pegvisomant; Cushing disease with surgery, then steroidogenesis inhibitors (osilodrostat, metyrapone) or pasireotide. Radiotherapy, increasingly stereotactic radiosurgery, controls residual or recurrent tumour. For aggressive tumours and carcinomas the European Society of Endocrinology guideline (2018) recommends temozolomide as first-line chemotherapy, with response predicted in part by low MGMT expression; checkpoint inhibitors have produced responses in corticotroph carcinomas in case series.\n\nOpen problems are defining aggressiveness before it declares itself, treatment after temozolomide failure (PRRT for SSTR-positive tumours, immunotherapy, bevacizumab), and the long-term endocrine and visual sequelae of treatment.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Pituitary_adenoma","links":[{"label":"NCI PDQ: pituitary tumours","url":"https://www.cancer.gov/types/pituitary"},{"label":"ESE guideline: aggressive pituitary tumours and carcinomas (2018)","url":"https://doi.org/10.1530/EJE-17-0796"},{"label":"Pituitary Society prolactinoma consensus (2023)","url":"https://doi.org/10.1038/s41574-023-00886-5"}],"tags":["nci-coverage","rare","endocrine","cns"],"related":["craniopharyngioma","meningioma","vestibular-schwannoma","cns-germ-cell-tumours"],"cancers":[],"sections":[],"technologies":["endocrine-therapy","sbrt","imrt-igrt","prrt","mri","cytotoxic-chemotherapy"],"targets":["sstr2"],"drugs":["octreotide-lanreotide","temozolomide","lutathera","bevacizumab","bromocriptine","cabergoline","pasireotide","pegvisomant","osilodrostat","metyrapone"],"companies":[],"institutions":[],"pathways":["pi3k-akt-mtor"],"terms":["mgmt","rare-cancers"],"trials":[],"people":[],"bottlenecks":["b-overdiagnosis","b-rare-cancers"],"keyPapers":["paper-petersenn-nat-rev-endocrinol","paper-raverot-eur-j-endocrinol"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"Pituitary tumours are among the most common intracranial tumours, found in about one in a thousand people clinically and far more often incidentally; true pituitary carcinoma with metastasis is extremely rare.","subtypes":["Lactotroph tumour (prolactinoma)","Somatotroph tumour (acromegaly)","Corticotroph tumour (Cushing disease, silent corticotroph)","Gonadotroph tumour (most non-functioning adenomas)","Thyrotroph tumour","Plurihormonal PIT1-lineage tumour (aggressive)","Pituitary carcinoma (metastatic)"],"biomarkers":["Serum prolactin, IGF-1, cortisol and ACTH, TSH","Transcription factor lineage (PIT1, TPIT, SF1) and hormone immunohistochemistry (WHO 2022)","Ki-67 and mitotic count","MGMT expression (temozolomide response)","Cavernous sinus invasion (Knosp grade) on MRI","Germline AIP and MEN1 in young or familial cases"],"standardOfCare":[{"setting":"Prolactinoma","approach":"Cabergoline first line, titrated to normal prolactin and tumour shrinkage; surgery for resistance, intolerance or pituitary apoplexy.","refs":["endocrine-therapy"],"guideline":{"version":"Pituitary Society international consensus on prolactinoma 2023","url":"https://doi.org/10.1038/s41574-023-00886-5"}},{"setting":"Acromegaly, Cushing disease, symptomatic non-functioning tumours","approach":"Endoscopic transsphenoidal resection; medical therapy for persistent disease (somatostatin analogues, pasireotide, pegvisomant for acromegaly; osilodrostat, metyrapone for Cushing); radiotherapy or radiosurgery for residual tumour.","refs":["octreotide-lanreotide","sbrt","imrt-igrt"],"guideline":{"version":"Endocrine Society guidelines: acromegaly (2014), Cushing (2015)","url":"https://doi.org/10.1210/jc.2014-2700"}},{"setting":"Aggressive PitNET or pituitary carcinoma","approach":"Temozolomide (standard schedule, at least 3 cycles before assessing response), with radiotherapy where not previously given; PRRT for SSTR-positive tumours, bevacizumab or checkpoint inhibitors in trials or case series after temozolomide failure.","refs":["temozolomide","prrt","lutathera","bevacizumab"],"guideline":{"version":"European Society of Endocrinology guideline 2018","url":"https://doi.org/10.1530/EJE-17-0796"}}],"stateOfArt":["Transcription-factor-based classification (WHO 2022) has replaced hormone staining alone and identifies high-risk lineages such as silent corticotroph and plurihormonal PIT1 tumours before they behave aggressively.","Endoscopic transsphenoidal surgery with intraoperative MRI or navigation has improved remission and reduced complications.","Temozolomide, borrowed from glioma, became the first effective chemotherapy for aggressive pituitary tumours and is guideline first line.","Radiosurgery offers durable control of residual tumour with less hypopituitarism than conventional fractionated radiotherapy in small targets."],"history":[{"year":1886,"title":"Pierre Marie describes acromegaly","refs":[]},{"year":1909,"title":"Cushing performs transsphenoidal pituitary surgery","refs":[]},{"year":1932,"title":"Cushing describes pituitary basophilism (Cushing disease)","refs":[]},{"year":1985,"title":"Bromocriptine and later cabergoline establish medical therapy of prolactinoma","refs":[]},{"year":2006,"title":"Temozolomide responses in aggressive pituitary tumours reported","refs":["temozolomide"]},{"year":2018,"title":"ESE guideline for aggressive pituitary tumours and carcinomas","note":"Temozolomide as first-line chemotherapy.","refs":["temozolomide"]},{"year":2022,"title":"WHO renames pituitary adenoma as PitNET","note":"Lineage-based classification.","refs":[]}],"pipeline":["temozolomide","prrt","sbrt"],"openProblems":["Predicting aggressive behaviour at diagnosis: lineage, Ki-67 and molecular markers are being combined into risk scores.","Salvage after temozolomide: PRRT, immunotherapy and bevacizumab have only case-series evidence.","Hypopituitarism and visual loss from tumour and treatment: radiosurgery and surgical technique aim to reduce them.","Incidentalomas: how to avoid overtreatment of the many small tumours found on imaging."],"parent":"brain-tumours"},{"id":"placental-site-trophoblastic-tumour","kind":"cancer","name":"Placental-site trophoblastic tumour and epithelioid trophoblastic tumour","aka":["PSTT","ETT","Intermediate trophoblastic tumours","Epithelioid trophoblastic tumour","Placental site trophoblastic tumor"],"tldr":"Placental-site and epithelioid trophoblastic tumours are the rare, slow-growing forms of gestational trophoblastic neoplasia, arising from the intermediate trophoblast cells that anchor the placenta rather than the hormone-producing cells behind choriocarcinoma. They make little hCG and respond poorly to chemotherapy, so hysterectomy comes first, with platinum chemotherapy when they have spread.","summary":"Placental-site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT) arise from the intermediate trophoblast of the implantation site and the chorion laeve respectively, cell types that produce human placental lactogen rather than large amounts of hCG. Both present, usually in women in their thirties, with abnormal bleeding or amenorrhoea months or years after a normal pregnancy, miscarriage or mole, with serum hCG only mildly raised or even normal and often with a high proportion of hCG-free beta subunit; ETT can sit in the cervix or lower uterine segment and mimic squamous cell carcinoma. Unlike choriocarcinoma, they infiltrate the myometrium slowly, spread by lymphatics as well as blood, and are relatively resistant to chemotherapy, so hCG cannot be relied on to track them and imaging matters more. The FIGO score does not apply; the prognostic factors are stage, an interval of more than four years since the causative pregnancy, deep myometrial invasion, high mitotic count and, for PSTT, the presence of metastases, with the long interval the single strongest predictor of death.\n\nHysterectomy is the treatment for disease confined to the uterus and cures the great majority; fertility-sparing resection is attempted only in exceptional cases with small, localised tumours and carries a risk of recurrence. Metastatic disease and tumours arising more than four years after the antecedent pregnancy are treated with multi-agent platinum-containing chemotherapy, most often EP-EMA or TP/TE, with surgical removal of residual disease, and high-dose chemotherapy with autologous stem cell rescue has been used for resistant cases; EMA-CO alone is inadequate. Because response is measured by imaging as much as by hCG, FDG-PET is used to define residual disease before and after surgery. Immune checkpoint inhibitors are being tried in resistant intermediate trophoblastic tumours because, like other trophoblastic tumours, they express PD-L1, and pembrolizumab has produced responses in case reports. Registration with a national trophoblastic disease centre is recommended for every case because expert pathology is needed to separate PSTT and ETT from exaggerated placental site reaction, placental site nodule and choriocarcinoma, each of which is managed differently.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Placental_site_trophoblastic_tumor","links":[{"label":"NCCN Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Placental_site_trophoblastic_tumor"}],"tags":["subtype-page","gynaecologic"],"related":["low-risk-gtn","high-risk-gtn","gestational-trophoblastic"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","mri","ct","pet-ct","fertility-preservation","cytotoxic-chemotherapy","autologous-stem-cell-transplant"],"targets":[],"drugs":["etoposide","cisplatin","methotrexate","dactinomycin","paclitaxel","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["tumour-markers","lymphadenectomy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-schmid-placental-site-trophoblastic-tumour-outcomes-lancet-2009","paper-froeling-pstt-ett-intensified-therapy-bjc-2019","paper-figo-cancer-report-gestational-trophoblastic-disease-ijgo-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"The rarest forms of gestational trophoblastic neoplasia, a few percent of cases, presenting months to years after a pregnancy with bleeding and only modestly raised hCG; most are cured by hysterectomy, but metastatic disease is chemoresistant.","subtypes":["Placental-site trophoblastic tumour confined to the uterus (stage I; hysterectomy)","Epithelioid trophoblastic tumour of the uterus or cervix (hysterectomy)","Metastatic placental-site or epithelioid trophoblastic tumour (platinum-based chemotherapy and surgery)","Intermediate trophoblastic tumour arising more than four years after the causative pregnancy (worst prognosis)","Mixed trophoblastic tumours with choriocarcinoma components"],"biomarkers":["Serum hCG (low or normal; high hCG-free beta subunit fraction)","Human placental lactogen by immunohistochemistry (PSTT) and p63 (ETT)","Interval since the antecedent pregnancy (over four years predicts poor outcome)","Stage, depth of myometrial invasion and mitotic count","Genotyping to confirm gestational origin and identify the causative pregnancy","FDG-PET/CT for residual or metastatic disease"],"standardOfCare":[{"setting":"Diagnosis","approach":"Expert pathology with immunohistochemistry (human placental lactogen, p63, Ki-67) and genotyping; pelvic MRI, chest CT and FDG-PET; registration with a trophoblastic disease centre.","refs":["histopathology-ihc","mri","ct","pet-ct","tumour-markers"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}},{"setting":"Disease confined to the uterus","approach":"Total hysterectomy with ovarian preservation; pelvic node sampling considered; fertility-sparing local resection only in exceptional cases with close follow-up.","refs":["fertility-preservation","lymphadenectomy"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}},{"setting":"Metastatic disease or interval over four years","approach":"Multi-agent platinum-based chemotherapy (EP-EMA or TP/TE) with resection of residual disease; EMA-CO alone is insufficient.","refs":["etoposide","cisplatin","methotrexate","dactinomycin","paclitaxel","cytotoxic-chemotherapy"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}},{"setting":"Resistant disease","approach":"Surgical excision of chemoresistant deposits; high-dose chemotherapy with autologous stem cell rescue in selected cases; pembrolizumab in trials or on a case basis.","refs":["autologous-stem-cell-transplant","pembrolizumab","pet-ct"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}},{"setting":"Follow-up","approach":"Clinical review with hCG and imaging, because hCG alone can miss recurrence; prolonged surveillance for late relapse.","refs":["tumour-markers","mri"],"guideline":{"version":"NCCN Guidelines: Gestational Trophoblastic Neoplasia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489"}}],"stateOfArt":["Hysterectomy cures most women with disease confined to the uterus.","The interval from the causative pregnancy is recognised as the key prognostic factor.","Platinum-based regimens and surgery salvage a proportion of metastatic cases."],"history":[{"year":1976,"title":"Kurman, Scully and Norris describe placental-site trophoblastic tumour","refs":[]},{"year":1998,"title":"Shih and Kurman define epithelioid trophoblastic tumour","refs":[]},{"year":2009,"title":"Charing Cross series identifies an interval of over four years as the strongest predictor of death","refs":[]},{"year":2017,"title":"Pembrolizumab responses reported in resistant trophoblastic tumours including intermediate types","refs":["pembrolizumab"]}],"pipeline":["pembrolizumab"],"openProblems":["Numbers are too small for any trial; all treatment rests on registry series.","hCG is an unreliable marker, so recurrence can be missed.","Chemotherapy has limited activity and no targeted therapy exists.","Fertility-sparing surgery is rarely safe, which weighs heavily on young women."],"parent":"gestational-trophoblastic"},{"id":"plasma-cell-leukaemia","kind":"cancer","name":"Plasma cell leukaemia","aka":["PCL","Primary plasma cell leukaemia","Secondary plasma cell leukaemia","Leukaemic myeloma"],"tldr":"Plasma cell leukaemia is myeloma in which the cancerous plasma cells spill into the bloodstream in large numbers. It is the most aggressive plasma cell cancer and is treated urgently with several myeloma drugs at once followed by a stem cell transplant.","summary":"The International Myeloma Working Group redefined plasma cell leukaemia in 2021 as 5 percent or more circulating plasma cells on a blood film in a patient with myeloma, replacing the older 20 percent threshold, because outcomes are equally poor above 5 percent. Primary plasma cell leukaemia presents de novo, often in younger patients with high tumour burden, kidney failure, hypercalcaemia, extramedullary disease and a high lactate dehydrogenase; secondary plasma cell leukaemia arises late in the course of established myeloma, and is worse still. High-risk cytogenetics, del(17p), t(14;16), 1q gain and del(1p), and TP53 mutations are far commoner than in ordinary myeloma.\n\nNo randomised trial exists. Treatment follows the most intensive myeloma regimens: a bortezomib-based induction with an immunomodulatory drug, dexamethasone and a CD38 antibody, or multi-agent chemotherapy combinations such as VTD-PACE or hyper-CVAD for rapid control, then autologous stem cell transplant in every fit patient, with tandem transplant or a reduced-intensity allogeneic transplant considered in the young, followed by maintenance. Prospective phase 2 series from the French and European myeloma groups with bortezomib-based induction and transplant report median survivals of around three years, against under a year with older chemotherapy. Secondary plasma cell leukaemia is treated as heavily relapsed myeloma with bispecific antibodies or CAR-T where available, though data are limited to small series.\n\nResearch is limited by rarity: registries, retrospective series and inclusion in high-risk myeloma trials are the evidence base. Whether BCMA-directed immunotherapy in the front line can change the outlook, as it has in relapsed myeloma, is the open question.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Plasma_cell_leukemia","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Plasma_cell_leukemia"},{"label":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}],"tags":["subtype-page"],"related":["myeloma-transplant-eligible","myeloma-transplant-ineligible","myeloma-relapsed-refractory","smouldering-myeloma"],"cancers":[],"sections":[],"technologies":["autologous-stem-cell-transplant","allogeneic-hsct","flow-cytometry-mrd"],"targets":["cd38","bcma","proteasome","tp53"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["high-risk-myeloma","tp53-mutated","autologous-transplant","leukaemia-type","proteasome-inhibitor","m-protein-free-light-chains","cyclin-d1-t11-14"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-r-iss-palumbo-jco-2015","paper-imwg-plasma-cell-leukaemia-definition-bcj-2021","paper-royer-plasma-cell-leukaemia-ifm-jco-2016","paper-imwg-criteria-rajkumar-lancet-oncol-2014"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"A rare and aggressive form of plasma cell cancer, a few percent of myeloma presentations at most; historically fatal within a year, now often controlled for several years with multi-drug induction and transplant.","subtypes":["Primary plasma cell leukaemia (de novo, 5 percent or more circulating plasma cells)","Secondary plasma cell leukaemia (leukaemic transformation of established myeloma)","Plasma cell leukaemia with high-risk cytogenetics (del(17p), t(14;16), 1q gain)"],"biomarkers":["Circulating plasma cells on blood film (5 percent or more) and by flow cytometry","Lactate dehydrogenase","FISH: del(17p), t(14;16), t(11;14), 1q gain, del(1p)","TP53 mutation","Renal function and calcium","Serum free light chains and M-protein","Extramedullary disease on PET-CT"],"standardOfCare":[{"setting":"Primary plasma cell leukaemia, induction","approach":"Bortezomib-based quadruplet (daratumumab with bortezomib, lenalidomide or cyclophosphamide, and dexamethasone), or VTD-PACE-type multi-agent chemotherapy for rapid control, with tumour lysis and renal precautions.","refs":["bortezomib","daratumumab","lenalidomide","cyclophosphamide","dexamethasone","carfilzomib","tumor-lysis-syndrome"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Consolidation","approach":"Autologous stem cell transplant for all fit patients; tandem autologous or reduced-intensity allogeneic transplant considered in young patients; continuous maintenance after transplant.","refs":["autologous-stem-cell-transplant","allogeneic-hsct","melphalan","lenalidomide","maintenance-therapy"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Secondary plasma cell leukaemia or relapse","approach":"Treated as heavily relapsed myeloma: BCMA or GPRC5D bispecific antibodies, CAR-T where feasible, selinexor or pomalidomide combinations; palliative care early.","refs":["teclistamab","talquetamab","ciltacabtagene-autoleucel","selinexor","pomalidomide"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}}],"stateOfArt":["Bortezomib-based multi-drug induction followed by autologous transplant has lifted median survival from under a year to around three years in prospective series.","The 2021 IMWG definition at 5 percent circulating plasma cells identifies more patients early.","Immune therapies are being borrowed from relapsed myeloma, with only small series to guide them."],"history":[{"year":1974,"title":"Kyle defines plasma cell leukaemia at 20 percent or 2 x 10^9/L circulating plasma cells","refs":[]},{"year":2013,"title":"IFM 2005-01 phase 2: bortezomib-based induction and transplant lengthens survival","refs":["bortezomib","autologous-stem-cell-transplant"]},{"year":2021,"title":"IMWG lowers the diagnostic threshold to 5 percent circulating plasma cells","refs":["flow-cytometry"]}],"pipeline":["teclistamab","ciltacabtagene-autoleucel","daratumumab","carfilzomib"],"openProblems":["No randomised trials; treatment is extrapolated from high-risk myeloma.","Secondary plasma cell leukaemia has no effective standard.","Whether front-line BCMA immunotherapy or allogeneic transplant improves long-term survival."],"parent":"multiple-myeloma"},{"id":"plasmablastic-lymphoma","kind":"cancer","name":"Plasmablastic lymphoma","aka":["PBL","Plasmablastic lymphoma of the oral cavity","Plasmablastic lymphoma, HIV-associated"],"tldr":"An aggressive lymphoma whose cells have taken on the appearance of plasma cells, so they no longer carry the CD20 marker that most B-cell lymphoma treatments aim at. It most often starts in the mouth or jaw, and about half of people diagnosed with it have HIV.","summary":"What it is. A large B-cell lymphoma whose cells have travelled most of the way to becoming plasma cells, the antibody factories that B cells turn into at the end of their life. That matters practically rather than philosophically: a plasma cell has switched off CD20, so rituximab and the antibody treatments that follow it cannot see the tumour. Instead the cells carry plasma cell markers, CD138 and MUM1, and the diagnosis is made on that pattern together with a very high proliferation index.\n\nWho gets it. In the largest United States analysis, 1,153 patients in SEER and 1,822 in the National Cancer Database diagnosed between 2010 and 2020, the incidence was 0.07 cases per 100,000 people a year, 77 per cent were men, and half had HIV. In an earlier SEER analysis of 248 treated patients, 82 per cent were men and 71 per cent were under 60, with the mouth and the gastrointestinal tract the commonest starting points at 23 and 19 per cent. It also occurs after organ transplant and in older people with age-related decline in immunity.\n\nThe site matters. Disease starting in the mouth was associated with better survival in the SEER analysis, and with less likelihood of advanced stage and of fevers and weight loss. That is a real signal and not only a statistical one: a lump on the gum or in the jaw is noticed early.\n\nWhat the figures say, and why two of them disagree. The United Kingdom population series that reports lymphoma by subtype found 24 cases among 5,796 lymphomas diagnosed between 2004 and 2012, an age-standardised rate of 0.07 per 100,000, with a five-year relative survival of 17.2 per cent. The United States analysis of patients treated between 2010 and 2020 reported median overall survival of 58.6 months among those who received multi-agent chemotherapy. Those two numbers describe different things: the first is everybody diagnosed in an earlier decade, the second is the subset who were well enough to be treated with combination chemotherapy in a later one. Both are quoted here because quoting only the second would flatter the disease and quoting only the first would date it.\n\nHow it is treated. More intensively than ordinary diffuse large B-cell lymphoma, because standard immunochemotherapy without rituximab does less well, and with antiretroviral therapy where there is HIV; HIV status did not affect survival in either of the United States analyses once treatment was given. Many cases carry a MYC rearrangement. Plasma-cell directed drugs such as bortezomib and lenalidomide have been added in series on the logic of the phenotype rather than on randomised evidence. The regimens are in the treatment layer of this family and on the HIV-associated lymphoma page.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Plasmablastic_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"Epidemiologic characteristics, treatment patterns and survival of plasmablastic lymphoma in the United States, a SEER and NCDB analysis (Clinical Lymphoma Myeloma and Leukemia 2024)","url":"https://doi.org/10.1016/j.clml.2023.12.014"},{"label":"Survival analysis in treated plasmablastic lymphoma patients, a population-based study of 248 patients (American Journal of Hematology 2020)","url":"https://doi.org/10.1002/ajh.25955"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"}],"tags":["heme","lymphoma","subtype-page"],"related":["hiv-associated-lymphoma","dlbcl","multiple-myeloma","primary-effusion-lymphoma","non-hodgkin-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","fdg-pet"],"targets":["myc"],"drugs":["bortezomib","lenalidomide"],"companies":[],"institutions":[],"pathways":[],"terms":["ebv-term","lymphoma-b-versus-t-cell","lymphoma-classification-2022","lymphoma-nodal-versus-extranodal"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"An incidence of 0.07 cases per 100,000 people a year in the United States, from the largest analysis to date (1,153 patients in SEER and 1,822 in the National Cancer Database, 2010 to 2020); 77 per cent of patients are men and half have HIV. In the United Kingdom population series, 24 of 5,796 lymphomas diagnosed between 2004 and 2012, an age-standardised rate of 0.07 per 100,000 and a median age of 70.9 years.","subtypes":["HIV-associated plasmablastic lymphoma","Post-transplant and other immune-deficiency-associated plasmablastic lymphoma","Plasmablastic lymphoma in an immunocompetent person, usually older"],"biomarkers":["A plasma cell phenotype: CD138 and MUM1 positive, CD20 and PAX5 usually negative, which is why anti-CD20 antibodies do not work","A very high Ki-67 proliferation index, usually above 80 per cent","Epstein-Barr virus by EBER in situ hybridisation, positive in most HIV-associated cases","MYC rearrangement, found in a large proportion","HIV status, which is positive in about half of patients and should be tested in every one"],"standardOfCare":[{"setting":"Making the diagnosis, and why it is missed","approach":"The cells look like plasma cells and the surface markers agree with that appearance, so the differential diagnosis includes myeloma with plasmablastic features rather than other lymphomas. What separates them is the clinical picture: a rapidly growing mass, usually in the mouth or jaw or the gut, in a younger person, often with HIV, with Epstein-Barr virus in the cells and a very high proliferation index. HIV testing belongs in every work-up.","refs":["histopathology-ihc","ebv-term","multiple-myeloma","myc"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Treatment","approach":"Combination chemotherapy more intensive than standard immunochemotherapy, because there is no CD20 for rituximab to attach to, together with antiretroviral therapy where there is HIV. In the two large United States analyses, HIV status did not affect survival once treatment was given. Drugs used in myeloma, such as bortezomib and lenalidomide, have been added in case series on the basis of the phenotype rather than on randomised evidence. The regimens are in the treatment layer of this family and on the HIV-associated lymphoma page.","refs":["hiv-associated-lymphoma","bortezomib","lenalidomide","cyclophosphamide","doxorubicin","etoposide","lymphoma-tx-regimen-alphabet"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":1997,"title":"Described in the mouths of people with HIV","note":"The first series described an aggressive lymphoma of the oral cavity in people with HIV whose cells had a plasma cell phenotype and did not carry CD20.","refs":[]},{"year":2020,"title":"A population picture of treated patients","note":"Among 248 patients treated with chemotherapy in the SEER registries between 2010 and 2016, three-year overall survival was 54 per cent, and disease starting in the mouth carried better survival than other sites.","refs":["hiv-associated-lymphoma"]},{"year":2024,"title":"The largest analysis, and HIV status not a predictor","note":"Across 1,153 SEER and 1,822 National Cancer Database patients, incidence was 0.07 per 100,000 a year, median overall survival among those given multi-agent chemotherapy was 58.6 months, and HIV status had no significant effect on survival.","refs":[]}],"pipeline":[],"openProblems":["No randomised trial has been run in plasmablastic lymphoma, and the regimens in use are chosen by analogy with other aggressive lymphomas and with myeloma.","There is no surface target. Every advance in B-cell lymphoma since 1997 has depended on CD20 or CD19, and this disease expresses neither reliably.","Half of patients have HIV, and the disease is a common first presentation of undiagnosed infection, so part of the burden belongs to HIV testing rather than to oncology."],"parent":"non-hodgkin-lymphoma"},{"id":"platinum-resistant-ovarian-cancer","kind":"cancer","name":"Platinum-resistant ovarian cancer","aka":["Platinum-resistant recurrent ovarian cancer","Platinum-refractory ovarian cancer","Platinum-free interval under six months","PROC"],"tldr":"Platinum-resistant ovarian cancer grows back within six months of platinum chemotherapy, or during it, and used to be treated with single chemotherapy drugs that shrink a tumour one time in ten. The antibody-drug conjugate mirvetuximab soravtansine, the cortisol-blocking drug relacorilant and pembrolizumab in PD-L1-positive tumours have each extended survival in phase 3 trials since 2023.","summary":"Resistance is defined by progression during platinum chemotherapy (refractory) or within six months of the last dose, though the boundary is arbitrary and the platinum-free interval is a continuum. Resistant tumours have usually restored DNA repair through BRCA reversion mutations, lost the drug-uptake pathways or acquired other changes after several lines of treatment, and prior PARP inhibitor exposure adds a further layer of cross-resistance. Symptoms come from peritoneal disease, bowel obstruction and ascites, and management is palliative in intent: control of disease, preservation of quality of life and, where possible, prolongation of survival. Single-agent weekly paclitaxel, pegylated liposomal doxorubicin, topotecan or gemcitabine each produce responses in roughly one patient in ten; AURELIA showed in 2014 that adding bevacizumab to any of them improves progression-free survival and symptom control, which became the standard for bevacizumab-naive patients.\n\nMIRASOL was the first phase 3 trial to improve survival in this state with a new drug. Mirvetuximab soravtansine, an antibody-drug conjugate against folate receptor alpha, was compared with investigator's choice chemotherapy in women whose tumours expressed the receptor highly and who had had one to three prior lines; median overall survival was 16.46 months against 12.75, a hazard ratio of 0.67, with progression-free survival of 5.62 against 3.98 months and less haematological toxicity, though blurred vision and keratopathy require eye examinations and steroid drops. ROSELLA then tested relacorilant, a glucocorticoid receptor antagonist that reverses cortisol-driven chemoresistance, with nab-paclitaxel against nab-paclitaxel alone and extended median survival from 11.9 to 16.0 months, a hazard ratio of 0.69. KEYNOTE-B96 added pembrolizumab to weekly paclitaxel with or without bevacizumab and extended median survival in tumours with a combined positive score of one or more from 14.0 to 18.2 months, a hazard ratio of 0.76. Relacorilant and pembrolizumab both gained approvals in 2026.\n\nThe pipeline is dominated by antibody-drug conjugates: raludotatug deruxtecan against CDH6 in REJOICE-Ovarian01, rinatabart sesutecan and luveltamab tazevibulin against folate receptor alpha in RAINFOL-01 and other trials, and agents against B7-H4 and TROP2, with the question of how to sequence them when they share payloads. Secondary surgery has no role, hyperthermic intraperitoneal chemotherapy is unproven here, and hormonal therapy has a small place in low-grade and receptor-positive tumours. Early palliative care, management of malignant bowel obstruction and honest discussion of goals remain the core of care for a state that is still incurable.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Ovarian_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Ovarian_cancer"}],"tags":["subtype-page"],"related":["platinum-sensitive-ovarian-cancer","high-grade-serous-ovarian-cancer","clear-cell-ovarian-cancer","mucinous-ovarian-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["brca-reversion-mutations"],"trials":["soraya"],"people":[],"bottlenecks":[],"keyPapers":["paper-mirasol-nejm-2023","paper-aurelia-bevacizumab-platinum-resistant-ovarian-pujade-lauraine-jco-2014","paper-rosella-relacorilant-lancet-2025"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"Every woman who relapses repeatedly eventually reaches this state, and about a quarter of advanced ovarian cancers are resistant from the start; median survival was around a year with single-agent chemotherapy, and it is where the first antibody-drug conjugate and the first new drug classes in a decade have arrived.","subtypes":["Platinum-refractory (progression during platinum)","Platinum-resistant relapse within six months","Folate receptor alpha-high (mirvetuximab soravtansine, MIRASOL)","PD-L1 combined positive score 1 or more (pembrolizumab with paclitaxel, KEYNOTE-B96)","Bevacizumab-naive (chemotherapy with bevacizumab, AURELIA)","Platinum-resistant after PARP inhibitor (cross-resistance)","High-grade serous and BRCA-reverted tumours (most cases)"],"biomarkers":["Platinum-free interval under six months","Folate receptor alpha immunohistochemistry (high expression required for mirvetuximab)","PD-L1 combined positive score (pembrolizumab)","Prior bevacizumab and PARP inhibitor exposure","CDH6, B7-H4 and TROP2 expression (antibody-drug conjugate trials)","BRCA reversion mutations","CA-125 and imaging for response"],"standardOfCare":[{"setting":"Folate receptor alpha-high","approach":"Mirvetuximab soravtansine with ophthalmic monitoring (MIRASOL).","refs":["mirvetuximab-soravtansine","mirasol","folr1","adc"]},{"setting":"PD-L1 CPS 1 or more","approach":"Pembrolizumab with weekly paclitaxel, with bevacizumab where not previously given (KEYNOTE-B96).","refs":["pembrolizumab","paclitaxel","bevacizumab","keynote-b96","pdl1"]},{"setting":"Any expression status","approach":"Relacorilant with nab-paclitaxel (ROSELLA); or single-agent weekly paclitaxel, pegylated liposomal doxorubicin, topotecan or gemcitabine with bevacizumab if bevacizumab-naive (AURELIA).","refs":["relacorilant","rosella","paclitaxel","pegylated-liposomal-doxorubicin","topotecan","gemcitabine","bevacizumab","aurelia"]},{"setting":"Later lines","approach":"Clinical trials of antibody-drug conjugates against CDH6, folate receptor alpha, B7-H4 and TROP2; hormonal therapy in receptor-positive low-grade disease.","refs":["raludotatug-deruxtecan","rejoice-ovarian01","rinatabart-sesutecan","rainfol-01","luveltamab-tazevibulin","letrozole"]},{"setting":"Supportive care","approach":"Early palliative care, drainage of ascites, management of bowel obstruction and nutritional support alongside anticancer treatment.","refs":["ovarian"]}],"stateOfArt":["MIRASOL made mirvetuximab soravtansine the first drug to improve survival in platinum-resistant disease in a phase 3 trial.","ROSELLA introduced glucocorticoid receptor antagonism as a new mechanism, and KEYNOTE-B96 brought checkpoint inhibition into a disease that had resisted it.","A crowded pipeline of antibody-drug conjugates is redefining later-line treatment."],"history":[{"year":1996,"title":"Topotecan and later pegylated liposomal doxorubicin approved for relapsed ovarian cancer","refs":["topotecan","pegylated-liposomal-doxorubicin"]},{"year":2014,"title":"AURELIA: bevacizumab with chemotherapy improves progression-free survival in platinum-resistant disease","refs":["bevacizumab"]},{"year":2022,"title":"Mirvetuximab soravtansine accelerated approval after SORAYA","refs":["mirvetuximab-soravtansine"]},{"year":2023,"title":"MIRASOL: mirvetuximab soravtansine extends survival, 16.46 versus 12.75 months","refs":["mirasol"]},{"year":2025,"title":"ROSELLA: relacorilant with nab-paclitaxel extends survival, 16.0 versus 11.9 months","refs":["rosella","relacorilant"]},{"year":2025,"title":"KEYNOTE-B96: pembrolizumab with paclitaxel extends survival in PD-L1-positive disease","refs":["keynote-b96","pembrolizumab"]},{"year":2026,"title":"Relacorilant and pembrolizumab approved for platinum-resistant ovarian cancer","refs":["relacorilant","pembrolizumab"]}],"pipeline":["raludotatug-deruxtecan","rejoice-ovarian01","rinatabart-sesutecan","rainfol-01","luveltamab-tazevibulin","relacorilant","idea-fra-adc-sequencing-ovarian"],"openProblems":["Sequencing antibody-drug conjugates that share topoisomerase or tubulin payloads.","Whether platinum resistance can be reversed rather than bypassed.","A definition of resistance based on biology rather than a six-month clock."],"parent":"ovarian"},{"id":"platinum-sensitive-ovarian-cancer","kind":"cancer","name":"Platinum-sensitive ovarian cancer","aka":["Platinum-sensitive relapsed ovarian cancer","Newly diagnosed ovarian cancer in response to platinum","Platinum-free interval over six months"],"tldr":"Platinum-sensitive ovarian cancer is disease that responded to carboplatin and either has not relapsed or relapses more than six months after the last dose. It is treated with further platinum chemotherapy, sometimes repeat surgery, and above all with maintenance PARP inhibitors, which keep BRCA-mutant tumours away for years and have raised long-term survival.","summary":"Platinum sensitivity is a clinical state rather than a histology. A tumour that shrinks on carboplatin-paclitaxel and stays away for more than six months after the last cycle is likely to respond to platinum again, and the longer the platinum-free interval the better the response; most high-grade serous and endometrioid cancers begin in this state and drift towards resistance with each relapse. Biologically, sensitivity tracks homologous recombination deficiency: BRCA1 or BRCA2 mutation, found in about a fifth of high-grade serous tumours, and other defects that together mark about half, cannot repair the DNA crosslinks platinum causes, and the same defect makes them vulnerable to PARP inhibition. Germline and somatic BRCA testing and HRD testing are therefore standard at diagnosis.\n\nMaintenance after first-line chemotherapy is the setting with the clearest gains. SOLO-1 gave two years of olaparib to women with BRCA-mutant tumours in response to platinum and cut the hazard of progression to 0.30; at seven years 67.0 percent were alive against 46.5 percent with placebo, a hazard ratio for death of 0.55 and the first sign that maintenance changes survival rather than delaying relapse. PRIMA extended niraparib to all comers with a progression-free survival gain from 8.2 to 13.8 months overall and from 10.4 to 21.9 months in HRD-positive tumours, though its final overall survival analysis showed no difference. PAOLA-1 added olaparib to bevacizumab maintenance and, in HRD-positive tumours, extended progression-free survival from 17.7 to 37.2 months with five-year survival of 65.5 percent against 48.4 percent. ATHENA-MONO confirmed the class with rucaparib. Which drug, whether to add bevacizumab, and whether HRD-negative tumours gain enough to justify treatment are decided by the tests.\n\nAt platinum-sensitive relapse, DESKTOP III showed that secondary cytoreductive surgery in women selected by a positive AGO score, complete resection at first surgery, good performance status and no ascites, extended median survival from 46.0 to 53.7 months when complete resection was achieved. Chemotherapy is a platinum doublet, carboplatin with pegylated liposomal doxorubicin, gemcitabine or paclitaxel, with bevacizumab in patients who have not had it, followed by PARP inhibitor maintenance if none was given before. Trials in relapse showed that PARP inhibitor maintenance after a later-line response delayed progression but did not improve survival in non-BRCA tumours and regulators narrowed those labels in 2022 and 2023, so the main benefit is now taken in the first line. Second PARP inhibitor exposure after progression, HRD-restoring reversion mutations and circulating tumour DNA to guide the duration of maintenance are the current research questions.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Ovarian_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Ovarian_cancer"}],"tags":["subtype-page"],"related":["platinum-resistant-ovarian-cancer","high-grade-serous-ovarian-cancer","low-grade-serous-ovarian-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["brca-reversion-mutations"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-solo-1-nejm-2018","paper-paola-1-nejm-2019","paper-prima-niraparib-nejm-2019","paper-desktop-iii-nejm-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"Most advanced ovarian cancers respond to first-line platinum, and the majority of relapses occur more than six months after the last platinum dose; this state covers the largest group of women on treatment and is where PARP inhibitor maintenance has changed the natural history.","subtypes":["Newly diagnosed advanced disease in response to first-line platinum (maintenance setting)","BRCA1 or BRCA2-mutant, platinum-sensitive (olaparib, SOLO-1)","HRD-positive, BRCA-wild-type (olaparib with bevacizumab, PAOLA-1; niraparib, PRIMA)","HRD-negative or proficient (niraparib or bevacizumab maintenance, smaller gains)","First platinum-sensitive relapse, AGO-score positive (secondary surgery, DESKTOP III)","Platinum-sensitive relapse after prior PARP inhibitor","High-grade serous carcinoma (most cases)"],"biomarkers":["Platinum-free interval (over six months defines sensitivity)","Germline and somatic BRCA1 and BRCA2","HRD genomic instability score","CA-125 kinetics","AGO score for secondary surgery (complete first resection, performance status, ascites)","BRCA reversion mutations at progression on PARP inhibitor"],"standardOfCare":[{"setting":"First-line maintenance, BRCA-mutant","approach":"Olaparib for two years (SOLO-1), or olaparib with bevacizumab (PAOLA-1); niraparib as an alternative.","refs":["olaparib","solo-1","paola-1","niraparib","brca","parp-inhibitor"]},{"setting":"First-line maintenance, HRD-positive BRCA-wild-type","approach":"Olaparib plus bevacizumab (PAOLA-1) or niraparib (PRIMA) after HRD testing.","refs":["olaparib","bevacizumab","paola-1","niraparib","prima","hrd-testing","hrd","parp-plus-bevacizumab"]},{"setting":"First-line maintenance, HRD-negative","approach":"Niraparib (PRIMA, smaller benefit) or bevacizumab; observation is reasonable after discussion.","refs":["niraparib","prima","bevacizumab","gog-0218-icon7"]},{"setting":"First platinum-sensitive relapse","approach":"Secondary cytoreduction in AGO-score-positive patients (DESKTOP III), then carboplatin doublet with pegylated liposomal doxorubicin, gemcitabine or paclitaxel, bevacizumab if not previously given, and PARP inhibitor maintenance if PARP-naive.","refs":["desktop-iii","carboplatin","pegylated-liposomal-doxorubicin","gemcitabine","paclitaxel","bevacizumab","olaparib","niraparib","rucaparib"]},{"setting":"Relapse after PARP inhibitor","approach":"Platinum doublet; PARP rechallenge has limited benefit; trials of ATR, WEE1 and next-generation PARP1-selective inhibitors.","refs":["carboplatin","saruparib","atr","wee1","athena-mono"]}],"stateOfArt":["SOLO-1's seven-year data showed PARP maintenance improves survival, not just time to relapse, in BRCA-mutant disease.","HRD testing sorts patients into three maintenance strategies.","DESKTOP III is the first randomised evidence that repeat surgery helps selected patients at relapse."],"history":[{"year":1989,"title":"Carboplatin approved; platinum-free interval emerges as the guide to re-treatment","refs":["carboplatin"]},{"year":2005,"title":"Synthetic lethality of PARP inhibition in BRCA-deficient cells","refs":["parp-inhibitor","brca"]},{"year":2014,"title":"Olaparib approved as the first PARP inhibitor, for BRCA-mutant relapsed disease","refs":["olaparib"]},{"year":2018,"title":"SOLO-1: olaparib maintenance, progression hazard ratio 0.30 in BRCA-mutant first-line disease","refs":["solo-1"]},{"year":2019,"title":"PRIMA and PAOLA-1 extend PARP maintenance to HRD-positive and all-comer populations","refs":["prima","paola-1"]},{"year":2020,"title":"DESKTOP III: secondary surgery extends survival in AGO-score-positive relapse","refs":["desktop-iii"]},{"year":2022,"title":"ATHENA-MONO confirms rucaparib maintenance; later-line PARP labels narrowed after survival data","refs":["athena-mono","rucaparib"]},{"year":2023,"title":"SOLO-1 seven-year overall survival: 67.0 versus 46.5 percent","refs":["solo-1"]}],"pipeline":["saruparib","atr","wee1","idea-ctdna-guided-parp-duration","hrd-testing","duo-o"],"openProblems":["Whether HRD-negative tumours gain enough from PARP inhibitors to justify two to three years of treatment.","Resistance through BRCA reversion and restored homologous recombination.","How long to continue maintenance, and whether circulating tumour DNA can tell."],"parent":"ovarian"},{"id":"pleural-mesothelioma","kind":"cancer","name":"Pleural mesothelioma","aka":["Malignant pleural mesothelioma","MPM"],"tldr":"Pleural mesothelioma grows in the lining of the lung after asbestos exposure and causes breathlessness and chest pain from fluid and thickening. It is rarely curable; the first-line choice is nivolumab with ipilimumab or pembrolizumab with chemotherapy, and surgery to remove the lining is no longer recommended outside trials.","summary":"Pleural mesothelioma is the commonest form of mesothelioma. It presents with pleural effusion, breathlessness and chest wall pain 20 to 50 years after asbestos exposure, and is diagnosed by thoracoscopic biopsy with immunohistochemistry (calretinin, WT1, D2-40) and loss of BAP1 or MTAP. Epithelioid histology, about two thirds of cases, carries a better outlook than biphasic or sarcomatoid disease. CheckMate 743 made nivolumab plus ipilimumab the first new first-line treatment in 16 years, and KEYNOTE-483 added pembrolizumab with platinum-pemetrexed; both are now standard, with histology guiding the choice. MARS 2 showed that extended pleurectomy and decortication harms rather than helps, so surgery is confined to diagnosis, pleurodesis and trials. Hemithoracic radiotherapy, tumour treating fields and mesothelin-directed therapies are the main lines of research.","asOf":"2026-09-16","wikipedia":"https://en.wikipedia.org/wiki/Mesothelioma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Mesothelioma"},{"label":"Mesothelioma UK","url":"https://www.mesothelioma.uk.com/"}],"tags":["subtype-page"],"related":["peritoneal-mesothelioma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["bap1-loss","cdkn2a-homozygous-deletion"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-checkmate-743-lancet-2021","paper-vogelzang-pemetrexed-mesothelioma-jco-2003","paper-mars-2-lancet-respir-med-2024","paper-keynote-483-lancet-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"thoracic","burden":"About four in five mesotheliomas arise in the pleura; roughly 2,500 cases a year in the UK and 3,000 in the US, almost all decades after asbestos exposure, with incidence still rising in countries that banned asbestos late.","subtypes":["Epithelioid (about two thirds)","Biphasic","Sarcomatoid (including desmoplastic)"],"biomarkers":["Histology (epithelioid versus non-epithelioid)","BAP1 loss","CDKN2A/MTAP deletion","Mesothelin expression","PD-L1 (not predictive for nivolumab plus ipilimumab)"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"CT and PET-CT; thoracoscopic biopsy with an immunohistochemistry panel; histology and BAP1/MTAP status recorded because they drive treatment.","refs":["mesothelioma"]},{"setting":"First line, non-epithelioid","approach":"Nivolumab plus ipilimumab (CheckMate 743).","refs":["nivolumab","ipilimumab","checkmate-743"]},{"setting":"First line, epithelioid","approach":"Pembrolizumab with platinum-pemetrexed (KEYNOTE-483), nivolumab plus ipilimumab, or platinum-pemetrexed with or without bevacizumab, by fitness and preference.","refs":["pembrolizumab","pemetrexed","keynote-483"]},{"setting":"Surgery","approach":"Not recommended for cure outside trials after MARS 2; talc pleurodesis or an indwelling pleural catheter controls effusion.","refs":["mars-2"]},{"setting":"Second line","approach":"Nivolumab (CONFIRM) if not given first line; chemotherapy rechallenge or gemcitabine or vinorelbine after immunotherapy.","refs":["nivolumab"]}],"stateOfArt":["Immunotherapy doubled the share of patients alive at five years compared with chemotherapy alone, but most patients still die of the disease within two years.","Randomised evidence has removed radical surgery from standard care, sparing patients a major operation with no benefit.","Mesothelin is expressed on almost every tumour cell, and the next generation of antibody-drug conjugates and CAR-T cells is built on it."],"history":[{"year":1960,"title":"Wagner links pleural mesothelioma to asbestos","note":"Thirty-three cases among asbestos miners and their neighbours in South Africa.","refs":[]},{"year":2003,"title":"Pemetrexed-cisplatin improves survival","refs":["pemetrexed"]},{"year":2020,"title":"CheckMate 743: first immunotherapy survival gain","refs":["checkmate-743"]},{"year":2024,"title":"MARS 2 ends radical surgery as standard","refs":["mars-2"]},{"year":2024,"title":"Pembrolizumab with chemotherapy approved","refs":["keynote-483"]}],"pipeline":["idea-adc-for-mesothelioma"],"openProblems":["No curative treatment for the majority; median survival with the best regimens is about 18 months.","Sarcomatoid disease responds poorly to everything except immunotherapy.","No screening test for exposed workers, though BAP1 germline carriers and asbestos cohorts are being followed."],"parent":"mesothelioma"},{"id":"pleuropulmonary-blastoma-dicer1","kind":"cancer","name":"Pleuropulmonary blastoma (types I, Ir, II and III)","aka":["PPB","Pleuropulmonary blastoma type I","Pleuropulmonary blastoma type Ir","Pleuropulmonary blastoma type II","Pleuropulmonary blastoma type III","DICER1-related pleuropulmonary blastoma"],"tldr":"Pleuropulmonary blastoma is a rare lung cancer of young children, and the signature tumour of the inherited DICER1 syndrome. It starts as a lung cyst (type I) that can turn into a solid, aggressive tumour (types II and III). Cysts are removed surgically with an excellent outlook; solid tumours need chemotherapy as well, and every family is offered DICER1 testing.","summary":"Pleuropulmonary blastoma is a dysontogenetic mesenchymal tumour of the lung and pleura of early childhood with three subtypes on a progression pathway, from type I (purely cystic) to type II (cystic and solid) and type III (solid), plus type Ir, a regressed cystic form; a germline DICER1 mutation is the cause in the majority (Messinger 2015). In the 350 registry-confirmed cases (85 of 435 submitted cases, 20 percent, proved to be another entity on review), five-year overall survival was 91 percent for type I and Ir, with all deaths in that group from progression to type II or III, and survival was significantly better for type II than type III (Messinger 2015). The DICER1 syndrome also produces ovarian Sertoli-Leydig cell tumours, cystic nephroma, thyroid nodules and other tumours in the same children and families (Gynecologic Oncology 2011).\n\nHow it differs from its parent: the parent page is the corpus's umbrella for all childhood lung and airway tumours; this page is the entity itself, with its subtype pathway, its registry survival figures and its syndrome. Adult pulmonary blastoma is a different tumour with its own page.\n\nHow common: no incidence figure; 350 confirmed cases in the international registry (Messinger 2015).\n\nTreatment: complete resection for type I and Ir cysts, with chemotherapy debated for type I; resection and multi-agent chemotherapy (registry regimens based on ifosfamide, vincristine, actinomycin and doxorubicin) for types II and III, with radiotherapy for residual disease; germline DICER1 testing and surveillance for the child and relatives (Messinger 2015; NCI PDQ rare cancers of childhood).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Pleuropulmonary_blastoma","links":[{"label":"NCI PDQ: rare cancers of childhood","url":"https://www.cancer.gov/types/childhood-cancers/patient/rare-childhood-cancers-pdq"},{"label":"Messinger 2015, Cancer: 350 central pathology-confirmed pleuropulmonary blastoma cases, International PPB Registry","url":"https://doi.org/10.1002/cncr.29032"},{"label":"Gynecologic Oncology 2011: ovarian sex cord-stromal tumours, pleuropulmonary blastoma and DICER1, International PPB Registry","url":"https://doi.org/10.1016/j.ygyno.2011.03.024"}],"tags":["subtype-page","wave4","rare"],"related":["pleuropulmonary-blastoma","pulmonary-blastoma","pineoblastoma","childhood-cancers","granulosa-cell-tumour"],"cancers":[],"sections":[],"technologies":["germline-testing"],"targets":["dicer1"],"drugs":["ifosfamide","vincristine","doxorubicin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Very rare: the International Pleuropulmonary Blastoma Registry confirmed 350 cases by central pathology review, 33 percent type I or Ir, 35 percent type II and 32 percent type III, with median ages at diagnosis of 8, 35 and 41 months (Messinger 2015).","subtypes":["Pleuropulmonary blastoma type I (cystic; median age 8 months; 91 percent five-year survival with type Ir)","Pleuropulmonary blastoma type Ir (regressed cystic)","Pleuropulmonary blastoma type II (cystic and solid; median age 35 months)","Pleuropulmonary blastoma type III (solid; median age 41 months; worst outcome)","Pleuropulmonary blastoma in DICER1 syndrome families"],"biomarkers":["Germline DICER1 mutation (the majority)","Subtype I, Ir, II or III on central pathology review","Somatic DICER1 RNase IIIb hotspot mutation","Family history of DICER1 syndrome tumours"],"standardOfCare":[{"setting":"Type I and Ir","approach":"Complete resection of the cyst; chemotherapy debated; DICER1 testing and surveillance.","refs":["pleuropulmonary-blastoma","germline-testing"]},{"setting":"Type II and III","approach":"Resection and multi-agent chemotherapy (ifosfamide, vincristine, actinomycin, doxorubicin), radiotherapy for residual disease.","refs":["ifosfamide","vincristine","doxorubicin","pleuropulmonary-blastoma"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"pleuropulmonary-blastoma"},{"id":"endometrial-pole-ultramutated","kind":"cancer","name":"POLE-ultramutated endometrial cancer","aka":["POLEmut endometrial cancer","POLE exonuclease domain mutant endometrial carcinoma","Ultramutated endometrial cancer"],"tldr":"POLE-ultramutated endometrial cancer carries a fault in the proofreading part of a DNA-copying enzyme, so its cells pile up enormous numbers of mutations. It looks aggressive under the microscope yet almost never comes back after surgery, so trials are testing whether radiotherapy and chemotherapy can be dropped altogether.","summary":"The Cancer Genome Atlas defined the POLE-ultramutated class in 2013: tumours with a hotspot mutation in the exonuclease domain of DNA polymerase epsilon, most often P286R or V411L, which carry more than a hundred mutations per megabase, far more even than mismatch-repair-deficient tumours. About seven percent of endometrial cancers fall into this class. They are more often high grade, endometrioid, with prominent lymphocyte infiltration and ambiguous histology, and they occur in younger, thinner women than the average endometrial cancer patient. Because the pathogenic hotspots are few, a targeted sequencing test settles the class, and the ProMisE algorithm and the WHO 2020 classification both place POLE testing first because a POLE mutation overrides an abnormal p53 or mismatch-repair result.\n\nThe defining clinical fact is an excellent outcome regardless of grade or stage. In the molecular analysis of PORTEC-3, women with POLE-ultramutated tumours had almost no recurrences in either arm, so chemotherapy added nothing; the same pattern appeared in PORTEC-1 and PORTEC-2 and in the TransPORTEC pooled cohorts. The ESGO/ESTRO/ESP 2021 guideline therefore lets clinicians omit adjuvant therapy for stage I and II POLE-ultramutated disease, and the RAINBO programme's POLEmut-BLUE trial is testing de-escalation prospectively: no adjuvant treatment for stage I and II tumours and radiotherapy alone for stage III. The rationale is that the ultramutated tumour is intensely immunogenic and any residual cells are cleared by the immune system after surgery.\n\nOpen questions are practical rather than therapeutic. Not every POLE variant is pathogenic, and misclassifying a passenger variant as a driver would deny a woman treatment she needs, so laboratories use a curated list of hotspots and a scoring scheme for other variants. The rare advanced or recurrent POLE-ultramutated tumour is expected to respond to checkpoint inhibitors because of its mutational load, but numbers are too small for trials. Universal molecular classification, now routine in the Netherlands, Canada and the United Kingdom, is the step that makes any of this possible, and it is still uneven elsewhere.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Endometrial_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Endometrial_cancer"}],"tags":["subtype-page"],"related":["advanced-recurrent-endometrial-cancer","endometrial-nsmp","endometrial-mmr-deficient","endometrial-p53-abnormal","uterine-carcinosarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["pole-ultramutation"],"trials":["portec-2"],"people":[],"bottlenecks":[],"keyPapers":["paper-promise-talhouk-cancer-2017","paper-esgo-estro-esp-endometrial-concin-ijgc-2021","paper-portec-3-molecular-leon-castillo-jco-2020","paper-church-pole-endometrial-jnci-2015"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"Roughly one in fourteen endometrial cancers, typically in younger women with high-grade endometrioid tumours; almost none recur after surgery, so the class matters mainly because it identifies women who can safely be spared adjuvant treatment.","subtypes":["POLE exonuclease domain hotspot mutation (P286R, V411L, S297F, A456P, S459F)","POLE-ultramutated with secondary p53 or MMR abnormality (multiple classifier, treated as POLE)","Stage I to II POLE-ultramutated (adjuvant therapy can be omitted)","Stage III POLE-ultramutated (RAINBO POLEmut-BLUE, radiotherapy alone)","High-grade endometrioid histology with ultramutated profile"],"biomarkers":["POLE exonuclease domain sequencing (first step of the ProMisE classifier)","Tumour mutational burden above 100 mutations per megabase","p53 and MMR immunohistochemistry (interpreted after POLE)","Tumour-infiltrating lymphocytes","Stage and lymphovascular space invasion"],"standardOfCare":[{"setting":"Diagnosis and classification","approach":"Hysterectomy with bilateral salpingo-oophorectomy and sentinel node mapping; molecular classification of every endometrial cancer with POLE sequencing, MMR and p53 immunohistochemistry.","refs":["endometrial-molecular-classes","histopathology-ihc","ngs","sentinel-node","fires-sentor","hysterectomy"]},{"setting":"Stage I to II after surgery","approach":"Observation without adjuvant treatment is acceptable under the ESGO/ESTRO/ESP guideline; vaginal brachytherapy where local protocol still requires it.","refs":["brachytherapy","endometrial-molecular-classes","idea-molecular-class-adjuvant-endometrial"]},{"setting":"Stage III after surgery","approach":"Pelvic radiotherapy without chemotherapy, as in RAINBO POLEmut-BLUE; chemoradiation with chemotherapy remains an option outside trials.","refs":["imrt-igrt","portec-3","carboplatin","paclitaxel","rainbo"]},{"setting":"Advanced or recurrent (rare)","approach":"Checkpoint inhibitor with or without chemotherapy by extrapolation from the mismatch-repair-deficient class.","refs":["pembrolizumab","dostarlimab","checkpoint-inhibitor"]}],"stateOfArt":["POLE testing is the first branch of every molecular classifier because it overrides the other classes.","PORTEC-3's molecular analysis showed that POLE-ultramutated tumours do not need chemotherapy.","RAINBO POLEmut-BLUE is the first prospective trial to omit adjuvant treatment on a molecular basis."],"history":[{"year":2013,"title":"TCGA defines the POLE-ultramutated class of endometrial cancer","refs":["endometrial-molecular-classes"]},{"year":2015,"title":"ProMisE classifier reproduces the TCGA classes with clinical tests","refs":[]},{"year":2020,"title":"PORTEC-3 molecular analysis: no benefit from chemotherapy in POLE-ultramutated tumours","refs":["portec-3"]},{"year":2021,"title":"ESGO/ESTRO/ESP guideline allows omission of adjuvant therapy for stage I to II POLE-ultramutated disease","refs":[]},{"year":2022,"title":"RAINBO programme opens, with POLEmut-BLUE testing de-escalation","refs":[]}],"pipeline":["idea-molecular-class-adjuvant-endometrial","endometrial-molecular-classes","mrd-testing"],"openProblems":["Deciding which non-hotspot POLE variants are pathogenic.","Whether stage III and IV disease can also be de-escalated.","Making molecular classification universal outside a few countries."],"parent":"endometrial"},{"id":"polycythaemia-vera","kind":"cancer","name":"Polycythaemia vera (PV)","aka":["Polycythemia vera","PV","Primary polycythaemia","Vaquez disease","Vaquez-Osler disease"],"tldr":"Polycythaemia vera is a slow blood cancer in which a single faulty gene, JAK2, makes the bone marrow produce too many red cells. Thick blood causes clots, so treatment thins it (blood removal, aspirin) and, for higher-risk patients, calms the marrow with hydroxyurea, interferon or ruxolitinib; a hepcidin mimic, rusfertide, now controls red cell counts without regular blood removal.","summary":"Polycythaemia vera is one of the classical myeloproliferative neoplasms. Almost every case carries a mutation in JAK2 (V617F in about 95 percent, exon 12 in most of the rest) that keeps the red-cell growth signal switched on without erythropoietin. The result is a high haematocrit, often with raised platelets and white cells, an enlarged spleen, itching after warm water, burning red hands and feet, and above all a raised risk of arterial and venous thrombosis, including clots in unusual places such as the hepatic veins. Diagnosis rests on the blood count, the JAK2 mutation, a hypercellular marrow and a low erythropoietin level. Treatment is risk-adapted: everyone has low-dose aspirin and phlebotomy to keep the haematocrit under 45 percent, a target proven by the CYTO-PV trial; people over 60 or with a prior clot add a cytoreductive drug, hydroxyurea or ropeginterferon alfa-2b, with ruxolitinib for those hydroxyurea fails. Rusfertide, a hepcidin mimetic that starves red-cell production of iron, was approved in 2026 for phlebotomy-dependent disease. Over decades a minority progress to post-PV myelofibrosis and a few percent to acute leukaemia, which is why the field is now chasing molecular remission with interferon and JAK2 V617F-selective inhibitors.","asOf":"2026-09-16","wikipedia":"https://en.wikipedia.org/wiki/Polycythemia_vera","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Polycythemia_vera"},{"label":"MPN Research Foundation","url":"https://www.mpnresearchfoundation.org/polycythemia-vera/"},{"label":"NCI PDQ: chronic myeloproliferative neoplasms","url":"https://www.cancer.gov/types/myeloproliferative/patient/chronic-treatment-pdq"}],"tags":["polycythaemia-vera","mpn"],"related":["essential-thrombocythaemia","primary-myelofibrosis"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["mpn-driver-mutations"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Around one to two new cases per 100,000 people a year, most diagnosed in their sixties; with treatment most people live for decades, and the main dangers are clots, bleeding and, late on, scarring of the marrow or leukaemia.","subtypes":["JAK2 V617F-positive (about 95 percent)","JAK2 exon 12-mutated (about 3 percent; often isolated erythrocytosis)","Masked PV (haemoglobin below the WHO threshold but marrow and mutation typical)","Post-PV myelofibrosis (spent phase)","PV in blast phase (transformation to acute myeloid leukaemia)"],"biomarkers":["JAK2 V617F allele burden (falls with interferon; a marker of molecular response)","JAK2 exon 12 mutations","Haematocrit, with treatment targeting below 45 percent","Serum erythropoietin (low in PV, high in secondary erythrocytosis)","Leukocyte count above 11 x 10^9/L (thrombosis risk)","Additional mutations in TET2, ASXL1, SRSF2, IDH1/2 (progression risk)","Age over 60 and prior thrombosis (the two risk factors that define high-risk disease)"],"standardOfCare":[{"setting":"Diagnosis","approach":"Full blood count, JAK2 V617F and exon 12 testing, serum erythropoietin, and bone marrow biopsy showing trilineage growth; WHO criteria (haemoglobin above 16.5 g/dL in men or 16.0 in women, or haematocrit above 49 or 48 percent). Secondary causes of a high red count (smoking, sleep apnoea, kidney or liver tumours, testosterone) are excluded first.","refs":["jak2","erythrocytosis"]},{"setting":"All patients","approach":"Low-dose aspirin unless contraindicated, phlebotomy to a haematocrit under 45 percent (CYTO-PV), and control of cardiovascular risk factors.","refs":["aspirin","cyto-pv","phlebotomy","haematocrit"]},{"setting":"Low risk (under 60, no prior clot)","approach":"Aspirin and phlebotomy alone; ropeginterferon alfa-2b is an option when phlebotomy is poorly tolerated or symptoms persist (Low-PV).","refs":["ropeginterferon-alfa-2b","low-pv"]},{"setting":"High risk (over 60 or prior clot)","approach":"Add cytoreduction: hydroxyurea, or ropeginterferon alfa-2b (PROUD-PV and CONTINUATION-PV), the latter preferred in younger patients and in pregnancy.","refs":["hydroxyurea","ropeginterferon-alfa-2b","proud-pv"]},{"setting":"Hydroxyurea resistance or intolerance","approach":"Ruxolitinib (RESPONSE, RESPONSE-2, MAJIC-PV) for haematocrit control, spleen shrinkage and symptom relief; interferon if not already tried.","refs":["ruxolitinib","response","response-2","majic-pv"]},{"setting":"Phlebotomy-dependent disease","approach":"Rusfertide, a hepcidin mimetic given by weekly injection, keeps the haematocrit under 45 percent and removes the need for phlebotomy in most patients (VERIFY).","refs":["rusfertide","verify","hepcidin"]},{"setting":"Itching and burning extremities","approach":"Antihistamines, aspirin for erythromelalgia, interferon or ruxolitinib for severe aquagenic pruritus.","refs":["aquagenic-pruritus","erythromelalgia"]},{"setting":"Post-PV myelofibrosis","approach":"Managed as myelofibrosis: JAK inhibitors for spleen and symptoms, momelotinib for anaemia, allogeneic stem cell transplant for fit higher-risk patients.","refs":["myeloproliferative-neoplasms","ruxolitinib","momelotinib","post-pv-myelofibrosis"]}],"stateOfArt":["Keeping the haematocrit under 45 percent cuts major clots and cardiovascular death to about a third, the single most important result in PV (CYTO-PV).","Ropeginterferon alfa-2b is the first drug shown to shrink the JAK2 mutant clone in a randomised trial, and its long-term molecular responses raise the prospect of changing the course of the disease rather than only controlling counts.","Ruxolitinib gives durable haematocrit and symptom control after hydroxyurea fails, and in MAJIC-PV a complete response tracked with fewer clots and progressions.","Rusfertide, approved in 2026, is the first mechanistically new PV drug in a decade: by mimicking hepcidin it starves red-cell production of iron and made three quarters of patients phlebotomy-free in VERIFY.","The unmet needs are a treatment that prevents progression to myelofibrosis and leukaemia, and a way to select who needs cytoreduction beyond age and clot history."],"history":[{"year":1892,"title":"Vaquez describes the disease","note":"Louis Henri Vaquez reports a patient with persistent excess red cells and an enlarged spleen.","refs":[]},{"year":1903,"title":"Osler defines a clinical syndrome","note":"William Osler collects cases of chronic cyanosis with polycythaemia and splenomegaly.","refs":[]},{"year":1951,"title":"Dameshek groups the myeloproliferative disorders","note":"PV, essential thrombocythaemia, myelofibrosis and CML proposed as related diseases of the marrow.","refs":["myeloproliferative-neoplasms"]},{"year":1967,"title":"Polycythemia Vera Study Group founded","note":"Louis Wasserman's cooperative group runs the first randomised PV trials, comparing phlebotomy, radiophosphorus and chlorambucil, and shows the leukaemia risk of alkylating agents.","refs":[]},{"year":2005,"title":"JAK2 V617F discovered","note":"Four groups report the mutation in almost all PV; the first molecular marker for BCR-ABL1-negative MPN and the target for the JAK inhibitors that followed.","refs":["jak2","jak2-v617f"]},{"year":2013,"title":"CYTO-PV proves the haematocrit target","note":"Keeping the haematocrit under 45 percent gives fewer cardiovascular deaths and major clots than a 45 to 50 percent target.","refs":["cyto-pv","haematocrit"]},{"year":2014,"title":"Ruxolitinib approved for PV","note":"FDA approval in December 2014 for hydroxyurea-resistant or intolerant PV on the RESPONSE trial; EU approval followed in 2015.","refs":["ruxolitinib","response"]},{"year":2019,"title":"Ropeginterferon alfa-2b approved in Europe","note":"The first interferon licensed for PV, on PROUD-PV and CONTINUATION-PV; FDA approval followed in November 2021.","refs":["ropeginterferon-alfa-2b","proud-pv"]},{"year":2021,"title":"Low-PV: interferon helps low-risk patients too","note":"Ropeginterferon plus phlebotomy kept more low-risk patients at target than phlebotomy alone.","refs":["low-pv"]},{"year":2023,"title":"MAJIC-PV links complete response to fewer events","note":"Ruxolitinib beat best available therapy after hydroxyurea failure, and complete responders had better event-free survival.","refs":["majic-pv","ruxolitinib"]},{"year":2025,"title":"VERIFY: a hepcidin mimetic replaces phlebotomy","note":"Rusfertide added to standard care made most patients phlebotomy-free over weeks 20 to 32.","refs":["verify","rusfertide"]},{"year":2026,"title":"Rusfertide approved","note":"FDA approval for phlebotomy-dependent polycythaemia vera.","refs":["rusfertide"]}],"pipeline":["givinostat","bomedemstat","nct06093672","idea-pv-clone-directed-therapy","idea-pv-hepcidin-first"],"openProblems":["No treatment has yet been shown to prevent progression to myelofibrosis or leukaemia; interferon's molecular responses are the strongest hint.","Risk stratification still rests on age and clot history; leukocyte count, allele burden and additional mutations are not yet built into treatment decisions.","Whether low-risk patients should have early cytoreduction (Low-PV suggests yes for interferon) remains unsettled and depends on cost and tolerability.","Aquagenic pruritus and fatigue are under-treated and poorly measured in trials.","Hepcidin mimetics control counts but their effect on thrombosis and long-term outcomes is not yet known."],"parent":"myeloproliferative-neoplasms"},{"id":"poorly-differentiated-chordoma","kind":"cancer","name":"Poorly differentiated chordoma (SMARCB1-deficient)","aka":["SMARCB1-deficient chordoma","INI1-negative chordoma","Paediatric poorly differentiated chordoma"],"tldr":"Poorly differentiated chordoma is a rare, aggressive form of chordoma of children and young adults, mostly at the base of the skull or in the neck, defined by loss of the SMARCB1 (INI1) protein. It grows faster and spreads more than ordinary chordoma, and the SMARCB1 loss makes it a candidate for drugs that block EZH2, though surgery and radiotherapy remain the treatment.","summary":"The WHO bone classification recognises poorly differentiated chordoma as a subtype defined by brachyury expression with loss of SMARCB1 (INI1), first characterised as a distinct molecular entity with much shorter survival (Acta Neuropathologica 2016). In the 19-patient series, tumours arose in the skull base and clivus (53 percent), cervical spine (32 percent) and sacrum or coccyx (16 percent), were composed of sheets of epithelioid cells rather than the physaliphorous cells of conventional chordoma, and had worse survival than the other subtypes (Modern Pathology 2018).\n\nHow it differs from its parent: age (children rather than adults in their fifties and sixties), the SMARCB1 deletion that groups it biologically with atypical teratoid/rhabdoid tumour and epithelioid sarcoma, and a much shorter survival.\n\nHow common: no incidence figure; 19 cases at one referral centre in 27 years (Modern Pathology 2018).\n\nTreatment: maximal safe resection and proton or photon radiotherapy as on the chordoma page; systemic therapy has no standard, and EZH2 inhibition (tazemetostat, approved for SMARCB1-deficient epithelioid sarcoma) is the rational agent under study for SMARCB1-deficient tumours.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Chordoma","links":[{"label":"NCI PDQ: rare cancers of childhood","url":"https://www.cancer.gov/types/childhood-cancers/patient/rare-childhood-cancers-pdq"},{"label":"Acta Neuropathologica 2016: poorly differentiated chordoma with SMARCB1/INI1 loss, a distinct entity with dismal prognosis","url":"https://doi.org/10.1007/s00401-016-1574-9"},{"label":"Modern Pathology 2018: clinicopathologic characteristics of poorly differentiated chordoma, 19 patients","url":"https://doi.org/10.1038/s41379-018-0002-1"}],"tags":["subtype-page","wave4","rare"],"related":["chordoma","dedifferentiated-chordoma","atrt","childhood-cancers"],"cancers":[],"sections":[],"technologies":["proton-therapy"],"targets":["smarcb1","tbxt"],"drugs":["tazemetostat"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"Very rare and mostly paediatric: the largest series holds 19 patients diagnosed at a median age of 11 (range 1 to 29) over 1990 to 2017 (Modern Pathology 2018).","subtypes":["Poorly differentiated chordoma of the skull base and clivus (about half)","Poorly differentiated chordoma of the cervical spine","Poorly differentiated chordoma of the sacrum or coccyx","Conventional and chondroid chordoma (the parent page; SMARCB1 retained)"],"biomarkers":["Brachyury (TBXT) positive with SMARCB1 (INI1) loss","SMARCB1 deletion on copy-number analysis","Cytokeratin positive; epithelioid morphology","Age under 30"],"standardOfCare":[{"setting":"All cases","approach":"Maximal safe resection and proton radiotherapy as on the chordoma page; EZH2 inhibition under study for SMARCB1-deficient tumours.","refs":["chordoma","proton-therapy","tazemetostat"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"chordoma"},{"id":"post-transplant-lymphoproliferative-disorder","kind":"cancer","name":"Post-transplant lymphoproliferative disorder (PTLD)","aka":["PTLD","EBV-positive PTLD","Immunodeficiency-associated lymphoproliferative disorder"],"tldr":"After an organ or stem cell transplant, the drugs that stop rejection also stop the immune system from policing Epstein-Barr virus, and infected B cells can grow into a lymphoma. The first move is to ease the immunosuppression; then the antibody rituximab, chemotherapy if needed, and, newest of all, off-the-shelf virus-specific T cells that restore the missing immune control.","summary":"PTLD spans a spectrum from EBV-driven polyclonal hyperplasia to monomorphic lymphoma (usually diffuse large B-cell, sometimes Burkitt, plasmablastic, T-cell or Hodgkin-like), classified under WHO 2022 as lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation. EBV is detectable in most early and paediatric cases and about half of late adult cases; EBV-negative PTLD arises later and behaves like de novo lymphoma. Risk is driven by the degree of T-cell suppression (T-cell-depleting induction, tacrolimus-based regimens), EBV-seronegative recipients of seropositive organs (the paediatric scenario), and organ type. In allogeneic stem cell transplant the risk factors are T-cell depletion, mismatched or cord blood donors and anti-thymocyte globulin.\n\nManagement is stepwise. Reduction of immunosuppression is the first intervention and alone induces remission in a minority, at the cost of rejection risk. Rituximab monotherapy follows for CD20-positive disease; the PTLD-1 trial (Trappe and colleagues, Lancet Oncology 2012) established sequential therapy with four doses of rituximab followed by CHOP, and its risk-stratified successor (JCO 2017) showed that patients in complete remission after rituximab can continue rituximab alone, reserving CHOP for the rest. Surgery or radiotherapy handles localised disease, and EBV DNA monitoring with pre-emptive rituximab is standard after high-risk stem cell transplants. The newest treatment restores what was lost: EBV-specific cytotoxic T cells. Tabelecleucel (Ebvallo), an allogeneic, HLA-matched, off-the-shelf EBV-specific T-cell product, received European approval in December 2022 for relapsed or refractory EBV-positive PTLD after at least one prior therapy, on the basis of the ALLELE study; in the United States it received a complete response letter in January 2025 tied to manufacturing inspection findings and it does not yet appear on the FDA list of approved cellular and gene therapy products, so US patients access EBV-specific T cells through trials and academic programmes. CD19 CAR-T and bispecific antibodies have been used in small numbers of refractory patients.\n\nOpen problems are the outcome of rituximab-refractory disease, balancing rejection against lymphoma control, EBV vaccination for seronegative transplant candidates, and paediatric access to virus-specific T cells.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Post-transplant_lymphoproliferative_disorder","links":[{"label":"NCI PDQ: adult non-Hodgkin lymphoma (post-transplant lymphoproliferative disorder)","url":"https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq"},{"label":"PTLD-1 sequential treatment (Lancet Oncol 2012)","url":"https://doi.org/10.1016/S1470-2045(11)70300-X"},{"label":"PTLD-1 risk-stratified sequential treatment (JCO 2017)","url":"https://doi.org/10.1200/JCO.2016.69.3564"},{"label":"EMA: Ebvallo (tabelecleucel)","url":"https://www.ema.europa.eu/en/medicines/human/EPAR/ebvallo"},{"label":"BSH guideline on PTLD (Br J Haematol 2021)","url":"https://doi.org/10.1111/bjh.17421"}],"tags":["nci-coverage","rare","haematologic","virus-associated"],"related":["dlbcl","hiv-associated-lymphoma","burkitt-lymphoma","hodgkin-lymphoma","primary-cns-lymphoma"],"cancers":[],"sections":[],"technologies":["monoclonal-antibody","allogeneic-cell-therapy","allogeneic-hsct","cytotoxic-chemotherapy","car-t","bispecific-antibody"],"targets":["cd20","cd19"],"drugs":["rituximab","cyclophosphamide","doxorubicin","vincristine","axicabtagene-ciloleucel","glofitamab","epcoritamab"],"companies":[],"institutions":[],"pathways":["oncogenic-viruses","antigen-presentation-immunoediting"],"terms":["ebv-term","plasma-ebv-dna","allogeneic-transplant","gvhd"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers","b-manufacturing-cell-therapy"],"keyPapers":["paper-trappe-lancet-oncol","paper-shah-br-j-haematol"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Occurs after roughly one to twenty percent of solid organ transplants depending on organ, EBV serostatus and age (highest in EBV-seronegative children receiving intestinal or lung grafts), and after a small percentage of allogeneic stem cell transplants (ISHLT; CIBMTR).","subtypes":["Non-destructive PTLD (plasmacytic hyperplasia, infectious mononucleosis-like, florid follicular hyperplasia)","Polymorphic PTLD","Monomorphic PTLD, B-cell (DLBCL-like, Burkitt-like, plasmablastic)","Monomorphic PTLD, T/NK-cell","Classical Hodgkin lymphoma-like PTLD","EBV-negative (late) PTLD"],"biomarkers":["EBV status of tumour (EBER in situ hybridisation) and plasma EBV DNA load","CD20 expression (rituximab eligibility)","Recipient EBV serostatus at transplant","Type and intensity of immunosuppression","LDH, stage, performance status and graft involvement (prognostic index)","HLA type (for matched EBV-specific T-cell products)"],"standardOfCare":[{"setting":"All PTLD, first step","approach":"Reduce immunosuppression as far as graft safety allows, with close monitoring for rejection; surgery or radiotherapy for localised disease.","refs":["ebv-term"],"guideline":{"version":"BSH guideline on PTLD (Br J Haematol 2021); ECIL guidelines for EBV after HSCT","url":"https://doi.org/10.1111/bjh.17421"}},{"setting":"CD20-positive PTLD not responding to reduced immunosuppression","approach":"Rituximab weekly for four doses; patients in complete remission continue rituximab consolidation alone, others proceed to R-CHOP (PTLD-1 risk-stratified sequential treatment).","refs":["rituximab","cyclophosphamide","doxorubicin","vincristine","cd20","ptld-1"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: B-Cell Lymphomas (PTLD); PTLD-1 RSST (JCO 2017)","url":"https://doi.org/10.1200/JCO.2016.69.3564"}},{"setting":"EBV-positive, relapsed or refractory","approach":"EBV-specific T cells: tabelecleucel (EMA approval 2022; under FDA review) or institutional virus-specific T-cell programmes; clinical trials.","refs":["allogeneic-cell-therapy","ebv-term"],"guideline":{"version":"EMA: Ebvallo (tabelecleucel) EPAR"}},{"setting":"After allogeneic HSCT, high risk","approach":"Weekly plasma EBV DNA monitoring with pre-emptive rituximab when load rises; reduction of immunosuppression where possible.","refs":["rituximab","allogeneic-hsct","plasma-ebv-dna"],"guideline":{"version":"ECIL-6 guidelines (Haematologica 2016)","url":"https://doi.org/10.3324/haematol.2016.144428"}}],"stateOfArt":["Risk-stratified sequential therapy (rituximab, then rituximab alone or R-CHOP by response) gives high response rates with less chemotherapy than lymphoma-standard regimens.","Off-the-shelf EBV-specific T cells restore immune control of the virus; tabelecleucel is approved in Europe and is the first allogeneic T-cell therapy approved anywhere.","Pre-emptive rituximab guided by EBV DNA load has made PTLD after stem cell transplant largely preventable.","Better induction and maintenance immunosuppression choices, and EBV-mismatch awareness in paediatric transplantation, reduce incidence."],"history":[{"year":1968,"title":"First reports of lymphoma after kidney transplantation","note":"Doak and colleagues; Penn's registry (1969) establishes the association with immunosuppression.","refs":[]},{"year":1980,"title":"EBV linked to PTLD","note":"Hanto and colleagues show EBV in lymphoproliferations of transplant recipients and regression with reduced immunosuppression.","refs":[]},{"year":1994,"title":"Donor-derived EBV-specific T cells prevent and treat PTLD","note":"Rooney, Heslop and colleagues (Lancet 1995) after stem cell transplant.","refs":["allogeneic-cell-therapy"]},{"year":2000,"title":"Rituximab in PTLD","note":"Case series and the French multicentre trial (Blood 2006) establish anti-CD20 therapy.","refs":["rituximab"]},{"year":2012,"title":"PTLD-1: sequential rituximab then CHOP","note":"Trappe and colleagues, Lancet Oncology 2012.","refs":["rituximab"]},{"year":2017,"title":"Risk-stratified sequential treatment","note":"Rituximab consolidation alone for complete responders (JCO 2017).","refs":["rituximab"]},{"year":2022,"title":"Tabelecleucel approved in the EU","note":"First allogeneic T-cell immunotherapy approved; December 2022, for relapsed or refractory EBV-positive PTLD.","refs":["allogeneic-cell-therapy"]}],"pipeline":["allogeneic-cell-therapy","rituximab","glofitamab","epcoritamab"],"openProblems":["Rituximab-refractory and EBV-negative PTLD have poor outcomes; EBV-specific T cells, CAR-T and bispecific antibodies are the routes being tested.","US access to tabelecleucel awaits FDA resolution of manufacturing findings; academic virus-specific T-cell banks fill the gap.","Balancing graft rejection against lymphoma control when immunosuppression is reduced; mTOR-inhibitor conversion and tailored regimens are studied.","Preventing PTLD in EBV-seronegative children needing transplants; EBV vaccine candidates are in early trials."],"parent":"non-hodgkin-lymphoma"},{"id":"primary-cns-lymphoma","kind":"cancer","name":"Primary CNS lymphoma","aka":["PCNSL"],"tldr":"Primary CNS lymphoma is a lymphoma confined to the brain, eyes and spinal fluid. Unlike most brain tumours it is chemo-sensitive: high-dose methotrexate-based treatment cures a substantial minority, and consolidation with a stem-cell transplant has replaced whole-brain radiation for the fit.","summary":"PCNSL is almost always a diffuse large B-cell lymphoma of activated B-cell type, with near-universal MYD88 L265P and CD79B mutations and 9p24 (PD-L1) gains. It presents with focal deficits or cognitive change; diagnosis needs stereotactic biopsy before steroids, plus eye examination and CSF cytology/flow.\n\nInduction is high-dose methotrexate (≥3 g/m²) combined with cytarabine, thiotepa and rituximab (MATRix, IELSG32) or with temozolomide/procarbazine (R-MPV). Consolidation with high-dose chemotherapy and autologous transplant matches or beats whole-brain radiotherapy with far less neurotoxicity (IELSG32, PRECIS), so radiation is reserved for the unfit or as salvage. Older patients receive methotrexate-based regimens with maintenance (temozolomide, lenalidomide or ibrutinib). Relapsed disease responds to ibrutinib, lenalidomide and PD-1 blockade transiently; CD19 CAR-T crosses into the CNS with responses in small series.\n\nThe open problems are neurotoxicity, the elderly majority who cannot receive intensive therapy, and the lack of a randomised standard beyond induction.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Primary_central_nervous_system_lymphoma","links":[{"label":"IELSG32 long-term (Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01582-5"},{"label":"NCCN Guidelines: CNS Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"},{"label":"NCI PDQ: primary CNS lymphoma","url":"https://www.cancer.gov/types/lymphoma/patient/primary-cns-lymphoma-treatment-pdq"}],"tags":["gap-fill","haematologic","cns"],"related":["dlbcl","hiv-associated-lymphoma","post-transplant-lymphoproliferative-disorder","primary-mediastinal-b-cell-lymphoma","myd88-l265p","cd79b-itam-mutation","lymphoma-roadmap"],"cancers":[],"sections":[],"technologies":["autologous-stem-cell-transplant","imrt-igrt","car-t","mri","liquid-biopsy","cgp","histopathology-ihc","clonality-testing"],"targets":["cd20","btk","cd19","cd79b","pd1","myd88","b2m","pdl1"],"drugs":["methotrexate","rituximab","temozolomide","ibrutinib","lenalidomide","nivolumab","axicabtagene-ciloleucel","thiotepa"],"companies":["roche-genentech","abbvie","johnson-johnson","curis"],"institutions":[],"pathways":["bcr-signalling","inflammation-nfkb","antigen-presentation-immunoediting"],"terms":["blood-brain-barrier","cell-of-origin","myd88-l265p","lymphoma-tx-transplant-role","lymphoma-tx-radiotherapy","lymphoma-tx-regimen-alphabet","lymphoma-tx-cns-prophylaxis","lymphoma-bio-lymphgen","lymphoma-bio-cell-of-origin-in-practice"],"trials":["prima-cns"],"people":[],"bottlenecks":[],"keyPapers":["paper-ferreri-leukemia"],"journals":[],"dependsOn":[],"notes":[],"group":"central nervous system","burden":"Primary CNS lymphoma affects about 0.5 per 100,000 per year and is ~4% of primary brain tumours, rising in the elderly and in the immunosuppressed.","subtypes":["Immunocompetent PCNSL (DLBCL, ABC type)","AIDS-related / post-transplant PCNSL (EBV-driven)","Primary vitreoretinal lymphoma","Primary leptomeningeal lymphoma"],"biomarkers":["MYD88 L265P and CD79B mutations (tissue and CSF ctDNA)","CSF cytology and flow cytometry","IL-10 in CSF/vitreous","MSKCC and IELSG prognostic scores (age, performance status)","Slit-lamp examination for ocular involvement"],"standardOfCare":[{"setting":"Newly diagnosed, fit (<65-70)","approach":"Rituximab + high-dose methotrexate + cytarabine ± thiotepa (MATRix) ×4, then high-dose thiotepa-based chemotherapy with autologous transplant (IELSG32, IELSG43).","refs":["methotrexate","rituximab","autologous-stem-cell-transplant","ielsg32","ielsg43"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: CNS Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Newly diagnosed, older/unfit","approach":"High-dose methotrexate with temozolomide, procarbazine or rituximab (e.g. MT-R, R-MP), then maintenance (temozolomide, lenalidomide) or reduced-dose WBRT; ibrutinib-based induction in trials.","refs":["methotrexate","temozolomide","rituximab","lenalidomide"],"guideline":{"version":"EANO/ESMO PCNSL guideline"}},{"setting":"Relapsed/refractory","approach":"Re-induction with methotrexate if durable first remission; ibrutinib, lenalidomide-rituximab, high-dose chemotherapy/ASCT if not done, WBRT; CD19 CAR-T and PD-1 inhibitors in trials or off-label.","refs":["ibrutinib","lenalidomide","axicabtagene-ciloleucel","nivolumab"]},{"setting":"Primary CNS lymphoma: why R-CHOP fails, and what is given instead","approach":"A diffuse large B-cell lymphoma confined to the brain, spinal cord, eyes or meninges. The drugs that cure it elsewhere do not reach it: cyclophosphamide, doxorubicin and vincristine cross the blood-brain barrier poorly, so R-CHOP produces responses in the body and not in the brain, and trials of it in this disease were abandoned decades ago. Surgery has no therapeutic role beyond biopsy, and debulking does not help. Corticosteroids shrink the tumour dramatically and dissolve the diagnostic material with it, so steroids are withheld until the biopsy is taken wherever the patient is stable enough to wait.\n\nInduction is built around high-dose methotrexate at 3 to 3.5 g per square metre or more, given with leucovorin rescue and urinary alkalinisation, every two to three weeks. MATRix adds cytarabine, thiotepa and rituximab: in the first randomisation of IELSG32 the complete remission rate was 49 per cent with MATRix against 23 per cent with methotrexate and cytarabine alone and 30 per cent with methotrexate, cytarabine and rituximab. Six per cent of patients died of toxicity, so it is for patients fit enough to take it. The contribution of rituximab itself is contested: HOVON 105 randomised it into a methotrexate-based regimen and did not show the benefit that IELSG32's arm B against arm A comparison suggested.","refs":["methotrexate","cytarabine","thiotepa","rituximab","cns-penetration","lymphoma-tx-regimen-alphabet","intrathecal-therapy","paper-ferreri-leukemia"],"guideline":{"version":"NCCN Central Nervous System Cancers; ESMO/EANO; IELSG32, HOVON 105","url":"https://www.cancer.gov/types/lymphoma/hp/primary-cns-lymphoma-treatment-pdq"}},{"setting":"Consolidation after methotrexate-based induction: transplant against whole-brain radiotherapy","approach":"Induction alone relapses, so responders are consolidated. The two options are thiotepa-based high-dose chemotherapy with an autologous stem cell transplant, or whole-brain radiotherapy, and the choice is dominated by what each does to thinking.\n\nMATRix/IELSG43 randomised consolidation in the largest trial ever run in this disease: three-year progression-free survival was 78 per cent (95 per cent confidence interval 69 to 85) with transplant against 51 per cent (41 to 60) with non-myeloablative R-DeVIC consolidation, hazard ratio 0.43, with overall survival also improved; the cost was more toxicity, a mean of 14.6 against 9.3 adverse events per patient and five against two fatal serious adverse events. In the earlier IELSG32 trial, whole-brain radiotherapy and autologous transplant were similarly effective, and at seven years the difference was cognitive: patients who had whole-brain radiotherapy lost attention and executive function, while those who had transplant improved in those domains, in memory and in quality of life. Seven-year overall survival was 21, 37 and 56 per cent for the three induction arms, and 70 per cent for patients who received MATRix and went on to consolidation.\n\nSo transplant is preferred for patients fit enough. Whole-brain radiotherapy is reserved for those who are not, usually at a reduced dose, and is increasingly deferred to relapse.","refs":["paper-matrix-ielsg43-asct-consolidation-pcnsl-illerhaus-lancet-2026","paper-ferreri-leukemia","autologous-stem-cell-transplant","thiotepa","carmustine","busulfan","lymphoma-tx-transplant-role","lymphoma-tx-radiotherapy","late-effects"],"guideline":{"version":"NCCN Central Nervous System Cancers; IELSG32 and IELSG43","url":"https://doi.org/10.1038/s41375-022-01582-5"}},{"setting":"Primary CNS lymphoma in older or less fit patients, and at relapse","approach":"Age is not by itself a reason to withhold methotrexate: reduced-intensity methotrexate-based combinations, usually with rituximab and an alkylating agent such as procarbazine or temozolomide, are given to patients in their seventies and eighties with attention to renal function, and produce durable remissions in a minority. Whole-brain radiotherapy in older patients carries a high risk of progressive cognitive decline and is generally avoided as first consolidation.\n\nAt relapse the options depend on the interval. Re-treatment with methotrexate is effective in patients who relapse late, and in the seven-year IELSG32 report it was the only salvage that clearly benefited anyone. Other options are high-dose cytarabine with thiotepa and transplant if not already given, whole-brain radiotherapy if not already given, ibrutinib, which crosses into the brain and has single-agent activity, lenalidomide with rituximab, temozolomide, and a clinical trial. Ocular involvement is treated with systemic therapy, often with intravitreal methotrexate or rituximab added.","refs":["methotrexate","rituximab","procarbazine","temozolomide","ibrutinib","lenalidomide","cytarabine","thiotepa","cns-penetration","lymphoma-tx-transplant-role","palliative-care"],"guideline":{"version":"NCCN Central Nervous System Cancers; IELSG32 seven-year report","url":"https://doi.org/10.1038/s41375-022-01582-5"}}],"stateOfArt":["Cure is possible: about half of fit patients treated with MATRix and autologous transplant are alive and disease-free at seven years (IELSG32).","Transplant consolidation has largely replaced whole-brain radiotherapy, avoiding its dementing neurotoxicity.","CSF ctDNA (MYD88 L265P) enables less invasive diagnosis and response monitoring.","BTK inhibition and CD19 CAR-T show CNS penetration and activity, though durability is limited outside transplant.","Primary CNS lymphoma sits almost entirely in one genetic subtype. MYD88 L265P and CD79B mutations co-occur here as they do in the MCD subtype of systemic large B-cell lymphoma and in primary testicular lymphoma, which is why the three are grouped together genetically despite sitting in different organs.","The practical consequence is a pathway that can be reached with a tablet that crosses into the brain: BTK inhibition has activity in this disease, and the mutations are the reason to expect it. No approval in Europe or the United States currently selects treatment on the genotype.","Loss of MHC class I and class II through 6p21 deletion is common, which is one reason this lymphoma survives in a site the immune system polices differently."],"history":[{"year":1980,"title":"High-dose methotrexate shown active in PCNSL","refs":["methotrexate"]},{"year":1992,"title":"Methotrexate before radiotherapy doubles survival (DeAngelis)","refs":["methotrexate"]},{"year":2010,"title":"G-PCNSL-SG-1: omitting WBRT does not shorten survival","note":"Sets the stage for radiation-free strategies.","refs":[]},{"year":2016,"title":"IELSG32: MATRix induction","note":"Adding rituximab and thiotepa to methotrexate-cytarabine improves response and survival.","refs":["rituximab","methotrexate"]},{"year":2017,"title":"Autologous transplant equals WBRT with less neurotoxicity","note":"IELSG32 second randomisation and PRECIS.","refs":["autologous-stem-cell-transplant"]},{"year":2017,"title":"Ibrutinib active in relapsed PCNSL","refs":["ibrutinib"]},{"year":2022,"title":"IELSG32 7-year update confirms cures","refs":["autologous-stem-cell-transplant"]}],"pipeline":["ibrutinib","axicabtagene-ciloleucel","lenalidomide","zamtocabtagene-autoleucel"],"openProblems":["Most patients are over 65 and cannot tolerate curative-intent therapy.","Neurocognitive decline from disease and therapy.","No randomised evidence for maintenance strategies.","Vitreoretinal lymphoma relapse and CNS spread."],"parent":"non-hodgkin-lymphoma"},{"id":"primary-cutaneous-anaplastic-large-cell-lymphoma","kind":"cancer","name":"Primary cutaneous anaplastic large cell lymphoma","aka":["Primary cutaneous ALCL","pcALCL","Primary cutaneous anaplastic large-cell lymphoma","Cutaneous anaplastic large cell lymphoma","Primary cutaneous CD30-positive T-cell lymphoproliferative disorder: primary cutaneous anaplastic large cell lymphoma"],"tldr":"A cutaneous T-cell lymphoma that appears as one or a few red-purple nodules on the skin, often ulcerated, which may shrink on their own. Despite cells that look alarming under the microscope it stays in the skin in almost everybody and is treated with surgery or local radiotherapy rather than chemotherapy.","summary":"What it is. A lymphoma of CD30-positive T cells that arises in the skin and stays there. It usually appears as a single firm red or violet nodule or tumour, often several centimetres across and often breaking down into an ulcer, on a limb, the trunk, the head or the neck. Sometimes there are a few nodules in one area. Up to a quarter of lesions shrink partly or completely without any treatment, which is unusual for a lymphoma and is shared with its relative lymphomatoid papulosis.\n\nHow it differs from the lymphoma it is named after. The cells look the same as those of systemic anaplastic large cell lymphoma and carry the same CD30, but the disease is a different thing: WHO-HAEM5 files it among the primary cutaneous T-cell lymphomas rather than with the systemic anaplastic lymphomas, explicitly acknowledging its relationship to the skin lymphomas and its highly favourable outcome in contrast to systemic ALK-negative disease. It does not carry ALK, and a skin tumour with the same appearance that does carry ALK is usually systemic disease that has reached the skin.\n\nHow it sits beside lymphomatoid papulosis. The two are ends of one spectrum of CD30-positive skin disease: lymphomatoid papulosis is small papules that come and go in crops, and this is larger, more persistent nodules. The same person can have both, and the same clone can be found in both. The distinction is made on the clinical picture over time, not on the biopsy, which is why the dermatologist's photographs and history matter as much as the pathology.\n\nWhat the outcome is. In the Stanford series of 56 patients with CD30-positive skin disease, disease-specific survival for this lymphoma was 85 per cent at both five and ten years. Localised and generalised skin disease behaved differently in that series, at 91 and 50 per cent five-year disease-specific survival, although with so few patients the difference was not statistically significant. Lesions recurred in 42 per cent, which is the usual course and is not a failure; three patients progressed beyond the skin.\n\nHow it is treated. Surgical excision or local radiotherapy for a single lesion or a few in one area, which is the great majority of patients. Low-dose methotrexate once a week for disease that keeps recurring in many places. Brentuximab vedotin for disease that is widespread or has spread beyond the skin: ALCANZA randomised patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large cell lymphoma to brentuximab vedotin or to the physician's choice of methotrexate or bexarotene, and the detail of that trial is on the cutaneous T-cell lymphoma page. Combination chemotherapy is reserved for disease outside the skin, because it produces short remissions and real harm in a disease that would otherwise be controlled for decades.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Anaplastic_large-cell_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"EORTC, ISCL and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma (Kempf, Blood 2011)","url":"https://doi.org/10.1182/blood-2011-05-351346"},{"label":"CD30-positive cutaneous lymphoproliferative disorders: the Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma, 56 patients (Liu, J Am Acad Dermatol 2003)","url":"https://doi.org/10.1016/S0190-9622(03)02484-8"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"}],"tags":["heme","lymphoma","subtype-page"],"related":["lymphomatoid-papulosis","cutaneous-t-cell-lymphoma","mycosis-fungoides","alk-negative-anaplastic-large-cell-lymphoma","sezary-syndrome"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","palliative-radiotherapy"],"targets":["cd30"],"drugs":["brentuximab-vedotin","methotrexate"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-classification-2022","lymphoma-tx-skin-directed-therapy","lymphoma-tx-radiotherapy","lymphoma-nodal-versus-extranodal","lymphoma-indolent-versus-aggressive"],"trials":["alcanza"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"In the United Kingdom population series that reports lymphoma by subtype, the primary cutaneous CD30-positive lymphoproliferative disorders, which group this disease with lymphomatoid papulosis, accounted for 37 of 5,796 lymphomas, a European age-standardised rate of 0.13 per 100,000 a year and a median age at diagnosis of 52.9 years, with five-year relative survival of 88.3 per cent. The European, American and international consensus group that writes the treatment recommendations describes the CD30-positive skin lymphomas as the second commonest form of cutaneous T-cell lymphoma after mycosis fungoides.","subtypes":[],"biomarkers":["CD30 on more than three-quarters of the large cells, which defines the group","Absence of ALK; an ALK-positive skin tumour is usually systemic disease that has reached the skin","Staging to confirm there is no disease outside the skin, which changes both the diagnosis and the treatment","A clonal T-cell receptor rearrangement, which may be shared with coexisting lymphomatoid papulosis","Whether the skin disease is localised or widespread, which the consensus recommendations use to choose treatment"],"standardOfCare":[{"setting":"Confirming it is confined to the skin","approach":"The diagnosis cannot be made on the biopsy alone, because the cells look identical to those of systemic anaplastic large cell lymphoma. It requires staging that shows no disease outside the skin, and a clinical history: how long the lesion has been there, whether others have come and gone, and whether the person has lymphomatoid papulosis or mycosis fungoides, which coexist with it. An ALK-positive skin tumour is usually systemic disease that has reached the skin, and is staged and treated as such.","refs":["histopathology-ihc","cd30","fdg-pet","lymphomatoid-papulosis","lugano-classification"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"A single lesion or a few in one area, which is most patients","approach":"Surgical excision or local radiotherapy. Both work; the choice is made on the site, the size and what will heal well. Lesions recur in a substantial proportion of patients, 42 per cent in the Stanford series, and recurrence in the skin is expected rather than a treatment failure: it is treated the same way again. Up to a quarter of lesions regress partly or completely without any treatment, so observing a lesion that is already shrinking is reasonable.","refs":["palliative-radiotherapy","lymphoma-tx-skin-directed-therapy","lymphoma-tx-radiotherapy"],"guideline":{"version":"EORTC, ISCL and USCLC consensus recommendations for primary cutaneous CD30-positive lymphoproliferative disorders (Blood 2011)","url":"https://doi.org/10.1182/blood-2011-05-351346"}},{"setting":"Widespread skin disease, or disease beyond the skin","approach":"Low-dose weekly methotrexate for disease that keeps recurring in many places. Brentuximab vedotin for widespread or extracutaneous disease: ALCANZA randomised patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large cell lymphoma to brentuximab vedotin against the physician's choice of methotrexate or bexarotene, and the figures are on the cutaneous T-cell lymphoma page. Combination chemotherapy is reserved for disease outside the skin: it produces short remissions and real harm in a disease otherwise controlled for decades, and over-treatment is the commonest avoidable harm here.","refs":["methotrexate","brentuximab-vedotin","alcanza","cutaneous-t-cell-lymphoma","lymphoma-tx-skin-directed-therapy"],"guideline":{"version":"EORTC, ISCL and USCLC consensus recommendations (Blood 2011); NCCN Primary Cutaneous Lymphomas","url":"https://doi.org/10.1182/blood-2011-05-351346"}}],"stateOfArt":[],"history":[{"year":2003,"title":"The Stanford series","note":"Fifty-six patients with CD30-positive skin lymphoproliferative disorders: disease-specific survival for primary cutaneous anaplastic large cell lymphoma was 85 per cent at five and ten years, lesions recurred in 42 per cent, and three patients progressed beyond the skin.","refs":[]},{"year":2011,"title":"International consensus recommendations","note":"A panel from the EORTC, the International Society for Cutaneous Lymphomas and the United States Cutaneous Lymphoma Consortium set out treatment recommendations for the CD30-positive skin lymphoproliferative disorders and noted that most published evidence is small retrospective series.","refs":["brentuximab-vedotin"]},{"year":2022,"title":"Filed with the skin lymphomas, not the systemic ones","note":"WHO-HAEM5 groups primary cutaneous anaplastic large cell lymphoma under the primary cutaneous T-cell lymphomas, acknowledging its relationship to them and its favourable outcome in contrast to systemic ALK-negative disease.","refs":["lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["The consensus recommendations that govern treatment state that most of the evidence behind them is small retrospective series and case reports, and that very few prospective or multicentre studies exist.","The line between this disease and lymphomatoid papulosis is drawn on the clinical course rather than on the biopsy, and in a person who has both there is no test that settles which lesion is which.","Over-treatment is the commonest harm: combination chemotherapy for skin-limited disease produces short remissions in a condition that is otherwise controlled for decades."],"parent":"cutaneous-t-cell-lymphoma"},{"id":"primary-cutaneous-follicle-centre-lymphoma","kind":"cancer","name":"Primary cutaneous follicle centre lymphoma","aka":["Primary cutaneous follicular lymphoma","Primary cutaneous follicle center lymphoma","PCFCL","Crosti lymphoma","Reticulohistiocytoma of the dorsum"],"tldr":"Primary cutaneous follicle centre lymphoma is a slow-growing lymphoma of germinal-centre B cells that stays in the skin, usually as lumps on the head or trunk. Its outlook is excellent, with about 95 in 100 people alive at five years, and radiotherapy or excision is usually all that is needed; the important thing is not to mistake it for the aggressive leg-type large B-cell lymphoma.","summary":"WHO-HAEM5 lists primary cutaneous follicle centre lymphoma among the cutaneous B-cell lymphomas as a distinct entity from follicular lymphoma, defined by follicle centre cells in the skin with no extracutaneous disease at staging (Alaggio 2022). It has a five-year overall survival of about 95 percent against about 50 percent for primary cutaneous large B-cell lymphoma, leg type, and the two are separated in practice by IgM staining, present in all 40 leg-type cases and only 5 of 53 follicle centre cases in the defining study (Am J Surg Pathol 2010). Its molecular landscape differs from classic follicular lymphoma: 27 percent lack CD10 but all express MEF2B and HGAL, TNFRSF14 is the most commonly mutated gene (40 percent, with a further 10 percent carrying 1p36 deletions), followed by CREBBP, TNFAIP3, KMT2D, SOCS1, EP300, STAT6 and FOXO1, and BCL2 rearrangements are usually absent (Human Pathology 2020).\n\nHow it differs from its parent: it is skin-confined, rarely carries the t(14;18) that defines nodal follicular lymphoma, is not graded or staged as follicular lymphoma is, and is cured locally in most cases; the parent's chemoimmunotherapy is reserved for the rare disseminated case.\n\nHow common: no registry share in the sources read.\n\nTreatment: local radiotherapy or excision for solitary or localised lesions; rituximab for multifocal skin disease; the parent's systemic pathways only for extracutaneous spread; skin relapses are common and treated locally again (Am J Surg Pathol 2010 for the survival figures).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Primary_cutaneous_follicle_center_lymphoma","links":[{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq"},{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"Am J Surg Pathol 2010: IgM distinguishes primary cutaneous large B-cell lymphoma, leg type from follicle centre lymphoma","url":"https://doi.org/10.1097/pas.0b013e3181e5060a"},{"label":"Human Pathology 2020: molecular landscape of primary cutaneous follicle centre lymphoma","url":"https://doi.org/10.1016/j.humpath.2020.09.014"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["follicular-lymphoma","primary-cutaneous-marginal-zone-lymphoma","dlbcl","cutaneous-t-cell-lymphoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["rituximab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare; the largest series in the sources read hold 53 patients (Am J Surg Pathol 2010) and 22 (Human Pathology 2020). Five-year overall survival is about 95 percent (Am J Surg Pathol 2010). No registry share is in the sources read.","subtypes":["Primary cutaneous follicle centre lymphoma, follicular growth pattern","Primary cutaneous follicle centre lymphoma, diffuse growth pattern (large centrocytes; still indolent)","Primary cutaneous follicle centre lymphoma of the leg (must be separated from leg-type large B-cell lymphoma)"],"biomarkers":["BCL6 positive; CD10 variable; MEF2B and HGAL positive","IgM negative (positive in leg-type large B-cell lymphoma)","TNFRSF14 mutation or 1p36 deletion","Usually no BCL2 rearrangement"],"standardOfCare":[{"setting":"Solitary or localised","approach":"Local radiotherapy or excision.","refs":["follicular-lymphoma"]},{"setting":"Multifocal or extracutaneous","approach":"Rituximab for multifocal skin disease; the parent's systemic pathways for the rare extracutaneous spread.","refs":["rituximab","follicular-lymphoma"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"follicular-lymphoma"},{"id":"primary-cutaneous-marginal-zone-lymphoma","kind":"cancer","name":"Primary cutaneous marginal zone lymphoma","aka":["Primary cutaneous marginal zone B-cell lymphoma","Primary cutaneous marginal zone lymphoproliferative disorder","Primary cutaneous immunocytoma","Cutaneous immunocytoma","PCMZL"],"tldr":"Primary cutaneous marginal zone lymphoma is a very slow-growing lymphoma that appears as pink or purple lumps in the skin, usually on the arms or trunk, and almost never spreads inside the body. WHO-HAEM5 now calls it a lymphoproliferative disorder because it behaves so well; surgery or radiotherapy clears most lesions, and relapses in the skin are common but harmless.","summary":"WHO-HAEM5 renamed this entity primary cutaneous marginal zone lymphoproliferative disorder to reflect its indolent behaviour, keeping it beside the other marginal zone lymphomas; it was once called immunocytoma because of its plasmacytic differentiation (Alaggio 2022). In 137 patients, 51 percent had a solitary lesion, 29 percent regional and 20 percent generalised skin disease; surgical excision, local radiotherapy or both were the initial treatment in 86 percent, complete remission followed in 88 percent (93 percent of solitary or localised and 71 percent of multifocal cases), and cutaneous relapses occurred in 44 percent without loss of survival (J Am Acad Dermatol 2013). Unlike other marginal zone lymphomas, 39 percent of primary cutaneous cases with plasmacytic differentiation express IgG4, the highest rate in any B-cell lymphoma, against 1 of 120 non-cutaneous cases (Modern Pathology 2013).\n\nHow it differs from its parent: it is confined to the skin at diagnosis, is treated by dermatologists with excision or radiotherapy rather than systemic therapy, and its relapses are skin-only; extracutaneous spread is the exception. Borrelia infection has been implicated in some European cases.\n\nHow common: no registry share in the sources read.\n\nTreatment: excision or low-dose radiotherapy for solitary or localised lesions; observation, intralesional steroids or rituximab for multifocal disease; systemic therapy only for the rare extracutaneous spread, following the parent page (J Am Acad Dermatol 2013; Zucca 2020).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Primary_cutaneous_marginal_zone_lymphoma","links":[{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"J Am Acad Dermatol 2013: primary cutaneous marginal zone B-cell lymphoma, 137 patients","url":"https://doi.org/10.1016/j.jaad.2013.04.047"},{"label":"Modern Pathology 2013: IgG4 expression in primary cutaneous marginal zone lymphomas","url":"https://doi.org/10.1038/modpathol.2013.106"},{"label":"Zucca 2020, Annals of Oncology: marginal zone lymphomas, ESMO clinical practice guidelines","url":"https://doi.org/10.1016/j.annonc.2019.10.010"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["marginal-zone-lymphoma","malt-lymphoma","primary-cutaneous-follicle-centre-lymphoma","cutaneous-t-cell-lymphoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["rituximab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare and indolent; the largest clinical series holds 137 patients, 51 percent presenting with a solitary lesion (J Am Acad Dermatol 2013). No registry share is in the sources read.","subtypes":["Primary cutaneous marginal zone lymphoproliferative disorder, solitary lesion (half of cases)","Multifocal or generalised cutaneous disease","Class-switched (IgG4-expressing) cutaneous marginal zone lymphoma","Borrelia-associated cutaneous marginal zone lymphoma (Europe)"],"biomarkers":["Plasmacytic differentiation with light chain restriction","IgG4 expression (39 percent)","Staging to exclude extracutaneous disease","Borrelia serology in endemic areas"],"standardOfCare":[{"setting":"Solitary or localised","approach":"Excision or low-dose radiotherapy.","refs":["marginal-zone-lymphoma"]},{"setting":"Multifocal","approach":"Observation, intralesional steroids or rituximab; systemic therapy only for extracutaneous spread.","refs":["rituximab","marginal-zone-lymphoma"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"marginal-zone-lymphoma"},{"id":"primary-effusion-lymphoma","kind":"cancer","name":"Primary effusion lymphoma","aka":["PEL","Body cavity-based lymphoma","Extracavitary primary effusion lymphoma","KSHV/HHV8-associated lymphoma","HHV8-positive primary effusion lymphoma"],"tldr":"A rare lymphoma that grows as fluid rather than as a lump: it fills the space around the lungs, the heart or the bowel without forming a mass. It is caused by Kaposi sarcoma herpesvirus and arises mostly in people with advanced HIV infection, and it is diagnosed by sending the fluid itself for testing.","summary":"What it is. A large B-cell lymphoma driven by Kaposi sarcoma herpesvirus, also called human herpesvirus 8, the same virus that causes Kaposi sarcoma. The lymphoma cells float free in a body cavity and produce fluid: a pleural effusion around the lung, a pericardial effusion around the heart, or ascites in the abdomen. Classically there is no tumour mass at all, which is why the diagnosis is made on the fluid.\n\nHow it differs from the lymphomas around it. WHO-HAEM5 groups it in a family of conditions caused by the same virus: multicentric Castleman disease, germinotropic lymphoproliferative disorder, primary effusion lymphoma, its extracavitary form, and KSHV/HHV8-positive diffuse large B-cell lymphoma. The classification acknowledges that the boundaries between them are not clean, that individual patients overlap, and that difficult cases should be settled in a multidisciplinary meeting rather than by rule. In particular, telling a lymph node-based extracavitary primary effusion lymphoma from a KSHV/HHV8-positive diffuse large B-cell lymphoma can be arbitrary; the International Consensus Classification prefers the latter diagnosis where Epstein-Barr virus is negative and the tumour expresses IgM lambda.\n\nThe lymphoma it is most often confused with, and the 2022 change that separates them. There is a second disease that also presents as lymphoma confined to a body cavity, in older people without immune deficiency who have heart failure, kidney failure or cirrhosis causing fluid to accumulate. It is not caused by Kaposi sarcoma herpesvirus, its cells look like ordinary mature B cells rather than plasmablasts, and it behaves considerably better. WHO-HAEM5 made it a separate entity in 2022, calling it fluid overload-associated large B-cell lymphoma; the International Consensus Classification calls it primary effusion-based lymphoma that is negative for both viruses, and lists it as provisional. Distinguishing the two matters because the outlook is different.\n\nWho gets it. Most often a person with advanced, often undiagnosed, HIV infection; it also occurs after organ transplant and in older people from regions where Kaposi sarcoma herpesvirus is common, including parts of the Mediterranean and sub-Saharan Africa. In people with HIV the tumour usually carries Epstein-Barr virus as well; in older HIV-negative people it usually does not.\n\nHow it is diagnosed and treated. The fluid is drained and sent for cell counts, cytology, flow cytometry and immunohistochemistry or in situ hybridisation for the virus. The cells are large and plasmablastic, usually lacking the B-cell markers (CD20 is typically negative) and carrying plasma cell markers instead, which is why anti-CD20 antibodies have no role. Treatment is combination chemotherapy together with full antiretroviral therapy where there is HIV; the regimens, which have never been compared in a randomised trial, sit in the treatment layer of this family and on the HIV-associated lymphoma page.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Primary_effusion_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"Trends in incidence and survival of patients with primary effusion lymphoma in the United States, a population-based cohort study of 236 patients (Hematological Oncology 2026)","url":"https://doi.org/10.1002/hon.70168"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["hiv-associated-lymphoma","dlbcl","plasmablastic-lymphoma","non-hodgkin-lymphoma","kaposi-sarcoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["hhv8-kshv","ebv-term","lymphoma-classification-2022","lymphoma-nodal-versus-extranodal","oncogenic-viruses"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"In the United States, 236 adults were recorded in the SEER registries between 2001 and 2021, with a median age of 51 years and 88 per cent of them men. The age-adjusted incidence rose from 1.0 to 1.6 cases per ten million person-years between the first and second halves of that period. Five-year relative survival improved from 21 to 37 per cent across the same two periods, and median overall survival from 4 to 12 months, which the authors attribute to advances in both lymphoma treatment and HIV care.","subtypes":["Classic primary effusion lymphoma, confined to a body cavity, which is an extranodal site with no mass","Extracavitary primary effusion lymphoma, which forms a mass with the same biology"],"biomarkers":["Kaposi sarcoma herpesvirus (human herpesvirus 8) in the tumour nuclei, by immunohistochemistry for the latency-associated nuclear antigen; this is the diagnosis","Epstein-Barr virus, usually positive in people with HIV and usually negative in older people without","A plasmablastic phenotype: CD45 positive, CD20 and CD79a usually negative, CD138 and MUM1 positive","HIV status, which changes the whole of the management","Absence of the virus, which moves the diagnosis to fluid overload-associated large B-cell lymphoma and changes the outlook"],"standardOfCare":[{"setting":"Making the diagnosis on the fluid","approach":"The effusion is drained and sent, fresh, for cytology, flow cytometry and immunohistochemistry. The diagnosis requires the Kaposi sarcoma herpesvirus latency-associated nuclear antigen in the tumour nuclei. A cavity lymphoma without the virus is a different disease, recognised separately in 2022, that arises in fluid overload from heart failure, kidney failure or cirrhosis and behaves better. HIV testing is part of the work-up in every case.","refs":["hhv8-kshv","ebv-term","histopathology-ihc","lymphoma-classification-2022"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Treatment","approach":"Combination chemotherapy, with antiretroviral therapy started or optimised at the same time where there is HIV, because controlling the HIV is part of controlling the lymphoma. Anti-CD20 antibodies have no role: the cells do not carry CD20. There has never been a randomised trial in this entity and the regimens come from series and from the HIV-associated lymphoma literature; they sit in the treatment layer of this family and on the HIV-associated lymphoma page. Entry into a trial is a reasonable first choice rather than a last resort.","refs":["hiv-associated-lymphoma","cyclophosphamide","doxorubicin","etoposide","lymphoma-tx-regimen-alphabet"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":1995,"title":"Kaposi sarcoma herpesvirus found in body cavity lymphomas","note":"The virus discovered in Kaposi sarcoma the year before was found in a group of lymphomas that grew in body cavities without forming a mass, which defined the disease.","refs":[]},{"year":2022,"title":"Separated from the lymphoma it most resembles","note":"WHO-HAEM5 made fluid overload-associated large B-cell lymphoma a separate entity: the same presentation in an older person with heart, kidney or liver failure, without the virus, with a mature B-cell rather than plasmablastic phenotype, and with a better outlook.","refs":["lymphoma-classification-2022"]},{"year":2026,"title":"A population picture, and survival that has improved","note":"Across 236 United States patients diagnosed between 2001 and 2021, five-year relative survival rose from 21 to 37 per cent and median overall survival from 4 to 12 months between the first and second halves of the period.","refs":["hiv-associated-lymphoma"]}],"pipeline":[],"openProblems":["There has never been a randomised trial in primary effusion lymphoma, and median overall survival in the most recent population series was 12 months.","The boundaries between the conditions caused by Kaposi sarcoma herpesvirus are acknowledged by the classification itself to be unclear, and individual patients overlap between them.","The commonest route to this diagnosis is advanced, undiagnosed HIV infection, which is a failure of testing rather than of oncology."],"parent":"non-hodgkin-lymphoma"},{"id":"primary-testicular-lymphoma","kind":"cancer","name":"Primary large B-cell lymphoma of the testis","aka":["Primary testicular lymphoma","PTL","Primary testicular diffuse large B-cell lymphoma","Testicular lymphoma","Primary diffuse large B-cell lymphoma of the testis","Primary large B-cell lymphoma of immune-privileged sites"],"tldr":"A large B-cell lymphoma that starts in a testicle rather than in a lymph node, usually in a man over 60, and shows itself as a painless swelling. It is the commonest cancer of the testicle in older men, and it behaves as one disease with lymphoma of the brain and of the eye, which is why treatment deliberately protects both.","summary":"What it is. A diffuse large B-cell lymphoma arising inside a testicle. It presents as a firm, usually painless swelling, and it is the commonest malignant tumour of the testis in men over 60, an age at which the germ cell tumours of younger men have become rare. The diagnosis is usually made on the testicle after it has been removed, because a solid testicular mass is removed rather than biopsied.\n\nHow it differs from its family, and this is the whole of the management. The testis is an immune-privileged site: a barrier of cells keeps the immune system out, which protects developing sperm from being attacked and also shelters a lymphoma from immune surveillance and from many drugs. The brain and the inside of the eye are protected in the same way. WHO-HAEM5 recognised in 2022 that large B-cell lymphomas at those three sites are one entity, which it called primary large B-cell lymphoma of immune-privileged sites, because they share an activated B-cell phenotype, concurrent MYD88 and CD79B mutations, loss of the machinery that displays antigen to the immune system, and a habit of relapsing in each other: a testicular lymphoma comes back in the brain or in the other testicle, and a lymphoma of the eye follows or precedes one in the brain.\n\nWhere the two classifications disagree. The International Consensus Classification discussed the same grouping and decided it was premature, on the grounds that lymphomas at some of those sites are heterogeneous and that a pathologist often does not know whether other sites are involved. It nevertheless recognises primary diffuse large B-cell lymphoma of the testis as a specific entity in its own right, closely related to lymphoma of the central nervous system and sharing the same genetic subgroup. So the two books agree about the biology and differ about the filing.\n\nHow it is treated, and why three things are done at once. The trial that set the standard, IELSG-10, treated 53 men with stage I or II disease with six to eight cycles of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone, four doses of methotrexate into the spinal fluid, and 30 Gy of radiotherapy to the remaining testicle, with the regional lymph nodes irradiated in stage II. At a median follow-up of 65 months, five-year progression-free survival was 74 per cent and overall survival 85 per cent. Ten patients relapsed, three of them in the central nervous system, giving a five-year cumulative incidence of relapse in the brain or spinal cord of 6 per cent. No patient relapsed in the remaining testicle. Those last two numbers are the reason the regimen looks the way it does.\n\nWhat is still unsettled. Irradiating the remaining testicle prevents relapse there but causes infertility and low testosterone, which matters to a minority of men who are diagnosed young. Whether methotrexate into the spinal fluid is the right prophylaxis against disease in the brain, or whether high-dose intravenous methotrexate would do better, has not been settled by a randomised trial. In the SEER analysis covering 1980 to 2005, survival in testicular lymphoma did not improve after rituximab came into use in the way it did in lymphoma of the lymph nodes, which the authors noted explicitly.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Primary_testicular_diffuse_large_B-cell_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, central nervous system prophylaxis and contralateral testis irradiation, IELSG-10 (Vitolo, J Clin Oncol 2011)","url":"https://doi.org/10.1200/JCO.2010.31.4187"},{"label":"Primary testicular diffuse large B-cell lymphoma, a population-based study of 769 patients on incidence, natural history and survival (Gundrum, J Clin Oncol 2009)","url":"https://doi.org/10.1200/JCO.2009.22.5896"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["primary-cns-lymphoma","dlbcl","testicular","non-hodgkin-lymphoma","intravascular-large-b-cell-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","fdg-pet","imrt-igrt"],"targets":[],"drugs":["rituximab","methotrexate"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-nodal-versus-extranodal","lymphoma-classification-2022","lymphoma-tx-cns-prophylaxis","lymphoma-tx-fertility-preservation","myd88-l265p","ipi-score"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"In the United States SEER registries, 769 men with primary testicular diffuse large B-cell lymphoma were identified between 1980 and 2005, with a median age at diagnosis of 68.0 years and an incidence that rose over the period; a later SEER analysis identified 1,169 patients between 1973 and 2013, median age 70 years, of whom 82.9 per cent had diffuse large B-cell lymphoma and 68.6 per cent had stage I or II disease at diagnosis. The corpus does not quote a United Kingdom incidence figure, because no source it could verify publishes one for this entity.","subtypes":[],"biomarkers":["An activated B-cell (non-germinal-centre) phenotype: CD10 negative, MUM1 positive, BCL6 positive","Concurrent MYD88 and CD79B mutations, the genetic signature shared with lymphoma of the brain and of the eye","Loss of MHC class I and II and of beta-2-microglobulin, which is how the tumour escapes immune recognition","Epstein-Barr virus, which is characteristically negative","Imaging of the brain and examination of the spinal fluid at diagnosis, because the central nervous system is where this disease relapses"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"A solid testicular mass is removed through the groin rather than biopsied, so the diagnosis is usually made on the removed testicle. Staging then has to cover the sites this disease travels to: computed tomography or PET-CT of the body, imaging of the brain, examination of the spinal fluid, and examination of the remaining testicle. Sperm banking is discussed before treatment where it is relevant, because radiotherapy to the remaining testicle causes infertility and low testosterone.","refs":["fdg-pet","lymphoma-tx-fertility-preservation","lugano-classification","histopathology-ihc"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"First-line treatment of stage I and II disease","approach":"Rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone for six to eight cycles, methotrexate into the spinal fluid, and radiotherapy to the remaining testicle. In IELSG-10, which treated 53 men this way, five-year progression-free survival was 74 per cent and overall survival 85 per cent at a median follow-up of 65 months; the five-year cumulative incidence of relapse in the central nervous system was 6 per cent and there were no relapses in the irradiated testicle. Grade 3 or 4 neutropenia occurred in 28 per cent and infection in 4 per cent.","refs":["rituximab","cyclophosphamide","doxorubicin","vincristine","prednisone","methotrexate","intrathecal-therapy","imrt-igrt","lymphoma-tx-cns-prophylaxis"],"guideline":{"version":"IELSG-10 (J Clin Oncol 2011); NCI PDQ adult non-Hodgkin lymphoma treatment","url":"https://doi.org/10.1200/JCO.2010.31.4187"}},{"setting":"What happens at relapse","approach":"Relapse is most often in the central nervous system, and it is treated on the pathway for lymphoma of the brain rather than on the pathway for nodal lymphoma: regimens built around high-dose methotrexate that crosses into the brain, and consideration of high-dose therapy with an autologous stem cell transplant using a conditioning regimen that also reaches the brain. The detail is on the primary central nervous system lymphoma page.","refs":["primary-cns-lymphoma","methotrexate","autologous-stem-cell-transplant","lymphoma-tx-transplant-role"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":2009,"title":"A population picture, and a gain that did not arrive","note":"Across 769 men in the SEER registries diagnosed between 1980 and 2005, median overall survival was 4.6 years and disease-specific survival was 71.5 per cent at three years, 62.4 per cent at five and 43.0 per cent at fifteen. Unlike nodal diffuse large B-cell lymphoma, disease-specific survival did not improve after the year 2000, when rituximab came into use.","refs":["rituximab"]},{"year":2011,"title":"IELSG-10 sets the standard","note":"Fifty-three men with stage I or II disease treated with rituximab-containing chemotherapy, methotrexate into the spinal fluid and radiotherapy to the remaining testicle: five-year progression-free survival 74 per cent, overall survival 85 per cent, no relapse in the irradiated testicle and a 6 per cent five-year risk of relapse in the central nervous system.","refs":["rituximab","methotrexate"]},{"year":2022,"title":"Grouped with lymphoma of the brain and the eye, by one classification of two","note":"WHO-HAEM5 created primary large B-cell lymphoma of immune-privileged sites, covering the central nervous system, the vitreoretina and the testis. The International Consensus Classification judged the grouping premature but recognised testicular lymphoma as an entity closely related to the central nervous system disease.","refs":["primary-cns-lymphoma","lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["Radiotherapy to the remaining testicle prevents relapse there and causes permanent infertility and low testosterone. Nobody has tested whether it can be omitted in men who receive modern systemic treatment.","The best way to protect the brain is not known. IELSG-10 used methotrexate into the spinal fluid; high-dose intravenous methotrexate reaches the brain tissue better and has not been compared against it in a randomised trial.","Survival in this disease did not improve after rituximab came into use in the way it did for lymphoma of the lymph nodes, and the reason is not established."],"parent":"non-hodgkin-lymphoma"},{"id":"primary-mediastinal-b-cell-lymphoma","kind":"cancer","name":"Primary mediastinal (thymic) large B-cell lymphoma","aka":["PMBCL","PMBL","Primary mediastinal large B-cell lymphoma","Thymic large B-cell lymphoma","Mediastinal grey zone lymphoma (related)"],"tldr":"Primary mediastinal B-cell lymphoma is a fast-growing lymphoma of the thymus behind the breastbone that mostly affects young women. Immunochemotherapy cures about nine in ten, radiotherapy can now be skipped when the end-of-treatment scan is clear, and PD-1 antibodies and CAR-T cells rescue many of those who relapse.","summary":"Primary mediastinal large B-cell lymphoma is a distinct entity in the WHO classification, arising from thymic medullary B cells and sharing biology with nodular sclerosis classical Hodgkin lymphoma: gains and rearrangements of 9p24.1 (PD-L1, PD-L2, JAK2), CIITA rearrangements with loss of MHC class II, JAK-STAT and NF-kappa-B activation, and weak CD30 expression. It expresses CD20, CD23 and MAL, typically lacks surface immunoglobulin, and presents as a bulky anterior mediastinal mass in patients with a median age around 35, with local spread to lung, pleura and pericardium but rarely to marrow. Mediastinal grey zone lymphoma sits between it and Hodgkin lymphoma.\n\nFirst-line treatment is rituximab-based immunochemotherapy. The National Cancer Institute series of dose-adjusted EPOCH-R (Dunleavy, NEJM 2013) treated 51 patients without radiotherapy with event-free survival of 93 percent and overall survival of 97 percent, and DA-EPOCH-R became the regimen that lets young patients avoid mediastinal radiotherapy; R-CHOP with consolidation radiotherapy is the alternative. The IELSG37 trial (2024) randomised patients in complete metabolic response on end-of-treatment PET to radiotherapy or observation and showed no loss of disease control without radiotherapy (30-month progression-free survival 96.7 versus 98.5 percent), so PET now decides who is irradiated and most patients are spared the heart and breast cancer risks of chest radiotherapy.\n\nRelapsed or refractory disease, about 10 to 15 percent of patients, is treated with salvage chemotherapy and autologous transplant when chemosensitive, and the 9p24.1 lesion makes it one of the most immunotherapy-sensitive B-cell lymphomas: pembrolizumab produced a 45 percent response rate in KEYNOTE-170 and was approved in June 2018, the first drug licensed specifically for this lymphoma; nivolumab plus brentuximab vedotin gave a 73 percent response rate in CheckMate 436; and the CD19 CAR-T products axicabtagene ciloleucel and lisocabtagene maraleucel are licensed for large B-cell lymphoma including primary mediastinal disease. Open questions are how to identify the few patients who fail first-line therapy early, whether checkpoint blockade belongs in first line, and how to reduce the late effects of anthracycline and radiotherapy in survivors who are mostly in their thirties.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Primary_mediastinal_B-cell_lymphoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Primary_mediastinal_B-cell_lymphoma"},{"label":"NCCN Guidelines: B-Cell Lymphomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1480"}],"tags":["subtype-page"],"related":["dlbcl","burkitt-lymphoma","primary-cns-lymphoma","hiv-associated-lymphoma","pd-ligand-9p24-alteration"],"cancers":[],"sections":[],"technologies":["fdg-pet","pet-adapted-therapy","checkpoint-inhibitor","car-t","autologous-stem-cell-transplant","adc","imrt-igrt","ctdna-lymphoma-monitoring","cytogenetics-fish","histopathology-ihc"],"targets":["cd20","cd30","cd19","pd1","pdl1","jak2","cd79b","ciita","socs1","stat6"],"drugs":["rituximab","doxorubicin","cyclophosphamide","etoposide","vincristine","prednisone","pembrolizumab","nivolumab","brentuximab-vedotin","axicabtagene-ciloleucel","lisocabtagene-maraleucel"],"companies":[],"institutions":[],"pathways":["pd1-checkpoint","jak-stat","antigen-presentation-immunoediting"],"terms":["r-chop","lugano-classification","deauville-score","autologous-transplant","crs","icans","lymphoma-tx-radiotherapy","lymphoma-tx-car-t-pathway","lymphoma-tx-fertility-preservation","lymphoma-tx-hodgkin-late-effects","lymphoma-tx-regimen-alphabet","lymphoma-bio-hodgkin-microenvironment","deauville"],"trials":["keynote-170","ielsg37","zuma-7","transform","zuma-1"],"people":["wyndham-wilson"],"bottlenecks":[],"keyPapers":["paper-who-2022-lymphoid-alaggio-leukemia-2022","paper-dunleavy-da-epoch-r-pmbcl-nejm-2013","paper-ielsg37-pmbcl-martelli-jco-2024","paper-keynote-170-pembrolizumab-pmbcl-armand-jco-2019"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About 2 to 4 percent of non-Hodgkin lymphomas, arising from thymic B cells in young adults, mostly women in their thirties, who present with a bulky anterior chest mass, cough, superior vena cava obstruction or breathlessness; most are cured with first-line immunochemotherapy.","subtypes":["Classic primary mediastinal B-cell lymphoma (young adults, anterior mediastinal mass, 9p24.1 gain)","Mediastinal grey zone lymphoma (features between primary mediastinal B-cell lymphoma and nodular sclerosis classical Hodgkin lymphoma)","Relapsed or refractory primary mediastinal B-cell lymphoma (PD-1 blockade, CAR-T, autologous transplant)"],"biomarkers":["CD20, CD23, MAL and weak or partial CD30 expression","9p24.1 gain or amplification (PD-L1, PD-L2, JAK2)","CIITA rearrangement and loss of MHC class II","End-of-treatment FDG PET (Deauville score) to decide on radiotherapy","Circulating tumour DNA for response monitoring (under study)"],"standardOfCare":[{"setting":"First line","approach":"Dose-adjusted EPOCH-R for six cycles without radiotherapy, or R-CHOP for six cycles with PET-guided consolidation radiotherapy; end-of-treatment PET decides whether radiotherapy is needed (IELSG37).","refs":["rituximab","doxorubicin","cyclophosphamide","etoposide","vincristine","prednisone","r-chop","fdg-pet","pet-adapted-therapy","ielsg37"],"guideline":{"version":"NCCN Guidelines: B-Cell Lymphomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1480"}},{"setting":"Residual PET-positive disease after immunochemotherapy","approach":"Biopsy where feasible; involved-site radiotherapy to the mediastinum (30 to 36 Gy) for persistent uptake; salvage therapy for proven refractory disease.","refs":["imrt-igrt","proton-therapy","fdg-pet","deauville-score"],"guideline":{"version":"NCCN Guidelines: B-Cell Lymphomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1480"}},{"setting":"Relapsed or refractory","approach":"Salvage chemotherapy then autologous stem cell transplant if chemosensitive; pembrolizumab (KEYNOTE-170) or nivolumab plus brentuximab vedotin; CD19 CAR-T (axicabtagene ciloleucel, lisocabtagene maraleucel) after two lines or as second line for early relapse.","refs":["autologous-stem-cell-transplant","pembrolizumab","keynote-170","nivolumab","brentuximab-vedotin","axicabtagene-ciloleucel","lisocabtagene-maraleucel","car-t"],"guideline":{"version":"NCCN Guidelines: B-Cell Lymphomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1480"}},{"setting":"Primary mediastinal B-cell lymphoma: which first-line regimen, and why radiotherapy is now usually avoided","approach":"A disease of young adults, more often women, presenting with a bulky mass between the lungs that can compress the superior vena cava. It is biologically closer to Hodgkin lymphoma than to diffuse large B-cell lymphoma, which is why PD-1 blockade works in it.\n\nDose-adjusted EPOCH-R for six cycles is the regimen most used in the United States, on the strength of a National Cancer Institute series in which five-year event-free survival was 93 per cent and overall survival 97 per cent, with radiotherapy avoided in 96 per cent of patients. R-CHOP with consolidation radiotherapy is the alternative used in much of Europe. There has never been a randomised comparison of the two.\n\nWhat has been settled is the radiotherapy. IELSG37 randomised patients with a negative end-of-treatment PET to mediastinal radiotherapy or observation: 30-month progression-free survival was 96.2 per cent with observation against 98.5 per cent with radiotherapy, non-inferior, and overall survival was 99 per cent in both arms. Since the patients are young and the field sits over the heart and breasts, avoiding it matters for the next forty years. Radiotherapy is still given where the end-of-treatment PET is positive.","refs":["paper-dunleavy-da-epoch-r-pmbcl-nejm-2013","paper-ielsg37-pmbcl-martelli-jco-2024","r-chop","rituximab","etoposide","doxorubicin","cyclophosphamide","vincristine","prednisone","fdg-pet","deauville","lymphoma-tx-radiotherapy","lymphoma-tx-hodgkin-late-effects","lymphoma-tx-fertility-preservation"],"guideline":{"version":"NCCN B-Cell Lymphomas; ESMO; IELSG37","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Primary mediastinal B-cell lymphoma that relapses or does not respond","approach":"Relapse is uncommon and almost always early, within the first year. CD19 CAR-T is the treatment of choice and primary mediastinal disease was included in the pivotal ZUMA-1 and TRANSCEND populations. Where CAR-T is not available or has failed, pembrolizumab has an established role: KEYNOTE-170 treated 53 patients whose disease had relapsed after autologous transplant or who could not have one after two or more lines, and reported an objective response of 45 per cent and complete response of 13 per cent, which led to accelerated approval in the United States on 13 June 2018, converted to traditional approval on 14 October 2020. Nivolumab with brentuximab vedotin is the other checkpoint-based option. Salvage chemotherapy with autologous transplant is used where the disease is still chemosensitive and CAR-T is not accessible. Mediastinal radiotherapy is added to a residual localised site.","refs":["keynote-170","pembrolizumab","nivolumab","brentuximab-vedotin","axicabtagene-ciloleucel","lisocabtagene-maraleucel","car-t","autologous-stem-cell-transplant","lymphoma-tx-car-t-pathway","lymphoma-tx-radiotherapy"],"guideline":{"version":"NCCN B-Cell Lymphomas; KEYNOTE-170","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":["DA-EPOCH-R cures about nine in ten patients without radiotherapy.","IELSG37 showed that radiotherapy can be omitted after a complete metabolic response on PET.","PD-1 blockade, alone or with brentuximab vedotin, rescues many relapsed patients because of the 9p24.1 lesion.","CD19 CAR-T labels for large B-cell lymphoma include this entity.","Primary mediastinal B-cell lymphoma shares its central lesion with classical Hodgkin lymphoma rather than with diffuse large B-cell lymphoma: amplification of 9p24.1, carrying both PD-1 ligand genes and JAK2, which raises the ligands by gene dose and by JAK2-driven transcription.","CIITA, the master transactivator of MHC class II, is rearranged in 38% of cases, the highest rate of any lymphoma. The fusions lower MHC class II on the tumour cell and in the same rearrangements place the PD-1 ligands under new promoters, so one event both hides the tumour and switches on the brake.","The practical consequence is that checkpoint blockade has activity here when it has very little in other B-cell non-Hodgkin lymphomas, and that the grey-zone lymphoma between this disease and Hodgkin lymphoma is a biological category and not only a morphological one."],"history":[{"year":1980,"title":"Mediastinal large B-cell lymphoma of thymic origin first described as a distinct clinical entity","refs":[]},{"year":2001,"title":"WHO classification lists primary mediastinal large B-cell lymphoma as a separate entity","refs":["non-hodgkin-lymphoma"]},{"year":2003,"title":"Gene expression profiling shows its kinship with classical Hodgkin lymphoma and the 9p24.1 lesion","refs":["hodgkin-lymphoma","pdl1","jak2"]},{"year":2013,"title":"Dunleavy: dose-adjusted EPOCH-R cures 93 percent without radiotherapy (NEJM)","refs":["rituximab","etoposide","doxorubicin","wyndham-wilson"]},{"year":2017,"title":"Axicabtagene ciloleucel approved for large B-cell lymphoma, including primary mediastinal disease","refs":["axicabtagene-ciloleucel","car-t"]},{"year":2018,"title":"Pembrolizumab approved for relapsed or refractory disease after KEYNOTE-170","refs":["pembrolizumab","keynote-170"]},{"year":2019,"title":"CheckMate 436: nivolumab plus brentuximab vedotin, 73 percent response rate","refs":["nivolumab","brentuximab-vedotin"]},{"year":2024,"title":"IELSG37: radiotherapy can be omitted after complete metabolic response","refs":["ielsg37","pet-adapted-therapy"]}],"pipeline":["ielsg37","keynote-170","ctdna-lymphoma-monitoring","glofitamab","epcoritamab","lisocabtagene-maraleucel"],"openProblems":["No validated way to identify the 10 to 15 percent who will fail first-line therapy before they do.","Checkpoint blockade in first line is untested in randomised trials.","Late cardiac and second-cancer effects of anthracyclines and radiotherapy fall on patients in their thirties.","Grey zone lymphoma has no trial-defined standard."],"parent":"non-hodgkin-lymphoma"},{"id":"primary-myelofibrosis","kind":"cancer","name":"Primary myelofibrosis","aka":["PMF","Myelofibrosis","Chronic idiopathic myelofibrosis","Agnogenic myeloid metaplasia","Post-PV and post-ET myelofibrosis (secondary myelofibrosis)"],"tldr":"Primary myelofibrosis is a blood cancer in which the marrow scars over, the spleen swells and patients become anaemic and exhausted. JAK inhibitors, ruxolitinib first (COMFORT) and then fedratinib, pacritinib and momelotinib (MOMENTUM), shrink the spleen and relieve symptoms; only a donor stem cell transplant can cure it.","summary":"Primary myelofibrosis arises from a haematopoietic stem cell carrying JAK2 V617F (about 60 percent), CALR (about 25 percent) or MPL (5 to 8 percent), or none of the three (triple negative, the worst group), with additional high-risk mutations in ASXL1, SRSF2, EZH2, IDH1/2 and U2AF1. The clone drives cytokine release and megakaryocyte abnormalities that scar the marrow; blood production moves to the spleen and liver, which enlarge, and patients develop anaemia, constitutional symptoms, early satiety and bone pain. A prefibrotic phase resembles essential thrombocythaemia. Risk scores (IPSS, DIPSS-plus, MIPSS70 and MIPSS70-plus v2 with mutations and cytogenetics) predict survival and steer the transplant decision; about one in five progress to blast phase, for which no treatment reliably works.\n\nJAK inhibitors treat the disease's consequences. Ruxolitinib, the first, shrank the spleen by 35 percent or more in 41.9 percent of patients against 0.7 percent on placebo at 24 weeks in COMFORT-I (2012), and beat best available therapy in COMFORT-II, with symptom scores halving in nearly half; approval came in 2011 and a survival advantage emerged in pooled long-term data. Fedratinib (JAKARTA, 2019 approval) works after ruxolitinib failure but carries a warning for Wernicke encephalopathy; pacritinib (PERSIST-2, approved 2022) is the option when platelets fall below 50 x 10^9/L; and momelotinib, which also blocks ACVR1 and so raises haemoglobin, was approved in 2023 after MOMENTUM, in which 25 percent of anaemic, previously treated patients had their symptom score halve against 9 percent on danazol, with more becoming transfusion independent. None of them clears the clone.\n\nAllogeneic transplant is the only cure and is offered to fit patients with higher-risk disease (MIPSS70 high, typically under 70), with a JAK inhibitor to shrink the spleen beforehand; transplant-related mortality is substantial, and timing is the central clinical judgement. Anaemia is managed with momelotinib, erythropoietin, danazol, transfusion and, in trials, luspatercept (INDEPENDENCE). Combinations of ruxolitinib with navitoclax (TRANSFORM-1) or the BET inhibitor pelabresib (MANIFEST-2) roughly doubled spleen responses in phase 3 but have not yet reached approval, imetelstat is being tested against survival itself in IMpactMF, and interferon, selinexor and anti-fibrotic approaches are in trials; whether any drug changes the disease's course rather than its symptoms is the field's central question.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Primary_myelofibrosis","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Primary_myelofibrosis"},{"label":"NCCN Guidelines: Myeloproliferative Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1477"}],"tags":["subtype-page"],"related":["essential-thrombocythaemia","polycythaemia-vera"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","allogeneic-hsct","transfusion-support"],"targets":["jak2"],"drugs":["danazol"],"companies":[],"institutions":[],"pathways":[],"terms":["jak2-v617f","post-pv-myelofibrosis","anaemia","allogeneic-transplant","mpn-driver-mutations","dipss-mipss70"],"trials":["manifest-2","momentum"],"people":[],"bottlenecks":[],"keyPapers":["paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012","paper-momentum-momelotinib-lancet-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"The rarest and most serious of the classic myeloproliferative neoplasms, about one new case per 100,000 people a year, mostly over 60; median survival is around six years but ranges from under two to more than fifteen depending on risk score.","subtypes":["Prefibrotic primary myelofibrosis","Overt primary myelofibrosis, lower risk (DIPSS low or intermediate-1, MIPSS70 low)","Overt primary myelofibrosis, higher risk (DIPSS intermediate-2 or high, MIPSS70 high; transplant candidates)","Myelofibrosis with anaemia (momelotinib, luspatercept trials)","Myelofibrosis with severe thrombocytopenia (pacritinib)","Post-polycythaemia vera and post-essential thrombocythaemia myelofibrosis","Accelerated or blast phase myelofibrosis (MPN blast phase)"],"biomarkers":["JAK2 V617F, CALR and MPL driver mutations (or triple negative)","High-molecular-risk mutations: ASXL1, SRSF2, EZH2, IDH1/2, U2AF1","DIPSS-plus and MIPSS70-plus v2 scores","Marrow fibrosis grade","Spleen volume by imaging","Haemoglobin, platelet count and transfusion dependence","Blast percentage","Symptom score (MPN-SAF TSS)"],"standardOfCare":[{"setting":"Lower-risk, asymptomatic","approach":"Observation; aspirin for thrombosis risk where platelets are high; hydroxyurea or interferon for proliferative features.","refs":["aspirin","hydroxyurea","ropeginterferon-alfa-2b","peginterferon-alfa-2b"],"guideline":{"version":"NCCN Guidelines: Myeloproliferative Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1477"}},{"setting":"Symptomatic splenomegaly or constitutional symptoms","approach":"Ruxolitinib (COMFORT-I and II) first; fedratinib after ruxolitinib failure or intolerance; pacritinib if platelets are below 50 x 10^9/L; momelotinib if anaemic.","refs":["ruxolitinib","fedratinib","pacritinib","momelotinib","comfort-i","comfort-ii"],"guideline":{"version":"NCCN Guidelines: Myeloproliferative Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1477"}},{"setting":"Anaemia of myelofibrosis","approach":"Momelotinib (MOMENTUM), erythropoiesis-stimulating agents where erythropoietin is low, danazol, transfusion with iron chelation; luspatercept in trials (INDEPENDENCE).","refs":["momelotinib","epoetin-alfa","transfusion-support","luspatercept","nct04717414","nct05320198"],"guideline":{"version":"NCCN Guidelines: Myeloproliferative Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1477"}},{"setting":"Higher-risk, fit for transplant","approach":"Allogeneic stem cell transplant, usually under 70 and at MIPSS70 high or DIPSS intermediate-2 or higher, after JAK inhibitor to reduce spleen size.","refs":["allogeneic-hsct","ruxolitinib","conditioning-regimen"],"guideline":{"version":"NCCN Guidelines: Myeloproliferative Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1477"}},{"setting":"Ruxolitinib failure and trials","approach":"Switch JAK inhibitor; combination trials of ruxolitinib with navitoclax, pelabresib, selinexor or imetelstat; imetelstat versus best available therapy in IMpactMF.","refs":["navitoclax","pelabresib","selinexor","imetelstat","nct04468984","nct04562389","impactmf","nct03441113"]}],"stateOfArt":["Four approved JAK inhibitors cover the main clinical problems: spleen and symptoms (ruxolitinib, fedratinib), low platelets (pacritinib) and anaemia (momelotinib).","Allogeneic transplant remains the only cure and the hardest decision, with mutation-based scores now guiding who and when.","Combination phase 3 trials doubled spleen responses but have not yet shown disease modification or survival gain."],"history":[{"year":1879,"title":"Heuck describes myelofibrosis","refs":[]},{"year":2005,"title":"JAK2 V617F discovered in most polycythaemia vera and half of myelofibrosis","refs":["jak2","jak2-v617f"]},{"year":2011,"title":"Ruxolitinib approved: the first JAK inhibitor, after COMFORT-I and II","refs":["ruxolitinib"]},{"year":2013,"title":"CALR mutations found in most JAK2-negative myelofibrosis","refs":[]},{"year":2018,"title":"MIPSS70 adds mutations to risk scoring for transplant decisions","refs":[]},{"year":2019,"title":"Fedratinib approved after JAKARTA","refs":["fedratinib"]},{"year":2022,"title":"Pacritinib approved for severe thrombocytopenia after PERSIST-2","refs":["pacritinib"]},{"year":2023,"title":"Momelotinib approved for anaemic myelofibrosis after MOMENTUM","refs":["momelotinib"]}],"pipeline":["momelotinib","pacritinib","navitoclax","pelabresib","imetelstat","luspatercept","nct04468984","nct04717414","impactmf","nct04562389","allogeneic-hsct"],"openProblems":["No drug has been shown to change the course of the disease rather than its symptoms.","Transplant timing: too early risks a fatal procedure in someone with years to live, too late loses the window.","Blast phase myelofibrosis has no effective treatment."],"parent":"myeloproliferative-neoplasms"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","aka":["Prostatic acinar adenocarcinoma","Acinar adenocarcinoma of the prostate","Adenocarcinoma of the prostate","Prostate carcinoma","Carcinoma of the prostate","CaP"],"tldr":"Prostate cancer is the home of theranostics: PSMA PET finds it, PSMA radioligands treat it. Hormonal therapy remains the foundation, with PARP and AKT inhibitors added by genotype.","summary":"Prostate cancer is the most common cancer in men in most high-income countries and a spectrum: most PSA-detected disease is indolent and safely watched (ProtecT: ~3% prostate-cancer mortality at 15 years whatever the strategy), while de novo metastatic disease, treated with hormonal doublets and triplets and since 2026 with radioligand therapy added, has a median overall survival of about five years in the trial populations behind those regimens, which means half of those men lived longer; it is the second most common cause of cancer death in men. Diagnosis now runs PSA → multiparametric MRI (PRECISION) → targeted biopsy → Grade Group, with germline and somatic HRR testing for advanced disease and PSMA PET for staging (proPSMA) and recurrence. Digital-pathology AI (ArteraAI Prostate, 2025) and gene-expression classifiers (Decipher) refine who needs treatment and who benefits from adding hormone therapy.\n\nTreatment is built on androgen deprivation, the first targeted cancer therapy (Huggins, 1941). Metastatic hormone-sensitive disease is treated with doublets (ADT + abiraterone, enzalutamide, apalutamide or darolutamide) or triplets adding docetaxel (ARASENS, PEACE-1), and since 31 July 2026 with 177Lu-PSMA-617 added to ADT + ARPI (PSMAddition, rPFS HR 0.72). PTEN-deficient disease gained capivasertib + abiraterone in 2026. In castration-resistant disease the sequence includes ARPI switch, PARP inhibitors for HRR-mutant tumours (PROfound, PROpel, TALAPRO-2 with OS benefit), docetaxel and cabazitaxel, radium-223 for bone-only disease, and 177Lu-PSMA-617 before or after chemotherapy (VISION, PSMAfore). Enzalutamide is approved even for high-risk PSA-only recurrence (EMBARK).\n\nProstate cancer is the proving ground for theranostics: PSMA PET selects and PSMA radioligands treat. Competing 177Lu-PSMA-I&T products (SPLASH, ECLIPSE) have improved progression but not yet survival; alpha-emitting 225Ac-PSMA agents are in phase 3 (AlphaBreak, AcTION) and produce responses after lutetium failure. T-cell engagers against STEAP1 (xaluritamig, XALute) and KLK2 (pasritamig) are the first immunotherapies with real activity in a disease that ignores checkpoint inhibitors; EZH2 inhibition (mevrometostat, MEVPRO) aims to re-sensitise to hormonal therapy. The unsolved problems are neuroendocrine transformation, AR-V7-driven resistance (the N-terminal-domain inhibitor masofaniten failed), Ac-225 supply, and the over- versus under-diagnosis tension in screening.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Prostate_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Prostate_cancer"},{"label":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"},{"label":"NICE NG131: prostate cancer, diagnosis and management (recommendations, including the Cambridge Prognostic Group table at 1.2.15)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"},{"label":"Royal College of Pathologists G084: dataset for histopathology reports for prostatic carcinoma, version 4, October 2024","url":"https://www.rcpath.org/static/8cc88604-2c8d-4df4-a99542df41c102af/G084-dataset-for-histopathology-reports-for-prostatic-carcinoma.pdf"},{"label":"WHO Classification of Tumours, 5th edition: tumours of the prostate (IARC, 2022)","url":"https://tumourclassification.iarc.who.int/chapters/36"},{"label":"Kench et al., Histopathology 2022: WHO Classification of Tumours fifth edition, evolving issues in the classification, diagnosis and prognostication of prostate cancer","url":"https://doi.org/10.1111/his.14711"},{"label":"Brierley et al., International Journal of Cancer 2026: the 9th edition of the UICC TNM classification of malignant tumours, updates and rationale for change (prostate at section 10.1)","url":"https://doi.org/10.1002/ijc.70561"},{"label":"UICC: the 9th edition of the TNM classification of malignant tumours, published 3 July 2025 and recommended to take effect from 1 January 2026","url":"https://www.uicc.org/news-and-updates/25-7-announcements/9th-edition-uicc-tnm-classification-malignant-tumours-now-available"},{"label":"GLOBOCAN prostate fact sheet (IARC Global Cancer Observatory, 2024 estimates)","url":"https://gco.iarc.who.int/media/globocan/factsheets/cancers/27-prostate-fact-sheet.pdf"},{"label":"SEER Cancer Stat Facts: prostate cancer (US incidence, stage distribution and survival by stage)","url":"https://seer.cancer.gov/statfacts/html/prost.html"},{"label":"Cancer Research UK: prostate cancer statistics (UK incidence, mortality, survival, stage at diagnosis and route to diagnosis)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/prostate-cancer"},{"label":"NHS: symptoms of prostate cancer, and what happens at the GP appointment","url":"https://www.nhs.uk/conditions/prostate-cancer/symptoms/"},{"label":"Ranasinha et al., BJUI Compass 2021: ductal adenocarcinoma of the prostate, a systematic review and meta-analysis of incidence, presentation, prognosis and management","url":"https://doi.org/10.1002/bco2.60"},{"label":"Netto et al., European Urology 2022: the 2022 WHO classification of tumours of the urinary system and male genital organs, part B (prostate and urinary tract)","url":"https://pubmed.ncbi.nlm.nih.gov/35965208/"},{"label":"Epstein et al., American Journal of Surgical Pathology 2016: the 2014 ISUP consensus conference on Gleason grading, and the grade group system","url":"https://doi.org/10.1097/PAS.0000000000000530"},{"label":"NHS: prostate cancer","url":"https://www.nhs.uk/conditions/prostate-cancer/"},{"label":"NHS: tests and next steps for prostate cancer","url":"https://www.nhs.uk/conditions/prostate-cancer/tests-and-next-steps/"},{"label":"NHS: treatment for prostate cancer","url":"https://www.nhs.uk/conditions/prostate-cancer/treatment/"},{"label":"NHS: help and support for prostate cancer","url":"https://www.nhs.uk/conditions/prostate-cancer/help-and-support/"},{"label":"NHS: erection problems (erectile dysfunction)","url":"https://www.nhs.uk/conditions/erection-problems-erectile-dysfunction/"},{"label":"NHS: priapism (painful erections)","url":"https://www.nhs.uk/symptoms/priapism-painful-erections/"},{"label":"NHS: urinary incontinence","url":"https://www.nhs.uk/conditions/urinary-incontinence/"},{"label":"NHS: sepsis","url":"https://www.nhs.uk/conditions/sepsis/"},{"label":"NHS: clinical trials","url":"https://www.nhs.uk/tests-and-treatments/clinical-trials/"},{"label":"NHS: carer's assessments","url":"https://www.nhs.uk/social-care-and-support/support-and-benefits-for-carers/carer-assessments/"},{"label":"NHS: benefits for carers","url":"https://www.nhs.uk/social-care-and-support/support-and-benefits-for-carers/benefits-for-carers/"},{"label":"NICE NG234: spinal metastases and metastatic spinal cord compression, recommendations","url":"https://www.nice.org.uk/guidance/ng234/chapter/Recommendations"},{"label":"Prostate Cancer UK: just diagnosed","url":"https://prostatecanceruk.org/prostate-information-and-support/just-diagnosed"},{"label":"Prostate Cancer UK: localised prostate cancer","url":"https://prostatecanceruk.org/prostate-information-and-support/just-diagnosed/localised-prostate-cancer"},{"label":"Prostate Cancer UK: dealing with my diagnosis","url":"https://prostatecanceruk.org/prostate-information-and-support/just-diagnosed/dealing-with-my-diagnosis"},{"label":"Prostate Cancer UK: choosing a treatment","url":"https://prostatecanceruk.org/prostate-information-and-support/treatments/choosing-a-treatment"},{"label":"Prostate Cancer UK: follow-up after treatment","url":"https://prostatecanceruk.org/prostate-information-and-support/treatments/follow-up-after-treatment"},{"label":"Prostate Cancer UK: how hormone therapy affects you","url":"https://prostatecanceruk.org/prostate-information-and-support/living-with-prostate-cancer/how-hormone-therapy-affects-you"},{"label":"Prostate Cancer UK: hot flushes","url":"https://prostatecanceruk.org/prostate-information-and-support/living-with-prostate-cancer/how-hormone-therapy-affects-you/hot-flushes"},{"label":"Prostate Cancer UK: sex and relationships","url":"https://prostatecanceruk.org/prostate-information-and-support/living-with-prostate-cancer/sex-and-relationships"},{"label":"Prostate Cancer UK: treatments for erection problems","url":"https://prostatecanceruk.org/prostate-information-and-support/living-with-prostate-cancer/sex-and-relationships/treatments-for-erection-problems"},{"label":"Prostate Cancer UK: urinary problems after prostate cancer treatment","url":"https://prostatecanceruk.org/prostate-information-and-support/living-with-prostate-cancer/urinary-problems"},{"label":"Prostate Cancer UK: pelvic floor muscle exercises","url":"https://prostatecanceruk.org/prostate-information-and-support/living-with-prostate-cancer/pelvic-floor-muscle-exercises"},{"label":"Prostate Cancer UK: fatigue","url":"https://prostatecanceruk.org/prostate-information-and-support/living-with-prostate-cancer/fatigue"},{"label":"Prostate Cancer UK: the emotional impact","url":"https://prostatecanceruk.org/prostate-information-and-support/living-with-prostate-cancer/the-emotional-impact"},{"label":"Prostate Cancer UK: physical activity and prostate cancer","url":"https://prostatecanceruk.org/prostate-information-and-support/living-with-prostate-cancer/physical-activity-and-prostate-cancer"},{"label":"Prostate Cancer UK: metastatic spinal cord compression (MSCC)","url":"https://prostatecanceruk.org/prostate-information-and-support/advanced-prostate-cancer/metastatic-spinal-cord-compression-mscc"},{"label":"Prostate Cancer UK: our specialist nurses","url":"https://prostatecanceruk.org/prostate-information-and-support/get-support/our-specialist-nurses"},{"label":"Macmillan: prostate cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/prostate-cancer"},{"label":"Macmillan: hormonal therapies","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/hormonal-therapies"},{"label":"Cancer Research UK: hormone therapy for prostate cancer","url":"https://www.cancerresearchuk.org/about-cancer/prostate-cancer/treatment/hormone-therapy"},{"label":"Royal Osteoporosis Society","url":"https://theros.org.uk/"},{"label":"Marie Curie: what is palliative care?","url":"https://www.mariecurie.org.uk/information/getting-care/palliative-care"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Hamdy et al., fifteen-year outcomes after monitoring, surgery, or radiotherapy for prostate cancer (NEJM 2023)","url":"https://doi.org/10.1056/NEJMoa2214122"},{"label":"Donovan et al., patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer (NEJM 2016)","url":"https://doi.org/10.1056/NEJMoa1606221"},{"label":"Donovan et al., patient-reported outcomes 12 years after localized prostate cancer treatment (NEJM Evidence 2023)","url":"https://doi.org/10.1056/EVIDoa2300018"},{"label":"Shahinian et al., risk of fracture after androgen deprivation for prostate cancer (NEJM 2005)","url":"https://doi.org/10.1056/NEJMoa041943"},{"label":"Keating et al., diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer (JCO 2006)","url":"https://doi.org/10.1200/JCO.2006.06.2497"},{"label":"Shore et al., oral relugolix for androgen-deprivation therapy in advanced prostate cancer (HERO, NEJM 2020)","url":"https://doi.org/10.1056/NEJMoa2004325"},{"label":"Irani et al., venlafaxine, medroxyprogesterone acetate and cyproterone acetate for vasomotor hot flushes (Lancet Oncology 2010)","url":"https://doi.org/10.1016/S1470-2045(09)70338-9"},{"label":"Nead et al., androgen deprivation therapy and depression, systematic review and meta-analysis (Urologic Oncology 2017)","url":"https://doi.org/10.1016/j.urolonc.2017.07.016"},{"label":"UK National Screening Committee: prostate cancer recommendation","url":"https://view-health-screening-recommendations.service.gov.uk/prostate-cancer/"},{"label":"NICE NG131: prostate cancer, diagnosis and management","url":"https://www.nice.org.uk/guidance/ng131"},{"label":"National Prostate Cancer Audit: State of the Nation 2025","url":"https://www.natcan.org.uk/wp-content/uploads/2025/10/NPCA-SotN-2025.pdf"},{"label":"Prostate Cancer UK","url":"https://prostatecanceruk.org/"}],"tags":["gu","spike"],"related":["radiopharma-roadmap","psma-pet-to-rlt","beta-then-alpha","parp-plus-arpi","ai-pathology-to-adt","src-urotoday","prostate-ductal-adenocarcinoma","prostate-nepc","prostate-low-risk","prostate-intermediate-risk","prostate-high-risk","prostate-bcr","prostate-mhspc","prostate-nmcrpc","prostate-mcrpc","prostate-roadmap","idea-prostate-hrr-testing-at-metastatic-diagnosis","idea-prostate-randomise-the-sequence-not-only-the-drugs","idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine","idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2","idea-prostate-metastatic-presentation-as-the-screening-endpoint","idea-prostate-other-cause-mortality-as-a-reported-service-outcome","idea-prostate-per-lesion-mri-audit-before-focal-treatment","ar-amplification","ar-ligand-binding-domain-mutation","ar-v7-splice-variant","hrr-gene-mutation","tmprss2-erg-fusion","spop-mutation","nepc-transformation","ctdna-tumour-fraction","psma-pet-expression","brca-germline","brca-somatic","pten-alteration","msi-high","dmmr-ihc","hrd-positive","tmb-high"],"cancers":[],"sections":[],"technologies":["psma-pet","radioligand-therapy","targeted-alpha-therapy","androgen-deprivation","parp-inhibitor","digital-pathology-ai","robotic-surgery","brachytherapy","hifu-histotripsy","hyperbaric-oxygen-radiation-injury","active-surveillance","mp-mri","t-cell-engager","epigenetic-drugs","germline-testing","cytotoxic-chemotherapy","palliative-care","palliative-radiotherapy","psycho-oncology","peer-support-groups","oncology-nutrition","pain-management","survivorship-care-plan","multidisciplinary-tumour-board","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","prehabilitation","prostate-screening-psa-mri","mri","pet","checkpoint-inhibitor","liquid-biopsy","wes-wgs","sbrt","cgp","histopathology-ihc","cytogenetics-fish","rna-seq","methylation-profiling","pet-ct"],"targets":["psma","androgen-receptor","parp","brca","akt","b7h3","dll3","steap1","klk2","grpr","ezh2","atm","cdk12","tp53","rb1","pten","erg","tmprss2","foxa1","spop","pik3ca","etv1","palb2","msh2","nkx3-1","apc","kmt2c","zbtb16","idh","aurka","cdkn1b"],"drugs":["paige-prostate","mitoxantrone","nilutamide","triptorelin","prednisone","padeliporfin","samarium-153-lexidronam","abiraterone","enzalutamide","apalutamide","darolutamide","docetaxel","cabazitaxel","estramustine","olaparib","rucaparib","niraparib","talazoparib","pluvicto","radium-223","sipuleucel-t","pembrolizumab","capivasertib","leuprolide","bicalutamide","zoledronic-acid","carboplatin"],"companies":["halda-therapeutics","orion-orion-pharma","shenzhen-ionova-life-sciences","futurechem","hinova-pharmaceuticals","mbrace-therapeutics","spectracure","novartis","bayer","pfizer","astellas","johnson-johnson","astrazeneca","amgen","lantheus","telix","curium","veracyte","artera"],"institutions":["royal-marsden","icr-london","peter-mac","ucla-jonsson","uke-hamburg","johns-hopkins","gustave-roussy","prostate-cancer-uk","uclh","leeds-cancer-centre","the-christie","clatterbridge","imperial-cancer-centre","velindre-cardiff","beatson-glasgow","northern-ireland-cancer-centre"],"pathways":["ar-signaling","pi3k-akt-mtor","ddr","prostate-cancer-signalling","homologous-recombination-repair","base-excision-repair-parp","synthetic-lethality-map","lineage-plasticity-neuroendocrine","p53-cell-cycle","mismatch-repair-msi","wnt","ubiquitin-proteasome-system","epigenetic-reprogramming","chromosomal-instability","clonal-evolution","intravasation-ctc-survival"],"terms":["psa","gleason-grade-group","castration-resistance","biochemical-recurrence","psa50","ar-v7","theranostics","oligometastatic","crossover","cambridge-prognostic-group","tnm-prostate-cancer","prostate-acinar-adenocarcinoma","intraductal-carcinoma-prostate","cribriform-prostate-cancer","percentage-gleason-pattern-4","psa-density","extraprostatic-extension","high-grade-pin","watchful-waiting","mcrpc-mhspc","psa-kinetics","active-surveillance-term","tnm-staging","grade-vs-stage","tumour-grade","prostatectomy","orchiectomy","bone-metastases","cancer-related-fatigue","curative-intent","late-effects","performance-status","quality-of-life","febrile-neutropenia","overdiagnosis","adt","hrd","msi","tmb","ctdna","ngs","ihc","screening","synthetic-lethality","hazard-ratio","radiotherapy","prostate-treatment-choice-localised","prostate-radiotherapy-fractionation","prostate-stampede-arms","prostate-adt-burden","prostate-crpc-sequencing","prostate-hrr-eligibility","prostate-failed-programmes","prostate-uk-drug-approvals","prostate-focal-therapy","lead-time-bias","overtreatment","number-needed-to-screen","other-cause-mortality","metastasis-free-survival","radiographic-progression-free-survival","chromoplexy","genome-wide-loss-of-heterozygosity","polygenic-risk-score","neuroendocrine-differentiation","whole-mount-pathology","pi-rads","template-mapping-biopsy","bipolar-androgen-therapy","intermittent-androgen-deprivation","germline-vs-somatic","gbrca-mutation","brca-reversion-mutations","lynch-syndrome","histologic-transformation","cfdna","liquid-biopsy","biopsy","gene-fusion","gene-amplification","amplification","copy-number-variation-term","driver-mutation","resistance","cross-resistance","vus","somatic-mutations-wxs-wgs","fish","tumour-agnostic"],"trials":["nct06136624","nct06136650","nct06952803","nct06120491","nct06855277","nct06780670","nct07365995","nct06764485","mcrpc","himalayas-1","nct07311694","nct07615101","nct07649122","nct05381103","rtog-9601","horrad","pop-rt","nct06629779","nct05348577","nct05939414","nct06520345","nct07028853","nct01436968","nct03706365","nct04076059","nct05884398","nct07213674","nct04446117","nct06925737","nct07052214","nct05171816","nct07611110","nct04691804","nct05794906","nct02489318","nct04557059","nct03348670","nct06235151","nct02257736","nct06754085","nct06970847","nct04821622","nct05288166","nct07225946","nct04497844","nct03767244","nct02531516","nct01946204","nct06056830","nct03851640","stampede","protect","chaarted","latitude","vision","profound","propel","talapro-2","magnitude","embark","arasens","peace-1","enzamet","prosper","aramis","alsympca","psmaddition","capitello-281","goteborg-2","promis","transform-prostate","chhip","pace-b"],"people":["chris-hoy","jenny-donovan","caroline-moore","nicholas-van-as","ros-eeles","rakesh-heer"],"bottlenecks":["b-overdiagnosis","b-early-detection","b-resistance","b-biomarker-validation","b-hereditary-risk","b-toxicity-qol","b-immunotherapy-response","b-trial-design","b-global-access","b-survivorship","b-undruggable-targets","b-tumor-heterogeneity","b-generic-repurposing","b-aging-comorbidity"],"keyPapers":["paper-taplin-ar-mutation-androgen-independent-prostate-nejm-1995","paper-quigley-structural-variation-mcrpc-cell-2018","paper-prophecy-arv7-validation-jco-2019","paper-scher-nuclear-arv7-taxane-vs-arsi-jama-oncol-2018","paper-barbieri-spop-foxa1-med12-prostate-nat-genet-2012","paper-abida-genomic-correlates-outcome-mcrpc-pnas-2019","paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018","paper-kumar-interindividual-genomic-diversity-metastatic-prostate-nat-med-2016","paper-stopsack-mcspc-genomic-alterations-outcomes-ccr-2020","paper-stopsack-prostate-genomes-by-race-ccr-2022","paper-ren-chinese-prostate-whole-genome-eur-urol-2018","paper-mateo-genomics-lethal-prostate-diagnosis-castration-resistance-jci-2020","paper-nicolosi-germline-variants-prostate-testing-guidelines-jama-oncol-2019","paper-castro-germline-brca-prostate-outcomes-jco-2013","paper-isaacsson-velho-intraductal-germline-dna-repair-prostate-2018","paper-taylor-germline-brca2-evolutionary-trajectories-nat-commun-2017","paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017","paper-jensen-clonal-haematopoiesis-cfdna-interference-prostate-jama-oncol-2021","paper-carver-pi3k-ar-reciprocal-feedback-prostate-cancer-cell-2011","paper-ferraldeschi-pten-protein-loss-abiraterone-eur-urol-2015","paper-ipatential150-ipatasertib-abiraterone-pten-lancet-2021","paper-pettersson-tmprss2-erg-outcome-meta-analysis-cebp-2012","paper-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019","paper-pritchard-complex-msh2-msh6-hypermutated-prostate-nat-commun-2014","paper-guedes-msh2-loss-primary-prostate-ccr-2017","paper-silver-psma-expression-normal-malignant-tissues-ccr-1997","paper-fendler-psma-pet-biochemical-recurrence-jama-oncol-2019","paper-epstein-neuroendocrine-prostate-morphologic-classification-ajsp-2014","paper-beltran-nepc-aurka-mycn-cancer-discov-2011","paper-ku-rb1-trp53-lineage-plasticity-science-2017","paper-bluemn-double-negative-prostate-fgf-mapk-cancer-cell-2017","paper-labrecque-mcrpc-phenotypes-jci-2019","paper-aparicio-aggressive-variant-prostate-tumour-suppressors-ccr-2016","paper-berchuck-cfdna-methylation-nepc-detection-ccr-2022","paper-wyatt-ctdna-tissue-concordance-mcrpc-jnci-2017","paper-annala-ctdna-resistance-abiraterone-enzalutamide-cancer-discov-2018","paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021","paper-beltran-nepc-divergent-evolution-nat-med-2016","paper-propsma-hofman-lancet-2020","paper-therap-lancet-2021","paper-profound-nejm-2020","paper-vision-nejm-2021","paper-visakorpi-androgen-receptor-amplification-nat-genet-1995","paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004","paper-antonarakis-ar-v7-resistance-nejm-2014","paper-tcga-molecular-taxonomy-primary-prostate-cell-2015","paper-grasso-mutational-landscape-lethal-crpc-nature-2012","paper-taylor-integrative-genomic-profiling-cancer-cell-2010","paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","paper-tomlins-tmprss2-ets-fusion-science-2005","paper-abida-triton2-rucaparib-brca-jco-2020","paper-mu-sox2-lineage-plasticity-science-2017"],"journals":["clinical-genitourinary-cancer","prostate-cancer-and-prostatic-diseases","urologic-oncology"],"dependsOn":[],"notes":["Which page is mine? Prostate cancer is described by five things at once, and each has its own page here. The type is almost always acinar adenocarcinoma, which is this page; if the report says ductal, or says the cancer turned neuroendocrine after hormone treatment, there is a page for each. The grade is a grade group from 1 to 5 with a Gleason score beside it. The stage is a TNM category. The risk band in Britain is a Cambridge Prognostic Group from 1 to 5, and the localised pages here are mapped to it: CPG 1 is the low-risk page, CPG 2 and 3 the intermediate-risk page, CPG 4 and 5 the high-risk page. The state is whether the cancer still responds to hormone treatment and whether it has spread, and there are pages for rising PSA after treatment, for metastatic hormone-sensitive disease, for non-metastatic and metastatic castration-resistant disease.","What prostate cancer is. The prostate is a gland the size of a walnut that sits below the bladder and surrounds the top of the urethra, and it makes the fluid that carries sperm. More than 95 in every 100 prostate cancers arise in its acini, the small glands that make that fluid, which is why the ordinary type is called acinar adenocarcinoma. It usually starts on the outer part of the gland, which is why it usually causes nothing at first, and why so much of it is found by a blood test rather than by a symptom.","Why the same cancer gets different risk labels on either side of the Atlantic. Britain and America stratify localised prostate cancer with different systems. NICE NG131 recommendation 1.2.15 uses the five Cambridge Prognostic Groups; the NCCN uses six bands, from very low to very high, and splits intermediate risk into favourable and unfavourable using criteria the Cambridge system does not have, including PSA density and the proportion of positive cores. NICE replaced its own three-tier table, which came from D'Amico, in the 2021 amendment because the three-tier model could not tell Gleason 3+4 from 4+3, and the Cambridge system can. A man reading an American source about his own diagnosis is reading a different map of the same ground.","Is the Gleason score being replaced by the grade group? No. They are used together, and a UK report in 2026 gives both. The Royal College of Pathologists dataset sets out the grade groups to be used 'in tangent with the Gleason score', and its proforma asks for each separately. The grade groups exist to split Gleason 7, which is really two diseases, 3+4 and 4+3, into grade groups 2 and 3. NICE's Cambridge table is written with both scales in every row for the same reason: the Gleason score is what appears in older notes and in most of the literature.","Why does my report mention cribriform or intraductal when my grade is only 7? Because since October 2024 the UK reporting dataset asks for it, and because within grade group 2 and 3 those patterns are where the risk sits. Invasive cribriform carcinoma is the worst-behaving form of Gleason pattern 4, and intraductal carcinoma is cancer filling ducts that still have their outer basal layer. Either one argues against active surveillance, and either one is a reason to be offered germline genetic testing under both the NCCN and the Philadelphia consensus recommendations.","Grade group 1 prostate cancer and the word cancer. Grade group 1, Gleason 6, is the grade that has prompted a long argument about whether it should be called cancer at all, because left alone it very rarely spreads. NICE's answer is practical rather than semantic: Cambridge Prognostic Group 1, which is grade group 1 with a PSA under 10 and stage T1 or T2, is the one band where active surveillance is offered first and radical treatment is a fallback if surveillance is unsuitable or unacceptable to the person (NG131 1.3.8).","Am I being watched, or watched and left? Active surveillance and watchful waiting are different plans with different intentions. Active surveillance monitors with PSA, repeat MRI and repeat biopsy so that a cancer that changes can still be cured. Watchful waiting, in NICE's own definition, is a strategy for controlling rather than curing, for people who do not want radical treatment or for whom it is not suitable, and relies on deferred hormone therapy. Both involve not treating today; only one keeps cure on the table.","How common is it, and what is the outlook? Worldwide, 1,546,112 new cases and 419,849 deaths a year, fourth for cases among all cancers and eighth for deaths (GLOBOCAN 2024). In the UK, 57,898 new cases and 12,300 deaths a year, and 78.9 percent of men survive ten years or more; the lifetime risk of being diagnosed is 17 percent (Cancer Research UK). In the United States 333,830 cases and 36,320 deaths are projected for 2026, and 69.5 percent are found while still confined to the prostate, where five-year relative survival is 100 percent (SEER). These are averages over everybody diagnosed and they are not a personal prognosis; for most men the question the numbers raise is not whether treatment will work but whether treatment is needed at all.","Why the histology tier here is short. The WHO fifth edition names ductal adenocarcinoma, treatment-related neuroendocrine prostatic carcinoma, adenoid cystic (basal cell) carcinoma, and squamous and adenosquamous carcinoma as types separate from acinar adenocarcinoma, and lists PIN-like carcinoma as a subtype of acinar adenocarcinoma with the atrophic, pseudohyperplastic, microcystic and foamy-gland appearances as patterns rather than entities. The first two have pages here because they change management; the rest are rare enough that the honest treatment is a sentence on this page and a glossary entry, not a thin page of their own. Urothelial carcinoma of the prostatic urethra is covered in the urinary tract chapter of the same classification, so it is not a prostate cancer record here.","Living with prostate cancer, care and decisions: This is orientation from public patient pages and guidelines, not advice for your case: your own team's instructions and 24-hour number come first. The eight decision rows on this page, the question sets for the urology, surgical, oncology, hormone therapy, sexual function and continence and palliative care appointments and for partners and carers, the first 60 days checklist and the red cards were written from NICE NG131 and NG234 and from the NHS, Prostate Cancer UK, Macmillan, Cancer Research UK, Marie Curie and Maggie's, with the patient-reported figures taken from the ProtecT trial's own publications rather than from summaries of them.","On the numbers in these rows. They come from ProtecT, a UK trial that randomly assigned 1,643 men aged 50 to 69 with PSA-detected, mostly Cambridge Prognostic Group 1 to 3 disease to active monitoring, prostatectomy or radiotherapy, and followed them for a median of 15 years with questionnaire response rates above 80 percent. They describe what happened to that group. They are not a forecast for one man, and no sentence here should be read as one. Where NICE has put the same figures into its own box 2, the guideline's wording is used, because that is the table a clinician is meant to work through with you.","On plain words. These pages call incontinence leaking and calls impotence not being able to get an erection, and gives both their numbers. Men do not raise either subject, surveys consistently find they are not asked about them either, and the result is that the commonest long-term consequences of treating this cancer arrive unannounced. NICE NG131 (1.1.12) requires that sexual function, physical appearance, continence and other aspects of masculinity are discussed before treatment. Nothing here assumes the reader is old, uninterested in sex, or has a partner.","On hormone therapy. It is the longest-running part of this illness for most men who need it and the least covered anywhere. The row on living with hormone therapy collects what NICE offers for each effect, because almost every one of them has an answer: medroxyprogesterone for hot flushes, a fracture risk assessment and bone drugs where osteoporosis is present, six-monthly metabolic checks, supervised resistance and aerobic exercise twice a week for 12 weeks for fatigue, prophylactic breast bud radiotherapy for men on long-term bicalutamide, psychosexual counselling for couples, and intermittent therapy where the setting allows it.","The words that carry the screening argument, in one place. Lead time is how much earlier a screening test found the cancer, and lead-time bias is the mistake of counting that extra knowing as extra life; overdiagnosis is a lead time longer than the rest of the man's life; overtreatment is the harm that follows when an overdiagnosed cancer is treated. The number needed to screen turns all of it into one figure a health service can weigh: at 16 years in the European randomised trial, 570 men invited and 18 extra cancers diagnosed to prevent one prostate cancer death.","Two words for the same scan, and they are not the same score. The international system is PI-RADS, now version 2.1, which builds a 1 to 5 assessment category from fixed per-sequence rules. NICE NG131 1.2.2 asks United Kingdom reports to use a 5-point Likert scale instead, which is the radiologist's overall probability judgement using the clinical picture as well as the images. Both run 1 to 5 and both trigger a biopsy at 3 or more, and a man reading an American source about his own scan is reading a different scale.","The science in detail, 1 of 7, in full; the one-sentence version is on the overview. The androgen receptor, five routes to the same place. Amplification of the gene at Xq12: 48.9% of 444 samples in prad_su2c_2019, 52.0% of 150 in prad_su2c_2015 and 57.0% of 149 in prad_fhcrc, against 1.0% of 489 TCGA primaries and 4.0% of 424 metastatic castration-sensitive samples, first shown as a treatment effect in 7 of 23 recurrent tumours with none in the matched pre-treatment specimens. Amplification of an intergenic enhancer 624 kb upstream, in 81% of 101 deeply sequenced metastases, invisible to coding-exon panels. Ligand-binding-domain mutation in 13.7 to 18.0% of castration-resistant cohorts against 0.4% of primaries, clustered on four residues: L702H, which makes the receptor responsive to glucocorticoid; T878A and H875Y, which open it to progestogens; and F877L, which turns enzalutamide and apalutamide into agonists. The AR-V7 splice variant, which deletes the drug-binding domain altogether, detectable in circulating tumour cells from 39% of men starting enzalutamide and 19% starting abiraterone. And simply raising receptor expression, which was shown in xenografts to be necessary and sufficient for resistance on its own. In plasma, some potential androgen receptor resistance alteration is present in 42% of 2,213 evaluable men, often polyclonal or compound.","The science in detail, 2 of 7, in full; the one-sentence version is on the overview. The landscape by stage. Localised disease, from the TCGA primary cohorts: ERG fusion 45.6% of 333, ETV1 8.7%, ETV4 4.8%, FLI1 1.2%; SPOP mutation 11.1%; FOXA1 mutation 5.7%; PTEN deep deletion 17.4%; TP53 mutation 11.5%, falling to 3.4% in the CPC-GENE localised whole genomes; NKX3-1 deletion 8.0 to 15.9%; CHD1 deletion 7.0%; MYC amplification 8.2%; RB1 deletion 9.4%; BRCA2 mutation 1.6% with deletion 3.5%; ATM mutation 4.0%; CDK12 mutation 1.8%. Metastatic castration-resistant disease, from prad_su2c_2019 and its companions: TP53 36.7%, PTEN deletion 25.7%, AR amplification 48.9%, MYC amplification 23.6%, RB1 deletion 9.7%, BRCA2 mutation 8.3%, ATM 6.1%, CDK12 5.9%, SPOP falling to 5.6%. Metastatic castration-sensitive disease sits between, from 424 men: TP53 30.4%, PTEN deletion 14.4%, AR amplification 4.0%, SPOP 12.5%. Ancestry adds a third axis: in 65 Chinese tumours, CHD1 deletion reaches 20.0% while ERG rearrangement is 6.2%, and in 2,069 men at one centre, tumours from Black men carried more AR alterations, fewer PTEN mutations and more 8q gain, and tumours from Asian men more FOXA1 and ZFHX3 alterations.","The science in detail, 3 of 7, in full; the one-sentence version is on the overview. DNA repair, germline against somatic. Inherited mutations in 20 repair genes were present in 82 of 692 men with metastatic prostate cancer unselected for family history, 11.8%: BRCA2 5.3%, ATM 1.6%, CHEK2 1.9%, BRCA1 0.9%, RAD51D 0.4% and PALB2 0.4%, against 4.6% in localised disease and 2.7% in a 53,105-person reference population, with no difference by family history or age at diagnosis. On a broader panel in 3,607 men, 17.2% had a positive result and only 30.7% of those were BRCA, with mismatch repair variants in 1.74% of all men tested and 37% of positives ineligible for testing under the guideline then in force. Somatically, BRCA2, BRCA1 and ATM aberrations together were 19.3% of 150 metastatic castration-resistant tumours. A tumour report cannot answer the germline question and a separate consented test is needed; a plasma report cannot answer it either, and in 10% of men an ATM, BRCA2 or CHEK2 variant in plasma has come from the bone marrow rather than the prostate, which a paired whole-blood control distinguishes. Pathology gives a hint: intraductal or ductal histology was present in 48% of germline carriers against 12% of non-carriers in one 150-man series, and localised tumours from germline BRCA2 carriers already look metastatic in their genomes.","The science in detail, 4 of 7, in full; the one-sentence version is on the overview. The four PARP inhibitor eligibility lists, read from the labels. Olaparib alone after enzalutamide or abiraterone: 14 genes, ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D and RAD54L, germline or somatic. Olaparib with abiraterone: BRCA1 and BRCA2 only. Rucaparib after androgen receptor-directed therapy: BRCA1 and BRCA2 only, germline and/or somatic. Niraparib with abiraterone: BRCA2 alone in castration-sensitive disease and BRCA1 or BRCA2 in castration-resistant disease. Talazoparib with enzalutamide: 12 genes, ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2 and RAD51C, of which ATR, FANCA, MLH1, MRE11A and NBN are not on olaparib's list and seven of olaparib's genes are not on this one, with the label stating that no approved test for them exists. The response data behind the widest list: among men with a single-gene alteration and measurable disease in PROfound, confirmed objective response was 24 of 43 with BRCA2, 56%, 3 of 30 with ATM, 10%, and 2 of 34 with CDK12, 6%, with none among the eleven rarer genes, one or two men each. PPP2R2A was enrolled and then left out of the indication for unfavourable benefit and risk.","The science in detail, 5 of 7, in full; the one-sentence version is on the overview. PSMA, an imaging target and a therapeutic one. The tissue survey behind it found PSMA detectable in prostatic epithelium, duodenal mucosa, a subset of proximal renal tubules and colonic neuroendocrine cells and in no other normal tissue, staining 33 of 35 primary prostate adenocarcinomas and 7 of 8 nodal metastases but only 8 of 18 bone metastases, with expression falling as tumours dedifferentiate. At staging, PSMA PET-CT was 27% more accurate than CT with bone scan in 302 randomised men, 92% against 65%, with sensitivity 85% against 38% and specificity 98% against 91%, management change in 28% against 15%, equivocal findings in 7% against 23%, and radiation of 8.4 against 19.2 mSv. At biochemical recurrence it localised disease in 475 of 635 men, 75%, with detection rates of 38% below PSA 0.5 ng/mL, 57% at 0.5 to 1.0, 84% at 1.0 to 2.0, 86% at 2.0 to 5.0 and 97% above 5.0, and positive predictive value 0.84 by histopathology. For radioligand therapy the criterion is lesion by lesion: at least one lesion with uptake greater than normal liver, and no lesion above a size threshold with uptake at or below liver. Of 291 men screened for TheraP, 200, 69%, were eligible. What the scan cannot do is give a histology or a genotype, and a PSMA-low, FDG-avid site in a man on hormonal treatment is one of the ways lineage change announces itself.","The science in detail, 6 of 7, in full; the one-sentence version is on the overview. Leaving the androgen receptor behind. The transition is epigenetic before it is genetic: whole-exome sequencing showed substantial genomic overlap between castration-resistant adenocarcinoma and neuroendocrine disease from the same men, fitting divergent clonal evolution, while methylation separated the two sharply and reassigned some tumours that looked like adenocarcinoma. The genotype that permits it is loss of both RB1 and TP53, shown in mouse models where Rb1 loss enabled lineage plasticity and metastasis and additional Trp53 loss caused antiandrogen resistance, with Ezh2 and Sox2 raised and EZH2 inhibition restoring receptor expression, and in human cells where the shift from luminal to basal-like identity required TP53 and RB1 loss and was mediated by SOX2. Combined RB1, TP53 and PTEN alterations were enriched in clinically defined aggressive variant disease, with RB1 copy loss the strongest single discriminator at 54% of 44 samples. Neuroendocrine is not the only exit: an androgen receptor-null, neuroendocrine-null phenotype sustained by FGF and MAPK signalling has emerged over two decades, and deep phenotyping resolves five states rather than two. Recognition is morphological first, using the six named categories, with AURKA and MYCN co-amplification in 40% of neuroendocrine tumours against 5% of adenocarcinomas, and cell-free DNA methylation discriminated the two states with an area under the curve of 0.96 and 1.0 in two cohorts totalling 101 men.","The science in detail, 7 of 7, in full; the one-sentence version is on the overview. Liquid biopsy, and why it matters more here. Prostate cancer metastasises to bone, and bone is the hardest tissue to biopsy well, so plasma is not a convenience here but often the only practical sample. Above a 2% tumour fraction, which 75.6% of paired samples reached, every somatic mutation found in a matched metastatic biopsy was also present in plasma, with copy-number calls in actionable genes 88.9% concordant. At scale, 94% of 3,334 men had detectable circulating tumour DNA at a median fraction of 7.5%, and 93% of tissue-detected BRCA mutations were found in plasma including 100% of predicted germline variants. Plasma sees more than tissue where it counts: potential androgen receptor resistance alterations in 42% of 2,213 men, including polyclonal and compound mutations and exon 8 deletions, and multiclonal BRCA2 reversions at PARP inhibitor resistance. It cannot separate germline from somatic without a consented germline test, cannot give a histology, cannot measure PSMA, and cannot by itself distinguish a repair-gene variant from the tumour from one from the bone marrow: at a 2% threshold, 19% of men had clonal haematopoiesis variants in plasma and 10% had one in a gene used to decide PARP inhibitor candidacy, most often ATM, accounting for almost half of all somatic repair-gene variants detected. A paired whole-blood control fixes it. Before treatment starts, the useful plasma signal is in BRCA2, ATM and TP53 rather than in the AR amplification that dominates the report.","Frequencies marked cBioPortal were computed from the public API on 25 September 2026 on the deposited sample lists of prad_tcga_pan_can_atlas_2018 (494 sequenced, 489 with copy number, 494 with structural variants), prad_tcga_pub (333), prad_broad (112), prad_cpcg_2017 (477, mutations only), prostate_dkfz_2018 (313, mutations only), prad_eururol_2017 (65), prad_p1000 (1,013), prad_mskcc_2017 (504), prostate_msk_2024 (2,260), prad_msk_stopsack_2021 (2,069), prad_cdk12_mskcc_2020 (1,465), prad_mcspc_mskcc_2020 (424), prad_su2c_2019 (444), prad_su2c_2015 (150), prad_mich (61), prad_fhcrc (141 sequenced, 149 with copy number), nepc_wcm_2016 (114, mutations only) and mpcproject_broad_2021 (82), as sample-level counts of non-synonymous mutation, high-level amplification, deep deletion or structural variant. They are not the papers' own percentages, which are quoted alongside where the abstract gives them.","What the deposits cannot see, stated once so the rows do not have to repeat it. Fusion counts come from the structural-variant profile, so a cohort with no such profile reads zero rather than negative for TMPRSS2-ERG, and a targeted DNA panel that does not bait the breakpoint introns reads about 25% where whole-exome and RNA cohorts read 41 to 46%. The metastatic whole-exome deposits call high-level amplification on chromosome arms gained as a block, so genes near a real amplicon read high: NBN at 8q21 reads 20.5% in prad_su2c_2019 next to MYC at 8q24, and BRIP1, RAD51C, ATR and PMS2 read similarly inflated there, which is why only AR, MYC and the ETS loci are quoted as focal from those deposits. The CPC-GENE and DKFZ localised deposits carry mutation calls only, so their low TP53 and PTEN figures are partly a property of the deposit. Panel cohorts mix primary and metastatic samples, so their figures sit between the two stages rather than describing either."],"group":"genitourinary","burden":"~1.5 million new cases per year worldwide; lifetime risk ~1 in 8 men in high-income countries; median age at diagnosis 67; most PSA-detected disease is indolent and safely watched. ~400,000 deaths per year worldwide, mostly from disease that was already metastatic at diagnosis.","subtypes":["Localised: low / favourable-intermediate / unfavourable-intermediate / high risk (NCCN)","Non-metastatic castration-resistant (nmCRPC)","Metastatic hormone-sensitive (mHSPC; FDA 2026 term 'androgen pathway modulation-naive or -sensitive'), de novo vs recurrent, high vs low volume (CHAARTED)","Metastatic castration-resistant (mCRPC)","HRR-mutant (~20-25% of mCRPC; BRCA2 most actionable)","PTEN-deficient (~25% on CAPItello-281's immunohistochemistry cut-off, 47% on IPATential150's)","PSMA-low / heterogeneous (about a tenth screened out on VISION's criteria, 31% on TheraP's)","Treatment-emergent neuroendocrine prostate cancer (10.5 to 17% of late mCRPC)","Ductal and intraductal / cribriform variants (aggressive)","Prostatic ductal adenocarcinoma","Rare histologies, treated as they are named by the WHO fifth edition: adenoid cystic (basal cell) carcinoma, squamous and adenosquamous carcinoma, prostatic stromal sarcoma","Cambridge Prognostic Group 1 to 5, the five-band NHS risk stratification of localised and locally advanced disease (NICE NG131 1.2.15)"],"biomarkers":["PSA","Gleason / Grade Group","PSMA PET","HRR genes (BRCA2, ATM, etc.)","PTEN","MSI","AR-V7 (research)","Decipher / ArteraAI","PSA, PSA density, PSA doubling time","Grade Group (Gleason) and cribriform/intraductal pattern","mpMRI PI-RADS score","PSMA PET (SUVmax, total tumour volume) for staging and radioligand eligibility","Germline and somatic HRR genes (BRCA2, BRCA1, ATM, PALB2, CDK12)","PTEN loss (IHC or NGS) for capivasertib","MSI/dMMR (~3%, pembrolizumab)","Decipher genomic classifier; ArteraAI digital pathology","AR-V7 (CTC) in research/limited use","Testosterone level (castration confirmation)","Neuroendocrine markers (chromogranin, synaptophysin, RB1/TP53 loss) on progression","Grade group and Gleason score together, as UK reports give both (RCPath G084, October 2024)","Percentage of Gleason pattern 4, a core reporting item in core biopsies since the 2024 UK dataset","Presence of intraductal carcinoma or invasive cribriform carcinoma, a core reporting item and a trigger for germline testing","PSA density, the PSA divided by the MRI prostate volume, used in the very-low-risk definition and in deciding against biopsy","Cambridge Prognostic Group 1 to 5, assigned by the MDT to every newly diagnosed localised or locally advanced case (NICE NG131 1.2.15)","TMPRSS2-ERG: 25-46%","SPOP: 6-14%","FOXA1: 2-16%","PTEN: 12-41%","TP53: 3-41%","AR: 1-57%","AR ligand-binding-domain mutation: 0.4-18%","RB1: 3-23%","BRCA2: 3-11%","ATM: 3-11%","CDK12: 1-6%","BRCA1: 0.2-2%","Mismatch repair genes: 0.2-3%","Microsatellite instability: 3.1%","PSMA (FOLH1): 80-95%"],"standardOfCare":[{"setting":"Screening","approach":"Shared-decision PSA testing from 50 (45 if Black or family history/BRCA), risk-adapted intervals; MRI before biopsy; avoid biopsy if MRI negative and PSA density low.","refs":["psa","mp-mri","precision-mri","germline-testing","erspc","plco-prostate"]},{"setting":"Biochemical recurrence","approach":"PSMA PET to localise; salvage radiotherapy ± ADT after prostatectomy; metastasis-directed SBRT for oligorecurrence (investigational for survival); enzalutamide ± ADT for high-risk BCR (EMBARK).","refs":["psma-pet","biochemical-recurrence","embark","enzalutamide","sbrt","idea-psma-pet-guided-mdt"]},{"setting":"Metastatic hormone-relapsed disease: what is in trials once the approved order runs out","approach":"The approved sequence is in the hormone-relapsed row above. After it, the options are trials: actinium-225 PSMA radioligand therapy for men who have progressed on lutetium-177 (AlphaBreak), the STEAP1 T-cell engager xaluritamig (XALUTE) and the KLK2 engager pasritamig, the EZH2 inhibitor mevrometostat with enzalutamide (MEVPRO-1), and, for treatment-emergent neuroendocrine disease, platinum with etoposide outside a trial and the DLL3 and B7-H3 agents borrowed from small cell lung cancer, tarlatamab and ifinatamab deruxtecan.","refs":["ac225-psma","alphabreak","xaluritamig","xalute","pasritamig","mevrometostat","mevpro-1","tarlatamab","ifinatamab-deruxtecan"]},{"setting":"Localised prostate cancer: monitoring, surgery or radiotherapy, and what each one costs you","approach":"This is the decision the whole of prostate cancer turns on, and it is unusual because the three options are not ranked. NICE NG131 (1.3.8 to 1.3.12) writes one recommendation per Cambridge Prognostic Group: active surveillance is offered first at CPG 1, a choice between all three is offered at CPG 2, radical treatment is offered at CPG 3 with surveillance kept open for men who choose not to be treated immediately, and surveillance is not offered at CPG 4 and 5. If you were given a risk band instead of a number, the bridge is that CPG 1 is low risk, CPG 2 and 3 are intermediate risk and CPG 4 and 5 are high risk; the group is worked out from your Gleason score or grade group, your PSA and your T stage, and a UK pathology report carries the Gleason score and the grade group together. For CPG 1 to 3, NICE (1.3.7) sends the conversation to its box 2, which is a table of what happened to 100 men offered each option in the UK ProtecT trial, and the honest summary of that table is that survival was the same and the harms were not. On survival, box 2 reports that at 10 years, 98 out of 100 men offered monitoring, 99 out of 100 offered prostatectomy and 99 out of 100 offered radiotherapy had not died of prostate cancer, and that the evidence does not show a difference between them. At a median of 15 years the trial found death from prostate cancer in 17 of 545 men (3.1 percent) on monitoring, 12 of 553 (2.2 percent) after prostatectomy and 16 of 545 (2.9 percent) after radiotherapy, with the overall comparison not significant. What treatment changed was spread: metastases in 51 men (9.4 percent) on monitoring against 26 (4.7 percent) and 27 (5.0 percent), and clinical progression in 141 (25.9 percent) against 58 (10.5 percent) and 60 (11.0 percent). A quarter of the monitoring group, 133 men, were alive at the end of follow-up with no prostate cancer treatment of any kind. On continence, box 2 reports moderate to severe incontinence at 6 months in 19 out of 100 men offered prostatectomy against 4 on monitoring and 6 after radiotherapy, and at 6 years in 13, 8 and 5. The trial's own patient-reported figures are blunter: pad use went from 1 percent before treatment to 46 percent at 6 months after surgery, against 4 percent and 5 percent in the other two groups, and was still 17 percent at 6 years and 18 to 24 percent through years 7 to 12. On sexual function, box 2 reports moderate or severe erectile dysfunction at 6 months in 66 out of 100 men offered prostatectomy, 48 after radiotherapy and 29 on monitoring, and at 6 years in 50, 36 and 40. Of the men in the trial, 67 percent could get an erection firm enough for intercourse before anything was done; at 6 months that was 12 percent after surgery, 22 percent after radiotherapy and 52 percent on monitoring, and by year 12 all three groups had converged at a low level. On bowels, radiotherapy is the one that costs: moderate to severe impact of bowel habits on quality of life at 6 months in 10 out of 100 men offered radiotherapy against 3 in each other group, and faecal leakage in 12 percent of the radiotherapy group against 6 percent of the others by year 12. Nothing in this row is a prediction about one man. It is what happened to 1,643 UK men aged 50 to 69 with mostly CPG 1 to 3 disease, and the reason to read it is that it names the trade-off rather than gesturing at it. NICE surrounds the choice with process: a decision aid in the clinic (1.1.6), nomograms with their limits explained (1.1.7), all relevant options discussed even when the local service does not offer them (1.1.9), an assessment by both a specialist surgical oncologist and a specialist clinical oncologist (1.3.5), and an explicit conversation about sexual function, physical appearance, continence and other aspects of masculinity with the man and, if he wishes, his partner (1.1.12).","refs":["active-surveillance","robotic-surgery","hypofractionated-radiotherapy","brachytherapy","protect","psa","gleason-grade-group","cambridge-prognostic-group","percentage-gleason-pattern-4","cribriform-prostate-cancer","mp-mri","multidisciplinary-tumour-board"],"guideline":{"version":"NICE NG131 (2019, updated December 2021)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"}},{"setting":"If you choose radiotherapy: the schedule, and the hormone therapy that comes with it","approach":"Choosing radiotherapy is choosing a schedule and a course of hormone therapy at the same time, and men are often surprised by the second part. On the schedule, NICE NG131 (1.3.19) says to offer hypofractionated radiotherapy, 60 Gy in 20 fractions, using image-guided intensity modulated radiation therapy unless contraindicated, with conventional radiotherapy, 74 Gy in 37 fractions, reserved for people who cannot have the shorter course. Twenty visits over four weeks is therefore the standard rather than a lesser version of it. NG131 (1.3.24) says to consider adding a brachytherapy boost, where radioactive sources are placed in the prostate itself, for CPG 2 to 5, and (1.3.25) not to offer brachytherapy alone at CPG 4 and 5, so whether a boost is available is a question about the centre. On the hormone therapy, NG131 (1.3.21) says to offer radical radiotherapy combined with androgen deprivation therapy rather than either alone for CPG 2, 3, 4 and 5, (1.3.22) six months of it before, during or after the radiotherapy, and (1.3.23) to consider continuing for up to 3 years at CPG 4 and 5 while discussing the benefits and risks of that with the person. This matters because almost everything men describe afterwards as the effect of radiotherapy is the effect of the hormone therapy: the hot flushes, the loss of sex drive, the weight around the waist, the tiredness. The radiotherapy's own signature is in the bowel and the bladder in the weeks around treatment, and in the small late risks: NG131 (1.3.6) asks that people are told about the small increase in the risk of colorectal cancer after radical external beam radiotherapy, and (1.3.42) that anyone with signs of radiation-induced enteropathy is cared for by a team with expertise in it. For high-risk disease starting long-term hormone therapy, NG131 (1.3.26) asks for a separate discussion about adding six cycles of docetaxel, with box 3 setting out both sides plainly: clear evidence that progression is delayed by about a year, a five-year survival difference of 84 against 80 out of 100 that might be chance, and 15 out of 100 developing a fever from a low white count with 1 in 100 dying of an infection they might not otherwise have had.","refs":["hypofractionated-radiotherapy","brachytherapy","sbrt","docetaxel","stampede","chhip","curative-intent"],"guideline":{"version":"NICE NG131 (2019, updated December 2021)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"}},{"setting":"Living with hormone therapy: hot flushes, bones, heart, weight and mood, and what is offered for each","approach":"Hormone therapy is the longest part of this illness for most men and the least well covered. It works by taking testosterone away, and testosterone was doing a great many other things. The effects last for as long as the treatment does, and Prostate Cancer UK says that after stopping it can take several months to several years for them to settle, while an orchidectomy cannot be reversed at all. Hot flushes are the commonest complaint: NICE NG131 (1.4.3) says to offer medroxyprogesterone 20 mg a day for an initial 10 weeks and to evaluate the effect at the end, and (1.4.4) to consider cyproterone acetate 50 mg twice a day for 4 weeks if that fails or is not tolerated; in a randomised trial of 309 men the median daily hot-flush score fell by 83.7 percent on medroxyprogesterone and 94.5 percent on cyproterone at one month, against 47.2 percent on venlafaxine. NG131 (1.4.5) also says plainly that there is no good-quality evidence for complementary therapies here. Bone thinning starts in the first year and increases with time on treatment: in 50,613 men, 19.4 percent of those on androgen deprivation surviving at least five years had a fracture against 12.6 percent of those not on it. NICE's four bone sentences run in a specific order: (1.4.12) do not routinely offer bisphosphonates to prevent osteoporosis, (1.4.13) consider assessing fracture risk, (1.4.14) offer bisphosphonates to those who have osteoporosis, and (1.4.15) consider denosumab where bisphosphonates are contraindicated or not tolerated. A DEXA scan is how the question is answered. On the heart and the metabolism, in 73,196 Medicare enrollees GnRH agonist use carried adjusted hazard ratios of 1.44 for new diabetes, 1.16 for coronary heart disease, 1.11 for myocardial infarction and 1.16 for sudden cardiac death; in the HERO trial, major adverse cardiovascular events occurred in 2.9 percent of 622 men on oral relugolix against 6.2 percent of 308 on leuprolide over 48 weeks. Prostate Cancer UK suggests general health checks roughly every six months: weight, blood pressure, cholesterol and a diabetes check. Body composition changes: muscle goes, fat arrives, particularly at the waist, and joint and muscle aches follow. NICE NG131 (1.4.18) says to tell people that fatigue is a recognised effect of the therapy and might not be the cancer, and (1.4.19) to offer supervised resistance and aerobic exercise at least twice a week for 12 weeks to reduce fatigue and improve quality of life, which is the single most concrete offer in this section. On mood, Prostate Cancer UK says hormone therapy itself can cause tearfulness, mood swings, low mood, anxiety and depression, and a meta-analysis of 18 studies in 168,756 men found a 41 percent higher risk of depression on androgen deprivation. Memory and concentration change too, though the evidence for a direct cause is weak. Gynaecomastia has its own answer: NG131 (1.4.16) says to offer prophylactic radiotherapy to both breast buds within the first month for people starting long-term bicalutamide monotherapy, a single 8 Gy fraction, with weekly tamoxifen considered if that does not work. And where treatment is long-term and not adjuvant, NG131 (1.4.1) says to consider intermittent therapy, discussing the limited evidence for a reduction in side effects and the effect on progression, with PSA measured every 3 months and treatment restarted at 10 nanogram/ml or above.","refs":["adt","hot-flushes-on-hormone-therapy","treatment-induced-bone-loss","gynaecomastia","relugolix","abiraterone","enzalutamide","bicalutamide","denosumab","zoledronic-acid","cancer-related-fatigue","exercise-during-chemotherapy","psycho-oncology"],"guideline":{"version":"NICE NG131 (2019, updated December 2021)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"}},{"setting":"Continence and sexual function: what happens, what help exists, and how to ask for it","approach":"These are the two things men do not raise, so this page raises them first. On continence: most men leak when the catheter comes out after a prostatectomy, usually seven to ten days after the operation, because the operation disturbs the sphincter and the pelvic floor. It improves. In ProtecT, pad use after surgery was 46 percent at six months and 17 percent at six years; radiotherapy barely touched continence at 4 to 5 percent. What helps, in the order the guideline puts it: pelvic floor muscle exercises, started four to six weeks before the operation and restarted as soon as the catheter is out; absorbent pads and pants, sheaths, bed protectors and clamps while things settle; bladder retraining for urgency; and, where it does not settle, medicines, an internal male sling for men leaking two to three pads a day at a year, or an artificial urinary sphincter for men still leaking heavily six months on. NICE NG131 (1.3.39) requires access to specialist continence services, (1.3.40) referral for consideration of an artificial urinary sphincter for intractable stress incontinence, and (1.3.41) rules out bulking agent injections. On sexual function: the figures are in the first row of this page, and they are worth reading with someone rather than alone. What is worth knowing is that the services exist and that starting early works better. NICE NG131 (1.3.36) says to offer access to specialist erectile dysfunction services after radical treatment, (1.3.37) to offer PDE5 inhibitor tablets, and (1.3.38) to offer vacuum devices, intraurethral inserts, penile injections or a penile prosthesis where tablets fail or are contraindicated; (1.4.8) extends the same access to men starting hormone therapy and (1.4.10, 1.4.11) repeats the ladder for them. All of it is free on the NHS whether the erection is wanted for sex or for masturbation, and there is no age limit. Prostate Cancer UK says to try each type of tablet at least eight times before moving on, that injections work within 5 to 10 minutes and often work even when desire is low, that about 3 in 100 implants get infected and roughly 5 in 100 inflatable implants need replacing within ten years, and that an erection lasting more than four hours is priapism and means going straight to accident and emergency. Two other things men are rarely told: the penis can become shorter or curved after surgery, and using a vacuum pump early, alone or with tablets, may help preserve it; and orgasm survives even when ejaculation does not, though it feels different, and some men leak urine at orgasm, which pelvic floor exercises help. Beside all of this NICE NG131 (1.1.13) offers the man and his partner the chance to talk to a healthcare professional experienced in psychosexual issues at any stage, and (1.4.9) considers psychosexual counselling for couples on long-term hormone therapy. Taking that offer is not an admission of anything.","refs":["stress-urinary-incontinence","pelvic-floor-muscle-exercises","artificial-urinary-sphincter","erectile-dysfunction-after-prostate-cancer","priapism","acute-urinary-retention","robotic-surgery","hypofractionated-radiotherapy","psycho-oncology","peer-support-groups","quality-of-life"],"guideline":{"version":"NICE NG131 (2019, updated December 2021)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"}},{"setting":"A rising PSA after treatment: what it means, how fast it is rising, and what happens next","approach":"After radical treatment the PSA becomes the thing everyone watches, and the waiting for each result has its own name in the clinic. NICE NG131 (1.3.47) says to check it no earlier than 6 weeks after treatment, then at least every 6 months for the first 2 years and at least once a year after that, and (1.3.48) not to do a routine rectal examination while it stays at baseline; (1.3.49) allows remote follow-up after the first 6 months for people with a stable PSA and no significant complications, which for many men means a blood test locally and a phone call. The most useful sentence in the guideline for anyone watching a number go up is (1.3.55): a rising PSA alone should not mean an immediate change in treatment. What matters is the speed, so (1.3.56) asks for the doubling time to be estimated from at least three measurements over at least six months. After a prostatectomy with no known metastases the standard answer is radiotherapy to the prostate bed (1.3.57), often still given with the aim of cure. NG131 (1.3.54) says not to offer routine MRI before salvage radiotherapy but to offer an isotope bone scan if symptoms or PSA trends suggest metastases, and (1.3.58) to consider entry to a clinical trial; in practice a PSMA PET scan is now what localises the disease, and the imaging rows on this page say what it can and cannot see. Hormone therapy is deliberately held back: (1.3.59) says not to offer it routinely for biochemical relapse unless there is symptomatic local progression, proven metastases, or a doubling time of less than three months, which is the guideline protecting men from years of side effects for a number rather than a disease. Where the risk is high, the EMBARK trial is the evidence for adding enzalutamide at this point, and that is a conversation for the multidisciplinary team rather than a default.","refs":["psa-doubling-time","psa","biochemical-recurrence","psma-pet","embark","psa50"],"guideline":{"version":"NICE NG131 (2019, updated December 2021)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"}},{"setting":"When prostate cancer reaches the bone: cord compression, pain, and protecting the skeleton","approach":"Prostate cancer goes to bone more reliably than almost any other cancer, and the emergency that follows is the one men are least often warned about. Metastatic spinal cord compression happens when deposits in or near the spine press on the spinal cord, and Prostate Cancer UK says about 4 in 100 people with prostate cancer develop it, with the risk highest once the cancer has reached the spine. Untreated it causes nerve damage and can cause paralysis; treated quickly, the risk of that being permanent falls. The signs are worth learning by heart: new, severe or progressive back or neck pain, pain worse on coughing, straining, lying down or at night, tenderness over the spine, a band of pain around the chest or abdomen, pain running down an arm or leg, weakness or unsteadiness in the legs, numbness or pins and needles that does not go away, and any loss of control of the bladder or bowel. NICE NG234 (1.3.2) says to immediately contact the metastatic spinal cord compression coordinator for anyone with a past or current cancer diagnosis and those signs, and to treat it as an oncological emergency; (1.3.3) asks for advice within 24 hours for the pain pattern alone; (1.5.2) asks for an MRI as soon as possible and always within 24 hours; and (1.4.1 to 1.4.3) ask for immobilisation and nursing flat while that is arranged. Prostate Cancer UK adds the practical instruction: do not wait to see if it settles, do not worry that it is the evening or the weekend, ask the team in advance to write down who to contact during the day, at night and at weekends, and if you cannot reach anyone, go to A and E and tell them you have prostate cancer and symptoms of spinal cord compression, because not everyone who sees you will be familiar with it. Alongside the emergency sits the ordinary work of protecting a skeleton. NICE NG131 (1.5.19) says to consider zoledronic acid to prevent or reduce skeletal-related events in hormone-relapsed metastatic disease and (1.5.20) bisphosphonates for pain where painkillers and palliative radiotherapy have not been enough; (1.3.35) says not to offer bisphosphonates to prevent bone metastases developing, and (1.4.12) not to offer them routinely to prevent osteoporosis on hormone therapy. Those are three different questions and NICE gives them three different answers, which is why a single yes or no about bone drugs usually means the wrong question was asked. Radium-223 remains an option for symptomatic bone-only disease that is no longer responding to hormone therapy, with bone protection alongside. A word about words: NICE calls that state hormone-relapsed prostate cancer, many hospitals and papers call it castration-resistant or castrate-resistant, and the three mean the same thing, which is prostate cancer that has started growing again despite testosterone being switched off.","refs":["metastatic-spinal-cord-compression","bone-metastases","radium-223","zoledronic-acid","denosumab","palliative-radiotherapy","pain-management"],"guideline":{"version":"NICE NG234 (2023) and NICE NG131 (2019, updated December 2021)","url":"https://www.nice.org.uk/guidance/ng234/chapter/Recommendations"}},{"setting":"A clinical trial or standard treatment","approach":"Prostate cancer has an unusually full trial landscape, because the number of things worth testing keeps growing: radioligands moving earlier in the disease, PARP inhibitor and AR-pathway combinations selected by genetics, T-cell engagers against STEAP1 and KLK2, and, at the other end, trials of how to monitor low-risk disease with fewer biopsies. NICE NG131 names trials at several points rather than as a last resort: (1.3.28) says high-intensity focused ultrasound and cryotherapy should be used for localised disease only in controlled trials comparing them with established treatments, which is the answer to give when a focal treatment is offered privately; (1.3.32 and 1.3.33) say the same about immediate post-operative radiotherapy and adjuvant hormone therapy after prostatectomy; (1.3.58) says to consider trial entry for biochemical relapse; and (1.2.5) restricts mapping transperineal template biopsy at initial assessment to trials. The practical questions are the ordinary ones. The NHS says you can ask your doctor or a patient organisation about trials you may be eligible to join, that you would usually be randomly assigned to the new treatment or to a control group, and that you can leave at any point without giving a reason and without it affecting your care. Worth asking as well: whether taking part means travelling, how many extra scans and biopsies it involves, whether the trial covers travel costs, and what happens to your treatment when the trial ends.","refs":["protect","stampede","embark","multidisciplinary-tumour-board"],"guideline":{"version":"NICE NG131 (2019, updated December 2021)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"}},{"setting":"When to talk about palliative care","approach":"Palliative care in prostate cancer is often needed for years rather than weeks, because men live a long time with metastatic disease, and the guideline treats it that way. NICE NG131 (1.5.4) says to ensure palliative care is available when needed and is not limited to the end of life, and that care should not be restricted to being associated with hospice care. NG131 (1.5.1) asks for tailored information and access to specialist urology and palliative care teams from the point of a metastatic diagnosis, (1.5.2) for palliative interventions to be integrated at any stage into coordinated care with smooth transitions between settings, (1.5.3) for personal preferences and the preferred place of care to be discussed as early as possible with the man, his partner and his carers, and (1.5.5) for a regular assessment of needs rather than waiting to be asked. In practice this is the team that manages bone pain, fatigue, bowel and bladder symptoms, the fear that arrives with each PSA result, and the conversations nobody else starts. Marie Curie says palliative care can be given alongside treatments aimed at controlling the illness, which is the sentence to quote if a referral feels like a verdict. Alongside it sit the things that keep a life working: Maggie's centres, which are free and need no appointment; Prostate Cancer UK's specialist nurses, one-to-one peer support and online community; a carer's assessment, which is free and is for the person doing the caring rather than the patient; and help with money and work, which is easier to arrange early than late.","refs":["palliative-care","psycho-oncology","peer-support-groups","financial-navigation","survivorship-care-plan","pain-management"],"guideline":{"version":"NICE NG131 (2019, updated December 2021)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"}},{"setting":"Localised prostate cancer, CPG 1 (low risk): the case for doing nothing yet","approach":"Active surveillance, with PSA, multiparametric MRI and repeat biopsy, is the standard and not a compromise. ProtecT randomised 1,643 men with PSA-detected localised disease and found prostate cancer mortality at 15 years of 3.1 percent under monitoring, 2.2 percent after prostatectomy and 2.9 percent after radiotherapy (p=0.53), while 24.4 percent of monitored men were alive at the end of follow-up having never had any treatment. Treatment halves metastasis (9.4 percent monitored against 4.7 and 5.0 percent) but the base rate is low. PIVOT, in a largely PSA-detected United States population, found no significant mortality benefit from surgery over observation at nearly 20 years and more incontinence and erectile dysfunction through 10 years. Padeliporfin vascular-targeted photodynamic therapy is licensed for this population but NICE TA546 does not recommend it.","refs":["protect","pivot","nct01310894","prostate-treatment-choice-localised","prostate-focal-therapy","active-surveillance","decipher-prostate"],"guideline":{"version":"NICE NG131; EAU prostate cancer guidelines","url":"https://www.nice.org.uk/guidance/ng131"}},{"setting":"Localised prostate cancer, CPG 2 to 3 (intermediate risk): surgery or radiotherapy, and how many visits","approach":"Radical prostatectomy and radical radiotherapy give the same cancer outcome and different side-effect shapes; ProtecT's patient-reported outcomes are the best guide to which. If radiotherapy is chosen, moderate hypofractionation is standard: CHHiP found 60 Gy in 20 fractions non-inferior to 74 Gy in 37 (5-year freedom from failure 90.6 against 88.3 percent), PROFIT found 60 Gy in 20 non-inferior to 78 Gy in 39 (85 percent in both arms) and RTOG 0415 found 70 Gy in 28 non-inferior to 73.8 Gy in 41 in low-risk disease. Five-fraction stereotactic body radiotherapy is non-inferior again (PACE-B, 5-year freedom from failure 95.8 against 94.6 percent) at the price of more late grade 2 or higher genitourinary toxicity (26.9 against 18.3 percent). Four to six months of androgen deprivation is added: RTOG 94-08 found 4 months raised 10-year overall survival from 57 to 62 percent, with the benefit confined to intermediate-risk men, and EORTC 22991 found 6 months halved biochemical failure at every radiation dose tested.","refs":["chhip","profit-trial","rtog-0415","pace-b","hypo-rt-pc","rtog-9408","eortc-22991","prostate-radiotherapy-fractionation","prostate-treatment-choice-localised"],"guideline":{"version":"NICE NG131; EAU prostate cancer guidelines","url":"https://www.nice.org.uk/guidance/ng131"}},{"setting":"Localised and locally advanced prostate cancer, CPG 4 to 5 (high risk): radiotherapy with long androgen deprivation","approach":"Radiotherapy plus long-course androgen deprivation, not either alone. SPCG-7 halved 10-year prostate cancer mortality by adding radiotherapy to hormones (11.9 against 23.9 percent) and the NCIC PR.3/MRC PR07 intergroup trial confirmed it in 1,205 men (overall survival hazard ratio 0.70). EORTC 22863 showed the reverse addition works too, raising 10-year overall survival from 39.8 to 58.1 percent. Duration is three years, not six months: EORTC 22961 failed to show non-inferiority for 6 months (5-year mortality 19.0 against 15.2 percent, hazard ratio 1.42), RTOG 92-02 found 28 months better than 4 on every endpoint and better for survival in Gleason 8 to 10 disease (45.1 against 31.9 percent at 10 years), and DART 01/05 GICOR found the same even at radiation doses above 76 Gy. A low-dose-rate brachytherapy boost doubles freedom from biochemical failure at 9 years (83 against 62 percent, ASCENDE-RT) without a survival difference. Adding abiraterone for two years improved 6-year metastasis-free survival from 69 to 82 percent in the STAMPEDE non-metastatic comparison; adding docetaxel improved 4-year overall survival from 89 to 93 percent in RTOG 0521.","refs":["spcg-7","nct00002633","eortc-22863","eortc-22961","rtog-9202","dart-01-05-gicor","ascende-rt","rtog-0521","stampede","prostate-adt-burden","imrt-igrt"],"guideline":{"version":"NICE NG131; EAU prostate cancer guidelines","url":"https://www.nice.org.uk/guidance/ng131"}},{"setting":"After radical prostatectomy with adverse pathology: wait for the PSA rather than irradiate everyone","approach":"An observation policy with early salvage radiotherapy triggered by a rising PSA, not adjuvant radiotherapy. RADICALS-RT (1,396 men), RAVES (333) and GETUG-AFU 17 (424) all found the same, and the prospectively planned ARTISTIC meta-analysis of all 2,153 gave an event-free survival hazard ratio of 0.95 (95 percent confidence interval 0.75 to 1.21), a 1 percentage point difference at 5 years. The gain is in what is avoided: only 33 percent of the RADICALS-RT observation group needed radiotherapy within 8 years, and adjuvant treatment caused more incontinence at 1 year and more grade 3 to 4 urethral stricture (6 against 4 percent). GETUG-AFU 17 measured the same harm larger: late grade 2 or worse genitourinary toxicity 27 against 7 percent and erectile dysfunction 28 against 8 percent. When salvage radiotherapy is given, add androgen deprivation: GETUG-AFU 16 raised 120-month progression-free survival from 49 to 64 percent with 6 months of goserelin, SPPORT raised 5-year freedom from progression from 70.9 to 81.3 percent by adding short-term androgen deprivation and to 87.4 percent by adding pelvic nodal radiotherapy as well, and RADICALS-HD found 24 months better than 6 (10-year metastasis-free survival 78.1 against 71.9 percent) at the cost of more grade 3 toxicity (19 against 14 percent).","refs":["radicals-rt","raves","getug-afu-17","artistic-meta-analysis","getug-afu-16","nct00567580","radicals-hd","rtog-9601","swog-8794","eortc-22911"],"guideline":{"version":"NICE NG131; EAU prostate cancer guidelines","url":"https://www.nice.org.uk/guidance/ng131"}},{"setting":"Metastatic hormone-sensitive prostate cancer: androgen deprivation is never given alone","approach":"Androgen deprivation plus at least one of an androgen receptor pathway inhibitor and docetaxel. Docetaxel: CHAARTED found median overall survival 57.6 against 44.0 months (hazard ratio 0.61) with the benefit concentrated in high-volume disease, and the STAMPEDE docetaxel comparison agreed; GETUG-AFU 15, with 385 men, was the underpowered exception. Androgen receptor pathway inhibitors: abiraterone in LATITUDE and STAMPEDE (hazard ratio for death 0.63 in STAMPEDE's 1,917 men), apalutamide in TITAN (24-month overall survival 82.4 against 73.5 percent, hazard ratio 0.67), enzalutamide in ARCHES and ENZAMET, darolutamide in ARANOTE. Triplets for fit men with de novo high-volume disease: ARASENS added darolutamide to docetaxel and androgen deprivation, PEACE-1 added abiraterone. For low-volume metastatic disease, radiotherapy to the prostate improved survival in the prespecified subgroup of the STAMPEDE radiotherapy comparison. Castration itself can be delivered orally with relugolix (NICE TA995) or, in trials, by transdermal oestradiol patches, which give fewer hot flushes (35 against 86 percent) and better bone density with no excess cardiovascular events. Continuous, not intermittent: SWOG 9346 could not exclude a 20 percent higher risk of death with treatment breaks.","refs":["chaarted","getug-afu-15","latitude","stampede","nct02489318","arches","enzamet","arasens","aranote","peace-1","patch-transdermal-oestradiol","swog-9346","prostate-stampede-arms","prostate-adt-burden"],"guideline":{"version":"NICE TA1110, TA712, TA741, TA1109, TA903; EAU prostate cancer guidelines","url":"https://www.nice.org.uk/guidance/ta1110"}},{"setting":"Hormone-relapsed non-metastatic prostate cancer with a fast-rising PSA","approach":"Apalutamide or darolutamide added to continuing androgen deprivation, for men whose PSA doubling time is 10 months or less. SPARTAN (1,207 men) found median metastasis-free survival 40.5 against 16.2 months with apalutamide (hazard ratio 0.28), and PROSPER and ARAMIS found the same size of effect with enzalutamide and darolutamide. The cost is measurable: in SPARTAN, rash 23.8 against 5.5 percent, hypothyroidism 8.1 against 2.0 percent and fracture 11.7 against 6.5 percent. In England NICE TA740 recommends apalutamide and TA660 darolutamide here; NICE TA580 does not recommend enzalutamide, so one of the three licensed options is not routinely funded. The whole setting is shrinking: men called non-metastatic on CT and bone scan are frequently metastatic on PSMA PET, and the three trials that defined it used conventional imaging.","refs":["nct01946204","prosper","aramis","psma-pet","prostate-uk-drug-approvals"],"guideline":{"version":"NICE TA740, TA660; NICE TA580 does not recommend enzalutamide","url":"https://www.nice.org.uk/guidance/ta740"}},{"setting":"Hormone-relapsed (castration-resistant) metastatic prostate cancer: the order the approved treatments are given in","approach":"An androgen receptor pathway inhibitor if none has been used (COU-AA-302, PREVAIL before chemotherapy; COU-AA-301, AFFIRM after docetaxel); docetaxel with prednisone (TAX 327, median survival 18.9 against 16.5 months against mitoxantrone, with pain relief in 35 against 22 percent); cabazitaxel after docetaxel (TROPIC, 15.1 against 12.7 months; PROSELICA showed 20 mg/m2 is non-inferior to 25 with grade 3 or 4 events in 39.7 against 54.5 percent); olaparib for BRCA-mutated disease after a newer hormonal treatment (NICE TA887; TRITON3 shows the effect is BRCA-dependent and absent in ATM-altered disease); lutetium-177 PSMA radioligand therapy (VISION, TheraP, PSMAfore, but NICE TA930 does not recommend it in England); radium-223 for symptomatic bone-predominant disease without visceral metastases (ALSYMPCA, NICE TA412, only after or instead of docetaxel), now with an overall survival benefit in combination with enzalutamide when bone-protecting agents are given (PEACE-3, 38.2 against 32.6 months). The one hard sequencing rule comes from CARD: after rapid failure of one androgen receptor pathway inhibitor, cabazitaxel beats switching to the other (imaging-based progression-free survival 8.0 against 3.7 months, overall survival 13.6 against 11.0 months).","refs":["cou-aa-301","cou-aa-302","affirm","prevail","tax-327","swog-9916","tropic","proselica","firstana","card","triton3","profound","vision","psmafore","therap","alsympca","peace-3","prostate-crpc-sequencing","prostate-hrr-eligibility"],"guideline":{"version":"NICE TA387, TA377, TA259, TA316, TA101, TA391, TA887, TA412; NICE TA930 does not recommend lutetium-177 vipivotide tetraxetan","url":"https://www.nice.org.uk/guidance/ta930"}},{"setting":"Combinations and strategies that were tested and abandoned","approach":"Checkpoint inhibitors in unselected men do not work: IMbassador250, KEYNOTE-641, KEYNOTE-921, KEYNOTE-991 and CA184-043 between them randomised more than 5,000 men and none improved survival. Anti-angiogenic drugs do not work: CALGB 90401 with bevacizumab and COMET-1 with cabozantinib both improved progression endpoints and neither improved survival, and bevacizumab quadrupled treatment-related deaths (4.0 against 1.2 percent). Endothelin A antagonists do not work: SWOG S0421 and ENTHUSE M1 were both flatly negative. Radium-223 must not be combined with abiraterone without bone protection: ERA 223 found fractures in 29 against 11 percent and no benefit. Two drugs improved radiographic progression-free survival substantially and did nothing for survival, orteronel in ELM-PC 4 and tasquinimod in 10TASQ10, which is why an imaging endpoint alone is not accepted here.","refs":["imbassador250","keynote-921","keynote-641","keynote-991","ca184-043-ipilimumab","calgb-90401","comet-1","swog-s0421-atrasentan","enthuse-m1-zibotentan","ready-dasatinib","era-223","elm-pc-4-orteronel","tasquinimod-10tasq10","prostate-failed-programmes"],"guideline":{"version":"Read from the primary publications; none of these is recommended in any guideline","url":"https://uroweb.org/guidelines/prostate-cancer"}}],"stateOfArt":["Radioligand therapy across the metastatic continuum: 177Lu-PSMA-617 approved post-taxane (2022), pre-taxane (2025), and at first metastatic diagnosis with ARPI (31 July 2026).","Triplet therapy (ADT + ARPI + docetaxel) for high-volume de novo disease, with OS HR ~0.7 (ARASENS, PEACE-1).","Genotype-directed doublets: PARP inhibitor + ARPI for HRR-mutant (OS benefit in TALAPRO-2) and capivasertib + abiraterone for PTEN-deficient disease (2026).","Diagnostic pathway rebuilt around MRI-first biopsy and PSMA PET staging; active surveillance is default for low-risk disease.","AI pathology (ArteraAI Prostate) is FDA-authorised to predict who benefits from adding hormone therapy to radiation.","First immunotherapies with real activity: STEAP1 and KLK2 T-cell engagers in phase 3, after checkpoint inhibitors failed in unselected disease.","The androgen receptor is reactivated by five different routes and most men with castration-resistant disease have more than one: amplification of the gene in about half of castration-resistant cohorts against 1% of untreated primaries, amplification of an enhancer 624 kb upstream in 81% of deeply sequenced metastases, ligand-binding-domain mutation in 13.7 to 18.0%, the AR-V7 splice variant, and raised receptor expression with no genomic change at all.","Stage moves every frequency in this disease more than ancestry or assay does. TP53 runs from 3.4% in localised whole genomes to 41% at rapid autopsy, AR amplification from 1.0% to 57%, PTEN deletion from 12% to 41%. A prostate cancer percentage quoted without its disease state is not usable.","DNA repair is the one axis that changes both treatment and a family's future: inherited mutations in 11.8% of 692 men with metastatic disease, led by BRCA2 at 5.3%, with no difference by family history or age, which is why germline testing is offered to everyone with metastatic disease.","The four PARP inhibitor routes ask for four different gene lists, from BRCA2 alone to a 14-gene panel, and the response evidence does not spread evenly across them: in PROfound, confirmed response was 56% with BRCA2, 10% with ATM and 6% with CDK12.","Mismatch repair deficiency is present in 3.1% of prostate cancers and is the only setting in this disease where checkpoint blockade gives durable responses; one carrier in five also has Lynch syndrome, and in prostate the gene is usually broken by a complex MSH2 or MSH6 rearrangement rather than by MLH1 methylation.","PSMA PET replaced CT and bone scan on accuracy, 92% against 65% in a randomised comparison, and it is the entry ticket for radioligand therapy, but about three men in ten screened for that treatment are ineligible because parts of their tumour no longer express the target.","The way out of androgen receptor dependence is a change of cell identity, not a mutation in the pathway. It requires loss of both RB1 and TP53, it is epigenetic before it is genetic, and it leads either to a neuroendocrine programme or to an androgen receptor-null, neuroendocrine-null state that runs on FGF and MAPK signalling.","Plasma works better here than in most cancers because the metastases are in bone: tumour DNA is detectable in 94% of men with advanced disease, BRCA concordance with tissue is 93%, and plasma sees the polyclonal androgen receptor and reversion events one biopsy cannot."],"history":[{"year":1941,"title":"A cancer is shown to depend on a hormone","note":"Huggins and Hodges castrated men with metastatic prostate cancer, or gave them oestrogen, and the disease regressed; androgen injection made it worse. The first demonstration that a human cancer depends on a circulating hormone, and the origin of systemic cancer therapy. Huggins shared the 1966 Nobel Prize for it.","refs":["paper-huggins-hodges-castration-serum-phosphatases-prostate-1941","androgen-deprivation"]},{"year":1966,"title":"Gleason grading system published","refs":["gleason-grade-group"]},{"year":1986,"title":"PSA test approved for monitoring; screening spreads in the 1990s","refs":["psa"]},{"year":1987,"title":"Prostate-specific antigen becomes a marker","note":"Stamey measured the antigen in 2,200 samples from 699 patients: it tracked tumour volume, fell to undetectable after prostatectomy with a half-life of 2.2 days, and detected recurrence. The same paper warned that it is raised in benign prostatic hyperplasia and is not specific.","refs":["paper-stamey-psa-serum-marker-nejm-1987"]},{"year":1991,"title":"The 4.0 threshold, and the start of population testing","note":"Catalona screened 1,653 healthy men over 50 and biopsied those at or above 4.0 micrograms per litre. Rectal examination alone would have missed 12 of the 37 cancers. Testing spread through primary care over the following decade with no randomised evidence that it saved lives.","refs":["paper-catalona-psa-screening-test-nejm-1991"]},{"year":1995,"title":"Castration resistance is shown to be an adaptation, not an escape","note":"Visakorpi found androgen receptor gene amplification in 7 of 23 tumours recurring on androgen deprivation and in none of the pre-treatment samples from the same men. Chen showed in 2004 that receptor overexpression alone is necessary and sufficient to convert sensitive disease to resistant, and turns antagonists into agonists.","refs":["paper-visakorpi-androgen-receptor-amplification-nat-genet-1995","paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004"]},{"year":1995,"title":"The receptor can also be rewired to read the wrong hormone","note":"In the same year as the amplification finding, ligand-binding-domain mutations that let progesterone, oestrogen and the antiandrogen itself switch the receptor on are found in 5 of 10 androgen-independent cancers, the second of the five routes out of castration.","refs":["paper-taplin-ar-mutation-androgen-independent-prostate-nejm-1995","androgen-receptor"]},{"year":1997,"title":"The map that made PSMA imaging possible","note":"An immunohistochemical survey shows PSMA is detectable in prostatic epithelium, duodenal mucosa and some renal tubules and almost nowhere else, while falling in dedifferentiated disease, predicting both the treatment and its limits.","refs":["paper-silver-psma-expression-normal-malignant-tissues-ccr-1997","psma"]},{"year":2004,"title":"The first drug to extend survival after hormone therapy fails","note":"TAX 327 gave median survival of 18.9 months with three-weekly docetaxel against 16.5 with mitoxantrone, and improved pain and quality of life; SWOG 9916 reported 17.5 against 15.6 months in the same issue. The end of therapeutic nihilism in castration-resistant disease.","refs":["paper-tannock-tax-327-docetaxel-prednisone-nejm-2004","paper-petrylak-swog-9916-docetaxel-estramustine-nejm-2004","docetaxel"]},{"year":2004,"title":"More receptor is enough on its own","note":"A modest rise in androgen receptor expression, with no mutation, is shown to be necessary and sufficient for antiandrogen resistance and to turn antagonists into agonists, which is the argument that produced abiraterone and enzalutamide.","refs":["paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004","androgen-receptor"]},{"year":2005,"title":"A gene fusion is found in a common carcinoma","note":"Tomlins found TMPRSS2 fused to ERG or ETV1 in 23 of 29 prostate tumours, putting a growth gene under the control of the hormone the prostate lives in. The first recurrent rearrangement described in a common solid cancer, and still without a drug twenty years later.","refs":["paper-tomlins-tmprss2-ets-fusion-science-2005","erg","tmprss2"]},{"year":2008,"title":"Castration-resistant disease is proved to be still hormone driven","note":"Attard's phase 1 of abiraterone in 21 men resistant to multiple hormonal therapies produced prostate-specific antigen falls of at least 50 percent in 12 of them, lasting up to at least 578 days. The disease was renamed from hormone-refractory to castration-resistant on the strength of results like this.","refs":["paper-attard-abiraterone-phase-1-cyp17-jco-2008"]},{"year":2009,"title":"The two screening trials report on the same day and disagree","note":"ERSPC found a 20 percent reduction in prostate cancer mortality, at 1,410 men screened and 48 extra cancers treated per death prevented. PLCO found no difference, with control-group screening at 52 percent by year six. Welch and Albertsen counted 1,305,600 extra United States diagnoses and 1,004,800 definitive treatments since 1986.","refs":["erspc","plco-prostate","paper-schroder-erspc-screening-mortality-nejm-2009","paper-andriole-plco-prostate-screening-nejm-2009","paper-welch-albertsen-psa-era-diagnosis-treatment-jnci-2009","paper-draisma-lead-time-overdiagnosis-psa-jnci-2009"]},{"year":2010,"title":"A second line opens","note":"TROPIC gave cabazitaxel after docetaxel: 15.1 against 12.7 months, with grade 3 or higher neutropenia in 82 percent. Prostate cancer became a sequencing problem rather than a single-treatment disease.","refs":["paper-de-bono-tropic-cabazitaxel-lancet-2010"]},{"year":2010,"title":"Copy-number burden as a risk measure","note":"Profiling 218 tumours on three platforms identifies NCOA2 as an oncogene in 11% and shows that counting copy-number changes separates high- from low-risk disease beyond Gleason score.","refs":["paper-taylor-integrative-genomic-profiling-cancer-cell-2010","ncoa2"]},{"year":2011,"title":"Abiraterone approved; enzalutamide follows in 2012","note":"Proof that castration-resistant disease is still AR-driven.","refs":["abiraterone","enzalutamide"]},{"year":2011,"title":"Neuroendocrine prostate cancer gets a molecular identity","note":"AURKA and MYCN are co-amplified in 40% of neuroendocrine prostate cancers against 5% of adenocarcinomas, and Aurora kinase inhibition switches off the neuroendocrine programme in models.","refs":["paper-beltran-nepc-aurka-mycn-cancer-discov-2011","aurka","mycn"]},{"year":2012,"title":"Screening is recommended against, and enzalutamide arrives","note":"The United States task force issued a grade D recommendation against prostate-specific antigen screening at any age; it moved men aged 55 to 69 to grade C in 2018. In the same year AFFIRM reported enzalutamide after chemotherapy, 18.4 against 13.6 months, with a prostate-specific antigen response rate of 54 percent against 2 percent.","refs":["paper-moyer-uspstf-prostate-screening-ann-intern-med-2012","paper-uspstf-prostate-screening-jama-2018","paper-scher-affirm-enzalutamide-nejm-2012","paper-beer-prevail-enzalutamide-nejm-2014"]},{"year":2012,"title":"The fusion-negative half of the disease is named","note":"Exome sequencing of 112 tumours makes SPOP the commonest point mutation in prostate cancer and shows SPOP-mutant tumours never carry an ETS fusion; rapid-autopsy sequencing of 50 lethal cancers adds CHD1 deletion, FOXA1 mutation and the chromatin genes that partner the androgen receptor.","refs":["paper-barbieri-spop-foxa1-med12-prostate-nat-genet-2012","paper-grasso-mutational-landscape-lethal-crpc-nature-2012","spop","foxa1"]},{"year":2013,"title":"Radium-223: first alpha emitter approved (ALSYMPCA)","refs":["radium-223","alsympca"]},{"year":2013,"title":"An inherited BRCA mutation is shown to change the disease","note":"Among 2,019 men, carriers present at higher grade and stage and live 8.6 years from diagnosis against 15.7 for non-carriers, which is why a carrier's localised disease is treated rather than watched.","refs":["paper-castro-germline-brca-prostate-outcomes-jco-2013","brca"]},{"year":2014,"title":"The first predictive resistance marker","note":"Antonarakis found AR-V7, an androgen receptor lacking the part the drugs bind, in circulating tumour cells: a zero percent prostate-specific antigen response rate to enzalutamide and abiraterone in the men who carried it, against 53 and 68 percent in those who did not.","refs":["paper-antonarakis-ar-v7-resistance-nejm-2014"]},{"year":2014,"title":"The tumours that change type get a morphological classification","note":"The Prostate Cancer Foundation working committee publishes the six categories that separate incidental neuroendocrine staining from small cell carcinoma, which is what makes treatment-emergent neuroendocrine disease countable at all.","refs":["paper-epstein-neuroendocrine-prostate-morphologic-classification-ajsp-2014"]},{"year":2015,"title":"CHAARTED and STAMPEDE: docetaxel at first metastatic diagnosis","refs":["chaarted","stampede"]},{"year":2015,"title":"The genome is classified, and DNA repair becomes a target","note":"TCGA put 74 percent of 333 primary tumours into seven subtypes and found DNA repair inactivation in 19 percent; the Stand Up To Cancer cohort sequenced 150 metastatic biopsies and found BRCA2, BRCA1 and ATM aberrations in 19.3 percent; TOPARP-A treated 50 unselected men with olaparib and 14 of the 16 with DNA repair defects responded. Gundem showed metastases seed other metastases.","refs":["paper-tcga-molecular-taxonomy-primary-prostate-cell-2015","paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","paper-mateo-toparp-a-olaparib-dna-repair-nejm-2015","paper-gundem-evolutionary-history-lethal-metastatic-prostate-nature-2015"]},{"year":2016,"title":"ProtecT validates active surveillance","refs":["protect","active-surveillance"]},{"year":2016,"title":"Inherited DNA repair faults turn out to be common and unpredictable","note":"Pritchard found presumed deleterious germline DNA repair mutations in 11.8 percent of 692 men with metastatic prostate cancer, BRCA2 in 5.3 percent, with no relation to family history or age at diagnosis. The argument for testing every man with metastatic disease rather than selecting by family history.","refs":["paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016"]},{"year":2016,"title":"The lineage change is mapped, and it is epigenetic before it is genetic","note":"Methylation separates neuroendocrine from castration-resistant adenocarcinoma far more sharply than mutations do, in a pattern fitting divergent clonal evolution from a common ancestor rather than a late mutational event.","refs":["paper-beltran-nepc-divergent-evolution-nat-med-2016"]},{"year":2017,"title":"LATITUDE and STAMPEDE: abiraterone in mHSPC","refs":["latitude","stampede"]},{"year":2017,"title":"Resistance by changing cell type, and imaging moves in front of the biopsy","note":"Mu and Ku showed that losing TP53 and RB1 lets a prostate cancer cell switch on SOX2 and stop needing the androgen receptor, reversibly in the laboratory. PROMIS showed multiparametric magnetic resonance imaging is 93 percent sensitive for clinically significant cancer against 48 percent for standard biopsy, and could spare a quarter of men a biopsy.","refs":["paper-mu-sox2-lineage-plasticity-science-2017","paper-ahmed-promis-multiparametric-mri-lancet-2017","paper-ku-rb1-trp53-lineage-plasticity-science-2017"]},{"year":2017,"title":"Plasma gets a threshold, and PARP resistance gets a mechanism","note":"Above a 2% tumour fraction, plasma reproduces every somatic mutation found in a matched metastatic biopsy, which is the number that makes a liquid biopsy reportable in this disease; in the same year BRCA2 reversion is identified as the mechanism of PARP inhibitor resistance.","refs":["paper-wyatt-ctdna-tissue-concordance-mcrpc-jnci-2017","paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017"]},{"year":2018,"title":"PRECISION: MRI before biopsy","refs":["precision-mri","mp-mri"]},{"year":2018,"title":"Two long-running localised trials read out, and the disparity question is reframed","note":"SPCG-4 at 29 years: surgery cut prostate cancer death by 45 percent in clinically detected disease and added a mean 2.9 years of life. PIVOT at 19.5 years, in a largely screen-detected population, found no significant difference. Dess showed that once treatment and access are equal, the excess prostate cancer mortality in Black men largely disappears while the excess other-cause mortality does not.","refs":["paper-bill-axelson-spcg-4-29-year-nejm-2018","paper-wilt-pivot-prostatectomy-observation-nejm-2017","paper-dess-black-race-prostate-mortality-jama-oncol-2019","paper-teply-restore-bipolar-androgen-therapy-lancet-oncol-2018"]},{"year":2018,"title":"The enhancer nobody was looking at, and the long tail","note":"Deep whole genomes of 101 metastases find the AR upstream enhancer amplified in 81% of men, invisible to exome panels; reanalysis of 1,013 exomes finds 97 driver genes, 70 of them new, most below 3%.","refs":["paper-quigley-structural-variation-mcrpc-cell-2018","paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018","androgen-receptor"]},{"year":2019,"title":"Rare but real: microsatellite instability, and PSMA PET measured properly","note":"Microsatellite instability-high or mismatch repair deficient disease is found in 3.1% of 1,033 men, with durable checkpoint inhibitor responses in 6 of 11 treated; gallium-68 PSMA-11 PET is shown prospectively to localise recurrence in 75% of 635 men with a rising PSA. RB1 alteration emerges as the only genomic marker independently predicting shorter survival in castration-resistant disease.","refs":["paper-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019","paper-fendler-psma-pet-biochemical-recurrence-jama-oncol-2019","paper-abida-genomic-correlates-outcome-mcrpc-pnas-2019","psma","rb1"]},{"year":2020,"title":"PSMA PET approved; PROfound approves olaparib for HRR-mutant mCRPC","refs":["ga68-psma-11","propsma","profound","olaparib"]},{"year":2020,"title":"PSMA PET replaces conventional staging","note":"In 302 randomised men, PSMA PET-CT is 27% more accurate than CT with bone scan, changes management twice as often and delivers less than half the radiation.","refs":["paper-propsma-hofman-lancet-2020","psma"]},{"year":2021,"title":"VISION: 177Lu-PSMA-617 improves survival; TheraP beats cabazitaxel on response","refs":["vision","therap"]},{"year":2021,"title":"Immunotherapy is measured and found wanting, and sequence is shown to matter","note":"KEYNOTE-199 gave objective response rates of 5 and 3 percent with pembrolizumab and PD-L1 predicted nothing, consistent with a median tumour mutational burden of 2.6 mutations per megabase. TRANSFORMER found identical progression-free survival for high-dose testosterone and enzalutamide and a difference of 8.6 months in progression-free survival through crossover depending on which came first.","refs":["paper-antonarakis-keynote-199-pembrolizumab-jco-2020","paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019","paper-denmeade-transformer-bipolar-androgen-therapy-jco-2021","paper-conti-trans-ancestry-gwas-prostate-nat-genet-2021"]},{"year":2021,"title":"Plasma at scale, and the noise it carries","note":"Circulating tumour DNA is detectable in 94% of 3,334 men with advanced prostate cancer and agrees with tissue on BRCA mutations 93% of the time; in parallel, clonal haematopoiesis is shown to account for almost half the somatic repair-gene variants found in plasma, most often in ATM.","refs":["paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021","paper-jensen-clonal-haematopoiesis-cfdna-interference-prostate-jama-oncol-2021"]},{"year":2022,"title":"Pluvicto approved; ARASENS establishes triplet therapy","refs":["pluvicto","arasens","darolutamide"]},{"year":2022,"title":"Detecting the lineage change without a biopsy, and measuring the disparity in the genome","note":"Cell-free DNA methylation separates neuroendocrine from castration-resistant adenocarcinoma with near-perfect discrimination in two small cohorts; a 2,069-man single-centre series shows tumour genomes differ by self-reported race after adjusting for clinical factors, with more 8q gain in tumours from Black men and an association between community income and 8q gain.","refs":["paper-berchuck-cfdna-methylation-nepc-detection-ccr-2022","paper-stopsack-prostate-genomes-by-race-ccr-2022"]},{"year":2023,"title":"PARP + ARPI combinations approved (TALAPRO-2, PROpel, MAGNITUDE); EMBARK for biochemical recurrence","refs":["talapro-2","propel","magnitude","embark"]},{"year":2023,"title":"PARP inhibition is confirmed, and the biomarker is shown not to be one thing","note":"TRITON3 randomised 405 men and found imaging-based progression-free survival of 11.2 against 6.4 months in the BRCA subgroup, and a hazard ratio of 0.95 in the ATM subgroup: no effect. 4,855 men were screened to randomise 405.","refs":["paper-fizazi-triton3-rucaparib-nejm-2023","paper-abida-triton2-rucaparib-brca-jco-2020"]},{"year":2024,"title":"SPLASH: second PSMA radioligand improves rPFS but not OS","refs":["splash","lu177-psma-it"]},{"year":2025,"title":"Pluvicto pre-chemotherapy (PSMAfore); ArteraAI Prostate FDA-authorised; PSMAddition positive; ECLIPSE positive; masofaniten discontinued","refs":["psmafore","artera-ai-prostate","psmaddition","eclipse-psma","masofaniten"]},{"year":2026,"title":"Pluvicto approved in metastatic hormone-sensitive disease (31 July); capivasertib + abiraterone approved for PTEN-deficient disease","refs":["psmaddition","pluvicto","capitello-281","capivasertib"]},{"year":2032,"title":"The platform and registry trials are due to complete","note":"ProBio's study completion is listed for December 2026, PSMAddition for 11 February 2027, CAPItello-281 for 31 March 2027, TALAPRO-3 for 28 August 2027, PROTEUS for 13 October 2028, PEACE III for December 2028, PSMA-DC for 3 October 2031, and STAMPEDE2, with 3,360 men planned, for March 2032.","refs":["prostate-roadmap","psmaddition","capitello-281","nct04821622","nct03767244","nct05939414","stampede"]}],"pipeline":["ac225-psma","ifinatamab-deruxtecan","capivasertib","tarlatamab","yl201","cetrelimab","hs-20093","qlc5508","opevesostat","saruparib","aglatimagene-besadenovec","gotistobart","aaa817","pf-07248144","bnt324","bms-986365","jnj-87189401","rinzimetostat","hrs-4357","fpi-2265","xnw5004","azd6621","azd9750","qlh12016","amo959","rv001v","vudalimab","vb15010","nuv-1511","alphabreak","xaluritamig","xalute","pasritamig","mevrometostat","mevpro-1","lu177-psma-it","eclipse-psma","idea-psma-pet-guided-mdt","idea-alpha-first-mhspc","grpr","mp-mri","active-surveillance","decipher-prostate","idea-prostate-hrr-testing-at-metastatic-diagnosis","idea-prostate-randomise-the-sequence-not-only-the-drugs","idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine","idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2","idea-prostate-metastatic-presentation-as-the-screening-endpoint","idea-prostate-other-cause-mortality-as-a-reported-service-outcome","idea-prostate-per-lesion-mri-audit-before-focal-treatment"],"openProblems":["Screening trade-off: PSA reduces mortality by ~20% but overdiagnoses; MRI-first and risk-adapted intervals are only partly adopted.","Neuroendocrine / lineage-plastic transformation in 10.5 to 17% of late mCRPC (Kench 2022; 17% of metastatic biopsies in Aggarwal) has no targeted therapy; DLL3 and B7-H3 agents are being borrowed from SCLC.","AR-V7 and N-terminal-domain resistance: masofaniten failed; AR degraders remain preclinical/early.","Radioligand sequencing and resistance: about a tenth of men screen out for PSMA-negative disease on VISION's single-tracer criteria and 31% on TheraP's PSMA plus FDG criteria, heterogeneity, and no proven therapy after 177Lu failure outside trials; Ac-225 supply is the constraint.","Overall survival has been hard to show for PSMA radioligands beyond VISION (SPLASH, PSMAfore, TheraP confounded by crossover).","Immunotherapy: checkpoint inhibitors fail in unselected disease; engagers bring cytokine release and need outpatient models.","Equity: Black men have ~70% higher incidence and double the mortality yet are under-enrolled in trials; earlier, risk-adapted screening is the lever.","Bone health, cardiovascular risk, and cognitive effects of long-term ADT in men living a decade or more.","Five classifications describe one disease and no single document reconciles them. A British man holds a histological type from the WHO 2022 classification, a grade on two scales at once, a TNM stage from an edition his guideline does not name, a Cambridge Prognostic Group from NICE and a disease state from the drug labels. Each is used by a different professional and the mapping between the American and British risk systems is approximate.","The staging system is being outrun by the scanners. TNM 8 set the clinical T category from a finger; MRI and PSMA PET see disease it cannot feel, and the TNM committee's own answer in the ninth edition is to record which scan produced the stage rather than to restage the disease. Two men both labelled stage IV, one by bone scan in 2015 and one by PSMA PET in 2026, do not have the same illness, and survival series that span the change cannot be pooled.","Grading still has an unresolved question at its centre. Whether intraductal carcinoma should be counted when the Gleason grade is assigned is decided differently by the two main urological pathology societies, and the WHO fifth edition declined to endorse either, asking only that pathologists say which convention they used. Grade drives the risk band, which drives the treatment.","Ductal histology has no trial of its own. It presents later, metastasises to unusual sites and survives worse than acinar cancer, and every treatment recommendation for it is borrowed from the disease it is not.","Overdiagnosis is real, unavoidable with the current test, and unquantified to within a factor of thirty: estimates across epidemiological, clinical and autopsy studies range from 1.7 to 67 percent, modelling puts it at 23 to 42 percent of screen-detected cancers in United States calibration and 66 percent in the Rotterdam one, and autopsy studies find prostate cancer in 18.5 to 38.5 percent of men who died of something else.","Overtreatment is the harm that overdiagnosis causes, and it is measured in the men who bear it: about 1 in 5 who have radical prostatectomy develop long-term urinary incontinence and 2 in 3 long-term erectile dysfunction, against about 1.3 prostate cancer deaths and about 3 metastatic cases prevented per 1,000 men screened over roughly 13 years.","Metastatic prostate cancer now has six classes of treatment that extend survival and no randomised evidence about the order to give them in; TRANSFORMER measured a difference of 8.6 months in progression-free survival through crossover between two sequences of the same two treatments, which is larger than the gain most of the individual drugs were licensed on.","The homologous recombination repair gene list is used as one biomarker and is not one: BRCA2 loss predicted response to olaparib in every case in TOPARP-A, ATM alteration gave a hazard ratio of 0.95 in TRITON3, and CDK12-altered tumours, 6 percent of the disease, are infrequently high for genome-wide loss of heterozygosity and are not homologous recombination deficient in the sense PARP inhibitors need.","In a minority of men, treatment turns prostate cancer into a different disease: combined TP53 and RB1 loss allows a switch to an androgen receptor-independent, often neuroendocrine phenotype, found in 17 percent of metastatic biopsies in one prospective cohort, for which there is no approved treatment and no prospective surveillance strategy.","Checkpoint immunotherapy does not work here and nobody can say which few patients it does work in: objective response rates of 5 percent in PD-L1-positive and 3 percent in PD-L1-negative disease, a median tumour mutational burden of 2.6 mutations per megabase, and mismatch repair deficiency in 4 percent of tumours, with durable responses in a subgroup that cannot be identified in advance.","Magnetic resonance imaging is reported as a patient-level test and used as a lesion-level map: sensitivity is 93 percent for whether a man has clinically significant cancer and 65 percent for whether a given significant lesion is seen, with at least one significant focus missed in 34 percent of men and 45 percent of those with multifocal disease, and no service publishes its own per-lesion figure.","The mortality gap that survives equal access is not a cancer gap: after adjustment for treatment and access, Black men in three United States cohorts had no excess prostate cancer mortality at the same stage, and a persistently higher hazard of dying of other causes, in a population treated for years with a hormone therapy that worsens metabolic and bone health.","The TMPRSS2-ERG fusion defines roughly half of all prostate cancers, has been known since 2005, and has produced no treatment; the same is true of the seven-subtype TCGA taxonomy, which leaves a quarter of primary tumours unclassified.","The commonest driver event in advanced prostate cancer, amplification of the AR enhancer 624 kb upstream of the gene, is invisible to every panel used to test for it.","Two of the four PARP inhibitor eligibility lists name genes for which almost no prostate response data exist. Across 142 men in the non-BRCA, non-ATM PROfound cohort, 89 had CDK12 and the remaining eleven genes supplied between one and twelve men each, with no responses; talazoparib's list names a mismatch repair gene, MLH1, and its own label states that no approved test for it exists.","The commonest genomic alteration in the disease, the TMPRSS2-ERG fusion, has no treatment and no prognostic value, and the drivers that might be treatable follow a long tail: 97 significantly mutated genes, 70 of them new, most below 3% prevalence.","AR-V7 is the closest this disease has to a test that chooses between two treatment classes and it is in no label, needs intact circulating tumour cells, and the two available assays disagree on 18% of samples.","Neuroendocrine transformation is recognised late because it is found by biopsying a lesion someone thought to biopsy. The genotype that permits it, combined RB1 and TP53 loss, is knowable in advance, and the non-invasive methylation test that detects it exists only as a research assay in cohorts of a few dozen men.","Clonal haematopoiesis accounts for almost half the somatic DNA repair variants found in plasma from men with advanced prostate cancer, most often in ATM, and the fix, a paired whole-blood control, is not universal.","Prostate cancer genomics is overwhelmingly a description of men of European ancestry. In the one large Chinese cohort the founder event that defines almost half of Western tumours is uncommon, and in a 2,069-man single-centre series tumours from Black men carried more 8q gain, an adverse feature, with community-level income associated with that gain after adjusting for race and ancestry.","PSMA PET has moved staging without anyone yet showing that treating the disease it finds changes survival, which is stage migration operating on a national scale."],"basics":{"symptoms":["Prostate cancer often has no symptoms at first, because it usually starts on the outer part of the gland and does not press on the urethra until it has grown or spread (NHS)","Changes in the way you pee: difficulty starting or straining, a weak flow, stop-start peeing, needing to pee urgently or often, feeling you still need to pee when you have just finished, and getting up in the night (NHS)","Other symptoms: erectile dysfunction, blood in the urine or the semen, and, in advanced disease, lower back pain and losing weight without trying (NHS)","These symptoms far more often mean benign prostatic enlargement, which is very common with age, than cancer; the NHS advice is not that they are alarming but that a change in them should be checked (NHS)","See a GP if you are having trouble peeing or have other symptoms, if you are over 40 and genetic testing has shown you carry a faulty BRCA2 gene, or if you are worried about your risk; you can ask about a PSA test even without symptoms, and the GP will weigh your risk in deciding whether it is the right test for you (NHS)","At the appointment the GP will ask whether anyone in the family has had prostate, pancreatic, ovarian or breast cancer, may examine the prostate with a gloved finger through the back passage, and may offer a PSA blood test with results in one to two weeks (NHS)"],"diagnosis":["Multiparametric MRI is offered first, before any biopsy, for suspected clinically localised prostate cancer, and is reported on a five-point Likert scale rather than PI-RADS (NICE NG131 1.2.2)","MRI-influenced biopsy is offered at Likert 3 or above; at Likert 1 or 2 omitting biopsy can be considered after a shared discussion of the risks and benefits, and systematic biopsy is offered to anyone who still wants one (NG131 1.2.3, 1.2.4)","Mapping transperineal template biopsy is not offered as part of an initial assessment outside a trial (NG131 1.2.5)","After a negative biopsy with an MRI Likert score of 3 or more, the case is discussed at the MDT with a view to repeating the biopsy; after a negative biopsy with Likert 1 or 2, PSA is repeated at 3 to 6 months (NG131 1.2.10, 1.2.12)","CT is considered where MRI is contraindicated and knowing the T or N stage would change management (NG131 1.2.14)","The pathology report gives the histological type, the Gleason score and the grade group, the tumour length in each core, the percentage of Gleason pattern 4 and whether intraductal or invasive cribriform carcinoma is present; on a prostatectomy specimen it adds extraprostatic extension, seminal vesicle invasion, margins and nodes (RCPath G084, October 2024)","Isotope bone scans are not routinely offered in Cambridge Prognostic Group 1 or 2 (NG131 1.2.16)"],"staging":["Five classifications are in use at once and they answer different questions: histology (what it is), grade (how abnormal it looks), TNM stage (how far it has spread), risk band (what those three add up to) and disease state (what it is doing now). A man can be described by all five simultaneously","Grade: Gleason score and grade group together. Group 1 is Gleason 6 or less, group 2 is 3+4=7, group 3 is 4+3=7, group 4 is Gleason 8 (4+4, 3+5 or 5+3), group 5 is Gleason 9 to 10 (RCPath G084, from the ISUP 2014 consensus)","Risk band in the UK: the Cambridge Prognostic Groups 1 to 5, which the MDT assigns to every newly diagnosed localised or locally advanced case, combining grade group, PSA and T stage. NICE writes its whole treatment section in these numbers (NG131 1.2.15, table 1)","Stage: T1 not palpable or visible (T1c is a cancer found on biopsy after a raised PSA), T2 confined within the prostate, T3a through the capsule, T3b into a seminal vesicle, T4 fixed to or invading rectum, sphincter, levator muscles or pelvic wall; N1 any regional pelvic node; M1a non-regional node, M1b bone, M1c elsewhere. There is no pT1 category and the eighth edition removed the substaging of pT2","UK pathology reports stage against UICC TNM 8, which the Royal College of Pathologists dataset names and reprints (G084, October 2024)","TNM 9 was published on 3 July 2025 and UICC recommends it from 1 January 2026. The prostate T, N and M categories are unchanged; the clinical stage grouping was clarified, and reports are now asked to record the imaging method as a suffix, cT2b(mr) for MRI and N1(PET) for a node found on PSMA PET, because prostate is the malignancy most affected by stage migration (Brierley 2026)","NICE NG131 names no TNM edition. Its risk table uses bare T1 to T4, which are identical in the eighth and ninth editions","Disease state, which is not a stage: hormone-sensitive or castration-resistant (which NICE calls hormone-relapsed), metastatic or not, and whether the PSA alone has risen after treatment (biochemical recurrence). Each of these has its own page here","In England 53 percent of prostate cancers with a known stage were diagnosed at stage I or II in 2022, against 37 percent in Scotland in 2023, 57 percent in Northern Ireland and 59 percent in Wales (Cancer Research UK)"],"sources":[{"label":"NICE NG131: prostate cancer, diagnosis and management (recommendations, including the Cambridge Prognostic Group table at 1.2.15)","url":"https://www.nice.org.uk/guidance/ng131/chapter/Recommendations"},{"label":"Royal College of Pathologists G084: dataset for histopathology reports for prostatic carcinoma, version 4, October 2024","url":"https://www.rcpath.org/static/8cc88604-2c8d-4df4-a99542df41c102af/G084-dataset-for-histopathology-reports-for-prostatic-carcinoma.pdf"},{"label":"Brierley et al., International Journal of Cancer 2026: the 9th edition of the UICC TNM classification of malignant tumours, updates and rationale for change (prostate at section 10.1)","url":"https://doi.org/10.1002/ijc.70561"},{"label":"NHS: symptoms of prostate cancer, and what happens at the GP appointment","url":"https://www.nhs.uk/conditions/prostate-cancer/symptoms/"},{"label":"Cancer Research UK: prostate cancer statistics (UK incidence, mortality, survival, stage at diagnosis and route to diagnosis)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/prostate-cancer"}]},"prognosis":{"text":"In the United States, 98.2% of men diagnosed with prostate cancer in 2016-2022 were alive five years later, relative to men of the same age without the disease. For the 69% found while confined to the prostate and the 14% with regional spread, five-year relative survival is 100%; for the 9% found with distant spread it is 40.1%. Most prostate cancers grow slowly, and for many men the question is whether treatment is needed at all rather than whether it will work.","sources":[{"label":"SEER Cancer Stat Facts: Prostate Cancer","url":"https://seer.cancer.gov/statfacts/html/prost.html"}]}},{"id":"pulmonary-blastoma","kind":"cancer","name":"Pulmonary blastoma (adult)","aka":["Classic biphasic pulmonary blastoma","Biphasic pulmonary blastoma","Adult pulmonary blastoma","Well-differentiated fetal adenocarcinoma (the monophasic epithelial form, now classed as fetal adenocarcinoma)"],"tldr":"Pulmonary blastoma is a very rare lung cancer of adults that mixes a fetal-looking gland component with a primitive sarcoma-like component, and so belongs with the sarcomatoid lung cancers. It is different from the pleuropulmonary blastoma of young children. Surgery is the treatment; chemotherapy has no proven benefit and the outlook is poor.","summary":"The WHO classification places classic biphasic pulmonary blastoma among the sarcomatoid carcinomas: a tumour with fetal-type adenocarcinoma glands and a primitive blastematous stroma, distinct from the pure fetal adenocarcinoma (formerly well-differentiated fetal adenocarcinoma) that sits with adenocarcinoma variants, and from pleuropulmonary blastoma, a childhood DICER1-related tumour with its own page (Nicholson 2022). Pulmonary blastomas make up 0.25 to 0.5 percent of malignant lung neoplasms; most patients are adults with an average age of 43, tobacco use is a causative factor, 40 percent are asymptomatic and the usual finding is a large peripheral nodule (Lung Cancer 2011). Somatic DICER1 mutations have been reported in adult-onset pulmonary blastoma, linking it biologically to the childhood tumour (European Respiratory Journal 2016).\n\nHow it differs from its parent: it is the only non-small-cell lung cancer with embryonic-type tissue, its patients are two decades younger than the lung cancer average, and it is not treated with the parent's driver or immunotherapy pathways because no evidence exists for them.\n\nHow common: 0.25 to 0.5 percent of malignant lung tumours (Lung Cancer 2011).\n\nTreatment: surgical excision is the treatment of choice; the efficacy of adjuvant chemotherapy and radiotherapy is not established; overall five-year survival is 16 percent, better for the fetal adenocarcinoma form, and worse with biphasic type, recurrence, metastasis at presentation, size over 5 cm and node involvement (Lung Cancer 2011).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Pulmonary_blastoma","links":[{"label":"Nicholson 2022, JTO: the 2021 WHO classification of lung tumours","url":"https://doi.org/10.1016/j.jtho.2021.11.003"},{"label":"Lung Cancer 2011: classic biphasic pulmonary blastoma, case report and review","url":"https://doi.org/10.1016/j.lungcan.2011.03.018"},{"label":"European Respiratory Journal 2016: somatic DICER1 mutations in adult-onset pulmonary blastoma","url":"https://doi.org/10.1183/13993003.00172-2016"}],"tags":["subtype-page","wave4","lung"],"related":["nsclc","pulmonary-sarcomatoid-carcinoma","pleuropulmonary-blastoma","lung-adenocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["lobectomy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"0.25 to 0.5 percent of malignant lung tumours; average age 43; overall five-year survival 16 percent (Lung Cancer 2011 review).","subtypes":["Classic biphasic pulmonary blastoma (fetal adenocarcinoma glands with blastematous stroma)","Fetal adenocarcinoma, low and high grade (the monophasic epithelial form, classed with adenocarcinoma)","DICER1-mutated adult pulmonary blastoma"],"biomarkers":["Biphasic histology with fetal-type glands","Somatic DICER1 mutation (reported)","Tumour size over 5 cm and node status (prognostic)"],"standardOfCare":[{"setting":"All stages","approach":"Surgical excision; adjuvant chemotherapy and radiotherapy of unproven benefit; no trial exists.","refs":["pulmonary-sarcomatoid-carcinoma","lobectomy"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"nsclc"},{"id":"rare-childhood-cancers","kind":"cancer","name":"Rare cancers of childhood (NCI PDQ umbrella)","aka":["Childhood cardiac tumours","Laryngeal papillomatosis","Recurrent respiratory papillomatosis","Childhood melanoma","Childhood carcinomas","Very rare tumours of childhood"],"tldr":"Some childhood cancers are so rare that no single hospital sees enough to learn from. The NCI groups them together: heart tumours, airway papillomas, cancers of the thyroid, adrenal, nose and throat, melanoma and carcinomas more typical of adults. The answer has been international registries and expert networks that pool every case, so treatment guidance exists even without trials.","summary":"The NCI PDQ summary on rare cancers of childhood collects tumours that fall outside the common paediatric disease groups: head and neck carcinomas (nasopharyngeal carcinoma, salivary, laryngeal, thyroid, oesthesioneuroblastoma, NUT carcinoma), thoracic tumours (pleuropulmonary blastoma, tracheobronchial tumours, thymoma, cardiac tumours, mesothelioma), abdominal tumours (adrenocortical carcinoma, gastrointestinal carcinomas, carcinoid, pancreatic tumours, pancreatoblastoma), genital and urinary tumours (bladder, testicular non-germ cell, ovarian epithelial), skin cancers (melanoma, basal and squamous cell carcinoma), and multiple endocrine neoplasia syndromes. Where OnCo has a dedicated record (nasopharyngeal, thyroid, adrenocortical, melanoma, pleuropulmonary blastoma, NUT carcinoma, sinonasal, pheochromocytoma-paraganglioma, multiple endocrine neoplasia) this page points to it; this record covers the residue and the organisational response.\n\nTwo entities on the NCI list have no other home. Childhood cardiac tumours are mostly benign rhabdomyomas associated with tuberous sclerosis complex, which regress spontaneously and, when obstructive, respond to mTOR inhibitors (everolimus or sirolimus) rather than surgery; fibromas, myxomas and rare sarcomas are treated surgically. Recurrent respiratory (laryngeal) papillomatosis is a benign HPV 6/11 disease acquired at birth that causes hoarseness and airway obstruction, requires repeated debulking, rarely transforms to squamous carcinoma, and is being prevented by HPV vaccination of mothers and reduced by systemic bevacizumab in refractory cases; the nonavalent vaccine as adjuvant therapy is also studied.\n\nThe defining feature of these tumours is that randomised trials are impossible, so the field built other tools: the COG Rare Tumors committee and its registry, the European Cooperative Study Group for Paediatric Rare Tumours (EXPeRT) and its consensus recommendations, the Pediatric MATCH molecular-assignment platform that accepts any refractory solid tumour, and the practice of borrowing adult protocols with paediatric dose adjustments. Adult-type carcinomas in children are often linked to germline predisposition (TP53, DICER1, mismatch repair, APC) and trigger genetic testing.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Childhood_cancer","links":[{"label":"NCI PDQ: rare cancers of childhood","url":"https://www.cancer.gov/types/childhood-cancers/patient/rare-childhood-cancers-pdq"},{"label":"NCI PDQ: childhood cardiac tumours","url":"https://www.cancer.gov/types/cardiac/patient-child-cardiac-treatment-pdq"},{"label":"EXPeRT: European Cooperative Study Group for Paediatric Rare Tumours","url":"https://www.raretumors-children.eu/"}],"tags":["nci-coverage","paediatric","umbrella"],"related":["nasopharyngeal","thyroid","adrenocortical","melanoma","pleuropulmonary-blastoma","nut-carcinoma","sinonasal","pheochromocytoma-paraganglioma","multiple-endocrine-neoplasia","race-for-children-act","paediatric-germ-cell-tumours","retinoblastoma","hepatoblastoma"],"cancers":[],"sections":[],"technologies":["hpv-vaccine","germline-testing","cancer-registries-surveillance"],"targets":[],"drugs":["everolimus","bevacizumab","gardasil-9"],"companies":["shanghai-fosun-pharmaceutical-industrial-development","shanghai-kechow-pharma","childrens-oncology-group","cclg"],"institutions":["siop-europe"],"pathways":[],"terms":["hereditary-cancer-syndromes","aya-oncology"],"trials":["pediatric-match","nct07407803"],"people":[],"bottlenecks":["b-rare-cancers","b-trial-enrolment"],"keyPapers":[],"journals":["journal-of-pediatric-hematology-oncology","journal-of-pediatric-hematology-oncology-nursing","pediatric-hematology-and-oncology"],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Individually vanishingly rare, but together the tumours grouped by the NCI as rare cancers of childhood account for roughly one in ten childhood cancers, and their share rises in adolescence (NCI PDQ).","subtypes":["Childhood cardiac tumours (rhabdomyoma with tuberous sclerosis, fibroma, myxoma, sarcoma)","Recurrent respiratory papillomatosis (HPV 6/11)","Childhood melanoma and non-melanoma skin cancer","Childhood head and neck carcinomas (nasopharyngeal, salivary, laryngeal, oesthesioneuroblastoma, NUT carcinoma)","Childhood gastrointestinal and pancreatic carcinomas (including pancreatoblastoma)","Childhood thoracic tumours (pleuropulmonary blastoma, thymoma, mesothelioma)","Childhood endocrine tumours (thyroid, adrenocortical, pheochromocytoma, MEN syndromes)"],"biomarkers":["Germline predisposition testing (TP53, DICER1, mismatch repair, APC, RET, SDHx)","Tuberous sclerosis complex (TSC1/TSC2) in cardiac rhabdomyoma","HPV 6/11 typing in respiratory papillomatosis","Tumour-specific adult markers borrowed by site"],"standardOfCare":[{"setting":"Cardiac rhabdomyoma with tuberous sclerosis","approach":"Observation for spontaneous regression; mTOR inhibitor (everolimus or sirolimus) for haemodynamically significant tumours; surgery reserved for obstruction unresponsive to medical therapy.","refs":["everolimus"],"guideline":{"version":"NCI PDQ: childhood cardiac tumours","url":"https://www.cancer.gov/types/cardiac/patient-child-cardiac-treatment-pdq"}},{"setting":"Recurrent respiratory papillomatosis","approach":"Repeated microdebrider or laser debulking to maintain the airway; systemic bevacizumab for severe refractory disease; HPV vaccination (prevention through maternal vaccination; adjuvant use under study).","refs":["bevacizumab","gardasil-9","hpv-vaccine"],"guideline":{"version":"NCI PDQ: laryngeal papillomatosis (rare cancers of childhood)","url":"https://www.cancer.gov/types/childhood-cancers/patient/rare-childhood-cancers-pdq"}},{"setting":"Adult-type carcinoma in a child","approach":"Treat per the adult site-specific standard with paediatric dose adjustment, enrol in the COG or EXPeRT rare tumour registry, and test for germline predisposition.","refs":["germline-testing","pediatric-match"],"guideline":{"version":"EXPeRT consensus recommendations; NCI PDQ","url":"https://www.cancer.gov/types/childhood-cancers/patient/rare-childhood-cancers-pdq"}}],"stateOfArt":["Registries and consensus networks (COG Rare Tumors, EXPeRT) supply evidence where trials cannot; their recommendations are now the reference for most of these tumours.","mTOR inhibition has replaced surgery for most obstructive cardiac rhabdomyomas in tuberous sclerosis.","HPV vaccination is beginning to reduce respiratory papillomatosis, and bevacizumab controls the most severe cases.","Germline testing is routine for adult-type cancers in children because a high proportion are hereditary."],"history":[{"year":2000,"title":"COG Rare Tumors committee established","note":"Creates a registry and protocols for infrequent tumours.","refs":[]},{"year":2008,"title":"EXPeRT founded","note":"European Cooperative Study Group for Paediatric Rare Tumours pools national registries (Italy, Germany, France, Poland, UK).","refs":[]},{"year":2012,"title":"Everolimus regresses cardiac rhabdomyoma in tuberous sclerosis","note":"Case series lead to medical management replacing surgery.","refs":["everolimus"]},{"year":2017,"title":"Pediatric MATCH opens","note":"Molecular assignment platform for any refractory childhood solid tumour.","refs":["pediatric-match"]},{"year":2020,"title":"Systemic bevacizumab for severe respiratory papillomatosis reported","refs":["bevacizumab"]}],"pipeline":["pediatric-match","everolimus","gardasil-9","tq-b3234"],"openProblems":["Evidence remains observational for almost every entity; international registries and adult-paediatric joint protocols are the response.","Adolescents with adult-type carcinomas fall between paediatric and adult services; AYA programmes and the RACE for Children Act (which requires paediatric evaluation of adult cancer drugs) aim to close the gap.","Access to molecular profiling and matched therapy for rare tumours outside major centres."],"parent":"childhood-cancers"},{"id":"rectal-cancer","kind":"cancer","name":"Rectal cancer","aka":["TCGA-READ","rectum adenocarcinoma (TCGA READ cohort)","Rectal adenocarcinoma","Cancer of the rectum","Locally advanced rectal cancer","Rectum cancer"],"tldr":"Rectal cancer is bowel cancer in the last part of the large intestine, where surgery can mean a permanent stoma. Treatment now usually gives all the chemotherapy and radiotherapy first, and about half of people whose tumour disappears completely can keep their rectum and avoid surgery altogether.","summary":"Rectal cancer is staged by pelvic MRI, which shows the depth of invasion, the distance to the mesorectal fascia, extramural venous invasion and nodal disease and so decides who needs treatment before surgery. Total mesorectal excision, described by Heald in 1982, cut local recurrence from a quarter of patients to well under a tenth, and the German CAO/ARO/AIO-94 trial (2004) moved chemoradiation to before surgery, halving local recurrence again. Early tumours (cT1-2, node-negative) go straight to surgery, and small T1 tumours can be removed through the anus.\n\nFor locally advanced disease the sequence has been rebuilt as total neoadjuvant therapy: RAPIDO (2020) gave one week of radiotherapy then all the chemotherapy before surgery and cut distant failure and doubled complete responses; PRODIGE 23 (2021) gave induction mFOLFIRINOX before chemoradiation and improved disease-free and, later, overall survival. OPRA (2022) showed that with chemoradiation followed by consolidation chemotherapy about half of patients could avoid surgery through watch and wait without losing disease control, building on the Habr-Gama series from Sao Paulo. PROSPECT (2023) then showed that intermediate-risk tumours suitable for sphincter-sparing surgery can be treated with FOLFOX alone, with radiotherapy reserved for the 9 percent who do not respond.\n\nThe 5 to 10 percent of rectal cancers that are mismatch-repair deficient respond so completely to PD-1 blockade that surgery and radiotherapy can be omitted: in the Memorial Sloan Kettering study every patient treated with six months of dostarlimab had a clinical complete response (NEJM 2022, expanded 2025), and AZUR-1 is the registration study. Metastatic rectal cancer is treated as metastatic colorectal cancer, by genotype and sidedness. Open questions are how to select watch and wait safely, whether circulating tumour DNA can guide surveillance, and how to reduce the bowel, sexual and urinary harm that survivors carry.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Colorectal_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Colorectal_cancer"},{"label":"NCCN Guidelines: Rectal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461"}],"tags":["subtype-page"],"related":["braf-v600e-colorectal","early-onset-colorectal","her2-amplified-colorectal","kras-g12c-colorectal","msi-high-colorectal"],"cancers":[],"sections":[],"technologies":["imrt-igrt","hypofractionated-radiotherapy","robotic-surgery","mri","checkpoint-inhibitor"],"targets":["pd1","egfr","vegf"],"drugs":["folfox","capox","dostarlimab","fluorouracil","capecitabine"],"companies":[],"institutions":[],"pathways":["colorectal-cancer-signalling"],"terms":["total-neoadjuvant-therapy","organ-preservation","clinical-complete-response","total-mesorectal-excision","chemoradiation","stoma","msi"],"trials":["rapido","prodige-23","opra","prospect","cao-aro-aio-94","azur-1","nct06640049"],"people":["angelita-habr-gama","julio-garcia-aguilar","andrea-cercek","luis-diaz"],"bottlenecks":[],"keyPapers":["paper-sauer-preoperative-chemoradiotherapy-rectal-nejm-2004","paper-bahadoer-rapido-short-course-radiotherapy-lancet-oncol-2021","paper-conroy-prodige-23-neoadjuvant-folfirinox-rectal-lancet-oncol-2021","paper-prospect-nejm-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About a third of colorectal cancers start in the rectum, the last 15 cm of the bowel; because the rectum sits in the narrow pelvis next to the bladder, sexual organs and sphincter, local recurrence, stomas and function matter more than for colon cancer.","subtypes":["Low rectal cancer (within 5 cm of the anal verge; the sphincter is at risk)","Mid and upper rectal cancer (anterior resection with anastomosis)","Locally advanced rectal cancer (cT3-4 or node-positive on MRI; total neoadjuvant therapy)","Mismatch-repair deficient rectal cancer (immunotherapy alone, no surgery)","Rectal cancer in clinical complete response under watch and wait"],"biomarkers":["Pelvic MRI: T stage, mesorectal fascia involvement, extramural venous invasion, lateral nodes","Mismatch repair / microsatellite status (immunotherapy alone if deficient)","RAS, BRAF V600E and HER2 in metastatic disease","Carcinoembryonic antigen (CEA)","Circulating tumour DNA after treatment (under study)","Clinical complete response on endoscopy and MRI"],"standardOfCare":[{"setting":"Early (cT1-2, node-negative)","approach":"Total mesorectal excision, increasingly robotic or laparoscopic; transanal local excision for small, well-differentiated T1 tumours; no radiotherapy.","refs":["total-mesorectal-excision","robotic-surgery","mri"],"guideline":{"version":"NCCN Guidelines: Rectal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461"}},{"setting":"Locally advanced, higher risk","approach":"Total neoadjuvant therapy: short-course radiotherapy then CAPOX or FOLFOX (RAPIDO), or induction mFOLFIRINOX then chemoradiation (PRODIGE 23); chemoradiation then consolidation chemotherapy when organ preservation is the goal (OPRA); surgery or watch and wait for complete responders.","refs":["rapido","prodige-23","opra","capox","folfox","hypofractionated-radiotherapy","total-neoadjuvant-therapy","organ-preservation","clinical-complete-response"],"guideline":{"version":"NCCN Guidelines: Rectal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461"}},{"setting":"Intermediate risk, sphincter-sparing surgery planned","approach":"Six cycles of FOLFOX with chemoradiation only if the tumour shrinks by less than 20 percent (PROSPECT), then total mesorectal excision.","refs":["prospect","folfox","chemoradiation","total-mesorectal-excision"],"guideline":{"version":"NCCN Guidelines: Rectal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461"}},{"setting":"Mismatch-repair deficient","approach":"Six months of dostarlimab or another PD-1 antibody with non-operative management for complete responders; surgery reserved for the rare non-responder.","refs":["dostarlimab","azur-1","msi","organ-preservation"],"guideline":{"version":"NCCN Guidelines: Rectal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461"}},{"setting":"Metastatic","approach":"As metastatic colorectal cancer: doublet chemotherapy with bevacizumab or, for RAS and BRAF wild-type left-sided tumours, an anti-EGFR antibody; primary tumour managed by symptoms; liver-limited disease resected.","refs":["folfox","folfiri","bevacizumab","cetuximab","panitumumab","hepatectomy"],"guideline":{"version":"NCCN Guidelines: Rectal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1461"}}],"stateOfArt":["Total neoadjuvant therapy (RAPIDO, PRODIGE 23, OPRA) has replaced chemoradiation then surgery then chemotherapy as the default for locally advanced disease.","Watch and wait after clinical complete response spares about half of selected patients the operation, with salvage surgery for the regrowths.","PROSPECT removed pelvic radiotherapy from the pathway for intermediate-risk tumours.","Mismatch-repair deficient rectal cancer is treated with immunotherapy alone."],"history":[{"year":1908,"title":"Miles describes the abdominoperineal resection with permanent colostomy","refs":["abdominoperineal-resection"]},{"year":1982,"title":"Heald describes total mesorectal excision, cutting local recurrence to under 10 percent","refs":["total-mesorectal-excision"]},{"year":2004,"title":"CAO/ARO/AIO-94: preoperative chemoradiation halves local recurrence","refs":["cao-aro-aio-94"]},{"year":2004,"title":"Habr-Gama reports watch and wait after complete clinical response in Sao Paulo","refs":["angelita-habr-gama","organ-preservation"]},{"year":2020,"title":"RAPIDO: short-course radiotherapy then chemotherapy establishes total neoadjuvant therapy","refs":["rapido","total-neoadjuvant-therapy"]},{"year":2021,"title":"PRODIGE 23: induction mFOLFIRINOX improves disease-free survival","refs":["prodige-23"]},{"year":2022,"title":"OPRA: about half of patients keep their rectum after total neoadjuvant therapy","refs":["opra","julio-garcia-aguilar"]},{"year":2022,"title":"Dostarlimab alone produces complete responses in every mismatch-repair deficient rectal cancer treated","refs":["dostarlimab","andrea-cercek","luis-diaz"]},{"year":2023,"title":"PROSPECT: FOLFOX with selective chemoradiation is as good as routine chemoradiation","refs":["prospect"]},{"year":2026,"title":"AZUR-1 confirms non-operative management with dostarlimab in mismatch-repair deficient rectal cancer","refs":["azur-1"]}],"pipeline":["azur-1","nct06640049","dostarlimab","signatera","idea-ctdna-guided-adjuvant-crc"],"openProblems":["No validated test predicts which clinical complete responders will regrow under watch and wait.","Long-term bowel, sexual and urinary function after total neoadjuvant therapy is poorly measured.","Whether circulating tumour DNA can safely guide surveillance after organ preservation is untested in randomised trials.","Lateral pelvic node disease is managed differently in Japan and the West with no comparative trial."],"parent":"colorectal"},{"id":"recurrent-metastatic-nasopharyngeal-carcinoma","kind":"cancer","name":"Recurrent and metastatic nasopharyngeal carcinoma","aka":["R/M NPC","Metastatic nasopharyngeal carcinoma","Locally recurrent nasopharyngeal carcinoma","Stage IVB nasopharyngeal carcinoma"],"tldr":"Recurrent or metastatic nasopharyngeal carcinoma is nasopharyngeal cancer that has come back after radiotherapy or spread to the bones, liver or lungs. Gemcitabine with cisplatin is the chemotherapy backbone, adding a PD-1 antibody such as toripalimab in JUPITER-02 and later trials lengthened survival and became standard, and local recurrence is treated with endoscopic surgery or re-irradiation.","summary":"Nasopharyngeal carcinoma recurs in two ways that are treated differently. Local or regional recurrence after radiotherapy, in the nasopharynx or neck, is potentially curable: endoscopic nasopharyngectomy, shown in a Chinese randomised trial (Lancet Oncology 2021) to give better survival and fewer complications than re-irradiation for resectable recurrence, neck dissection for nodal relapse, and hyperfractionated intensity-modulated re-irradiation, which in a further randomised trial (Lancet 2023) reduced the severe late toxicity of a second course of radiotherapy. Distant metastases, most often to bone, liver and lung, are incurable in most patients, although a minority with oligometastatic disease gain from locoregional radiotherapy of the primary added to chemotherapy, as a Chinese phase 3 (JAMA Oncology 2020) showed.\n\nSystemic therapy for metastatic disease was standardised by the GEM20110714 trial (Lancet 2016), in which gemcitabine and cisplatin beat fluorouracil and cisplatin on progression-free survival (7.0 against 5.6 months) and overall survival. Because EBV-driven tumours are inflamed and PD-L1-rich, PD-1 antibodies were tested next, almost entirely by Chinese companies and investigators: JUPITER-02 (Nature Medicine 2021, JAMA 2023) added toripalimab to gemcitabine-cisplatin in 289 patients and lengthened progression-free survival from 8.0 to 11.7 months with a survival benefit, leading to approval in China in 2021 and in the United States in October 2023, the first approval of a Chinese-developed PD-1 antibody there and the first drug approved for nasopharyngeal carcinoma; CAPTAIN-1st (camrelizumab, Lancet Oncology 2021) and RATIONALE-309 (tislelizumab) showed the same pattern, and penpulimab with gemcitabine-cisplatin was approved in the United States in April 2025. PD-1 antibodies alone are used after platinum failure (nivolumab, pembrolizumab, camrelizumab and toripalimab all have phase 2 data), and later lines include gemcitabine-based or taxane-based chemotherapy, capecitabine and the anti-EGFR antibody nimotuzumab in China. The pipeline is dominated by antibody-drug conjugates, notably the EGFR-directed MRG003 and the EGFR-HER3 bispecific BL-B01D1 and the B7-H3-directed YL201, in phase 3 against chemotherapy, and by EBV-specific T-cell therapies, which have produced durable responses in small trials. Plasma EBV DNA tracks response, and locoregional radiotherapy for de novo metastatic disease with a good chemotherapy response is now guideline-endorsed.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Nasopharyngeal_carcinoma","links":[{"label":"JUPITER-02 (JAMA 2023)","url":"https://doi.org/10.1001/jama.2023.20181"},{"label":"CSCO-ASCO NPC guideline 2021","url":"https://doi.org/10.1200/JCO.20.03237"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Nasopharyngeal_carcinoma"}],"tags":["subtype-page","head-and-neck"],"related":["locoregionally-advanced-nasopharyngeal-carcinoma","nasopharyngeal","recurrent-metastatic-hnscc"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","platinum","imrt-igrt","proton-therapy","tors","tcr-t","liquid-biopsy","sbrt","adc"],"targets":["pd1","pdl1","egfr"],"drugs":["gemcitabine-cisplatin","toripalimab","camrelizumab","tislelizumab","penpulimab","nivolumab","pembrolizumab","capecitabine","cisplatin"],"companies":[],"institutions":[],"pathways":[],"terms":["plasma-ebv-dna","re-irradiation","ebv-term","ctdna"],"trials":["jupiter-02","captain-1st","nct04974398","taishan-301","nct05294172","nct06118333","nct06976190","nct05126719","nct06839066"],"people":[],"bottlenecks":[],"keyPapers":["paper-jupiter-02-toripalimab-chemotherapy-npc-nat-med-2021","paper-zhang-gemcitabine-cisplatin-vs-fluorouracil-cisplatin-rm-npc-lancet-2016","paper-captain-1st-camrelizumab-chemotherapy-npc-lancet-oncol-2021","paper-mai-jama"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"About one in ten patients present with distant metastases and a further fifth relapse after chemoradiotherapy; bone, liver and lung are the usual sites, and survival with modern chemo-immunotherapy now runs to several years.","subtypes":["Locally recurrent nasopharyngeal carcinoma, resectable (endoscopic nasopharyngectomy)","Locally recurrent nasopharyngeal carcinoma, unresectable (hyperfractionated re-irradiation)","Regional nodal recurrence (neck dissection)","De novo metastatic nasopharyngeal carcinoma (chemo-immunotherapy, locoregional radiotherapy in responders)","Oligometastatic nasopharyngeal carcinoma (local therapy to metastases)","Platinum-refractory metastatic nasopharyngeal carcinoma (PD-1 monotherapy, antibody-drug conjugate trials)"],"biomarkers":["Plasma EBV DNA (response and surveillance)","Extent and resectability of local recurrence on MRI and endoscopy","Number and sites of metastases (oligometastatic definition)","PD-L1 (not required; PD-1 benefit regardless)","EGFR, HER3 and B7-H3 expression (antibody-drug conjugate trials)","HLA type and EBV antigen expression (EBV-specific T-cell therapy trials)"],"standardOfCare":[{"setting":"Resectable local recurrence","approach":"Endoscopic nasopharyngectomy (better survival and fewer complications than re-irradiation in a randomised trial); neck dissection for nodal recurrence.","refs":["tors","robotic-surgery","lymphadenectomy"],"guideline":{"version":"CSCO/ASCO guideline on nasopharyngeal carcinoma 2021; NCCN Head and Neck Cancers","url":"https://doi.org/10.1200/JCO.20.03237"}},{"setting":"Unresectable local recurrence","approach":"Hyperfractionated intensity-modulated re-irradiation or proton therapy with careful dose constraints; systemic therapy where re-irradiation is unsafe.","refs":["re-irradiation","imrt-igrt","proton-therapy"],"guideline":{"version":"CSCO/ASCO guideline on nasopharyngeal carcinoma 2021; NCCN Head and Neck Cancers","url":"https://doi.org/10.1200/JCO.20.03237"}},{"setting":"Metastatic disease, first line","approach":"Gemcitabine and cisplatin with a PD-1 antibody (toripalimab, JUPITER-02; camrelizumab, CAPTAIN-1st; tislelizumab; penpulimab), then PD-1 maintenance; locoregional radiotherapy to the primary in patients with a good response.","refs":["gemcitabine-cisplatin","toripalimab","jupiter-02","camrelizumab","captain-1st","tislelizumab","penpulimab","nct04974398","imrt-igrt","checkpoint-inhibitor"],"guideline":{"version":"CSCO/ASCO guideline on nasopharyngeal carcinoma 2021; NCCN Head and Neck Cancers","url":"https://doi.org/10.1200/JCO.20.03237"}},{"setting":"After platinum and PD-1 therapy","approach":"Gemcitabine, taxane or capecitabine-based chemotherapy; nivolumab or pembrolizumab if no prior PD-1 antibody; trials of antibody-drug conjugates (MRG003, BL-B01D1, YL201) and EBV-specific T cells.","refs":["nivolumab","pembrolizumab","capecitabine","taishan-301","nct05294172","nct06118333","nct06976190","nct05126719","nct06839066","tcr-t"],"guideline":{"version":"CSCO/ASCO guideline on nasopharyngeal carcinoma 2021; NCCN Head and Neck Cancers","url":"https://doi.org/10.1200/JCO.20.03237"}},{"setting":"Oligometastatic disease","approach":"Stereotactic radiotherapy or resection of limited metastases with systemic therapy.","refs":["sbrt"],"guideline":{"version":"CSCO/ASCO guideline on nasopharyngeal carcinoma 2021; NCCN Head and Neck Cancers","url":"https://doi.org/10.1200/JCO.20.03237"}}],"stateOfArt":["Chemo-immunotherapy with a PD-1 antibody is standard first line and has produced the first drug approvals for the disease.","Endoscopic surgery and hyperfractionated re-irradiation have made local recurrence curable with less harm.","Antibody-drug conjugates and EBV-specific T cells are the next wave, largely from Chinese trials."],"history":[{"year":2016,"title":"GEM20110714: gemcitabine-cisplatin becomes first-line standard for metastatic disease","refs":["gemcitabine-cisplatin"]},{"year":2020,"title":"Locoregional radiotherapy added to chemotherapy improves survival in de novo metastatic disease","refs":["imrt-igrt"]},{"year":2021,"title":"JUPITER-02 and CAPTAIN-1st: PD-1 antibodies with gemcitabine-cisplatin lengthen progression-free survival; endoscopic nasopharyngectomy beats re-irradiation","refs":["jupiter-02","captain-1st","toripalimab","camrelizumab"]},{"year":2023,"title":"Toripalimab approved in the United States for nasopharyngeal carcinoma; hyperfractionated re-irradiation trial published","refs":["toripalimab","re-irradiation"]},{"year":2025,"title":"Penpulimab with gemcitabine-cisplatin approved in the United States","refs":["penpulimab","nct04974398"]}],"pipeline":["taishan-301","nct05294172","nct06118333","nct06976190","nct05126719","nct06839066","yl201","kl-a167","mrg003","hmbd-001","tcr-t"],"openProblems":["Median survival in metastatic disease is still a few years.","Which patients with local recurrence should have surgery rather than re-irradiation depends on surgical expertise concentrated in a few centres.","Most trials are Chinese and endemic; applicability to non-endemic keratinising disease is uncertain.","EBV-specific cell therapies have not yet reached a positive phase 3."],"parent":"nasopharyngeal"},{"id":"recurrent-metastatic-cervical-cancer","kind":"cancer","name":"Recurrent or metastatic cervical cancer","aka":["Persistent, recurrent or metastatic cervical cancer","Stage IVB cervical cancer","Advanced cervical cancer"],"tldr":"Recurrent or metastatic cervical cancer has spread beyond the pelvis or come back where it cannot be cured by surgery or radiotherapy. Pembrolizumab added to chemotherapy and bevacizumab is the first treatment, and the antibody-drug conjugate tisotumab vedotin or the PD-1 antibody cemiplimab extend life when it progresses.","summary":"Persistent disease after chemoradiation, recurrence outside a previously irradiated field and stage IVB disease at presentation are managed together. Isolated central pelvic recurrence after radiotherapy can still be cured by exenteration, and an isolated para-aortic or lung metastasis is sometimes treated with radiotherapy or resection, but most patients need systemic therapy. Cisplatin-paclitaxel was the reference doublet, with carboplatin an equivalent substitute after JCOG0505. GOG-240 added bevacizumab to chemotherapy in 2014 and extended median survival to about seventeen months, the first targeted therapy in the disease. Squamous, adenocarcinoma and adenosquamous histologies are treated alike, and PD-L1 combined positive score is measured because most trials selected or stratified by it.\n\nKEYNOTE-826 added pembrolizumab to platinum-paclitaxel with or without bevacizumab and extended median overall survival in all comers from 16.8 to 26.4 months, with a hazard ratio of 0.63, and to 28.6 months in tumours with a combined positive score of one or more; it was approved in 2021 and is the first-line standard. BEATcc added atezolizumab to chemotherapy plus bevacizumab and reached a median survival of 32.1 months against 22.8, and COMPASSION-16 in China added the PD-1 and CTLA-4 bispecific cadonilimab with a survival hazard ratio of 0.64, confirming the class effect. Fitness for bevacizumab, prior pelvic radiotherapy and the risk of fistula shape the choice of partner drugs.\n\nAfter platinum and immunotherapy, tisotumab vedotin, an antibody-drug conjugate against tissue factor, improved median survival from 9.5 to 11.5 months against chemotherapy in innovaTV 301 and gained full approval in 2024; ocular toxicity requires eye care and steroid drops. Cemiplimab improved survival from 8.5 to 12.0 months against chemotherapy in EMPOWER-Cervical 1 in immunotherapy-naive patients and remains relevant where first-line immunotherapy was not given. Trastuzumab deruxtecan produced responses in half of HER2-expressing cervical cancers in DESTINY-PanTumor02, sacituzumab tirumotecan is in phase 3, and tumour-infiltrating lymphocyte therapy has shown durable responses in small studies. How to sequence antibody-drug conjugates after first-line immunotherapy, and how to bring any of this to the low-income countries where most deaths occur, are the pressing questions.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Cervical_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Cervical_cancer"}],"tags":["subtype-page"],"related":["early-cervical-cancer","locally-advanced-cervical-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["innovatv-301","empower-cervical-1"],"people":[],"bottlenecks":[],"keyPapers":["paper-keynote-826-nejm-2021","paper-innovatv-301-tisotumab-nejm-2024","paper-empower-cervical-1-cemiplimab-nejm-2022","paper-gog-240-bevacizumab-cervical-nejm-2014"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"Around one in ten cervical cancers present with distant spread and a third of locally advanced cases relapse; median survival was about a year before 2014, and first-line chemo-immunotherapy has now more than doubled it for many women.","subtypes":["Stage IVB at presentation (distant metastasis)","Persistent or recurrent disease after chemoradiation","PD-L1 combined positive score 1 or more (largest pembrolizumab benefit)","Squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma (treated alike)","HER2-expressing cervical cancer (trastuzumab deruxtecan)","Isolated central pelvic recurrence (exenteration with curative intent)","Small cell neuroendocrine carcinoma of the cervix (platinum-etoposide, separate pathway)"],"biomarkers":["PD-L1 combined positive score","Tissue factor expression (not required for tisotumab vedotin)","HER2 immunohistochemistry (trastuzumab deruxtecan)","HPV type and circulating HPV DNA","Prior pelvic radiotherapy and fistula risk (bevacizumab)","MSI and tumour mutational burden (rare)"],"standardOfCare":[{"setting":"First line","approach":"Pembrolizumab with cisplatin or carboplatin, paclitaxel and, when safe, bevacizumab (KEYNOTE-826); atezolizumab with chemotherapy and bevacizumab (BEATcc) or cadonilimab with chemotherapy (COMPASSION-16, China) as alternatives.","refs":["pembrolizumab","keynote-826","cisplatin","carboplatin","paclitaxel","bevacizumab","atezolizumab","beatcc","cadonilimab","compassion-16","pdl1"]},{"setting":"Second line after platinum","approach":"Tisotumab vedotin (innovaTV 301) with prophylactic eye care; cemiplimab (EMPOWER-Cervical 1) if no prior immunotherapy.","refs":["tisotumab-vedotin","innovatv-301","cemiplimab","empower-cervical-1","adc"]},{"setting":"HER2-expressing disease","approach":"Trastuzumab deruxtecan after prior therapy (DESTINY-PanTumor02).","refs":["trastuzumab-deruxtecan","destiny-pantumor02","her2"]},{"setting":"Later lines","approach":"Single-agent chemotherapy (topotecan, gemcitabine, pemetrexed, vinorelbine) with modest response; clinical trials of new antibody-drug conjugates and cell therapy preferred.","refs":["topotecan","gemcitabine","sacituzumab-tirumotecan","lifileucel"]},{"setting":"Isolated pelvic recurrence after radiotherapy","approach":"Pelvic exenteration in fit patients without sidewall fixation.","refs":["robotic-surgery","imrt-igrt"]}],"stateOfArt":["KEYNOTE-826 made chemo-immunotherapy first-line standard and lifted median survival past two years.","Tisotumab vedotin was the first antibody-drug conjugate approved in a gynaecological cancer.","Three different checkpoint agents have now shown survival gains in the first line."],"history":[{"year":2009,"title":"GOG-0204: cisplatin-paclitaxel confirmed as the reference doublet","refs":["cisplatin","paclitaxel"]},{"year":2014,"title":"GOG-0240: bevacizumab extends survival in advanced cervical cancer","refs":["bevacizumab"]},{"year":2021,"title":"KEYNOTE-826: pembrolizumab with chemotherapy extends median survival to 26.4 months","refs":["keynote-826"]},{"year":2021,"title":"Tisotumab vedotin accelerated approval; EMPOWER-Cervical 1 positive for cemiplimab","refs":["tisotumab-vedotin","empower-cervical-1"]},{"year":2023,"title":"innovaTV 301 and BEATcc positive","refs":["innovatv-301","beatcc"]},{"year":2024,"title":"Tisotumab vedotin full approval; COMPASSION-16 positive for cadonilimab in China","refs":["tisotumab-vedotin","compassion-16"]}],"pipeline":["sacituzumab-tirumotecan","trastuzumab-deruxtecan","lifileucel","cadonilimab","idea-hpv-ctdna-cervical"],"openProblems":["Sequencing antibody-drug conjugates and immunotherapy after first-line chemo-immunotherapy.","Fistula and bleeding risk with bevacizumab after pelvic radiotherapy.","Access to any of these drugs in the countries with most deaths."],"parent":"cervical"},{"id":"recurrent-metastatic-hnscc","kind":"cancer","name":"Recurrent or metastatic head and neck squamous cell carcinoma","aka":["R/M HNSCC","Advanced head and neck cancer","Platinum-refractory head and neck cancer"],"tldr":"When head and neck cancer comes back where it cannot be removed, or spreads elsewhere, it is treated to extend life rather than cure: pembrolizumab, alone or with chemotherapy, is the first choice, cetuximab-based regimens and cheap oral chemotherapy are alternatives, and antibodies that hit two targets at once are in late-stage trials.","summary":"Recurrent or metastatic head and neck squamous cell carcinoma covers disease that returns in the head and neck after radiotherapy or surgery and cannot be salvaged, and disease that has spread to the lungs, bone or liver. A minority with locoregional recurrence are cured by salvage surgery or re-irradiation, and a few with a single metastasis are treated with stereotactic radiotherapy; for the rest treatment is systemic and palliative. Work-up includes biopsy, PD-L1 combined positive score, HPV status of oropharyngeal primaries and the interval since platinum, since progression within six months of platinum defines platinum-refractory disease.\n\nFirst-line treatment was defined for a decade by EXTREME (2008), in which cetuximab with platinum and fluorouracil gave median overall survival of 10.1 against 7.4 months. CheckMate 141 (2016) then showed that nivolumab extended survival after platinum failure (7.5 against 5.1 months), and KEYNOTE-048 (2019) moved immunotherapy to the front: pembrolizumab alone gave median survival of 14.9 against 10.7 months in tumours with a combined positive score of 20 or more, and pembrolizumab with chemotherapy gave 13.0 against 10.7 months in the whole population, with a durable tail at five years. Pembrolizumab-based treatment is now the standard, EXTREME or its docetaxel variant TPExtreme the option for rapidly progressing disease or after immunotherapy, and cetuximab sarotalocan photoimmunotherapy is approved in Japan for locoregional recurrence.\n\nThe frontier is combinations that lift response rates above the roughly one in five seen with pembrolizumab alone. Petosemtamab, a bispecific antibody against EGFR and LGR5, produced responses in about six in ten untreated patients with pembrolizumab in phase 2 and is in the phase 3 LiGeR-HN1 and LiGeR-HN2 trials; ficerafusp alfa, which blocks EGFR and traps TGF-beta, is in FORTIFI-HN01 for HPV-negative disease; HB-200, an arenavirus-based vaccine against HPV16 E6 and E7, has been tested with pembrolizumab in HPV16-positive disease; and the EGFR antibody-drug conjugate MRG003 is in phase 3 against cetuximab or methotrexate. In India, Tata Memorial trials showed that oral methotrexate with celecoxib beat intravenous cisplatin (median survival 7.5 against 6.1 months), that adding one-twentieth of the usual nivolumab dose raised one-year survival from 16.3 to 43.4 percent, and, in METRO PLUS, that adding metronomic tablets to paclitaxel-carboplatin doubled median survival from 5 to 10 months.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Head_and_neck_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Head_and_neck_cancer"}],"tags":["subtype-page","head-and-neck","state-page"],"related":["hpv-negative-head-and-neck-cancer","laryngeal-cancer","oral-cavity-cancer","oropharyngeal-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["celecoxib","hb-200"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["tpextreme"],"people":[],"bottlenecks":[],"keyPapers":["paper-keynote-048-lancet-2019","paper-patil-low-dose-nivolumab-jco-2023","paper-extreme-vermorken-nejm-2008","paper-tpextreme-lancet-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"A large share of patients treated for locally advanced head and neck cancer relapse, most within two years; median survival was 7.4 months on platinum-fluorouracil in the EXTREME control arm and 13.0 months with pembrolizumab and chemotherapy in KEYNOTE-048.","subtypes":["Locoregional recurrence after radiotherapy (candidates for salvage surgery or re-irradiation)","Distant metastatic disease (lung, bone, liver)","Platinum-sensitive versus platinum-refractory disease (progression within six months of platinum)","PD-L1 combined positive score 20 or more, 1 to 19, and under 1","HPV-positive versus HPV-negative recurrent disease","Oligometastatic disease treated with stereotactic radiotherapy"],"biomarkers":["PD-L1 combined positive score (22C3 assay)","HPV and p16 status of oropharyngeal primaries","Platinum-free interval","EGFR expression (near universal, not predictive)","Circulating tumour DNA and HPV DNA (emerging)","Tumour mutational burden (pembrolizumab for 10 or more mutations per megabase)"],"standardOfCare":[{"setting":"First line, combined positive score 1 or more","approach":"Pembrolizumab alone for indolent disease, especially with a score of 20 or more; pembrolizumab with platinum and fluorouracil for bulky or symptomatic disease (KEYNOTE-048).","refs":["pembrolizumab","keynote-048","pd-l1-testing","cps"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"First line, combined positive score under 1 or immunotherapy unsuitable","approach":"Pembrolizumab with platinum-fluorouracil, or cetuximab with platinum-fluorouracil (EXTREME) or with docetaxel and platinum (TPExtreme).","refs":["pembrolizumab","cisplatin","carboplatin","fluorouracil","cetuximab","docetaxel","extreme","keynote-048"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"After platinum and immunotherapy","approach":"Cetuximab, docetaxel, paclitaxel or methotrexate as single agents; nivolumab or pembrolizumab if not given before (CheckMate 141); clinical trials.","refs":["nivolumab","checkmate-141","cetuximab","docetaxel","paclitaxel","methotrexate"],"guideline":{"nccn":"Category 1 (nivolumab, pembrolizumab)","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Locoregional recurrence","approach":"Salvage surgery where resectable; re-irradiation with intensity-modulated or stereotactic techniques in selected patients; cetuximab sarotalocan photoimmunotherapy in Japan.","refs":["imrt-igrt","sbrt","cetuximab-sarotalocan","photoimmunotherapy"],"guideline":{"esmoMcbs":"2 (cetuximab sarotalocan, single-arm)","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Resource-limited settings","approach":"Oral metronomic methotrexate with celecoxib; low-dose nivolumab added where affordable; metronomic tablets with paclitaxel-carboplatin (METRO PLUS).","refs":["methotrexate","metronomic-vs-cisplatin-tmh","low-dose-nivolumab-tmh","metro-plus-varanasi"]},{"setting":"Symptom control","approach":"Palliative radiotherapy for bleeding, pain or airway compromise; early involvement of palliative care, nutrition and speech and swallowing teams.","refs":["palliative-radiotherapy"]}],"stateOfArt":["Pembrolizumab-based first-line treatment gives a minority of patients survival measured in years, something no chemotherapy regimen did.","Response rates to immunotherapy alone remain low, so the field is racing to add a second antibody, an antibody-drug conjugate or a vaccine.","India has shown that cheap oral chemotherapy and fractional immunotherapy doses extend life at a small fraction of Western cost."],"history":[{"year":2006,"title":"Cetuximab approved for head and neck cancer","refs":["cetuximab","bonner-cetuximab-rt"]},{"year":2008,"title":"EXTREME: first survival gain in recurrent disease","refs":["extreme"]},{"year":2016,"title":"CheckMate 141: nivolumab after platinum","refs":["checkmate-141"]},{"year":2019,"title":"KEYNOTE-048: pembrolizumab first line","refs":["keynote-048"]},{"year":2020,"title":"Tata Memorial: oral metronomic chemotherapy beats cisplatin","refs":["metronomic-vs-cisplatin-tmh"]},{"year":2023,"title":"Tata Memorial: low-dose nivolumab nearly triples one-year survival","refs":["low-dose-nivolumab-tmh"]},{"year":2025,"title":"Petosemtamab with pembrolizumab: phase 2 responses in about six in ten; phase 3 under way","refs":["petosemtamab","liger-hn1"]}],"pipeline":["petosemtamab","liger-hn1","nct06496178","ficerafusp-alfa","fortifi-hn01","nct07807163","mrg003","nct05751512","nct06601335","nct07276399","bnt113","monalizumab","cetuximab-sarotalocan","nct06699212"],"openProblems":["Most patients still die within two years.","No test yet identifies the minority who gain years from immunotherapy.","Salvage surgery and re-irradiation carry high complication rates.","Access to pembrolizumab and cetuximab in the countries with the most cases."],"parent":"head-and-neck"},{"id":"all-paediatric-relapsed","kind":"cancer","name":"Relapsed and refractory acute lymphoblastic leukaemia in children","aka":["Relapsed childhood ALL","Refractory paediatric B-ALL","Second-line childhood ALL"],"tldr":"When childhood leukaemia comes back, chemotherapy alone cures fewer than half. Three immune treatments changed this: blinatumomab, which links the child's T-cells to leukaemia cells and beat chemotherapy in two trials; tisagenlecleucel, the first approved CAR T-cell therapy, which put over eight in ten pretreated children into remission; and the antibody-drug conjugate inotuzumab ozogamicin.","summary":"Relapse is classified by time from diagnosis, site and response. Early relapse, within 18 months of diagnosis or within six months of finishing treatment, is much harder to cure than late relapse; isolated extramedullary relapse in the central nervous system or testis does better than marrow relapse; and residual disease after the first reinduction block sorts children into those who can be cured with chemotherapy alone and those who need transplant. T-cell ALL relapse carries the worst prognosis. The UK ALLR3 trial in 2010 showed that mitoxantrone in reinduction beat idarubicin, three-year progression-free survival 64.6 percent against 35.9 percent, and mitoxantrone-based reinduction with allogeneic transplant for high-risk relapse became the international standard.\n\nBlinatumomab, a CD19 and CD3 bispecific T-cell engager, was tested against chemotherapy in two randomised trials of first relapse published together in 2021. In COG AALL1331, children with high- and intermediate-risk relapse given blinatumomab instead of two chemotherapy blocks before transplant had two-year disease-free survival of 54.4 percent against 39.0 percent and overall survival of 71.3 percent against 58.4 percent, with more reaching transplant in remission and fewer deaths from infection. In the European IntReALL trial, high-risk first relapse treated with one blinatumomab cycle instead of a third consolidation block had events in 31 percent against 57 percent and residual-disease remission in 90 percent against 54 percent. Tisagenlecleucel, an autologous CD19 CAR T-cell product, produced an overall remission rate of 81 percent within three months in 75 children and young adults with second or later relapse or refractory disease in ELIANA, with event-free survival of 50 percent and overall survival of 76 percent at twelve months; it was approved in August 2017, the first CAR T-cell therapy for any cancer, and long-term follow-up shows durable remissions in a substantial minority without transplant. Inotuzumab ozogamicin, a CD22 antibody-drug conjugate, gave complete remissions in most children in the ITCC-059 and COG AALL1621 studies and was approved for children from the age of one in March 2024.\n\nSequencing is now the question: antigen loss (CD19-negative relapse after blinatumomab or CAR T-cells, CD22 loss after inotuzumab), lineage switch in KMT2A-rearranged disease and T-cell exhaustion each shape the next choice, and whether to consolidate a CAR T-cell remission with transplant depends on prior therapy and residual disease by next-generation sequencing. Trials are testing blinatumomab and CAR T-cells earlier, in low-risk first relapse and in first-line high-risk therapy, dual CD19 and CD22 CAR T-cells, allogeneic off-the-shelf CAR T-cells, and menin inhibitors for KMT2A-rearranged relapse. Relapsed T-ALL still depends on nelarabine and transplant, with CD7 CAR T-cells and venetoclax combinations in early trials, and access to CAR T-cells outside a handful of countries is the widest gap of all.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Tisagenlecleucel","links":[{"label":"Wikipedia: Tisagenlecleucel","url":"https://en.wikipedia.org/wiki/Tisagenlecleucel"},{"label":"NCI PDQ: Childhood ALL Treatment","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}],"tags":["subtype-page","paediatric"],"related":["all-paediatric-standard-risk","all-paediatric-high-risk","all-infant","all-ph-like","all-paediatric-ph-positive"],"cancers":[],"sections":[],"technologies":["car-t","t-cell-engager","adc","allogeneic-hsct"],"targets":["cd19","cd22","cd3"],"drugs":[],"companies":["childrens-oncology-group"],"institutions":[],"pathways":[],"terms":["crs","icans","mrd"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-eliana-tisagenlecleucel-nejm-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About one child in ten with acute lymphoblastic leukaemia relapses, and relapsed ALL remains one of the leading causes of cancer death in children.","subtypes":["Late marrow relapse of B-ALL (36 months or more from diagnosis; chemotherapy with or without immunotherapy)","Early or very early marrow relapse of B-ALL (immunotherapy then allogeneic transplant)","Isolated central nervous system or testicular relapse","Primary refractory B-ALL (induction failure)","Second or later relapse, or relapse after transplant (CAR T-cells)","Relapsed T-cell ALL (nelarabine-based salvage and transplant)"],"biomarkers":["Time from diagnosis and from end of treatment","Site of relapse (marrow, CNS, testis, combined)","MRD after reinduction by flow cytometry and next-generation sequencing","CD19 and CD22 expression on blasts","KMT2A rearrangement (lineage switch risk)","Prior exposure to blinatumomab or CAR T-cells"],"standardOfCare":[{"setting":"First relapse: reinduction","approach":"Mitoxantrone-based reinduction (UKALLR3) with vincristine, dexamethasone, asparaginase and intrathecal therapy; MRD after the block sets the path.","refs":["mitoxantrone","vincristine","dexamethasone","asparaginase","methotrexate","flow-cytometry-mrd","ukallr3"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"First relapse, high or intermediate risk: consolidation","approach":"Blinatumomab in place of chemotherapy blocks (AALL1331, IntReALL), then allogeneic transplant in MRD-negative remission.","refs":["blinatumomab","allogeneic-hsct","cd19","t-cell-engager","aall1331","intreall-sr-2010"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Second or later relapse, or refractory disease","approach":"Tisagenlecleucel (ELIANA) or inotuzumab ozogamicin, with transplant after inotuzumab and after CAR T-cells in selected children.","refs":["tisagenlecleucel","eliana","inotuzumab-ozogamicin","car-t","crs","icans","allogeneic-hsct"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Relapsed T-cell ALL","approach":"Nelarabine with cyclophosphamide and etoposide, then allogeneic transplant; venetoclax combinations and CD7 CAR T-cells in trials.","refs":["nelarabine","cyclophosphamide","etoposide","allogeneic-hsct","venetoclax"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Relapsed KMT2A-rearranged ALL","approach":"Revumenib (approved from the age of one) alone or in trials with chemotherapy, as a bridge to transplant.","refs":["revumenib","augment-101","allogeneic-hsct"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}}],"stateOfArt":["Blinatumomab replaced chemotherapy consolidation in high- and intermediate-risk first relapse after two randomised trials in 2021.","Tisagenlecleucel, the first approved CAR T-cell therapy, produces durable remissions in a substantial minority of children with multiply relapsed disease.","Inotuzumab ozogamicin is approved for children, adding a CD22 option when CD19 is lost."],"history":[{"year":2010,"title":"UKALLR3: mitoxantrone reinduction nearly doubles progression-free survival in relapsed childhood ALL","refs":["mitoxantrone"]},{"year":2014,"title":"Blinatumomab approved for relapsed or refractory B-ALL in adults","refs":["blinatumomab"]},{"year":2017,"title":"Tisagenlecleucel approved: the first CAR T-cell therapy for any cancer, for children and young adults with relapsed B-ALL","refs":["tisagenlecleucel","eliana"]},{"year":2018,"title":"ELIANA published: 81 percent remission in 75 heavily pretreated children","refs":["paper-eliana-tisagenlecleucel-nejm-2018","eliana"]},{"year":2021,"title":"AALL1331 and IntReALL: blinatumomab beats chemotherapy in first relapse","refs":["blinatumomab"]},{"year":2024,"title":"Inotuzumab ozogamicin approved for children with relapsed or refractory CD22-positive B-ALL","refs":["inotuzumab-ozogamicin"]}],"pipeline":["tisagenlecleucel","blinatumomab","inotuzumab-ozogamicin","obecabtagene-autoleucel","felix","revumenib","ngs-mrd-clonoseq","car-t","venetoclax"],"openProblems":["CD19-negative relapse and lineage switch after CD19-directed therapy.","Which children need transplant after a CAR T-cell remission.","Relapsed T-ALL has no approved immunotherapy, and CAR T-cell access is limited to a handful of countries."],"parent":"all-leukemia"},{"id":"relapsed-refractory-hodgkin-lymphoma","kind":"cancer","name":"Relapsed and refractory classical Hodgkin lymphoma","aka":["Relapsed Hodgkin lymphoma","Refractory Hodgkin lymphoma","R/R cHL","Hodgkin lymphoma after first-line failure"],"tldr":"Relapsed or refractory classical Hodgkin lymphoma is Hodgkin lymphoma that comes back or does not respond after first-line chemotherapy. The standard path is salvage chemotherapy, often with brentuximab vedotin or a PD-1 antibody, then high-dose chemotherapy with an autologous stem cell transplant; for those who relapse again, nivolumab and pembrolizumab give lasting control in many.","summary":"Classical Hodgkin lymphoma that relapses after or is refractory to first-line therapy has been treated since the 1990s with salvage chemotherapy (ICE, DHAP, GVD, bendamustine-based regimens) followed by high-dose chemotherapy with autologous stem cell transplantation, which cures about half of patients; achieving a PET-negative remission before transplant is the strongest predictor of cure. Two classes of drug then transformed the field. Brentuximab vedotin, an antibody-drug conjugate against CD30, produced responses in three quarters of patients relapsing after transplant in its pivotal trial and was approved in 2011, and the AETHERA trial (Lancet 2015) showed that giving it as consolidation after transplant to high-risk patients lengthened progression-free survival from 24.1 to 42.9 months. PD-1 antibodies exploit the near-universal 9p24.1 amplification of PD-L1 in Reed-Sternberg cells: nivolumab (CheckMate 205) and pembrolizumab (KEYNOTE-087) produced responses in about two thirds of heavily pretreated patients and were approved in 2016 and 2017, and KEYNOTE-204 (Lancet Oncology 2021) showed pembrolizumab beat brentuximab vedotin in relapsed disease with progression-free survival of 13.2 against 8.3 months.\n\nThese agents have moved earlier. Salvage regimens now combine brentuximab vedotin or a PD-1 antibody with chemotherapy or with each other (brentuximab-nivolumab, pembrolizumab-GVD) to reach PET-negative remission in more patients before transplant, and trials ask whether some patients with a complete response to immunotherapy-based salvage can skip transplantation altogether. After failure of transplant, brentuximab vedotin and a PD-1 antibody, allogeneic transplantation, which can cure a minority with acceptable risk after PD-1 blockade with careful management, and clinical trials of CD30-directed CAR T cells (CHARIOT), bispecific antibodies and novel combinations are the options; older agents such as bendamustine, gemcitabine and everolimus retain a role. Because first-line nivolumab-AVD and brentuximab-AVD are now standard, the definition of relapse after these regimens and the best salvage for patients already exposed to both classes is the open question, and cardiac, pulmonary and second-cancer late effects of cumulative therapy need lifelong attention.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Hodgkin_lymphoma","links":[{"label":"AETHERA (Lancet 2015)","url":"https://doi.org/10.1016/S0140-6736(15)60165-9"},{"label":"KEYNOTE-204 (Lancet Oncology 2021)","url":"https://doi.org/10.1016/S1470-2045(21)00005-X"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Hodgkin_lymphoma"},{"label":"Lymphoma Action: helpline services","url":"https://lymphoma-action.org.uk/information-and-support/support-you/helpline-services"},{"label":"Lymphoma Action: questions to ask your medical team about lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/questions-ask-your-medical-team-about-lymphoma"},{"label":"Lymphoma Action: follow-up after lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/follow-after-lymphoma-treatment"},{"label":"Lymphoma Action: infections, risk and prevention","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/infections-risk-and-prevention"},{"label":"Lymphoma Action: neutropenia (low neutrophils)","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/neutropenia-low-neutrophils"},{"label":"Lymphoma Action: cancer-related fatigue","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/cancer-related-fatigue"},{"label":"Lymphoma Action: lymphoma, work and you","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/day-day-living/lymphoma-work-and-you"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Lymphoma Action: autologous (your own) stem cell transplant","url":"https://lymphoma-action.org.uk/information-and-support/lymphoma-treatment/stem-cell-transplants/self-autologous-stem-cell"},{"label":"Lymphoma Action: when lymphoma comes back, or does not respond","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/lymphoma-comes-back-relapses-or-doesnt-respond"},{"label":"Lymphoma Action: CAR-T cell therapy","url":"https://lymphoma-action.org.uk/information-and-support/lymphoma-treatment/car-t-cell-therapy"},{"label":"Lymphoma Action: late effects of lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/late-effects-lymphoma-treatment"}],"tags":["subtype-page","haematologic"],"related":["advanced-stage-classical-hodgkin-lymphoma","early-stage-classical-hodgkin-lymphoma","hodgkin-lymphoma","dlbcl"],"cancers":[],"sections":[],"technologies":["autologous-stem-cell-transplant","allogeneic-hsct","adc","checkpoint-inhibitor","fdg-pet","imrt-igrt","ctdna-lymphoma-monitoring","car-t","palliative-care","psycho-oncology","peer-support-groups","survivorship-care-plan","fertility-preservation","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","multidisciplinary-tumour-board","oncology-nutrition","prehabilitation"],"targets":["cd30","pd1","pdl1"],"drugs":["brentuximab-vedotin","nivolumab","pembrolizumab","penpulimab","gemcitabine","everolimus"],"companies":[],"institutions":[],"pathways":[],"terms":["deauville-score","reed-sternberg-cell","late-effects","lymphoma-tx-radiotherapy","lymphoma-tx-hodgkin-late-effects","lymphoma-tx-fertility-preservation","lymphoma-tx-transplant-role","lymphoma-tx-uk-versus-us","lymphoma-tx-uk-access","lymphoma-tx-regimen-alphabet","cancer-related-fatigue","febrile-neutropenia","neutropenia","financial-toxicity","central-venous-access","hypogammaglobulinaemia","performance-status","quality-of-life","lymphoma-decision-local-or-car-t-centre","lymphoma-decision-trial","lymphoma-living-hodgkin-survivorship-screening","lymphoma-living-infection-years-after","lymphoma-living-fatigue"],"trials":["aethera","keynote-204","checkmate-205","nct04268706"],"people":[],"bottlenecks":[],"keyPapers":["paper-keynote-204-pembrolizumab-vs-brentuximab-rr-hodgkin-lancet-oncol-2021","paper-aethera-brentuximab-consolidation-after-asct-hodgkin-lancet-2015","paper-checkmate-205-nivolumab-rr-hodgkin-extended-follow-up-jco-2018"],"journals":[],"dependsOn":[],"notes":["Relapsed Hodgkin lymphoma, the transplant route and what living near a centre asks of a household: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the 24-hour number they gave you come first, and no figure here is a prediction about you. The decision records, the question sets, the first 60 days checklist and the red cards on this page were written from the NHS, Lymphoma Action, Macmillan and Cancer Research UK patient pages, from NICE NG52, NG47, CG151 and NG234, from the NHS Breast Screening Programme protocols and the Green Book, and from the trial reports named beside each figure, all read on 1 October 2026."],"group":"haematologic","burden":"A tenth to a quarter of classical Hodgkin lymphoma relapses or fails to respond to first-line treatment; most of these patients are still cured with salvage chemotherapy and transplantation, and immunotherapy has changed the outlook for the rest.","subtypes":["Primary refractory classical Hodgkin lymphoma (no complete response to first line)","Early relapse within twelve months of first-line therapy","Late relapse after twelve months (favourable, may be retreated with less)","Relapsed classical Hodgkin lymphoma after autologous transplantation (brentuximab vedotin, PD-1 antibodies, allogeneic transplant)","Relapse after first-line brentuximab-AVD or nivolumab-AVD","Multiply relapsed classical Hodgkin lymphoma (CAR T and bispecific trials)"],"biomarkers":["PET-negative remission before transplant (Deauville 1 to 3; strongest predictor of cure)","Time to relapse (under or over twelve months) and primary refractory status","Extranodal disease, B symptoms and prior lines (AETHERA high-risk criteria)","CD30 expression (brentuximab target)","9p24.1 amplification and PD-L1 expression (PD-1 responsiveness)","Circulating tumour DNA (research)"],"standardOfCare":[{"setting":"Salvage before transplant","approach":"Platinum-based chemotherapy (ICE, DHAP, GVD) increasingly combined with brentuximab vedotin or pembrolizumab, or brentuximab vedotin with nivolumab, to reach PET-negative remission.","refs":["brentuximab-vedotin","nivolumab","pembrolizumab","gemcitabine","fdg-pet","deauville-score"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Consolidation","approach":"High-dose chemotherapy with autologous stem cell transplantation for chemosensitive relapse; brentuximab vedotin maintenance for a year in high-risk patients (AETHERA).","refs":["autologous-stem-cell-transplant","brentuximab-vedotin","aethera"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Relapse after transplant","approach":"Pembrolizumab (KEYNOTE-204) or nivolumab (CheckMate 205); brentuximab vedotin if not previously given; PD-1 antibodies in China include penpulimab and others.","refs":["pembrolizumab","keynote-204","nivolumab","checkmate-205","brentuximab-vedotin","penpulimab","checkpoint-inhibitor"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Failure of PD-1 antibodies and brentuximab","approach":"Allogeneic transplantation for fit patients; bendamustine, gemcitabine or everolimus; CD30 CAR T cells and bispecific antibodies in trials.","refs":["allogeneic-hsct","gemcitabine","everolimus","nct04268706","idea-cd30-car-t-hodgkin"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"Transplant-ineligible patients","approach":"PD-1 antibody with or without brentuximab vedotin as ongoing therapy; palliative radiotherapy for symptomatic sites.","refs":["nivolumab","brentuximab-vedotin","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Hodgkin Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439"}},{"setting":"First relapse of classical Hodgkin lymphoma: salvage to a negative PET, then autologous transplant","approach":"The aim of salvage treatment is not a response but a negative PET, because the proportion of patients cured by the transplant that follows depends more on the depth of the remission before it than on which salvage regimen produced it.\n\nSalvage regimens in use: brentuximab vedotin with bendamustine; brentuximab vedotin with nivolumab, which produces high complete response rates without chemotherapy; ICE or IGEV or DHAP or ESHAP. There is no randomised trial ranking them, and the choice is made on toxicity, on stem cell mobilisation and on what the patient has already had. Two to three cycles, then a PET; if it is negative, proceed to BEAM conditioning and autologous transplant; if it is positive, change salvage rather than proceeding.\n\nConsolidation after transplant with brentuximab vedotin is standard for patients at high risk of relapse, on the strength of AETHERA, which randomised 329 such patients to brentuximab vedotin or placebo and gave median progression-free survival of 42.9 against 24.1 months (hazard ratio 0.57). High risk means primary refractory disease, relapse within twelve months, or extranodal disease at relapse. Patients who received brentuximab vedotin in first-line treatment are a group in whom this is less clear.","refs":["aethera","brentuximab-vedotin","nivolumab","bendamustine","ifosfamide","carboplatin","etoposide","cisplatin","cytarabine","carmustine","melphalan","autologous-stem-cell-transplant","fdg-pet","deauville","lymphoma-tx-transplant-role","paper-aethera-brentuximab-consolidation-after-asct-hodgkin-lancet-2015"],"guideline":{"nccn":"Category 1 (brentuximab vedotin consolidation, high-risk)","version":"NCCN Hodgkin Lymphoma; ESMO; AETHERA","url":"https://www.cancer.gov/types/lymphoma/hp/adult-hodgkin-treatment-pdq"}},{"setting":"Relapse after autologous transplant, or where transplant is not possible: PD-1 blockade","approach":"Classical Hodgkin lymphoma has amplification of chromosome 9p24.1, which drives expression of PD-L1 and PD-L2, and it is the disease in which PD-1 blockade works best of all.\n\nNivolumab. CheckMate 205 treated 243 patients after autologous transplant failure and reported an objective response of 69 per cent, with responses lasting in many. It is also active after both autologous transplant and brentuximab vedotin have failed.\n\nPembrolizumab. KEYNOTE-204 randomised 304 patients with relapsed or refractory classical Hodgkin lymphoma to pembrolizumab or brentuximab vedotin and gave median progression-free survival of 13.2 against 8.3 months (hazard ratio 0.65), which established PD-1 blockade as preferred over brentuximab vedotin at this point for patients who have had one or the other.\n\nCombinations of brentuximab vedotin with nivolumab are used as a bridge to transplant and in later lines. Where a response is achieved in a fit younger patient who has already had an autologous transplant, an allogeneic transplant with reduced-intensity conditioning is considered, although PD-1 blockade before allogeneic transplant increases the risk of severe graft-versus-host disease and the timing has to be planned with the transplant team.","refs":["checkmate-205","keynote-204","nivolumab","pembrolizumab","brentuximab-vedotin","allogeneic-hsct","paper-checkmate-205-nivolumab-rr-hodgkin-extended-follow-up-jco-2018","paper-keynote-204-pembrolizumab-vs-brentuximab-rr-hodgkin-lancet-oncol-2021"],"guideline":{"nccn":"Category 1","version":"NCCN Hodgkin Lymphoma; ESMO; KEYNOTE-204, CheckMate 205","url":"https://www.cancer.gov/types/lymphoma/hp/adult-hodgkin-treatment-pdq"}},{"setting":"After brentuximab vedotin and PD-1 blockade have both failed","approach":"This is a small group and there is no standard. Options, roughly in the order they are usually considered: re-treatment with a PD-1 antibody after a chemotherapy-induced response, because chemotherapy can restore sensitivity; an allogeneic transplant with reduced-intensity conditioning in a fit younger patient, which is the only treatment with curative potential; anti-CD30 CAR-T, which has produced responses in phase 1 and 2 studies and is not approved; gemcitabine-based or single-agent chemotherapy for control; involved-site radiotherapy for a symptomatic site, which is highly effective in a radiosensitive disease; and a clinical trial, which at this point is often the best available treatment.\n\nThe conversation about aim belongs here explicitly. Palliative radiotherapy and low-intensity chemotherapy can give good quality of life for a long time in Hodgkin lymphoma, and early involvement of a palliative care team alongside oncology is recommended rather than deferred.","refs":["brentuximab-vedotin","nivolumab","pembrolizumab","gemcitabine","bendamustine","allogeneic-hsct","car-t","palliative-radiotherapy","palliative-care","paper-cd30-hodgkin-lymphoma-j-clin-oncol-2020"],"guideline":{"version":"NCCN Hodgkin Lymphoma; no standard beyond this point","url":"https://www.cancer.gov/types/lymphoma/hp/adult-hodgkin-treatment-pdq"}}],"stateOfArt":["Immunotherapy-based salvage gets more patients to a PET-negative transplant and may let some skip it.","PD-1 antibodies give durable control to many patients who relapse after transplant.","CD30 CAR T cells and bispecific antibodies are the next layer for multiply relapsed disease."],"history":[{"year":1993,"title":"Randomised trial confirms autologous transplantation improves outcomes in relapsed Hodgkin lymphoma","refs":["autologous-stem-cell-transplant"]},{"year":2011,"title":"Brentuximab vedotin approved for relapsed Hodgkin lymphoma after transplant","refs":["brentuximab-vedotin","cd30"]},{"year":2015,"title":"AETHERA: brentuximab vedotin consolidation after transplant lengthens progression-free survival","refs":["aethera","brentuximab-vedotin"]},{"year":2016,"title":"Nivolumab approved after CheckMate 205","refs":["nivolumab","checkmate-205"]},{"year":2017,"title":"Pembrolizumab approved after KEYNOTE-087","refs":["pembrolizumab"]},{"year":2021,"title":"KEYNOTE-204: pembrolizumab beats brentuximab vedotin in relapsed disease","refs":["keynote-204","pembrolizumab","brentuximab-vedotin"]}],"pipeline":["nct04268706","idea-cd30-car-t-hodgkin","brentuximab-vedotin","pembrolizumab","nivolumab","ctdna-lymphoma-monitoring"],"openProblems":["Which patients in complete remission after immunotherapy salvage can safely skip transplantation is unproven.","Salvage for patients already exposed to brentuximab and PD-1 antibodies in first line is undefined.","Allogeneic transplant after PD-1 blockade carries a risk of severe graft-versus-host disease.","Cumulative cardiac and lung toxicity limits options in multiply treated patients."],"parent":"hodgkin-lymphoma"},{"id":"cll-relapsed","kind":"cancer","name":"Relapsed or refractory chronic lymphocytic leukaemia","aka":["Relapsed CLL","Refractory CLL","Double-refractory CLL (after BTK and BCL-2 inhibitors)","CLL after BTK inhibitor failure"],"tldr":"When chronic lymphocytic leukaemia returns, the usual move is to switch drug class: venetoclax-based therapy after a BTK inhibitor, or a BTK inhibitor after venetoclax. Pirtobrutinib (BRUIN) works after the older BTK inhibitors fail, and CAR-T is approved for patients who have run out of both classes.","summary":"Relapse is usually slow and treatment resumes only when iwCLL criteria are met again. The regimen depends on what was given first and why it stopped: progression on a covalent BTK inhibitor usually means a BTK C481 mutation or PLCG2 mutation and calls for venetoclax-based therapy or the non-covalent inhibitor pirtobrutinib; intolerance to one covalent BTK inhibitor can be managed by switching to another (ALPINE found zanubrutinib superior to ibrutinib in relapsed disease, progression-free survival hazard ratio 0.65, with less atrial fibrillation, 5.2 versus 13.3 percent); relapse a year or more after fixed-duration venetoclax can be treated with venetoclax again; TP53 aberrant disease and complex karyotype shorten every remission.\n\nThe landmark trials each defined a setting. RESONATE (2014) established ibrutinib against ofatumumab in relapsed disease (hazard ratio 0.22 for progression, median 44.1 versus 8.1 months on long follow-up). MURANO (2018) established two years of venetoclax-rituximab against bendamustine-rituximab, with two-year progression-free survival of 84.9 versus 36.3 percent and a survival gain, the first fixed-duration targeted regimen. BRUIN CLL-321 (2024) showed pirtobrutinib beat investigator's choice of idelalisib-rituximab or bendamustine-rituximab after covalent BTK inhibitor failure, and pirtobrutinib was approved in 2023 for patients previously treated with both a BTK and a BCL-2 inhibitor. Lisocabtagene maraleucel, a CD19 CAR-T, was approved in 2024 for the same double-exposed group after TRANSCEND CLL 004 (complete remission in about a fifth, undetectable MRD in the blood in two thirds).\n\nDouble-refractory disease after covalent BTK inhibitor and venetoclax remains the unmet need: median survival is short, and pirtobrutinib responses last about a year and a half. BTK degraders (bexobrutideg, NX-5948), the next BCL-2 inhibitor sonrotoclax, the non-covalent inhibitor nemtabrutinib, bispecific antibodies (epcoritamab) and allogeneic transplant in the young are the options being tested, and about one in twenty relapses proves to be Richter transformation rather than CLL.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia"},{"label":"NCCN Guidelines: CLL/SLL","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}],"tags":["subtype-page"],"related":["cll-treatment-naive","richter-transformation-cll"],"cancers":[],"sections":[],"technologies":["car-t","bcl2-inhibitors","flow-cytometry-mrd"],"targets":["btk","bcl2","cd19","cd20"],"drugs":[],"companies":[],"institutions":[],"pathways":["bcr-signalling","apoptosis-bcl2"],"terms":["del17p-tp53","resistance","umrd","richter-transformation","btki-bcl2i-resistance-mutations"],"trials":["murano"],"people":[],"bottlenecks":[],"keyPapers":["paper-murano-venetoclax-rituximab-nejm-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Most patients treated for chronic lymphocytic leukaemia relapse eventually, though often after many years; the small group whose disease resists both a BTK inhibitor and venetoclax has the shortest survival and the most active research.","subtypes":["Relapse after chemoimmunotherapy (BTK inhibitor or venetoclax-based)","Relapse after fixed-duration venetoclax (retreatment or BTK inhibitor)","Progression on a covalent BTK inhibitor (BTK C481 or PLCG2 mutation)","Intolerance to a covalent BTK inhibitor (switch agent)","Double-refractory CLL after BTK inhibitor and venetoclax (pirtobrutinib, CAR-T, trials)","Relapsed CLL with del(17p) or TP53 mutation"],"biomarkers":["BTK C481S and PLCG2 resistance mutations","BCL2 G101V mutation","del(17p) and TP53 mutation re-tested at relapse","Complex karyotype","IGHV status","Time since fixed-duration therapy ended","Biopsy of a rapidly growing node to exclude Richter transformation"],"standardOfCare":[{"setting":"Relapse after a BTK inhibitor","approach":"Venetoclax plus rituximab for two years (MURANO) or venetoclax-obinutuzumab; pirtobrutinib after covalent BTK inhibitor failure (BRUIN CLL-321).","refs":["venetoclax","rituximab","obinutuzumab","pirtobrutinib","bruin-cll-321"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Relapse after venetoclax","approach":"Acalabrutinib or zanubrutinib (ALPINE) continuously, or ibrutinib; venetoclax retreatment if the prior remission lasted a year or more.","refs":["acalabrutinib","zanubrutinib","ibrutinib","venetoclax","alpine","resonate"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Double-refractory after BTK inhibitor and venetoclax","approach":"Pirtobrutinib; lisocabtagene maraleucel CAR-T (TRANSCEND CLL 004); idelalisib-rituximab; clinical trials of BTK degraders, sonrotoclax and bispecifics; allogeneic transplant in fit young patients.","refs":["pirtobrutinib","lisocabtagene-maraleucel","transcend-cll-004","idelalisib","rituximab","sonrotoclax","nemtabrutinib","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}}],"stateOfArt":["Class switching between BTK inhibitors and venetoclax gives most patients years more control.","Pirtobrutinib overcomes the resistance mutations that stop covalent BTK inhibitors, and CAR-T is approved for double-refractory disease.","BTK degraders and the next BCL-2 inhibitor are in phase 3 for the double-refractory group."],"history":[{"year":2014,"title":"RESONATE: ibrutinib beats ofatumumab in relapsed CLL; idelalisib approved","refs":["resonate","ibrutinib","idelalisib"]},{"year":2016,"title":"Venetoclax approved for relapsed del(17p) CLL","refs":["venetoclax"]},{"year":2018,"title":"MURANO: two years of venetoclax-rituximab beats chemoimmunotherapy","refs":["venetoclax","rituximab"]},{"year":2022,"title":"ALPINE: zanubrutinib beats ibrutinib head to head","refs":["alpine","zanubrutinib","ibrutinib"]},{"year":2023,"title":"Pirtobrutinib approved after BTK and BCL-2 inhibitor failure","refs":["pirtobrutinib"]},{"year":2024,"title":"BRUIN CLL-321 reads out; lisocabtagene maraleucel approved for double-refractory CLL","refs":["bruin-cll-321","lisocabtagene-maraleucel","transcend-cll-004"]}],"pipeline":["pirtobrutinib","sonrotoclax","nemtabrutinib","lisocabtagene-maraleucel","bellwave-011","cadance-304"],"openProblems":["Double-refractory disease after BTK inhibitor and venetoclax has no durable option.","Whether venetoclax retreatment works as well the second time, and after how long an interval.","Distinguishing CLL progression from Richter transformation early enough."],"parent":"cll"},{"id":"myeloma-relapsed-refractory","kind":"cancer","name":"Relapsed or refractory multiple myeloma","aka":["RRMM","Relapsed myeloma","Triple-class refractory myeloma","Penta-refractory myeloma"],"tldr":"Myeloma almost always returns, and each return is harder to treat. Two kinds of immune therapy aimed at the BCMA protein on myeloma cells, CAR-T cells (KarMMa-3, CARTITUDE-4) and off-the-shelf bispecific antibodies (MajesTEC), now give deep remissions after other drugs fail, and a second target, GPRC5D, gives another option.","summary":"Relapse is defined by a rising M-protein or light chains, and refractory disease by progression on or within 60 days of a treatment. Choice at each relapse depends on which classes the disease has already resisted: proteasome inhibitors, immunomodulatory drugs and CD38 antibodies define triple-class exposure, and their five main members define penta-exposure. Early relapse after a lenalidomide-based first line is usually treated with a carfilzomib or pomalidomide triplet with a CD38 antibody, or with belantamab mafodotin combinations after DREAMM-7 (belantamab-bortezomib-dexamethasone versus daratumumab-bortezomib-dexamethasone, median progression-free survival 36.6 versus 13.4 months, hazard ratio 0.41, with a survival gain) and DREAMM-8 returned the antibody-drug conjugate to the market in 2025.\n\nBCMA-directed T-cell therapies changed the outlook for later lines. Idecabtagene vicleucel was the first CAR-T approved (2021); KarMMa-3 then showed it beat standard regimens after two to four prior lines, median progression-free survival 13.3 versus 4.4 months (hazard ratio 0.49). Ciltacabtagene autoleucel produced responses in 98 percent of heavily pretreated patients in CARTITUDE-1, with a third still progression-free at five years without further treatment, and CARTITUDE-4 showed it after one to three prior lines cut progression or death by about three quarters (hazard ratio 0.26) and lengthened life (hazard ratio 0.55), moving CAR-T to second line in 2024. Bispecific antibodies give an off-the-shelf alternative: teclistamab (MajesTEC-1, response rate 63 percent, approved 2022), elranatamab (MagnetisMM-3, 61 percent) and linvoseltamab (LINKER-MM1, 70 percent, approved 2025) against BCMA, and talquetamab (MonumenTAL-1, about 73 percent, approved 2023) against GPRC5D, which works after BCMA therapy fails. MajesTEC-3 (2025) showed teclistamab with daratumumab beating standard combinations in early relapse.\n\nThe price is toxicity and logistics: cytokine release syndrome and neurotoxicity with both approaches, delayed neurological and Parkinsonian events with cilta-cel, profound infections and hypogammaglobulinaemia with continuous BCMA bispecifics requiring immunoglobulin replacement, taste and skin toxicity with talquetamab, and manufacturing slots and hospital capacity for CAR-T. Sequencing (CAR-T before or after bispecific, BCMA then GPRC5D), fixed-duration bispecific dosing, CELMoDs such as iberdomide and mezigdomide, and trispecific antibodies are the current frontier.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Multiple_myeloma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Multiple_myeloma"},{"label":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}],"tags":["subtype-page"],"related":["myeloma-transplant-eligible","myeloma-transplant-ineligible","plasma-cell-leukaemia","smouldering-myeloma"],"cancers":[],"sections":[],"technologies":["car-t","t-cell-engager","bispecific-antibody","celmods","car-t-manufacturing-process"],"targets":["bcma","gprc5d","cd38","xpo1","cereblon"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["step-up-dosing","crs","icans","proteasome-inhibitor","imid","mrd-negativity-myeloma"],"trials":["majestec-1"],"people":[],"bottlenecks":[],"keyPapers":["paper-cartitude-4-cilta-cel-nejm-2023","paper-karmma-3-ide-cel-nejm-2023","paper-majestec-1-teclistamab-nejm-2022","paper-monumental-1-talquetamab-nejm-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Almost everyone with myeloma relapses eventually; with each line of treatment remissions shorten, and until 2021 patients whose disease resisted the three main drug classes survived about a year.","subtypes":["First relapse after lenalidomide-based therapy (lenalidomide-refractory)","Early relapse, one to three prior lines (cilta-cel, CARTITUDE-4; belantamab combinations)","Triple-class exposed or refractory myeloma (CAR-T, bispecifics)","Penta-refractory myeloma","Relapse after BCMA-directed therapy (GPRC5D-directed talquetamab)","Extramedullary relapse","Functional high-risk myeloma (relapse within 18 months of diagnosis)"],"biomarkers":["Classes and agents the disease is refractory to","Time from last therapy and depth of prior response","BCMA and GPRC5D expression and BCMA loss after prior BCMA therapy","Soluble BCMA","Extramedullary disease on PET-CT","Cytogenetics at relapse (del(17p), 1q gain)","Lymphocyte count and fitness for apheresis"],"standardOfCare":[{"setting":"First relapse, lenalidomide-refractory","approach":"Daratumumab or isatuximab with carfilzomib or pomalidomide and dexamethasone; belantamab mafodotin with bortezomib- or pomalidomide-dexamethasone (DREAMM-7, DREAMM-8); cilta-cel after one to three lines (CARTITUDE-4).","refs":["daratumumab","isatuximab","carfilzomib","pomalidomide","dexamethasone","belantamab-mafodotin","dreamm-7","dreamm-8","ciltacabtagene-autoleucel","cartitude-4"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Triple-class exposed, two or more prior lines","approach":"BCMA CAR-T (cilta-cel or ide-cel, KarMMa-3) where slots and fitness allow; BCMA bispecific (teclistamab, elranatamab, linvoseltamab) otherwise; teclistamab-daratumumab (MajesTEC-3).","refs":["ciltacabtagene-autoleucel","idecabtagene-vicleucel","karmma-3","cartitude-1","teclistamab","elranatamab","linvoseltamab","majestec-1","majestec-3","linker-mm1","magnetismm-3"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"After BCMA-directed therapy","approach":"Talquetamab against GPRC5D (MonumenTAL-1); selinexor combinations; CELMoDs and trispecifics in trials.","refs":["talquetamab","monumental-1","selinexor","iberdomide","mezigdomide","bcma-then-gprc5d"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Toxicity management","approach":"Step-up dosing and tocilizumab for cytokine release syndrome, immunoglobulin replacement and antimicrobial prophylaxis on bispecifics, neurological monitoring after cilta-cel, ocular examinations on belantamab.","refs":["step-up-dosing","crs","icans","bispecific-infection-prophylaxis"]}],"stateOfArt":["BCMA CAR-T now belongs in second line after CARTITUDE-4 lengthened life; a third of CARTITUDE-1 patients remain progression-free at five years after a single infusion.","Four approved bispecific antibodies, three against BCMA and one against GPRC5D, give off-the-shelf immune therapy with response rates of 60 to 70 percent in heavily pretreated patients.","Belantamab mafodotin returned in 2025 for early relapse with a survival gain in DREAMM-7."],"history":[{"year":2003,"title":"Bortezomib approved for relapsed myeloma: the first proteasome inhibitor","refs":["bortezomib"]},{"year":2012,"title":"Carfilzomib approved; pomalidomide follows in 2013","refs":["carfilzomib","pomalidomide"]},{"year":2015,"title":"Daratumumab, the first CD38 antibody, approved for heavily pretreated myeloma","refs":["daratumumab"]},{"year":2021,"title":"Ide-cel: first BCMA CAR-T approved","refs":["idecabtagene-vicleucel"]},{"year":2022,"title":"Teclistamab: first BCMA bispecific approved (MajesTEC-1)","refs":["teclistamab","majestec-1"]},{"year":2023,"title":"KarMMa-3 and CARTITUDE-4: CAR-T beats standard regimens in randomised trials; talquetamab and elranatamab approved","refs":["karmma-3","cartitude-4","talquetamab","elranatamab"]},{"year":2025,"title":"Linvoseltamab approved; belantamab returns after DREAMM-7 and DREAMM-8; MajesTEC-3 reads out","refs":["linvoseltamab","belantamab-mafodotin","dreamm-7","majestec-3"]}],"pipeline":["ciltacabtagene-autoleucel","teclistamab","talquetamab","linvoseltamab","belantamab-mafodotin","iberdomide","mezigdomide","arlocabtagene-autoleucel","immagine-1","quintessential-2","idea-bio1-adaptive-car-antigen-switch"],"openProblems":["Sequencing CAR-T and bispecifics, and whether a second T-cell therapy works after the first.","Infections on continuous BCMA bispecifics, and whether fixed-duration dosing is safe.","CAR-T manufacturing capacity, slots and cost, and the patients who progress while waiting."],"parent":"multiple-myeloma"},{"id":"rcc","kind":"cancer","name":"Renal cell carcinoma","aka":["RCC"],"tldr":"Kidney cancer is where anti-angiogenic drugs and immunotherapy came together, and where a Nobel-winning oxygen-sensing pathway yielded a drug, belzutifan.","summary":"Renal cell carcinoma is a cancer of the kidney's tubules, increasingly found by chance on scans done for other reasons. Three quarters are clear-cell tumours defined by loss of the VHL gene, which leaves the oxygen-sensing HIF-2α switch permanently on and makes the tumour intensely vascular and immune-infiltrated. That biology explains the whole modern treatment story: anti-VEGF pills (2005-2012), immunotherapy (2015 onward), their combination (2018 onward), and the first HIF-2α inhibitor, belzutifan (2021).\n\nFor metastatic disease, four immunotherapy-based first-line regimens have survival benefit: nivolumab-ipilimumab (CheckMate 214, durable remissions in a fifth of intermediate/poor-risk patients, still visible at eight years) and three IO-TKI doublets (pembrolizumab-axitinib, nivolumab-cabozantinib, lenvatinib-pembrolizumab). Attempts to do better in first line with triplets failed on survival (COSMIC-313) or fell short (LITESPARK-012), and two trials (CONTACT-03, TiNivo-2) showed that restarting immunotherapy after it fails does not help. After surgery, adjuvant pembrolizumab (KEYNOTE-564) was the first adjuvant immunotherapy in any solid tumour to improve overall survival, and in 2026 belzutifan plus pembrolizumab (LITESPARK-022) became the first adjuvant combination, though three other adjuvant immunotherapy trials were negative.\n\nWhat comes next: selecting who needs adjuvant therapy (ctDNA is weak in RCC; CAIX PET and gene signatures are candidates); CAIX theranostics with radiolabelled girentuximab; zanzalintinib and next-generation TKIs; HIF-2α combinations in the right setting; CD70 and CAIX cell therapies; treatment-free survival as an endpoint; and better management of the small renal masses that make up an increasing share of diagnoses, many of which need no treatment at all. Non-clear-cell histologies (papillary, chromophobe, translocation) remain under-served.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Renal_cell_carcinoma","links":[{"label":"NCI PDQ: renal cell cancer treatment","url":"https://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq"},{"label":"CheckMate 214 8-year follow-up","url":"https://www.annalsofoncology.org/article/S0923-7534(24)01516-3/fulltext"}],"tags":["gu"],"related":["src-urotoday"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","antiangiogenic","thermal-ablation","sbrt","allogeneic-cell-therapy","kinase-inhibitors","partial-nephrectomy-active-surveillance","caix-pet","robotic-surgery","radioimmunotherapy"],"targets":["hif2a","vegf","pd1","ctla4","cd70","cdh6","met","akt"],"drugs":[],"companies":["scancell","vyriad","bms","merck","pfizer","exelixis","eisai","novartis","aveo","telix","roche-genentech"],"institutions":["mskcc","md-anderson","dana-farber","gustave-roussy","cleveland-clinic"],"pathways":["hif-vhl","vegf-angiogenesis","renal-cell-carcinoma-signalling","pd1-checkpoint","pi3k-akt-mtor"],"terms":["imdc-risk","sarcomatoid-rcc","neoadjuvant-adjuvant","oligometastatic","nephrectomy"],"trials":["nct07227402","nct07489495","renaviv","nct04523272","nct03873402","nct04810078","nct05043090","nct07011719","nct03091192","nct04586231","nct05899049","nct07197580"],"people":["arnaud-mejean"],"bottlenecks":[],"keyPapers":[],"journals":["clinical-genitourinary-cancer","urologic-oncology"],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Renal cell carcinoma causes about 430,000 cases a year worldwide, with incidence rising as imaging finds more small tumours, many of which need no treatment; ~20-30% are metastatic at diagnosis, and immunotherapy doublets now give durable remissions in about a fifth of those patients. ~180,000 deaths a year; registry five-year survival for metastatic disease is ~15% overall, higher with modern IO regimens.","subtypes":["Clear-cell (~75%; VHL loss, HIF-2α driven)","Papillary type 1 (MET) and type 2 (FH, others)","Chromophobe","Translocation (TFE3/TFEB)","Collecting duct and medullary (SMARCB1)","Sarcomatoid differentiation (any histology, ~10%)","Hereditary syndromes: VHL, HLRCC (FH), BHD (FLCN), HPRC (MET)"],"biomarkers":["Clear-cell vs non-clear-cell histology","VHL","IMDC risk","CAIX (imaging, 89Zr-girentuximab)","IMDC risk group (six clinical factors)","Histology and sarcomatoid features","VHL / HIF-2α axis (belzutifan)","PD-L1 (not used for selection)","CAIX (imaging; theranostic target)","CD70 (CAR-T target)","MET (papillary type 1)","Gene-expression signatures (angiogenesis vs T-effector; research)","ctDNA (low shedding; research)"],"standardOfCare":[{"setting":"Localised","approach":"Partial/radical nephrectomy or ablation; adjuvant pembrolizumab ± belzutifan for high risk.","refs":["robotic-surgery","thermal-ablation","pembrolizumab","belzutifan"],"guideline":{"version":"NCCN Guidelines: Kidney Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440"}},{"setting":"Metastatic","approach":"IO-TKI or IO-IO doublet; belzutifan, cabozantinib, lenvatinib-everolimus later.","refs":["nivolumab","ipilimumab","pembrolizumab","belzutifan"],"guideline":{"version":"NCCN Guidelines: Kidney Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440"}},{"setting":"Small renal mass (<4 cm)","approach":"Active surveillance, partial nephrectomy (usually robotic), or thermal ablation depending on growth, comorbidity, and biopsy; renal mass biopsy increasingly used.","refs":["partial-nephrectomy-active-surveillance","robotic-surgery","thermal-ablation"],"guideline":{"nccn":"2A","version":"NCCN Kidney v3.2026"}},{"setting":"Localised T1b-T3","approach":"Partial or radical nephrectomy; no adjuvant therapy for low/intermediate risk.","refs":["robotic-surgery"],"guideline":{"nccn":"1 (surgery)"}},{"setting":"High-risk after nephrectomy (clear-cell)","approach":"Adjuvant pembrolizumab for 1 year (KEYNOTE-564, OS benefit); pembrolizumab + belzutifan approved 2026 (LITESPARK-022); sunitinib adjuvant rarely used.","refs":["pembrolizumab","keynote-564","belzutifan","litespark-022"],"guideline":{"nccn":"1 (pembrolizumab)","esmoMcbs":"A"}},{"setting":"Metastatic, intermediate/poor risk, first line","approach":"Nivolumab + ipilimumab, or an IO-TKI doublet (pembrolizumab + axitinib, nivolumab + cabozantinib, lenvatinib + pembrolizumab); cytoreductive nephrectomy deferred or omitted (CARMENA) except in selected cases.","refs":["nivolumab","ipilimumab","checkmate-214","pembrolizumab","axitinib","keynote-426","cabozantinib","checkmate-9er","lenvatinib","clear","risk-directed-first-line-rcc"],"guideline":{"nccn":"1 (preferred: all four regimens)","esmoMcbs":"4"}},{"setting":"Metastatic, favourable risk, first line","approach":"IO-TKI doublet (PFS benefit; OS benefit unproven in this group) or single-agent TKI (sunitinib, pazopanib) with deferred IO; active surveillance for indolent low-volume disease.","refs":["pembrolizumab","axitinib","lenvatinib","cabozantinib","sunitinib","imdc-risk"],"guideline":{"nccn":"1 (IO-TKI); 2A (TKI alone)"}},{"setting":"Second line after IO-based therapy","approach":"Single-agent TKI (cabozantinib, axitinib, lenvatinib + everolimus, tivozanib); belzutifan after both IO and VEGF-TKI (LITESPARK-005). Do not rechallenge PD-1 (CONTACT-03, TiNivo-2).","refs":["cabozantinib","belzutifan","litespark-005","tivozanib","everolimus","io-rechallenge-caution-rcc","contact-03","tinivo-2"],"guideline":{"nccn":"1 (cabozantinib, belzutifan)"}},{"setting":"Oligometastatic / oligoprogressive disease","approach":"Metastasectomy or SBRT to limited sites with continuation of systemic therapy or observation.","refs":["sbrt"],"guideline":{"nccn":"2A"}},{"setting":"Non-clear-cell RCC","approach":"Cabozantinib (PAPMET), lenvatinib + pembrolizumab (KEYNOTE-B61), or nivolumab + cabozantinib; MET inhibitors for MET-driven papillary; trials preferred.","refs":["cabozantinib","lenvatinib","pembrolizumab","nivolumab"],"guideline":{"nccn":"2A"}},{"setting":"VHL disease","approach":"Belzutifan for VHL-associated RCC, CNS haemangioblastoma, and pNET not requiring immediate surgery (LITESPARK-004).","refs":["belzutifan"],"guideline":{"nccn":"1"}}],"stateOfArt":["Adjuvant immunotherapy with OS benefit.","HIF-2α inhibition.","Four immunotherapy-based first-line regimens with survival benefit; durable remissions off treatment in ~20% with nivolumab-ipilimumab at 8 years.","Adjuvant pembrolizumab improves overall survival (KEYNOTE-564); pembrolizumab + belzutifan approved as adjuvant combination (2026).","Belzutifan validates HIF-2α as a target in VHL disease and pretreated RCC.","Two negative rechallenge trials (CONTACT-03, TiNivo-2) and two failed first-line intensification trials (COSMIC-313, LITESPARK-012) have sharpened the algorithm rather than widened it.","Active surveillance and nephron-sparing approaches are standard for small renal masses.","CAIX PET (ZIRCON) offers non-invasive diagnosis of clear-cell RCC; approval delayed by a 2025 CRL."],"history":[{"year":1992,"title":"High-dose IL-2 approved","refs":[]},{"year":1992,"title":"High-dose IL-2 approved: first immunotherapy for RCC, with rare cures","refs":["cytokine-therapy"]},{"year":1993,"title":"VHL gene identified; the molecular basis of clear-cell RCC","refs":["hif2a"]},{"year":2001,"title":"Cytoreductive nephrectomy improves survival with interferon (SWOG 8949)","refs":[]},{"year":2005,"title":"Sorafenib/sunitinib: VEGF era","refs":[]},{"year":2005,"title":"Sorafenib approved: first VEGF-pathway TKI in RCC","refs":["antiangiogenic"]},{"year":2006,"title":"Sunitinib approved; replaces interferon","refs":["sunitinib"]},{"year":2009,"title":"Everolimus approved second line (RECORD-1)","refs":["everolimus"]},{"year":2012,"title":"Axitinib approved (AXIS)","refs":["axitinib"]},{"year":2015,"title":"Nivolumab beats everolimus (CheckMate 025): immunotherapy returns to RCC","refs":["nivolumab"]},{"year":2016,"title":"Cabozantinib approved (METEOR)","refs":["cabozantinib"]},{"year":2018,"title":"Nivolumab-ipilimumab first line","refs":[]},{"year":2018,"title":"Nivolumab-ipilimumab first line (CheckMate 214); CARMENA questions cytoreductive nephrectomy","refs":["checkmate-214"]},{"year":2019,"title":"Pembrolizumab-axitinib and avelumab-axitinib: IO-TKI era begins","refs":["keynote-426","axitinib","avelumab"]},{"year":2021,"title":"Belzutifan approved","refs":["belzutifan"]},{"year":2021,"title":"Nivolumab-cabozantinib, lenvatinib-pembrolizumab, adjuvant pembrolizumab, belzutifan (VHL), tivozanib approved","refs":["checkmate-9er","clear","keynote-564","belzutifan","tivozanib"]},{"year":2023,"title":"COSMIC-313 triplet fails on OS; CONTACT-03 closes IO rechallenge; belzutifan approved after IO/TKI (LITESPARK-005); ZIRCON validates CAIX PET","refs":["cosmic-313","contact-03","litespark-005","caix-pet"]},{"year":2024,"title":"KEYNOTE-564 shows OS benefit; CheckMate 214 8-year data; TiNivo-2 negative","refs":["keynote-564","checkmate-214","tinivo-2"]},{"year":2026,"title":"LITESPARK-022 positive and approved (adjuvant belzutifan + pembrolizumab); LITESPARK-012 first-line triplet falls short","refs":["litespark-022","litespark-012"]}],"pipeline":["raludotatug-deruxtecan","intismeran-autogene","pf-08634404","zanzalintinib","abexinostat","al8326","gotistobart","tqb2450","ibi363","jk08","adi-270","litespark-022","caix-pet","idea-caix-theranostics","idea-adjuvant-selection-rcc","belzutifan","risk-directed-first-line-rcc","io-rechallenge-caution-rcc","allogeneic-cell-therapy","partial-nephrectomy-active-surveillance","radioimmunotherapy"],"openProblems":["Non-clear-cell histologies understudied.","No validated predictive biomarker for IO.","No predictive biomarker to choose between IO-IO and IO-TKI, or to identify the 20% who achieve durable remission.","Adjuvant therapy treats many who would never relapse; ctDNA shedding is too low for standard MRD approaches.","Favourable-risk disease has no proven OS benefit from any first-line combination.","Non-clear-cell histologies lack dedicated phase 3 evidence.","First-line intensification (triplets) has failed twice; the next step in first line is unclear.","Treatment-free survival and de-escalation after deep response are unstudied prospectively.","Toxicity and dose reductions with lenvatinib-pembrolizumab limit real-world durability.","Small renal mass overtreatment and the absence of a reliable non-invasive diagnostic (CAIX PET awaits approval)."],"prognosis":{"text":"In the United States, 79.2% of people diagnosed with kidney or renal pelvis cancer in 2016-2022 were alive five years later, relative to people of the same age without the disease. Two thirds (66%) are found while confined to the kidney, often incidentally on a scan for something else, with five-year relative survival of 93.6%; it is 77.6% for regional disease (17% of cases) and 20.3% for distant disease (15% of cases). The distant-stage figure only partly reflects the immunotherapy combinations that became first-line treatment during this period.","sources":[{"label":"SEER Cancer Stat Facts: Kidney and Renal Pelvis Cancer","url":"https://seer.cancer.gov/statfacts/html/kidrp.html"}]}},{"id":"renal-medullary-carcinoma","kind":"cancer","name":"Renal medullary carcinoma (SMARCB1-deficient)","aka":["SMARCB1-deficient renal medullary carcinoma","Renal medullary carcinoma","RMC","Sickle cell nephropathy-associated carcinoma"],"tldr":"Renal medullary carcinoma is a rare kidney cancer of young people with the sickle cell trait, driven by loss of SMARCB1. Platinum chemotherapy and removing the kidney are the main treatments. Most have spread when found; in the 52-patient series median survival was 13.0 months, 16.4 with nephrectomy against 7.0 without. So few centres see it that a trial and a second opinion are worth asking for.","summary":"The 2022 WHO classification names SMARCB1-deficient renal medullary carcinoma as a molecularly defined type (Moch 2022). It shares site, size and poorly differentiated histology with collecting duct carcinoma but is set apart by complete loss of SMARCB1 (INI1) expression, found in all six renal medullary carcinomas and only one of 22 collecting duct carcinomas in the defining study, with loss of one SMARCB1 allele and cyclin D1 expression (Histopathology 2012; Am J Surg Pathol 2012). It occurs in adolescents and young adults with sickle haemoglobinopathies; the proposed mechanism is that hypoxia, hypertonicity and ischaemia from red cell sickling in the renal medulla drive deletions and translocations of SMARCB1, which lies in a fragile region of chromosome 22, explaining the age dependence and the predilection for the right kidney (Clin Cancer Res 2018). In the 52-patient series median overall survival was 13.0 months; 75 percent had nephrectomy, and those who did survived longer than patients given systemic therapy alone (16.4 against 7.0 months) (BJU International 2017).\n\nHow it differs from its parent: age, the sickle cell association, the SMARCB1 loss that groups it biologically with other SMARCB1-deficient tumours, and resistance to the renal cell carcinoma drugs.\n\nHow common: no registry figure; 52 cases across eight centres in 15 years (BJU International 2017).\n\nTreatment: platinum-based chemotherapy is the mainstay and provides palliation, with nephrectomy associated with longer survival in the series; no targeted or immune therapy has proven benefit, and trials of EZH2 and other epigenetic drugs suited to SMARCB1 loss are the research direction (BJU International 2017).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Renal_medullary_carcinoma","links":[{"label":"NCI PDQ: renal cell cancer treatment","url":"https://www.cancer.gov/types/kidney/patient/kidney-treatment-pdq"},{"label":"Moch 2022, European Urology: the 2022 WHO classification of urinary and male genital tumours, part A (renal, penile, testicular)","url":"https://doi.org/10.1016/j.eururo.2022.06.016"},{"label":"Histopathology 2012: SMARCB1/INI1 inactivation in renal medullary carcinoma","url":"https://doi.org/10.1111/j.1365-2559.2012.04228.x"},{"label":"Clin Cancer Res 2018: a model linking sickle cell haemoglobinopathies and SMARCB1 loss in renal medullary carcinoma","url":"https://doi.org/10.1158/1078-0432.ccr-17-3296"},{"label":"BJU International 2017: management and outcomes of 52 patients with renal medullary carcinoma","url":"https://doi.org/10.1111/bju.13705"},{"label":"Am J Surg Pathol 2012: collecting duct carcinoma and renal medullary carcinoma, 52 cases","url":"https://doi.org/10.1097/pas.0b013e3182635954"}],"tags":["subtype-page","wave4","kidney","rare"],"related":["rcc","collecting-duct-carcinoma","clear-cell-rcc","papillary-rcc"],"cancers":[],"sections":[],"technologies":[],"targets":["smarcb1"],"drugs":["cisplatin","carboplatin","gemcitabine"],"companies":[],"institutions":[],"pathways":[],"terms":["nephrectomy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Very rare: 52 patients treated at eight North American and French academic centres over 2000 to 2015, median age 28 (range 9 to 48), 94 percent stage III or IV, 37 of 52 male (BJU International 2017). No registry figure was found in the sources read.","subtypes":["Renal medullary carcinoma in sickle cell trait (the usual setting; right kidney)","Renal medullary carcinoma without sickle haemoglobinopathy (renal cell carcinoma unclassified with medullary phenotype)","Collecting duct carcinoma with retained SMARCB1 (own page)"],"biomarkers":["SMARCB1 (INI1) loss on immunohistochemistry","Sickle cell trait or disease","OCT3/4 expression","Stage at diagnosis"],"standardOfCare":[{"setting":"All stages","approach":"Platinum-based chemotherapy and nephrectomy where possible; no proven targeted or immune therapy; trials where available.","refs":["nephrectomy","cisplatin","carboplatin","gemcitabine"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"rcc"},{"id":"resectable-pdac","kind":"cancer","name":"Resectable pancreatic ductal adenocarcinoma","aka":["Resectable pancreatic cancer","Operable pancreatic cancer","Early-stage PDAC","Stage I to II pancreatic adenocarcinoma"],"tldr":"Resectable pancreatic cancer is the minority of pancreatic cancer that the surgeon can remove with clear margins because it has not wrapped around the main arteries or spread. Treatment is an operation, usually a Whipple procedure, followed by six months of combination chemotherapy, which is what turns surgery alone into a real chance of cure.","summary":"Pancreatic ductal adenocarcinoma is called resectable when CT shows no contact with the superior mesenteric or coeliac arteries, no more than abutment of the portal or superior mesenteric vein, and no metastases. Most such tumours sit in the head of the gland and present with painless jaundice; body and tail tumours present later and are less often removable. Staging is a pancreas-protocol CT, a chest CT and CA 19-9, with endoscopic ultrasound and biopsy where the diagnosis is in doubt or neoadjuvant treatment is planned, and staging laparoscopy in some centres to find small peritoneal or liver deposits that CT misses.\n\nThe operation is a pancreatoduodenectomy (Whipple) for head tumours or a distal pancreatectomy with splenectomy for body and tail tumours, both with regional lymphadenectomy, increasingly by robotic or laparoscopic approach in high-volume centres. Surgery alone cures few patients: CONKO-001 (2007) showed that adjuvant gemcitabine roughly doubles the number alive without recurrence, ESPAC-4 (2017) that gemcitabine plus capecitabine does better, and PRODIGE 24 (2018) that six months of modified FOLFIRINOX after surgery gives the longest survival yet seen in the disease for patients fit enough to receive it. Roughly half of patients never complete adjuvant chemotherapy because of slow recovery, which is the main argument for giving some or all of it before surgery.\n\nWhether upfront chemotherapy helps clearly resectable tumours is not settled: PREOPANC-1 showed a benefit for neoadjuvant chemoradiation over upfront surgery in a mixed resectable and borderline population, but NORPACT-1 (2024) found no survival gain from neoadjuvant FOLFIRINOX in resectable disease, and the ALLIANCE A021806 trial is testing the question with modern chemotherapy. Every patient should be offered germline testing, because a BRCA, PALB2 or ATM variant changes chemotherapy choice and matters to relatives. Recurrence is common even after a complete resection and adjuvant chemotherapy, most often in the liver, and adjuvant trials of personalised mRNA vaccines (autogene cevumeran) and of the pan-RAS inhibitor daraxonrasib are trying to lower it.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Pancreatic_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Pancreatic_cancer"},{"label":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}],"tags":["subtype-page","gastrointestinal"],"related":["borderline-resectable-pdac","locally-advanced-pdac","metastatic-pdac","brca-palb2-pdac","ipmn-cystic-precursors","ampullary"],"cancers":[],"sections":[],"technologies":["robotic-surgery","cytotoxic-chemotherapy","ct","endoscopic-ultrasound-systems","biliary-stenting-drainage","germline-testing","neoantigen-mrna-vaccine","kras-inhibitors","eras-perioperative-nutrition","liquid-biopsy"],"targets":["kras","brca"],"drugs":["folfirinox","gemcitabine","capecitabine","gemcitabine-nab-paclitaxel","autogene-cevumeran","daraxonrasib","eli-002-7p"],"companies":["biontech","roche-genentech","revolution-medicines","elicio-therapeutics"],"institutions":[],"pathways":["pancreatic-cancer-signalling","ras-mapk"],"terms":["resectability","whipple","ca19-9","resection-margins","neoadjuvant-adjuvant","obstructive-jaundice","lymphadenectomy","ctdna","mrd","gbrca-mutation"],"trials":["prodige-24","preopanc","nct05968326","nct07252232","nct06538857","nct04969731","amplify-7p"],"people":["thierry-conroy","marc-besselink","vinod-balachandran","jurgen-weitz","richard-schulick","eileen-oreilly"],"bottlenecks":[],"keyPapers":["paper-prodige-24-adjuvant-mfolfirinox-pancreatic-nejm-2018","paper-espac-4-gemcitabine-capecitabine-adjuvant-pancreatic-lancet-2017","paper-rojas-mrna-neoantigen-vaccine-pancreatic-nature-2023","paper-burris-gemcitabine-pancreatic-jco-1997"],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About one in five pancreatic cancers is judged removable at diagnosis, usually because a tumour in the head of the pancreas blocked the bile duct and caused jaundice early. It is the only stage at which the disease is routinely cured.","subtypes":["Resectable PDAC of the pancreatic head (Whipple procedure)","Resectable PDAC of the body or tail (distal pancreatectomy)","Resectable PDAC with a raised CA 19-9 or large tumour (higher risk of occult spread, neoadjuvant chemotherapy considered)","Resectable PDAC with a germline BRCA or PALB2 variant (platinum-based chemotherapy)","Resectable PDAC arising in an IPMN (often earlier stage and better outcome)"],"biomarkers":["Pancreas-protocol CT for vessel contact and metastases (defines resectability)","CA 19-9 before and after surgery (prognosis, response, recurrence)","Resection margin status (R0 versus R1) and lymph node ratio","Germline testing for BRCA1, BRCA2, PALB2, ATM and Lynch genes in every patient","Tumour KRAS, TP53, CDKN2A and SMAD4 status (prognostic; SMAD4 loss favours distant spread)","Circulating tumour DNA after surgery (investigational marker of residual disease)"],"standardOfCare":[{"setting":"Staging","approach":"Pancreas-protocol CT, chest CT and CA 19-9; endoscopic ultrasound with biopsy when tissue is needed before treatment; biliary stenting only for cholangitis, deep jaundice or delayed surgery.","refs":["ct","ca19-9","endoscopic-ultrasound-systems","biliary-stenting-drainage","resectability"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Surgery","approach":"Pancreatoduodenectomy for head tumours, distal pancreatectomy with splenectomy for body and tail tumours, with regional lymphadenectomy; open, laparoscopic or robotic in high-volume centres.","refs":["whipple","robotic-surgery","lymphadenectomy","resection-margins"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Adjuvant chemotherapy","approach":"Six months of modified FOLFIRINOX for fit patients (PRODIGE 24); gemcitabine plus capecitabine (ESPAC-4) or gemcitabine alone (CONKO-001) for those who cannot tolerate it, started within twelve weeks of surgery.","refs":["folfirinox","prodige-24","gemcitabine","capecitabine","neoadjuvant-adjuvant","conko-001","espac-4"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Neoadjuvant chemotherapy","approach":"Considered for tumours with high-risk features (large size, very high CA 19-9, suspicious nodes) and increasingly offered in trials for all resectable disease; PREOPANC and NORPACT-1 are the evidence for and against.","refs":["folfirinox","preopanc","gemcitabine-nab-paclitaxel","neoadjuvant-adjuvant","norpact-1"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Germline testing","approach":"Offered to every patient at diagnosis; carriers of BRCA, PALB2 or ATM variants receive platinum-based chemotherapy and their relatives are offered testing and surveillance.","refs":["germline-testing","gbrca-mutation","pancreatic-surveillance"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Follow-up","approach":"CA 19-9 and CT every three to six months for two years then less often; recurrence is treated as metastatic or locally advanced disease.","refs":["ca19-9","ct"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Modified FOLFIRINOX after surgery (PRODIGE 24) is the adjuvant standard for fit patients and gives the longest survival recorded in a pancreatic cancer trial.","Neoadjuvant chemotherapy is spreading to resectable disease so that every patient receives systemic treatment, though NORPACT-1 did not show a survival gain.","Adjuvant trials of autogene cevumeran (personalised mRNA vaccine) and daraxonrasib are the first to attack recurrence with something other than chemotherapy.","Robotic pancreatoduodenectomy and enhanced recovery programmes shorten recovery and help more patients reach adjuvant chemotherapy."],"history":[{"year":1935,"title":"Allen Whipple describes the pancreatoduodenectomy that carries his name","refs":["whipple"]},{"year":2007,"title":"CONKO-001: adjuvant gemcitabine after resection lengthens disease-free survival","refs":["gemcitabine"]},{"year":2017,"title":"ESPAC-4: gemcitabine plus capecitabine beats gemcitabine alone after surgery","refs":["gemcitabine","capecitabine"]},{"year":2018,"title":"PRODIGE 24: six months of modified FOLFIRINOX after surgery sets the adjuvant standard","refs":["prodige-24","folfirinox","thierry-conroy"]},{"year":2020,"title":"PREOPANC-1: neoadjuvant chemoradiation before surgery improves long-term survival in resectable and borderline disease","refs":["preopanc","chemoradiation"]},{"year":2023,"title":"Autogene cevumeran phase 1: personalised mRNA vaccine after surgery raises T cells that track with staying recurrence-free","refs":["autogene-cevumeran","vinod-balachandran","paper-rojas-mrna-neoantigen-vaccine-pancreatic-nature-2023"]},{"year":2024,"title":"NORPACT-1: neoadjuvant FOLFIRINOX does not lengthen survival in clearly resectable disease","refs":["folfirinox"]}],"pipeline":["nct05968326","nct07252232","autogene-cevumeran","daraxonrasib","eli-002-7p","amplify-7p","nct06538857","nct04969731","idea-ras-inhibitor-neoadjuvant-pdac","idea-bio2-mrd-triggered-neoantigen-vaccine","idea-bio2-prehabilitation-standard"],"openProblems":["Half of patients never complete adjuvant chemotherapy; whether giving it first helps clearly resectable tumours is unproven.","Recurrence after a complete resection and full chemotherapy remains common, and no marker reliably identifies who is cured.","Circulating tumour DNA and CA 19-9 kinetics are not yet validated to guide who needs more or less treatment.","Outcomes differ sharply between high-volume and low-volume surgical centres."],"parent":"pancreatic"},{"id":"resectable-nsclc","kind":"cancer","name":"Resectable stage I to III non-small-cell lung cancer","aka":["Early-stage non-small-cell lung cancer","Operable lung cancer","Stage I, II and IIIA NSCLC","Perioperative NSCLC"],"tldr":"Lung cancer caught before it has spread is treated with surgery, now often keyhole or robotic and sometimes removing only part of a lobe. Immunotherapy given before and after the operation, or a targeted pill afterwards for EGFR or ALK tumours, cuts the chance of the cancer coming back by between a third and four fifths.","summary":"Surgery has cured lung cancer since Evarts Graham's pneumonectomy in 1933, and lobectomy with mediastinal node dissection became the standard after the 1995 Lung Cancer Study Group trial found more recurrences with lesser resections. Staging rests on PET-CT and, for central or node-suspicious tumours, endobronchial ultrasound sampling of the mediastinum; brain MRI is added from stage II. Two trials in 2022 and 2023, JCOG0802 and CALGB 140503, showed that segmentectomy or wedge resection is as good as lobectomy for peripheral tumours of 2 cm or less, the tumours that screening finds, and most resections are now by video-assisted or robotic thoracoscopy. Stereotactic radiotherapy cures most stage I tumours in patients who cannot have surgery (CHISEL, JCOG0403). Adjuvant cisplatin doublet chemotherapy, established by the LACE meta-analysis in 2008, adds about 5 percent to five-year survival in stage II and III.\n\nThe decade since 2020 has added systemic therapy on both sides of the operation. ADAURA (2020) showed that three years of adjuvant osimertinib in EGFR-mutated stage IB to IIIA cut recurrence by 83 percent and improved five-year survival from 78 to 88 percent, and ALINA (2024) did the same for two years of alectinib in ALK-positive disease (hazard ratio 0.24). For the majority without a driver, IMpower010 (2021) showed adjuvant atezolizumab improved disease-free survival in PD-L1-positive stage II to IIIA (hazard ratio 0.66), CheckMate 816 (2022) showed that three cycles of nivolumab with chemotherapy before surgery raised pathological complete response from 2 to 24 percent and improved event-free and, later, overall survival, and the perioperative trials that give immunotherapy before and after surgery, KEYNOTE-671 (pembrolizumab, event-free survival hazard ratio 0.58, overall survival hazard ratio 0.72), AEGEAN (durvalumab, hazard ratio 0.68) and CheckMate 77T (nivolumab, hazard ratio 0.58), all followed, with approvals between 2022 and 2024.\n\nThe open questions are practical: whether the adjuvant phase adds anything for patients who already had a complete pathological response, whether circulating tumour DNA after surgery can pick out who needs more treatment and who needs none, how to avoid immunotherapy toxicity that prevents an operation, and how to stage patients accurately enough to give the right group neoadjuvant treatment. Driver testing before any neoadjuvant immunotherapy is now essential because EGFR- and ALK-positive tumours gain little and should go to targeted adjuvant therapy instead.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Lung_cancer_surgery","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Lung_cancer_surgery"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":["stage-iii-unresectable-nsclc","egfr-mutant-nsclc","alk-positive-nsclc","pdl1-high-nsclc"],"cancers":[],"sections":[],"technologies":["robotic-surgery","sbrt","checkpoint-inhibitor","kinase-inhibitors","pet-ct","mri","low-dose-ct-screening","robotic-bronchoscopy","mrd-testing","cytotoxic-chemotherapy","platinum"],"targets":["pd1","pdl1","egfr","alk"],"drugs":["nivolumab","pembrolizumab","durvalumab","atezolizumab","osimertinib","alectinib","cisplatin","carboplatin","pemetrexed","paclitaxel","vinorelbine"],"companies":["bms","merck","astrazeneca","roche-genentech","alliance-oncology","jcog"],"institutions":["iaslc"],"pathways":["pd1-checkpoint"],"terms":["lobectomy","segmentectomy","pneumonectomy","minimally-invasive-surgery","neoadjuvant-adjuvant","pcr","major-pathological-response","efs","tnm-staging","cancer-stage","bronchoscopy","ctdna"],"trials":["checkmate-816","keynote-671","nct03800134","nct04025879","nct02486718","adaura","alina","calgb-140503","chisel","jcog0403","nlst-nelson","alchemist"],"people":["patrick-forde","jonathan-spicer","tina-cascone","heather-wakelee","john-heymach","enriqueta-felip","roy-herbst","wu-yi-long"],"bottlenecks":[],"keyPapers":["paper-checkmate-816-nejm-2022","paper-adaura-nejm-2020","paper-adaura-8-year-os-jto-2026","paper-nlst-nejm-2011"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"About a quarter to a third of non-small-cell lung cancers are found while still resectable, a share rising with low-dose CT screening; five-year survival ranges from over 80 percent for screen-detected stage IA tumours to about 40 percent for stage IIIA.","subtypes":["Stage IA peripheral adenocarcinoma 2 cm or less (sublobar resection or lobectomy)","Stage IB to IIIA adenocarcinoma or squamous cell carcinoma without a driver (perioperative or neoadjuvant chemoimmunotherapy)","Resected EGFR-mutated adenocarcinoma (adjuvant osimertinib)","Resected ALK-positive adenocarcinoma (adjuvant alectinib)","Medically inoperable stage I (stereotactic radiotherapy)","Superior sulcus (Pancoast) tumour (chemoradiation then surgery)"],"biomarkers":["TNM stage by PET-CT, brain MRI (stage II and above) and mediastinal sampling by endobronchial ultrasound or mediastinoscopy","EGFR and ALK status before any systemic treatment (targeted adjuvant therapy; neoadjuvant immunotherapy avoided)","PD-L1 tumour proportion score (adjuvant atezolizumab and pembrolizumab eligibility)","Pathological complete and major pathological response after neoadjuvant therapy","Circulating tumour DNA after surgery (molecular residual disease; under study)","Pulmonary function and cardiac fitness for surgery"],"standardOfCare":[{"setting":"Stage IA, peripheral, 2 cm or less","approach":"Segmentectomy or lobectomy by video-assisted or robotic thoracoscopy with node dissection (CALGB 140503, JCOG0802); no systemic therapy; stereotactic radiotherapy if not fit for surgery.","refs":["calgb-140503","lobectomy","segmentectomy","robotic-surgery","minimally-invasive-surgery","sbrt","chisel","jcog0403"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Stage IB to IIIA without EGFR or ALK alteration","approach":"Neoadjuvant nivolumab plus platinum chemotherapy for three cycles (CheckMate 816) or perioperative pembrolizumab (KEYNOTE-671), durvalumab (AEGEAN) or nivolumab (CheckMate 77T) with chemotherapy before and immunotherapy for a year after surgery; or surgery first then adjuvant cisplatin doublet and atezolizumab or pembrolizumab if PD-L1-positive (IMpower010).","refs":["checkmate-816","nivolumab","keynote-671","pembrolizumab","nct03800134","durvalumab","nct04025879","nct02486718","atezolizumab","cisplatin","carboplatin","pemetrexed","neoadjuvant-adjuvant","pcr","major-pathological-response"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Resected EGFR-mutated stage IB to IIIA","approach":"Adjuvant platinum chemotherapy where indicated, then three years of osimertinib (ADAURA).","refs":["adaura","osimertinib","egfr-exon19-l858r"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Resected ALK-positive stage IB to IIIA","approach":"Two years of adjuvant alectinib in place of chemotherapy (ALINA).","refs":["alina","alectinib"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Staging and surveillance","approach":"PET-CT and mediastinal sampling before surgery; CT every six months for two years then yearly; circulating tumour DNA surveillance in trials.","refs":["pet-ct","bronchoscopy","ct","mrd-testing","ctdna","tnm-staging"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Perioperative chemoimmunotherapy (CheckMate 816, KEYNOTE-671, AEGEAN, CheckMate 77T) cuts recurrence by about 40 percent and improves survival in driver-negative disease.","Targeted adjuvant therapy for EGFR (ADAURA) and ALK (ALINA) tumours with hazard ratios of 0.17 and 0.24 for recurrence.","Sublobar resection is an accepted standard for small peripheral tumours.","Low-dose CT screening is shifting diagnoses toward stage I."],"history":[{"year":1933,"title":"Evarts Graham performs the first successful pneumonectomy for lung cancer","refs":["pneumonectomy"]},{"year":1995,"title":"Lung Cancer Study Group: lobectomy beats limited resection, setting the standard for 30 years","refs":["lobectomy"]},{"year":2008,"title":"LACE meta-analysis: adjuvant cisplatin chemotherapy adds about 5 percent to five-year survival","refs":["cisplatin","vinorelbine"]},{"year":2011,"title":"NLST: low-dose CT screening cuts lung cancer mortality by 20 percent, finding more early-stage tumours","refs":["nlst-nelson","low-dose-ct-screening","paper-nlst-nejm-2011"]},{"year":2020,"title":"ADAURA: adjuvant osimertinib for EGFR-mutated disease","refs":["adaura","osimertinib","roy-herbst","wu-yi-long"]},{"year":2021,"title":"IMpower010: adjuvant atezolizumab improves disease-free survival in PD-L1-positive stage II to IIIA","refs":["nct02486718","atezolizumab","enriqueta-felip","heather-wakelee"]},{"year":2022,"title":"CheckMate 816: neoadjuvant nivolumab plus chemotherapy raises pathological complete response from 2 to 24 percent","refs":["checkmate-816","nivolumab","patrick-forde","jonathan-spicer","paper-checkmate-816-nejm-2022"]},{"year":2023,"title":"KEYNOTE-671 and AEGEAN: perioperative pembrolizumab and durvalumab; CALGB 140503: sublobar resection non-inferior","refs":["keynote-671","nct03800134","calgb-140503","heather-wakelee","john-heymach"]},{"year":2024,"title":"ALINA: adjuvant alectinib for ALK-positive disease; CheckMate 77T perioperative nivolumab approved","refs":["alina","alectinib","nct04025879","tina-cascone"]}],"pipeline":["mrd-testing","ctdna","nct04025879","idea-tr2-ctdna-mrd-qualification","idea-tr2-neoadjuvant-combo-platform","idea-bio2-neoadjuvant-biomarker-engine","low-dose-ct-screening","robotic-bronchoscopy"],"openProblems":["Whether adjuvant immunotherapy adds anything after neoadjuvant treatment and surgery, especially for complete pathological responders, has not been tested directly.","Circulating tumour DNA after surgery identifies high-risk patients but no trial yet shows that acting on it improves survival.","About a fifth of patients given neoadjuvant therapy never reach surgery, from progression, toxicity or decline.","Screening uptake is low in most countries, so most lung cancers are still found late."],"parent":"nsclc"},{"id":"ret-fusion-nsclc","kind":"cancer","name":"RET fusion-positive non-small-cell lung cancer","aka":["RET-rearranged lung cancer","KIF5B-RET lung cancer","RET+ NSCLC"],"tldr":"RET fusion lung cancer is a rare adenocarcinoma driven by a fused RET gene. The selective pill selpercatinib shrinks most tumours and more than doubles the time to progression compared with chemotherapy and immunotherapy, and pralsetinib is a second option.","summary":"RET fusions were found in lung cancer in 2012, but the first drugs tried, the multikinase inhibitors cabozantinib and vandetanib, produced responses in fewer than a third of patients with heavy off-target toxicity. Selective RET inhibitors designed from 2014 onward changed that: in LIBRETTO-001 selpercatinib produced a 64 percent response rate in patients who had received platinum chemotherapy and 85 percent in treatment-naive patients, with intracranial responses in most patients with measurable brain disease, and it received accelerated approval in May 2020. Pralsetinib followed in September 2020 on the ARROW study, with response rates of 61 percent after platinum and 70 percent in treatment-naive patients.\n\nLIBRETTO-431 (2023) was the randomised confirmation: selpercatinib against platinum-pemetrexed with or without pembrolizumab first line gave median progression-free survival of 24.8 versus 11.2 months (hazard ratio 0.46) and far fewer brain progressions, so selective RET inhibition became the first-line standard. Side effects are hypertension, liver enzyme rises, dry mouth, oedema and, rarely, hypersensitivity; QT prolongation is monitored. Checkpoint inhibitors work poorly in RET fusion disease.\n\nResistance arises through solvent-front mutations (G810) and through bypass via MET amplification or KRAS; next-generation RET inhibitors designed for G810 are in early trials, and chemotherapy remains active. Open questions are how to treat resistance, and whether adjuvant selpercatinib (LIBRETTO-432) prevents recurrence after surgery.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/RET_proto-oncogene","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/RET_proto-oncogene"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":["alk-positive-nsclc","ros1-positive-nsclc","ntrk-fusion-nsclc","met-altered-nsclc","braf-v600e-nsclc","egfr-mutant-nsclc"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","cgp","radiosurgery-srs"],"targets":["ret"],"drugs":["selpercatinib","pralsetinib","pemetrexed","pembrolizumab"],"companies":["eli-lilly","roche-genentech","blueprint-medicines"],"institutions":[],"pathways":["nsclc-signalling","rtk-activation","ras-mapk"],"terms":["gene-fusion","oncogene-addiction","gatekeeper-mutation","brain-metastases","tki-term"],"trials":["libretto-431","nct03157128","nct04819100"],"people":["alexander-drilon","justin-gainor","zhou-caicun"],"bottlenecks":[],"keyPapers":["paper-libretto-001-selpercatinib-nsclc-nejm-2020","paper-libretto-431-nejm-2023","paper-arrow-pralsetinib-gainor-lancet-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"About 1 to 2 percent of non-small-cell lung cancers carry a RET fusion, most often KIF5B-RET, in adenocarcinomas of younger patients who have never smoked; brain metastases are common.","subtypes":["KIF5B-RET fusion adenocarcinoma (about 70 percent of RET fusions)","CCDC6-RET and other RET fusion adenocarcinoma","RET fusion disease with brain metastases at diagnosis","Solvent-front (G810) resistance after selpercatinib or pralsetinib"],"biomarkers":["RET fusion by RNA sequencing or DNA panel (RNA preferred; fluorescence in situ hybridisation less reliable)","RET resistance mutations (G810) and bypass alterations at progression","Brain MRI at diagnosis and during follow-up","Blood pressure, liver enzymes and QT interval on RET inhibitors"],"standardOfCare":[{"setting":"Advanced, first line","approach":"Selpercatinib (LIBRETTO-431) as preferred; pralsetinib as an alternative.","refs":["selpercatinib","libretto-431","nct03157128","pralsetinib","brain-metastases"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, after a RET inhibitor","approach":"Platinum-pemetrexed with or without pembrolizumab; clinical trial of a next-generation RET inhibitor; local radiotherapy for oligoprogression.","refs":["pemetrexed","carboplatin","pembrolizumab","sbrt","oligoprogression","gatekeeper-mutation"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Selpercatinib first line: progression-free survival 24.8 versus 11.2 months against chemoimmunotherapy in LIBRETTO-431.","Two approved selective RET inhibitors with brain activity after years of poor results from multikinase drugs.","Adjuvant selpercatinib under test after resection."],"history":[{"year":2012,"title":"RET fusions (KIF5B-RET) found in lung adenocarcinoma","refs":["ret","gene-fusion"]},{"year":2020,"title":"Selpercatinib (LIBRETTO-001) and pralsetinib (ARROW) approved","refs":["selpercatinib","nct03157128","pralsetinib","alexander-drilon","justin-gainor"]},{"year":2023,"title":"LIBRETTO-431: selpercatinib beats chemotherapy plus pembrolizumab first line","refs":["libretto-431","selpercatinib","zhou-caicun"]}],"pipeline":["selpercatinib","libretto-431"],"openProblems":["Solvent-front resistance mutations have no approved inhibitor.","Whether adjuvant selpercatinib prevents recurrence is not yet known.","RNA-based testing is needed to find all fusions but is not universally available."],"parent":"nsclc"},{"id":"retinoblastoma","kind":"cancer","name":"Retinoblastoma","aka":[],"tldr":"An eye cancer of infants caused by loss of the RB1 gene, the first tumour-suppressor gene ever found. In rich countries almost every child survives and most eyes are saved by chemotherapy delivered through the eye's artery; in low-income countries, where most cases occur, survival depends on finding it early, and that is the global gap.","summary":"Retinoblastoma arises from biallelic loss of RB1 in developing retinal cells (Knudson's two-hit hypothesis, 1971; RB1 cloned 1986), or rarely from MYCN amplification with intact RB1. Heritable disease (~40%, germline RB1) is usually bilateral and multifocal, presents earlier, and carries lifelong risk of second cancers (osteosarcoma, melanoma, sarcomas), especially after radiation. Leukocoria and strabismus are the presenting signs; diagnosis is clinical and by imaging (biopsy is avoided), and staging uses the International Intraocular Retinoblastoma Classification (groups A-E) and the TNMH system.\n\nTreatment aims first at life, then at eye and vision. Advanced unilateral eyes (group E) are enucleated with pathologic high-risk features guiding adjuvant chemotherapy; salvageable eyes receive intra-arterial melphalan via the ophthalmic artery (Abramson, 2008), systemic chemoreduction (carboplatin, etoposide, vincristine) with focal laser/cryotherapy, and intravitreal melphalan for vitreous seeds. External-beam radiation is avoided in germline carriers. Extraocular and metastatic disease is treated with intensive chemotherapy and autologous stem-cell rescue; trilateral disease (pineal) is rarely curable. Aqueous-humour cell-free DNA (2017) is the first liquid biopsy for a tumour that cannot be biopsied. Genetic counselling and screening of siblings and offspring are integral.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Retinoblastoma","links":[{"label":"NCI PDQ: retinoblastoma","url":"https://www.cancer.gov/types/retinoblastoma/patient/retinoblastoma-treatment-pdq"},{"label":"Global Retinoblastoma Study (JAMA Oncol 2020)","url":"https://doi.org/10.1001/jamaoncol.2019.6716"},{"label":"World Eye Cancer Hope","url":"https://wechope.org/"}],"tags":["gap-fill","paediatric","eye","hereditary"],"related":["neuroblastoma","wilms-tumor","hepatoblastoma","rare-childhood-cancers"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","brachytherapy","germline-testing","liquid-biopsy","autologous-stem-cell-transplant","mri"],"targets":["tp53"],"drugs":["melphalan","carboplatin","etoposide","vincristine","topotecan","cyclophosphamide"],"companies":["childrens-oncology-group"],"institutions":["mskcc"],"pathways":["p53-cell-cycle"],"terms":["germline-vs-somatic"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-global-retinoblastoma-study-jama-oncol"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About 1 in 16,000-18,000 live births (~8,000 children per year worldwide); survival >95% in high-income countries but 30-60% in low-income countries where most cases occur.","subtypes":["Heritable (germline RB1; usually bilateral)","Non-heritable unilateral (somatic RB1)","MYCN-amplified RB1-wild-type (infants, aggressive)","Trilateral retinoblastoma (with pineoblastoma)","Retinoma (benign precursor)"],"biomarkers":["Germline RB1 testing (proband and family)","IIRC group A-E and TNMH stage","High-risk pathology after enucleation (massive choroidal invasion, post-laminar optic nerve, scleral invasion)","Aqueous humour cfDNA (6p gain, RB1 status)","MYCN amplification","MRI of brain for pineal/optic nerve involvement"],"standardOfCare":[{"setting":"Advanced unilateral (group E, no vision potential)","approach":"Primary enucleation with long optic nerve segment; adjuvant chemotherapy (VEC) for high-risk pathology; orbital implant.","refs":["vincristine","etoposide","carboplatin"],"guideline":{"version":"NCI PDQ; ABS/ISOO consensus","url":"https://www.cancer.gov/types/retinoblastoma/hp/retinoblastoma-treatment-pdq"}},{"setting":"Eye-salvage (groups B-D, bilateral)","approach":"Intra-arterial melphalan (± topotecan, carboplatin) via ophthalmic artery, or systemic chemoreduction (vincristine, etoposide, carboplatin) with consolidating laser, cryotherapy or plaque brachytherapy; intravitreal melphalan for vitreous seeds.","refs":["melphalan","carboplatin","etoposide","vincristine","topotecan","brachytherapy"],"guideline":{"version":"NCI PDQ"}},{"setting":"Extraocular / metastatic","approach":"Intensive multi-agent chemotherapy with autologous stem-cell rescue; radiotherapy to orbit; CNS disease is the hardest to cure.","refs":["cyclophosphamide","carboplatin","etoposide","autologous-stem-cell-transplant","imrt-igrt"]},{"setting":"Surveillance and genetics","approach":"Serial examinations under anaesthesia until ~7 years; germline RB1 testing; screening of at-risk relatives from birth; lifelong second-cancer awareness in carriers.","refs":["germline-testing"]}],"stateOfArt":["Intra-arterial chemotherapy saves eyes that would have been removed, with globe salvage ~70-90% in group D and few systemic effects.","Radiation has been almost eliminated because of second cancers in RB1 carriers.","Aqueous-humour cfDNA gives molecular information without biopsy.","The gap is global: >90% survival where diagnosis is early, versus much lower survival with orbital and metastatic disease where it is not (Global Retinoblastoma Study, 2020)."],"history":[{"year":1809,"title":"Wardrop recommends enucleation for 'fungus haematodes'","note":"First curative approach.","refs":[]},{"year":1971,"title":"Knudson's two-hit hypothesis","note":"Statistical analysis of hereditary vs sporadic retinoblastoma predicts tumour-suppressor genes.","refs":[]},{"year":1986,"title":"RB1 cloned (Friend, Weinberg, Dryja)","note":"The first tumour-suppressor gene identified.","refs":["tp53"]},{"year":1996,"title":"Systemic chemoreduction with focal therapy replaces radiation (Shields, Gallie)","refs":["carboplatin"]},{"year":2008,"title":"Intra-arterial melphalan via ophthalmic artery (Abramson)","refs":["melphalan"]},{"year":2012,"title":"Intravitreal melphalan for vitreous seeds (Munier)","refs":["melphalan"]},{"year":2017,"title":"Aqueous humour as liquid biopsy (Berry)","refs":["liquid-biopsy"]},{"year":2020,"title":"Global Retinoblastoma Study: survival tied to national income (JAMA Oncol)","refs":[]}],"pipeline":["melphalan","liquid-biopsy"],"openProblems":["Late diagnosis in low-income countries; paediatric ophthalmology access is the lever.","Second primary cancers in RB1 carriers across life.","Vision outcomes after eye salvage.","Metastatic and CNS disease."],"parent":"childhood-cancers"},{"id":"retroperitoneal-germ-cell-tumour","kind":"cancer","name":"Retroperitoneal germ cell tumour","aka":["Primary retroperitoneal germ cell tumour","Extragonadal retroperitoneal germ cell tumour","Burned-out testicular tumour presenting in the retroperitoneum"],"tldr":"A retroperitoneal germ cell tumour is a germ cell tumour found in the back of the abdomen with no obvious tumour in the testis. Many turn out to be spread from a tiny testicular tumour that has scarred over, so the testes are examined closely; treatment and cure rates are close to those of testicular disease.","summary":"Retroperitoneal germ cell tumours present as a mass around the aorta and vena cava, the first drainage site of the testis, in a man whose testes feel normal. Whether they are true extragonadal primaries is disputed: in a series of 26 patients treated as primary retroperitoneal germ cell tumours, ultrasound of the testes was abnormal in all 20 examined and testicular histology in 25 showed viable tumour in three, intratubular germ cell neoplasia in four, scar tissue in 12 and sclerosis or fibrosis in six; the authors concluded that such tumours should be regarded as metastases of a viable or burned-out testicular cancer until proven otherwise (Scholz 2002). The NCI PDQ summary keeps the retroperitoneum as one of the two main extragonadal sites.\n\nHow it differs from its parent: outcome is better than for the mediastinal site. In the pooled analysis, 63 percent of patients with retroperitoneal non-seminoma were alive after platinum chemotherapy against 49 percent with mediastinal non-seminoma, and no haematological malignancies occurred with retroperitoneal primaries (Bokemeyer 2002; Hartmann 2000). Seminoma survival was 88 percent whatever the site, and seminoma treated with radiotherapy alone had a lower progression-free survival than with chemotherapy (Bokemeyer 2002). In children the retroperitoneum is a site of teratoma: 8 of 11 children in one hospital series had teratomas, average age at diagnosis 18 months (Cancer 1985, PMID 2988749).\n\nHow common: no separate incidence figure is published.\n\nTreatment follows the parent page: retroperitoneal non-seminoma is staged by the International Germ Cell Cancer Collaborative Group risk group as testicular disease is, with three or four cycles of BEP and resection of residual masses over one centimetre; seminoma has cisplatin-based chemotherapy. A testicular ultrasound and, where it is abnormal, orchidectomy are part of the work-up because of the burned-out primary (Scholz 2002).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Germ_cell_tumor","links":[{"label":"NCI PDQ: extragonadal germ cell tumours treatment","url":"https://www.cancer.gov/types/extragonadal-germ-cell/patient/extragonadal-treatment-pdq"},{"label":"Bokemeyer 2002, JCO: extragonadal germ cell tumours of the mediastinum and retroperitoneum, 635 patients","url":"https://doi.org/10.1200/jco.2002.07.062"},{"label":"Scholz 2002, Annals of Oncology: retroperitoneal germ cell tumour, evidence of origin in the testis","url":"https://doi.org/10.1093/annonc/mdf003"},{"label":"Hartmann 2000, JNCI: haematological disorders with primary mediastinal non-seminomatous germ cell tumours","url":"https://doi.org/10.1093/jnci/92.1.54"},{"label":"Retroperitoneal germ cell tumours in childhood, Cancer 1985 (PMID 2988749)","url":"https://europepmc.org/article/MED/2988749"}],"tags":["subtype-page","wave4","rare"],"related":["extragonadal-germ-cell-tumour","mediastinal-germ-cell-tumour","testicular","non-seminoma","seminoma","paediatric-germ-cell-tumours"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["bleomycin","etoposide","cisplatin"],"companies":[],"institutions":[],"pathways":[],"terms":["afp","tumour-markers"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Rare and not counted separately by GLOBOCAN. In the international analysis of 635 extragonadal germ cell tumours, 283 (45 percent) arose in the retroperitoneum (Bokemeyer 2002).","subtypes":["Retroperitoneal seminoma","Retroperitoneal non-seminomatous germ cell tumour (embryonal carcinoma, yolk sac tumour, teratoma, mixed)","Retroperitoneal metastasis of a burned-out testicular primary (scar or intratubular germ cell neoplasia in the testis)","Retroperitoneal teratoma of childhood"],"biomarkers":["Alpha-fetoprotein, beta-hCG and lactate dehydrogenase","Testicular ultrasound for a burned-out primary","Isochromosome 12p"],"standardOfCare":[{"setting":"All histologies","approach":"Treated as the parent: chemotherapy by risk group, resection of residual masses, and testicular ultrasound with orchidectomy where the testis is abnormal.","refs":["extragonadal-germ-cell-tumour","bleomycin","etoposide","cisplatin"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"extragonadal-germ-cell-tumour"},{"id":"retroperitoneal-sarcoma","kind":"cancer","name":"Retroperitoneal sarcoma","aka":["Retroperitoneal soft tissue sarcoma","RPS","Abdominal sarcoma"],"tldr":"Retroperitoneal sarcomas grow silently at the back of the abdomen until they are the size of a melon. The treatment is one carefully planned operation in a sarcoma centre that removes the tumour with the neighbouring organs it touches. The STRASS trial showed radiotherapy before surgery does not help overall; a second trial is testing chemotherapy before surgery in the most aggressive types.","summary":"Retroperitoneal sarcomas are a site-defined group: well-differentiated and dedifferentiated liposarcoma make up about two thirds, leiomyosarcoma about a fifth, and solitary fibrous tumour, MPNST and undifferentiated pleomorphic sarcoma most of the rest. They present late as huge painless masses that displace the kidney, colon and pancreas, and the dominant pattern of failure differs by histology: liposarcoma recurs locally in the abdomen, often repeatedly and years later, while leiomyosarcoma metastasises to the liver and lungs. The Transatlantic Australasian Retroperitoneal Sarcoma Working Group consensus documents define the modern approach.\n\nComplete en bloc resection at first presentation, removing adjacent organs such as kidney, colon and psoas to secure a margin, is the only curative treatment and has been associated with better local control in reference centres since the reports of Gronchi and Bonvalot in 2009. Adjuvant therapies were tested in the EORTC STRASS trial, which randomised 266 patients to preoperative radiotherapy plus surgery or surgery alone and found no improvement in abdominal recurrence-free survival overall, though an unplanned analysis suggested benefit in well-differentiated and low-grade dedifferentiated liposarcoma. Preoperative radiotherapy is therefore not routine and is discussed case by case for liposarcoma.\n\nSystemic therapy is histology-driven: doxorubicin with ifosfamide for dedifferentiated liposarcoma, doxorubicin with dacarbazine or trabectedin for leiomyosarcoma (LMS-04), and eribulin and MDM2 inhibitors for liposarcoma. The STRASS2 trial is testing neoadjuvant chemotherapy against surgery alone in high-risk dedifferentiated liposarcoma and leiomyosarcoma, and repeat surgery for recurrence, selected by growth rate and multifocality, remains the main tool after relapse.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Sarcoma","links":[{"label":"TARPSWG","url":"https://www.tarpswg.org"}],"tags":["subtype-page"],"related":["liposarcoma","leiomyosarcoma","sarcoma","extremity-soft-tissue-sarcoma","undifferentiated-pleomorphic-sarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-esmo-sts-guideline-gronchi-ann-oncol-2021","paper-strass-lancet-oncol-2020","paper-tarpswg-retroperitoneal-sarcoma-gronchi-ann-surg-2016","paper-bonvalot-retroperitoneal-sarcoma-compartmental-jco-2009"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"About 15 percent of soft tissue sarcomas, mostly well-differentiated and dedifferentiated liposarcoma and leiomyosarcoma, diagnosed as very large masses in the space behind the bowel; local recurrence, not metastasis, kills most patients with liposarcoma, and outcomes depend heavily on treatment in a specialist centre.","subtypes":["Well-differentiated liposarcoma of the retroperitoneum (local recurrence, no metastasis)","Dedifferentiated liposarcoma of the retroperitoneum (grade 1 to 3)","Retroperitoneal leiomyosarcoma (including inferior vena cava; distant metastasis)","Solitary fibrous tumour and MPNST of the retroperitoneum","Undifferentiated pleomorphic sarcoma of the retroperitoneum"],"biomarkers":["Histological subtype and grade on preoperative core biopsy","MDM2 amplification (liposarcoma)","Multifocality and growth rate at recurrence","Sarculator nomogram risk"],"standardOfCare":[{"setting":"Primary, resectable","approach":"Single-stage complete en bloc resection with adjacent organs in a sarcoma reference centre, after core biopsy and multidisciplinary planning; preoperative radiotherapy not routine after STRASS, considered in well-differentiated and low-grade dedifferentiated liposarcoma.","refs":["strass","imrt-igrt","ct","fnclcc-grade"]},{"setting":"High-risk dedifferentiated liposarcoma or leiomyosarcoma","approach":"Neoadjuvant chemotherapy within STRASS2 (doxorubicin-ifosfamide or doxorubicin-dacarbazine) or up-front surgery; no proven adjuvant therapy.","refs":["doxorubicin","ifosfamide","dacarbazine"]},{"setting":"Recurrent or metastatic","approach":"Repeat resection for slowly growing, unifocal recurrence; histology-driven chemotherapy (doxorubicin plus trabectedin for leiomyosarcoma, LMS-04; eribulin or trabectedin for liposarcoma); MDM2 inhibitor trials.","refs":["trabectedin","lms-04","eribulin","mdm2-inhibitors","pazopanib"]}],"stateOfArt":["STRASS settled that preoperative radiotherapy does not improve outcomes across all retroperitoneal sarcomas.","Extended en bloc resection in expert centres is the intervention with the largest effect on local control.","STRASS2 is testing neoadjuvant chemotherapy in the histologies most likely to metastasise."],"history":[{"year":2009,"title":"Gronchi and Bonvalot report improved local control with extended en bloc resection","refs":[]},{"year":2015,"title":"TARPSWG consensus on management of primary retroperitoneal sarcoma","refs":[]},{"year":2019,"title":"STRASS2 opens: neoadjuvant chemotherapy versus surgery alone","refs":["doxorubicin","ifosfamide"]},{"year":2020,"title":"STRASS: preoperative radiotherapy does not improve abdominal recurrence-free survival","refs":["strass"]}],"pipeline":["mdm2-inhibitors","eribulin","trabectedin"],"openProblems":["Liposarcoma recurs in the abdomen in most patients even after complete surgery.","Neither radiotherapy nor chemotherapy has a proven adjuvant benefit.","Outcomes still depend on referral to a specialist centre before the first operation."],"parent":"sarcoma"},{"id":"rhabdomyosarcoma","kind":"cancer","name":"Rhabdomyosarcoma","aka":[],"tldr":"A childhood soft-tissue sarcoma, a cancer of muscle-like cells found anywhere from the eye socket to the bladder. Most children are cured with chemotherapy, surgery and radiation, and a fusion gene (PAX-FOXO1) now decides how intensively to treat.","summary":"Rhabdomyosarcoma (RMS) has two main types: embryonal (~70%, younger children, RAS-pathway mutations, favourable) and alveolar (~25%, adolescents, PAX3- or PAX7-FOXO1 fusion in ~80%, unfavourable). Fusion status has replaced histology in risk stratification since fusion-negative alveolar RMS behaves like embryonal. Sites range from orbit and parameningeal head and neck to genitourinary and extremity; risk groups combine site, size, nodal status, metastases, age and fusion status.\n\nTherapy is VAC (vincristine, actinomycin D, cyclophosphamide) in North America or IVA (ifosfamide) in Europe, with local control by surgery and/or radiotherapy at week ~13. Key trial results: adding irinotecan (VAC/VI, ARST0531) did not improve outcomes but reduced cyclophosphamide exposure; maintenance vinorelbine-cyclophosphamide after standard therapy improved survival in high-risk localised disease (EpSSG RMS 2005, Lancet Oncol 2019); temsirolimus added to chemotherapy improved event-free survival in intermediate-risk disease (ARST1431, reported 2024). Metastatic disease (especially bone/marrow, age >10) has survival under 30% and is the target of the FaR-RMS international trial. Relapse is usually fatal outside low-risk cases.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Rhabdomyosarcoma","links":[{"label":"NCI PDQ: childhood rhabdomyosarcoma","url":"https://www.cancer.gov/types/soft-tissue-sarcoma/patient/rhabdomyosarcoma-treatment-pdq"},{"label":"EpSSG RMS 2005 maintenance (Lancet Oncol 2019)","url":"https://doi.org/10.1016/S1470-2045(19)30617-5"},{"label":"FaR-RMS trial","url":"https://clinicaltrials.gov/study/NCT04625907"}],"tags":["gap-fill","paediatric","sarcoma"],"related":["ewing-sarcoma","osteosarcoma","synovial-sarcoma","alveolar-soft-part-sarcoma"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","imrt-igrt","proton-therapy","brachytherapy","car-t","pet-ct"],"targets":["b7h3","cdk4-6","fgfr2","tp53"],"drugs":["vincristine","dactinomycin","cyclophosphamide","ifosfamide","irinotecan","vinorelbine","temsirolimus","etoposide","doxorubicin","temozolomide"],"companies":["pfizer","childrens-oncology-group"],"institutions":[],"pathways":["ras-mapk","pi3k-akt-mtor"],"terms":["gene-fusion","foxo1-fusion-status"],"trials":["ccss"],"people":[],"bottlenecks":[],"keyPapers":["paper-bisogno-lancet-oncol"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"The most common soft-tissue sarcoma of childhood (~350 cases per year in the US, ~3% of childhood cancers); survival ~70% overall, >90% low risk, <30% metastatic.","subtypes":["Embryonal RMS (botryoid and spindle cell variants)","Alveolar RMS, PAX3/PAX7-FOXO1 fusion-positive","Fusion-negative alveolar RMS (behaves as embryonal)","Spindle cell / sclerosing RMS (MYOD1-mutant, aggressive; VGLL2-fused infantile, indolent)","Pleomorphic RMS (adults)"],"biomarkers":["PAX3/PAX7-FOXO1 fusion status (FISH/RT-PCR)","Site (favourable: orbit, non-parameningeal head and neck, GU non-bladder/prostate)","IRS group and TNM stage","Nodal status (PET-CT, biopsy for extremity/paratesticular)","MYOD1 L122R (poor)","Age (>10 years, <1 year unfavourable)"],"standardOfCare":[{"setting":"Low risk (embryonal, favourable site, complete resection)","approach":"VA ± reduced cyclophosphamide for 22-24 weeks; radiotherapy for microscopic residual disease.","refs":["vincristine","dactinomycin","cyclophosphamide"],"guideline":{"version":"COG ARST0331 / EpSSG RMS 2005","url":"https://doi.org/10.1016/S1470-2045(19)30617-5"}},{"setting":"Intermediate risk","approach":"VAC (or VAC/VI) 42 weeks with radiotherapy at week 13 (COG); IVA with maintenance vinorelbine-cyclophosphamide 6 months (EpSSG); temsirolimus-VAC/VI per ARST1431 where adopted.","refs":["vincristine","dactinomycin","cyclophosphamide","ifosfamide","irinotecan","vinorelbine","temsirolimus","imrt-igrt"],"guideline":{"version":"COG ARST1431; EpSSG RMS 2005"}},{"setting":"High risk (metastatic)","approach":"Intensive multi-agent chemotherapy (VAC/IE, vincristine-irinotecan windows) with radiotherapy to primary and metastases; maintenance; FaR-RMS trial questions.","refs":["vincristine","irinotecan","ifosfamide","etoposide","doxorubicin","imrt-igrt"],"guideline":{"version":"COG ARST0431; FaR-RMS"}},{"setting":"Relapsed","approach":"Vinorelbine-cyclophosphamide, irinotecan-temozolomide, surgery/RT; trials (mTOR, FGFR4, CDK4/6, IGF-1R, B7-H3 CAR-T).","refs":["vinorelbine","cyclophosphamide","irinotecan","temozolomide","temsirolimus"]}],"stateOfArt":["Fusion status has replaced histology in risk stratification in both COG and European protocols.","Maintenance chemotherapy (EpSSG RMS 2005) is the first survival gain in decades for high-risk localised disease.","Temsirolimus is the first targeted agent to improve event-free survival in a randomised RMS trial (ARST1431).","Metastatic disease remains the unsolved problem; international FaR-RMS trial pools patients across continents."],"history":[{"year":1972,"title":"Intergroup Rhabdomyosarcoma Study (IRS-I) begins","note":"Establishes VAC and cooperative-group model.","refs":[]},{"year":1993,"title":"PAX3-FOXO1 fusion identified (Galili, Barr)","refs":["gene-fusion"]},{"year":2010,"title":"Fusion-negative alveolar RMS behaves like embryonal (Williamson, JCO)","note":"Leads to fusion-based risk stratification.","refs":[]},{"year":2019,"title":"EpSSG RMS 2005: maintenance vinorelbine-cyclophosphamide improves survival (Lancet Oncol)","refs":["vinorelbine","cyclophosphamide"]},{"year":2019,"title":"ARST0531: irinotecan does not improve outcome but spares cyclophosphamide","refs":["irinotecan"]},{"year":2024,"title":"ARST1431: temsirolimus + chemotherapy improves EFS in intermediate risk","refs":["temsirolimus"]}],"pipeline":["temsirolimus","vinorelbine","car-t","b7h3","cobolimab"],"openProblems":["Metastatic alveolar RMS: survival <30% for 30 years.","PAX3-FOXO1 is an undrugged fusion transcription factor.","Local-control morbidity in young children (orbit, bladder, prostate).","Relapse after intermediate-risk therapy is rarely curable."],"parent":"sarcoma"},{"id":"richter-transformation-cll","kind":"cancer","name":"Richter transformation of chronic lymphocytic leukaemia","aka":["Richter syndrome","Richter's transformation","CLL transformed to diffuse large B-cell lymphoma","Transformed CLL"],"tldr":"Richter transformation is the sudden change of slow chronic lymphocytic leukaemia into a fast-growing lymphoma, usually of the diffuse large B-cell type. It is treated with lymphoma chemotherapy followed by a donor transplant where possible, and newer drugs such as pirtobrutinib, venetoclax combinations and bispecific antibodies are being tested because standard chemotherapy rarely cures it.","summary":"Suspected when a patient with CLL develops a rapidly enlarging node, fever, weight loss, a sharply rising lactate dehydrogenase or a new bright focus on PET-CT, and confirmed by excision biopsy of the hottest node. About 95 percent of cases are diffuse large B-cell lymphoma and the rest Hodgkin-type; the distinction that matters most is clonal relationship to the CLL, since the 80 percent of large-cell cases that share the CLL's immunoglobulin rearrangement carry TP53, NOTCH1, CDKN2A and MYC lesions and do badly, while clonally unrelated cases behave like ordinary de novo lymphoma. Transformation can occur on any therapy, including BTK inhibitors and venetoclax, and is sometimes the reason a CLL treatment seems to fail.\n\nStandard treatment is anthracycline-based chemoimmunotherapy, R-CHOP or R-EPOCH, with responses in fewer than half of clonally related cases and remissions that are short unless consolidated by an allogeneic stem cell transplant, which offers long-term survival to a minority of fit patients who respond. Autologous transplant is an option in chemosensitive disease when no donor is available. Hodgkin-type transformation is treated with Hodgkin regimens and has a better outlook.\n\nEvery new CLL and lymphoma drug is being tried: venetoclax added to R-EPOCH, the non-covalent BTK inhibitor pirtobrutinib (active in the BRUIN Richter cohort), covalent BTK inhibitors with checkpoint inhibitors (nivolumab or pembrolizumab with ibrutinib or acalabrutinib), the CD20 x CD3 bispecific antibodies epcoritamab and glofitamab, and CD19 CAR-T in small series, with response rates that are encouraging but durations still measured in months. Richter transformation is excluded from most CLL and lymphoma trials, so dedicated studies remain small.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Richter%27s_transformation","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Richter%27s_transformation"},{"label":"NCCN Guidelines: CLL/SLL","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}],"tags":["subtype-page"],"related":["cll-treatment-naive","cll-relapsed","tp53-del17p","double-hit-rearrangement","ig-tcr-clonality"],"cancers":[],"sections":[],"technologies":["allogeneic-hsct","car-t","pet-ct","t-cell-engager","cgp","fdg-pet","cytogenetics-fish","clonality-testing"],"targets":["btk","cd20","cd19","tp53","myc-gene","cdkn2a","notch1"],"drugs":[],"companies":[],"institutions":[],"pathways":["p53-mdm2-axis","myc","clonal-evolution"],"terms":["richter-transformation","r-chop","tp53-mutated","del17p-tp53","lymphoma-bio-transformation","deauville"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-rossi-richter-syndrome-blood-2018","paper-who-2022-lymphoid-alaggio-leukemia-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Between two and ten percent of people with chronic lymphocytic leukaemia develop Richter transformation, an aggressive lymphoma arising from the leukaemia; when the lymphoma is clonally related to the CLL, median survival has historically been under a year.","subtypes":["Richter transformation, diffuse large B-cell type, clonally related (TP53, NOTCH1, CDKN2A, MYC)","Richter transformation, diffuse large B-cell type, clonally unrelated","Hodgkin-type Richter transformation","Richter transformation on BTK inhibitor or venetoclax therapy"],"biomarkers":["PET-CT maximum SUV of the hottest node","Lactate dehydrogenase","Clonal relationship by IGHV sequencing","TP53, NOTCH1, CDKN2A and MYC lesions","Ki-67 on biopsy","Hodgkin versus large B-cell histology","Circulating tumour DNA (research)"],"standardOfCare":[{"setting":"Diagnosis","approach":"Excision biopsy of the PET-hottest node, histology with clonality studies, TP53 and MYC testing; restage CLL and check for cause such as BTK inhibitor progression.","refs":["pet-ct","richter-transformation","tp53-mutated"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Diffuse large B-cell type, first treatment","approach":"R-CHOP or R-EPOCH chemoimmunotherapy, with venetoclax added in trials; pirtobrutinib or a bispecific antibody in patients unfit for chemotherapy or within trials.","refs":["rituximab","cyclophosphamide","prednisone","r-chop","venetoclax","pirtobrutinib","nct04623541"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Consolidation in responders","approach":"Allogeneic stem cell transplant for fit patients with a donor; autologous transplant where chemosensitive and no donor.","refs":["allogeneic-hsct","autologous-stem-cell-transplant"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Relapsed or chemotherapy-refractory","approach":"Clinical trial: bispecific antibodies (epcoritamab, glofitamab), BTK inhibitor with checkpoint inhibitor, CD19 CAR-T, pirtobrutinib; palliative care.","refs":["pirtobrutinib","acalabrutinib","car-t","nct04623541","nct02029443"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}}],"stateOfArt":["Chemoimmunotherapy with allogeneic transplant consolidation is the only route to long-term survival, and reaches a minority.","Pirtobrutinib, venetoclax combinations and CD20 bispecifics produce responses in a disease where chemotherapy usually fails.","Clonal relationship to the CLL is the single most important prognostic fact.","Richter transformation is a change in a clone rather than a second cancer, and its genetics are its own. Across 86 pathologically proven cases, TP53 disruption was present in 47.1% and MYC abnormality in 26.2%, while the usual drivers of de novo diffuse large B-cell lymphoma were rare or absent.","Whether the large-cell clone is related to the leukaemic clone matters more than any drug currently does. Clonally unrelated cases had median survival of 62.5 months against 14.2 months for related ones, and less TP53 disruption, 23.1% against 60.0%, so establishing the relationship changes the expected course.","What prompts the suspicion is one site growing much faster than the rest, new B symptoms, a rising LDH or a PET scan with one area far brighter than the others, and what settles it is a biopsy of that area."],"history":[{"year":1928,"title":"Maurice Richter describes reticular cell sarcoma arising in chronic lymphocytic leukaemia","refs":["richter-transformation"]},{"year":2011,"title":"Rossi and colleagues show clonally related transformation carries TP53 and NOTCH1 lesions and a poor outcome","refs":["tp53-mutated"]},{"year":2013,"title":"Richter transformation described on ibrutinib, a mode of BTK inhibitor failure","refs":["ibrutinib"]},{"year":2023,"title":"Pirtobrutinib and bispecific antibodies report activity in Richter cohorts","refs":["pirtobrutinib"]}],"pipeline":["pirtobrutinib","venetoclax","nct04623541","nct02029443","car-t"],"openProblems":["No regimen reliably produces durable remission in clonally related disease.","Richter transformation is excluded from most trials, so evidence comes from small cohorts.","Predicting which CLL patients will transform, and whether BTK inhibitors change that risk."],"parent":"cll"},{"id":"ros1-positive-nsclc","kind":"cancer","name":"ROS1-positive non-small-cell lung cancer","aka":["ROS1-rearranged lung cancer","ROS1 fusion NSCLC","CD74-ROS1 lung cancer"],"tldr":"ROS1-positive lung cancer is a rare fusion-driven adenocarcinoma treated with a pill. Crizotinib was the first, and the newer drugs repotrectinib and taletrectinib control the disease for about three years, reach the brain and work against the resistance mutation that defeated the older drugs.","summary":"ROS1 fusions were identified in lung cancer in 2007 alongside ALK, and because the two kinases are closely related the ALK inhibitor crizotinib also blocked ROS1. In the ROS1 cohort of PROFILE 1001 the response rate was 72 percent and median progression-free survival 19.2 months, and crizotinib was approved for ROS1-positive lung cancer in March 2016 on that single-arm evidence. Its weaknesses were poor brain penetration and resistance through the G2032R solvent-front mutation.\n\nEntrectinib, a ROS1, NTRK and ALK inhibitor with brain penetration, was approved in August 2019 on an integrated analysis of its phase 1 and 2 studies (STARTRK-2 among them) with a response rate of 77 percent and intracranial responses. Repotrectinib, a compact macrocycle designed to fit around solvent-front mutations, was approved in November 2023 on TRIDENT-1: a 79 percent response rate and median progression-free survival of 35.7 months in inhibitor-naive patients, and a 38 percent response rate after one prior inhibitor, including G2032R disease. Taletrectinib, tested in the TRUST-I and TRUST-II studies, was approved in June 2025 with high response rates in both inhibitor-naive and crizotinib-pretreated patients and less dizziness than repotrectinib.\n\nZidesamtinib (NVL-520) is designed to spare TRK and so avoid the dizziness and weight gain of the current drugs. Chemotherapy with platinum-pemetrexed remains effective once inhibitors are exhausted, and checkpoint inhibitors add little. Open questions are the best first drug now that three brain-penetrant inhibitors exist and how to treat bypass resistance through MET or KRAS.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/ROS1","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/ROS1"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":["alk-positive-nsclc","ret-fusion-nsclc","ntrk-fusion-nsclc","egfr-mutant-nsclc","met-altered-nsclc","braf-v600e-nsclc"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","radiosurgery-srs","cgp"],"targets":["ros1","ntrk","met"],"drugs":["repotrectinib","taletrectinib","entrectinib","crizotinib","zidesamtinib"],"companies":["bms","nuvation-bio","roche-genentech","pfizer","nuvalent"],"institutions":[],"pathways":["nsclc-signalling","rtk-activation"],"terms":["gene-fusion","oncogene-addiction","gatekeeper-mutation","brain-metastases","tki-term"],"trials":["nct03093116","nct04395677","nct02568267"],"people":["alexander-drilon","ross-camidge","cho-byoung-chul"],"bottlenecks":[],"keyPapers":["paper-trident-1-repotrectinib-nejm-2024","paper-shaw-crizotinib-ros1-nejm-2014","paper-drilon-entrectinib-ros1-lancet-oncol-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"About 1 to 2 percent of non-small-cell lung cancers carry a ROS1 fusion, typically adenocarcinoma in younger patients who have never smoked; about a third have brain metastases at some point.","subtypes":["ROS1 fusion adenocarcinoma, inhibitor-naive (repotrectinib, taletrectinib, entrectinib or crizotinib)","ROS1-positive disease with brain metastases at diagnosis","Crizotinib-resistant ROS1 disease (G2032R solvent-front mutation; repotrectinib, taletrectinib)","Bypass resistance through MET or KRAS after ROS1 inhibitors"],"biomarkers":["ROS1 fusion by RNA sequencing, fluorescence in situ hybridisation or immunohistochemistry with confirmation","ROS1 resistance mutations at progression (G2032R, D2033N, L2026M)","Brain MRI at diagnosis and during follow-up","Bypass alterations (MET amplification, KRAS) at progression"],"standardOfCare":[{"setting":"Advanced, first line","approach":"Repotrectinib (TRIDENT-1) or taletrectinib as preferred; entrectinib or crizotinib as alternatives, entrectinib when brain metastases are present.","refs":["repotrectinib","nct03093116","taletrectinib","nct04395677","entrectinib","nct02568267","crizotinib","brain-metastases"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, after crizotinib or entrectinib","approach":"Repotrectinib or taletrectinib, which cover G2032R; zidesamtinib in trials; platinum-pemetrexed once inhibitors are exhausted.","refs":["repotrectinib","taletrectinib","zidesamtinib","gatekeeper-mutation","pemetrexed","carboplatin"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Brain metastases","approach":"Brain-penetrant inhibitors (repotrectinib, taletrectinib, entrectinib) with stereotactic radiosurgery for large or symptomatic lesions.","refs":["repotrectinib","entrectinib","radiosurgery-srs","brain-metastases"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Repotrectinib and taletrectinib give about three years of control first line and cover the G2032R mutation.","Three brain-penetrant inhibitors approved between 2019 and 2025 after crizotinib's decade alone.","Zidesamtinib designed to spare TRK and remove the dizziness and weight gain of dual ROS1/TRK inhibitors."],"history":[{"year":2007,"title":"ROS1 fusions identified in lung cancer","refs":["ros1","gene-fusion"]},{"year":2014,"title":"PROFILE 1001 ROS1 cohort: crizotinib response rate 72 percent","refs":["crizotinib"]},{"year":2016,"title":"Crizotinib approved for ROS1-positive lung cancer","refs":["crizotinib"]},{"year":2019,"title":"Entrectinib approved for ROS1 lung cancer and NTRK fusion tumours","refs":["entrectinib","nct02568267","alexander-drilon"]},{"year":2023,"title":"TRIDENT-1: repotrectinib approved with activity against G2032R","refs":["repotrectinib","nct03093116","alexander-drilon"]},{"year":2025,"title":"Taletrectinib approved after TRUST-I and TRUST-II","refs":["taletrectinib","nct04395677"]}],"pipeline":["zidesamtinib","taletrectinib","nct04395677"],"openProblems":["No randomised trial compares the ROS1 inhibitors; choice rests on single-arm response rates and side-effect profiles.","Dizziness, weight gain and paraesthesia from TRK inhibition limit the current brain-penetrant drugs.","Resistance through MET, KRAS and other bypass routes has no approved targeted option."],"parent":"nsclc"},{"id":"rosai-dorfman-disease","kind":"cancer","name":"Rosai-Dorfman-Destombes disease","aka":["Rosai-Dorfman disease","RDD","Sinus histiocytosis with massive lymphadenopathy","R-group histiocytosis","Destombes-Rosai-Dorfman disease"],"tldr":"Rosai-Dorfman disease is a rare histiocytosis in which large immune cells called histiocytes fill the neck lymph nodes or grow in the skin, bones, nose, brain coverings or kidneys. Many cases fade without treatment, so it is watched unless it threatens an organ, when surgery, steroids, sirolimus or, for the third with a growth-pathway mutation, MEK inhibitors such as cobimetinib are used.","summary":"Rosai-Dorfman-Destombes disease was described in 1965 and 1969 as sinus histiocytosis with massive lymphadenopathy: large S100-positive, CD68-positive, CD1a-negative histiocytes with abundant pale cytoplasm containing intact lymphocytes (emperipolesis) distend the sinuses of lymph nodes. The classical form presents in children and young adults with enormous painless cervical nodes, fever and raised inflammatory markers; extranodal disease, commoner in adults, affects the skin, nasal cavity and sinuses, bone, orbit, meninges (mimicking meningioma), kidneys and retroperitoneum, and can occur without any node involvement. Long thought reactive, it was found from 2017 onward to carry activating KRAS, MAP2K1 and other MAPK pathway mutations in about a third of cases, which places it in the R group of the 2016 histiocytosis classification and among the histiocytic neoplasms in the 2022 WHO classification. Associations include IgG4-related disease, autoimmune cytopenias, a familial form due to SLC29A3 mutations (H syndrome) and, rarely, lymphoma.\n\nBecause many cases regress spontaneously, the 2018 consensus recommendations (Blood) advise observation for asymptomatic nodal or cutaneous disease and treatment only for symptoms or organ threat. Surgery is curative for a single extranodal lesion and relieves compressive disease; corticosteroids shrink nodes but the disease returns as they are withdrawn; sirolimus with prednisone, cladribine, methotrexate, lenalidomide and rituximab (for the IgG4-associated form) have all produced responses in small series; radiotherapy is used for localised refractory lesions, particularly in the orbit and airway. For patients with MAPK pathway mutations or multifocal refractory disease, MEK inhibition works: the cobimetinib phase 2 trial included patients with Rosai-Dorfman disease among its responders, and the 2022 United States approval of cobimetinib for histiocytic neoplasms covers the disease. Central nervous system involvement, which can cause seizures and cranial nerve palsies, is treated more aggressively, and long follow-up is needed because the course is relapsing and remitting over years.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Rosai%E2%80%93Dorfman_disease","links":[{"label":"RDD consensus recommendations (Blood 2018)","url":"https://doi.org/10.1182/blood-2018-03-839753"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Rosai%E2%80%93Dorfman_disease"}],"tags":["subtype-page","haematologic"],"related":["erdheim-chester-disease","histiocytoses","lch-single-system"],"cancers":[],"sections":[],"technologies":["fdg-pet","cgp","mri","histopathology-ihc","kinase-inhibitors","active-surveillance","imrt-igrt"],"targets":["braf"],"drugs":["cobimetinib","cladribine","methotrexate","rituximab"],"companies":[],"institutions":[],"pathways":[],"terms":["driver-mutation","retroperitoneum"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2022-myeloid-khoury-leukemia-2022","paper-rosai-dorfman-destombes-consensus-recommendations-blood-2018","paper-emile-revised-classification-of-histiocytoses-blood-2016"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"A rare disorder classically of children and young adults with huge painless neck nodes, and of older adults with extranodal disease; many cases resolve on their own and only a minority need systemic treatment.","subtypes":["Classical nodal Rosai-Dorfman disease (massive cervical lymphadenopathy, children and young adults)","Extranodal Rosai-Dorfman disease (skin, sinonasal, bone, orbit, kidney)","Neurological Rosai-Dorfman disease (meningeal or parenchymal, mimics meningioma)","Cutaneous-only Rosai-Dorfman disease (often self-limiting)","Rosai-Dorfman disease with KRAS or MAP2K1 mutations (MEK inhibitor responsive)","Familial Rosai-Dorfman disease (SLC29A3, H syndrome) and IgG4-associated disease"],"biomarkers":["S100 and CD68 positive, CD1a and langerin negative histiocytes with emperipolesis","KRAS, MAP2K1 and other MAPK pathway mutations (about a third)","FDG-PET/CT for extent and response","IgG4-positive plasma cells (IgG4-related overlap)","Immunoglobulin levels, autoimmune screen and SLC29A3 testing where familial disease is suspected","MRI of brain and spine for neurological disease"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Excisional biopsy with immunohistochemistry and MAPK pathway sequencing; FDG-PET/CT; MRI where neurological disease is suspected; immunoglobulins and autoimmune screen.","refs":["histopathology-ihc","cgp","fdg-pet","mri"],"guideline":{"version":"Consensus recommendations for Rosai-Dorfman-Destombes disease (Blood 2018)","url":"https://doi.org/10.1182/blood-2018-03-839753"}},{"setting":"Asymptomatic nodal or cutaneous disease","approach":"Observation, because spontaneous regression is common.","refs":["active-surveillance"],"guideline":{"version":"Consensus recommendations for Rosai-Dorfman-Destombes disease (Blood 2018)","url":"https://doi.org/10.1182/blood-2018-03-839753"}},{"setting":"Single or compressive extranodal lesion","approach":"Surgical excision or debulking; radiotherapy for unresectable localised disease (orbit, airway).","refs":["imrt-igrt"],"guideline":{"version":"Consensus recommendations for Rosai-Dorfman-Destombes disease (Blood 2018)","url":"https://doi.org/10.1182/blood-2018-03-839753"}},{"setting":"Multifocal or organ-threatening disease","approach":"Corticosteroids for rapid control; sirolimus with prednisone, cladribine, methotrexate or lenalidomide; rituximab for IgG4-associated disease.","refs":["cladribine","methotrexate","rituximab"],"guideline":{"version":"Consensus recommendations for Rosai-Dorfman-Destombes disease (Blood 2018)","url":"https://doi.org/10.1182/blood-2018-03-839753"}},{"setting":"MAPK-mutant or refractory disease","approach":"Cobimetinib (approved 2022 for histiocytic neoplasms) or trametinib.","refs":["cobimetinib","ras-mapk","kinase-inhibitors"],"guideline":{"version":"Consensus recommendations for Rosai-Dorfman-Destombes disease (Blood 2018)","url":"https://doi.org/10.1182/blood-2018-03-839753"}}],"stateOfArt":["The discovery of MAPK mutations moved the disease from reactive to neoplastic and opened MEK inhibition.","Observation remains correct for many patients because the disease often resolves.","Cobimetinib's 2022 approval is the first drug approval covering Rosai-Dorfman disease."],"history":[{"year":1965,"title":"Destombes describes the disease in Paris","refs":[]},{"year":1969,"title":"Rosai and Dorfman define sinus histiocytosis with massive lymphadenopathy","refs":[]},{"year":2016,"title":"Revised histiocytosis classification creates the R group for Rosai-Dorfman disease","refs":[]},{"year":2017,"title":"KRAS and MAP2K1 mutations identified, establishing a neoplastic subset","refs":["ras-mapk"]},{"year":2018,"title":"First consensus recommendations for diagnosis and treatment (Blood)","refs":[]},{"year":2022,"title":"Cobimetinib approved for histiocytic neoplasms; WHO lists Rosai-Dorfman disease among histiocytic neoplasms","refs":["cobimetinib"]}],"pipeline":["cobimetinib"],"openProblems":["Which patients will regress spontaneously cannot be predicted.","Two thirds of cases have no identified driver mutation.","All systemic treatments rest on case series; there has never been a randomised trial.","Neurological disease can leave permanent deficits despite treatment."],"parent":"histiocytoses"},{"id":"salivary-duct-carcinoma","kind":"cancer","name":"Salivary duct carcinoma","aka":["SDC","High-grade salivary duct carcinoma","Androgen receptor-positive salivary carcinoma"],"tldr":"Salivary duct carcinoma is an aggressive cancer of the parotid gland that behaves like a high-grade breast cancer and carries the same switches: most tumours run on the androgen receptor and about a third on HER2, so hormone blockers borrowed from prostate cancer and trastuzumab borrowed from breast cancer now shrink many of them.","summary":"Salivary duct carcinoma is a high-grade adenocarcinoma of the salivary ducts, usually of the parotid gland in men over sixty, that under the microscope looks like high-grade ductal carcinoma of the breast with comedo necrosis, and sometimes arises within a long-standing pleomorphic adenoma. It spreads early to the neck nodes and to lung and bone, and facial nerve palsy at presentation is common. The great majority of tumours express the androgen receptor, about a third have HER2 amplification, and TP53, PIK3CA and HRAS mutations are frequent, so molecular profiling at diagnosis is standard.\n\nLocal treatment is parotidectomy with sacrifice of the facial nerve when it is involved, neck dissection and postoperative radiotherapy or chemoradiation, but most patients relapse at a distance, and systemic treatment borrowed from breast and prostate cancer is what has changed the disease. For HER2-positive tumours a Japanese phase 2 of trastuzumab with docetaxel in 57 patients produced responses in 70.2 percent with median progression-free survival of 8.9 months and median overall survival of 39.7 months, and trastuzumab deruxtecan and trastuzumab emtansine have produced responses in HER2-positive salivary cancers in tumour-agnostic studies.\n\nFor androgen receptor-positive disease, a phase 2 of leuprorelin with bicalutamide in 36 patients produced responses in 41.7 percent with median progression-free survival of 8.8 months, and the EORTC 1206 trial randomised androgen deprivation against chemotherapy; enzalutamide gave more modest responses in a phase 2, and apalutamide with a GnRH agonist is in trial. Patients whose tumours have both markers may be treated sequentially, and combined anti-HER2 and anti-androgen treatment is being explored; platinum-based chemotherapy and pembrolizumab for the rare PD-L1-high or mutation-rich tumour are the remaining options.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Salivary_duct_carcinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Salivary_duct_carcinoma"}],"tags":["subtype-page","head-and-neck"],"related":["adenoid-cystic-carcinoma","mucoepidermoid-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bernier-eortc-22931-nejm-2004","paper-laurie-licitra-salivary-systemic-jco-2006","paper-takahashi-trastuzumab-docetaxel-salivary-duct-jco-2019","paper-fushimi-androgen-deprivation-salivary-duct-ann-oncol-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"A rare, aggressive salivary cancer that resembles high-grade breast ductal carcinoma, mostly in older men and mostly in the parotid; the great majority express the androgen receptor and about a third overexpress HER2, which has made it the most drug-targetable salivary cancer.","subtypes":["Salivary duct carcinoma of the parotid (the great majority)","HER2-amplified salivary duct carcinoma (about a third)","Androgen receptor-positive, HER2-negative salivary duct carcinoma","Salivary duct carcinoma arising in a pleomorphic adenoma (carcinoma ex pleomorphic adenoma)","Micropapillary and sarcomatoid variants"],"biomarkers":["Androgen receptor immunohistochemistry","HER2 immunohistochemistry and in situ hybridisation","TP53, PIK3CA and HRAS mutations","PD-L1 and tumour mutational burden (usually low)","Extranodal extension and margin status"],"standardOfCare":[{"setting":"Localised, resectable","approach":"Total parotidectomy (or resection of the affected gland) with facial nerve sacrifice where involved, neck dissection and postoperative radiotherapy, with cisplatin for extranodal extension or positive margins.","refs":["imrt-igrt","cisplatin","chemoradiation"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"HER2-positive recurrent or metastatic","approach":"Trastuzumab with docetaxel (phase 2, response rate 70 percent); trastuzumab deruxtecan on progression or as an alternative.","refs":["trastuzumab","docetaxel","trastuzumab-deruxtecan","her2"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Androgen receptor-positive recurrent or metastatic","approach":"Androgen deprivation with leuprorelin and bicalutamide; enzalutamide or apalutamide as alternatives or after progression.","refs":["leuprolide","bicalutamide","enzalutamide","apalutamide","androgen-deprivation","nct04325828"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Marker-negative or after targeted treatment","approach":"Platinum-based chemotherapy (carboplatin-paclitaxel or cisplatin-based); pembrolizumab for PD-L1-positive, mutation-rich or mismatch repair-deficient tumours.","refs":["cisplatin","carboplatin","paclitaxel","pembrolizumab"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}}],"stateOfArt":["Routine HER2 and androgen receptor testing has given two lines of targeted therapy to a cancer that once had none.","Trastuzumab-docetaxel and androgen deprivation give responses in a majority and a large minority respectively, though relapse remains the rule.","Antibody-drug conjugates against HER2 are the next step, following their success in breast and gastric cancer."],"history":[{"year":1968,"title":"Kleinsasser describes salivary duct carcinoma as a breast-like tumour of the parotid","refs":[]},{"year":2018,"title":"Leuprorelin with bicalutamide: phase 2 response rate 41.7 percent","refs":["leuprolide","bicalutamide"]},{"year":2019,"title":"Trastuzumab with docetaxel: phase 2 response rate 70.2 percent","refs":["trastuzumab","docetaxel"]},{"year":2020,"title":"Apalutamide with a GnRH agonist enters trial for androgen receptor-positive salivary cancer","refs":["nct04325828"]}],"pipeline":["trastuzumab-deruxtecan","apalutamide","nct04325828","enzalutamide"],"openProblems":["Almost all responses to targeted treatment are followed by relapse.","Whether to give anti-HER2 or anti-androgen treatment first when both targets are present.","No randomised trial has compared targeted treatment with chemotherapy except EORTC 1206.","Adjuvant targeted treatment after surgery is untested."],"parent":"salivary-gland"},{"id":"salivary-gland","kind":"cancer","name":"Salivary gland cancers","aka":["Adenoid cystic carcinoma","Mucoepidermoid carcinoma","Salivary duct carcinoma","Secretory carcinoma"],"tldr":"Salivary gland cancers are a family of over 20 rare cancers, each with its own behaviour and often its own gene fusion. Surgery and radiation treat most; drug therapy is now chosen by the specific subtype, from anti-HER2 or anti-androgen drugs to NTRK inhibitors.","summary":"Salivary gland carcinomas are defined increasingly by fusion genes: MYB-NFIB in adenoid cystic carcinoma (ACC), CRTC1-MAML2 in mucoepidermoid carcinoma, ETV6-NTRK3 in secretory carcinoma, PLAG1/HMGA2 fusions in carcinoma ex pleomorphic adenoma, and androgen receptor and HER2 in salivary duct carcinoma (SDC). Adenoid cystic carcinoma is the archetype of slow-growing disease with perineural spread and late lung metastases; salivary duct carcinoma is aggressive and resembles apocrine breast cancer.\n\nSurgery with post-operative radiotherapy (or neutron/carbon-ion therapy for unresectable ACC) is standard for localised disease; RTOG 1008 tested adding cisplatin. Systemic therapy is subtype-directed: trastuzumab-docetaxel or T-DXd for HER2-positive SDC; androgen deprivation (leuprorelin ± bicalutamide, enzalutamide) for AR-positive SDC; larotrectinib or entrectinib for ETV6-NTRK3 secretory carcinoma; lenvatinib, axitinib or rivoceranib for progressive ACC (~10-15% response, high disease control); and chemotherapy (CAP, carboplatin-paclitaxel) for others. Checkpoint inhibitors have low activity except in a minority with high TMB or PD-L1. Notch-mutant ACC (~15%, aggressive) is a target for gamma-secretase inhibitors.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Salivary_gland_tumour","links":[{"label":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"},{"label":"ESMO-EURACAN salivary gland guideline (2022)","url":"https://doi.org/10.1016/j.esmoop.2022.100602"},{"label":"Adenoid Cystic Carcinoma Research Foundation","url":"https://www.accrf.org/"}],"tags":["gap-fill","head-and-neck","rare"],"related":[],"cancers":[],"sections":[],"technologies":["imrt-igrt","carbon-ion","proton-therapy","adc","kinase-inhibitors","androgen-deprivation","cgp"],"targets":["her2","androgen-receptor","ntrk","vegf","met"],"drugs":["trastuzumab","docetaxel","trastuzumab-deruxtecan","enzalutamide","larotrectinib","entrectinib","lenvatinib","axitinib","cisplatin","carboplatin","paclitaxel","pembrolizumab"],"companies":["bayer","roche-genentech","daiichi-sankyo","eisai"],"institutions":[],"pathways":["ar-signaling","vegf-angiogenesis"],"terms":["gene-fusion","tumour-agnostic"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-van-herpen-esmo-open"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"About 1 per 100,000 per year; ~5% of head and neck cancers; more than 20 histologic types, most individually very rare.","subtypes":["Adenoid cystic carcinoma (MYB-NFIB; NOTCH1-mutant subset)","Mucoepidermoid carcinoma (CRTC1/3-MAML2)","Salivary duct carcinoma (AR+, HER2+ in ~30%)","Secretory carcinoma (ETV6-NTRK3)","Acinic cell carcinoma (NR4A3)","Carcinoma ex pleomorphic adenoma","Polymorphous adenocarcinoma, myoepithelial and others"],"biomarkers":["Histotype with fusion confirmation (MYB, MAML2, ETV6-NTRK3, NR4A3)","HER2 IHC/ISH and androgen receptor IHC (salivary duct carcinoma)","NTRK fusion (secretory carcinoma)","NOTCH1 mutation (adenoid cystic, shorter survival)","Perineural invasion, grade, margin status","PD-L1 / TMB (rarely high)"],"standardOfCare":[{"setting":"Localised, resectable","approach":"Complete resection (parotidectomy with facial-nerve preservation where possible) and neck dissection for high-grade; post-operative radiotherapy for high-grade, close margins, perineural invasion, T3-4 or node-positive disease.","refs":["imrt-igrt","proton-therapy"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck (Salivary)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Unresectable localised","approach":"Definitive radiotherapy; carbon-ion or neutron therapy for adenoid cystic carcinoma where available (COSMIC, Heidelberg).","refs":["carbon-ion","imrt-igrt"],"guideline":{"version":"ESMO salivary gland guideline 2022"}},{"setting":"Recurrent/metastatic, subtype-directed","approach":"HER2+ SDC: trastuzumab + docetaxel or trastuzumab deruxtecan; AR+ SDC: androgen deprivation (leuprorelin/bicalutamide; enzalutamide); NTRK-fused secretory carcinoma: larotrectinib or entrectinib; ACC: lenvatinib or axitinib for progressive disease, observation if indolent.","refs":["trastuzumab","docetaxel","trastuzumab-deruxtecan","enzalutamide","larotrectinib","entrectinib","lenvatinib","axitinib"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck (Salivary)"}},{"setting":"Recurrent/metastatic, other","approach":"Platinum-based chemotherapy (CAP, carboplatin-paclitaxel); pembrolizumab for TMB-H/MSI-H or PD-L1-positive; clinical trials.","refs":["cisplatin","doxorubicin","cyclophosphamide","carboplatin","paclitaxel","pembrolizumab"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck (Salivary)"}}],"stateOfArt":["Salivary gland cancer is where fusion-defined pathology has most changed practice: ETV6-NTRK3 secretory carcinoma responds to NTRK inhibitors in ~90%.","Salivary duct carcinoma is treated like a HER2+/AR+ breast cancer, with T-DXd giving durable responses.","VEGFR inhibitors stabilise adenoid cystic carcinoma but rarely shrink it; NOTCH inhibition targets its worst subset.","Carbon-ion therapy for unresectable ACC is an example of particle therapy with a clear niche."],"history":[{"year":1859,"title":"Billroth describes 'cylindroma' (adenoid cystic carcinoma)","refs":[]},{"year":1994,"title":"Neutron therapy trial (RTOG-MRC) in unresectable salivary cancer","refs":[]},{"year":2003,"title":"CRTC1-MAML2 fusion in mucoepidermoid carcinoma (Tonon)","refs":["gene-fusion"]},{"year":2009,"title":"MYB-NFIB fusion in adenoid cystic carcinoma (Persson, PNAS)","refs":[]},{"year":2010,"title":"Mammary analogue secretory carcinoma with ETV6-NTRK3 described (Skálová)","refs":["ntrk"]},{"year":2018,"title":"Larotrectinib approved tumour-agnostically, including secretory carcinoma","refs":["larotrectinib"]},{"year":2019,"title":"Trastuzumab-docetaxel in HER2+ salivary duct carcinoma (Takahashi, JCO); lenvatinib in ACC (Tchekmedyian, JCO)","refs":["trastuzumab","docetaxel","lenvatinib"]},{"year":2022,"title":"ESMO-EURACAN salivary gland guideline","refs":[]}],"pipeline":["trastuzumab-deruxtecan","lenvatinib","larotrectinib","carbon-ion","gotistobart","rem-422"],"openProblems":["Adenoid cystic carcinoma: no drug induces meaningful shrinkage; 20-year survival remains poor.","Trials are tiny; most evidence is phase 2 or retrospective.","Facial nerve sacrifice and disfigurement in surgery.","Immunotherapy largely inactive."]},{"id":"sarcoma","kind":"cancer","name":"Sarcomas (soft tissue, bone, GIST)","aka":["Soft Tissue Sarcoma"],"tldr":"Sarcomas are dozens of rare cancers of bone and connective tissue. GIST was the first solid tumour cured-in-practice by a targeted pill; synovial sarcoma got the first TCR-T therapy.","summary":"Sarcomas are cancers of connective tissue: more than 70 subtypes of soft-tissue sarcoma (liposarcoma, leiomyosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, angiosarcoma and others), bone sarcomas (osteosarcoma, Ewing sarcoma, chondrosarcoma), gastrointestinal stromal tumour (GIST), and locally aggressive but non-metastasising tumours such as desmoid fibromatosis and tenosynovial giant cell tumour. Together they are about 1% of adult and 15% of childhood cancers. Because each subtype is rare, expertise concentrates in reference centres, and treatment is increasingly by histotype and genotype: FNCLCC grade, size and depth define risk in soft-tissue sarcoma; KIT/PDGFRA mutations define GIST therapy; fusion genes (SS18-SSX, EWSR1-FLI1, FUS-DDIT3) define entities and, increasingly, targets.\n\nSurgery with negative margins remains the curative act, with limb-salvage now standard and radiotherapy improving local control in soft-tissue sarcoma. Neoadjuvant anthracycline-ifosfamide benefits high-risk localised soft-tissue sarcoma (ISG-STS 1001), and multi-agent chemotherapy cures the majority of localised osteosarcoma (MAP) and Ewing sarcoma (VDC/IE, INT-0091 and Euro Ewing 2012). Advanced soft-tissue sarcoma still depends on doxorubicin with a median survival around 18-20 months; olaratumab's failure (ANNOUNCE) showed how hard that bar is to move. Subtype-specific drugs then fill in: trabectedin and eribulin for L-sarcomas, pazopanib for non-adipocytic sarcomas, and, in GIST, the sequence imatinib (3 years adjuvant, SSGXVIII), sunitinib, regorafenib and ripretinib (INVICTUS), with avapritinib for PDGFRA D842V and ctDNA-genotype-directed selection (INSIGHT) arriving. Desmoid tumours gained their first drug in nirogacestat (DeFi, 2023) and tenosynovial giant cell tumour its second in vimseltinib (MOTION, February 2025); tazemetostat for epithelioid sarcoma was withdrawn worldwide in March 2026 over secondary blood cancers.\n\nSarcoma is also where solid-tumour T-cell engineering first succeeded: afamitresgene autoleucel (MAGE-A4 TCR-T) was approved in 2024 and fully approved with extension to adolescents in June 2026, and letetresgene autoleucel (NY-ESO-1) has a BLA due by end-2026. Checkpoint inhibitors help a minority (alveolar soft-part sarcoma, UPS, angiosarcoma); most sarcomas are immunologically cold. The unsolved problems are metastatic osteosarcoma and Ewing sarcoma (survival unchanged in 30 years), the HLA restriction of TCR therapies, chemoresistance of most adult subtypes, and trial feasibility in diseases with a few hundred cases a year.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Sarcoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Sarcoma"}],"tags":["rare","spike"],"related":["ctdna-genotype-gist-tki","doxorubicin-cardio-caution","chordoma","desmoid-tumour","tenosynovial-giant-cell-tumour","vascular-tumours","uterine-sarcoma"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","tcr-t","carbon-ion","hyperthermia","proton-therapy","limb-salvage-surgery","cytotoxic-chemotherapy","liquid-biopsy","cardio-oncology"],"targets":["kit","mage-a4","ntrk","ezh2","cdk4-6","fap","vegf"],"drugs":["sirolimus-albumin-bound","tasonermin"],"companies":["philogen-s-p-a","haihe-biopharma","epicentrx","qbiotics","ranok-therapeutics-hangzhou","deciphera","springworks","us-worldmeds","novartis","johnson-johnson","sanofi","adaptimmune","immatics","childrens-oncology-group","curie-nki-eortc"],"institutions":["mskcc","md-anderson","royal-marsden","gustave-roussy","int-milan"],"pathways":[],"terms":["fnclcc-grade","sarcoma-histotype-tailoring","orr","pfs","limb-salvage-term"],"trials":["invincible-3","nct07174427","nct03016819","nct06127407"],"people":["kate-granger","sid-sijbrandij"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"Sarcomas make up ~1% of adult cancers (~13,500 soft-tissue and ~3,900 bone sarcomas in the US per year) and ~15% of paediatric cancers, across >70 histologic subtypes. Five-year survival is ~65% overall and ~15-30% for metastatic disease.","subtypes":["Soft-tissue sarcoma: liposarcoma (well-differentiated/dedifferentiated, myxoid, pleomorphic), leiomyosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, myxofibrosarcoma, angiosarcoma, MPNST, rhabdomyosarcoma (paediatric)","Bone sarcoma: osteosarcoma, Ewing sarcoma, chondrosarcoma, chordoma","Gastrointestinal stromal tumour (KIT, PDGFRA, SDH-deficient, NF1)","Desmoid tumour (CTNNB1/APC; locally aggressive, non-metastasising)","Tenosynovial giant cell tumour (CSF1-driven; benign)","Epithelioid sarcoma (INI1/SMARCB1 loss)","Alveolar soft-part sarcoma (ASPSCR1-TFE3; IO-responsive)","Fusion-defined and NTRK-fusion sarcomas"],"biomarkers":["Histologic subtype","KIT/PDGFRA (GIST)","MAGE-A4 + HLA-A*02","NTRK fusions","INI1 loss","CDK4/MDM2 amplification (liposarcoma)","Histologic subtype and FNCLCC grade","KIT/PDGFRA mutation and secondary mutations (tissue or ctDNA) in GIST","SS18-SSX, EWSR1-FLI1, FUS-DDIT3, ASPSCR1-TFE3 fusions","MAGE-A4 or NY-ESO-1 expression + HLA-A*02 for TCR-T","INI1 (SMARCB1) loss","MDM2/CDK4 amplification (liposarcoma)","CTNNB1/APC mutation (desmoid)","CSF1 translocation (TGCT)","Sarculator nomogram risk"],"standardOfCare":[{"setting":"Localised STS","approach":"Wide excision + radiation; neoadjuvant chemotherapy for high-risk.","refs":["imrt-igrt","proton-therapy","hyperthermia"],"guideline":{"version":"NCCN Guidelines: Soft Tissue Sarcoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1464"}},{"setting":"Advanced","approach":"Doxorubicin ± ifosfamide; subtype-directed: imatinib, afami-cel, larotrectinib (tazemetostat was withdrawn in March 2026).","refs":["imatinib","afamitresgene-autoleucel"],"guideline":{"version":"NCCN Guidelines: Soft Tissue Sarcoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1464"}},{"setting":"Localised extremity/trunk soft-tissue sarcoma, low grade","approach":"Wide resection (limb-salvage) ± radiotherapy for margins or size >5 cm; observation thereafter.","refs":["limb-salvage-surgery","imrt-igrt","fnclcc-grade"],"guideline":{"nccn":"Category 1 (surgery ± RT)","version":"NCCN Soft Tissue Sarcoma 2026"}},{"setting":"Localised high-risk soft-tissue sarcoma (grade 3, >5 cm, deep)","approach":"Neoadjuvant anthracycline-ifosfamide × 3 (ISG-STS 1001) ± preoperative radiotherapy, then wide resection; regional hyperthermia with chemotherapy where available (EORTC 62961).","refs":["isg-sts-1001","doxorubicin","ifosfamide","imrt-igrt","hyperthermia","limb-salvage-surgery"],"guideline":{"nccn":"Category 2A (neoadjuvant chemotherapy for high-risk)","esmoMcbs":"A (ISG-STS 1001)","version":"NCCN 2026 / ESMO 2021"}},{"setting":"Advanced soft-tissue sarcoma, first line","approach":"Doxorubicin 75 mg/m2 (single agent) or doxorubicin-ifosfamide for symptomatic/rapid disease (EORTC 62012: PFS but not OS benefit); histotype exceptions: trabectedin or gemcitabine-docetaxel for leiomyosarcoma, paclitaxel for angiosarcoma. Adding olaratumab to doxorubicin gave no survival benefit (ANNOUNCE).","refs":["doxorubicin","ifosfamide","trabectedin","announce","sarcoma-histotype-tailoring"],"guideline":{"nccn":"Category 1 (anthracycline-based)","version":"NCCN 2026"}},{"setting":"Advanced soft-tissue sarcoma, later lines","approach":"Trabectedin (L-sarcomas), eribulin (liposarcoma), pazopanib (non-adipocytic), gemcitabine-docetaxel, dacarbazine; pembrolizumab for alveolar soft-part sarcoma or UPS; larotrectinib for NTRK fusion; afami-cel or lete-cel for MAGE-A4/NY-ESO-1+ synovial sarcoma and MRCLS.","refs":["trabectedin","pazopanib","pembrolizumab","afamitresgene-autoleucel","letetresgene-autoleucel","ignyte-eso"],"guideline":{"nccn":"Category 2A","version":"NCCN 2026"}},{"setting":"GIST, localised","approach":"Resection; adjuvant imatinib 3 years for high risk (SSGXVIII), longer under study; none for PDGFRA D842V or SDH-deficient (imatinib-insensitive).","refs":["imatinib","ssgxviii"],"guideline":{"nccn":"Category 1 (imatinib 3 years, high-risk)","esmoMcbs":"A","version":"NCCN 2026"}},{"setting":"GIST, advanced","approach":"Imatinib 400 mg (800 mg for exon 9) → sunitinib → regorafenib → ripretinib (INVICTUS); avapritinib for PDGFRA D842V; ctDNA KIT genotyping to choose ripretinib vs sunitinib second line (INSIGHT); surgery for oligoprogression.","refs":["imatinib","ripretinib","invictus","insight-gist","avapritinib","ctdna-genotype-gist-tki"],"guideline":{"nccn":"Category 1 sequence","version":"NCCN 2026"}},{"setting":"Osteosarcoma","approach":"Neoadjuvant MAP (methotrexate, doxorubicin, cisplatin) → limb-salvage resection → adjuvant MAP; no benefit from adding ifosfamide-etoposide or interferon (EURAMOS-1); metastatic/relapsed: surgery of lung metastases, regorafenib/cabozantinib.","refs":["doxorubicin","limb-salvage-surgery","childrens-oncology-group"]},{"setting":"Ewing sarcoma","approach":"Interval-compressed VDC/IE (INT-0091, AEWS0031, Euro Ewing 2012) with surgery and/or radiotherapy for local control; high-dose busulfan-melphalan for selected high-risk (Euro-EWING 99 R2); relapse: irinotecan-temozolomide, cabozantinib, trials.","refs":["int-0091","euro-ewing-2012","doxorubicin","ifosfamide","proton-therapy","aews0031"]},{"setting":"Desmoid tumour","approach":"Active surveillance first (many regress); nirogacestat (DeFi) for progressing symptomatic disease; sorafenib alternative; surgery only for select sites; cryoablation for extra-abdominal tumours.","refs":["nirogacestat","defi","thermal-ablation","idea-desmoid-intermittent-dosing"],"guideline":{"nccn":"Category 1 (nirogacestat)","version":"NCCN 2026"}},{"setting":"Tenosynovial giant cell tumour","approach":"Surgery for localised disease; vimseltinib (MOTION) or pexidartinib (REMS for hepatotoxicity) for diffuse disease not amenable to surgery.","refs":["vimseltinib","motion"],"guideline":{"nccn":"Category 2A","version":"NCCN 2026"}}],"stateOfArt":["Subtype-specific targeted and cellular therapies.","First engineered T-cell therapies for a solid tumour: afami-cel (full approval and age ≥12 in June 2026) and lete-cel (BLA due 2026) for synovial sarcoma and MRCLS.","GIST as a model of genotype-directed sequencing: four approved TKIs, a mutation-specific drug for D842V, and ctDNA-selected phase 3 (INSIGHT).","New indications for benign but destructive tumours: nirogacestat (desmoid, 2023) and vimseltinib (TGCT, 2025).","Neoadjuvant chemotherapy for high-risk soft-tissue sarcoma validated (ISG-STS 1001), while histotype-tailored chemotherapy was not superior.","Ewing sarcoma treatment unified on VDC/IE after Euro Ewing 2012; interval compression and busulfan-melphalan refine it.","Withdrawal of tazemetostat (March 2026) removed the only EZH2 drug from epithelioid sarcoma, a reminder that rare-disease approvals rest on thin safety data."],"history":[{"year":1970,"title":"Adjuvant chemotherapy for osteosarcoma (Jaffe, Rosen) turns a 20% survival into 60%","refs":["doxorubicin"]},{"year":1980,"title":"Limb-salvage surgery shown equivalent to amputation (Rosenberg, NCI)","refs":["limb-salvage-surgery"]},{"year":1982,"title":"Adjuvant radiotherapy improves local control after limb-sparing surgery (NCI randomised trial)","refs":["imrt-igrt"]},{"year":1998,"title":"KIT mutations discovered in GIST (Hirota)","refs":["kit"]},{"year":2002,"title":"Imatinib for GIST","refs":["imatinib"]},{"year":2002,"title":"Imatinib approved for GIST: the first solid tumour controlled by a targeted pill","refs":["imatinib"]},{"year":2003,"title":"INT-0091: ifosfamide-etoposide added to Ewing sarcoma therapy","refs":["int-0091"]},{"year":2007,"title":"Trabectedin approved in Europe for soft-tissue sarcoma","refs":["trabectedin"]},{"year":2010,"title":"EORTC 62961: regional hyperthermia with chemotherapy improves survival in high-risk STS","refs":["hyperthermia"]},{"year":2012,"title":"SSGXVIII: 3-year adjuvant imatinib; pazopanib approved (PALETTE)","refs":["ssgxviii","pazopanib"]},{"year":2017,"title":"ISG-STS 1001: neoadjuvant anthracycline-ifosfamide for high-risk STS","refs":["isg-sts-1001"]},{"year":2019,"title":"ANNOUNCE fails; olaratumab withdrawn","refs":["announce"]},{"year":2020,"title":"Ripretinib (INVICTUS) and avapritinib (D842V) approved; tazemetostat approved for epithelioid sarcoma","refs":["ripretinib","invictus","avapritinib"]},{"year":2022,"title":"Euro Ewing 2012 unifies VDC/IE; DeFi positive","refs":["euro-ewing-2012","defi"]},{"year":2023,"title":"Nirogacestat: first drug for desmoid tumours","refs":["nirogacestat"]},{"year":2024,"title":"Afami-cel: first TCR-T for a solid tumour","refs":["afamitresgene-autoleucel"]},{"year":2024,"title":"Afami-cel: first TCR-T for a solid tumour; MOTION positive; IGNYTE-ESO reports","refs":["afamitresgene-autoleucel","motion","ignyte-eso"]},{"year":2025,"title":"Vimseltinib approved (14 Feb); lete-cel and Tecelra transferred to US WorldMeds","refs":["vimseltinib","letetresgene-autoleucel","us-worldmeds"]},{"year":2026,"title":"Tazemetostat withdrawn worldwide (9 March); afami-cel full approval and age ≥12 (June); INSIGHT positive","refs":["afamitresgene-autoleucel","insight-gist","ezh2"]}],"pipeline":["fap-2286","carbon-ion","hs-20093","gotistobart","int230-6","tbi-1301","t3011","letetresgene-autoleucel","ignyte-eso","insight-gist","ctdna-genotype-gist-tki","idea-tcr-t-beyond-hla-a2","idea-desmoid-intermittent-dosing","vimseltinib","nirogacestat","limb-salvage-surgery"],"openProblems":["Rarity limits trials.","Chemoresistance of most subtypes.","Metastatic osteosarcoma and Ewing sarcoma: survival ~20-30%, unchanged for three decades; no targeted or immune therapy has worked.","Advanced soft-tissue sarcoma still depends on a 1970s drug (doxorubicin); every attempt to improve first-line survival (olaratumab, evofosfamide, aldoxorubicin) failed.","TCR-T is limited to HLA-A*02 carriers, requires antigen screening, and is available at few centres.","Most sarcomas are immunologically cold; checkpoint inhibitors help only alveolar soft-part sarcoma, some UPS and angiosarcoma.","Rarity fragments evidence: 70+ subtypes, few randomised trials, and reliance on reference-centre expertise that is unevenly distributed.","Long-term survivors of childhood bone sarcoma carry anthracycline cardiotoxicity, infertility and second cancers.","Epithelioid sarcoma lost its only drug (tazemetostat) in 2026; INI1-loss tumours need new approaches.","Desmoid and TGCT therapies raise chronic-dosing questions (ovarian toxicity, cost) in non-malignant diseases."]},{"id":"pulmonary-sarcomatoid-carcinoma","kind":"cancer","name":"Sarcomatoid carcinoma of the lung","aka":["Pulmonary sarcomatoid carcinoma","Sarcomatoid carcinoma of the lung","Pleomorphic carcinoma of the lung","Spindle cell carcinoma of the lung","Giant-cell carcinoma of the lung","Giant cell carcinoma of the lung","Pulmonary carcinosarcoma"],"tldr":"Sarcomatoid carcinoma is a rare, aggressive form of lung cancer in which part or all of the tumour looks like a sarcoma, with spindle-shaped or giant cells. It is treated like other non-small-cell lung cancers, but is worth testing for a MET gene fault, which is found in a sizeable minority and can be treated with a tablet.","summary":"The WHO classification groups five poorly differentiated non-small-cell carcinomas under sarcomatoid carcinoma: pleomorphic carcinoma (a carcinoma with at least 10 percent spindle or giant cells), spindle cell carcinoma, giant cell carcinoma, carcinosarcoma (carcinoma with true sarcoma such as bone, cartilage or skeletal muscle) and pulmonary blastoma, which has its own page (Nicholson 2022). Patients are mostly men who smoke: in the French series of 93 cases, 77 percent were men, median age 63, 84 percent smokers, and about 70 percent presented with locally advanced or metastatic disease; median survival after surgery was 16.4 months and distant recurrence was common (Vieira 2016).\n\nHow it differs from its parent: it is the most treatment-refractory histology of non-small-cell lung cancer, and it carries MET alterations far more often. Whole-exome sequencing of pulmonary sarcomatoid carcinoma found MET exon 14 skipping mutations at high frequency, and a patient with advanced disease responded to the MET inhibitor crizotinib (Liu 2016); a later multicentre study of 124 resected cases found MET exon 14 skipping in 7.3 percent, MET amplification in 4.8 percent and MET protein overexpression in 20.2 percent, the exon 14 cases being pleomorphic, spindle cell and carcinosarcoma (Translational Oncology 2020).\n\nHow common: 0.4 percent of lung cancers in SEER (Yendamuri 2012).\n\nTreatment: no randomised trial exists for the histology; stage-based treatment follows the parent page, and MET exon 14 skipping is treated on the MET-altered page with capmatinib or tepotinib. Checkpoint inhibitors are used as for other non-small-cell lung cancer.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Sarcomatoid_carcinoma","links":[{"label":"Nicholson 2022, JTO: the 2021 WHO classification of lung tumours","url":"https://doi.org/10.1016/j.jtho.2021.11.003"},{"label":"Yendamuri 2012, Surgery: outcomes of sarcomatoid carcinoma of the lung, SEER analysis","url":"https://doi.org/10.1016/j.surg.2012.05.007"},{"label":"Vieira 2016, Clinical Lung Cancer: characteristics and outcomes of 93 sarcomatoid carcinomas of the lung","url":"https://doi.org/10.1016/j.cllc.2016.03.001"},{"label":"Liu 2016, JCO: sequencing of pulmonary sarcomatoid carcinoma reveals frequent MET exon 14 mutations","url":"https://doi.org/10.1200/jco.2015.62.0674"},{"label":"Translational Oncology 2020: MET exon 14 skipping, amplification and overexpression in 124 pulmonary sarcomatoid carcinomas","url":"https://doi.org/10.1016/j.tranon.2020.100868"}],"tags":["subtype-page","wave4","lung"],"related":["nsclc","met-altered-nsclc","pulmonary-blastoma","large-cell-lung-carcinoma","lung-adenocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":["met"],"drugs":["capmatinib","tepotinib","crizotinib","savolitinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"0.4 percent of lung cancers: 3,647 of 878,810 patients in the US SEER registry (Yendamuri 2012). Pleomorphic carcinoma is the commonest form, 64 percent of 93 cases in two French centres (Vieira 2016).","subtypes":["Pleomorphic carcinoma (at least 10 percent spindle or giant cells; the commonest)","Spindle cell carcinoma","Giant cell carcinoma","Carcinosarcoma (carcinoma with heterologous sarcoma)","Pulmonary blastoma (own page)","MET exon 14-mutated sarcomatoid carcinoma"],"biomarkers":["MET exon 14 skipping (7.3 percent), MET amplification and overexpression","KRAS, TP53, PIK3CA, STK11 and RB1 mutations (Liu 2016)","PD-L1","Cytokeratin positivity in the spindle component (distinguishes it from sarcoma)"],"standardOfCare":[{"setting":"All stages","approach":"Treated as non-small-cell lung cancer by stage; MET exon 14 skipping treated on the MET-altered page with capmatinib or tepotinib.","refs":["nsclc","met-altered-nsclc","capmatinib","tepotinib"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"nsclc"},{"id":"aml-secondary","kind":"cancer","name":"Secondary and therapy-related acute myeloid leukaemia","aka":["Therapy-related AML","t-AML","Secondary AML","AML with myelodysplasia-related changes","AML arising from MDS or MPN"],"tldr":"Secondary acute myeloid leukaemia grows out of an earlier marrow disorder or follows chemotherapy or radiotherapy for another cancer. It resists standard treatment more than other leukaemias; a liposomal form of the two classic chemotherapy drugs, CPX-351, lengthens life in fit older patients, and transplant is the only route to cure.","summary":"Two histories lead here. Secondary AML transforms from myelodysplastic syndromes, chronic myelomonocytic leukaemia or a myeloproliferative neoplasm, and carries their spliceosome and chromatin mutations (SRSF2, SF3B1, ASXL1, RUNX1) or a complex karyotype. Therapy-related AML follows alkylating agents and radiotherapy after five to ten years, usually with chromosome 5 and 7 losses and TP53 mutations, or follows topoisomerase II inhibitors within two to three years with KMT2A rearrangements. The WHO and ICC 2022 classifications group most of these as AML with myelodysplasia-related gene mutations or cytogenetics, and the ELN counts them as adverse risk.\n\nCPX-351 packs cytarabine and daunorubicin in a fixed 5:1 molar ratio inside a liposome that concentrates in marrow. Its phase 3 trial (Study 301) randomised 309 patients aged 60 to 75 with newly diagnosed secondary or therapy-related AML against 7+3: median overall survival 9.56 versus 5.95 months (hazard ratio 0.69), and 18 percent versus 8 percent alive at five years, most of the survivors having reached transplant. It was approved in the United States in 2017 and in Europe in 2018 and is the intensive induction of choice for this group. Patients unfit for intensive therapy receive venetoclax with azacitidine, which works less well here than in de novo disease, especially with TP53 mutations.\n\nTP53-mutated disease remains the hardest problem in leukaemia: remissions are short with every regimen, magrolimab and other CD47 antibodies failed in phase 3, and transplant cures only a minority. Avoiding the disease, by choosing regimens for the first cancer that spare the marrow and by watching clonal haematopoiesis in survivors, is as much a research aim as treating it.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Acute_myeloid_leukemia","links":[{"label":"Wikipedia: Acute myeloid leukaemia","url":"https://en.wikipedia.org/wiki/Acute_myeloid_leukemia"},{"label":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}],"tags":["subtype-page"],"related":["aml-older-unfit","aml-idh","aml-flt3","apl"],"cancers":[],"sections":[],"technologies":["allogeneic-hsct","cd47-blockade"],"targets":["tp53","cd47"],"drugs":[],"companies":[],"institutions":[],"pathways":["clonal-haematopoiesis"],"terms":["secondary-malignancy","tp53-mutated","eln-risk","hma","aml-myelodysplasia-related"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-viale-a-venetoclax-azacitidine-nejm-2020","paper-eln-2022-aml-dohner-blood-2022","paper-who-2022-myeloid-khoury-leukemia-2022","paper-cpx-351-study-301-lancet-je-jco-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Roughly a quarter of adult acute myeloid leukaemia arises from a prior marrow disorder or after chemotherapy or radiotherapy for another cancer; it strikes older people and has always done worse than leukaemia arising on its own.","subtypes":["Secondary AML arising from myelodysplastic syndromes or CMML","Post-MPN blast phase (myelofibrosis, polycythaemia or thrombocythaemia transforming to AML)","Therapy-related AML after alkylating agents or radiotherapy (chromosome 5 and 7 loss, TP53)","Therapy-related AML after topoisomerase II inhibitors (KMT2A-rearranged)","AML with myelodysplasia-related gene mutations"],"biomarkers":["TP53 mutation and allelic state","Complex or monosomal karyotype","Myelodysplasia-related mutations (SRSF2, SF3B1, ASXL1, RUNX1, U2AF1, EZH2, BCOR, STAG2)","KMT2A rearrangement","Prior clonal haematopoiesis","ELN 2022 risk group"],"standardOfCare":[{"setting":"Newly diagnosed, fit for intensive chemotherapy, age 60 to 75","approach":"CPX-351 induction (Study 301) followed by allogeneic transplant in remission; 7+3 where CPX-351 is unavailable.","refs":["cpx-351","cpx-351-301","cytarabine-7-3","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Newly diagnosed, unfit for intensive chemotherapy","approach":"Venetoclax plus azacitidine or decitabine; hypomethylating agent alone for TP53-mutated disease where venetoclax adds little; trials.","refs":["venetoclax","azacitidine","decitabine","viale-a"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Consolidation and relapse","approach":"Allogeneic transplant is the only curative option; genotype-directed drugs where a FLT3, IDH or KMT2A target exists.","refs":["allogeneic-hsct","gilteritinib","ivosidenib","revumenib"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}}],"stateOfArt":["CPX-351 is the standard intensive induction for fit patients with secondary or therapy-related AML, with more patients reaching transplant and surviving five years than with 7+3.","TP53-mutated AML has no effective standard: every phase 3 that targeted it, including CD47 blockade, has failed.","Clonal haematopoiesis before chemotherapy is now known to predict which survivors will develop therapy-related leukaemia."],"history":[{"year":1970,"title":"Therapy-related leukaemia recognised after alkylating agents for Hodgkin lymphoma","refs":["secondary-malignancy"]},{"year":2016,"title":"WHO defines AML with myelodysplasia-related changes as its own group","refs":[]},{"year":2017,"title":"CPX-351 approved after Study 301 lengthens life in secondary AML","refs":["cpx-351-301","cpx-351"]},{"year":2023,"title":"Magrolimab with azacitidine fails in TP53-mutated AML","refs":["magrolimab"]}],"pipeline":["cpx-351","venetoclax","myelomatch","idea-chip-risk-modifiers"],"openProblems":["No regimen produces durable remissions in TP53-mutated AML.","Whether CPX-351 helps patients under 60 or those fit enough for transplant regardless of induction.","Predicting and preventing therapy-related leukaemia in cancer survivors with clonal haematopoiesis."],"parent":"aml"},{"id":"secretory-carcinoma-breast","kind":"cancer","name":"Secretory carcinoma of the breast","aka":["Juvenile carcinoma of the breast","Secretory breast carcinoma","SBC","ETV6-NTRK3 fusion-positive breast carcinoma"],"tldr":"Secretory carcinoma is a very rare, slow-growing breast cancer first described in children, whose cells make milk-like secretions. It is usually triple-negative but almost always carries the ETV6-NTRK3 gene fusion, so the rare patient whose tumour spreads can be treated with an NTRK inhibitor tablet, and most need no chemotherapy.","summary":"Secretory breast carcinoma is a rare subtype of infiltrating ductal-origin carcinoma that expresses the ETV6-NTRK3 gene fusion, first cloned in paediatric mesenchymal cancers; the fusion was confirmed in 12 of 13 cases (92 percent) but in no other ductal carcinomas, and its expression transformed mammary epithelial cells into gland-forming tumours in mice, establishing it as a primary oncogenic event (Tognon 2002). Histologically the tumour shows microcystic, solid and tubular patterns with abundant intracellular and extracellular secretion, is usually low grade and often triple-negative or weakly ER-positive with a basal-like immunophenotype (Cserni 2021; Thomas 2023). The European Working Group for Breast Screening Pathology places secretory carcinoma among the triple-negative special types with an indolent course whose patients are unlikely to benefit from systemic chemotherapy, favouring surgery with or without radiotherapy (Cserni 2021). Because the ETV6-NTRK3 fusion is an NTRK fusion, the tumour-agnostic approvals of larotrectinib and entrectinib apply to the rare metastatic case.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Secretory_carcinoma","links":[{"label":"Tognon, Cancer Cell 2002: the ETV6-NTRK3 gene fusion as a primary event in secretory breast carcinoma","url":"https://doi.org/10.1016/s1535-6108(02)00180-0"},{"label":"Cserni, Cancers 2021: triple-negative breast cancer histological subtypes with a favourable prognosis (European Working Group for Breast Screening Pathology)","url":"https://doi.org/10.3390/cancers13225694"},{"label":"Thomas, NPJ Breast Cancer 2023: rare subtypes of triple-negative breast cancer","url":"https://doi.org/10.1038/s41523-023-00554-x"}],"tags":["breast","tnbc","subtype-page"],"related":["tnbc","adenoid-cystic-carcinoma-breast"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["larotrectinib","entrectinib"],"companies":[],"institutions":[],"pathways":[],"terms":["tumour-agnostic","tumour-grade"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"Very rare (under 0.15 percent of breast cancers in most series; the review literature counts it among the 5 to 10 percent of triple-negative cancers that are rare subtypes); it can occur in children and young adults as well as adults (Thomas 2023).","subtypes":["Secretory carcinoma arising in children and adolescents (juvenile carcinoma)","Adult secretory carcinoma (the majority of cases)","Invasive carcinoma of no special type (ductal) with secretory features"],"biomarkers":["ETV6-NTRK3 fusion (about 92 percent) and pan-TRK immunohistochemistry","Triple-negative or low ER status with low grade","S100 and mammaglobin expression"],"standardOfCare":[{"setting":"Localised disease","approach":"Surgery with clear margins, radiotherapy after breast conservation; chemotherapy is usually not indicated for this indolent type (European working group consensus).","refs":["lumpectomy","mastectomy","sentinel-node"]},{"setting":"Metastatic disease (rare)","approach":"NTRK inhibitors (larotrectinib, entrectinib) under their tumour-agnostic approvals for NTRK fusion-positive solid tumours.","refs":["larotrectinib","entrectinib","tumour-agnostic"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"tnbc"},{"id":"seminoma","kind":"cancer","name":"Seminoma","aka":["Classic seminoma","Pure seminoma","Germinoma (when in the brain)"],"tldr":"Seminoma is the slower, more radiosensitive half of testicular cancer. After removal of the testicle most men need no further treatment and are simply monitored; those who relapse or present with spread are cured with a short course of chemotherapy.","summary":"Seminoma arises from germ cell neoplasia in situ and presents as a painless testicular mass, with modest rises in hCG and LDH but never AFP, which would mark a non-seminomatous element. After radical inguinal orchidectomy, stage I disease is managed by surveillance in most men, since only about one in six relapse and all are salvageable; a single dose of carboplatin (MRC TE19) or, rarely now, para-aortic radiotherapy are alternatives. Stage II disease with small nodes is treated with radiotherapy or chemotherapy, and bulkier or metastatic disease with three cycles of BEP or four of EP, curing more than 90 percent; residual masses after chemotherapy are assessed with PET rather than removed. Long-term follow-up watches for second cancers and cardiovascular effects of treatment.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Seminoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Seminoma"}],"tags":["subtype-page"],"related":["non-seminoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-igcccg-classification-jco-1997","paper-mrc-te19-carboplatin-seminoma-oliver-lancet-2005","paper-sempet-de-santis-jco-2004"],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Just over half of testicular germ cell tumours, peaking in men in their thirties; almost every patient is cured, and the effort now goes into giving the least treatment that keeps it that way.","subtypes":["Stage I seminoma (surveillance)","Stage II seminoma (nodal)","Advanced seminoma (IGCCCG good or intermediate risk)","Spermatocytic tumour (older men, almost never metastasises)"],"biomarkers":["hCG (mildly raised in a minority) and LDH","AFP normal by definition","Tumour size and rete testis invasion (relapse risk in stage I)","PET after chemotherapy for residual masses over 3 cm"],"standardOfCare":[{"setting":"Stage I","approach":"Orchidectomy then surveillance; single-dose carboplatin as an alternative; radiotherapy now rarely used because of second cancers.","refs":["carboplatin","active-surveillance"]},{"setting":"Stage II","approach":"Radiotherapy for small-volume nodes or chemotherapy (BEP or EP) for larger nodes; de-escalation trials of carboplatin with radiotherapy ongoing.","refs":["cisplatin","etoposide","bleomycin","imrt-igrt"]},{"setting":"Advanced","approach":"Three cycles of BEP or four of EP for good risk, four cycles of BEP for intermediate risk; PET-directed management of residual masses.","refs":["bleomycin","etoposide","cisplatin","pet"]}],"stateOfArt":["Surveillance has replaced adjuvant radiotherapy as the standard for stage I, sparing most men any treatment beyond surgery.","Cure rates above 95 percent make late toxicity, second cancers and heart disease the main concern.","De-escalation trials aim to cut chemotherapy and radiotherapy doses further in stage II."],"history":[{"year":1977,"title":"Einhorn's cisplatin combination cures metastatic germ cell tumours","refs":["cisplatin"]},{"year":2005,"title":"MRC TE19: single-dose carboplatin equals radiotherapy in stage I","refs":["carboplatin"]},{"year":2011,"title":"Surveillance endorsed as the preferred stage I option in Europe","refs":[]}],"pipeline":["carboplatin","pet"],"openProblems":["Predicting which stage I patients will relapse.","Late effects of platinum and radiotherapy decades on.","Rare relapses more than five years out."],"parent":"testicular"},{"id":"colorectal-serrated-adenocarcinoma","kind":"cancer","name":"Serrated adenocarcinoma of the colon and rectum","aka":["Serrated adenocarcinoma","Serrated pathway colorectal cancer","Colorectal carcinoma arising from a sessile serrated lesion"],"tldr":"Serrated adenocarcinoma is a form of bowel cancer that grows out of sessile serrated polyps rather than ordinary adenomas, keeping their saw-tooth pattern. Most cases carry a KRAS or BRAF mutation and the BRAF-mutant ones are often mismatch-repair deficient. It is treated like other bowel cancer, with the BRAF and mismatch repair results guiding drugs when it has spread.","summary":"The WHO classification recognises serrated adenocarcinoma as a colorectal adenocarcinoma type with serrated glands, eosinophilic cytoplasm and vesicular nuclei, arising through the serrated pathway of sessile serrated lesions and traditional serrated adenomas (Nagtegaal 2020). In 42 serrated adenocarcinomas, KRAS and BRAF mutations were present in 45 and 33 percent against 27 and 0 percent of non-serrated carcinomas; BRAF mutation was specific for serrated adenocarcinoma and marked a subset with gene methylation and a tendency to microsatellite instability, while the high KRAS rate suggests many KRAS-mutant colorectal cancers arise from serrated precursors (Histopathology 2011). In 89 cases KRAS mutation (42.7 percent) was more prevalent than BRAF (25.8 percent), MGMT loss was more frequent than in conventional carcinoma (50.6 against 25.3 percent), and most serrated adenocarcinomas were microsatellite stable, differing from sporadic MSI-high carcinomas (International Journal of Cancer 2012).\n\nHow it differs from its parent: its precursor is the sessile serrated lesion rather than the adenoma, so it is the histology behind the right-sided BRAF-mutant and CpG island methylator cancers on the colorectal and BRAF pages, and its KRAS-mutant, microsatellite-stable majority has a worse outlook than the MSI-high minority.\n\nHow common: no registry share was found in the sources read.\n\nTreatment: as the colorectal page by stage, BRAF, RAS and mismatch repair status (encorafenib with cetuximab for BRAF V600E metastatic disease; checkpoint inhibitors for MSI-high); there is no trial in the histology.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Sessile_serrated_lesion","links":[{"label":"Nagtegaal 2020, Histopathology: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"Histopathology 2011: KRAS and BRAF mutations in colorectal serrated adenocarcinoma","url":"https://doi.org/10.1111/j.1365-2559.2011.03821.x"},{"label":"International Journal of Cancer 2012: serrated adenocarcinoma, oncogene mutations and MSI in 89 cases","url":"https://doi.org/10.1002/ijc.27454"}],"tags":["subtype-page","wave4","colorectal"],"related":["colorectal","braf-v600e-colorectal","msi-high-colorectal","colon-cancer","colorectal-mucinous-adenocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":["braf","kras"],"drugs":["encorafenib","cetuximab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"The defining series compared 42 and 89 serrated adenocarcinomas with conventional carcinomas (Histopathology 2011; International Journal of Cancer 2012); no registry share was found in the sources read, and the serrated pathway is thought to account for a larger share of colorectal cancer than the strictly defined histology.","subtypes":["BRAF-mutant serrated adenocarcinoma (methylated; often MSI-high; right-sided)","KRAS-mutant serrated adenocarcinoma (microsatellite stable; the majority)","Serrated adenocarcinoma arising in a traditional serrated adenoma"],"biomarkers":["BRAF V600E and KRAS mutation","Mismatch repair status and MLH1 methylation","MGMT loss","CpG island methylator phenotype (research)"],"standardOfCare":[{"setting":"All stages","approach":"Treated as the colorectal page by stage and molecular status: encorafenib with cetuximab for BRAF V600E metastatic disease, checkpoint inhibitors for MSI-high disease.","refs":["colorectal","braf-v600e-colorectal","encorafenib","cetuximab"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"colorectal"},{"id":"sertoli-cell-tumour","kind":"cancer","name":"Sertoli cell tumour of the testis","aka":["Sertoli cell tumour","Sertoli cell tumor","Sertoli cell tumour, not otherwise specified","Large cell calcifying Sertoli cell tumour","Androblastoma of the testis"],"tldr":"Sertoli cell tumour is a rare testicular tumour arising from the cells that support sperm production. Most are benign and cured by removing the testis. About one in ten spread, and no systemic treatment has been shown to work for those, so care is planned case by case at a specialist centre. A calcifying form occurs in boys with Peutz-Jeghers or Carney syndromes, usually with breast enlargement.","summary":"Sertoli cell tumours are sex cord-stromal tumours of the testis; the WHO classification separates the not otherwise specified type from the large cell calcifying and the intratubular large cell hyalinising types (Moch 2016). In the series of 60 tumours not otherwise specified, presentation was usually a slowly enlarging painless mass, all were unilateral, size ranged from 0.3 to 15 cm (mean 3.6), nuclear atypia was absent or mild in 54, and four patients had metastases at presentation (Young 1998). Exon 3 mutations of CTNNB1 with nuclear beta-catenin were found in 10 of 14 tumours, linking the tumour to WNT pathway activation (Am J Surg Pathol 2014). In boys, intratubular Sertoli cell proliferations and large cell calcifying tumours occur with Peutz-Jeghers syndrome and gynaecomastia (Am J Surg Pathol 2001).\n\nHow it differs from its parent: like Leydig cell tumours it is not a germ cell tumour, does not respond to cisplatin chemotherapy, does not raise the germ cell markers and is usually benign; malignancy is judged from size over 5 cm, necrosis, vascular invasion, atypia and mitoses.\n\nHow common: no incidence figure in the sources read.\n\nTreatment: orchidectomy (testis-sparing in syndromic boys with bilateral tumours); retroperitoneal lymph node dissection for malignant features; no effective systemic therapy for metastatic disease.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Sertoli_cell_tumour","links":[{"label":"NCI PDQ: testicular cancer treatment","url":"https://www.cancer.gov/types/testicular/treatment"},{"label":"Moch 2016, European Urology: the 2016 WHO classification of urinary and male genital tumours, part A","url":"https://doi.org/10.1016/j.eururo.2016.02.029"},{"label":"Young 1998, Am J Surg Pathol: Sertoli cell tumours of the testis, not otherwise specified, 60 cases","url":"https://doi.org/10.1097/00000478-199806000-00008"},{"label":"Am J Surg Pathol 2014: frequent CTNNB1 mutation and nuclear beta-catenin in Sertoli cell tumours of the testis","url":"https://doi.org/10.1097/pas.0b013e31829cdbc6"},{"label":"Am J Surg Pathol 2001: intratubular Sertoli cell proliferations of the infantile testis in Peutz-Jeghers syndrome","url":"https://doi.org/10.1097/00000478-200110000-00003"}],"tags":["subtype-page","wave4","testicular","rare"],"related":["testicular","leydig-cell-tumour","granulosa-cell-tumour","childhood-cancers"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Rare: the defining series holds 60 tumours not otherwise specified, patient age 15 to 80 (mean 45), four with metastatic disease at presentation (Young 1998). No registry figure was found in the sources read.","subtypes":[],"biomarkers":["Inhibin, calretinin and nuclear beta-catenin; germ cell markers negative","CTNNB1 exon 3 mutation","Size, necrosis, vascular invasion, atypia and mitotic count (malignancy risk)","Peutz-Jeghers or Carney syndrome features in boys"],"standardOfCare":[{"setting":"All cases","approach":"Orchidectomy, testis-sparing in syndromic boys; node dissection for malignant features; no systemic therapy has proven benefit in metastatic disease, so trials and referral to a specialist testicular centre are the route.","refs":["testicular"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"testicular"},{"id":"sezary-syndrome","kind":"cancer","name":"Sezary syndrome","aka":["Sézary syndrome","Sezary disease","Sézary disease","Leukaemic cutaneous T-cell lymphoma","Sezary syndrome (erythroderma with blood involvement)"],"tldr":"Sezary syndrome is the leukaemic form of skin lymphoma: the whole skin turns red and scaly, the lymph nodes swell, and malignant T cells circulate in the blood. It is treated to control rather than cure, with photopheresis, the antibody mogamulizumab, and drugs such as bexarotene and interferon, and a stem cell transplant is the only treatment that can cure it in fit patients.","summary":"WHO-HAEM5 keeps Sezary syndrome as a distinct entity from mycosis fungoides, defined by the triad of erythroderma, generalised lymphadenopathy and clonal neoplastic T cells in skin, nodes and blood, with a blood tumour burden of 1,000 or more Sezary cells per microlitre or equivalent flow cytometry criteria (Alaggio 2022; EORTC 2023). The EORTC consensus recommendations, updated in 2017 and 2023, set the stage-adapted treatment for mycosis fungoides and Sezary syndrome, noting that controlled studies remain few; the 2023 update incorporates chlormethine, brentuximab vedotin and mogamulizumab, recommends pegylated interferon after the withdrawal of unpegylated interferons, and adds guidance on supportive care and older patients (EORTC 2017; EORTC 2023). Mogamulizumab, the anti-CCR4 antibody, is the drug with a randomised trial in this setting (MAVORIC, linked here).\n\nHow it differs from its parent: the parent page covers mycosis fungoides, in which most patients have a normal life expectancy with skin-directed treatment; Sezary syndrome is advanced-stage disease by definition, blood-borne, immunosuppressing and life-shortening, treated systemically from the outset.\n\nHow common: no figure for the syndrome alone in the sources read; cutaneous T-cell lymphoma overall is about 6 per million a year (Criscione and Weinstock 2007).\n\nTreatment: extracorporeal photopheresis with or without interferon or bexarotene as first-line systemic therapy; mogamulizumab (MAVORIC) or low-dose methotrexate, pralatrexate, brentuximab vedotin in CD30-positive disease, or histone deacetylase inhibitors later; allogeneic stem cell transplant for fit patients with a response; skin-directed therapy and infection control throughout (EORTC 2023).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/S%C3%A9zary_disease","links":[{"label":"NCI PDQ: mycosis fungoides (including Sezary syndrome) treatment","url":"https://www.cancer.gov/types/lymphoma/patient/mycosis-fungoides-treatment-pdq"},{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"EORTC consensus recommendations for mycosis fungoides and Sezary syndrome, update 2023 (Eur J Cancer)","url":"https://doi.org/10.1016/j.ejca.2023.113343"},{"label":"EORTC consensus recommendations for mycosis fungoides and Sezary syndrome, update 2017 (Eur J Cancer)","url":"https://doi.org/10.1016/j.ejca.2017.02.027"},{"label":"Criscione and Weinstock 2007, Arch Dermatol: incidence of cutaneous T-cell lymphoma in the United States 1973 to 2002","url":"https://doi.org/10.1001/archderm.143.7.854"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["cutaneous-t-cell-lymphoma","peripheral-t-cell-lymphoma","t-cell-prolymphocytic-leukaemia","primary-cutaneous-marginal-zone-lymphoma","ig-tcr-clonality"],"cancers":[],"sections":[],"technologies":["allogeneic-hsct","flow-cytometry-mrd","clonality-testing"],"targets":["ccr4","cd52","stat3","stat5","jak1","jak3"],"drugs":["mogamulizumab","methoxsalen-ecp","bexarotene","interferon-alfa","methotrexate","pralatrexate","brentuximab-vedotin","romidepsin","vorinostat","resminostat","alemtuzumab","chlorambucil"],"companies":[],"institutions":[],"pathways":["jak-stat"],"terms":["allogeneic-transplant","lymphoma-tx-skin-directed-therapy","lymphoma-tx-pjp-and-infection-prophylaxis","lymphoma-bio-lineage-antigen-cost"],"trials":["mavoric","nct04930653","nct02953301"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"A small fraction of cutaneous T-cell lymphoma, which itself had an age-adjusted incidence of 6.4 per million a year in the United States over 1973 to 2002, higher in men (8.7) than women (4.6) and in black (9.0) than white (6.1) Americans (Criscione and Weinstock 2007). No registry figure for Sezary syndrome alone is in the sources read.","subtypes":["Sezary syndrome arising de novo (the usual form)","Sezary syndrome evolving from erythrodermic mycosis fungoides","Sezary syndrome with large-cell transformation"],"biomarkers":["Sezary cell count of 1,000 per microlitre or more, or CD4:CD8 ratio of 10 or more with loss of CD7 or CD26","Clonal T-cell receptor rearrangement matching in skin and blood","CCR4 expression (mogamulizumab target)","CD30 expression (brentuximab vedotin)"],"standardOfCare":[{"setting":"First-line systemic","approach":"Extracorporeal photopheresis with or without interferon or bexarotene (EORTC 2023).","refs":["methoxsalen-ecp","bexarotene","interferon-alfa","cutaneous-t-cell-lymphoma"]},{"setting":"Later lines","approach":"Mogamulizumab (MAVORIC), methotrexate, pralatrexate, brentuximab vedotin for CD30-positive disease, romidepsin or vorinostat; allogeneic transplant for fit responders.","refs":["mogamulizumab","mavoric","methotrexate","pralatrexate","brentuximab-vedotin","romidepsin","vorinostat","allogeneic-transplant"]},{"setting":"Sezary syndrome: treatment aimed at the blood as well as the skin","approach":"Sezary syndrome is the leukaemic form: erythroderma covering most of the body, lymphadenopathy, intractable itch and a clone of malignant T cells in the blood. It is treated as advanced disease from the start, and treatment has to reduce the blood compartment, not only the skin.\n\nExtracorporeal photopheresis is the treatment most specific to it: the patient's white cells are drawn off, exposed to methoxsalen and ultraviolet A light, and returned, usually on two consecutive days every two to four weeks. It is well tolerated, works slowly over months, and is often combined with interferon alfa or bexarotene. It has been approved for the skin manifestations of cutaneous T-cell lymphoma in the United States since 1999.\n\nMogamulizumab is the systemic drug of choice where the blood is heavily involved, because in MAVORIC the response rate in the blood compartment was 68 per cent, far above its skin response; median progression-free survival was 7.7 against 3.1 months for vorinostat. Other options are bexarotene, interferon, low-dose methotrexate, romidepsin, alemtuzumab at low subcutaneous dose, chlorambucil with prednisolone for an older patient, and allogeneic transplant with reduced-intensity conditioning for fit younger patients, which is the only treatment that produces durable remission.\n\nSkin care, control of itch and prevention of staphylococcal sepsis matter at least as much as the lymphoma treatment; erythrodermic skin loses heat, fluid and protein and is an open door to infection.","refs":["methoxsalen-ecp","mogamulizumab","bexarotene","interferon-alfa","methotrexate","romidepsin","alemtuzumab","chlorambucil","prednisone","allogeneic-hsct","paper-mavoric-mogamulizumab-lancet-oncol-2018","lymphoma-tx-skin-directed-therapy","lymphoma-tx-pjp-and-infection-prophylaxis"],"guideline":{"version":"NCCN Primary Cutaneous Lymphomas; ESMO; MAVORIC","url":"https://www.cancer.gov/types/lymphoma/hp/mycosis-fungoides-treatment-pdq"}}],"stateOfArt":["Sezary syndrome is the leukaemic form, so the measurement is in blood rather than in skin: flow cytometry counts the circulating clone, and the same immunoglobulin or T-cell receptor sequence can be followed afterwards.","CCR4 is expressed in more than 80% of cases, which is why mogamulizumab is used; depleting it also removes regulatory T cells, with the rash and the transplant risk that follow.","JAK-STAT lesions recur in this family of diseases, and the STAT5B N642H substitution, which prolongs the active phosphorylated form, is the best-characterised of them."],"history":[],"pipeline":[],"openProblems":[],"parent":"cutaneous-t-cell-lymphoma"},{"id":"medulloblastoma-shh","kind":"cancer","name":"SHH-activated medulloblastoma","aka":["SHH medulloblastoma","Sonic hedgehog medulloblastoma","Desmoplastic/nodular medulloblastoma","SHH-activated TP53-mutant medulloblastoma"],"tldr":"SHH-activated medulloblastoma is driven by the sonic hedgehog growth pathway, the signal that normally tells the developing cerebellum to grow. In infants it is often cured with chemotherapy alone and no radiotherapy; in adults it responds for a time to hedgehog-blocking pills such as vismodegib; and when it carries a TP53 mutation in an older child, often inherited, it resists everything.","summary":"The SHH group arises from cerebellar granule neuron precursors and is defined by activation of the sonic hedgehog pathway: loss of PTCH1 or SUFU, activating SMO mutations, or amplification of GLI2 or MYCN downstream. Age fixes the biology. Infants have PTCH1 or SUFU alterations (germline in a fifth, including Gorlin syndrome), desmoplastic/nodular or extensive-nodularity histology and a good prognosis; adults have PTCH1 and SMO mutations and an intermediate outcome; children aged around eight to seventeen carry TP53 mutations, half of them germline (Li-Fraumeni syndrome), with GLI2 and MYCN amplification and chromothripsis, and do very badly. WHO 2021 therefore splits SHH-activated tumours into TP53-wildtype and TP53-mutant.\n\nThe German HIT-SKK'92 trial, reported in the New England Journal of Medicine in 2005, treated infants with cyclophosphamide, vincristine, methotrexate, carboplatin, etoposide and intraventricular methotrexate without radiotherapy and found that desmoplastic histology, which is nearly all SHH, predicted a high cure rate, so radiotherapy-sparing chemotherapy became the infant standard; ACNS1221, which tried to reproduce this without the intraventricular methotrexate, closed early for excess relapses, showing the intraventricular drug matters. For children over three, SHH tumours receive the same craniospinal radiotherapy and chemotherapy as other groups, and TP53-mutant SHH disease relapses despite it: a 2013 pooled analysis found five-year overall survival of 41 percent with a TP53 mutation against 81 percent without in the SHH group. Smoothened inhibitors developed for basal cell carcinoma were tested by the Pediatric Brain Tumor Consortium: vismodegib produced responses only in SHH tumours with upstream PTCH1 or SMO lesions, mostly in adults, that lasted months, and it fuses growth plates in growing children, so it is limited to skeletally mature patients.\n\nNothing yet helps TP53-mutant SHH disease, which resists radiotherapy and chemotherapy and cannot use SMO inhibitors because its pathway activation is downstream; CDK4/6 inhibitors, bromodomain inhibitors aimed at GLI and MYCN, and immunotherapy are in early trials, and germline TP53 testing at diagnosis matters for the family and for avoiding radiotherapy-induced second tumours. For infants the question is which SHH tumours can be cured with less: SJYC07 and the current SIOP and COG trials stratify by methylation subtype, with high-dose chemotherapy and stem cell rescue kept for the poorer subgroups. Adult SHH medulloblastoma is treated with craniospinal radiotherapy and, increasingly, chemotherapy, with SMO inhibitors reserved for relapse in patients whose tumours carry an upstream mutation.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Medulloblastoma","links":[{"label":"Wikipedia: Medulloblastoma","url":"https://en.wikipedia.org/wiki/Medulloblastoma"},{"label":"NCI PDQ: Childhood Medulloblastoma Treatment","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}],"tags":["subtype-page","paediatric","cns"],"related":["medulloblastoma-wnt","medulloblastoma-group-3-4","basal-cell-carcinoma"],"cancers":[],"sections":[],"technologies":["proton-therapy","methylation-profiling","autologous-stem-cell-transplant"],"targets":["smoothened","tp53"],"drugs":[],"companies":["childrens-oncology-group"],"institutions":["st-jude","siop-europe"],"pathways":["hedgehog"],"terms":["li-fraumeni","late-effects","secondary-malignancy","medulloblastoma-molecular-groups"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2021-cns-louis-neuro-oncology-2021","paper-taylor-medulloblastoma-consensus-acta-neuropathol-2012","paper-robinson-vismodegib-shh-medulloblastoma-jco-2015","paper-zhukova-tp53-medulloblastoma-jco-2013"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About three medulloblastomas in ten are SHH-activated; they cluster in infants under three and in adults, and the TP53-mutant form in older children is among the childhood brain tumours with the lowest survival.","subtypes":["SHH-activated medulloblastoma, TP53-wildtype, in infants (PTCH1 or SUFU; desmoplastic/nodular or extensive nodularity; chemotherapy without radiotherapy)","SHH-activated medulloblastoma, TP53-wildtype, in children and adults (PTCH1, SMO)","SHH-activated medulloblastoma, TP53-mutant (children 8 to 17; often germline Li-Fraumeni; GLI2 and MYCN amplification; very poor)","SHH-activated medulloblastoma in Gorlin syndrome (germline PTCH1 or SUFU; radiotherapy causes field basal cell carcinomas)","Adult SHH medulloblastoma with upstream PTCH1 or SMO mutation (smoothened inhibitor-responsive)"],"biomarkers":["GAB1, YAP1 and filamin A immunohistochemistry for SHH","PTCH1, SUFU and SMO mutations","TP53 mutation, somatic and germline","GLI2 and MYCN amplification","DNA methylation subtype (SHH infant, child, adult)","Germline PTCH1, SUFU and TP53 testing","Chromosome 9q loss"],"standardOfCare":[{"setting":"Infants under three, TP53-wildtype","approach":"HIT-SKK-type chemotherapy with intraventricular methotrexate and no radiotherapy; high-dose chemotherapy with stem cell rescue for poorer methylation subtypes.","refs":["cyclophosphamide","vincristine","methotrexate","carboplatin","etoposide","thiotepa","autologous-stem-cell-transplant"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"Children over three and adults, TP53-wildtype","approach":"Maximal safe resection, craniospinal radiotherapy (23.4 Gy average risk, 36 Gy high risk) with boost, then cisplatin, vincristine and cyclophosphamide or lomustine.","refs":["proton-therapy","imrt-igrt","cisplatin","vincristine","cyclophosphamide","lomustine"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"TP53-mutant","approach":"High-risk therapy with germline testing of the child and family; trials of novel agents; radiotherapy weighed against second-tumour risk in Li-Fraumeni syndrome.","refs":["carboplatin","cisplatin","vincristine","cyclophosphamide","germline-testing","tp53","li-fraumeni"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"Relapsed, skeletally mature, upstream PTCH1 or SMO lesion","approach":"Vismodegib or sonidegib for temporary control; other relapses receive temozolomide-based chemotherapy or re-irradiation.","refs":["vismodegib","sonidegib","smoothened","hedgehog","temozolomide"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"Survivorship","approach":"Neurocognitive, endocrine and hearing follow-up; skin surveillance for basal cell carcinoma in Gorlin syndrome after radiotherapy.","refs":["late-effects","secondary-malignancy"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}}],"stateOfArt":["Infants with desmoplastic SHH tumours are cured with chemotherapy including intraventricular methotrexate and no radiotherapy.","TP53 status splits SHH medulloblastoma into a curable disease and one that is rarely cured; germline testing is part of diagnosis.","Smoothened inhibitors work only in upstream-mutant tumours in skeletally mature patients and for months rather than years."],"history":[{"year":1996,"title":"Germline PTCH1 mutations found in Gorlin syndrome, linking hedgehog signalling to medulloblastoma","refs":[]},{"year":2005,"title":"HIT-SKK'92: infants with desmoplastic medulloblastoma cured with chemotherapy and no radiotherapy","refs":["methotrexate"]},{"year":2009,"title":"First report of a metastatic medulloblastoma responding to a smoothened inhibitor","refs":["vismodegib"]},{"year":2013,"title":"TP53 mutation identified as the marker of very poor outcome within the SHH group","refs":["tp53"]},{"year":2015,"title":"PBTC-025B and 032: vismodegib responses confined to SHH tumours with upstream lesions","refs":["vismodegib"]},{"year":2020,"title":"ACNS1221 closes early: dropping intraventricular methotrexate raises infant relapse","refs":["methotrexate"]},{"year":2021,"title":"WHO 2021 splits SHH-activated medulloblastoma by TP53 status","refs":["methylation-profiling"]}],"pipeline":["vismodegib","sonidegib","methylation-profiling","proton-therapy","germline-testing"],"openProblems":["No therapy improves TP53-mutant SHH medulloblastoma.","Smoothened inhibitors fuse growth plates and fail against downstream activation.","Which infant SHH tumours can safely receive less chemotherapy."],"parent":"medulloblastoma"},{"id":"colorectal-signet-ring-cell-carcinoma","kind":"cancer","name":"Signet ring cell carcinoma of the colon and rectum","aka":["Signet-ring cell colorectal cancer","Signet ring cell carcinoma","Signet ring cell adenocarcinoma of the colon","Signet-ring cell carcinoma of the colorectum"],"tldr":"Signet ring cell carcinoma is a rare form of bowel cancer, about one in a hundred, in which the cells fill with mucus that pushes the nucleus aside, like a ring. It occurs in younger people, favours the right colon, is usually found at an advanced stage and often spreads across the lining of the abdomen, so its outlook is poor; it is treated like other bowel cancer for want of trials of its own.","summary":"The WHO classification defines signet ring cell carcinoma by signet ring cells making up more than 50 percent of the tumour (Nagtegaal 2020). The review evidence associates it with young age, proximal site, advanced stage, high grade, frequent node involvement, peritoneal metastasis and significantly shorter survival; molecularly, the classic WNT, RAS-MAPK and PI3K pathways are mutated less often than in ordinary adenocarcinoma while RNF43, CDH1, SMAD4 and TGF-beta pathway genes are altered more often, and many but not all studies report more BRAF mutation and microsatellite instability (Pathology Oncology Research 2021). In the meta-analysis, signet ring cell patients were younger and twice as likely to have right-sided disease (odds ratio 2.12), and five-year overall survival was worse than adenocarcinoma (hazard ratio 2.54 for signet ring and mucinous combined) (Discover Oncology 2021). In the Munich registry it was diagnosed at more advanced stages, with reduced survival (J Cancer Res Clin Oncol 2016).\n\nHow it differs from its parent: it is the histology with the worst outlook among colorectal cancers and with peritoneal rather than liver spread, and it shares its cell type and CDH1 biology with diffuse gastric cancer rather than with ordinary colon adenocarcinoma.\n\nHow common: about 1 percent (Discover Oncology 2021).\n\nTreatment: as the parent by stage and mismatch repair status; peritoneal disease follows the colorectal page's approach to peritoneal metastases; there is no trial in the type.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Signet_ring_cell_carcinoma","links":[{"label":"Nagtegaal 2020, Histopathology: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"Pathology Oncology Research 2021: clinicopathological and molecular characteristics of colorectal signet ring cell carcinoma (review)","url":"https://doi.org/10.3389/pore.2021.1609859"},{"label":"Discover Oncology 2021: signet ring cell and mucinous carcinoma versus adenocarcinoma, meta-analysis of 1,087,055 patients","url":"https://doi.org/10.1007/s12672-021-00398-6"},{"label":"J Cancer Res Clin Oncol 2016: mucinous and signet ring cell colorectal cancer in 28,056 Munich registry patients","url":"https://doi.org/10.1007/s00432-016-2224-2"}],"tags":["subtype-page","wave4","colorectal"],"related":["colorectal","colon-cancer","colorectal-mucinous-adenocarcinoma","early-onset-colorectal","appendiceal-adenocarcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["folfox"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"About 1 percent of colorectal cancers: 11,510 of 1,087,055 patients (1.06 percent) in the meta-analysis (Discover Oncology 2021) and 160 of 28,056 (0.6 percent) in the Munich registry (J Cancer Res Clin Oncol 2016).","subtypes":["Signet ring cell carcinoma, mismatch-repair deficient (MSI-high; right-sided)","Signet ring cell carcinoma, mismatch-repair proficient (CDH1, RNF43 and SMAD4 altered; peritoneal spread)","Mucinous adenocarcinoma with signet ring cells under 50 percent (classified as mucinous)"],"biomarkers":["Signet ring cells over 50 percent of the tumour","Mismatch repair status","CDH1, RNF43 and SMAD4 alterations (research)","Peritoneal disease on imaging"],"standardOfCare":[{"setting":"All stages","approach":"Treated as the colorectal page by stage and mismatch repair status; no trial in the type.","refs":["colorectal","colon-cancer","folfox"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"colorectal"},{"id":"lch-single-system","kind":"cancer","name":"Single-system Langerhans cell histiocytosis (bone, skin or one other organ)","aka":["Single-system LCH","Eosinophilic granuloma","Unifocal bone LCH","Skin-only LCH","Pulmonary Langerhans cell histiocytosis (adult smokers)"],"tldr":"Single-system Langerhans cell histiocytosis is the milder form of this rare histiocytosis, in which the abnormal immune cells affect only one organ, usually a bone or the skin, in a child or young adult. Single bone lesions often heal after biopsy or curettage, skin disease may fade by itself, and gentle vinblastine and prednisone is kept for multiple bone lesions or lesions near the brain.","summary":"Langerhans cell histiocytosis is a clonal myeloid neoplasm of CD1a- and langerin-positive dendritic-like cells, driven in most cases by BRAF V600E or another MAPK pathway mutation. Its behaviour depends on how many organs are involved. Single-system disease, most often a lytic bone lesion of the skull, femur, ribs or vertebrae in a child of school age, or a skin eruption in an infant, carries almost no mortality; the classic eponyms eosinophilic granuloma (bone), Hand-Schüller-Christian and Letterer-Siwe disease have given way to a classification by organ count and risk-organ involvement. Pulmonary Langerhans cell histiocytosis in adults who smoke is a distinct single-system form that often improves with smoking cessation. The Histiocyte Society staging separates unifocal bone disease, multifocal bone disease, special-site lesions (skull base, orbit, mastoid and vertebrae with soft tissue extension, which carry a risk of later pituitary or neurodegenerative involvement) and single-system disease of skin, lymph node or lung.\n\nTreatment is proportionate. A single bone lesion is treated by biopsy with curettage, sometimes with an intralesional steroid injection, and many heal spontaneously; indomethacin or bisphosphonates help painful bone disease; skin-only disease in infants is observed or treated topically and often resolves, though a proportion of infants later develop multisystem disease and must be followed. Multifocal bone disease and special-site lesions are treated with the same vinblastine and prednisone regimen used for multisystem disease, given for twelve months after LCH-III showed longer treatment reduced reactivation, in order to prevent recurrence and the late central nervous system complications. Reactivation is common but rarely dangerous. Adults with single-system disease may receive cytarabine or cladribine instead because vinblastine is more toxic in adults, and BRAF or MEK inhibitors are reserved for refractory disease. The main long-term concerns are diabetes insipidus and neurodegenerative disease after skull-base lesions, and orthopaedic sequelae after vertebral collapse, so follow-up continues for years.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosis","links":[{"label":"NCI PDQ Langerhans cell histiocytosis","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosis"}],"tags":["subtype-page","paediatric"],"related":["lch-multisystem","langerhans-cell-histiocytosis","rosai-dorfman-disease"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","kinase-inhibitors","mri","fdg-pet","ultrasound","histopathology-ihc","active-surveillance"],"targets":["braf"],"drugs":["vinblastine","cladribine","vemurafenib","dabrafenib-trametinib","cobimetinib"],"companies":[],"institutions":[],"pathways":[],"terms":["braf-v600-mutation","late-effects"],"trials":["lch-iii"],"people":[],"bottlenecks":[],"keyPapers":["paper-lch-iii-therapy-prolongation-multisystem-lch-blood-2013","paper-badalian-very-braf-mutations-lch-blood-2010","paper-emile-revised-classification-of-histiocytoses-blood-2016"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About two thirds of childhood Langerhans cell histiocytosis is confined to one organ system, most often bone; the outlook is excellent and many lesions heal with minimal or no treatment.","subtypes":["Unifocal bone Langerhans cell histiocytosis (eosinophilic granuloma; curettage or observation)","Multifocal bone Langerhans cell histiocytosis (vinblastine and prednisone)","Special-site Langerhans cell histiocytosis (skull base, orbit, mastoid, vertebra; treated to prevent CNS complications)","Skin-only Langerhans cell histiocytosis in infants (observation, may progress)","Single-system lymph node or thymic Langerhans cell histiocytosis","Pulmonary Langerhans cell histiocytosis in adult smokers (smoking cessation)"],"biomarkers":["CD1a and langerin (CD207) positive histiocytes on biopsy","BRAF V600E in tissue (present in over half) and cell-free DNA","MAP2K1 and other MAPK alterations","Skeletal survey or whole-body MRI or PET for occult lesions","Pituitary MRI and water balance for special-site disease","Chest CT and pulmonary function in adult pulmonary disease"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Biopsy with immunohistochemistry and BRAF testing; skeletal survey or whole-body imaging, blood count, liver tests and abdominal ultrasound to exclude multisystem disease.","refs":["histopathology-ihc","braf-v600-mutation","mri","fdg-pet","ultrasound"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}},{"setting":"Unifocal bone disease","approach":"Biopsy with curettage, with or without intralesional methylprednisolone; observation of healing; indomethacin for pain.","refs":["active-surveillance"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}},{"setting":"Multifocal bone or special-site disease","approach":"Vinblastine and prednisone for twelve months (LCH-III schedule) to reduce reactivation and central nervous system risk.","refs":["vinblastine","lch-iii"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}},{"setting":"Skin-only disease","approach":"Observation or topical corticosteroids; systemic therapy only for extensive symptomatic disease; regular review for progression to multisystem disease.","refs":["active-surveillance"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}},{"setting":"Adult single-system or refractory disease","approach":"Cytarabine or cladribine; smoking cessation for pulmonary disease; BRAF or MEK inhibitors (vemurafenib, dabrafenib-trametinib, cobimetinib) for refractory disease.","refs":["cladribine","vemurafenib","dabrafenib-trametinib","cobimetinib","kinase-inhibitors"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}}],"stateOfArt":["Most single-system disease is cured with minimal treatment and near-zero mortality.","Special-site lesions are treated systemically to prevent the late neurological complications.","BRAF testing links the mildest and the most severe forms of the disease as one neoplasm."],"history":[{"year":1940,"title":"Eosinophilic granuloma of bone described by Lichtenstein and Jaffe","refs":[]},{"year":1953,"title":"Lichtenstein unifies eosinophilic granuloma, Hand-Schüller-Christian and Letterer-Siwe disease as histiocytosis X","refs":[]},{"year":1987,"title":"Histiocyte Society founded; disease renamed Langerhans cell histiocytosis","refs":[]},{"year":2010,"title":"BRAF V600E found in over half of lesions","refs":["braf","ras-mapk"]},{"year":2013,"title":"LCH-III: twelve months of vinblastine and prednisone reduces reactivation","refs":["lch-iii","vinblastine"]}],"pipeline":["dabrafenib-trametinib","vemurafenib","cobimetinib"],"openProblems":["Which infants with skin-only disease will progress cannot be predicted.","Whether treating special-site lesions truly prevents neurodegeneration is inferred rather than proven.","Adults have no trial-based standard.","Reactivation rates remain high even after twelve months of therapy."],"parent":"langerhans-cell-histiocytosis"},{"id":"sinonasal-undifferentiated-carcinoma","kind":"cancer","name":"Sinonasal undifferentiated carcinoma (SNUC) and SWI/SNF-deficient sinonasal carcinoma","aka":["SNUC","IDH2-mutant sinonasal carcinoma","SMARCB1-deficient sinonasal carcinoma","SMARCA4-deficient sinonasal carcinoma","Undifferentiated carcinoma of the paranasal sinuses"],"tldr":"Sinonasal undifferentiated carcinoma is a rare, fast-growing cancer of the nasal cavity and sinuses made of primitive cells with no clear line of differentiation, most carrying an IDH2 mutation. It presents as a large mass pressing on the eye or brain and is treated with chemotherapy first, then surgery or chemoradiotherapy depending on response; SMARCB1- or SMARCA4-deficient tumours are separate.","summary":"Sinonasal undifferentiated carcinoma was defined in 1986 as a high-grade carcinoma of the sinonasal tract without squamous or glandular differentiation, negative for EBV and for the neuroendocrine and NUT markers that define its mimics. Genomic studies from 2017 found IDH2 R172 mutations in most cases, giving the tumour a molecular identity and a possible drug target; the 2022 WHO classification also carved out SMARCB1 (INI1)-deficient and SMARCA4-deficient sinonasal carcinomas, which look similar but are driven by loss of SWI/SNF chromatin remodelling proteins, and NUT carcinoma, which has its own page. All present late with a bulky mass causing nasal obstruction, proptosis, diplopia or headache, invading the orbit, skull base and dura, and about a fifth have neck node metastases at diagnosis.\n\nHistorically, surgery followed by radiotherapy cured few patients because of the extent of disease, and the MD Anderson group changed the paradigm by giving chemotherapy first. In their series of 95 patients (Journal of Clinical Oncology 2019), those whose tumour responded to induction platinum-etoposide did better with definitive chemoradiotherapy than with surgery, while those who did not respond did better with surgery followed by radiotherapy or chemoradiotherapy, so the response to induction now decides the local treatment. Intensity-modulated or proton radiotherapy is used to spare the optic pathways and brain, and elective neck treatment is standard because nodal relapse is common. Metastatic disease is treated with platinum-etoposide as for neuroendocrine carcinoma, and PD-1 antibodies have produced responses in case series of SMARCB1-deficient and other sinonasal carcinomas. The IDH2 inhibitor enasidenib, approved for IDH2-mutant leukaemia, is being tested in IDH2-mutant sinonasal carcinoma, and EZH2 inhibitors, active in other SMARCB1-deficient tumours, are being explored for the SWI/SNF-deficient group. Five-year survival remains low overall, and referral to a skull base centre with molecular pathology is recommended for every patient.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Sinonasal_undifferentiated_carcinoma","links":[{"label":"Induction chemotherapy in SNUC (JCO 2019)","url":"https://doi.org/10.1200/JCO.18.00353"},{"label":"NCCN Head and Neck Cancers (ethmoid and maxillary sinus)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Sinonasal_undifferentiated_carcinoma"}],"tags":["subtype-page","head-and-neck"],"related":["esthesioneuroblastoma","sinonasal","nut-carcinoma","extrapulmonary-nec"],"cancers":[],"sections":[],"technologies":["imrt-igrt","proton-therapy","robotic-surgery","cytotoxic-chemotherapy","checkpoint-inhibitor","histopathology-ihc","mri","ct","pet-ct"],"targets":["idh","pd1"],"drugs":["cisplatin","etoposide","platinum-etoposide","pembrolizumab","nivolumab","enasidenib"],"companies":[],"institutions":[],"pathways":[],"terms":["head-neck-subsites","rare-cancers","chemoradiation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-amit-induction-chemotherapy-response-snuc-jco-2019","paper-jo-idh2-r172-mutations-snuc-mod-pathol-2017"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"A rare and aggressive sinonasal cancer of middle-aged adults, usually presenting as a large mass invading the orbit or skull base; historically most patients died within a few years, and induction chemotherapy has improved that.","subtypes":["IDH2-mutant sinonasal undifferentiated carcinoma (the majority; enasidenib in trials)","IDH2 wild-type sinonasal undifferentiated carcinoma","SMARCB1 (INI1)-deficient sinonasal carcinoma (SWI/SNF-deficient; separate WHO entity)","SMARCA4-deficient sinonasal carcinoma (SWI/SNF-deficient; separate WHO entity)","Induction-responsive sinonasal undifferentiated carcinoma (definitive chemoradiotherapy)","Induction-refractory sinonasal undifferentiated carcinoma (surgery then radiotherapy)"],"biomarkers":["IDH2 R172 mutation (diagnosis; enasidenib eligibility)","SMARCB1 (INI1) and SMARCA4 immunohistochemistry (SWI/SNF-deficient carcinomas)","NUT immunohistochemistry (exclude NUT carcinoma) and EBV (exclude nasopharyngeal-type carcinoma)","Response to induction chemotherapy on imaging (decides surgery versus chemoradiotherapy)","Neck node status","PD-L1 (investigational)"],"standardOfCare":[{"setting":"Diagnosis","approach":"Biopsy with immunohistochemistry (cytokeratins, NUT, INI1, SMARCA4, neuroendocrine markers, EBER) and IDH2 testing; MRI and CT of the sinuses, skull base and neck; PET-CT.","refs":["histopathology-ihc","mri","ct","pet-ct"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers (ethmoid and maxillary sinus tumours)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Locally advanced disease, first step","approach":"Induction chemotherapy with cisplatin and etoposide (or docetaxel-platinum) for two to three cycles.","refs":["cisplatin","etoposide","platinum-etoposide","cytotoxic-chemotherapy"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers (ethmoid and maxillary sinus tumours)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Responders to induction","approach":"Definitive chemoradiotherapy with concurrent cisplatin (intensity-modulated or proton), including elective neck irradiation.","refs":["cisplatin","imrt-igrt","proton-therapy","chemoradiation"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers (ethmoid and maxillary sinus tumours)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Non-responders to induction","approach":"Surgical resection where feasible followed by radiotherapy or chemoradiotherapy.","refs":["robotic-surgery","imrt-igrt","chemoradiation"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers (ethmoid and maxillary sinus tumours)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Metastatic or recurrent disease","approach":"Platinum-etoposide; PD-1 antibodies (pembrolizumab, nivolumab) on case series evidence; enasidenib for IDH2-mutant tumours in trials; EZH2 inhibitors for SWI/SNF-deficient carcinoma in trials.","refs":["platinum-etoposide","pembrolizumab","nivolumab","enasidenib","checkpoint-inhibitor"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers (ethmoid and maxillary sinus tumours)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}}],"stateOfArt":["Response to induction chemotherapy now decides between surgery and chemoradiotherapy.","IDH2 mutations give the tumour an identity and a drug target.","SWI/SNF-deficient carcinomas have been separated as distinct diseases with their own emerging therapies."],"history":[{"year":1986,"title":"Frierson and colleagues define sinonasal undifferentiated carcinoma","refs":[]},{"year":2014,"title":"SMARCB1-deficient sinonasal carcinoma described","refs":[]},{"year":2017,"title":"IDH2 R172 mutations found in most sinonasal undifferentiated carcinomas","refs":["idh"]},{"year":2019,"title":"MD Anderson series: induction response guides local therapy and improves survival","refs":["platinum-etoposide"]},{"year":2022,"title":"WHO classification recognises SWI/SNF-deficient sinonasal carcinomas as separate entities","refs":[]}],"pipeline":["enasidenib","proton-therapy","pembrolizumab"],"openProblems":["No randomised trial exists and the induction-response strategy rests on one centre's series.","Enasidenib's activity in IDH2-mutant sinonasal carcinoma is unproven.","Most patients still die of the disease within a few years.","Orbital and skull base surgery and radiotherapy carry heavy functional costs."],"parent":"sinonasal"},{"id":"skin-cancer","kind":"cancer","name":"Skin cancer (all types)","aka":["Skin Cancer","Skin cancers","Cutaneous malignancies","Keratinocyte cancer","Non-melanoma skin cancer","NMSC","Skin carcinoma","Cancer of the skin","C44","C43"],"tldr":"Skin cancer covers the very common and rarely dangerous basal cell and squamous cell carcinomas, the less common but more serious melanoma, and rarer tumours such as Merkel cell carcinoma and Kaposi sarcoma. Almost all of it is caused by ultraviolet light and most of it is found and cured by simple surgery.","summary":"Skin cancers share a cause, ultraviolet light, and a first line of defence, sun protection and early recognition of a changing spot, but they differ sharply in behaviour. Basal cell carcinoma almost never spreads and is cured by excision, Mohs surgery, topical treatment or radiotherapy. Cutaneous squamous cell carcinoma usually behaves the same way but can spread in immunosuppressed people or when neglected, where PD-1 blockade now works well. Melanoma accounts for most skin cancer deaths; caught early it is cured by excision, and at advanced stages checkpoint immunotherapy and BRAF and MEK inhibitors have transformed survival. Merkel cell carcinoma, Kaposi sarcoma and cutaneous lymphomas are rarer and have their own pages. This page is the entry point for readers who have been told only 'skin cancer'.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Skin_cancer","links":[{"label":"NCI: Skin cancer","url":"https://www.cancer.gov/types/skin"},{"label":"GLOBOCAN 2020 (Sung 2021)","url":"https://doi.org/10.3322/caac.21660"},{"label":"NHS: non-melanoma skin cancer","url":"https://www.nhs.uk/conditions/non-melanoma-skin-cancer/"},{"label":"NHS: treatment for non-melanoma skin cancer","url":"https://www.nhs.uk/conditions/non-melanoma-skin-cancer/treatment/"},{"label":"NHS: scars (reviewed 18 September 2023, next review due 18 September 2026)","url":"https://www.nhs.uk/conditions/scars/"},{"label":"NHS: sunscreen and sun safety","url":"https://www.nhs.uk/live-well/seasonal-health/sunscreen-and-sun-safety/"},{"label":"NHS: sunburn","url":"https://www.nhs.uk/conditions/sunburn/"},{"label":"NHS: sepsis","url":"https://www.nhs.uk/conditions/sepsis/"},{"label":"NHS: when to use 111","url":"https://www.nhs.uk/nhs-services/urgent-and-emergency-care-services/when-to-use-111/"},{"label":"NHS: when to call 999","url":"https://www.nhs.uk/nhs-services/urgent-and-emergency-care-services/when-to-call-999/"},{"label":"British Association of Dermatologists: basal cell carcinoma, patient information leaflet (updated July 2025)","url":"https://www.skinhealthinfo.org.uk/condition/basal-cell-carcinoma/"},{"label":"British Association of Dermatologists: squamous cell carcinomas, patient information leaflet (updated April 2022; the leaflet gives its own next review date as April 2025 and no newer version exists at this address or at bad.org.uk)","url":"https://www.skinhealthinfo.org.uk/condition/squamous-cell-carcinomas/"},{"label":"British Association of Dermatologists and British Society for Dermatological Surgery: Mohs micrographic surgery, patient information leaflet (updated June 2025)","url":"https://www.skinhealthinfo.org.uk/condition/mohs-micrographic-surgery/"},{"label":"British Association of Dermatologists and BSSCII: skin cancer advice for organ transplant recipients, patient information leaflet (June 2024)","url":"https://www.skinhealthinfo.org.uk/condition/skin-cancer-in-organ-transplant-recipients/"},{"label":"British Association of Dermatologists: the sun protection fact sheet (the page states no production, update or review date)","url":"https://www.skinhealthinfo.org.uk/sun-awareness/the-sunscreen-fact-sheet/"},{"label":"Nasr et al., British Association of Dermatologists guidelines for the management of adults with basal cell carcinoma 2021 (Br J Dermatol)","url":"https://doi.org/10.1111/bjd.20524"},{"label":"Keohane et al., British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma 2020 (Br J Dermatol)","url":"https://doi.org/10.1111/bjd.19621"},{"label":"Cancer Research UK: types of surgery for non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/treatment/surgery/treatment-surgery-types"},{"label":"Cancer Research UK: problems after surgery for non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/treatment/surgery/problems-after-surgery"},{"label":"Cancer Research UK: Mohs micrographic surgery","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/treatment/surgery/mohs-micrographic-surgery-mms"},{"label":"Cancer Research UK: follow-up after non-melanoma skin cancer treatment","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/treatment/follow-up-appointments"},{"label":"Cancer Research UK: skin care after non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/living-with/skin-care-after-skin-cancer"},{"label":"Cancer Research UK: coping with non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/living-with/coping"},{"label":"Cancer Research UK: referral to a skin cancer specialist","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/getting-diagnosed/referral-specialist"},{"label":"Cancer Research UK: photodynamic therapy for non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/treatment/photodynamic-therapy"},{"label":"Cancer Research UK: chemotherapy cream for non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/treatment/chemotherapy-cream"},{"label":"Macmillan: skin cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/skin-cancer"},{"label":"Changing Faces: support for people with a visible difference","url":"https://www.changingfaces.org.uk/"},{"label":"Thomson et al., interventions for basal cell carcinoma of the skin: Cochrane review of 52 randomised trials and 6,690 participants (2020)","url":"https://doi.org/10.1002/14651858.CD003412.pub3"},{"label":"Bath-Hextall et al., surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma, SINS (Lancet Oncology 2014)","url":"https://doi.org/10.1016/S1470-2045(13)70530-8"},{"label":"Williams et al., surgery versus 5% imiquimod for nodular and superficial basal cell carcinoma, 5-year results of the SINS randomised controlled trial (J Invest Dermatol 2017)","url":"https://doi.org/10.1016/j.jid.2016.10.019"},{"label":"Arits et al., photodynamic therapy versus topical imiquimod versus topical fluorouracil for superficial basal-cell carcinoma, randomised trial of 601 patients (Lancet Oncology 2013)","url":"https://doi.org/10.1016/S1470-2045(13)70143-8"},{"label":"Jansen et al., five-year results of a randomised controlled trial comparing photodynamic therapy, topical imiquimod and topical 5-fluorouracil in superficial basal cell carcinoma (J Invest Dermatol 2018)","url":"https://doi.org/10.1016/j.jid.2017.09.033"},{"label":"van Loo et al., surgical excision versus Mohs micrographic surgery for basal cell carcinoma of the face: randomised clinical trial with 10-year follow-up (Eur J Cancer 2014)","url":"https://doi.org/10.1016/j.ejca.2014.08.018"},{"label":"Marcil and Stern, risk of developing a subsequent non-melanoma skin cancer in patients with a history of non-melanoma skin cancer: review and meta-analysis (Arch Dermatol 2000)","url":"https://doi.org/10.1001/archderm.136.12.1524"},{"label":"Brantsch et al., analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: prospective study of 615 patients (Lancet Oncology 2008)","url":"https://doi.org/10.1016/S1470-2045(08)70178-5"},{"label":"Schmults et al., factors predictive of recurrence and death from cutaneous squamous cell carcinoma: 10-year, single-institution cohort study of 985 patients (JAMA Dermatology 2013)","url":"https://doi.org/10.1001/jamadermatol.2013.2139"},{"label":"Lansbury et al., interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies (BMJ 2013)","url":"https://doi.org/10.1136/bmj.f6153"},{"label":"Krynitz et al., risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008, Swedish population-based study of 10,476 recipients (Int J Cancer 2013)","url":"https://doi.org/10.1002/ijc.27765"},{"label":"Garrett et al., incidence of and risk factors for skin cancer in organ transplant recipients in the United States, 10,649 recipients (JAMA Dermatology 2017)","url":"https://doi.org/10.1001/jamadermatol.2016.4920"},{"label":"Morecroft et al., immunotherapy and radiation for clinical perineural invasion in cutaneous squamous cell carcinoma (Cancers 2025)","url":"https://doi.org/10.3390/cancers17243921"},{"label":"Van Coile et al., the impact of basal cell carcinoma on the quality of life in older patients, 400 patients scored on the BaSQoL questionnaire (Scientific Reports 2024)","url":"https://doi.org/10.1038/s41598-024-67740-0"},{"label":"Psychological symptoms, quality of life and resilience in patients with recurrent non-melanoma skin cancer, 160 patients after surgery for facial disease (Healthcare 2026)","url":"https://doi.org/10.3390/healthcare14172833"},{"label":"Cancer Research UK: types of non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/types"},{"label":"Cancer Research UK: about non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/about-skin-cancer"},{"label":"Cancer Research UK: stages and grades of non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/stages-grades"},{"label":"Cancer Research UK: survival for non-melanoma skin cancer (net survival for skin squamous cell carcinoma, England, first tumours diagnosed 2014 to 2016, from the NDRS Get Data Out programme)","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/survival"},{"label":"Cancer Research UK: non-melanoma skin cancer incidence statistics (UK)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/non-melanoma-skin-cancer/incidence"},{"label":"NHS: non-melanoma skin cancer, symptoms","url":"https://www.nhs.uk/conditions/non-melanoma-skin-cancer/symptoms/"},{"label":"Royal College of Pathologists G123: dataset for histopathological reporting of primary cutaneous basal cell carcinoma, version 4, February 2019 (Slater and Barrett)","url":"https://www.rcpath.org/resourceLibrary/g123-dataset-basal.html"},{"label":"Royal College of Pathologists G124: dataset for histopathological reporting of primary invasive cutaneous squamous cell carcinoma and regional lymph nodes, version 4, February 2019 (Slater and Barrett)","url":"https://www.rcpath.org/resourceLibrary/g124datasetsquamous-pdf.html"},{"label":"Royal College of Pathologists appendix A, version 3, 6 November 2025: UICC TNM 9 pathological staging of primary cutaneous carcinoma (basal cell), combining the UICC chapters for skin carcinoma of the head and neck and carcinoma of the skin","url":"https://www.rcpath.org/resourceLibrary/basal-cell-tnm9.html"},{"label":"Keohane, Proby, Newlands, Motley, Nasr and Mohd Mustapa, British Journal of Dermatology 2018;179:824 to 828: the new 8th edition of TNM staging and its implications for skin cancer, a review by the British Association of Dermatologists and the Royal College of Pathologists, UK","url":"https://doi.org/10.1111/bjd.16892"},{"label":"Venables et al., British Journal of Dermatology 2019;181(3):474 to 482: epidemiology of basal and cutaneous squamous cell carcinoma in the UK 2013 to 2015, a cohort study (the paper that introduced the first-per-person-per-annum count)","url":"https://doi.org/10.1111/bjd.17873"},{"label":"Kwiatkowska et al., Skin Health and Disease 2021;1(4):e61: an updated report on the incidence and epidemiological trends of keratinocyte cancers in the United Kingdom 2013 to 2018","url":"https://doi.org/10.1002/ski2.61"},{"label":"Mistry, Levell, Karponis, Wakkee, Whiteman, Proby and Venables, British Journal of Dermatology 2026: trends in keratinocyte cancers in England 2013 to 2022, basal cell carcinoma incidence, cutaneous squamous cell carcinoma incidence and non-melanoma skin cancer mortality","url":"https://doi.org/10.1093/bjd/ljag315"},{"label":"van Bodegraven et al., British Journal of Dermatology 2023;188(6):777 to 784: 'Get Data Out' Skin, national cancer registry incidence and survival rates for all registered skin tumour groups for 2013 to 2019 in England","url":"https://doi.org/10.1093/bjd/ljad033"},{"label":"Ahmed et al., British Journal of Dermatology 2026;194:273 to 282: ethnicity and the epidemiology of skin cancer incidence, a national retrospective population-based study in England, 2013 to 2020","url":"https://doi.org/10.1093/bjd/ljaf352"},{"label":"Office for National Statistics: cancer registration statistics quality and methodology information (the statement that non-melanoma skin cancer is greatly under-registered, and that all-cancer figures are ICD-10 C00 to C97 excluding C44), last revised 23 February 2016","url":"https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/methodologies/cancerregistrationstatisticsqmi"},{"label":"Philipp-Dormston et al., Acta Dermato-Venereologica 2024;104:adv40601: a European consensus on the consistent use of the term 'keratinocyte cancer'","url":"https://doi.org/10.2340/actadv.v104.40601"},{"label":"NICE NG12: suspected cancer, skin cancers (recommendations 1.7.1 to 1.7.7)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"},{"label":"NHS England: implementing a timed skin cancer diagnostic pathway","url":"https://www.england.nhs.uk/wp-content/uploads/2018/04/B1350_Skin-cancer-timed-diagnostic-pathway.pdf"},{"label":"NICE CSG8: improving outcomes for people with skin tumours including melanoma","url":"https://www.nice.org.uk/guidance/csg8"},{"label":"GIRFT dermatology national specialty report","url":"https://gettingitrightfirsttime.co.uk/wp-content/uploads/2021/09/DermatologyReport-Sept21o.pdf"},{"label":"NICE NG34: sunlight exposure, risks and benefits","url":"https://www.nice.org.uk/guidance/ng34/chapter/Recommendations"}],"tags":["umbrella"],"related":["melanoma","basal-cell-carcinoma","cutaneous-scc","merkel-cell-carcinoma","kaposi-sarcoma","uveal-melanoma","bowens-disease","dermatofibrosarcoma-protuberans","cutaneous-t-cell-lymphoma"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","dermoscopy-ai","psycho-oncology","peer-support-groups","survivorship-care-plan","multidisciplinary-tumour-board","chemoprevention","financial-navigation","cbt-fatigue-distress","palliative-care"],"targets":["braf","mek","pd1"],"drugs":["pembrolizumab","nivolumab","cemiplimab","dabrafenib","vismodegib"],"companies":[],"institutions":["melanoma-focus","skcin","british-association-of-dermatologists","guys-st-thomas","leeds-cancer-centre","newcastle-cancer-centre","addenbrookes-cambridge","birmingham-cancer-centre","velindre-cardiff"],"pathways":[],"terms":["mohs-surgery","wide-local-excision","perineural-invasion","late-effects","quality-of-life","curative-intent","field-cancerisation","keratinocyte-cancer","actinic-keratosis","keratinocyte-cancer-counting","bcc-growth-pattern","cscc-subtype-and-grade","tnm-skin-carcinoma","bwh-staging-cscc","skin-cancer-high-risk-features","keratoacanthoma","inherited-skin-cancer-syndromes","carcinoma-in-situ","resection-margins","surgical-margins-keratinocyte-cancer","curettage-and-cautery","topical-and-destructive-treatment-bcc","radiotherapy-for-skin-cancer","hedgehog-inhibitor-tolerability","skin-cancer-after-organ-transplant"],"trials":["mohs-versus-excision-facial-bcc","sins-trial","mal-pdt-imiquimod-fluorouracil-superficial-bcc","avril-surgery-versus-radiotherapy-bcc","trog-05-01","c-post","molemate","mcc-rational-treatment","impact-bcc","spot-it","scc-after"],"people":["hywel-williams","nick-levell"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Living with a keratinocyte skin cancer: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the number they gave you come first, and no figure on this page is a prediction about you. The five rows above, the question sets for diagnosis, the operation, Mohs, sun protection and immunosuppression, the first 60 days checklist and the red cards were written together on 25 September 2026 for the person who has just been told they have a basal cell or squamous cell carcinoma, which on the numbers is more people than any other cancer diagnosis.","On what is here and what is not. The decision about how a low-risk basal cell carcinoma is treated, with the comparative figures, is on the basal cell carcinoma page; which squamous cell carcinomas are dangerous, and the lymph nodes and perineural spread, are on the cutaneous squamous cell carcinoma page. This page carries only what is true of both and of the person rather than the tumour: the operation on the face, the Mohs day, the sun, the mind, and immunosuppression. Melanoma is a different disease with a different page and nothing here restates it; if the thing you are worried about is a changing mole, go there.","On the survival and recurrence figures used on the subtype pages. They come from the Cochrane review of 52 randomised trials in basal cell carcinoma, the UK SINS trial of 501 participants, a Dutch three-arm trial of 601 patients, a Dutch Mohs trial of 612 facial tumours followed for ten years, a prospective German cohort of 615 squamous cell carcinomas and a Boston cohort of 985 patients with 1,832 tumours. Each describes the people in it. None of them is a prediction about a particular reader, and the pages say so where the numbers appear.","On the word cured. The British Association of Dermatologists says basal cell carcinomas can almost always be cured and are almost never a danger to life, and that most squamous cell carcinomas are low-risk and can be cured. That is the honest headline and it is given first. The exactness comes after it: the thickness above which a squamous cell carcinoma starts to metastasise, the 2.1 percent of one cohort who died of it, the transplant recipient for whom this is a different disease, and the 44 percent chance of a second basal cell carcinoma within three years. A page that only reassured would be useless to the reader who needs it most.","On scars, which is the reason this layer exists in the form it does. A scar on a face is neither trivial nor a tragedy, almost no patient material says anything about it at all, and the concrete help that does exist (skin camouflage on prescription with self-referral, silicone gels from a pharmacist, and a GP referral for talking therapy if the scar is affecting your mental health) is buried in the NHS scars page rather than in anything a skin cancer patient is given.","Which page is mine? Start with three things you already know: where the lesion is, what it looks like, and what the biopsy said. The biopsy wins if you have it. If the report says basal cell carcinoma, or BCC, your page is basal cell carcinoma, and that covers about 75 in every 100 non-melanoma skin cancers. If it says squamous cell carcinoma, cutaneous squamous cell carcinoma, cSCC or keratinocyte carcinoma of squamous type, your page is cutaneous squamous cell carcinoma, about 25 in every 100 (Cancer Research UK's own sentence says 25 out of every 100 skin cancers, where its basal cell figure is 75 out of every 100 non-melanoma skin cancers). If it says in situ, intraepidermal, or Bowen's disease, your page is Bowen's disease, which is squamous cell carcinoma that has not broken out of the outer layer of skin. If it says melanoma, your page is melanoma, which is a different disease from a different cell and is not what the rest of this page is about. If it says Merkel cell carcinoma, that has its own page and is rare and serious. If it says actinic or solar keratosis, that is sun damage rather than cancer, and the glossary entry explains it.","Which page is mine, continued: if you have not had a biopsy yet. Where the mark is narrows it. Basal cell carcinoma and squamous cell carcinoma both occur mostly on skin that has had the most sun, the head, face, ears, neck, shoulders, back, hands and lower legs, and a squamous cell carcinoma can also arise in an old scar or burn. What it looks like narrows it further, with the strong caution that nobody, including a dermatologist, diagnoses skin cancer reliably by eye. A slow-growing smooth firm lump, a patch of scaly skin, or an area of shiny skin that looks like a scar suggests basal cell carcinoma. A pink or red scaly bump or patch that may be sore and may ulcerate, and that has grown over weeks rather than years, suggests squamous cell carcinoma. A red scaly patch on a lower leg that has been there for months or years and is slowly enlarging suggests Bowen's disease. A mole that has changed shape, colour or size, or a new dark mark, suggests melanoma. The NHS rule for going to a GP does not require you to decide which: a growth that is getting bigger or changing, or any area that hurts, itches, bleeds, crusts or scabs for more than 4 weeks, is the trigger.","Which page is mine, continued: the words that are not pages. A growth pattern is not a page. Nodular, superficial, morphoeic, sclerosing, micronodular, infiltrative and basosquamous are all descriptions of one disease, basal cell carcinoma, and they change the operation rather than the page; the glossary entry explains each. A grade is not a page: well, moderately and poorly differentiated describe a squamous cell carcinoma, not a different cancer. A stage is not a page either, and most people here are never given one. Low risk and high risk are not pages but they are the words that decide the most in Britain, and they have their own entry. Keratoacanthoma is a word for a way a squamous cell carcinoma can look. Non-melanoma skin cancer is a name for a group and is being replaced by keratinocyte cancer. And if you were told you have several lesions rather than one, that is usual in this family and does not mean the cancer has spread: it means the skin around them has been damaged too.","What skin cancer is. The outer layer of the skin, the epidermis, is built almost entirely of keratinocytes, which are made at its base and push upwards as they mature into the flat dead cells that form the surface. Scattered among them at the base are melanocytes, which make the pigment that colours skin and protects it from ultraviolet light, and Merkel cells, which are involved in touch. Each of those cells can become cancerous and each gives a different disease: basal cell carcinoma and squamous cell carcinoma from keratinocytes, melanoma from melanocytes, Merkel cell carcinoma from Merkel cells. Ultraviolet light from the sun and from sunbeds is the cause of almost all of it, which is why these cancers appear on the parts of the body that have had the most sun and why they become commoner with age. Because the epidermis has no blood or lymphatic vessels of its own, a cancer confined to it cannot spread anywhere, which is what the phrase in situ means and why it matters so much.","Why this family is counted worse than any other, and what to do about it when you read a number. Registries were designed for cancers a person gets once. These are cancers a person gets repeatedly, and in 1999 the UK and Ireland Association of Cancer Registries ruled that only the first basal cell carcinoma and the first squamous cell carcinoma in a lifetime would be registered. England now publishes on a first-per-person-per-year basis instead, which found 67 percent more basal cell carcinomas and 42 percent more squamous cell carcinomas over 2013 to 2022 and still undercounts. Scotland collects only the first basal cell carcinoma per person but registers every squamous cell carcinoma. Wales counts annually and on that basis non-melanoma skin cancer was 40 percent of all its cancer cases in 2020. And the headline total leaves the group out: the Office for National Statistics defines all cancers as ICD-10 C00 to C97 excluding C44, because non-melanoma skin cancer is, in its words, greatly under-registered. So the figure of just over 400,000 new cancers a year in the UK does not include roughly 156,000 counted non-melanoma skin cancers, which are themselves a floor. Every incidence figure on these pages links to the term that says this.","Which cancers of the skin are not in this family, and why. Kaposi sarcoma and dermatofibrosarcoma protuberans arise in the dermis from vessels and fibroblasts rather than from the epidermis, and they sit under sarcoma here; the cutaneous lymphomas are lymphomas that happen to live in the skin and sit under lymphoma. They are reached from this page through its links. The reason for keeping them where they are is the same reason mesothelioma is not a lung cancer: the classification, the treatment and the specialists all follow the cell of origin, not the address. The one place this family does follow the address is the organ drawing, which shows every cancer of the skin together because a drawing is anatomy, not taxonomy.","Is it cancer if it cannot spread? This question comes up three times in this family and gets three different answers, which is why the boundary is drawn explicitly here. An actinic keratosis is sun-damaged skin: not a neoplasm in ICD-10, not registered as cancer anywhere in the UK, and a glossary term here. Bowen's disease is squamous cell carcinoma in situ: a carcinoma, coded in the neoplasm chapter as D04, staged pTis, with a national guideline of its own, and a page here. A basal cell carcinoma is an invasive cancer that virtually never metastasises, and the UK reporting dataset notes that there is not even consensus on whether the superficial pattern is in situ or invasive, which is why that dataset avoids the phrase invasive basal cell carcinoma in its own title. Biology does not supply a clean line and neither does the word cancer; what supplies a usable line is the coding boundary, and that is what the corpus uses.","How common it is, with its caveat attached. Around 156,000 new non-melanoma skin cancers are recorded a year in the UK, against 403,601 of all other cancers combined and around 19,400 melanomas, and 48 percent of the non-melanoma cases are in people aged 75 and over (Cancer Research UK). On the annual counting method, the research estimate is 234,861 a year across the UK for 2016 to 2018, 184,280 basal cell and 50,582 squamous cell carcinomas, and about one person in five in England will develop at least one of these cancers at some point, roughly one in four men and one in six women (Kwiatkowska 2021). Rates have risen by 169 percent in the UK since the early 1990s, partly disease and partly counting. In England 1,445,377 skin cancers were registered across 2013 to 2019 (van Bodegraven 2023)."],"group":"skin","burden":"The commonest cancer worldwide: about 1.2 million non-melanoma skin cancers and 325,000 melanomas recorded in 2020 (GLOBOCAN), with non-melanoma cases badly under-counted because many registries do not record them.","subtypes":["Keratinocyte cancers, from the cells that make up most of the epidermis: basal cell carcinoma (about 75 out of every 100 non-melanoma skin cancers) and cutaneous squamous cell carcinoma (about 25 out of every 100, which Cancer Research UK writes against skin cancers rather than non-melanoma skin cancers)","Bowen's disease, squamous cell carcinoma in situ, which is a carcinoma confined to the epidermis and has its own page","Melanoma, from melanocytes, which is a different disease with its own pages and its own subtypes","Rare skin cancers: Merkel cell carcinoma, the adnexal carcinomas, extramammary Paget disease, and the skin cancers that are not epithelial at all, Kaposi sarcoma, dermatofibrosarcoma protuberans and the cutaneous lymphomas","Actinic keratosis, which is sun damage rather than cancer and is a glossary term here, not a page"],"biomarkers":["Dermoscopy and biopsy for diagnosis","PD-L1 and tumour mutational burden as imperfect immunotherapy markers","Merkel cell polyomavirus status","The histological type on the biopsy report, which is what chooses a page: basal cell, squamous cell, in situ, melanoma or something rarer","For basal cell carcinoma, the growth pattern: nodular, superficial and fibroepithelial are low risk, infiltrating, sclerosing or morphoeic and micronodular are high risk, and basosquamous differentiation is high risk (RCPath G123)","For squamous cell carcinoma, the grade (well, moderately or poorly differentiated) and the subtype (acantholytic, desmoplastic, spindle cell and adenosquamous are high risk) (RCPath G124)","Margins: involved at 0 mm, or clear but under 1 mm, are both defined high-risk features in the UK datasets","Perineural and lymphovascular invasion, depth, and level of invasion relative to the subcutaneous fat","For melanoma, Breslow thickness, ulceration, sentinel node status and BRAF V600 status, which are on the melanoma pages"],"standardOfCare":[{"setting":"Surgery on the face: grafts, flaps, and what the scar does in the first year","approach":"Start with the reassurance, because it is true: the British Association of Dermatologists says basal cell carcinomas can almost always be cured and very rarely spread, and that most squamous cell carcinomas are low-risk skin cancers and can be cured. What frightens people is not the cancer, it is the operation, and almost nothing is written about it. There are four ways a wound on the face is closed and it is worth knowing which is yours before the day. Stitches, if the edges will meet. A skin graft, a thin sheet taken from a donor site (Cancer Research UK says usually somewhere not too obvious such as the inner thigh) and laid over the defect, which means a second wound where it came from; a shaved donor site heals by itself, a cut one is stitched. A skin flap, skin from immediately beside the wound moved across while still attached to its own blood supply, which is why the colour and texture usually match better; only specially trained dermatologists or plastic surgeons do them and more than one operation is sometimes needed. And fourth, the one people are least often warned about, leaving the wound open under a dressing to heal on its own over several weeks and up to two months, which is a recognised choice and not a failure. Near the eyelid, the nose, the ear and the lip the reconstruction is often handed to a different team, and the BAD names maxillofacial, oculoplastic and plastic surgeons as the ones who may repair a Mohs wound, so who removes the cancer and who closes the wound are two separate questions. Afterwards: Cancer Research UK says the scar is quite noticeable and red to start with and gets paler over time, that some are thick and raised, and that numbness, tingling and pain in the area are nerve injury and may improve with time. The NHS says most scars fade but that this can take up to two years or more, and that massage with a water-based cream, keeping the scar covered in the sun for at least a year and SPF 30 or more all help. One small thing nobody mentions: after a local anaesthetic to the middle or lower face you cannot feel anything until it wears off, so avoid hot food and drink because of the risk of burns.","refs":["skin-graft-and-flap-reconstruction","facial-scar-after-skin-cancer","mohs-surgery","wide-local-excision","curettage-and-cautery","late-effects"],"guideline":{"version":"Cancer Research UK patient information: types of surgery for non-melanoma skin cancer (reviewed May 2026), with the British Association of Dermatologists and British Society for Dermatological Surgery Mohs leaflet (updated June 2025) and the NHS page on scars (reviewed September 2023)","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/treatment/surgery/treatment-surgery-types"}},{"setting":"Mohs surgery as a day, not as a technique","approach":"Mohs is described everywhere as a technique and almost nowhere as a day, which is the thing you have to get through. The British Association of Dermatologists leaflet describes it honestly. You arrive as for any appointment and are taken to a surgical suite. The surgeon marks and photographs the lesion, injects local anaesthetic (it stings for less than 30 seconds), removes the tumour with a rim of normal-looking skin, dresses the wound and sends you to a recovery bay. Your sample goes to the laboratory and is read under a microscope while you wait; the leaflet says it can take up to three hours to get the result. If any cancer remains, more anaesthetic is injected and another layer is taken, and the clock restarts. In 90 percent of cases the cancer has gone after one or two stages, but you could be in hospital for up to a day, and the leaflet says in its own words that more than one set of injections is often needed and that it can be a long and tiring day. You do not know at the start how much will come out or how big the wound will be, which is the part people find hardest, and the wound is only closed once the surgeon is satisfied. The drawbacks the BAD names itself are worth hearing: waiting lists are usually longer than for standard excision because fewer cases fit in a day, so the cancer could grow while you wait; it takes half a day on average against minutes for a standard excision; and not all skin cancers should be removed this way. What it buys: in the Dutch randomised trial of high-risk facial basal cell carcinoma, ten-year recurrence was 4.4 percent after Mohs against 12.2 percent after excision for primary tumours (not statistically significant) and 3.9 percent against 13.5 percent for recurrent ones (significant). Practical matters the leaflet is specific about: someone must drive you there and back, public transport is not advised afterwards, you can eat and drink, and bring something to do.","refs":["mohs-surgery","skin-graft-and-flap-reconstruction","wide-local-excision","curative-intent","multidisciplinary-tumour-board"],"guideline":{"version":"British Association of Dermatologists and British Society for Dermatological Surgery patient information: Mohs micrographic surgery (produced March 2013, updated June 2025), with the 10-year randomised trial of Mohs against surgical excision for facial basal cell carcinoma","url":"https://www.skinhealthinfo.org.uk/condition/mohs-micrographic-surgery/"}},{"setting":"Sun protection after a diagnosis, for someone who still goes outside","approach":"Written as a list a real person can follow rather than as a warning. Cancer Research UK's version for someone who has had one of these cancers is: close-weave cotton clothing, long sleeves and trousers; a wide-brimmed hat that shades the face and neck; sunglasses with 100 percent UV protection; shade between 11am and 3pm in the UK; never a sunbed; and sunscreen of at least SPF 30 with four or five UVA stars, used generously, reapplied regularly, alongside the shade and the clothing rather than instead of them, even on a cloudy day. A specialist may suggest SPF 50 on exposed skin. The BAD adds the timing that makes the difference: apply plenty 15 to 30 minutes before going out and reapply every two hours and straight after swimming and towel-drying. NICE NG34 (1.1.1) names the groups public health activity should focus on and a reader of this page is in at least one of them: a personal or family history of skin cancer, immunosuppression, a tendency to burn rather than tan, outdoor work or outdoor hobbies. Two things are usually left out. The first is vitamin D: Cancer Research UK says covering up reduces it, and that the Scientific Advisory Committee on Nutrition recommends a 10 microgram daily supplement between October and March, and all year for people who are mostly indoors or who cover up outdoors, so ask rather than guess. The second is that none of this is retrospective. The damage that caused this cancer was done years ago and cannot be undone by anything you do now; what sun protection changes is the chance of the next one, which in a meta-analysis of 17 studies ran at 44 percent within three years of a first basal cell carcinoma. That is a figure for a group of people, not a prediction for you.","refs":["sun-protection-after-skin-cancer","second-primary-skin-cancer","skin-cancer-after-organ-transplant","chemoprevention","field-cancerisation"],"guideline":{"version":"NICE NG34 (2016) with Cancer Research UK and British Association of Dermatologists patient information","url":"https://www.nice.org.uk/guidance/ng34/chapter/Recommendations"}},{"setting":"The part nobody counts: a face you did not choose, and the fear of the next mark","approach":"Three things happen at once and only one of them is ever discussed. The first is the face. The BAD says larger basal cell carcinomas may leave larger scars after surgery which may cause concern, especially on prominent areas such as the face, and that is as close as most patient material comes to naming it. The practical answers exist and are underused: the NHS says a GP can refer you for skin camouflage or you can refer yourself online, that a trained professional colour-matches creams and powders to your skin, that they can be prescribed, and that a GP can refer you for talking therapy if a scar is affecting your mental health. Changing Faces is the UK charity for visible difference. The second is watchfulness. Once you have had one of these cancers, you are being asked to examine your own skin monthly, which means every new mark is now a question rather than a mark; in a study of 160 people after surgery for facial non-melanoma skin cancer, those with recurrent disease had a higher adjusted symptom severity score and poorer psychological quality of life than those treated once. The third is the one people find hardest to say out loud, that everyone around them has decided this does not count. It is not baseless: Cancer Research UK's own coping page says nearly everyone diagnosed with skin cancer can have a simple treatment that will cure the cancer, and that is true and is also the sentence people hear instead of sympathy. In the study of 400 patients scored on the disease-specific BaSQoL questionnaire, the mean subscores were 1.20 for the 'other people' domain, 1.01 for diagnosis and treatment, 0.90 for worries, 0.78 for behaviour and 0.40 for appearance; the overall impact was low to moderate and the highest-scoring domain was not the one about how you look. Both things can be true. It is the cancer most likely to be cured, and it is still a cancer, and being told how lucky you are is not the same as being listened to.","refs":["facial-scar-after-skin-cancer","second-primary-skin-cancer","psycho-oncology","peer-support-groups","quality-of-life","cbt-fatigue-distress","survivorship-care-plan"],"guideline":{"version":"NHS patient information: scars (reviewed September 2023), with Cancer Research UK on coping with non-melanoma skin cancer and two quality-of-life cohorts in keratinocyte cancer","url":"https://www.nhs.uk/conditions/scars/"}},{"setting":"If your immune system is suppressed, this is a different disease","approach":"If you take drugs that suppress your immune system, and above all if you have had an organ transplant, almost every sentence on this page is more serious for you and the leaflets addressed to you are rarely the ones you are handed. The scale, from the joint leaflet of the British Association of Dermatologists and the British Society for Skin Care in Immunosuppressed Individuals: squamous cell carcinoma is 150 times more common in transplant recipients than in the general population and is the commonest skin cancer in this group, basal cell carcinoma is up to 10 times more common, a UK study found one in three people transplanted for more than 10 years had developed a skin cancer, by about 20 years roughly half will have had one, and two in three of those who have had one go on to have several. The population studies agree: in 10,476 Swedish recipients the standardised incidence ratio for squamous cell carcinoma was 121 and 198 for heart and lung recipients, and in a prospective study of 615 squamous cell carcinomas immunosuppression was an independent predictor of metastasis with a hazard ratio of 4.32. Four things follow. What counts as suspicious is different: pain in a growing skin lump is specifically flagged, and any new, painful, bleeding or non-healing mark goes to a doctor rather than to a wait-and-see. Sun protection is stricter: SPF 50 with five UVA stars, daily, all year, to all exposed skin including a balding scalp and the ears, and it applies to people with brown and black skin on immunosuppressants where routine sun protection would otherwise rarely be needed in the UK. Surveillance is individual: ask your team for the frequency and setting of your in-clinic skin checks rather than assuming there is a standard. And the immunosuppression itself is on the table: where someone has multiple or more serious skin cancers, the dermatologist may discuss with the transplant physicians whether reducing or switching it would reduce future cancers, and preventive acitretin or nicotinamide may be added. None of that is a decision to make on your own, and none of it should be a surprise.","refs":["skin-cancer-after-organ-transplant","second-primary-skin-cancer","sun-protection-after-skin-cancer","chemoprevention","field-cancerisation","multidisciplinary-tumour-board"],"guideline":{"version":"British Association of Dermatologists and the British Society for Skin Care in Immunosuppressed Individuals patient information: skin cancer advice for organ transplant recipients (June 2024), with the Swedish population-based cohort of 10,476 transplant recipients","url":"https://www.skinhealthinfo.org.uk/condition/skin-cancer-in-organ-transplant-recipients/"}},{"setting":"The operation, and the rim of skin around it","approach":"Excision with a measured margin of normal-looking skin, under local anaesthetic, in a few minutes. The standard margin is 4 mm, and it is not a convention: for basal cell carcinomas under 2 cm, marking the skin in 2 mm increments before Mohs surgery showed that 4 mm cleared more than 95 per cent of tumours, and the same method in cutaneous squamous cell carcinoma gave 4 mm for ordinary tumours and at least 6 mm for high-risk ones, meaning 2 cm or larger, grade 2 or higher, invading the fat, or in a high-risk site. Two practical corrections matter: a specimen shrinks between the skin and the pathologist's ruler, by 70 to 80 per cent of the measured width in one series, and dermoscopy moves the visible edge outwards in about one tumour in six. Cure is high and the cancer is almost always gone for good.","refs":["surgical-margins-keratinocyte-cancer","resection-margins","mohs-surgery","dermoscopy-ai"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Basal Cell Skin Cancer and Squamous Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}},{"setting":"When the excision is incomplete","approach":"Tumour at the inked edge means the operation did not clear it. It happens in roughly 3 to 15 per cent of excisions depending on the site and the series, most often on the nose, in infiltrative, morphoeic, micronodular and superficial multifocal subtypes, and where invasion goes below the dermis. What follows is a judgement: re-excision or Mohs surgery for aggressive subtypes, central facial sites and any squamous cell carcinoma, radiotherapy where further surgery is not possible, and observation where a frail person has a low-risk basal cell carcinoma at a low-risk site. In one series of 23 incompletely excised facial basal cell carcinomas, six recurred and all six were superficial multifocal, infiltrative or micronodular.","refs":["surgical-margins-keratinocyte-cancer","mohs-surgery","radiotherapy-for-skin-cancer"],"guideline":{"version":"Long-term follow-up of positive margins in facial basal cell carcinoma (Dermatologic Surgery 2015)","url":"https://doi.org/10.1097/DSS.0000000000000394"}},{"setting":"Mohs micrographic surgery, and when it is worth it","approach":"The tumour is removed in thin layers, each mapped and checked under the microscope while the patient waits, until every edge is clear. Because the whole margin is examined rather than a few slices of it, it clears more tumour with less normal skin, which is why it is used on the face and on aggressive subtypes. The evidence is one randomised trial, in 612 high-risk facial basal cell carcinomas in the Netherlands. For tumours that had already recurred it is clearly better: ten-year recurrence 3.9 against 13.5 per cent (p=0.023). For tumours being treated for the first time the difference never reached significance, 4.4 against 12.2 per cent at ten years (p=0.100), and at five years it was 2.5 against 4.1 per cent. The finding that should change practice is that 56 per cent of the primary-tumour recurrences happened after year five, which is why the five-year papers in this disease understate the problem. Mohs surgery cost 1,248 euros against 990 for ordinary excision.","refs":["mohs-versus-excision-facial-bcc","mohs-surgery","surgical-margins-keratinocyte-cancer"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}},{"setting":"Curettage and cautery","approach":"Scraping the tumour out with a curette and burning the base, in minutes, with no specimen to check. For the right tumour it is reasonable and it is how a large share of low-risk basal cell carcinomas are treated worldwide. The Danish Skin Cancer Registry followed 47,358 tumours treated this way in office dermatology and found five-year recurrence of 9.9 per cent and eight-year recurrence of 13.3 per cent, dominated by selection: 25.1 per cent at eight years for head and neck tumours, 16.7 per cent for tumours over 10 mm and 8.4 per cent for superficial ones. Used on aggressive histological subtypes it fails, with 27 per cent recurrence at a median 6.5 years in one series of 37 tumours, which is an argument for a biopsy first in anything not obviously superficial.","refs":["curettage-and-cautery","surgical-margins-keratinocyte-cancer"],"guideline":{"nccn":"Category 2A for low-risk tumours","version":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}},{"setting":"Radiotherapy, and who it suits","approach":"Radiotherapy cures most skin cancers without an operation and is chosen for the person rather than the tumour: someone in whom surgery would cost an eyelid, a nostril or a lip, someone too frail or unwell for an operation, someone who refuses one, and after an incomplete excision that cannot be re-operated. It is second and not first because of the only randomised comparison ever run, in 347 patients with facial basal cell carcinoma, where the four-year failure rate was 0.7 per cent after surgery against 7.5 per cent after radiotherapy (p=0.003) and the cosmetic result was better after surgery on four of five independent judgements. Irradiated skin does not improve with time as a scar does. The techniques in that trial are not today's, so the gap is probably narrower now, but no one has repeated it.","refs":["radiotherapy-for-skin-cancer","avril-surgery-versus-radiotherapy-bcc","brachytherapy","electron-beam-therapy-systems"],"guideline":{"nccn":"Category 2A when surgery is not suitable","version":"NCCN Guidelines: Basal Cell Skin Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1416"}},{"setting":"What is different about melanoma","approach":"Everything above is the treatment of the keratinocyte cancers, basal cell and squamous cell carcinoma, which is what most people who are told they have skin cancer have. Melanoma is treated by a different logic: the margin is set by the thickness of the tumour rather than by a fixed 4 mm, the lymph nodes are staged with a sentinel node biopsy, and advanced disease is treated with checkpoint immunotherapy or with BRAF and MEK inhibitors. Creams, curettage and photodynamic therapy have no role in invasive melanoma. The melanoma page carries all of it and this page does not repeat it.","refs":["melanoma","sentinel-lymph-node-biopsy","checkpoint-inhibitor"],"guideline":{"nccn":"See the melanoma guideline","version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}}],"stateOfArt":["The operation has barely changed and is still overwhelmingly the right answer. A 4 mm margin, chosen in 1987 and 1992 by measuring how far tumours actually reach beyond their visible edge, clears more than 95 per cent of basal cell carcinomas under 2 cm and most squamous cell carcinomas, and every alternative that has been randomised against it has lost on cure rate and won on appearance.","Mohs micrographic surgery has exactly one randomised trial behind it, in 612 high-risk facial basal cell carcinomas. It is clearly better for tumours that have already recurred and not significantly better for primary ones, and the ten-year report showed that 56 per cent of the primary-tumour recurrences had not yet happened at five years, which is a warning about every five-year paper in this disease.","The non-surgical options are now ranked rather than assumed. Photodynamic therapy was the treatment of choice for superficial basal cell carcinoma until a 601-patient trial put it last of three, behind imiquimod and fluorouracil, at both one and five years, and found it the most expensive of the three as well."],"history":[{"year":1987,"title":"The 4 mm margin is measured rather than agreed","note":"117 basal cell carcinomas marked in 2 mm increments before Mohs surgery showed that 4 mm clears more than 95 per cent of tumours under 2 cm; the 1992 companion study did the same for squamous cell carcinoma and gave 4 mm, or at least 6 mm for high-risk tumours.","refs":["surgical-margins-keratinocyte-cancer"]},{"year":1997,"title":"Surgery beats radiotherapy for facial basal cell carcinoma","note":"347 patients randomised at the Institut Gustave Roussy: four-year failure 0.7 against 7.5 per cent and a better cosmetic result after surgery on four of five independent judgements. The comparison has never been repeated.","refs":["avril-surgery-versus-radiotherapy-bcc"]},{"year":2008,"title":"The only randomised trial of Mohs surgery reports at five years","note":"Mohs surgery better for recurrent facial basal cell carcinoma (2.4 against 12.1 per cent) and not significantly better for primary tumours; the ten-year report in 2014 found 4.4 against 12.2 per cent for primary tumours with 56 per cent of recurrences after year five.","refs":["mohs-versus-excision-facial-bcc"]},{"year":2011,"title":"Ipilimumab and vemurafenib approved for advanced melanoma","note":"The first checkpoint inhibitor and the first BRAF inhibitor, the two routes that transformed melanoma.","refs":["ipilimumab","vemurafenib"]},{"year":2012,"title":"Vismodegib approved for advanced basal cell carcinoma","note":"First hedgehog pathway inhibitor.","refs":["vismodegib"]},{"year":2014,"title":"PD-1 blockade approved in melanoma","note":"Pembrolizumab and nivolumab approved for advanced melanoma, later moving to adjuvant and neoadjuvant use.","refs":["pembrolizumab","nivolumab"]},{"year":2014,"title":"SINS: the cream is inferior to the operation, and stays inferior","note":"501 people randomised in the United Kingdom; clinical success at three years 84 against 98 per cent and at five years 82.5 against 97.7 per cent.","refs":["sins-trial"]},{"year":2018,"title":"Photodynamic therapy loses its place at the front","note":"Five-year results of the 601-patient Dutch trial: tumour-free survival 80.5 per cent with imiquimod, 70.0 with fluorouracil and 62.7 with methyl aminolevulinate photodynamic therapy.","refs":["mal-pdt-imiquimod-fluorouracil-superficial-bcc"]},{"year":2025,"title":"C-POST: the first drug shown to stop high-risk skin squamous cancer coming back","note":"415 patients randomised after surgery and radiotherapy; 24-month disease-free survival 87.1 against 64.1 per cent with adjuvant cemiplimab.","refs":["c-post"]}],"pipeline":["fianlimab","lifileucel"],"openProblems":["Melanoma incidence continues to rise in fair-skinned populations.","The commonest cancer in the world is the one nobody can count. UK registries long recorded only the first basal cell carcinoma and the first squamous cell carcinoma in a person's lifetime; counting one of each per person per year instead finds 67 percent more basal cell carcinomas and 42 percent more squamous cell carcinomas, and still misses about 14 basal cell carcinomas per 100 patients. The Office for National Statistics leaves the whole group out of the national cancer total on the stated ground that it is greatly under-registered. Services are planned on the number that is published.","Incidence and mortality are moving in opposite directions to the reassurance. Basal cell carcinoma rates in England stabilised after 2015, but squamous cell carcinoma rates went on rising, and non-melanoma skin cancer mortality rose about 4 percent a year from 2013, twice as fast in men. A group of cancers officially too trivial for the national total is killing more people each year.","The pathology report cannot see half of what decides the risk. The UK datasets list the pathological high-risk features and then say in terms that a low-risk tumour on histology may be upgraded once the clinician adds site, recurrence, immunosuppression and growth rate, and that risk stratification is better done by a clinician or a multidisciplinary team than recorded in the report. The joint audit found risk status was one of the most frequently omitted items in skin cancer reports.","Squamous cell carcinoma has two staging systems that disagree about who is high risk, and the disagreement is unresolved in guidelines. The anatomical systems put almost everyone in one or two categories; the alternative built to fix that has been validated only in single-centre cohorts, and the Royal College of Pathologists has published its objection to the risk bands derived from it. Meanwhile the decision those systems exist to inform, who needs nodal staging or adjuvant treatment, is being made anyway.","Skin cancer statistics are almost entirely about white skin, and the gap is visible in the data. Incidence rates in England are 26 to 27 times higher for basal cell carcinoma and 13 to 14 times higher for squamous cell carcinoma in the White ethnic group than in the Asian or Black groups, ethnicity is unknown for 19.2 percent of registered basal cell carcinomas, and acral melanoma, which is commonest in the Black ethnic group, is less likely to be referred on the urgent suspected cancer pathway and more likely to present late (Ahmed 2026).","The commonest cancer operation on earth rests on two observational margin studies from 1987 and 1992 and one randomised trial of Mohs surgery from the Netherlands. Nothing of that size has been attempted since, and the reason is that a cancer nobody dies of attracts no trial funding.","Five years is the wrong follow-up for basal cell carcinoma and the whole literature uses it. In the only long trial, 56 per cent of the recurrences after primary tumour treatment happened after year five, which means every five-year cure rate quoted for a cream, for light or for curettage is an overestimate of unknown size.","Curettage and cautery treats a large share of the world's basal cell carcinomas and has never been randomised against anything. Its evidence is a Danish registry of 47,358 tumours, which cannot separate the treatment from the choice of tumour.","Appearance is the outcome patients choose on and it is measured worse than recurrence is. Photographic and observer scales differ between trials, patient and doctor ratings disagree by 20 to 40 percentage points in the same cohort, and no trial has asked what trade in cure rate a person would actually accept."],"basics":{"symptoms":["The main symptom of non-melanoma skin cancer is a growth or an unusual patch on the skin (NHS)","Any part of the skin can be affected, but it is most common in areas exposed to the sun: the head, face and ears, the neck and shoulders, the back, the hands and the lower legs (NHS)","The growths or patches vary in colour, size and texture. They may be raised and smooth with clear edges, bumpier, rough or crusty, or a flat discoloured patch; they can be purple, brown or red, and they may look darker on brown or black skin (NHS)","A basal cell carcinoma is usually slow growing and may be a smooth firm lump, a patch of scaly skin, or an area of shiny skin that looks like a scar; on darker skin tones it may look like a dark growth resembling a mole (Cancer Research UK)","A squamous cell carcinoma may be a pink or red scaly bump or patch that can be sore or painless and may ulcerate in the middle; on darker skin it may look crusty, scaly or like a dark nodule. It can grow slowly or quickly (Cancer Research UK)","Bowen's disease usually looks like a red scaly patch, often on a lower leg, that slowly enlarges and may crust or ulcerate (Cancer Research UK)","See a GP if you have a growth on your skin that is getting bigger or has changed colour or texture, or a growth or area of skin that hurts, itches, bleeds, crusts or scabs for more than 4 weeks (NHS)"],"diagnosis":["The diagnosis is made on a biopsy. Everything on this page and its subtype pages is decided by what the pathologist reports, not by what the lesion looked like","The report gives the type, and for basal cell carcinoma the growth pattern, and for squamous cell carcinoma the subtype and grade; then the depth, the level of invasion, whether nerves or vessels are involved, and the margins (RCPath G123 and G124)","When a biopsy is taken only to establish a diagnosis, such as a punch or incisional biopsy, the report can be limited to the diagnosis and the indicators of high risk; a full dataset is completed when the procedure was done with therapeutic intent (RCPath G123)","Frozen sections in skin cancer are for Mohs micrographic surgery, where horizontal sections assess the whole margin; vertical frozen sections should not be used for margins because they are insufficiently representative (RCPath G123)","Low-risk basal cell carcinomas can be treated in primary care by appropriately trained and accredited practitioners; everything else is treated in secondary care, and high-risk tumours with involved margins, people needing Mohs surgery and immunocompromised people go to the skin cancer multidisciplinary team (RCPath G123)"],"staging":["Most skin cancer is never given a stage. Cancer Research UK states that most basal cell carcinomas do not need staging because it is very rare for them to spread, and that staging is more likely with a squamous cell carcinoma because those can spread, although that is still rare","UK reports that do stage a skin carcinoma use the UICC system, not the American AJCC one. The Royal College of Pathologists assessed both and chose UICC, noting that UICC TNM is the version favoured by NCRAS in the UK and that the decision rested on the staging of non-melanoma skin cancer (RCPath G123)","The systems differ in coverage. AJCC 8 covers cutaneous carcinoma of the head and neck only and has no staging system for squamous cell carcinoma on the rest of the body; UICC has a head-and-neck chapter and a separate carcinoma-of-the-skin chapter for trunk and limbs, and both include basal cell carcinoma","UICC TNM 9, in force in the UK from the appendix dated 6 November 2025: pTis carcinoma in situ; pT1 20 mm or less; pT2 over 20 up to 40 mm; pT3 over 40 mm, or minor bone erosion, or perineural invasion, or deep invasion; pT4a gross cortical or marrow invasion; pT4b axial skeleton invasion. Stage 0 is Tis, I is T1N0, II is T2N0, III is T3N0 or N1, IV is anything beyond","Deep invasion means beyond the subcutaneous fat, or more than 6 mm from the granular layer of adjacent normal epidermis to the base of the tumour. Perineural invasion means tumour in the sheath of a nerve deeper than the dermis, or 0.1 mm or more in calibre, or five or more nerves in a section","In Britain the words that actually decide care are low risk and high risk, not a stage number, and the feature lists are short and published (see `skin-cancer-high-risk-features`)","Squamous cell carcinoma has a second, competing system, the Brigham and Women's Hospital classification, which counts four risk factors rather than measuring the tumour. It is not used in UK reports and the Royal College of Pathologists has published its disagreement with the risk bands built on it, but its evidence is why everyone accepts that the anatomical stage alone does not identify the dangerous tumours (see `bwh-staging-cscc`)","Melanoma is staged differently again, on Breslow thickness, ulceration and sentinel node status, and that is on the melanoma pages"],"sources":[{"label":"NHS: non-melanoma skin cancer, symptoms","url":"https://www.nhs.uk/conditions/non-melanoma-skin-cancer/symptoms/"},{"label":"Cancer Research UK: types of non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/types"},{"label":"Cancer Research UK: stages and grades of non-melanoma skin cancer","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/stages-grades"},{"label":"Royal College of Pathologists G123: dataset for histopathological reporting of primary cutaneous basal cell carcinoma, version 4, February 2019 (Slater and Barrett)","url":"https://www.rcpath.org/resourceLibrary/g123-dataset-basal.html"},{"label":"Royal College of Pathologists G124: dataset for histopathological reporting of primary invasive cutaneous squamous cell carcinoma and regional lymph nodes, version 4, February 2019 (Slater and Barrett)","url":"https://www.rcpath.org/resourceLibrary/g124datasetsquamous-pdf.html"},{"label":"Royal College of Pathologists appendix A, version 3, 6 November 2025: UICC TNM 9 pathological staging of primary cutaneous carcinoma (basal cell), combining the UICC chapters for skin carcinoma of the head and neck and carcinoma of the skin","url":"https://www.rcpath.org/resourceLibrary/basal-cell-tnm9.html"}]},"prognosis":{"text":"Almost all skin cancer is cured, and the exceptions are worth being exact about. Cancer Research UK says doctors can almost always cure basal cell carcinomas, that it is extremely rare for one to spread, and that people almost never die from this type of cancer, although in a small number the cancer comes back in the skin and needs further treatment. For squamous cell carcinoma there are no UK-wide survival statistics; for England, among people diagnosed with their first squamous cell carcinoma between 2014 and 2016, excluding tumours starting in the genitals, 90 out of 100 survived their cancer for 5 years or more. Melanoma and Merkel cell carcinoma are the two in this family that kill most often and have their own pages. Against all of that sits a fact that should temper any reassurance: deaths recorded as non-melanoma skin cancer in England have been rising by about 4 percent a year since 2013, roughly twice as fast in men as in women. These are averages over everybody diagnosed in a period, they are counted on a rule that records only some of the tumours people actually have, and they are not a personal prognosis. What moves the outlook for an individual is the type, the size, how deep it is, where it is on the body, how fast it grew, and whether their immune system is working, which is why a transplant recipient with a squamous cell carcinoma is in a different situation from a retired gardener with one.","sources":[{"label":"Cancer Research UK: survival for non-melanoma skin cancer (net survival for skin squamous cell carcinoma, England, first tumours diagnosed 2014 to 2016, from the NDRS Get Data Out programme)","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/survival"},{"label":"Mistry, Levell, Karponis, Wakkee, Whiteman, Proby and Venables, British Journal of Dermatology 2026: trends in keratinocyte cancers in England 2013 to 2022, basal cell carcinoma incidence, cutaneous squamous cell carcinoma incidence and non-melanoma skin cancer mortality","url":"https://doi.org/10.1093/bjd/ljag315"},{"label":"Cancer Research UK: basal cell carcinoma","url":"https://www.cancerresearchuk.org/about-cancer/skin-cancer/types/basal-cell-carcinoma"},{"label":"Venables et al., British Journal of Dermatology 2019;181(3):474 to 482: epidemiology of basal and cutaneous squamous cell carcinoma in the UK 2013 to 2015, a cohort study (the paper that introduced the first-per-person-per-annum count)","url":"https://doi.org/10.1111/bjd.17873"}]}},{"id":"cervical-small-cell-neuroendocrine-carcinoma","kind":"cancer","name":"Small cell neuroendocrine carcinoma of the cervix","aka":["Small cell carcinoma of the cervix","Neuroendocrine carcinoma","Neuroendocrine carcinoma (rare; SCLC-like)","Small cell neuroendocrine carcinoma of the cervix","SCCC"],"tldr":"Small cell neuroendocrine carcinoma of the cervix is a rare, aggressive cervical cancer that behaves like small cell lung cancer, spreading early to nodes and distant organs even when the tumour is small. Fewer than four in ten women with early disease are alive at five years, and treatment combines the cervical cancer approach with the chemotherapy used for small cell lung cancer.","summary":"The WHO classification of female genital tumours lists small cell neuroendocrine carcinoma among the neuroendocrine carcinomas of the cervix, HPV-associated in most cases (usually HPV18). The Gynecologic Cancer InterGroup consensus review describes it as a rare histological entity with a poor outcome because of the high incidence of nodal or distant metastasis even in early stage, and reviews epidemiology, pathology and initial treatment (GCIG 2014). In 188 patients (136 from the literature and 52 from four hospitals), 135 had stage I to IIA, 45 stage IIB to IVA and 8 stage IVB disease; 55.3 percent had surgery, 16.0 percent chemoradiation, 12.8 percent radiation and 3.2 percent chemotherapy alone; five-year disease-specific survival was 36.8 percent for stage I to IIA, 9.8 percent for IIB to IVA and 0 percent for IVB, and adjuvant chemotherapy or chemoradiation was associated with higher survival (Am J Obstet Gynecol 2010).\n\nHow it differs from its parent: it is the cervical cancer in which systemic chemotherapy is part of treatment at every stage, in which brain imaging and prophylaxis are considered, and in which surgery alone is never enough.\n\nHow common: no registry share in the sources read; rare.\n\nTreatment: radical hysterectomy or chemoradiation according to stage, always with platinum and etoposide chemotherapy as for small cell lung cancer; checkpoint inhibitors with chemotherapy are used by analogy with extensive-stage small cell lung cancer, following the extrapulmonary neuroendocrine carcinoma page (GCIG 2014; Am J Obstet Gynecol 2010).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Cervical_cancer","links":[{"label":"NCI PDQ: cervical cancer treatment","url":"https://www.cancer.gov/types/cervical/treatment"},{"label":"Am J Obstet Gynecol 2010: small cell carcinoma of the cervix, treatment and survival of 188 patients","url":"https://doi.org/10.1016/j.ajog.2010.04.019"},{"label":"Int J Gynecol Cancer 2014: GCIG consensus review for small cell carcinoma of the cervix","url":"https://doi.org/10.1097/igc.0000000000000262"}],"tags":["subtype-page","wave4","rare"],"related":["cervical","extrapulmonary-nec","cervical-adenosquamous-carcinoma","recurrent-metastatic-cervical-cancer","sclc"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["cisplatin","etoposide","atezolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["chemoradiation","hpv-p16"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"A rare histological entity of cervical cancer (GCIG 2014); the largest pooled analysis holds 188 patients, 135 with stage I to IIA disease (Am J Obstet Gynecol 2010). No registry share is in the sources read.","subtypes":["Small cell neuroendocrine carcinoma of the cervix, early stage (surgery plus platinum-etoposide)","Small cell neuroendocrine carcinoma of the cervix, locally advanced (chemoradiation plus platinum-etoposide)","Large cell neuroendocrine carcinoma of the cervix (related, treated the same)","Mixed neuroendocrine and squamous or adenocarcinoma of the cervix"],"biomarkers":["Synaptophysin, chromogranin and INSM1","HPV18 and p16","Node and distant staging including brain imaging","Ki-67 (very high)"],"standardOfCare":[{"setting":"All stages","approach":"Surgery or chemoradiation by stage, always with platinum and etoposide as for small cell lung cancer; checkpoint inhibitors by analogy with extensive-stage small cell lung cancer.","refs":["cervical","extrapulmonary-nec","cisplatin","etoposide","atezolizumab","chemoradiation"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"cervical"},{"id":"small-intestinal-net","kind":"cancer","name":"Small intestinal neuroendocrine tumours","aka":["Midgut neuroendocrine tumour","Small bowel NET","Ileal carcinoid","Jejunoileal neuroendocrine tumour","SI-NET"],"tldr":"Small intestinal neuroendocrine tumours are slow-growing hormone-producing tumours of the ileum and jejunum, often found only after they have spread to lymph nodes and the liver. Monthly somatostatin analogue injections control symptoms and growth, lutetium-177 dotatate is the main second treatment, and everolimus, cabozantinib and surgery fill in.","summary":"Small intestinal neuroendocrine tumours arise from enterochromaffin cells of the distal jejunum and ileum, are often multiple along the same segment, and stay small while their mesenteric node metastases and the fibrosis around them grow large enough to kink the bowel and its blood supply. Most are well differentiated with a low Ki-67 index, nearly all express somatostatin receptor 2, and about a fifth to a third of patients with liver metastases develop carcinoid syndrome from serotonin that escapes the liver's first-pass clearance; years of exposure can scar the right-sided heart valves. Diagnosis rests on somatostatin receptor PET, chromogranin A and 24-hour urinary 5-HIAA, and the grade is read from Ki-67 and mitotic count on biopsy.\n\nThe treatment sequence was built by a short chain of trials. PROMID (Journal of Clinical Oncology 2009) randomised 85 patients with treatment-naive metastatic midgut tumours to octreotide LAR or placebo and lengthened time to progression from 6.0 to 14.3 months, the first proof that a somatostatin analogue slows growth as well as symptoms; CLARINET (New England Journal of Medicine 2014) did the same for lanreotide across enteropancreatic tumours, with the median progression-free survival not reached against 18.0 months on placebo. NETTER-1 (New England Journal of Medicine 2017) then randomised 231 patients with midgut tumours progressing on octreotide to lutetium-177 dotatate with octreotide or to high-dose octreotide; 65.2 percent against 10.8 percent were progression-free at 20 months, responses rose from 3 to 18 percent, and the final analysis gave median overall survival of 48.0 against 36.3 months, a difference that did not reach statistical significance because of crossover. Lutathera was approved in 2018, and NETTER-2 (Lancet 2024) moved it to first line for grade 2 and 3 tumours with a Ki-67 of 10 percent or more, lengthening progression-free survival from 8.5 to 22.8 months. Everolimus earned its gut indication in RADIANT-4 (Lancet 2016), where progression-free survival was 11.0 against 3.9 months in non-functional lung and gastrointestinal tumours, and cabozantinib was approved in 2025 after the extra-pancreatic cohort of CABINET (New England Journal of Medicine 2024) showed 8.4 against 3.9 months.\n\nSurgery keeps its place even in metastatic disease: resection of the primary with its mesenteric nodes prevents obstruction and ischaemia, and liver metastases are debulked, ablated or embolised when the liver dominates. Carcinoid syndrome is treated by raising the somatostatin analogue dose, adding telotristat ethyl for diarrhoea that persists (TELESTAR, 2017), and giving octreotide by infusion around operations and embolisation to prevent carcinoid crisis. The order of radioligand therapy, everolimus and cabozantinib after somatostatin analogues has never been randomised; COMPETE (Lancet 2025) showed 177Lu-edotreotide beat everolimus on progression-free survival in grade 1 to 2 gastroenteropancreatic tumours, alpha-emitting radioligands are in phase 3 after lutetium failure, and the oral somatostatin agonist paltusotine and a subcutaneous octreotide depot are being tested for carcinoid syndrome.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor","links":[{"label":"PROMID (JCO 2009)","url":"https://doi.org/10.1200/JCO.2009.22.8510"},{"label":"NETTER-1 (NEJM 2017)","url":"https://doi.org/10.1056/NEJMoa1607427"},{"label":"NETTER-2 (Lancet 2024)","url":"https://doi.org/10.1016/S0140-6736(24)00701-3"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor"}],"tags":["subtype-page","endocrine"],"related":["extrapulmonary-nec","grade-3-net","lung-net","pancreatic-net"],"cancers":[],"sections":[],"technologies":["sstr-pet","prrt","radioligand-therapy","tace","radioembolisation-tare","thermal-ablation"],"targets":["sstr2","mtor"],"drugs":["octreotide-lanreotide","lutathera","everolimus","cabozantinib","telotristat-ethyl","ga68-dotatate","itm-11","paltusotine"],"companies":[],"institutions":[],"pathways":[],"terms":["carcinoid-syndrome","chromogranin-a","net-grade-ki67","prrt-term","liver-directed-therapy"],"trials":["promid","clarinet","netter-1","nct03972488","radiant-3-4","cabinet","compete"],"people":[],"bottlenecks":[],"keyPapers":["paper-netter-2-lancet-2024","paper-clarinet-lanreotide-nejm-2014","paper-netter-1-nejm-2017","paper-promid-rinke-jco-2009"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"The commonest neuroendocrine tumour of the gut in Western series and now the commonest cancer of the small intestine; most are grade 1 or 2 and many are found only after they have reached the mesenteric nodes or the liver.","subtypes":["Ileal neuroendocrine tumour (the classic site, often multifocal)","Jejunal neuroendocrine tumour","Duodenal neuroendocrine tumour (gastrinoma, somatostatinoma, ampullary)","Small bowel NET with carcinoid syndrome and liver metastases","Small bowel NET with mesenteric fibrosis and obstruction","Grade 1 (Ki-67 under 3 percent) and grade 2 (3 to 20 percent) small intestinal NET"],"biomarkers":["Ki-67 index and mitotic count (WHO grade, nearly always grade 1 or 2)","Chromogranin A (monitoring, raised by proton-pump inhibitors and kidney disease)","24-hour urinary 5-HIAA (carcinoid syndrome)","Somatostatin receptor PET with gallium-68 or copper-64 DOTATATE (staging and radioligand eligibility)","Echocardiography for carcinoid heart disease","Germline CDKN1B in familial small intestinal NET (rare)"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Biopsy with Ki-67 grading, somatostatin receptor PET, cross-sectional imaging of the liver, chromogranin A and urinary 5-HIAA, echocardiography if carcinoid syndrome is present.","refs":["sstr-pet","ga68-dotatate","net-grade-ki67","chromogranin-a","carcinoid-syndrome"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Localised or resectable disease","approach":"Segmental small bowel resection with mesenteric lymphadenectomy, inspecting the whole small bowel for further primaries; the primary is often removed even when liver metastases are present.","refs":["robotic-surgery","hepatectomy"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Advanced, first line","approach":"Octreotide LAR or lanreotide (PROMID, CLARINET); lutetium-177 dotatate first line for grade 2 to 3 tumours with a Ki-67 of 10 percent or more (NETTER-2).","refs":["octreotide-lanreotide","promid","clarinet","lutathera","nct03972488","prrt"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Progression on a somatostatin analogue","approach":"Lutetium-177 dotatate (NETTER-1); everolimus (RADIANT-4); cabozantinib (CABINET); liver-directed therapy for hepatic-dominant disease.","refs":["lutathera","netter-1","everolimus","radiant-3-4","cabozantinib","cabinet","tace","radioembolisation-tare","thermal-ablation","liver-directed-therapy"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Carcinoid syndrome","approach":"Somatostatin analogue dose escalation, telotristat ethyl for refractory diarrhoea, octreotide infusion around procedures to prevent carcinoid crisis, valve surgery for carcinoid heart disease.","refs":["octreotide-lanreotide","telotristat-ethyl","carcinoid-syndrome"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"After radioligand therapy","approach":"Everolimus or cabozantinib; 177Lu-edotreotide if approved; alpha-emitting radioligands and retreatment in trials.","refs":["everolimus","cabozantinib","itm-11","compete","ryz101","action-1","alphamedix"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}}],"stateOfArt":["NETTER-1 made this the first cancer treated by a modern radioligand and NETTER-2 has moved that treatment to first line for the faster-growing tumours.","Somatostatin analogues remain the first drug for almost every patient, controlling both hormone symptoms and growth.","Cabozantinib gives a fourth approved systemic option, and COMPETE was the first head-to-head win for a radioligand over a targeted tablet."],"history":[{"year":1907,"title":"Oberndorfer names the small bowel tumours 'Karzinoid'","refs":[]},{"year":1954,"title":"Carcinoid syndrome described","refs":["carcinoid-syndrome"]},{"year":1988,"title":"Octreotide approved for carcinoid syndrome symptoms","refs":["octreotide-lanreotide"]},{"year":2009,"title":"PROMID: octreotide LAR slows midgut tumour growth","refs":["promid","octreotide-lanreotide"]},{"year":2014,"title":"CLARINET: lanreotide halves the risk of progression in enteropancreatic tumours","refs":["clarinet"]},{"year":2016,"title":"RADIANT-4 extends everolimus to gut and lung tumours; gallium-68 DOTATATE PET approved","refs":["radiant-3-4","everolimus","sstr-pet","ga68-dotatate"]},{"year":2017,"title":"NETTER-1 published; telotristat ethyl approved for carcinoid syndrome diarrhoea","refs":["netter-1","telotristat-ethyl"]},{"year":2018,"title":"Lutathera approved in the United States and Europe","refs":["lutathera","prrt"]},{"year":2024,"title":"NETTER-2: lutetium-177 dotatate first line for grade 2 to 3 tumours; CABINET published","refs":["nct03972488","lutathera","cabinet"]},{"year":2025,"title":"Cabozantinib approved for previously treated neuroendocrine tumours; COMPETE published","refs":["cabozantinib","compete"]}],"pipeline":["itm-11","compete","ryz101","action-1","alphamedix","nct06943755","nct07087054","cam2029","idea-net-antagonist-ligands","idea-net-dosimetry-prrt"],"openProblems":["No randomised trial orders radioligand therapy, everolimus and cabozantinib after somatostatin analogues.","Whether removing the primary improves survival in patients with liver metastases has never been tested prospectively.","Chromogranin A is unreliable and no blood test yet replaces imaging for follow-up.","Overall survival gains are hard to show because patients live for years and cross over."],"parent":"neuroendocrine"},{"id":"small-bowel","kind":"cancer","name":"Small intestine cancer (small bowel adenocarcinoma)","aka":["Small bowel adenocarcinoma","Duodenal cancer","Jejunal and ileal cancer","SBA"],"tldr":"Cancers of the small intestine are rare and often found late because the small bowel is hard to see and symptoms are vague. Surgery cures early disease, chemotherapy borrowed from bowel cancer helps after surgery and in advanced disease, and a large minority of tumours have a repair defect that makes them respond well to immunotherapy.","summary":"Small bowel adenocarcinoma (SBA) is the epithelial cancer of the duodenum, jejunum and ileum; the small intestine also gives rise to neuroendocrine tumours (the most common small bowel malignancy in some registries), gastrointestinal stromal tumours and lymphoma, each covered on their own pages. Risk factors for SBA are inflammatory and hereditary: Crohn's disease (ileal tumours), coeliac disease (jejunal tumours, often MSI-high), Lynch syndrome, familial adenomatous polyposis (duodenal and periampullary tumours) and Peutz-Jeghers syndrome. Molecularly, SBA sits between colorectal and gastric cancer: KRAS and TP53 mutations are common, APC mutation is less common than in colon cancer, and mismatch-repair deficiency is found in a larger share than in colorectal cancer, with a further subset carrying HER2 amplification or ERBB2 mutations.\n\nSegmental resection with regional lymphadenectomy (pancreatoduodenectomy for duodenal tumours) is the curative treatment. Adjuvant chemotherapy has been extrapolated from colorectal cancer; the international BALLAD trial (NCT02502370) is the first randomised test of adjuvant fluoropyrimidine with or without oxaliplatin versus observation in stage I to III disease. For advanced disease, CAPOX or FOLFOX is first line; pembrolizumab is the first-line choice for MSI-high or mismatch-repair-deficient tumours, where response rates are high and durable. The NCCN small bowel adenocarcinoma guideline (2019 onwards) and the ASCO 2024 guideline now give the disease its own recommendations rather than a footnote in the colon guideline.\n\nOpen questions include the BALLAD result, second-line therapy beyond taxanes and irinotecan, HER2-directed therapy, and better ways to image the small bowel in high-risk patients (capsule endoscopy, MR enterography).","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Small_intestine_cancer","links":[{"label":"NCI PDQ: small intestine cancer","url":"https://www.cancer.gov/types/small-intestine"},{"label":"ASCO guideline: small bowel adenocarcinoma (JCO 2024)","url":"https://www.asco.org/guidelines"},{"label":"NCCN: Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"},{"label":"BALLAD trial (NCT02502370)","url":"https://clinicaltrials.gov/study/NCT02502370"},{"label":"SEER: small intestine cancer","url":"https://seer.cancer.gov/statfacts/html/smint.html"}],"tags":["nci-coverage","rare","gastrointestinal"],"related":["neuroendocrine","gist","colorectal","ampullary"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","checkpoint-inhibitor","endoscopy","mri","cgp","germline-testing"],"targets":["her2","kras","pd1"],"drugs":["capox","folfox","folfiri","pembrolizumab","paclitaxel","trastuzumab-deruxtecan"],"companies":[],"institutions":[],"pathways":["mismatch-repair-msi","ras-mapk","wnt"],"terms":["msi","lynch-syndrome","hereditary-cancer-syndromes","whipple","lymphadenectomy"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers","b-trial-enrolment","b-early-detection"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"The small intestine is three quarters of the gut's length but hosts only a few percent of gastrointestinal cancers; adenocarcinoma, neuroendocrine tumours, lymphoma and GIST each make up a share (SEER).","subtypes":["Duodenal adenocarcinoma (most common site; FAP-associated)","Jejunal adenocarcinoma (coeliac-associated)","Ileal adenocarcinoma (Crohn's-associated)","MSI-high / mismatch-repair-deficient SBA","Small bowel neuroendocrine tumour (see neuroendocrine)","Small bowel GIST (see GIST)","Small bowel lymphoma (including enteropathy-associated T-cell lymphoma)"],"biomarkers":["MSI / mismatch repair (dMMR) status","HER2 amplification or ERBB2 mutation","KRAS, BRAF (rarely V600E), TP53","Germline testing where Lynch, FAP or Peutz-Jeghers is suspected","CEA and CA 19-9 for monitoring","Coeliac serology and Crohn's history in the work-up"],"standardOfCare":[{"setting":"Localised","approach":"Segmental resection with en bloc lymphadenectomy; pancreatoduodenectomy for duodenal tumours not amenable to segmental resection.","refs":["whipple","lymphadenectomy"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Small Bowel Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490"}},{"setting":"Adjuvant (stage III; selected stage II)","approach":"Fluoropyrimidine with oxaliplatin (CAPOX or FOLFOX) for six months, extrapolated from colon cancer; BALLAD is the randomised test.","refs":["capox","folfox","ballad"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Small Bowel Adenocarcinoma; ASCO guideline 2024","url":"https://www.asco.org/guidelines"}},{"setting":"Advanced, MSI-high / dMMR","approach":"Pembrolizumab first line (tumour-agnostic approval; ZEBRA and KEYNOTE-158 cohorts).","refs":["pembrolizumab","msi","mismatch-repair-msi"],"guideline":{"nccn":"Category 2A (preferred)","version":"NCCN Guidelines: Small Bowel Adenocarcinoma"}},{"setting":"Advanced, MSS","approach":"CAPOX or FOLFOX first line; taxane- or irinotecan-based second line; HER2-directed therapy in trials; clinical trial enrolment encouraged.","refs":["capox","folfox","folfiri","paclitaxel"],"guideline":{"version":"NCCN Guidelines: Small Bowel Adenocarcinoma"}}],"stateOfArt":["Small bowel adenocarcinoma has its own NCCN (2019) and ASCO (2024) guidelines; it is no longer treated purely as a colon cancer analogue.","Immunotherapy transformed the outlook for the MSI-high minority, which is larger than in colorectal cancer.","BALLAD, an international academic trial, is answering whether adjuvant chemotherapy helps at all; results are awaited.","Capsule endoscopy and MR enterography make the small bowel visible, allowing surveillance in Lynch, FAP, coeliac and Crohn's patients."],"history":[{"year":1746,"title":"First description of duodenal carcinoma","note":"Hamburger's case report.","refs":[]},{"year":2005,"title":"Systematic profiling of SBA begins","note":"Registry analyses show the distinct site distribution and association with Crohn's, coeliac and FAP.","refs":[]},{"year":2015,"title":"Molecular landscape of SBA published","note":"Schrock and colleagues (JAMA Oncol 2017) later show SBA is genomically distinct from colorectal and gastric cancer, with frequent dMMR and ERBB2 alterations.","refs":[]},{"year":2016,"title":"BALLAD adjuvant trial opens","note":"First randomised trial in resected small bowel adenocarcinoma (NCT02502370).","refs":[]},{"year":2017,"title":"Pembrolizumab tumour-agnostic approval for MSI-high cancers","note":"Small bowel adenocarcinoma is one of the eligible tumours.","refs":["pembrolizumab"]},{"year":2019,"title":"NCCN publishes dedicated SBA guideline","refs":[]},{"year":2024,"title":"ASCO guideline on small bowel adenocarcinoma","refs":["capox","folfox"]}],"pipeline":["pembrolizumab","trastuzumab-deruxtecan","signatera"],"openProblems":["Adjuvant chemotherapy benefit is unproven; BALLAD is the randomised answer.","Second-line therapy for MSS disease is weak; HER2 antibody-drug conjugates and trials in rare GI tumours are the route.","Late diagnosis because the small bowel is hard to image; capsule endoscopy and MR enterography surveillance in high-risk groups is being formalised.","Rarity fragments research; international registries and platform trials are the response."]},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","aka":["Small cell lung carcinoma","SCLC","Oat cell carcinoma","Small cell carcinoma of the lung"],"tldr":"A fast-growing lung cancer. About a third of cases are confined to one side of the chest and are treated to cure with chemotherapy and radiotherapy together; the rest respond to chemotherapy and relapse quickly. After 30 years without progress, durvalumab consolidation, the T-cell engager tarlatamab and antibody-drug conjugates have each lengthened survival since 2024.","summary":"Small-cell lung cancer is a high-grade neuroendocrine carcinoma, almost always caused by smoking, defined by near-universal loss of TP53 and RB1 and by explosive growth. It presents as extensive-stage disease in two thirds of patients, responds to chemotherapy in most, and relapses in almost all. For three decades the treatment was platinum-etoposide, thoracic radiotherapy for limited-stage disease, prophylactic cranial irradiation, and topotecan at relapse.\n\nThe field moved in three steps. First-line chemo-immunotherapy (IMpower133 2018, CASPIAN 2019, ASTRUM-005 2022) added two to five months of median survival and a small tail of long-term survivors. Consolidation durvalumab after chemoradiotherapy for limited-stage disease (ADRIATIC, approved December 2024) was the first curative-intent advance in 30 years, lifting median survival to nearly five years. In relapsed disease, tarlatamab, the DLL3 T-cell engager, became the first drug to beat chemotherapy on overall survival (DeLLphi-304; full FDA approval November 2025), and lurbinectedin plus atezolizumab became the first approved first-line maintenance regimen (IMforte, October 2025).\n\nWhat is next: maintenance intensification with tarlatamab (DeLLphi-305), the B7-H3 ADC ifinatamab deruxtecan in second line (IDeate-Lung02), alpha-emitting SSTR radioligands (RYZ101), subtype-directed therapy (ASCL1, NEUROD1, POU2F3, inflamed), bispecific and trispecific DLL3 engagers, and the settled question of whether MRI surveillance can replace prophylactic cranial irradiation. Screening remains limited to low-dose CT in smokers, which detects few small-cell cancers early.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Small-cell_carcinoma","links":[{"label":"NCI PDQ: small cell lung cancer treatment","url":"https://www.cancer.gov/types/lung/hp/small-cell-lung-treatment-pdq"},{"label":"IASLC: tarlatamab first-line maintenance data","url":"https://www.iaslc.org/iaslc-news/press-release/tarlatamab-anti-pd-l1-first-line-maintenance-after-chemo-immunotherapy-es"},{"label":"NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"},{"label":"NICE NG122: lung cancer, management","url":"https://www.nice.org.uk/guidance/ng122/chapter/Management"},{"label":"NICE NG122: lung cancer, palliative interventions and supportive and palliative care","url":"https://www.nice.org.uk/guidance/ng122/chapter/Palliative-interventions-and-supportive-and-palliative-care"},{"label":"NICE NG122: lung cancer, support from clinical nurse specialists","url":"https://www.nice.org.uk/guidance/ng122/chapter/Support-from-clinical-nurse-specialists"},{"label":"NICE NG122: lung cancer, follow-up and patient perspectives","url":"https://www.nice.org.uk/guidance/ng122/chapter/Follow-up-and-patient-perspectives"},{"label":"Macmillan: small cell lung cancer (SCLC)","url":"https://www.macmillan.org.uk/cancer-information-and-support/lung-cancer/small-cell-lung-cancer"},{"label":"Roy Castle Lung Cancer Foundation: advanced lung cancer","url":"https://roycastle.org/learn-about-lung-cancer/advanced-lung-cancer/"},{"label":"Roy Castle Lung Cancer Foundation: living with lung cancer","url":"https://roycastle.org/learn-about-lung-cancer/living-with-cancer/"},{"label":"Macmillan: breathlessness","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/breathlessness"},{"label":"Macmillan: superior vena cava obstruction (SVCO)","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/superior-vena-cava-obstruction"},{"label":"Cancer Research UK: coping with breathlessness when you have lung cancer","url":"https://www.cancerresearchuk.org/about-cancer/lung-cancer/living-with/coping-with-breathlessness"},{"label":"Cancer Research UK: fluid on the lungs (pleural effusion)","url":"https://www.cancerresearchuk.org/about-cancer/coping/physically/breathing-problems/fluid-on-lungs-pleural-effusion"},{"label":"Marie Curie: what is palliative care?","url":"https://www.mariecurie.org.uk/information/getting-care/palliative-care"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Temel et al., early palliative care for patients with metastatic non-small-cell lung cancer (NEJM 2010)","url":"https://doi.org/10.1056/NEJMoa1000678"}],"tags":["lung"],"related":["nsclc","lung-cancer","lung-lcnec","lung-net","dll3-expression"],"cancers":[],"sections":[],"technologies":["t-cell-engager","adc","checkpoint-inhibitor","targeted-alpha-therapy","nhs-targeted-lung-health-check","cytotoxic-chemotherapy","imrt-igrt","sbrt","prophylactic-cranial-irradiation","mri","palliative-care","palliative-radiotherapy","psycho-oncology","peer-support-groups","oncology-nutrition","pain-management","survivorship-care-plan","multidisciplinary-tumour-board","financial-navigation","cbt-fatigue-distress"],"targets":["dll3","b7h3","pdl1","sstr2","tp53","pd1","bcl2","atr","parp","rb1","notch1"],"drugs":[],"companies":["epicentrx","genprex","amgen","roche-genentech","astrazeneca","daiichi-sankyo","merck","jazz","pharmamar","henlius","bms"],"institutions":["mskcc","md-anderson","dana-farber","gustave-roussy"],"pathways":["p53-cell-cycle","sclc-signalling","apoptosis-bcl2","pd1-checkpoint","lineage-plasticity-neuroendocrine","notch","transcription-addiction"],"terms":["limited-extensive-stage","crs","os","pfs","pci-term","pack-year","smoking-cessation","tnm-9-lung-cancer","ebus-tbna","pancoast-tumour","superior-vena-cava-obstruction","malignant-pleural-effusion","brain-metastases","pleural-effusion","pleurodesis","radiation-pneumonitis","irae","cancer-related-fatigue","anaemia","cachexia","performance-status","curative-intent","neutropenia","febrile-neutropenia","bone-metastases","histologic-transformation","driver-mutation"],"trials":["nct07739758","nct06616532","nct06247605","slotman-pci-es-sclc","takahashi-pci","nct06712316","nct02486718","nct03164616","nct05555732","nct06627647","nct06692738","nct03178552","nct06561386","nct05984277","nct07513376","nct06077760","nct06422143","nct07361497","nct03800134","nct06312137","nct06767514","nct06726265","nct05920356","nct07361510","nct06417814","nct05215340","nct06216301","nct06687369","nct06500026","nct06838273","nct06758401","nct06382129","nct06801834","nct06128837","nct06899126","nct06357533","nct04624204","nct07472517","nct03390686","nct04613596","nct04923906","nct06712355","nct05654454","nct06170788","nct05089734","nct01064466","nct06793215","nct07145333","nct06881784","nct06350097","nct07183189","nct06041776","nct07502300","nct06617416","nct07010263","nct06074588","nct06348199","nct06305754","nct07625644","nct02411448","nct04316364","nct06928389","nct05840016"],"people":[],"bottlenecks":[],"keyPapers":["paper-george-sclc-genomic-profiles-nature-2015","paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","paper-gay-sclc-subtypes-inflamed-cancer-cell-2021","paper-baine-sclc-subtype-immunohistochemistry-jto-2020","paper-lee-clonal-history-small-cell-transformation-jco-2017","paper-marcoux-egfr-small-cell-transformation-outcomes-jco-2019"],"journals":["clinical-lung-cancer","lung-cancer-journal","thoracic-cancer","chinese-journal-of-lung-cancer"],"dependsOn":[],"notes":["Living with small-cell lung cancer: This is orientation from public patient pages and guidelines, not advice for your case: your own team's instructions and 24-hour number come first. The timeline is the thing that catches people out. NICE NG122 (1.8.1) asks for an assessment by a thoracic oncologist within 1 week of deciding to recommend treatment, and (1.10.2) for radiotherapy to start during the first or second cycle of chemotherapy in limited-stage disease, so decisions arrive close together and the practical, financial and family arrangements are better made early than left. Written from NICE NG122 and the NHS, Roy Castle Lung Cancer Foundation, Macmillan, Cancer Research UK, Maggie's and Marie Curie patient pages, all read on 25 September 2026.","Molecular layer. One genotype and four states. Whole-genome sequencing of 110 tumours found biallelic inactivation of TP53 and RB1 in nearly all of them, sometimes through complex rearrangement rather than point mutation, so a mutation call reads lower (85.8% and 72.5% in the public deposit) than the biology; the two cases with intact RB1 reached the same end through chromothripsis and cyclin D1 overexpression. NOTCH family inactivation in 25%, oncogenic TP73 rearrangements, and chromatin regulators (KMT2D 18.3%, EP300 10.8%, CREBBP 9.2%) make up most of the rest, with kinase mutations only in rare individual cases (George 2015).","Molecular layer. The heterogeneity is transcriptional. Four subtypes are defined by ASCL1, NEUROD1 and POU2F3 expression or by the absence of all three: in 174 patient samples, 69% were ASCL1-dominant, 17% NEUROD1-dominant, 7% POU2F3-positive and the rest double-negative, with 37% co-expressing ASCL1 and NEUROD1, far more overlap than laboratory models predicted (Rudin 2019, Baine 2020). Expression analysis resolved the fourth class as inflamed rather than YAP1-driven, and that class gained most from adding immunotherapy to chemotherapy; the others carry distinct vulnerabilities to PARP, Aurora kinase and BCL-2 inhibition, and platinum shifts tumours towards the inflamed state, which would make subtype a moving target (Gay 2021).","Molecular layer. Subtype decides whether the surface target is there. ASCL1-dominant and NEUROD1-dominant tumours are neuroendocrine-marker high, TTF-1 high and DLL3 high; POU2F3 and other double-negative tumours are low for all three, so a DLL3-directed medicine addresses roughly the 86% that are neuroendocrine-high rather than the whole disease (Baine 2020).","Molecular layer. Some small-cell lung cancer starts as adenocarcinoma. Transformation under EGFR blockade requires RB1 and TP53 loss, which is present from the earliest adenocarcinoma stage and gives a 43-fold risk (Lee 2017, Offin 2019); after transformation the founder EGFR mutation is retained, platinum and etoposide work, checkpoint inhibitors produced no responses in 17 patients, and median survival is 10.9 months (Marcoux 2019)."],"group":"lung","burden":"Small-cell lung cancer makes up about 15% of lung cancers, roughly 250,000 cases a year worldwide, almost entirely in current or former smokers. Limited-stage disease is treated with curative intent and now with durvalumab consolidation. In ADRIATIC, median survival with durvalumab consolidation after chemoradiotherapy was 55.9 months against 33.4 with placebo; in extensive-stage disease first-line chemo-immunotherapy gives a median of about a year. Both are medians in trial populations, so half of those patients lived longer.","subtypes":["Limited-stage (one hemithorax, ~30%)","Extensive-stage (~70%)","SCLC-A (ASCL1-driven, DLL3-high; ~50%)","SCLC-N (NEUROD1)","SCLC-P (POU2F3, tuft-cell-like)","SCLC-I (inflamed, IO-responsive)","Transformed SCLC (from EGFR-mutant NSCLC under TKI)","Combined small-cell / non-small-cell histology"],"biomarkers":["DLL3 (not required for tarlatamab)","B7-H3","SCLC-A/N/P/I subtypes (research)","Stage (limited vs extensive) is the dominant decision","B7-H3 (I-DXd trials)","SSTR2 (RYZ101)","Transcription-factor subtype (ASCL1/NEUROD1/POU2F3/YAP1, research)","PD-L1 and TMB (not predictive in SCLC)","SLFN11 (chemotherapy/PARP sensitivity, research)","ctDNA (research)"],"standardOfCare":[{"setting":"Screening and diagnosis","approach":"Low-dose CT screening in heavy smokers finds some SCLC but stage shift is limited; diagnosis by bronchoscopic or CT-guided biopsy; staging with PET/CT and brain MRI.","refs":["ct","pet-ct","mri"],"guideline":{"nccn":"SCLC guideline, staging workup","version":"NCCN SCLC v2.2026"}},{"setting":"Very limited stage (T1-2 N0, ~5%)","approach":"Lobectomy with mediastinal node dissection or SBRT, followed by adjuvant platinum-etoposide; PCI or MRI surveillance.","refs":["sbrt","platinum-etoposide","prophylactic-cranial-irradiation"],"guideline":{"nccn":"2A"}},{"setting":"Limited stage","approach":"Concurrent cisplatin-etoposide with thoracic radiotherapy (45 Gy twice daily or 60-70 Gy once daily), then durvalumab consolidation up to 2 years (ADRIATIC); PCI or MRI surveillance.","refs":["platinum-etoposide","imrt-igrt","durvalumab","adriatic","convert","prophylactic-cranial-irradiation"],"guideline":{"nccn":"1 (durvalumab consolidation, category 1)","esmoMcbs":"A","version":"NCCN SCLC v2.2026"}},{"setting":"Extensive stage, first line","approach":"Carboplatin-etoposide plus atezolizumab or durvalumab (4 cycles), then maintenance immunotherapy; lurbinectedin added to atezolizumab maintenance since 2025 (IMforte). Serplulimab-chemotherapy where approved. Consolidative thoracic radiotherapy for residual thoracic disease in good responders.","refs":["platinum-etoposide","atezolizumab","durvalumab","lurbinectedin","impower133","caspian","imforte","serplulimab"],"guideline":{"nccn":"1 (chemo-IO); 2A (lurbinectedin maintenance)","esmoMcbs":"3"}},{"setting":"Relapsed, platinum-sensitive (≥90 days)","approach":"Tarlatamab (preferred, OS benefit); platinum-etoposide rechallenge; lurbinectedin; topotecan.","refs":["tarlatamab","dellphi-304","lurbinectedin","topotecan"],"guideline":{"nccn":"1 (tarlatamab)","esmoMcbs":"4"}},{"setting":"Relapsed, platinum-resistant (<90 days)","approach":"Tarlatamab; lurbinectedin; topotecan; clinical trials (I-DXd, RYZ101, DLL3 bispecifics).","refs":["tarlatamab","lurbinectedin","topotecan","ifinatamab-deruxtecan","ideate-lung02","ryz101"],"guideline":{"nccn":"1 (tarlatamab)"}},{"setting":"Brain metastases","approach":"Whole-brain radiotherapy or, increasingly, stereotactic radiosurgery for limited numbers of lesions; PCI decisions individualised.","refs":["sbrt","prophylactic-cranial-irradiation","mri"]},{"setting":"Transformed SCLC (from EGFR-mutant NSCLC)","approach":"Platinum-etoposide, often with continued EGFR TKI; immunotherapy benefit uncertain; trials.","refs":["platinum-etoposide","osimertinib"]},{"setting":"Small-cell lung cancer: why the timeline is faster, and what that means for your decisions","approach":"Small-cell lung cancer moves faster than non-small-cell lung cancer, in both directions: it grows quickly and it shrinks quickly with treatment. NICE NG122 builds that into the standard. It says (1.8.1) to arrange for people with small-cell lung cancer to have an assessment by a thoracic oncologist within 1 week of deciding to recommend treatment, which is a far shorter interval than anything in the non-small-cell pathway, and (1.10.2) to start radiotherapy during the first or second cycle of chemotherapy for limited-stage disease rather than after the chemotherapy is finished. What that means for you is that the decisions arrive close together and the waiting-for-results pattern that suits advanced non-small-cell disease does not apply here. The treatment divides at limited against extensive stage. Limited stage: 4 to 6 cycles of cisplatin-based combination chemotherapy, with carboplatin substituted where kidney function, performance status or other illnesses make that safer (1.10.1); twice-daily radiotherapy given with the chemotherapy for people with a performance status of 0 or 1 whose disease fits in a radical radiotherapy volume, or once daily if they decline or cannot manage twice (1.10.2 and 1.10.3); sequential radiotherapy for people who are not well enough for concurrent treatment but respond to chemotherapy (1.10.4); preventive radiotherapy to the brain at 25 Gy in 10 fractions for performance status 0 to 2 where the disease has not progressed (1.10.5); and durvalumab afterwards where the disease has not progressed after chemoradiotherapy (1.10.6). Extensive stage: platinum-based combination chemotherapy if you are fit enough, to a maximum of 6 cycles depending on response and toxicity (1.11.1 and 1.11.2), with durvalumab or atezolizumab added (1.11.3), and thoracic radiotherapy with preventive brain radiotherapy considered for people who responded (1.11.4 and 1.11.5). NICE is unusually frank about the cost of preventive brain radiotherapy, saying it can adversely affect quality of life and that the survival benefits are limited, and has an open research question about replacing it with regular MRI scans. At relapse it says to offer assessment by a thoracic oncologist (1.12.1), to tell people whose disease did not respond to first-line treatment that there is very limited evidence that second-line chemotherapy will benefit them (1.12.2), to offer an anthracycline-containing or a further platinum-based regimen to a maximum of 6 cycles where chemotherapy is suitable (1.12.3), and to offer radiotherapy for palliation of local symptoms (1.12.5). Because the decisions arrive close together, three things are worth doing in the first weeks rather than later: the palliative care referral alongside treatment, for symptom control and not instead of it; the conversation with your team about what matters to you; and the practical paperwork Roy Castle's getting organised material covers.","refs":["cisplatin","carboplatin","etoposide","durvalumab","atezolizumab","adriatic","caspian","impower133","palliative-care","performance-status"],"guideline":{"version":"NICE NG122 (2019, updated March 2024)","url":"https://www.nice.org.uk/guidance/ng122/chapter/Management"}}],"stateOfArt":["Tarlatamab: first OS improvement in relapsed SCLC in decades.","Immunotherapy consolidation in limited stage.","Limited-stage: chemoradiation followed by durvalumab consolidation (ADRIATIC), median OS approaching five years.","Extensive-stage first line: chemo-immunotherapy, now with lurbinectedin-atezolizumab maintenance (IMforte, 2025).","Relapse: tarlatamab (DLL3×CD3) improved OS over chemotherapy (DeLLphi-304) and received full approval in November 2025.","B7-H3 ADC ifinatamab deruxtecan and alpha-emitting SSTR radioligand RYZ101 are in phase 3.","MRI surveillance is displacing prophylactic cranial irradiation while the definitive trial (SWOG S1827) reads out.","Molecular subtypes (A/N/P/I) explain heterogeneity and are moving toward prospective use."],"history":[{"year":1973,"title":"VA Lung Study Group defines limited vs extensive stage","refs":["limited-extensive-stage"]},{"year":1985,"title":"Platinum-etoposide becomes the standard regimen","refs":["platinum-etoposide"]},{"year":1992,"title":"Meta-analysis: thoracic radiotherapy improves survival in limited-stage disease","refs":["imrt-igrt"]},{"year":1996,"title":"Topotecan approved for relapsed disease","refs":["topotecan"]},{"year":1999,"title":"Prophylactic cranial irradiation improves survival in complete responders","refs":["prophylactic-cranial-irradiation"]},{"year":1999,"title":"Twice-daily 45 Gy (Turrisi) sets the limited-stage radiotherapy standard","refs":["imrt-igrt"]},{"year":2017,"title":"CONVERT: once-daily 66 Gy not superior to twice-daily 45 Gy","refs":["convert"]},{"year":2017,"title":"Japanese trial: PCI gives no survival benefit in extensive-stage disease with MRI surveillance","refs":["prophylactic-cranial-irradiation"]},{"year":2018,"title":"IMpower133: first survival gain in decades with atezolizumab","refs":["impower133","atezolizumab"]},{"year":2019,"title":"Rovalpituzumab tesirine (first DLL3 ADC) fails","refs":["dll3"]},{"year":2019,"title":"CASPIAN confirms chemo-immunotherapy with durvalumab","refs":["caspian","durvalumab"]},{"year":2020,"title":"Lurbinectedin accelerated approval in relapsed SCLC","refs":["lurbinectedin"]},{"year":2021,"title":"SCLC molecular subtypes (A, N, P, I) proposed","refs":["idea-sclc-subtype-directed"]},{"year":2024,"title":"Tarlatamab accelerated approval; ADRIATIC changes limited-stage care","refs":["tarlatamab","adriatic"]},{"year":2025,"title":"DeLLphi-304 OS benefit and full approval of tarlatamab; IMforte maintenance approved","refs":["dellphi-304","imforte","lurbinectedin"]},{"year":2026,"title":"Phase 3 readouts pending for I-DXd and tarlatamab maintenance","refs":["ideate-lung02","dellphi-305"]}],"pipeline":["ifinatamab-deruxtecan","ryz101","tarlatamab","pf-08634404","yl201","pm8002","in10018","ak117","al8326","tng260","au-007","or502","dellphi-305","ideate-lung02","serplulimab","lurbinectedin","idea-sclc-subtype-directed","idea-mri-surveillance-replaces-pci","prophylactic-cranial-irradiation","tarlatamab-vs-idxd-sequence","chemo-io-then-maintenance-sclc","t-cell-engager","targeted-alpha-therapy"],"openProblems":["Extensive-stage disease almost always relapses after first-line therapy, so maintenance (lurbinectedin-atezolizumab, tarlatamab) is the current lever; median survival is still barely over a year.","No validated predictive biomarker for immunotherapy benefit; PD-L1 and TMB do not work in SCLC.","Sequencing of tarlatamab, I-DXd, lurbinectedin, and platinum rechallenge is untested.","Cytokine release syndrome and neurotoxicity of T-cell engagers require inpatient step-up dosing that many community centres cannot provide.","Prophylactic cranial irradiation versus MRI surveillance remains unresolved until SWOG S1827 reads out.","Transformed SCLC arising from EGFR-mutant NSCLC has no dedicated evidence base.","Screening rarely catches SCLC early; prevention is tobacco control.","Trials rarely enrol patients with poor performance status, who are common in this disease."],"parent":"lung-cancer"},{"id":"smouldering-myeloma","kind":"cancer","name":"Smouldering multiple myeloma","aka":["Smoldering multiple myeloma","SMM","High-risk smouldering myeloma","Asymptomatic myeloma"],"tldr":"Smouldering myeloma is myeloma that has not yet damaged bones, kidneys or blood counts. Most people are watched, but those at high risk of progressing can now be treated: the AQUILA trial showed daratumumab alone delays active myeloma, and it was approved for this use in 2025.","summary":"Smouldering myeloma is defined by a serum M-protein of 30 g/L or more, or urinary M-protein of 500 mg a day or more, or clonal marrow plasma cells of 10 to 60 percent, with none of the myeloma-defining events (the CRAB features of hypercalcaemia, renal failure, anaemia and bone lesions, or the SLiM markers of 60 percent plasma cells, a light chain ratio of 100 or more, or more than one focal lesion on MRI). The Mayo 20/2/20 model, with M-protein above 20 g/L, a free light chain ratio above 20 and marrow plasma cells above 20 percent, separates a high-risk group in which about half progress within two years from a low-risk group that may never need treatment. Whole-body MRI or PET-CT to exclude occult bone disease is part of the work-up.\n\nActive monitoring every three to six months was the only standard until lenalidomide was tested: the ECOG E3A06 trial (2020) showed lenalidomide alone delayed progression in intermediate- and high-risk disease, with three-year progression-free survival of 91 percent against 66 percent under observation, at the price of side effects that most patients on a watch-and-wait footing found hard to accept. AQUILA, reported in 2024, randomised 390 patients with high-risk smouldering myeloma to subcutaneous daratumumab monotherapy for up to three years or active monitoring: five-year progression-free survival 63.1 percent versus 40.8 percent (hazard ratio 0.49), with a survival signal, and daratumumab was approved for high-risk smouldering myeloma in the United States in late 2025, the first drug licensed before myeloma becomes active.\n\nWhether to treat at all remains argued: many high-risk patients would have lived years without symptoms, no trial has yet shown that early treatment lengthens life, and intensive curative-intent regimens (carfilzomib-lenalidomide-dexamethasone and transplant in the Spanish GEM-CESAR and US ASCENT studies) trade heavy therapy for deep remissions of uncertain meaning. Bispecific antibodies such as linvoseltamab and quadruplets are being tested in the same population, and population screening for M-protein (iStopMM in Iceland) is asking whether finding the disease earlier helps anyone.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Smouldering_myeloma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Smouldering_myeloma"},{"label":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}],"tags":["subtype-page"],"related":["myeloma-transplant-eligible","myeloma-transplant-ineligible","plasma-cell-leukaemia","myeloma-relapsed-refractory"],"cancers":[],"sections":[],"technologies":["whole-body-mri","pet-ct"],"targets":["cd38"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["smoldering-myeloma","high-risk-myeloma","r-iss","m-protein-free-light-chains"],"trials":["aquila"],"people":[],"bottlenecks":[],"keyPapers":["paper-aquila-daratumumab-smouldering-nejm-2025","paper-e3a06-lenalidomide-smouldering-lonial-jco-2020","paper-imwg-criteria-rajkumar-lancet-oncol-2014","paper-mateos-20-2-20-smouldering-bcj-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Found in about one in seven people diagnosed with a plasma cell cancer, usually by chance on a blood test; about one in ten progress to active myeloma each year for the first five years, and the high-risk half progress much faster.","subtypes":["Low-risk smouldering myeloma (Mayo 20/2/20 score 0)","Intermediate-risk smouldering myeloma","High-risk smouldering myeloma (20/2/20 score 2 or more; about half progress within two years)","Monoclonal gammopathy of undetermined significance (MGUS, precursor with under 10 percent plasma cells)"],"biomarkers":["Serum M-protein and immunofixation","Free light chain ratio","Marrow plasma cell percentage","Mayo 20/2/20 and IMWG risk scores","High-risk cytogenetics: t(4;14), del(17p), gain 1q","Whole-body MRI or PET-CT for focal lesions","Evolving M-protein over time"],"standardOfCare":[{"setting":"Low- and intermediate-risk","approach":"Active monitoring with blood tests every three to six months and imaging when the M-protein or light chains rise; no treatment.","refs":["smoldering-myeloma","whole-body-mri"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"High-risk (Mayo 20/2/20 or IMWG high risk)","approach":"Daratumumab monotherapy for up to three years (AQUILA), or lenalidomide with or without dexamethasone (E3A06), or a clinical trial; monitoring remains acceptable after shared decision-making.","refs":["daratumumab","lenalidomide","dexamethasone","smoldering-myeloma"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Trials of interception","approach":"Bispecific antibodies (linvoseltamab), isatuximab-lenalidomide-dexamethasone and curative-intent quadruplets in high-risk disease; population screening studies.","refs":["linvoseltamab","isatuximab","nct07393282","nct05955508","nct04270409","istopmm"]}],"stateOfArt":["AQUILA made daratumumab the first drug approved for high-risk smouldering myeloma, delaying progression to active disease.","Risk models based on M-protein, light chains and marrow burden separate patients who need close watching from those who may never need treatment.","Whether early treatment lengthens life, rather than only delaying the diagnosis of active myeloma, is still unproven."],"history":[{"year":1980,"title":"Kyle and Greipp define smouldering multiple myeloma","refs":["smoldering-myeloma"]},{"year":2007,"title":"Mayo series: about 10 percent a year progress in the first five years","refs":["smoldering-myeloma"]},{"year":2014,"title":"IMWG adds the SLiM biomarkers, moving the highest-risk patients into active myeloma","refs":["smoldering-myeloma"]},{"year":2020,"title":"E3A06: lenalidomide delays progression in higher-risk disease","refs":["lenalidomide"]},{"year":2024,"title":"AQUILA: daratumumab monotherapy delays progression in high-risk disease","refs":["daratumumab"]},{"year":2025,"title":"Daratumumab approved for high-risk smouldering myeloma in the United States","refs":["daratumumab"]}],"pipeline":["daratumumab","linvoseltamab","isatuximab","istopmm","nct07393282","nct05955508"],"openProblems":["No trial has shown that treating smouldering myeloma lengthens life rather than delaying the label of active disease.","Risk models still misclassify many patients in both directions.","Whether curative-intent treatment of a precursor is justified, and for whom."],"parent":"multiple-myeloma"},{"id":"extremity-soft-tissue-sarcoma","kind":"cancer","name":"Soft tissue sarcoma of the extremity (localised and advanced)","aka":["Limb sarcoma","Extremity STS","Localised soft tissue sarcoma","Advanced soft tissue sarcoma"],"tldr":"Most soft tissue sarcomas arise in an arm or leg. Limb-saving surgery with radiotherapy cures most localised tumours and is as safe as amputation. For spread disease doxorubicin is the backbone: adding ifosfamide shrinks more tumours without lengthening life, and in leiomyosarcoma adding trabectedin doubles the time the disease stays controlled.","summary":"Extremity soft tissue sarcoma is the stage and site framework for the histology-specific records: undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, myxofibrosarcoma, MPNST and others. Risk is set by FNCLCC grade, size and depth, and prognostic tools such as Sarculator translate these into individual estimates. The Rosenberg NCI trial of 1982 established that limb-sparing surgery with radiotherapy gives the same survival as amputation, and the NCIC SR2 trial of 2002 showed preoperative radiotherapy (50 Gy) and postoperative radiotherapy (66 Gy) give equal local control, with more acute wound complications after preoperative treatment but less late fibrosis, oedema and joint stiffness, which is why preoperative radiotherapy is now preferred for large deep tumours.\n\nPerioperative chemotherapy has been contested for decades: the EORTC 62931 adjuvant trial was negative, but the Italian Sarcoma Group ISG-STS 1001 trial found that three cycles of neoadjuvant full-dose epirubicin-ifosfamide improved relapse-free and overall survival in high-risk limb and trunk sarcoma compared with histotype-tailored regimens, and it is offered to fit patients with large, deep, high-grade tumours. Isolated limb perfusion and regional hyperthermia with chemotherapy are used in selected centres to make unresectable tumours operable.\n\nFor advanced disease, EORTC 62012 randomised 455 patients to doxorubicin plus ifosfamide or doxorubicin alone: response and progression-free survival improved with the combination (median 7.4 versus 4.6 months) but overall survival did not significantly (14.3 versus 12.8 months), so doxorubicin alone remains standard unless tumour shrinkage is needed. The ANNOUNCE trial of olaratumab with doxorubicin was negative and withdrew the drug. Histology now drives later lines: gemcitabine-docetaxel and pazopanib across subtypes, trabectedin and eribulin for liposarcoma and leiomyosarcoma, and in leiomyosarcoma the French LMS-04 trial showed doxorubicin plus trabectedin followed by trabectedin maintenance roughly doubled progression-free survival compared with doxorubicin alone (median 12.2 versus 6.2 months), making it the first-line option for fit patients.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Soft-tissue_sarcoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Soft-tissue_sarcoma"}],"tags":["subtype-page"],"related":["sarcoma","leiomyosarcoma","liposarcoma","synovial-sarcoma","undifferentiated-pleomorphic-sarcoma","retroperitoneal-sarcoma","myxofibrosarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-eortc-62012-doxorubicin-ifosfamide-judson-lancet-oncol-2014","paper-esmo-sts-guideline-gronchi-ann-oncol-2021","paper-ncic-sr2-preoperative-vs-postoperative-radiotherapy-osullivan-lancet-2002","paper-isg-sts-1001-gronchi-lancet-oncol-2017"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"About 60 percent of soft tissue sarcomas arise in the limbs, most often the thigh, across dozens of histologies; deep, high-grade tumours over five centimetres metastasise to the lungs in roughly a third to a half of patients, and advanced disease has a median survival of one to two years with chemotherapy.","subtypes":["Localised low-grade soft tissue sarcoma of the limb (surgery, selective radiotherapy)","Localised high-grade, deep, over 5 cm soft tissue sarcoma of the limb (preoperative radiotherapy, neoadjuvant chemotherapy)","Locally advanced unresectable limb sarcoma (isolated limb perfusion, hyperthermia)","Oligometastatic lung disease (metastasectomy, stereotactic radiotherapy)","Advanced or metastatic soft tissue sarcoma (doxorubicin-based chemotherapy)","Advanced leiomyosarcoma (doxorubicin plus trabectedin, LMS-04)"],"biomarkers":["FNCLCC grade, size over 5 cm and depth (Sarculator risk)","Histological subtype by expert pathology and molecular testing","Margin status after resection","Lung CT staging and surveillance"],"standardOfCare":[{"setting":"Localised, resectable","approach":"Limb-sparing wide resection with preoperative (50 Gy) or postoperative (66 Gy) radiotherapy for high-grade or deep tumours over 5 cm; surgery alone for small superficial low-grade tumours.","refs":["limb-salvage-surgery","imrt-igrt","brachytherapy","fnclcc-grade"]},{"setting":"High-risk localised (large, deep, high grade)","approach":"Neoadjuvant anthracycline-ifosfamide (ISG-STS 1001) in fit patients; regional hyperthermia with chemotherapy or isolated limb perfusion for borderline resectable tumours.","refs":["isg-sts-1001","doxorubicin","ifosfamide","hyperthermia","isolated-limb-perfusion"]},{"setting":"Advanced, first line","approach":"Doxorubicin alone, or doxorubicin plus ifosfamide when shrinkage is needed (EORTC 62012); doxorubicin plus trabectedin for leiomyosarcoma (LMS-04); olaratumab withdrawn after ANNOUNCE.","refs":["doxorubicin","ifosfamide","eortc-62012","trabectedin","lms-04","announce"]},{"setting":"Later lines and oligometastatic","approach":"Gemcitabine-docetaxel, pazopanib, trabectedin, eribulin (liposarcoma); pulmonary metastasectomy or stereotactic radiotherapy for limited lung disease; histology-directed agents and trials.","refs":["gemcitabine","docetaxel","pazopanib","trabectedin","eribulin","sbrt","sarcoma-histotype-tailoring"]}],"stateOfArt":["Preoperative radiotherapy with limb-sparing surgery is the standard for large deep limb sarcomas, trading early wound problems for better long-term function.","ISG-STS 1001 revived neoadjuvant chemotherapy for high-risk disease after the negative EORTC 62931 adjuvant trial.","LMS-04 made doxorubicin plus trabectedin the first histology-specific first-line regimen with a randomised progression-free survival gain."],"history":[{"year":1982,"title":"Rosenberg NCI trial: limb-sparing surgery plus radiotherapy equals amputation","refs":["limb-salvage-surgery"]},{"year":2002,"title":"NCIC SR2: preoperative and postoperative radiotherapy give equal control, with different toxicities","refs":["imrt-igrt"]},{"year":2012,"title":"EORTC 62931: adjuvant doxorubicin-ifosfamide does not improve survival","refs":["doxorubicin","ifosfamide"]},{"year":2014,"title":"EORTC 62012: doxorubicin plus ifosfamide improves response but not overall survival","refs":["eortc-62012"]},{"year":2017,"title":"ISG-STS 1001: neoadjuvant epirubicin-ifosfamide improves survival in high-risk limb sarcoma","refs":["isg-sts-1001"]},{"year":2019,"title":"ANNOUNCE: olaratumab fails and is withdrawn","refs":["announce"]},{"year":2022,"title":"LMS-04: doxorubicin plus trabectedin doubles progression-free survival in leiomyosarcoma","refs":["lms-04"]}],"pipeline":["lms-04","isg-sts-1001","trabectedin","pembrolizumab"],"openProblems":["A third to a half of high-risk limb sarcomas still metastasise to the lungs.","Chemotherapy prolongs control but rarely survival in advanced disease.","Trials pool dozens of histologies that behave differently."],"parent":"sarcoma"},{"id":"solid-pseudopapillary-neoplasm","kind":"cancer","name":"Solid pseudopapillary neoplasm of the pancreas","aka":["Solid pseudopapillary neoplasm (young women; CTNNB1; low-grade malignant; cured by resection in about 95 percent)","Solid pseudopapillary tumour","SPN","SPT","Frantz tumour","Hamoudi tumour","Papillary cystic neoplasm of the pancreas","Solid and papillary epithelial neoplasm"],"tldr":"Solid pseudopapillary neoplasm is a rare, slow-growing pancreatic tumour of young women that is classed as a low-grade cancer. It is driven by a fault in the beta-catenin gene rather than the KRAS mutation of ordinary pancreatic cancer, is often found by chance as a large mass, and surgery cures more than nineteen in twenty patients, although it can recur years later.","summary":"What it is. A low-grade malignant epithelial neoplasm of uncertain cell origin, listed by the WHO among the pancreatic neoplasms distinct from ductal adenocarcinoma (Nagtegaal 2020). Almost all carry an activating mutation of CTNNB1 (beta-catenin): nuclear beta-catenin accumulation in 19 of 20 tumours and mutations in 18 of 20, with cyclin D1 overexpression in 74 percent, while none had a KRAS mutation, SMAD4 (DPC4) expression was intact in all and p53 overexpression was seen in only 3 of 19, showing a genetic pathway divergent from ductal cancer and shared with pancreatoblastoma and acinar cell carcinoma (Abraham 2002).\n\nHow it differs from its parent. A systematic review of 2,744 patients found 87.8 percent were female with a mean age of 28.5 years; abdominal pain was the commonest symptom (63.6 percent) and 38.1 percent were found incidentally; mean tumour size was 8.6 cm; 2,285 underwent pancreatic resection; among 1,952 with follow-up (mean 36 months), 95.6 percent remained disease-free and 4.4 percent recurred, at a median of 50.5 months (Law 2014). Reports rose seven-fold after 2000 as cross-sectional imaging spread.\n\nHow common it is. Not counted by registries; the literature series above is the best measure. Cancer Research UK lists it among the cystic tumours of the pancreas that may be removed or kept under surveillance.\n\nHow it is treated. Resection is the treatment and is curative in the great majority: distal pancreatectomy for body and tail tumours, pancreatoduodenectomy for the head, with parenchyma-sparing operations considered in young patients because lymph node spread is rare. Recurrences and the rare liver metastases are resected where possible; there is no established systemic therapy and no trial. Long follow-up is needed because recurrence can come after four years or more.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Solid_pseudopapillary_tumour","links":[{"label":"Law, Pancreas 2014: systematic review of 2,744 solid-pseudopapillary neoplasms","url":"https://doi.org/10.1097/mpa.0000000000000061"},{"label":"Abraham, Am J Pathol 2002: solid-pseudopapillary tumours are genetically distinct and almost always carry beta-catenin mutations","url":"https://doi.org/10.1016/s0002-9440(10)62563-1"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"},{"label":"CRUK: types of pancreatic cancer","url":"https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/stages-types-grades/types"}],"tags":["gi","pancreatic","subtype-page"],"related":["pancreatic","pancreatoblastoma","pancreatic-acinar-cell-carcinoma","pancreatic-net","ipmn-cystic-precursors","mcn-associated-carcinoma"],"cancers":[],"sections":[],"technologies":["robotic-surgery","histopathology-ihc","mri","ct"],"targets":["kras"],"drugs":[],"companies":[],"institutions":[],"pathways":["wnt","pancreatic-cancer-signalling"],"terms":["distal-pancreatectomy","whipple","tumour-grade","oligometastatic"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"Rare but increasingly recognised: 2,744 patients in 484 publications to 2012, 87.8 percent of them reported after 2000; 87.8 percent female, mean age 28.5; no registry count is published.","subtypes":["Classical solid pseudopapillary neoplasm (young women; resected; disease-free in 95.6 percent)","Solid pseudopapillary neoplasm with metastases or recurrence (liver most often; resected where possible)","Solid pseudopapillary neoplasm in men or older patients (a minority; distinguished from pancreatic NET and from ductal PDAC on biopsy)"],"biomarkers":["Nuclear beta-catenin on immunohistochemistry and CTNNB1 exon 3 mutation (about 90 percent)","Loss of membranous E-cadherin; CD10, progesterone receptor and cyclin D1 positive; chromogranin negative (distinguishes it from neuroendocrine tumour)","No KRAS mutation and intact SMAD4 (unlike ductal adenocarcinoma)"],"standardOfCare":[{"setting":"Localised","approach":"Complete resection: distal pancreatectomy for body and tail tumours, pancreatoduodenectomy for the head, parenchyma-sparing surgery considered in young patients; no adjuvant therapy; long-term follow-up imaging for late recurrence.","refs":["distal-pancreatectomy","whipple","robotic-surgery","mri"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Recurrent or metastatic","approach":"Resection of recurrences and liver metastases where feasible; no established systemic therapy; case reports only.","refs":["oligometastatic","distal-pancreatectomy"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["Recognised as a beta-catenin-driven, low-grade cancer distinct from ductal adenocarcinoma, with excellent long-term outcomes after surgery."],"history":[{"year":1959,"title":"Frantz describes the tumour (papillary tumour of the pancreas)","refs":["tumour-grade"]},{"year":2002,"title":"Beta-catenin mutations found in almost all solid pseudopapillary tumours","refs":["wnt"]},{"year":2014,"title":"Systematic review of 2,744 cases: 95.6 percent disease-free after resection","refs":["distal-pancreatectomy"]}],"pipeline":[],"openProblems":["No systemic therapy is established for the few patients with unresectable recurrence.","The optimal length of follow-up is unknown because recurrences are late and rare.","Small biopsies confuse it with neuroendocrine tumours; beta-catenin staining is the key."],"parent":"pancreatic"},{"id":"somatostatinoma","kind":"cancer","name":"Somatostatinoma","aka":["Somatostatin-secreting neuroendocrine tumour","Duodenal somatostatinoma","Delta-cell tumour","Inhibitory syndrome tumour"],"tldr":"Somatostatinoma is one of the rarest neuroendocrine tumours, arising in the pancreas or the duodenum and secreting somatostatin, a hormone that switches off digestion, which can cause mild diabetes, gallstones and fatty diarrhoea. Duodenal cases are often linked to neurofibromatosis type 1 and rarely cause symptoms. Surgery is the main treatment and the outlook depends on site and grade.","summary":"Somatostatinoma is a rare neuroendocrine tumour of delta cells, about 1 percent of gastroenteropancreatic endocrine neoplasms, most often in the duodenum followed by the pancreas; it may be sporadic or associated with neurofibromatosis type 1, MEN1 and von Hippel-Lindau disease, and functional tumours cause the inhibitory syndrome of mild diabetes, cholelithiasis and diarrhoea or steatorrhoea by suppressing gallbladder motility and endocrine and exocrine secretion, while non-functional tumours are asymptomatic or obstructive (J Gastroenterol Hepatol 2008). The incidence is about 1 in 40 million; duodenal and periampullary tumours cause jaundice or pancreatitis, and the NF1 association reflects RAS-MAPK pathway dysfunction, with the Pacak-Zhuang syndrome (EPAS1) a rarer genetic setting; surgery is central where feasible and prognosis depends on location and WHO grade (Experimental and Therapeutic Medicine 2020).\n\nHow it differs from its parent: it is the functioning tumour whose hormone inhibits rather than stimulates, so its syndrome is subtle and most cases are found by obstruction or incidentally; duodenal tumours are usually small, often psammomatous and syndromic, whereas pancreatic tumours are larger and more often metastatic.\n\nHow common: about 1 in 40 million (Experimental and Therapeutic Medicine 2020).\n\nTreatment: resection (pancreatoduodenectomy or local excision by size and site); the parent page's pathways (somatostatin analogues, everolimus, sunitinib, peptide receptor radionuclide therapy) for metastatic disease, with grade guiding the choice; NF1 patients are screened for other tumours.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Somatostatinoma","links":[{"label":"NCI PDQ: pancreatic neuroendocrine (islet cell) tumour treatment","url":"https://www.cancer.gov/types/pancreatic/neuroendocrine-tumors/treatment"},{"label":"J Gastroenterol Hepatol 2008: somatostatinoma, three cases and literature review","url":"https://doi.org/10.1111/j.1440-1746.2007.05053.x"},{"label":"Experimental and Therapeutic Medicine 2020: somatostatinoma beyond neurofibromatosis type 1 (review)","url":"https://doi.org/10.3892/etm.2020.8965"}],"tags":["subtype-page","wave4","rare"],"related":["pancreatic-net","glucagonoma","vipoma","small-intestinal-net","men1-syndrome"],"cancers":[],"sections":[],"technologies":["prrt"],"targets":["nf1"],"drugs":["everolimus","sunitinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"About 1 percent of gastroenteropancreatic endocrine neoplasms, with roughly 200 published cases by 2008 (J Gastroenterol Hepatol 2008); an incidence of about 1 in 40 million people (Experimental and Therapeutic Medicine 2020).","subtypes":["Duodenal somatostatinoma (often NF1-associated, psammomatous, small)","Pancreatic somatostatinoma (larger, more often metastatic)","Functional somatostatinoma with the inhibitory syndrome","Non-functional somatostatin-expressing neuroendocrine tumour (incidental or obstructive)"],"biomarkers":["Plasma somatostatin","NF1 status; MEN1 and VHL in syndromic cases","WHO grade (Ki-67) and site","Somatostatin receptor imaging"],"standardOfCare":[{"setting":"All cases","approach":"Resection by size and site; the parent page's pathways for metastatic disease; screening of NF1 patients for other tumours.","refs":["pancreatic-net","everolimus","sunitinib","prrt"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"pancreatic-net"},{"id":"somatotroph-pitnet","kind":"cancer","name":"Somatotroph pituitary neuroendocrine tumour (acromegaly)","aka":["Somatotroph tumour","Somatotroph tumour (acromegaly)","Growth hormone-secreting pituitary adenoma","GH-secreting PitNET","Somatotroph adenoma","Gigantism (in children)"],"tldr":"A somatotroph tumour is a pituitary tumour that makes too much growth hormone, causing acromegaly in adults (enlarging hands, feet and face, diabetes, heart and joint disease) or gigantism in children. Surgery through the nose comes first; if hormone levels stay high, somatostatin analogue injections, the blocker pegvisomant or radiotherapy bring them down, restoring a normal life expectancy.","summary":"The 2022 WHO classification places the somatotroph tumour in the PIT1 lineage with densely and sparsely granulated subtypes (the sparsely granulated tumour being larger, more invasive and less responsive to first-generation somatostatin analogues) beside the mammosomatotroph and mixed tumours (Asa 2022). The 13th Acromegaly Consensus Conference (2019) set out multidisciplinary management at pituitary tumour centres of excellence: surgery, radiotherapy and medical therapy, their results and side effects, and how they are combined and personalised (Giustina 2020); the 2013 consensus on medical treatment defined biochemical, clinical and tumour-volume goals and the place of somatostatin receptor ligands, the growth hormone receptor antagonist and dopamine agonists (Giustina 2014).\n\nHow it differs from its parent: the harm comes from the hormone rather than the mass, so biochemical control (normal IGF-1 and growth hormone) is the treatment target and predicts survival; the granulation subtype predicts drug response; and the disease is often diagnosed a decade after onset because the changes are slow.\n\nHow common: no separate incidence figure in the sources read.\n\nTreatment: transsphenoidal surgery first; first-generation somatostatin analogues (octreotide, lanreotide) or pasireotide, pegvisomant, or cabergoline for persistent disease, alone or combined; radiotherapy including radiosurgery for residual tumour not controlled medically, as the consensus documents describe (Giustina 2020; Giustina 2014).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Acromegaly","links":[{"label":"NCI PDQ: pituitary tumours treatment","url":"https://www.cancer.gov/types/pituitary/treatment"},{"label":"Asa 2022, Endocrine Pathology: overview of the 2022 WHO classification of pituitary tumours","url":"https://doi.org/10.1007/s12022-022-09703-7"},{"label":"Giustina 2020, Rev Endocr Metab Disord: multidisciplinary management of acromegaly, a consensus","url":"https://doi.org/10.1007/s11154-020-09588-z"},{"label":"Giustina 2014, Nature Reviews Endocrinology: consensus on the medical treatment of acromegaly","url":"https://doi.org/10.1038/nrendo.2014.21"}],"tags":["subtype-page","wave4","rare"],"related":["pituitary-tumours","lactotroph-pitnet","corticotroph-pitnet","gonadotroph-pitnet","thyrotroph-pitnet"],"cancers":[],"sections":[],"technologies":["radiosurgery-srs"],"targets":[],"drugs":["pasireotide","pegvisomant","cabergoline"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"The pituitary tumour behind acromegaly; the acromegaly consensus conferences give its clinical figures and the parent page the pituitary tumour figures. GLOBOCAN does not count pituitary tumours.","subtypes":["Densely granulated somatotroph pituitary tumour (responds to first-generation somatostatin analogues)","Sparsely granulated somatotroph pituitary tumour (larger, invasive, less responsive)","Mammosomatotroph and mixed somatotroph-lactotroph tumours","Somatotroph tumour in gigantism (children; AIP or GPR101 germline in some)"],"biomarkers":["IGF-1 and growth hormone after glucose","Granulation pattern and cytokeratin staining; PIT1 lineage","Somatostatin receptor 2 and 5 expression (drug response)","AIP and GPR101 germline testing in young or familial cases"],"standardOfCare":[{"setting":"First line","approach":"Transsphenoidal surgery at a pituitary centre.","refs":["pituitary-tumours"]},{"setting":"Persistent disease","approach":"Somatostatin analogues or pasireotide, pegvisomant, cabergoline, alone or combined; radiotherapy for residual tumour not controlled medically.","refs":["pasireotide","pegvisomant","cabergoline","radiosurgery-srs"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"pituitary-tumours"},{"id":"spermatocytic-tumour","kind":"cancer","name":"Spermatocytic tumour of the testis","aka":["Spermatocytic seminoma","Spermatocytic tumour (older men, indolent)","Spermatocytic tumour (older men, almost never metastasises)","Spermatocytic tumor"],"tldr":"Spermatocytic tumour, once called spermatocytic seminoma, is a rare testicular germ cell tumour of older men that arises from maturing sperm precursors rather than from the fetal germ cells behind ordinary testicular cancer. It almost never spreads, so removing the testis is the whole treatment and no chemotherapy or radiotherapy is needed.","summary":"The 2016 WHO classification renamed spermatocytic seminoma as spermatocytic tumour and placed it among the germ cell tumours unrelated to germ cell neoplasia in situ, because it derives from postpubertal spermatogonia rather than from the arrested fetal germ cells that give rise to seminoma and non-seminoma (Moch 2016). Marker studies identified two types characterised by OCT2 or SSX2-4 expression, corresponding to distinct spermatogonial subpopulations, supporting a spermatogonial stem cell origin (Journal of Pathology 2011). In the Australian registry study it made up 1.1 percent of seminomas, with a mean age of 53.5 but a range from 19 to 92, occurring as often under 55 as over (Journal of Urology 2007).\n\nHow it differs from its parent: it lacks isochromosome 12p and germ cell neoplasia in situ, is not associated with cryptorchidism or the other risk factors of testicular cancer, does not raise the serum markers, and metastasises almost never except in the rare sarcomatous transformation, so the surveillance and chemotherapy pathways of seminoma do not apply.\n\nHow common: 0.4 per million men a year (Journal of Urology 2007).\n\nTreatment: radical orchidectomy alone, with no adjuvant therapy and no routine retroperitoneal imaging beyond a baseline scan; the rare tumour with sarcomatous transformation is treated as a sarcoma.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Spermatocytic_tumor","links":[{"label":"NCI PDQ: testicular cancer treatment","url":"https://www.cancer.gov/types/testicular/treatment"},{"label":"Moch 2016, European Urology: the 2016 WHO classification of urinary and male genital tumours, part A","url":"https://doi.org/10.1016/j.eururo.2016.02.029"},{"label":"Journal of Urology 2007: population-based incidence and age distribution of spermatocytic seminoma","url":"https://doi.org/10.1016/j.juro.2007.03.024"},{"label":"Journal of Pathology 2011: OCT2, SSX and SAGE1 reveal the spermatogonial origin of spermatocytic seminoma","url":"https://doi.org/10.1002/path.2919"}],"tags":["subtype-page","wave4","testicular","rare"],"related":["testicular","seminoma","germ-cell-neoplasia-in-situ","leydig-cell-tumour"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["tumour-markers"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"58 of 9,658 primary malignant testicular tumours in Australia over 1982 to 2002, 1.1 percent of all seminomas, an age-standardised incidence of 0.4 per million men a year; age 19 to 92, mean 53.5 (Journal of Urology 2007).","subtypes":[],"biomarkers":["OCT2 or SSX2-4 expression; OCT4 negative (unlike seminoma)","No isochromosome 12p","Normal alpha-fetoprotein and beta-hCG","Sarcomatous component (the only malignant course)"],"standardOfCare":[{"setting":"All cases","approach":"Radical orchidectomy alone; no adjuvant therapy.","refs":["testicular","seminoma"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"testicular"},{"id":"spinal-cord-tumours","kind":"cancer","name":"Spinal cord tumours (intramedullary and intradural)","aka":["Intramedullary spinal cord tumour","Spinal ependymoma","Spinal astrocytoma","Intradural extramedullary tumour","Spinal cord glioma"],"tldr":"Tumours inside or around the spinal cord are rare and usually slow growing, but they press on the cord and threaten walking and bladder control. Most are removed by a surgeon watching nerve signals during the operation; radiotherapy is used when a tumour cannot be fully removed or is high grade, and there are few drugs.","summary":"Spinal cord tumours are grouped by compartment. Intramedullary tumours, inside the cord, are mostly ependymomas in adults (WHO 2021 recognises spinal ependymoma, a MYCN-amplified aggressive subtype, and myxopapillary ependymoma of the filum terminale, now grade 2) and astrocytomas in children, with haemangioblastoma (a third of which are part of von Hippel-Lindau disease) and rare gangliogliomas; diffuse midline gliomas with H3 K27 alteration also occur in the cord and carry that diagnosis. Intradural extramedullary tumours are meningiomas and nerve sheath tumours (schwannoma, neurofibroma), often multiple in NF2-related schwannomatosis and neurofibromatosis type 1. Metastases to the vertebrae and cord compression from them are a separate, far commoner problem handled on the metastatic cancer page.\n\nSurgery with intraoperative neurophysiological monitoring is the mainstay: ependymomas and haemangioblastomas have a plane and can usually be removed completely, which is curative for most; astrocytomas infiltrate and are debulked or biopsied. Radiotherapy follows incomplete resection of ependymoma, any high-grade tumour, and recurrence, with intensity-modulated or proton techniques to spare the cord and adjacent organs. Chemotherapy has a small role, largely temozolomide for high-grade astrocytoma by extrapolation from brain gliomas; belzutifan is approved for von Hippel-Lindau-associated haemangioblastomas that do not need immediate surgery and can shrink cord lesions.\n\nOutcome depends more on neurological state at diagnosis than on any treatment, so early recognition of back pain with progressive weakness or sensory change matters. Long-term follow-up with MRI is standard because recurrence can be late. Molecular classification, including methylation profiling and MYCN status for ependymoma, is beginning to refine prognosis, and NF2-related tumours are the subject of the same targeted trials as vestibular schwannoma.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Spinal_tumor","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Spinal_tumor"},{"label":"NCI: adult central nervous system tumours treatment (PDQ)","url":"https://www.cancer.gov/types/brain/hp/adult-brain-treatment-pdq"}],"tags":["subtype-page","cns"],"related":["brain-tumours","ependymoma","meningioma","vestibular-schwannoma","dipg-dmg","metastatic-cancer","secondary-brain-tumours"],"cancers":[],"sections":[],"technologies":["mri","imrt-igrt","proton-therapy","radiosurgery-srs","methylation-profiling"],"targets":[],"drugs":["belzutifan","temozolomide"],"companies":[],"institutions":[],"pathways":[],"terms":["h3k27m","ependymoma-molecular-groups"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2021-cns-louis-neuro-oncology-2021","paper-belzutifan-vhl-jonasch-nejm-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"central nervous system","burden":"A small fraction of central nervous system tumours, mostly benign or low grade; ependymoma is the commonest intramedullary tumour in adults and astrocytoma in children, and meningioma and schwannoma dominate the intradural extramedullary space.","subtypes":["Spinal ependymoma (intramedullary, adults; MYCN-amplified subtype aggressive)","Myxopapillary ependymoma of the filum terminale and cauda equina","Spinal cord astrocytoma (pilocytic or diffuse, mostly children)","Diffuse midline glioma, H3 K27-altered, of the spinal cord","Haemangioblastoma (sporadic or von Hippel-Lindau)","Intradural extramedullary meningioma and schwannoma (spinal, often NF2-related)"],"biomarkers":["Compartment on MRI (intramedullary, intradural extramedullary, extradural)","MYCN amplification in spinal ependymoma","H3 K27M status in cord gliomas","Germline VHL testing for haemangioblastoma","NF2 germline status in multiple nerve sheath tumours","Pre-operative neurological grade (McCormick scale)"],"standardOfCare":[{"setting":"Intramedullary ependymoma or haemangioblastoma","approach":"Gross total resection with intraoperative neurophysiological monitoring; complete removal is usually curative and needs no adjuvant treatment.","refs":["mri"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Incompletely resected, high grade or recurrent","approach":"Focal radiotherapy with intensity-modulated or proton techniques; temozolomide for high-grade astrocytoma by extrapolation.","refs":["imrt-igrt","proton-therapy","temozolomide"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Von Hippel-Lindau haemangioblastoma not needing immediate surgery","approach":"Belzutifan, the HIF-2 alpha inhibitor approved for VHL-associated central nervous system haemangioblastomas, with surveillance imaging.","refs":["belzutifan"],"guideline":{"version":"FDA label 2021"}},{"setting":"Intradural extramedullary meningioma or schwannoma","approach":"Resection when symptomatic or growing; radiosurgery for residual or recurrent tumour where the cord dose allows; observation for small asymptomatic lesions.","refs":["radiosurgery-srs","active-surveillance"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}}],"stateOfArt":["Intraoperative monitoring has made complete removal of intramedullary ependymoma and haemangioblastoma routine with acceptable neurological risk.","Belzutifan is the first drug to shrink von Hippel-Lindau haemangioblastomas and defer surgery.","WHO 2021 gave spinal ependymoma its own type and flagged MYCN amplification as the marker of the aggressive minority."],"history":[{"year":1887,"title":"Gowers and Horsley remove a spinal cord tumour","note":"The first successful operation for an intradural spinal tumour.","refs":[]},{"year":1907,"title":"Von Eiselsberg resects an intramedullary tumour","refs":[]},{"year":1993,"title":"VHL gene identified","note":"Haemangioblastoma of the cord and cerebellum recognised as a hallmark of the syndrome.","refs":[]},{"year":2021,"title":"WHO 2021 lists spinal ependymoma, MYCN-amplified, and regrades myxopapillary ependymoma to grade 2","refs":[]},{"year":2021,"title":"Belzutifan approved for von Hippel-Lindau tumours including CNS haemangioblastomas","refs":["belzutifan"]}],"pipeline":["belzutifan","proton-therapy","methylation-profiling"],"openProblems":["Almost no trial evidence; treatment is extrapolated from brain tumours and case series.","Infiltrating cord astrocytomas cannot be removed and have no effective drug.","Radiotherapy to the cord is limited by myelopathy risk.","Neurological deficit at presentation, not treatment, decides most outcomes, so diagnosis is often too late."],"parent":"brain-tumours"},{"id":"splenic-b-cell-lymphoma-leukaemia-prominent-nucleoli","kind":"cancer","name":"Splenic B-cell lymphoma/leukaemia with prominent nucleoli (formerly B-cell prolymphocytic leukaemia and hairy cell leukaemia variant)","aka":["SBLPN","B-cell prolymphocytic leukaemia","B-cell prolymphocytic leukemia","B-PLL","Hairy cell leukaemia variant","HCL-v","Splenic B-cell lymphoma/leukemia with prominent nucleoli"],"tldr":"Splenic B-cell lymphoma/leukaemia with prominent nucleoli is the new WHO name for a rare group of B-cell leukaemias of older adults with a big spleen, large cells with obvious nucleoli and a poor response to standard treatment; it absorbs the old diagnoses B-cell prolymphocytic leukaemia and hairy cell leukaemia variant. It is treated with rituximab-based chemotherapy or newer targeted drugs.","summary":"WHO-HAEM5 discontinued B-cell prolymphocytic leukaemia as an entity and reframed hairy cell leukaemia variant, placing cases previously classified as CD5-negative B-PLL and as hairy cell leukaemia variant, together with splenic marginal zone and splenic diffuse red pulp lymphomas with many medium or large nucleolated cells, in a new category, splenic B-cell lymphoma/leukaemia with prominent nucleoli, as a temporary holding ground for cases that do not fit the existing classification; B-PLL had overlapped with chronic lymphocytic leukaemia and mantle cell lymphoma, and hairy cell leukaemia variant lacked consistent features (Alaggio 2022; British Journal of Haematology 2024). The old B-PLL literature described an aggressive mature B-cell disorder with p53 abnormalities in about half: loss of heterozygosity at 17p in 53 percent and TP53 mutations in 53 percent of 19 cases, a pattern distinct from CLL (Lens 1997). A three-case series of the renamed entity describes middle-aged men with cytopenias and CD25-negative or dim hairy cells that respond worse to therapy than classic hairy cell leukaemia (J Cancer Res Ther 2024).\n\nHow it differs from its parent: it is a diagnosis of exclusion among the splenic B-cell leukaemias, made after CLL with prolymphocytoid progression, mantle cell lymphoma (cyclin D1, SOX11) and classic hairy cell leukaemia (BRAF V600E, CD25, annexin A1) have been ruled out, and it behaves worse than any of them.\n\nHow common: no figure for the new category; the constituent diagnoses were uncommon (British Journal of Haematology 2024).\n\nTreatment: no trial exists; rituximab with chemotherapy (bendamustine or cladribine-based regimens borrowed from hairy cell leukaemia variant practice), BTK inhibitors and venetoclax by analogy with TP53-disrupted CLL, and allogeneic transplant for fit patients, following the CLL and hairy cell leukaemia pages.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/B-cell_prolymphocytic_leukemia","links":[{"label":"NCI PDQ: chronic lymphocytic leukaemia treatment","url":"https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq"},{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"British Journal of Haematology 2024: understanding splenic B-cell lymphoma/leukaemia with prominent nucleoli","url":"https://doi.org/10.1111/bjh.19754"},{"label":"Lens 1997, Blood: p53 abnormalities in B-cell prolymphocytic leukaemia","url":"https://doi.org/10.1182/blood.v89.6.2015"},{"label":"J Cancer Res Ther 2024: splenic B-cell lymphoma/leukaemia with prominent nucleoli, three cases and review","url":"https://doi.org/10.4103/jcrt.jcrt_1931_22"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["leukaemia","cll","hairy-cell-leukemia","splenic-marginal-zone-lymphoma","mantle-cell-lymphoma","t-cell-prolymphocytic-leukaemia"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["rituximab","bendamustine","ibrutinib","venetoclax"],"companies":[],"institutions":[],"pathways":[],"terms":["allogeneic-transplant"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare: B-PLL and hairy cell leukaemia variant diagnoses were uncommon and the new category is a holding ground for cases that fit neither the classic types nor CLL (British Journal of Haematology 2024). No registry figure exists for the new category.","subtypes":["Former CD5-negative B-cell prolymphocytic leukaemia","Former hairy cell leukaemia variant (CD25-negative, BRAF wild-type)","Splenic marginal zone or diffuse red pulp lymphoma with prominent nucleolated cells"],"biomarkers":["Large nucleolated B cells in blood and marrow; CD5 negative, CD25 negative or dim, BRAF V600E absent","TP53 mutation or 17p deletion (about half of former B-PLL)","Exclusion of cyclin D1 and SOX11 (mantle cell lymphoma) and of CLL immunophenotype","Splenomegaly with lymphocytosis"],"standardOfCare":[{"setting":"All cases","approach":"Rituximab with chemotherapy borrowed from hairy cell leukaemia variant practice; BTK inhibitors or venetoclax by analogy with TP53-disrupted CLL; allogeneic transplant for fit patients; no trial exists.","refs":["rituximab","bendamustine","ibrutinib","venetoclax","cll","hairy-cell-leukemia"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"leukaemia"},{"id":"splenic-marginal-zone-lymphoma","kind":"cancer","name":"Splenic marginal zone lymphoma","aka":["SMZL","Splenic lymphoma with villous lymphocytes","Splenic marginal zone B-cell lymphoma"],"tldr":"Splenic marginal zone lymphoma is a slow-growing lymphoma that grows in the spleen and bone marrow, causing a very large spleen and a raised lymphocyte count but rarely swollen lymph nodes. Many people need no treatment for years; when they do, rituximab has largely replaced removal of the spleen, and hepatitis C should be treated first where it is present.","summary":"WHO-HAEM5 keeps splenic marginal zone lymphoma as the splenic member of the marginal zone lymphoma family, defined by massive splenomegaly, moderate lymphocytosis with or without villous lymphocytes, marrow involvement, rare peripheral lymphadenopathy and an indolent course; with no randomised trials there is no formal standard of care, and splenectomy, done for many years, is no longer encouraged first-line because rituximab is as effective with less toxicity (Alaggio 2022; Rev Bras Hematol Hemoter 2017). Its genome carries recurrent NOTCH2, KLF2 and TP53 mutations, with TNFAIP3, KMT2D and TRAF3 also recurrent across 475 cases, though exome studies agree poorly with one another (Scientific Reports 2019). An association with hepatitis C virus is recognised in the ESMO guideline, which recommends antiviral therapy as first treatment in infected patients (Zucca 2020).\n\nHow it differs from its parent: it is diagnosed from blood, marrow and spleen rather than a tissue biopsy of an organ or node; it carries the NOTCH2 and KLF2 lesions the other marginal zone lymphomas mostly lack; and its differential diagnosis includes hairy cell leukaemia and the new WHO-HAEM5 category of splenic B-cell lymphoma/leukaemia with prominent nucleoli.\n\nHow common: no registry share in the sources read; rare.\n\nTreatment: watch and wait while asymptomatic; antiviral therapy for hepatitis C-associated disease; rituximab alone or with chemotherapy for symptomatic disease; splenectomy for selected patients; BTK inhibitors and lenalidomide-rituximab as on the parent page (Zucca 2020; Rev Bras Hematol Hemoter 2017).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Splenic_marginal_zone_lymphoma","links":[{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq"},{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"Zucca 2020, Annals of Oncology: marginal zone lymphomas, ESMO clinical practice guidelines","url":"https://doi.org/10.1016/j.annonc.2019.10.010"},{"label":"Rev Bras Hematol Hemoter 2017: splenic marginal zone lymphoma, review of diagnostic and therapeutic challenges","url":"https://doi.org/10.1016/j.bjhh.2016.09.014"},{"label":"Scientific Reports 2019: systematic review of somatic mutations in splenic marginal zone lymphoma, 475 cases","url":"https://doi.org/10.1038/s41598-019-46906-1"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["marginal-zone-lymphoma","malt-lymphoma","nodal-marginal-zone-lymphoma","hairy-cell-leukemia","splenic-b-cell-lymphoma-leukaemia-prominent-nucleoli"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["rituximab","bendamustine","zanubrutinib","lenalidomide"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-tx-watch-and-wait","lymphoma-tx-pjp-and-infection-prophylaxis"],"trials":["augment"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare; the systematic review of its mutations gathered 475 sequenced cases from fourteen studies (Scientific Reports 2019). The ESMO guideline treats it as the least common of the three marginal zone lymphomas; no registry share is in the sources read.","subtypes":["Splenic marginal zone lymphoma with villous lymphocytes","Hepatitis C-associated splenic marginal zone lymphoma","Splenic marginal zone lymphoma with NOTCH2 or KLF2 mutation","Transformed splenic marginal zone lymphoma (diffuse large B-cell)"],"biomarkers":["Villous lymphocytes and marrow intrasinusoidal infiltration","NOTCH2, KLF2 and TP53 mutations","Hepatitis C serology","Immunophenotype: CD20 positive, CD5, CD10, CD103 and annexin A1 negative"],"standardOfCare":[{"setting":"Asymptomatic","approach":"Watch and wait; antiviral therapy first if hepatitis C is present.","refs":["marginal-zone-lymphoma"]},{"setting":"Symptomatic","approach":"Rituximab alone or with chemotherapy; splenectomy for selected patients; BTK inhibitors or lenalidomide-rituximab later.","refs":["rituximab","bendamustine","zanubrutinib","lenalidomide","augment"]},{"setting":"Splenic marginal zone lymphoma: hepatitis C first, then rituximab, then splenectomy","approach":"An indolent disease of the spleen, marrow and blood. A patient with no symptoms, no cytopenias and a spleen that is not troublesome is watched, sometimes for years.\n\nWhen treatment is needed, the order is: test and treat hepatitis C if present, because direct-acting antivirals alone produce lymphoma remission in a proportion of hepatitis C-associated cases and that is a reason to check before giving any chemotherapy. Then rituximab alone, weekly for four to eight doses, which corrects cytopenias and shrinks the spleen in the large majority and has displaced splenectomy as first treatment. Chemoimmunotherapy with bendamustine and rituximab is used for disease that does not respond or that transforms.\n\nSplenectomy is now reserved for patients who cannot have rituximab, whose disease is confined to the spleen and who need a diagnosis, or who have refractory painful splenomegaly. It requires pneumococcal, Haemophilus influenzae type b and meningococcal vaccination at least two weeks beforehand where possible, and lifelong penicillin prophylaxis afterwards. Zanubrutinib has activity in relapsed disease across marginal zone subtypes.","refs":["rituximab","bendamustine","zanubrutinib","lymphoma-tx-watch-and-wait","lymphoma-tx-pjp-and-infection-prophylaxis","paper-magnolia-zanubrutinib-mzl-ccr-2021","paper-esmo-marginal-zone-lymphoma-zucca-ann-oncol-2020"],"guideline":{"version":"ESMO marginal zone lymphomas; NCCN B-Cell Lymphomas","url":"https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-haematological-malignancies"}}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"marginal-zone-lymphoma"},{"id":"lung-squamous-cell-carcinoma","kind":"cancer","name":"Squamous cell carcinoma of the lung","aka":["Squamous-cell carcinoma of the lung","Lung squamous cell carcinoma","Squamous NSCLC","Squamous","Squamous cell carcinoma (~25-30%)","Epidermoid carcinoma of the lung","Keratinising and non-keratinising squamous cell carcinoma of the lung"],"tldr":"Squamous cell carcinoma is the second most common type of lung cancer and the one most tightly linked to smoking; it starts in the flat cells lining the large central airways. Unlike adenocarcinoma it rarely carries a mutation a tablet can target, so treatment rests on chemotherapy with immunotherapy, and pemetrexed and bevacizumab are not used.","summary":"Squamous cell carcinoma shows keratinisation, intercellular bridges or, when poorly differentiated, expression of p40 or p63 without TTF-1; the WHO classification divides it into keratinising, non-keratinising and basaloid forms (the last has its own page) and in 2021 moved lymphoepithelial carcinoma into the squamous group (Nicholson 2022). Tumours are typically central and cavitate. Genomically it is a disease of complex, smoking-related damage rather than single drivers: the 178 tumours of the Cancer Genome Atlas averaged 360 exonic mutations each, TP53 was mutated in nearly all, NFE2L2 or KEAP1 in 34 percent and the squamous differentiation genes in 44 percent, and loss-of-function mutations in HLA-A were a new finding (TCGA 2012). EGFR mutations and ALK fusions are rare enough that guidelines test only never-smokers or mixed tumours.\n\nHow it differs from its parent: the non-small-cell lung cancer page and its driver subpages are largely about adenocarcinoma. In squamous disease the driver pathway rarely applies, pemetrexed is inactive and bevacizumab is avoided because of bleeding from central tumours, so the chemotherapy backbone is platinum with paclitaxel, nab-paclitaxel or gemcitabine.\n\nHow common: about 25 percent of lung cancers (NCI PDQ); Cancer Research UK lists it as the second most common type.\n\nTreatment: for metastatic disease carboplatin with paclitaxel or nab-paclitaxel plus pembrolizumab, the KEYNOTE-407 regimen linked here, or cemiplimab with chemotherapy (EMPOWER-Lung 3) or the PD-L1-high pathway on the parent page; the EGFR antibody necitumumab added a small survival gain to gemcitabine and cisplatin in SQUIRE and is licensed but little used; afatinib and docetaxel are second-line options; the Lung-MAP master protocol tests biomarker-matched drugs in previously treated squamous disease. Early-stage disease is treated as the parent's resectable and stage III pages describe.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Squamous-cell_carcinoma_of_the_lung","links":[{"label":"NCI PDQ (health professional): non-small cell lung cancer treatment, histological shares","url":"https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq"},{"label":"Cancer Research UK: types of lung cancer","url":"https://www.cancerresearchuk.org/about-cancer/lung-cancer/stages-types/types"},{"label":"Nicholson 2022, JTO: the 2021 WHO classification of lung tumours","url":"https://doi.org/10.1016/j.jtho.2021.11.003"},{"label":"TCGA 2012, Nature: comprehensive genomic characterisation of squamous cell lung cancers","url":"https://doi.org/10.1038/nature11404"},{"label":"SQUIRE (Thatcher 2015, Lancet Oncology): necitumumab with gemcitabine and cisplatin in squamous NSCLC","url":"https://doi.org/10.1016/s1470-2045(15)00021-2"},{"label":"Lancet Respir Med 2025: estimated worldwide variation and trends in incidence of lung cancer by histological subtype in 2022 and over time (GLOBOCAN 2022 with Cancer Incidence in Five Continents)","url":"https://doi.org/10.1016/s2213-2600(24)00428-4"},{"label":"Nicholson, J Thorac Oncol 2022: the 2021 WHO classification of lung tumours, impact of advances since 2015","url":"https://doi.org/10.1016/j.jtho.2021.11.003"}],"tags":["subtype-page","wave4","lung"],"related":["nsclc","lung-adenocarcinoma","basaloid-squamous-cell-carcinoma-lung","lymphoepithelial-carcinoma-lung","large-cell-lung-carcinoma","pdl1-high-nsclc","lung-adenosquamous-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab","carboplatin","paclitaxel","nab-paclitaxel","gemcitabine","cisplatin","necitumumab","nedaplatin","afatinib","docetaxel","ramucirumab","cemiplimab"],"companies":[],"institutions":[],"pathways":[],"terms":["ttf1-p40","haemoptysis"],"trials":["keynote-407","lung-map","lung-map-s1400i","sqnsclc","empower-lung-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["How common it is, worldwide and by sex. Of 1,572,045 lung cancers in men in 2022, 461,171 (29.4 percent) were squamous cell carcinoma; of 908,630 in women, 155,598 (17.1 percent). The highest age-standardised rates are in eastern Europe for men (21.70 per 100,000) and north America for women (5.28) (Lancet Respiratory Medicine 2025). The sex difference is the clearest signature of the smoking epidemic in the histology data: squamous cell carcinoma tracks tobacco more closely than adenocarcinoma does.","Where the 2021 WHO classification moved things. Lymphoepithelial carcinoma of the lung was moved into the squamous cell carcinomas in the fifth edition, and basaloid squamous cell carcinoma remains a recognised pattern; both have their own pages in this corpus (Nicholson 2022)."],"group":"lung","burden":"About 25 percent of lung cancers (NCI PDQ), and about 400,000 deaths a year worldwide in the 2012 genome atlas estimate (TCGA 2012). GLOBOCAN counts it within lung cancer.","subtypes":["Keratinising squamous cell carcinoma","Non-keratinising squamous cell carcinoma (p40-positive, TTF-1-negative)","Basaloid squamous cell carcinoma (own page)","Lymphoepithelial carcinoma (own page)","Squamous cell carcinoma in a never-smoker (test for drivers as adenocarcinoma)"],"biomarkers":["p40 and p63 on immunohistochemistry, TTF-1 negative","PD-L1 tumour proportion score","TP53, NFE2L2 and KEAP1 mutations (prognostic, not yet actionable)","Driver testing in never-smokers or mixed histology only"],"standardOfCare":[{"setting":"Metastatic, first line","approach":"Carboplatin with paclitaxel or nab-paclitaxel plus pembrolizumab (KEYNOTE-407); cemiplimab with chemotherapy or the parent's PD-L1-high pathway as alternatives.","refs":["keynote-407","pembrolizumab","carboplatin","paclitaxel","nab-paclitaxel","cemiplimab","pdl1-high-nsclc"]},{"setting":"Metastatic, later lines","approach":"Docetaxel with or without ramucirumab; afatinib; biomarker-matched drugs through Lung-MAP.","refs":["docetaxel","ramucirumab","afatinib","lung-map","lung-map-s1400i"]},{"setting":"Early stage","approach":"Treated as the parent's resectable and stage III pages describe.","refs":["resectable-nsclc","stage-iii-unresectable-nsclc"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"nsclc"},{"id":"urethral-squamous-cell-carcinoma","kind":"cancer","name":"Squamous cell carcinoma of the urethra","aka":["Urethral squamous cell carcinoma","Squamous cell carcinoma (distal urethra; HPV-associated in some)","Distal urethral carcinoma"],"tldr":"Squamous cell carcinoma of the urethra is the type of urethral cancer that grows in the outer part of the urethra, where the lining is skin-like; in some cases HPV is involved. It is treated like anal or vulval cancer of the same cell type, with chemotherapy and radiotherapy together to avoid removing the urethra.","summary":"Squamous cell carcinoma arises in the distal (penile or anterior) urethra in men and the distal urethra and meatus in women, where the lining is squamous, and in the EAU classification it is one of the three principal histologies of primary urethral carcinoma with urothelial carcinoma and adenocarcinoma (Gakis 2013). It made up 30 percent of the 154 patients in the international collaboration (Gakis 2016). The parent page notes HPV in a proportion of cases, and p16 staining is listed among its terms.\n\nHow it differs from its parent: its site is distal, so it presents with a palpable mass, bleeding or obstruction near the meatus and drains to the inguinal nodes, like penile and vulval cancer, rather than to the pelvic nodes; that changes the surgery and the radiotherapy fields. Its treatment is borrowed from anal and vulval squamous cell carcinoma rather than from bladder cancer.\n\nHow common: no incidence figure for the squamous type alone is published; the parent's figure of fewer than one case per million a year covers all types.\n\nTreatment follows the EAU guideline for the parent, with no randomised trial: local excision or partial urethrectomy for small distal tumours, and for larger or node-positive disease chemoradiation with fluorouracil and mitomycin or cisplatin, as in anal cancer, so that the urethra can be kept (EAU Guidelines: primary urethral carcinoma; NCI PDQ). Inguinal node management follows penile and vulval cancer practice as the parent page describes.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Urethral_cancer","links":[{"label":"NCI PDQ: urethral cancer treatment","url":"https://www.cancer.gov/types/urethral/patient/urethral-treatment-pdq"},{"label":"EAU Guidelines: primary urethral carcinoma","url":"https://uroweb.org/guidelines/primary-urethral-carcinoma"},{"label":"Gakis 2013, European Urology: EAU guidelines on primary urethral carcinoma","url":"https://doi.org/10.1016/j.eururo.2013.03.044"},{"label":"Gakis 2016, World J Urol: international collaboration on primary urethral carcinoma, 154 patients","url":"https://doi.org/10.1007/s00345-015-1583-7"},{"label":"Derksen 2013, World J Urol: primary urethral carcinoma in females, Netherlands registry","url":"https://doi.org/10.1007/s00345-012-0882-5"}],"tags":["subtype-page","wave4","rare"],"related":["urethral","urethral-urothelial-carcinoma","urethral-adenocarcinoma","anal","vulvar","penile"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["fluorouracil","mitomycin","cisplatin"],"companies":[],"institutions":[],"pathways":[],"terms":["hpv-p16","chemoradiation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"The second histology: 46 of 154 patients (30 percent) in the international collaboration's series (Gakis 2016). In the Netherlands, urethral cancer in women had a crude incidence of 0.7 per million a year over 1989 to 2008 (Derksen 2013); no registry counts the squamous type alone.","subtypes":["Squamous cell carcinoma of the distal (penile) urethra in men","Squamous cell carcinoma of the distal urethra and meatus in women","HPV-associated squamous cell carcinoma of the urethra"],"biomarkers":["p16 and HPV status","Inguinal and pelvic node status","Depth of invasion and involvement of the corpus spongiosum"],"standardOfCare":[{"setting":"All stages","approach":"Treated as the parent page describes: urethra-sparing excision when small and distal; chemoradiation with fluorouracil and mitomycin or cisplatin when larger or node-positive, borrowed from anal cancer.","refs":["urethral","fluorouracil","mitomycin","cisplatin","chemoradiation"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"urethral"},{"id":"stage-ii-melanoma","kind":"cancer","name":"Stage IIB and IIC melanoma","aka":["High-risk stage II melanoma","Thick node-negative melanoma","Stage IIB/IIC melanoma"],"tldr":"Stage IIB and IIC melanomas are thick or ulcerated skin melanomas that have not reached the lymph nodes but still carry a real risk of coming back. A year of pembrolizumab or nivolumab after surgery lowers that risk, though most people in this group would have been cured by surgery alone, so the decision weighs a modest benefit against a year of treatment.","summary":"Stage II melanoma is node-negative disease staged by Breslow thickness and ulceration: IIB is a 2 to 4 millimetre ulcerated or a thicker non-ulcerated primary, IIC a primary over 4 millimetres with ulceration. Sentinel node biopsy defines the stage; if it is negative, treatment was for decades surgery alone with surveillance, since adjuvant interferon added little. Yet relapse and death rates for IIB and IIC exceed those of IIIA, and because stage II is so much commoner than stage III it contributes more melanoma deaths in absolute numbers.\n\nKEYNOTE-716 (2021) randomised 976 patients with resected IIB or IIC disease to a year of pembrolizumab or placebo and improved twelve-month recurrence-free survival from 83.1 to 90.5 percent (hazard ratio 0.65), with distant metastasis-free survival also improved and the benefit sustained at five years; pembrolizumab was approved for this stage in December 2021. CheckMate 76K (2023) found the same with nivolumab (twelve-month recurrence-free survival 89.0 against 79.4 percent, hazard ratio 0.42), approved in October 2023. INTerpath-001 (2026), which included stage IIB and IIC, met its endpoints for intismeran autogene added to pembrolizumab.\n\nThe absolute gain is smaller than in stage III, most patients would never have relapsed, and around one in five who receive a PD-1 antibody has an immune side effect that is sometimes permanent, so guidelines list adjuvant therapy as an option to discuss rather than a default. Circulating tumour DNA, gene-expression profiles and the sentinel node itself are being studied to pick out the minority who will relapse, and the adjuvant COLUMBUS-AD trial is testing encorafenib-binimetinib in BRAF-mutant stage II disease.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Melanoma","links":[{"label":"KEYNOTE-716 (Lancet 2022)","url":"https://doi.org/10.1016/S0140-6736(22)00562-1"},{"label":"CheckMate 76K (Nature Medicine 2023)","url":"https://doi.org/10.1038/s41591-023-02583-2"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Melanoma"}],"tags":["subtype-page"],"related":["stage-iii-melanoma","advanced-melanoma","braf-v600-melanoma"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","sentinel-node","liquid-biopsy"],"targets":["pd1"],"drugs":["pembrolizumab","nivolumab","intismeran-autogene"],"companies":[],"institutions":[],"pathways":[],"terms":["breslow-thickness","ulceration-melanoma","neoadjuvant-adjuvant","ctdna"],"trials":["keynote-716","nct04099251","interpath-001","nct05270044"],"people":["jason-luke"],"bottlenecks":[],"keyPapers":["paper-keynote-716-lancet-2022","paper-checkmate-76k-nat-med-2023","paper-ajcc-8-melanoma-gershenwald-ca-2017"],"journals":[],"dependsOn":[],"notes":[],"group":"skin","burden":"Stage IIB and IIC melanomas are thick or ulcerated primaries with a negative sentinel node; in the eighth staging edition five-year melanoma-specific survival is about 87 percent for IIB and 82 percent for IIC, worse than stage IIIA, and because stage II is far commoner than stage III it accounts for a large share of melanoma deaths.","subtypes":["Stage IIB (T3b, ulcerated 2 to 4 mm, or T4a, over 4 mm without ulceration)","Stage IIC (T4b, ulcerated and over 4 mm)","Stage IIA (not eligible for adjuvant therapy; surveillance)","BRAF V600-mutant stage II (COLUMBUS-AD adjuvant targeted therapy trial)","Thick nodular melanoma with negative sentinel node"],"biomarkers":["Breslow thickness","Ulceration of the primary","Sentinel lymph node status (must be negative for stage II)","Mitotic rate","BRAF V600 mutation (trial eligibility)","Circulating tumour DNA and gene-expression profiles (under study to select who needs adjuvant therapy)"],"standardOfCare":[{"setting":"Diagnosis and surgery","approach":"Wide local excision with margins set by thickness and sentinel lymph node biopsy for primaries over 0.8 mm or with ulceration.","refs":["wide-local-excision","sentinel-node","breslow-thickness"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Adjuvant, stage IIB or IIC","approach":"One year of pembrolizumab (KEYNOTE-716) or nivolumab (CheckMate 76K), or observation after a shared decision about a modest benefit and immune side effects.","refs":["keynote-716","nct04099251","pembrolizumab","nivolumab"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Adjuvant vaccine (emerging)","approach":"Intismeran autogene with pembrolizumab met its endpoints in INTerpath-001, which included stage IIB and IIC; regulatory review pending.","refs":["interpath-001","intismeran-autogene"]},{"setting":"Surveillance","approach":"Skin and nodal examination and, for higher-risk disease, imaging at intervals; patient education on self-examination.","refs":["skin-cancer-screening","dermoscopy-ai"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}}],"stateOfArt":["Adjuvant pembrolizumab and nivolumab lower relapse risk in stage IIB and IIC melanoma, extending immunotherapy to node-negative disease.","The debate over treating many to help few has made this stage the test bed for circulating tumour DNA and gene-expression selection.","The first positive phase 3 personalised vaccine trial included this stage."],"history":[{"year":2017,"title":"Eighth edition staging shows stage IIB and IIC outcomes worse than IIIA","refs":["breslow-thickness","ulceration-melanoma"]},{"year":2021,"title":"KEYNOTE-716: adjuvant pembrolizumab approved for stage IIB and IIC","refs":["keynote-716","pembrolizumab"]},{"year":2023,"title":"CheckMate 76K: adjuvant nivolumab approved for stage IIB and IIC","refs":["nct04099251","nivolumab"]},{"year":2026,"title":"INTerpath-001 positive in resected stage IIB to IV melanoma","refs":["interpath-001","intismeran-autogene"]}],"pipeline":["interpath-001","intismeran-autogene","nct05270044","idea-ctdna-guided-adjuvant-melanoma","liquid-biopsy"],"openProblems":["Roughly four in five patients would have been cured by surgery alone and cannot yet be told apart from the fifth.","No overall survival benefit has yet been shown for adjuvant therapy in stage II.","Permanent endocrine side effects in a minority weigh heavily when the absolute benefit is a few percentage points."],"parent":"melanoma"},{"id":"stage-iii-melanoma","kind":"cancer","name":"Stage III melanoma (after surgery)","aka":["Resected stage III melanoma","Node-positive melanoma","Regional melanoma","Adjuvant melanoma setting"],"tldr":"Stage III melanoma has spread to nearby lymph nodes but not further, and after surgery a year of immunotherapy, or of targeted pills if the cancer has a BRAF mutation, roughly halves the chance of it coming back. The newest trials show that giving immunotherapy before the operation instead of after works even better and lets most people stop treatment early.","summary":"Stage III melanoma is defined by regional nodal, satellite or in-transit disease and is staged by primary thickness and ulceration together with the number and size of nodal deposits. MSLT-II (2017) showed that removing the whole nodal basin after a positive sentinel node does not improve melanoma-specific survival, so most patients now keep their nodes and are watched with ultrasound. For decades the only adjuvant drug was high-dose interferon alfa, with a small relapse-free benefit and heavy toxicity; adjuvant ipilimumab (EORTC 18071, 2015) improved survival but at the cost of frequent severe immune toxicity.\n\nCheckMate 238 (2017) showed nivolumab beat ipilimumab for recurrence-free survival (70.5 against 60.8 percent at one year) with a third of the serious toxicity, and KEYNOTE-054 (2018) showed pembrolizumab beat placebo (75.4 against 61.0 percent at one year, 55.4 against 38.3 percent at five years). COMBI-AD (2017) showed a year of dabrafenib-trametinib halved relapse risk in BRAF-mutant disease (ten-year relapse-free survival 48 against 32 percent). Adding ipilimumab to nivolumab (CheckMate 915) or relatlimab to nivolumab (RELATIVITY-098) after surgery added nothing, so a year of single-agent anti-PD-1 antibody, or the BRAF-MEK doublet, became the adjuvant standard.\n\nThe neoadjuvant trials then changed the timing. SWOG S1801 (2022) moved three of eighteen pembrolizumab doses to before surgery and improved two-year event-free survival from 49 to 72 percent with the same total drug. NADINA (2024) gave two cycles of ipilimumab plus nivolumab before surgery and adjuvant therapy only to poor responders, and cut events by two thirds against adjuvant nivolumab (twelve-month event-free survival 83.7 against 57.2 percent); about six in ten patients had a major pathological response and needed no further treatment. Neoadjuvant immunotherapy is now the preferred approach for macroscopic nodal disease. INTerpath-001 (2026) added the personalised mRNA vaccine intismeran autogene to adjuvant pembrolizumab and met its recurrence-free survival endpoint in resected stage IIB to IV disease, confirming the phase 2b KEYNOTE-942 signal (eighteen-month recurrence-free survival 78.6 against 62.2 percent).","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Melanoma","links":[{"label":"CheckMate 238 (NEJM 2017)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa1709030"},{"label":"KEYNOTE-054 (NEJM 2018)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa1802357"},{"label":"NADINA (NEJM 2024)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2402604"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Melanoma"}],"tags":["subtype-page"],"related":["stage-ii-melanoma","advanced-melanoma","braf-v600-melanoma"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","sentinel-node","neoantigen-mrna-vaccine"],"targets":["pd1","ctla4","braf"],"drugs":["nivolumab","pembrolizumab","ipilimumab","dabrafenib-trametinib","intismeran-autogene","daromun"],"companies":[],"institutions":[],"pathways":[],"terms":["neoadjuvant-adjuvant","major-pathological-response","breslow-thickness","ulceration-melanoma","efs","interferon-gamma-signature"],"trials":["checkmate-238","nct02362594","combi-ad","swog-s1801","nadina","interpath-001","mslt-ii","checkmate-915","nct03897881"],"people":["alexander-eggermont","jeffrey-weber","christian-blank","georgina-long","sapna-patel"],"bottlenecks":[],"keyPapers":["paper-nadina-nejm-2024","paper-mslt-ii-faries-nejm-2017","paper-checkmate-238-nejm-2017","paper-keynote-054-eggermont-nejm-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"skin","burden":"Stage III means the melanoma has reached the regional lymph nodes or produced satellite or in-transit deposits in the skin; in the eighth edition of the staging system five-year melanoma-specific survival ranges from 93 percent for stage IIIA to 32 percent for stage IIID, so it is the stage where preventing relapse matters most.","subtypes":["Stage IIIA (microscopic nodal disease, thin primary)","Stage IIIB and IIIC (clinically detected nodes, satellites or in-transit metastases)","Stage IIID (thick ulcerated primary with matted or numerous nodes)","Resectable macroscopic stage III (neoadjuvant immunotherapy candidates, NADINA)","BRAF V600-mutant stage III (adjuvant dabrafenib-trametinib option)","Sentinel node-positive with no palpable disease (observation of the basin after MSLT-II)"],"biomarkers":["Sentinel node status and nodal tumour burden","Breslow thickness and ulceration of the primary","BRAF V600 mutation (adjuvant targeted therapy option)","Pathological response after neoadjuvant immunotherapy (major pathological response guides omission of adjuvant therapy)","Circulating tumour DNA after surgery (trials of adjuvant selection)","Interferon-gamma gene signature (exploratory predictor in NADINA)"],"standardOfCare":[{"setting":"Positive sentinel node, no palpable disease","approach":"Wide local excision, no completion lymph node dissection (MSLT-II), nodal ultrasound surveillance, then adjuvant systemic therapy.","refs":["mslt-ii","sentinel-node","wide-local-excision"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Resectable macroscopic nodal disease","approach":"Neoadjuvant ipilimumab plus nivolumab for two cycles then surgery, with adjuvant therapy only if the pathological response is poor (NADINA); or neoadjuvant then adjuvant pembrolizumab (SWOG S1801).","refs":["nadina","swog-s1801","nivolumab","ipilimumab","pembrolizumab","major-pathological-response"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Adjuvant, after upfront surgery","approach":"One year of nivolumab (CheckMate 238) or pembrolizumab (KEYNOTE-054); dabrafenib-trametinib for one year is the alternative in BRAF V600-mutant disease (COMBI-AD).","refs":["checkmate-238","nct02362594","combi-ad","nivolumab","pembrolizumab","dabrafenib-trametinib"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Adjuvant vaccine (emerging)","approach":"Intismeran autogene with pembrolizumab met its endpoints in INTerpath-001 (2026); regulatory review pending.","refs":["interpath-001","intismeran-autogene","neoantigen-mrna-vaccine"]},{"setting":"In-transit disease","approach":"Excision where feasible; intralesional talimogene laherparepvec or the immunocytokine daromun before surgery; isolated limb perfusion for extensive limb disease.","refs":["talimogene-laherparepvec","nct02938299","nct03567889","isolated-limb-perfusion","electrochemotherapy"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}}],"stateOfArt":["A year of anti-PD-1 antibody or of dabrafenib-trametinib after surgery roughly halves the risk of relapse.","Neoadjuvant immunotherapy (SWOG S1801, NADINA) beats the same drugs given only after surgery and lets most responders stop treatment early.","The first positive phase 3 personalised cancer vaccine trial (INTerpath-001) was in this setting."],"history":[{"year":1996,"title":"ECOG 1684: high-dose interferon alfa becomes the first adjuvant therapy","refs":["interferon-alfa"]},{"year":2015,"title":"EORTC 18071: adjuvant ipilimumab improves relapse-free and overall survival at high toxicity","refs":["ipilimumab"]},{"year":2017,"title":"MSLT-II: completion lymph node dissection abandoned; CheckMate 238 and COMBI-AD set adjuvant nivolumab and dabrafenib-trametinib","refs":["mslt-ii","checkmate-238","combi-ad"]},{"year":2018,"title":"KEYNOTE-054: adjuvant pembrolizumab beats placebo","refs":["nct02362594","pembrolizumab"]},{"year":2022,"title":"SWOG S1801: three doses before surgery beat the same drug given only after","refs":["swog-s1801"]},{"year":2023,"title":"KEYNOTE-942: intismeran autogene plus pembrolizumab lowers relapse in phase 2b","refs":["intismeran-autogene"]},{"year":2024,"title":"NADINA: neoadjuvant ipilimumab plus nivolumab cuts events by two thirds","refs":["nadina"]},{"year":2026,"title":"INTerpath-001: first positive phase 3 personalised vaccine trial","refs":["interpath-001","intismeran-autogene"]}],"pipeline":["interpath-001","intismeran-autogene","idea-ctdna-guided-adjuvant-melanoma","nct04079166","nct05280314","relativity-098"],"openProblems":["Most stage IIIA patients would never have relapsed, so a year of immunotherapy with lifelong endocrine side effects in some is given to many who do not need it.","No biomarker yet tells who can safely skip adjuvant therapy; circulating tumour DNA trials are testing this.","Overall survival gains from adjuvant PD-1 blockade are small because relapsing patients receive the same drugs later."],"parent":"melanoma"},{"id":"all-paediatric-standard-risk","kind":"cancer","name":"Standard-risk B-cell acute lymphoblastic leukaemia in children","aka":["NCI standard-risk B-ALL","Average-risk childhood ALL","Low-risk childhood ALL"],"tldr":"Standard-risk acute lymphoblastic leukaemia is the commonest and most curable childhood cancer: a child aged one to nine with a modest white cell count and favourable genetics. Two to three years of chemotherapy cures about nine in ten, and adding the immune drug blinatumomab to the chemotherapy in the AALL1731 trial cut relapses further.","summary":"The National Cancer Institute criteria of 1996 put children aged one to nine with a presenting white count under 50 x 10^9/L into the standard-risk group, about two thirds of B-cell precursor ALL. Within it, the ETV6::RUNX1 fusion and high hyperdiploidy with trisomies of chromosomes 4 and 10 mark the most favourable disease, and measurable residual disease (MRD) by flow cytometry at the end of the four-week induction, below 0.01 percent, is the strongest single predictor of cure. Children with central nervous system disease, testicular involvement, hypodiploidy, iAMP21 or high end-induction MRD are moved to high-risk therapy whatever their age and count.\n\nTreatment follows the Berlin-Frankfurt-Münster and Children's Oncology Group backbone worked out over five decades: a three-drug induction of vincristine, dexamethasone and pegylated asparaginase; consolidation with cyclophosphamide, cytarabine and mercaptopurine or, for the lowest risk, mercaptopurine and vincristine alone; interim maintenance with escalating methotrexate; a delayed intensification block; and maintenance with daily mercaptopurine, weekly methotrexate and pulses of vincristine and steroid to two years or more, with intrathecal methotrexate throughout in place of cranial irradiation. UKALL 2003, reported in 2013, showed that MRD-low children could safely receive one delayed intensification instead of two, with five-year event-free survival around 95 percent in both arms, while MRD-high children gained from augmented therapy. AALL1731, reported in the New England Journal of Medicine in 2025, randomised 1,440 children with standard-risk average or higher B-ALL to two cycles of blinatumomab added to chemotherapy: three-year disease-free survival 96.0 percent against 87.9 percent with chemotherapy alone, and the trial was stopped early for benefit. Blinatumomab was approved for consolidation of newly diagnosed CD19-positive B-ALL in children and adults in June 2024 on E1910 and this trial.\n\nThe cure rate leaves the research questions on the other side: how much therapy can be removed. Vincristine and steroid pulses in maintenance, the second delayed intensification and anthracycline exposure have each been trimmed in trials without loss; asparaginase allergy and silent inactivation, osteonecrosis in adolescents and the cognitive cost of intrathecal methotrexate are the toxicities that remain. Whether blinatumomab lets chemotherapy be shortened rather than merely added to, whether MRD by next-generation sequencing at day 8 or day 29 can select children for even less, and how to make a two-year outpatient regimen deliverable in low-income countries, where most children with ALL live and where cure rates are far lower, are the live questions.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia","links":[{"label":"Wikipedia: Acute lymphoblastic leukaemia","url":"https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia"},{"label":"NCI PDQ: Childhood ALL Treatment","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}],"tags":["subtype-page","paediatric"],"related":["all-paediatric-high-risk","all-paediatric-relapsed","all-infant","all-ph-like","all-paediatric-ph-positive"],"cancers":[],"sections":[],"technologies":["flow-cytometry-mrd","t-cell-engager"],"targets":["cd19"],"drugs":["aminopterin"],"companies":["childrens-oncology-group"],"institutions":["st-jude"],"pathways":[],"terms":["mrd","efs","b-all-cytogenetic-risk"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-aall1731-blinatumomab-children-nejm-2025"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"Acute lymphoblastic leukaemia is the commonest childhood cancer, and roughly two thirds of children with the B-cell form fall into the standard-risk group at diagnosis: aged one to nine with a white cell count below 50 x 10^9/L.","subtypes":["Standard-risk favourable B-ALL (ETV6::RUNX1 or double trisomy 4 and 10, end-induction MRD below 0.01 percent)","Standard-risk average B-ALL (neutral genetics, MRD-low)","Standard-risk high B-ALL (end-induction MRD 0.01 percent or higher, moved to intensified therapy)","Down syndrome-associated B-ALL (standard-risk criteria but higher toxicity, CRLF2 rearrangements common)"],"biomarkers":["Age and presenting white cell count (NCI criteria)","ETV6::RUNX1 fusion","High hyperdiploidy with trisomies 4 and 10","Flow cytometry MRD at day 8 and day 29","CNS status at diagnosis","TPMT and NUDT15 genotype for mercaptopurine dosing"],"standardOfCare":[{"setting":"Induction (four weeks)","approach":"Vincristine, dexamethasone and pegylated asparaginase with intrathecal methotrexate; flow cytometry MRD at day 29 decides the post-induction arm.","refs":["vincristine","dexamethasone","asparaginase","methotrexate","flow-cytometry-mrd"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Consolidation and interim maintenance","approach":"Cyclophosphamide, cytarabine and mercaptopurine, then escalating methotrexate; two cycles of blinatumomab added for standard-risk average and high disease (AALL1731).","refs":["cyclophosphamide","cytarabine","mercaptopurine","methotrexate","blinatumomab","aall1731","blinatumomab-frontline-consolidation"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Delayed intensification and maintenance","approach":"One delayed intensification block with vincristine, dexamethasone, doxorubicin, asparaginase, cyclophosphamide, cytarabine and thioguanine; then daily mercaptopurine, weekly methotrexate and vincristine-steroid pulses to two years or more.","refs":["vincristine","dexamethasone","doxorubicin","cyclophosphamide","thioguanine","mercaptopurine","methotrexate"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Relapse","approach":"Reinduction chemotherapy with blinatumomab for high- and intermediate-risk relapse; tisagenlecleucel or inotuzumab ozogamicin for later relapse (see the relapsed ALL page).","refs":["blinatumomab","tisagenlecleucel","inotuzumab-ozogamicin","all-paediatric-relapsed"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}}],"stateOfArt":["About nine in ten children with standard-risk B-ALL are cured with chemotherapy alone, and blinatumomab consolidation raised three-year disease-free survival to 96 percent in AALL1731.","End-induction flow cytometry MRD is the pivot of every protocol: it moves children up to intensified therapy and, in MRD-low children, permits less.","Cranial irradiation has gone from standard-risk therapy altogether, replaced by intrathecal methotrexate."],"history":[{"year":1948,"title":"Farber produces temporary remissions in childhood leukaemia with aminopterin, the first antifolate","refs":["methotrexate"]},{"year":1962,"title":"St Jude Total Therapy: combination chemotherapy with central nervous system-directed treatment begins to cure children","refs":["st-jude"]},{"year":1996,"title":"National Cancer Institute risk criteria by age and white count adopted","refs":[]},{"year":2013,"title":"UKALL 2003: MRD-directed reduction of therapy is safe for low-risk children","refs":["flow-cytometry-mrd","mrd"]},{"year":2024,"title":"Blinatumomab approved for consolidation of newly diagnosed CD19-positive B-ALL","refs":["blinatumomab","e1910"]},{"year":2025,"title":"AALL1731: blinatumomab added to chemotherapy lifts three-year disease-free survival to 96 percent","refs":["aall1731","paper-aall1731-blinatumomab-children-nejm-2025"]}],"pipeline":["blinatumomab","aall1731","ngs-mrd-clonoseq","blinatumomab-frontline-consolidation","idea-tr2-paediatric-combo-prea"],"openProblems":["Whether blinatumomab allows chemotherapy to be shortened rather than only added to.","Asparaginase hypersensitivity and silent inactivation, and osteonecrosis in older children.","Delivering a two-year outpatient regimen in low- and middle-income countries, where most children with ALL live."],"parent":"all-leukemia"},{"id":"sdh-deficient-renal-cell-carcinoma","kind":"cancer","name":"Succinate dehydrogenase-deficient renal cell carcinoma","aka":["SDH-deficient renal cell carcinoma","SDHB-deficient renal cell carcinoma","Succinate dehydrogenase-deficient RCC"],"tldr":"Succinate dehydrogenase-deficient renal cell carcinoma is a very rare kidney cancer of younger adults who carry a faulty SDH gene, the same fault that causes hereditary paraganglioma and some stomach stromal tumours. Most are low grade and cured by surgery, but a minority spread years later, so patients and relatives need gene testing and follow-up.","summary":"The 2016 WHO classification recognised succinate dehydrogenase-deficient renal cell carcinoma as a type, kept in 2022 (Moch 2016; Moch 2022). It arises in people with germline mutations of SDH subunit genes, who are prone to paraganglioma, gastrointestinal stromal tumour and, rarely, renal cell carcinoma. In the defining series of 11 tumours from 10 patients (median age 40; two with paragangliomas, one with bilateral tumours), tumours were 2 to 20 cm, WHO/ISUP grade 2 in ten, stage pT1a to pT2b, and composed of uniform eosinophilic cells with vacuoles or flocculent cytoplasmic inclusions, entrapped renal tubules and mast cells; SDHB immunohistochemistry was negative in all; one patient developed widespread metastases 16 years after nephrectomy and died six years later (Modern Pathology 2015). A low-grade FH-deficient carcinoma can mimic it (Histopathology 2017).\n\nHow it differs from its parent: it is a hereditary metabolic cancer of young adults, diagnosed by loss of SDHB staining, indolent in most but with a long tail of late metastasis, and its finding should prompt germline testing and screening for paraganglioma.\n\nHow common: no registry share; under 0.2 percent of renal cell carcinomas is the usual estimate in the pathology literature, but the sources read give case series only.\n\nTreatment: surgery, with long-term follow-up for late metastasis; germline SDH testing and paraganglioma surveillance for the patient and relatives; advanced disease treated on the renal cell carcinoma page without a dedicated standard.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Renal_cell_carcinoma","links":[{"label":"Moch 2016, European Urology: the 2016 WHO classification of urinary and male genital tumours, part A","url":"https://doi.org/10.1016/j.eururo.2016.02.029"},{"label":"Moch 2022, European Urology: the 2022 WHO classification of urinary and male genital tumours, part A (renal, penile, testicular)","url":"https://doi.org/10.1016/j.eururo.2022.06.016"},{"label":"Modern Pathology 2015: succinate dehydrogenase-deficient renal cell carcinoma, 11 tumours","url":"https://doi.org/10.1038/modpathol.2014.86"},{"label":"Histopathology 2017: a low-grade oncocytic FH-deficient RCC resembling SDH-deficient RCC","url":"https://doi.org/10.1111/his.13183"}],"tags":["subtype-page","wave4","kidney","rare"],"related":["rcc","fh-deficient-renal-cell-carcinoma","hereditary-ppgl","chromophobe-rcc","gist"],"cancers":[],"sections":[],"technologies":["germline-testing"],"targets":["sdhb"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["nephrectomy","hereditary-cancer-syndromes"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Very rare: the defining series holds 11 tumours from 10 patients aged 22 to 72 (median 40) (Modern Pathology 2015). No registry share exists.","subtypes":[],"biomarkers":["Loss of SDHB immunohistochemistry","Germline SDHB (or SDHC, SDHA, SDHD) mutation","Flocculent cytoplasmic inclusions and entrapped tubules","WHO/ISUP grade (usually 2)"],"standardOfCare":[{"setting":"All stages","approach":"Surgery with long follow-up; germline SDH testing and paraganglioma surveillance for patient and relatives; advanced disease on the renal cell carcinoma page.","refs":["rcc","germline-testing","nephrectomy","hereditary-ppgl"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"rcc"},{"id":"synovial-sarcoma","kind":"cancer","name":"Synovial sarcoma","aka":["SS18-SSX sarcoma"],"tldr":"Synovial sarcoma is a young person's sarcoma driven by a single fusion gene, SS18-SSX, that scrambles how genes are switched on. It is treated with surgery, radiotherapy and ifosfamide-based chemotherapy, and in 2024 it became the first solid tumour with an approved engineered T-cell receptor therapy.","summary":"Synovial sarcoma has nothing to do with the synovium; it is defined by the SS18-SSX fusion, which hijacks the BAF chromatin remodelling complex. It presents as a slow-growing deep mass near the knee, ankle or other joints in people aged 15 to 40, and is graded high by default. Treatment is wide resection with radiotherapy, and chemotherapy with ifosfamide and doxorubicin is used more readily than in other sarcomas because responses are frequent, including in the neoadjuvant setting; pazopanib and trabectedin have activity in advanced disease. Most tumours express the cancer-testis antigens MAGE-A4 and NY-ESO-1, and afamitresgene autoleucel, a MAGE-A4-directed T-cell receptor therapy, was approved in the United States in 2024 for advanced disease in HLA-A*02 patients, with letetresgene autoleucel against NY-ESO-1 following in trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Synovial_sarcoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Synovial_sarcoma"}],"tags":["subtype-page"],"related":["extremity-soft-tissue-sarcoma","malignant-peripheral-nerve-sheath-tumour","epithelioid-sarcoma","alveolar-soft-part-sarcoma","leiomyosarcoma","undifferentiated-pleomorphic-sarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-spearhead-1-lancet-2024","paper-eortc-62012-doxorubicin-ifosfamide-judson-lancet-oncol-2014","paper-clark-syt-ssx-synovial-sarcoma-nat-genet-1994","paper-dangelo-ny-eso-1-tcr-synovial-sarcoma-cancer-discov-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"Five to ten percent of soft-tissue sarcomas, typically in adolescents and young adults near the joints of the limbs; about half eventually metastasise, often to the lungs, and it is one of the few sarcomas where chemotherapy clearly helps.","subtypes":["Monophasic synovial sarcoma","Biphasic synovial sarcoma","Poorly differentiated (round cell) synovial sarcoma"],"biomarkers":["SS18-SSX fusion (FISH or RNA sequencing; SS18-SSX antibody)","MAGE-A4 and NY-ESO-1 expression with HLA-A*02 typing (TCR therapy eligibility)","Size over 5 cm and poorly differentiated component (prognosis)"],"standardOfCare":[{"setting":"Localised","approach":"Wide resection with pre- or postoperative radiotherapy; neoadjuvant or adjuvant ifosfamide-doxorubicin for large high-risk tumours.","refs":["imrt-igrt","ifosfamide","doxorubicin"]},{"setting":"Advanced, first line","approach":"Ifosfamide-based chemotherapy, doxorubicin; pazopanib or trabectedin later.","refs":["ifosfamide","doxorubicin","pazopanib","trabectedin"]},{"setting":"Advanced, HLA-A*02 and MAGE-A4-positive","approach":"Afamitresgene autoleucel after chemotherapy; NY-ESO-1 TCR therapy in trials.","refs":["afamitresgene-autoleucel"]}],"stateOfArt":["Afamitresgene autoleucel is the first T-cell receptor therapy approved for any solid tumour, with responses in about 40 percent of heavily pretreated patients.","Chemosensitivity sets synovial sarcoma apart and justifies perioperative chemotherapy in high-risk cases.","The single fusion driver makes it a model for epigenetic drugs such as BRD9 degraders."],"history":[{"year":1994,"title":"SS18-SSX fusion identified","refs":[]},{"year":2012,"title":"Pazopanib approved for soft-tissue sarcoma including synovial sarcoma","refs":["pazopanib"]},{"year":2024,"title":"Afamitresgene autoleucel approved: first TCR therapy for a solid tumour","refs":["afamitresgene-autoleucel"]}],"pipeline":["letetresgene-autoleucel"],"openProblems":["TCR therapy needs a matching HLA type and antigen, excluding most patients.","Late lung metastases years after treatment.","Fertility and growth in adolescent patients receiving chemotherapy."],"parent":"sarcoma"},{"id":"systemic-mastocytosis","kind":"cancer","name":"Systemic mastocytosis","aka":["SM","Advanced systemic mastocytosis (AdvSM)","Indolent systemic mastocytosis (ISM)","Smouldering systemic mastocytosis","Aggressive systemic mastocytosis","Mast cell leukaemia","SM with an associated haematological neoplasm (SM-AHN)"],"tldr":"Systemic mastocytosis is a clonal disease of mast cells, the immune cells that release histamine; almost every case is driven by a single mutation in the KIT gene. Precise KIT-blocking pills now shrink the mast cell burden, ease symptoms and, in the aggressive forms, prolong life. Most patients have the indolent form, where the goal is controlling symptoms and preventing anaphylaxis.","summary":"Systemic mastocytosis (SM) is a myeloid neoplasm defined by multifocal mast cell infiltrates in marrow or other organs, with KIT D816V present in about nine of ten patients. WHO 2022 divides it into indolent SM (ISM; the majority, with skin lesions, mediator symptoms and anaphylaxis risk but near-normal life expectancy), smouldering SM, and advanced SM (AdvSM), comprising aggressive SM, mast cell leukaemia and SM with an associated haematological neoplasm (SM-AHN), where the associated CMML, MDS or AML often decides outcome. Diagnosis uses serum tryptase (with correction for hereditary alpha-tryptasaemia), high-sensitivity KIT D816V PCR in peripheral blood, and marrow biopsy with CD25/CD30 mast cell immunophenotyping; additional mutations (SRSF2, ASXL1, RUNX1, the S/A/R panel) mark high-risk disease.\n\nTreatment is stratified. In ISM, antihistamines, cromolyn, omalizumab, epinephrine autoinjectors and trigger avoidance manage mediator symptoms; osteoporosis is treated. The 2023 approval of avapritinib for ISM (PIONEER: 25 mg daily improved total symptom scores and reduced tryptase, KIT D816V allele burden and skin lesions) made it the first disease-modifying therapy for the indolent form. In AdvSM, midostaurin (2017; multikinase KIT inhibitor, responses in about 60 percent in the pivotal trial) was the first approved drug, and avapritinib (2021; PATHFINDER and EXPLORER, selective KIT D816V inhibition with high response rates including complete remissions) is now the preferred first-line agent for patients with platelets above 50 x 10^9/L. Cladribine remains an option, interferon is historic, and allogeneic transplant is used for mast cell leukaemia or SM-AHN with high-risk associated neoplasms. Next-generation KIT D816V inhibitors, bezuclastinib (Summit and Apex trials) and elenestinib (Harbor), aim for equal efficacy with less intracranial bleeding and cognitive toxicity.\n\nOpen problems are the associated haematological neoplasm in SM-AHN, avapritinib's bleeding risk at low platelet counts, and the years-long diagnostic delay in indolent disease.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Mastocytosis","links":[{"label":"NCI PDQ: mastocytosis (within myeloproliferative neoplasms)","url":"https://www.cancer.gov/types/myeloproliferative"},{"label":"PATHFINDER: avapritinib in advanced SM (Nature Medicine 2021)","url":"https://doi.org/10.1038/s41591-021-01539-8"},{"label":"PIONEER: avapritinib in indolent SM (NEJM Evidence 2023)","url":"https://doi.org/10.1056/EVIDoa2200339"},{"label":"Midostaurin in advanced SM (NEJM 2016)","url":"https://doi.org/10.1056/NEJMoa1513098"},{"label":"NCCN: Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1463"}],"tags":["nci-coverage","rare","haematologic"],"related":["cmml","mds","aml","gist"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","allogeneic-hsct","liquid-biopsy","histopathology-ihc","flow-cytometry-mrd"],"targets":["kit","flt3"],"drugs":["avapritinib","midostaurin","cladribine","interferon-alfa","azacitidine","imatinib"],"companies":[],"institutions":[],"pathways":["rtk-activation","clonal-haematopoiesis"],"terms":["driver-mutation","cytopenias","molecular-response"],"trials":["nct04910685"],"people":[],"bottlenecks":["b-rare-cancers","b-toxicity-qol"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Roughly one to two new cases per 100,000 per year, most of them indolent; advanced forms are rare, and many indolent cases go undiagnosed for years because symptoms mimic allergy (WHO; ECNM registry).","subtypes":["Indolent systemic mastocytosis (with or without skin involvement)","Bone marrow mastocytosis","Smouldering systemic mastocytosis","Aggressive systemic mastocytosis","Systemic mastocytosis with an associated haematological neoplasm (SM-AHN)","Mast cell leukaemia","Cutaneous mastocytosis (children; usually resolves)"],"biomarkers":["Serum tryptase (adjusted for hereditary alpha-tryptasaemia)","KIT D816V by high-sensitivity ddPCR in blood (allele burden tracks response)","Marrow mast cell aggregates with CD25, CD2, CD30 expression","C-findings (cytopenias, liver dysfunction, hypoalbuminaemia, malabsorption, lytic bone lesions) defining advanced disease","SRSF2, ASXL1, RUNX1 (S/A/R) mutations; MARS and IPSM prognostic scores","Platelet count (avapritinib eligibility in AdvSM)"],"standardOfCare":[{"setting":"Indolent SM, symptomatic","approach":"H1 and H2 antihistamines, cromolyn, leukotriene antagonists, omalizumab for anaphylaxis, epinephrine autoinjector, bone protection; avapritinib 25 mg daily for moderate to severe symptoms uncontrolled by these (PIONEER).","refs":["avapritinib"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Systemic Mastocytosis; PIONEER (NEJM Evidence 2023)","url":"https://doi.org/10.1056/EVIDoa2200339"}},{"setting":"Advanced SM, first line","approach":"Avapritinib 200 mg daily (platelets above 50 x 10^9/L) as preferred agent; midostaurin as alternative or where platelets are low.","refs":["avapritinib","midostaurin","kit","kinase-inhibitors"],"guideline":{"nccn":"Category 2A (preferred: avapritinib)","version":"NCCN Guidelines: Systemic Mastocytosis; PATHFINDER (Nature Medicine 2021)","url":"https://doi.org/10.1038/s41591-021-01539-8"}},{"setting":"Advanced SM, subsequent lines","approach":"Switch between avapritinib and midostaurin; cladribine; clinical trials (bezuclastinib, elenestinib); allogeneic transplant for mast cell leukaemia or high-risk SM-AHN.","refs":["cladribine","allogeneic-hsct","midostaurin","avapritinib"]},{"setting":"SM-AHN","approach":"Treat the dominant component: KIT inhibitor for mast cell burden plus the standard therapy for the associated CMML, MDS or AML (hypomethylating agents, intensive chemotherapy, transplant).","refs":["azacitidine","allogeneic-hsct","avapritinib"]}],"stateOfArt":["Selective KIT D816V inhibition with avapritinib gives deep molecular and morphological responses in advanced disease and is the first drug to improve symptoms in indolent disease.","Midostaurin (2017) was the first approved therapy and remains important where platelets are low or avapritinib is not tolerated.","Blood-based KIT D816V allele burden now tracks response, reducing repeat marrow biopsies.","Second-generation KIT inhibitors aim to remove the intracranial bleeding and cognitive side effects seen with avapritinib."],"history":[{"year":1869,"title":"Urticaria pigmentosa described","note":"Nettleship and Tay describe the skin lesions; Unna links them to mast cells in 1887.","refs":[]},{"year":1949,"title":"Systemic involvement recognised","note":"Ellis reports mast cell infiltration of internal organs at autopsy.","refs":[]},{"year":1993,"title":"KIT D816V identified in mastocytosis","note":"Nagata and colleagues (1995) confirm the activating mutation in most patients.","refs":["kit"]},{"year":2001,"title":"WHO classification of mastocytosis","note":"Valent criteria; imatinib found inactive against D816V.","refs":[]},{"year":2016,"title":"Midostaurin in advanced SM","note":"Gotlib and colleagues (NEJM 2016); FDA approval April 2017.","refs":["midostaurin"]},{"year":2021,"title":"Avapritinib approved for advanced SM","note":"EXPLORER and PATHFINDER; FDA approval June 2021.","refs":["avapritinib"]},{"year":2023,"title":"Avapritinib approved for indolent SM","note":"PIONEER; FDA approval May 2023, the first therapy for the indolent form.","refs":["avapritinib"]}],"pipeline":["avapritinib","allogeneic-hsct","elenestinib"],"openProblems":["Avapritinib carries intracranial bleeding risk at low platelet counts and cognitive effects; bezuclastinib and elenestinib are designed to avoid them.","The associated neoplasm in SM-AHN, not the mast cells, usually determines survival; combination strategies with hypomethylating agents and transplant are being studied.","Diagnostic delay of years in indolent disease; blood KIT D816V testing and tryptase genotyping are shortening it.","Long-term safety of chronic KIT inhibition in indolent patients with a normal life expectancy."]},{"id":"t-large-granular-lymphocytic-leukaemia","kind":"cancer","name":"T-cell large granular lymphocytic leukaemia","aka":["Large granular lymphocytic leukemia","Large granular lymphocytic leukaemia","LGL leukaemia","T-LGL leukaemia","T-LGLL","Chronic lymphoproliferative disorder of NK cells (related NK-cell form)"],"tldr":"T-cell large granular lymphocytic leukaemia is a slow, usually non-fatal leukaemia in which a clone of cytotoxic T cells builds up in the blood and marrow and turns the immune system against the body, causing low neutrophil counts, anaemia and often rheumatoid arthritis. It is treated only when it causes problems, with low-dose immune-suppressing drugs rather than chemotherapy.","summary":"WHO-HAEM5 keeps T-cell large granular lymphocytic leukaemia as a mature T-cell leukaemia of clonal CD3-positive CD8-positive cytotoxic lymphocytes, beside the related chronic lymphoproliferative disorder of NK cells (Alaggio 2022). Exome sequencing found somatic STAT3 mutations in 31 of 77 patients (40 percent), all in the SH2 domain (Y640F 17 percent, D661V and D661Y 9 percent each, N647I 4 percent), causing STAT3 phosphorylation and nuclear localisation; the disease is often associated with autoimmune disorders and immune-mediated cytopenias (Koskela 2012). In 204 patients, therapy was needed mostly for anaemia and neutropenia; methotrexate, cyclosporin and cyclophosphamide each gave overall responses of 40 to 50 percent, sequential use responded in most, only 10 to 20 percent needed salvage (antithymocyte globulin, alemtuzumab, tofacitinib, splenectomy or abatacept), methotrexate gave the most durable responses, and STAT3-mutated patients needed therapy more often but had better overall survival (Leukemia and Lymphoma 2018).\n\nHow it differs from its parent: it is indolent and immune-mediated rather than proliferative; its harm comes from cytopenias and autoimmunity, not from tumour bulk; and its treatment is immunosuppression, with JAK-STAT inhibition the rational new direction from the STAT3 findings.\n\nHow common: no registry figure in the sources read.\n\nTreatment: observation without cytopenias or symptoms; low-dose oral methotrexate, cyclosporin or cyclophosphamide when treatment is indicated, used sequentially; salvage with alemtuzumab, JAK inhibitors, splenectomy or abatacept; the PI3K-delta inhibitor and anti-CD94 antibody trials linked here (Leukemia and Lymphoma 2018).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Large_granular_lymphocytic_leukemia","links":[{"label":"NCI PDQ: chronic lymphocytic leukaemia treatment","url":"https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq"},{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"Koskela 2012, NEJM: somatic STAT3 mutations in large granular lymphocytic leukaemia","url":"https://doi.org/10.1056/nejmoa1114885"},{"label":"Leukemia and Lymphoma 2018: clinical features and treatment outcomes in 204 patients with large granular lymphocytic leukaemia","url":"https://doi.org/10.1080/10428194.2017.1339880"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["leukaemia","t-cell-prolymphocytic-leukaemia","hepatosplenic-t-cell-lymphoma","cll"],"cancers":[],"sections":[],"technologies":[],"targets":["stat3"],"drugs":["methotrexate","cyclophosphamide","alemtuzumab","ruxolitinib"],"companies":[],"institutions":[],"pathways":["jak-stat"],"terms":[],"trials":["nct06224257","nct05475925"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare and chronic; the largest treatment series holds 204 patients meeting uniform criteria, followed for a median of 36 months (Leukemia and Lymphoma 2018). No registry figure is in the sources read.","subtypes":["T-cell large granular lymphocytic leukaemia, STAT3-mutated (40 percent; more often symptomatic)","T-cell large granular lymphocytic leukaemia, STAT3 wild-type (STAT5B in a minority)","Large granular lymphocytic leukaemia with rheumatoid arthritis or Felty syndrome","Chronic lymphoproliferative disorder of NK cells (related)"],"biomarkers":["Clonal T-cell receptor rearrangement with increased large granular lymphocytes","STAT3 SH2 domain mutations (Y640F, D661V, D661Y, N647I)","Neutrophil count and haemoglobin (treatment indication)","Rheumatoid factor and autoimmune screen"],"standardOfCare":[{"setting":"Symptomatic or cytopenic","approach":"Low-dose methotrexate, cyclosporin or cyclophosphamide, used sequentially; salvage with alemtuzumab, JAK inhibitors or splenectomy.","refs":["methotrexate","cyclophosphamide","alemtuzumab","ruxolitinib","leukaemia"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"leukaemia"},{"id":"t-cell-prolymphocytic-leukaemia","kind":"cancer","name":"T-cell prolymphocytic leukaemia","aka":["T-PLL","T-cell prolymphocytic leukemia","T-prolymphocytic leukaemia","T-cell chronic lymphocytic leukaemia (retired term)"],"tldr":"T-cell prolymphocytic leukaemia is a rare, aggressive leukaemia of mature T cells in older adults, with a very high white cell count, a big spleen and liver, swollen nodes and sometimes skin changes. The antibody alemtuzumab given into a vein clears it in most people, but it returns within a year or two unless a stem cell transplant is done in remission.","summary":"WHO-HAEM5 keeps T-cell prolymphocytic leukaemia as a mature T-cell leukaemia defined by inversion or translocation of chromosome 14 activating TCL1A (or MTCP1 on the X chromosome), with a small-cell variant that was once called T-cell chronic lymphocytic leukaemia (Alaggio 2022). The T-PLL International Study Group's 2019 consensus set standard criteria for diagnosis, treatment indication and response assessment so that trials can be compared (Staber 2019). In 119 patients at one centre, complex karyotype was present in 65 percent and chromosome 14 aberrations in 52 percent, 80 percent had died at analysis and median overall survival from diagnosis was 19 months (Annals of Oncology 2017). Intravenous alemtuzumab as first-line treatment gave an overall response of 91 percent with 81 percent complete responses in 32 patients, while the subcutaneous route responded in only 3 of 9 and was abandoned (Dearden 2011).\n\nHow it differs from its parent: the leukaemia page groups the leukaemias; this is a mature T-cell disease with a specific chromosome 14 lesion, resistant to conventional chemotherapy and dependent on a single antibody and transplant, and it can be inactive for months before accelerating, so the consensus criteria define when to treat.\n\nHow common: no registry figure in the sources read.\n\nTreatment: intravenous alemtuzumab to best response, then allogeneic (or autologous) stem cell transplant in fit patients, because remissions without consolidation are short; pentostatin with alemtuzumab, and venetoclax with or without ibrutinib or the MDM2 inhibitor trial linked here, for relapsed disease (Staber 2019; Dearden 2011).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/T-cell-prolymphocytic_leukemia","links":[{"label":"NCI PDQ: chronic lymphocytic leukaemia treatment","url":"https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq"},{"label":"Alaggio 2022, Leukemia: the 5th edition WHO classification of haematolymphoid tumours, lymphoid neoplasms","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"Staber 2019, Blood: consensus criteria for diagnosis, staging and response assessment of T-PLL","url":"https://doi.org/10.1182/blood.2019000402"},{"label":"Annals of Oncology 2017: characteristics, outcomes and treatment of 119 patients with T-PLL","url":"https://doi.org/10.1093/annonc/mdx163"},{"label":"Dearden 2011, Blood: alemtuzumab in T-PLL, intravenous against subcutaneous","url":"https://doi.org/10.1182/blood-2011-08-372854"}],"tags":["subtype-page","wave4","haematologic","rare"],"related":["leukaemia","cll","sezary-syndrome","t-large-granular-lymphocytic-leukaemia","splenic-b-cell-lymphoma-leukaemia-prominent-nucleoli"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["alemtuzumab","venetoclax","ibrutinib"],"companies":[],"institutions":[],"pathways":[],"terms":["allogeneic-transplant"],"trials":["nct04496349","nct02029443"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Rare: the largest single-centre series holds 119 consecutive patients seen between 1990 and 2016 (Annals of Oncology 2017). No registry figure is in the sources read.","subtypes":["T-cell prolymphocytic leukaemia, typical (TCL1A rearrangement)","Small-cell variant of T-PLL (about a fifth of cases; formerly T-CLL)","Cerebriform variant of T-PLL","Inactive T-PLL (watch until the consensus treatment criteria are met)"],"biomarkers":["inv(14) or t(14;14) with TCL1A expression, or MTCP1 rearrangement","Complex karyotype and ATM mutations","CD52 expression (alemtuzumab target)","Lymphocyte count and doubling time (treatment indication)"],"standardOfCare":[{"setting":"Active disease","approach":"Intravenous alemtuzumab to best response, then allogeneic or autologous stem cell transplant in fit patients.","refs":["alemtuzumab","allogeneic-transplant","leukaemia"]},{"setting":"Relapsed","approach":"Venetoclax with or without ibrutinib; trials such as the MDM2 inhibitor study linked here.","refs":["venetoclax","ibrutinib","nct04496349"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"leukaemia"},{"id":"t-cell-histiocyte-rich-large-b-cell-lymphoma","kind":"cancer","name":"T-cell/histiocyte-rich large B-cell lymphoma","aka":["THRLBCL","T-cell/histiocyte-rich large B-cell lymphoma","T-cell-rich B-cell lymphoma","T-cell/histiocyte rich large B cell lymphoma"],"tldr":"A lymphoma in which the cancer cells are a tiny minority of what the pathologist sees: scattered large B cells in a dense crowd of normal T cells and macrophages. It is a form of large B-cell lymphoma, it usually presents with disease in the liver, spleen or bone marrow, and it is easy to mistake for a different disease in both directions.","summary":"What it is. A large B-cell lymphoma in which the malignant cells make up a very small fraction of the tissue. The rest is a reaction: sheets of normal T cells and histiocytes, the tissue form of the macrophage. The diagnosis therefore depends on recognising the scattered large B cells in a background that looks inflammatory, and on the pattern of markers they carry.\n\nHow it differs from its family. Ordinary diffuse large B-cell lymphoma is made of sheets of tumour cells. Here the tumour is outnumbered, and the clinical behaviour is different too: it tends to present at an advanced stage with the liver, the spleen and the bone marrow involved rather than with enlarged lymph nodes alone, and it affects men more often and at a younger age than most large B-cell lymphomas.\n\nThe boundary problem, which is the most important thing on this page. T-cell/histiocyte-rich large B-cell lymphoma sits at one end of a spectrum whose other end is nodular lymphocyte predominant Hodgkin lymphoma, a condition that usually behaves indolently. WHO-HAEM5 lists six growth patterns of nodular lymphocyte predominant Hodgkin lymphoma, and the last of them, pattern E, is described as diffuse and resembling this disease. The classification states plainly that in some cases a clear distinction may not be possible, and that it is especially difficult on a small biopsy. The International Consensus Classification renamed the Hodgkin disease nodular lymphocyte predominant B-cell lymphoma partly in recognition of that relationship.\n\nThe biology agrees that the boundary is soft. In a study that profiled gene expression in the tumour cells themselves, the three conditions did not cluster apart, and only a few genes were consistently different, and those only moderately. What differed was the surrounding tissue, the infiltrating T cells and histiocytes. That is an unusual situation in oncology: two diseases with different names, different stages at presentation and different treatments whose cancer cells look the same at the level of gene expression.\n\nHow it is treated. As a diffuse large B-cell lymphoma, with the same immunochemotherapy, which is a reasonable approach for a disease that behaves aggressively and carries CD20. The series are small and no randomised trial has been confined to it. The regimens are on the diffuse large B-cell lymphoma page and in the treatment layer of this family.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Diffuse_large_B-cell_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"Nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma, endpoints of a spectrum of one disease? (PLoS One 2013)","url":"https://doi.org/10.1371/journal.pone.0078812"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"}],"tags":["heme","lymphoma","subtype-page"],"related":["dlbcl","nodular-lymphocyte-predominant-hodgkin-lymphoma","hodgkin-lymphoma","non-hodgkin-lymphoma","mediastinal-grey-zone-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","fdg-pet"],"targets":["cd20"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-classification-2022","lymphoma-b-versus-t-cell","lymphoma-indolent-versus-aggressive","ipi-score"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"In the United Kingdom population series that reports lymphoma by subtype, 32 of 5,796 lymphomas (0.6 per cent) diagnosed between 2004 and 2012, a crude incidence of 0.30 and a European age-standardised rate of 0.10 per 100,000 a year, with a median age at diagnosis of 65.5 years. Five-year relative survival in that series was 67.9 per cent, with a wide confidence interval (46.8 to 82.0 per cent) because of the small number of patients.","subtypes":[],"biomarkers":["Scattered large B cells, fewer than about one in ten of the cells present, in a background of small T cells and histiocytes","The large cells express CD20 and BCL6; nuclear BCL6 was positive in 26 of 29 cases in one series","A background rich in CD8-positive T cells and CD68-positive histiocytes, which is part of the diagnosis rather than incidental","Absence of the nodular meshworks of follicular dendritic cells and of the small B cells that mark nodular lymphocyte predominant Hodgkin lymphoma","Epstein-Barr virus, which is characteristically negative"],"standardOfCare":[{"setting":"Making the diagnosis, and the two ways it goes wrong","approach":"Both errors are common and they point in opposite directions. Called inflammatory, the lymphoma is missed, because the tumour cells are a small minority and the tissue looks reactive. Called nodular lymphocyte predominant Hodgkin lymphoma, an aggressive disease is treated as an indolent one. WHO-HAEM5 states that a clear distinction from the diffuse pattern of that disease may not be possible in some cases, and that small biopsies are the hardest. A generous biopsy, read by a haematopathologist, with the surrounding cells examined as carefully as the tumour cells, is the answer the classification gives.","refs":["histopathology-ihc","nodular-lymphocyte-predominant-hodgkin-lymphoma","cd20","lymphoma-classification-2022"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"Treatment","approach":"Treated as diffuse large B-cell lymphoma, with rituximab-containing immunochemotherapy, which is appropriate for a disease that carries CD20 and behaves aggressively. The staging usually finds advanced disease with the liver, spleen or bone marrow involved. No randomised trial has been confined to this entity; the regimens, the cycles and the evidence are on the diffuse large B-cell lymphoma page and in the treatment layer of this family.","refs":["dlbcl","rituximab","r-chop","lymphoma-tx-regimen-alphabet"],"guideline":{"version":"NCI PDQ: adult non-Hodgkin lymphoma treatment","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":[],"history":[{"year":2002,"title":"Recognised as heterogeneous and germinal-centre derived","note":"A review of 30 cases separated three appearances of the large cells and showed nuclear BCL6 in 26 of 29, placing the tumour cell in the germinal centre.","refs":[]},{"year":2013,"title":"Gene expression finds no clear line to the Hodgkin disease","note":"Profiling the microdissected tumour cells of nodular lymphocyte predominant Hodgkin lymphoma, its diffuse pattern and this disease found no consistent differences between them; the differences were in the surrounding T cells and histiocytes.","refs":["nodular-lymphocyte-predominant-hodgkin-lymphoma"]},{"year":2022,"title":"The relationship written into both classifications","note":"WHO-HAEM5 tabulates six growth patterns of nodular lymphocyte predominant Hodgkin lymphoma and names the diffuse one after this disease; the International Consensus Classification renamed that disease a B-cell lymphoma partly on the strength of the relationship.","refs":["lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["The line between this disease and the diffuse pattern of nodular lymphocyte predominant Hodgkin lymphoma cannot always be drawn, and the two are treated differently.","The cancer cells of the two conditions are not distinguishable by gene expression. What differs is the immune cells around them, and nobody knows why the same tumour cell produces an indolent disease in one person and an aggressive one in another.","No trial has been confined to this entity, so the treatment is borrowed from diffuse large B-cell lymphoma on the strength of the shared surface marker."],"parent":"non-hodgkin-lymphoma"},{"id":"tenosynovial-giant-cell-tumour","kind":"cancer","name":"Tenosynovial giant cell tumour (TGCT)","aka":["TGCT","Pigmented villonodular synovitis","PVNS","Giant cell tumour of the tendon sheath"],"tldr":"TGCT is a benign but destructive tumour of the joint lining, classed with soft-tissue sarcomas, in which a few cells carrying a CSF1 gene fusion recruit a crowd of normal immune cells that eat away at the joint. Surgery cures most localised cases, and for diffuse or recurrent disease two pills that block the CSF1 receptor, pexidartinib and vimseltinib, shrink tumours and restore joint function.","summary":"TGCT is a locally aggressive neoplasm of synovium, bursa and tendon sheath. Its biology is a landscape effect: a minority of neoplastic cells carry a translocation placing CSF1 under the COL6A3 promoter, overproducing colony-stimulating factor 1, which recruits CSF1R-expressing macrophages and osteoclast-like giant cells that make up most of the mass and cause pain, swelling, haemarthrosis and cartilage destruction. Localised (nodular) disease is cured by excision; diffuse disease (formerly pigmented villonodular synovitis) recurs after synovectomy in a large fraction of cases and can lead to joint replacement in young adults.\n\nBecause the tumour depends on CSF1 signalling, CSF1R inhibition is mechanistically exact. Pexidartinib (ENLIVEN, Lancet 2019) was the first FDA-approved systemic therapy for TGCT (August 2019), with objective responses and improved range of motion; it carries a boxed warning and REMS programme for serious and occasionally fatal cholestatic hepatotoxicity, which limited uptake and blocked EU approval. Vimseltinib, a switch-control CSF1R inhibitor, showed improved response and function versus placebo in MOTION (Lancet 2024) without the hepatotoxicity signal and was approved by the FDA in February 2025. Emactuzumab (anti-CSF1R antibody) is in the phase 3 TANGENT trial.\n\nOpen questions are treatment duration and rebound after stopping, the role of neoadjuvant CSF1R inhibition before surgery, and how to handle the many patients with disease that is symptomatic but not surgically threatening.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Giant-cell_tumor_of_the_tendon_sheath","links":[{"label":"NCI PDQ: soft tissue sarcoma","url":"https://www.cancer.gov/types/soft-tissue-sarcoma"},{"label":"MOTION (Lancet 2024)","url":"https://doi.org/10.1016/S0140-6736(24)00885-7"},{"label":"ENLIVEN (Lancet 2019)","url":"https://doi.org/10.1016/S0140-6736(19)30764-0"},{"label":"FDA approval of vimseltinib","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vimseltinib-symptomatic-tenosynovial-giant-cell-tumor"}],"tags":["nci-coverage","rare","sarcoma"],"related":["desmoid-tumour","dermatofibrosarcoma-protuberans","pecoma","inflammatory-myofibroblastic-tumour"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","monoclonal-antibody","mri","limb-salvage-surgery"],"targets":["csf1r"],"drugs":["pexidartinib","vimseltinib","imatinib","nilotinib"],"companies":["deciphera","daiichi-sankyo"],"institutions":[],"pathways":["tumor-microenvironment"],"terms":["rare-cancers"],"trials":["motion","nct05417789","nct05804045","nct04488822"],"people":[],"bottlenecks":["b-rare-cancers","b-toxicity-qol"],"keyPapers":["paper-tap-lancet","paper-gelderblom-lancet"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"Localised disease is relatively common (tens of cases per million per year); the diffuse form that needs drugs is rare, at a few cases per million, mostly in adults aged 20 to 50.","subtypes":["Localised (nodular) TGCT","Diffuse TGCT (pigmented villonodular synovitis)","Malignant TGCT (very rare)"],"biomarkers":["CSF1 rearrangement (COL6A3-CSF1) in neoplastic cells","CSF1R-positive macrophage-rich infiltrate","MRI pattern (haemosiderin blooming on gradient echo)","Liver function tests before and during pexidartinib (REMS)"],"standardOfCare":[{"setting":"Localised TGCT","approach":"Marginal excision; recurrence is uncommon and re-excision is curative in most cases.","refs":["limb-salvage-surgery"],"guideline":{"version":"NCCN Soft Tissue Sarcoma; TGCT consensus (Stacchiotti, Cancer Treat Rev 2023)","url":"https://doi.org/10.1016/j.ctrv.2022.102491"}},{"setting":"Diffuse TGCT, resectable","approach":"Open or arthroscopic synovectomy by a sarcoma orthopaedic team; consider neoadjuvant CSF1R inhibition for large tumours (trial setting).","refs":["limb-salvage-surgery"]},{"setting":"Diffuse TGCT where surgery would cause severe morbidity or after recurrence","approach":"CSF1R inhibitor: vimseltinib (MOTION) or pexidartinib (ENLIVEN, with REMS hepatic monitoring); imatinib or nilotinib off label where neither is available.","refs":["vimseltinib","pexidartinib","motion","imatinib","nilotinib"],"guideline":{"nccn":"Category 2A","version":"NCCN Soft Tissue Sarcoma"}}],"stateOfArt":["TGCT is a textbook case of targeting the signal rather than the neoplastic cell: blocking CSF1R removes the recruited macrophage mass that causes symptoms.","Vimseltinib (MOTION, 2024; FDA 2025) delivers the class benefit without the cholestatic liver injury that has restricted pexidartinib to a REMS programme in the US and kept it off the EU market.","Patient-reported function and stiffness were co-primary or key secondary endpoints in both phase 3 trials, an unusual and appropriate design for a non-lethal tumour.","Surgery remains curative for localised disease; the medical advance is for the diffuse minority."],"history":[{"year":1941,"title":"Jaffe describes pigmented villonodular synovitis","refs":[]},{"year":2006,"title":"CSF1 translocation identified","note":"West and colleagues show a CSF1-expressing neoplastic minority recruits the macrophage majority (PNAS).","refs":[]},{"year":2015,"title":"Pexidartinib phase 1 responses","note":"Tap and colleagues, NEJM: high response rate in diffuse TGCT.","refs":["pexidartinib"]},{"year":2019,"title":"ENLIVEN phase 3 and FDA approval of pexidartinib","note":"First systemic therapy approved for TGCT (August 2019), with a boxed hepatotoxicity warning.","refs":["pexidartinib"]},{"year":2020,"title":"EMA refuses pexidartinib","note":"Hepatotoxicity judged to outweigh benefit for a non-lethal disease.","refs":[]},{"year":2024,"title":"MOTION phase 3 positive for vimseltinib","note":"Gelderblom and colleagues, Lancet.","refs":["vimseltinib","motion"]},{"year":2025,"title":"Vimseltinib approved","note":"FDA approval 14 February 2025 for symptomatic TGCT where surgery would worsen function.","refs":["vimseltinib"]}],"pipeline":["vimseltinib","motion","emactuzumab","pimicotinib"],"openProblems":["Duration of CSF1R therapy and rebound after stopping: extension cohorts and intermittent schedules are being studied.","Hepatotoxicity of pexidartinib: newer agents (vimseltinib, emactuzumab) are designed to avoid it.","Neoadjuvant use to make surgery smaller or unnecessary: phase 2 studies under way.","Access and cost for a benign disease in health systems that price by survival gain."],"parent":"sarcoma"},{"id":"testicular","kind":"cancer","name":"Testicular germ cell tumours","aka":["Seminoma","Non-seminomatous germ cell tumour","NSGCT"],"tldr":"Testicular germ cell tumours are the most curable adult solid cancer: cisplatin-based chemotherapy cures the large majority even when the disease has spread to distant sites. Today's research is about giving less treatment to the majority who are cured, rescuing the minority who relapse, and limiting lifelong survivorship harms.","summary":"Testicular germ cell tumours (GCTs) are seminomas or non-seminomas (embryonal carcinoma, yolk sac tumour, choriocarcinoma, teratoma, mixed), arising from germ cell neoplasia in situ, almost universally carrying 12p gain (i(12p)). Serum tumour markers (AFP, hCG, LDH) stage and monitor the disease; miR-371a-3p is a more sensitive marker entering practice. The IGCCCG classification (1997, updated 2021) divides metastatic disease into good, intermediate and poor prognosis with 5-year survival of ~95%, ~90% and ~65-70%.\n\nOrchiectomy is followed by surveillance for most stage I disease; adjuvant carboplatin (seminoma) or one cycle of BEP (non-seminoma) are options for high-risk stage I. Metastatic disease receives BEP ×3 (good risk) or ×4 (intermediate/poor), or EP ×4 when bleomycin is contraindicated; residual masses after chemotherapy in non-seminoma are resected (retroperitoneal lymph node dissection). Relapse is treated with conventional-dose salvage (TIP, VeIP) or high-dose chemotherapy with autologous stem-cell rescue (TI-CE); the TIGER trial directly compares these. Survivorship (cardiovascular risk, second cancers, hypogonadism, infertility, ototoxicity, neuropathy) is a central concern because patients live 50+ years after cure.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Testicular_cancer","links":[{"label":"NCCN Guidelines: Testicular Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1468"},{"label":"IGCCCG Update (JCO 2021)","url":"https://doi.org/10.1200/JCO.20.03296"},{"label":"NCI PDQ: testicular cancer","url":"https://www.cancer.gov/types/testicular/patient/testicular-treatment-pdq"}],"tags":["gap-fill","genitourinary","aya"],"related":["paediatric-germ-cell-tumours"],"cancers":[],"sections":[],"technologies":["platinum","cytotoxic-chemotherapy","autologous-stem-cell-transplant","active-surveillance","fertility-preservation","survivorship-care-plan"],"targets":["tp53"],"drugs":["cisplatin","carboplatin","etoposide","bleomycin","ifosfamide","paclitaxel","vinblastine"],"companies":[],"institutions":[],"pathways":[],"terms":["afp","late-recurrence","retroperitoneum"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["journal-of-adolescent-and-young-adult-oncology"],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"The most common cancer in men aged 15-40; about 75,000 cases per year worldwide (GLOBOCAN) with cure rates above 95% overall and ~80% even in metastatic disease.","subtypes":["Seminoma","Non-seminoma: embryonal carcinoma, yolk sac, choriocarcinoma, teratoma, mixed","Germ cell neoplasia in situ (precursor)","Extragonadal (mediastinal, retroperitoneal) GCT","Spermatocytic tumour (older men, indolent)"],"biomarkers":["AFP, hCG, LDH (S stage; IGCCCG risk)","miR-371a-3p (emerging, high sensitivity for viable GCT)","i(12p) / 12p gain","Rete testis and lymphovascular invasion (stage I risk)","Tumour size >4 cm (seminoma stage I risk)"],"standardOfCare":[{"setting":"Stage I seminoma","approach":"Orchiectomy then surveillance (preferred); adjuvant carboplatin AUC 7 ×1 or para-aortic radiotherapy for those declining surveillance.","refs":["carboplatin","active-surveillance"],"guideline":{"nccn":"Category 2A (surveillance preferred)","version":"NCCN Guidelines: Testicular Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1468"}},{"setting":"Stage I non-seminoma","approach":"Surveillance (relapse ~15-50% by LVI status, all salvageable); or BEP ×1 or nerve-sparing RPLND for high-risk.","refs":["bleomycin","etoposide","cisplatin","active-surveillance"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Testicular Cancer"}},{"setting":"Metastatic, IGCCCG good risk","approach":"BEP ×3 or EP ×4; post-chemotherapy RPLND for residual non-seminoma masses >1 cm.","refs":["bleomycin","etoposide","cisplatin"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Testicular Cancer"}},{"setting":"Metastatic, intermediate/poor risk","approach":"BEP ×4 (or VIP if bleomycin contraindicated); early marker-decline assessment to intensify (GETUG-13); brain metastases treated multimodally.","refs":["bleomycin","etoposide","cisplatin","ifosfamide","getug-13"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Testicular Cancer"}},{"setting":"Relapsed","approach":"TIP or VeIP conventional-dose salvage, or high-dose carboplatin-etoposide with autologous stem-cell rescue (TI-CE); TIGER phase 3 compares the two; late relapse and teratoma need surgery.","refs":["paclitaxel","ifosfamide","cisplatin","carboplatin","etoposide","autologous-stem-cell-transplant"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Testicular Cancer"}}],"stateOfArt":["Cure rates above 95% are the benchmark for what chemotherapy can do; the field now works on de-escalation (surveillance for stage I, single-cycle adjuvant therapy) and survivorship.","miR-371a-3p promises to replace marker-negative uncertainty with a sensitive blood test for viable disease.","High-dose chemotherapy cures a substantial fraction of relapsed patients; TIGER will define its place.","Poor-risk disease and platinum-refractory GCT remain the unsolved minority; immunotherapy failed here."],"history":[{"year":1960,"title":"Li and colleagues: actinomycin D, methotrexate and chlorambucil active in GCT","refs":["methotrexate","dactinomycin"]},{"year":1974,"title":"Einhorn introduces cisplatin (PVB)","note":"Cure rates in metastatic disease jump from ~10% to ~60-70%.","refs":["cisplatin"]},{"year":1987,"title":"BEP replaces PVB (Williams, NEJM)","note":"Etoposide substitutes vinblastine with better efficacy and less neurotoxicity.","refs":["etoposide","bleomycin"]},{"year":1989,"title":"BEP ×3 sufficient for good-risk disease (Einhorn)","refs":[]},{"year":1997,"title":"IGCCCG prognostic classification","note":"Updated in 2021 with LDH and age refinements.","refs":[]},{"year":2005,"title":"Carboplatin ×1 equals radiotherapy for stage I seminoma (MRC TE19)","refs":["carboplatin"]},{"year":2014,"title":"Surveillance becomes standard for stage I","refs":[]},{"year":2019,"title":"miR-371a-3p validated as a serum marker (Dieckmann, JCO)","refs":[]}],"pipeline":["autologous-stem-cell-transplant","carboplatin"],"openProblems":["Platinum-refractory disease has no effective therapy; checkpoint inhibitors were inactive.","Late effects of cisplatin (cardiovascular disease, second cancers, hearing loss) in men cured in their 20s.","Over-treatment of stage I disease without reliable predictors.","Access to high-dose chemotherapy and expert RPLND outside specialist centres."]},{"id":"tfe3-rearranged-renal-cell-carcinoma","kind":"cancer","name":"TFE3-rearranged (translocation) renal cell carcinoma","aka":["Translocation renal cell carcinoma","Xp11 translocation renal cell carcinoma","MiT family translocation renal cell carcinoma","TFE3-translocation RCC","TFEB-altered renal cell carcinoma","Translocation (TFE3/TFEB)","Translocation Renal Cell Carcinoma"],"tldr":"Translocation renal cell carcinoma is a rare kidney cancer, more often seen in children and young adults, driven by a rearrangement of the TFE3 gene (or its relative TFEB). It can look like clear cell or papillary kidney cancer under the microscope, so it is found by testing for the gene. There is no standard treatment for advanced disease, which is treated with the usual kidney cancer drugs.","summary":"The 2022 WHO classification groups TFE3-rearranged and TFEB-altered (rearranged or amplified) renal cell carcinomas as the molecularly defined MiT family translocation carcinomas (Moch 2022). TFE3-translocation carcinoma is highly heterogeneous clinically and genetically: among 63 untreated primaries studied by whole-exome and RNA sequencing, the ASPSCR1-TFE3 fusion and copy-number changes including loss of 22q went with aggressive features and poor outcome, most tumours (except MED15-TFE3) showed low PD-L1 expression and low T-cell infiltration, and five transcriptional clusters with distinct angiogenesis, stroma, proliferation and KRAS-down signatures tracked with fusion type and prognosis (Nature Communications 2021). A mouse model expressing PRCC-TFE3 in the kidney reproduced the histology, showed elevated RET expression that the RET inhibitor vandetanib suppressed, and identified GPNMB as a diagnostic marker (Molecular Cancer Research 2019).\n\nHow it differs from its parent: it is defined by a fusion rather than by VHL loss, occurs at a younger age, is misdiagnosed as clear cell or papillary carcinoma without TFE3 immunohistochemistry or FISH, and lacks the immune-rich microenvironment that makes clear cell carcinoma respond to checkpoint inhibitors.\n\nHow common: no registry share was found in the sources read.\n\nTreatment: surgery for localised disease; for advanced disease there is no standard, and the VEGF-directed and checkpoint combinations of the renal cell carcinoma page are used with retrospective evidence only (Nature Communications 2021). A registry trial of agnostic therapy in rare solid tumours lists translocation renal cell carcinoma among its conditions.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Renal_cell_carcinoma","links":[{"label":"NCI PDQ: renal cell cancer treatment","url":"https://www.cancer.gov/types/kidney/patient/kidney-treatment-pdq"},{"label":"Moch 2022, European Urology: the 2022 WHO classification of urinary and male genital tumours, part A (renal, penile, testicular)","url":"https://doi.org/10.1016/j.eururo.2022.06.016"},{"label":"Nature Communications 2021: integrated exome and RNA sequencing of 63 TFE3-translocation renal cell carcinomas","url":"https://doi.org/10.1038/s41467-021-25618-z"},{"label":"Molecular Cancer Research 2019: TFE3 Xp11.2 translocation RCC mouse model and GPNMB as a diagnostic marker","url":"https://doi.org/10.1158/1541-7786.mcr-18-1235"}],"tags":["subtype-page","wave4","kidney","rare"],"related":["rcc","clear-cell-rcc","papillary-rcc","wilms-tumor","renal-medullary-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":["tfe3"],"drugs":["cabozantinib","sunitinib","nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["nct06638931"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"Rare, and commonest in children and young adults; the largest molecular series holds 63 untreated primary tumours (Nature Communications 2021). No registry share was found in the sources read.","subtypes":["TFE3-rearranged renal cell carcinoma with ASPSCR1-TFE3 fusion (aggressive)","TFE3-rearranged renal cell carcinoma with PRCC-, SFPQ-, NONO- or MED15-TFE3 fusion","TFEB-rearranged renal cell carcinoma (t(6;11); indolent)","TFEB-amplified renal cell carcinoma (aggressive)","Translocation carcinoma resembling clear cell or papillary renal cell carcinoma on morphology"],"biomarkers":["TFE3 or TFEB rearrangement by FISH or RNA sequencing; TFE3 immunohistochemistry","Fusion partner (ASPSCR1 versus others) and 22q loss (prognostic)","Cathepsin K and melanocytic markers (Melan-A, HMB45)","GPNMB expression (research marker)"],"standardOfCare":[{"setting":"All stages","approach":"Surgery when localised; advanced disease treated on the renal cell carcinoma page's VEGF and checkpoint pathways without a dedicated standard.","refs":["rcc","cabozantinib","sunitinib","nivolumab"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"rcc"},{"id":"thymic-carcinoma","kind":"cancer","name":"Thymic carcinoma","aka":["Thymic squamous cell carcinoma","Type C thymoma (obsolete)","Thymic carcinoma","Malignant thymic epithelial tumour"],"tldr":"Thymic carcinoma is the aggressive kind of thymic epithelial tumour, a cancer of the thymus that behaves like carcinoma elsewhere and has often spread when found. Surgery is attempted when possible, carboplatin with paclitaxel is the usual chemotherapy, and sunitinib, lenvatinib and the PD-1 antibody pembrolizumab have shown responses in trials, with lenvatinib approved in Japan.","summary":"Thymic carcinoma differs from thymoma in every way that matters: its cells are overtly malignant, it lacks the immature T lymphocytes and the organotypic features of thymoma, it is rarely associated with myasthenia gravis, and it presents with local invasion, pleural spread or distant metastases in most patients. Squamous cell carcinoma is the commonest subtype, followed by lymphoepithelioma-like, basaloid, mucoepidermoid, sarcomatoid and NUT carcinoma (covered on its own page); thymic neuroendocrine carcinomas are classified separately. KIT mutations occur in about a tenth of thymic carcinomas, mostly squamous, and respond to imatinib in case series, and TP53, CDKN2A and epigenetic regulator mutations are common; PD-L1 is often highly expressed.\n\nComplete resection is attempted for localised disease, followed by postoperative radiotherapy, and chemotherapy is given before surgery for borderline tumours. For advanced disease the guidelines favour carboplatin and paclitaxel, which produced responses in about a fifth of patients with thymic carcinoma in prospective series, with CAP or platinum-etoposide as alternatives. After platinum, three phase 2 trials define the options: sunitinib (Lancet Oncology 2015) produced responses in about a quarter of 23 patients with thymic carcinoma; lenvatinib in the Japanese REMORA trial (Lancet Oncology 2020) produced responses in 38 percent of 42 patients and was approved in Japan in 2021; and pembrolizumab (Lancet Oncology 2018) produced responses in 22.5 percent of 40 patients with durable benefit but severe immune-related adverse events, including myocarditis, in 15 percent, a rate high enough that PD-1 antibodies are used only with monitoring and are avoided in thymoma. Newer agents in trials include the multikinase inhibitor KC1036, the TROP2 antibody-drug conjugate sacituzumab tirumotecan, ramucirumab with carboplatin and paclitaxel, and CAR-NK cells against CD30 or mesothelin.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Thymic_carcinoma","links":[{"label":"REMORA lenvatinib (Lancet Oncology 2020)","url":"https://doi.org/10.1016/S1470-2045(20)30162-5"},{"label":"Pembrolizumab in thymic carcinoma (Lancet Oncology 2018)","url":"https://doi.org/10.1016/S1470-2045(18)30062-7"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Thymic_carcinoma"}],"tags":["subtype-page","thoracic"],"related":["thymoma","thymic-epithelial","extrapulmonary-nec"],"cancers":[],"sections":[],"technologies":["robotic-surgery","imrt-igrt","proton-therapy","kinase-inhibitors","checkpoint-inhibitor","cytotoxic-chemotherapy"],"targets":["kit","pd1","vegf"],"drugs":["carboplatin","paclitaxel","cisplatin","doxorubicin","cyclophosphamide","sunitinib","lenvatinib","pembrolizumab","everolimus","imatinib"],"companies":[],"institutions":[],"pathways":[],"terms":["irae","tmb","staging-systems"],"trials":["nct05683886","nct07324629","nct07598955"],"people":[],"bottlenecks":[],"keyPapers":["paper-remora-lenvatinib-thymic-carcinoma-lancet-oncol-2020","paper-giaccone-pembrolizumab-thymic-carcinoma-lancet-oncol-2018","paper-esmo-thymic-epithelial-tumours-guideline-ann-oncol-2015","paper-who-2021-thymus-mediastinum-classification-marx-jto-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"thoracic","burden":"About a fifth of thymic epithelial tumours; usually found at an advanced stage with invasion of the mediastinum or spread to pleura, nodes and distant organs, and rarely tied to myasthenia gravis.","subtypes":["Thymic squamous cell carcinoma (the commonest form; KIT mutations in a subset)","Lymphoepithelioma-like thymic carcinoma (EBV-associated in some)","Basaloid, mucoepidermoid and adenocarcinoma of the thymus","Sarcomatoid thymic carcinoma","Resectable thymic carcinoma (surgery and postoperative radiotherapy)","Advanced or metastatic thymic carcinoma (carboplatin-paclitaxel, then kinase inhibitors or pembrolizumab)"],"biomarkers":["Histological subtype and CD5, CD117 (KIT) and p63 immunohistochemistry","TNM and Masaoka-Koga stage","Completeness of resection","KIT mutation (imatinib-responsive subset)","PD-L1 expression (high in many; not required for pembrolizumab)","Baseline troponin and autoimmune screen before PD-1 therapy"],"standardOfCare":[{"setting":"Resectable disease","approach":"Complete resection with thymectomy and involved structures; postoperative radiotherapy for all stages of thymic carcinoma; chemotherapy considered after incomplete resection.","refs":["robotic-surgery","imrt-igrt","proton-therapy"],"guideline":{"version":"NCCN Guidelines: Thymomas and Thymic Carcinomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1469"}},{"setting":"Borderline resectable","approach":"Induction chemotherapy (carboplatin-paclitaxel or CAP) followed by surgery or radiotherapy according to response.","refs":["carboplatin","paclitaxel","cisplatin","doxorubicin","cyclophosphamide"],"guideline":{"version":"NCCN Guidelines: Thymomas and Thymic Carcinomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1469"}},{"setting":"Advanced, first line","approach":"Carboplatin and paclitaxel; CAP or platinum-etoposide as alternatives.","refs":["carboplatin","paclitaxel","cytotoxic-chemotherapy"],"guideline":{"version":"NCCN Guidelines: Thymomas and Thymic Carcinomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1469"}},{"setting":"After platinum","approach":"Sunitinib; lenvatinib (approved in Japan, REMORA); pembrolizumab with cardiac and autoimmune monitoring; everolimus; imatinib for KIT-mutant tumours.","refs":["sunitinib","lenvatinib","pembrolizumab","everolimus","imatinib","irae","kinase-inhibitors","checkpoint-inhibitor"],"guideline":{"version":"NCCN Guidelines: Thymomas and Thymic Carcinomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1469"}},{"setting":"Trials","approach":"KC1036, sacituzumab tirumotecan, CAR-NK cells, ramucirumab combinations.","refs":["nct05683886","nct07324629","nct07598955","kc1036","eb-car30-nk"],"guideline":{"version":"NCCN Guidelines: Thymomas and Thymic Carcinomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1469"}}],"stateOfArt":["Carboplatin and paclitaxel is the accepted first-line regimen on prospective phase 2 evidence.","Lenvatinib is the first drug approved anywhere specifically for thymic carcinoma.","Pembrolizumab gives durable responses in a fifth of patients but at a real risk of myocarditis."],"history":[{"year":1999,"title":"WHO classification separates thymic carcinoma (then type C) from thymoma","refs":[]},{"year":2004,"title":"KIT mutations and imatinib responses described in thymic carcinoma","refs":["imatinib"]},{"year":2015,"title":"Sunitinib phase 2 reports responses in thymic carcinoma after platinum","refs":["sunitinib"]},{"year":2018,"title":"Pembrolizumab phase 2 in thymic carcinoma: 22.5 percent response, 15 percent severe immune toxicity","refs":["pembrolizumab","irae"]},{"year":2020,"title":"REMORA: lenvatinib 38 percent response rate in thymic carcinoma","refs":["lenvatinib"]},{"year":2021,"title":"Lenvatinib approved in Japan for unresectable thymic carcinoma","refs":["lenvatinib"]}],"pipeline":["lenvatinib","sunitinib","pembrolizumab","kc1036","eb-car30-nk","nct07324629","nct05683886"],"openProblems":["No randomised trial has compared any two regimens in thymic carcinoma.","The sequence of kinase inhibitors and immunotherapy is unstudied.","Predicting which patients will develop myocarditis on PD-1 antibodies is not yet possible.","Long-term survival in metastatic disease remains poor."],"parent":"thymic-epithelial"},{"id":"thymoma","kind":"cancer","name":"Thymoma (WHO types A, AB, B1, B2 and B3)","aka":["Thymoma","Type A thymoma","Type AB thymoma","Type B thymoma","Thymoma with myasthenia gravis"],"tldr":"Thymoma is the slower-growing kind of thymic epithelial tumour, an indolent cancer of the thymus gland behind the breastbone that often announces itself through the autoimmune disease myasthenia gravis. Complete surgical removal cures most patients, radiotherapy is added when the tumour has grown through its capsule, and chemotherapy is used to shrink large tumours or control spread in the chest.","summary":"Thymomas are tumours of thymic epithelial cells mixed with non-neoplastic immature T lymphocytes, classified by the WHO into types A, AB, B1, B2 and B3 by the shape of the epithelial cells and the density of lymphocytes, with B3 the most aggressive and A and AB the most indolent. Type A and AB tumours nearly all carry the GTF2I L424H mutation, a finding unique to thymoma, while B thymomas have few recurrent mutations. Because the thymus educates T cells, thymomas are tied to autoimmunity: about a third of patients have myasthenia gravis, others have pure red cell aplasia, hypogammaglobulinaemia (Good syndrome) or other autoimmune conditions, and acetylcholine receptor antibodies are checked before any operation so that myasthenia can be controlled first. Stage, whether by the Masaoka-Koga system or the TNM system introduced in 2017, and completeness of resection matter more than histology for survival.\n\nSurgery is the treatment. Encapsulated tumours are removed whole with the thymus, increasingly by video-assisted or robotic approaches, and the guidelines advise against preoperative biopsy of a resectable encapsulated mass. Postoperative radiotherapy is recommended for stage III disease and for incomplete resection and considered for stage II B2 to B3 tumours, and unresectable or bulky tumours are given induction chemotherapy with cisplatin, doxorubicin and cyclophosphamide (CAP) or a platinum-etoposide doublet before reassessment for surgery. Pleural spread is treated with repeated resection or, in some centres, pleurectomy. For recurrent disease not amenable to local treatment, chemotherapy is repeated, octreotide with prednisone helps octreotide-scan-positive tumours, everolimus produced disease control in a phase 2 trial, and sunitinib and lenvatinib have activity; PD-1 antibodies are used with great caution because thymoma patients develop severe myocarditis, myositis and other immune toxicity far more often than other cancer patients. Thymoma recurs late and slowly, so follow-up runs for at least ten years.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Thymoma","links":[{"label":"NCCN Thymomas and Thymic Carcinomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1469"},{"label":"ESMO thymic epithelial tumours guideline 2015","url":"https://doi.org/10.1093/annonc/mdv277"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Thymoma"}],"tags":["subtype-page","thoracic"],"related":["thymic-carcinoma","thymic-epithelial","lung-net"],"cancers":[],"sections":[],"technologies":["robotic-surgery","imrt-igrt","proton-therapy","kinase-inhibitors","ct","mri"],"targets":["vegf"],"drugs":["cisplatin","doxorubicin","cyclophosphamide","carboplatin","paclitaxel","octreotide-lanreotide","everolimus","sunitinib","lenvatinib"],"companies":[],"institutions":[],"pathways":[],"terms":["irae","staging-systems"],"trials":["nct05683886","nct07598955"],"people":[],"bottlenecks":[],"keyPapers":["paper-esmo-thymic-epithelial-tumours-guideline-ann-oncol-2015","paper-who-2021-thymus-mediastinum-classification-marx-jto-2022","paper-masaoka-thymoma-clinical-staging-cancer-1981"],"journals":[],"dependsOn":[],"notes":[],"group":"thoracic","burden":"The commonest tumour of the anterior mediastinum in adults yet rare in absolute terms; most are found at stage I or II, and about a third of patients have myasthenia gravis.","subtypes":["Type A thymoma (spindle cell, indolent, GTF2I mutant)","Type AB thymoma (mixed, indolent, GTF2I mutant)","Type B1 thymoma (lymphocyte-rich)","Type B2 thymoma","Type B3 thymoma (epithelial-rich, the most aggressive thymoma)","Thymoma with myasthenia gravis or other paraneoplastic autoimmunity","Micronodular thymoma with lymphoid stroma (rare, indolent)","Stage III to IVA thymoma with pleural spread"],"biomarkers":["WHO histotype","Masaoka-Koga and TNM stage","Completeness of resection (R0, R1, R2)","Acetylcholine receptor antibodies (myasthenia screen before surgery)","GTF2I L424H mutation (type A and AB)","Octreotide scan or somatostatin receptor PET (somatostatin analogue eligibility)"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Contrast CT of the chest, acetylcholine receptor antibodies and neurology review; no biopsy of a resectable encapsulated mass; MRI to separate thymoma from cysts and hyperplasia.","refs":["ct","mri"],"guideline":{"version":"NCCN Guidelines: Thymomas and Thymic Carcinomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1469"}},{"setting":"Resectable (stage I to III)","approach":"Complete thymectomy with the tumour, by sternotomy or minimally invasive or robotic approaches for smaller tumours; en bloc resection of involved pericardium, lung or vessels for stage III.","refs":["robotic-surgery"],"guideline":{"version":"NCCN Guidelines: Thymomas and Thymic Carcinomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1469"}},{"setting":"After surgery","approach":"Postoperative radiotherapy for stage III or incomplete resection; considered for stage II B2 to B3 tumours; observation for completely resected stage I and II type A to B1.","refs":["imrt-igrt","proton-therapy"],"guideline":{"version":"NCCN Guidelines: Thymomas and Thymic Carcinomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1469"}},{"setting":"Unresectable or bulky disease","approach":"Induction chemotherapy with cisplatin, doxorubicin and cyclophosphamide (CAP) or a platinum doublet, then surgery or radiotherapy according to response.","refs":["cisplatin","doxorubicin","cyclophosphamide","carboplatin","paclitaxel"],"guideline":{"version":"NCCN Guidelines: Thymomas and Thymic Carcinomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1469"}},{"setting":"Recurrent or metastatic disease","approach":"Repeat resection of pleural recurrences where feasible; chemotherapy rechallenge; octreotide with prednisone for octreotide-scan-positive tumours; everolimus, sunitinib or lenvatinib; PD-1 antibodies avoided or given only in trials because of severe immune toxicity.","refs":["octreotide-lanreotide","everolimus","sunitinib","lenvatinib","irae","nct05683886","nct07598955"],"guideline":{"version":"NCCN Guidelines: Thymomas and Thymic Carcinomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1469"}}],"stateOfArt":["Complete resection cures most thymomas and minimally invasive thymectomy is now routine for small tumours.","The 2017 TNM system unified staging across the world's thymic registries.","Immunotherapy is the one modern treatment largely closed to thymoma patients because of autoimmune toxicity."],"history":[{"year":1981,"title":"Masaoka staging system published, later refined by Koga","refs":["staging-systems"]},{"year":1999,"title":"WHO histological classification of thymic epithelial tumours (types A to C)","refs":[]},{"year":2014,"title":"GTF2I L424H mutation found in most type A and AB thymomas","refs":[]},{"year":2017,"title":"TNM staging for thymic tumours adopted in the eighth edition of the AJCC and UICC manuals","refs":["staging-systems"]},{"year":2018,"title":"Everolimus phase 2 shows disease control in pretreated thymic epithelial tumours; severe immune toxicity of PD-1 antibodies in thymoma reported","refs":["everolimus","irae"]}],"pipeline":["everolimus","sunitinib","lenvatinib","nct05683886","nct07598955","kc1036","eb-car30-nk"],"openProblems":["Randomised trials are almost absent; postoperative radiotherapy for stage II disease rests on registry data.","No systemic therapy is approved specifically for thymoma.","Autoimmune toxicity keeps checkpoint inhibitors off the table for most patients.","Late recurrence a decade or more after surgery makes trial endpoints slow."],"parent":"thymic-epithelial"},{"id":"thymic-epithelial","kind":"cancer","name":"Thymoma and thymic carcinoma","aka":["Thymic epithelial tumours","TET","Thymus Cancer"],"tldr":"Thymoma and thymic carcinoma are rare tumours of the thymus gland in the chest. Thymomas grow slowly, often cause autoimmune diseases such as myasthenia gravis, and are usually cured by surgery; thymic carcinomas behave like other aggressive cancers and have few effective drugs.","summary":"Thymic epithelial tumours range from indolent thymomas (WHO types A, AB, B1-B3) to thymic carcinoma (type C, mostly squamous) and thymic neuroendocrine tumours. Thymomas have the lowest tumour mutational burden of any adult cancer (GTF2I L424H in ~40% of type A/AB) and are uniquely associated with paraneoplastic autoimmunity (myasthenia gravis in ~30%, pure red cell aplasia, hypogammaglobulinaemia/Good syndrome). Staging uses Masaoka-Koga and the TNM 8th edition (ITMIG/IASLC).\n\nComplete resection is the treatment for resectable disease, with post-operative radiotherapy for stage II-III thymoma with high-risk features and for thymic carcinoma. Unresectable disease is treated with induction chemotherapy (cisplatin-doxorubicin-cyclophosphamide, CAP, or carboplatin-paclitaxel for thymic carcinoma) followed by surgery or radiotherapy. Recurrent disease is treated with re-resection where possible, chemotherapy, octreotide plus prednisone for octreoscan-positive thymoma, and in thymic carcinoma with sunitinib or lenvatinib (REMORA). PD-1 inhibitors show activity in thymic carcinoma (pembrolizumab ~20% response) but cause severe immune-related adverse events, especially myocarditis and myositis, and are avoided in thymoma. Everolimus and KIT inhibitors (for the ~10% of thymic carcinomas with KIT mutations) are options.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Thymoma","links":[{"label":"NCCN Guidelines: Thymomas and Thymic Carcinomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1469"},{"label":"ITMIG","url":"https://itmig.org/"},{"label":"NCI PDQ: thymoma and thymic carcinoma","url":"https://www.cancer.gov/types/thymoma/patient/thymoma-treatment-pdq"}],"tags":["gap-fill","thoracic","rare"],"related":[],"cancers":[],"sections":[],"technologies":["robotic-surgery","imrt-igrt","proton-therapy","kinase-inhibitors","checkpoint-inhibitor","cardio-oncology"],"targets":["kit","pd1","vegf"],"drugs":["cisplatin","doxorubicin","cyclophosphamide","carboplatin","paclitaxel","sunitinib","lenvatinib","pembrolizumab","everolimus","octreotide-lanreotide","imatinib"],"companies":["pfizer","eisai","merck"],"institutions":[],"pathways":[],"terms":["irae","tmb"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"thoracic","burden":"About 1.5-3 per million per year; the most common anterior mediastinal tumour in adults; a third of thymoma patients have myasthenia gravis.","subtypes":["Thymoma type A / AB (indolent)","Thymoma type B1 / B2 / B3","Thymic carcinoma (squamous, others)","Thymic neuroendocrine tumours (carcinoid, associated with MEN1)","Micronodular thymoma with lymphoid stroma"],"biomarkers":["WHO histotype and Masaoka-Koga / TNM stage","Completeness of resection (R0)","Acetylcholine-receptor antibodies (myasthenia screening before surgery)","GTF2I L424H (type A/AB thymoma)","KIT mutation (thymic carcinoma subset)","Octreotide scan positivity (somatostatin therapy)"],"standardOfCare":[{"setting":"Resectable (stage I-III)","approach":"Complete thymectomy (minimally invasive for small tumours) after myasthenia control; post-operative radiotherapy for stage III, R1/R2, or thymic carcinoma.","refs":["robotic-surgery","imrt-igrt"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Thymomas and Thymic Carcinomas","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1469"}},{"setting":"Locally advanced unresectable","approach":"Induction chemotherapy (CAP or carboplatin-paclitaxel) then surgery if resectable, otherwise definitive radiotherapy ± chemotherapy.","refs":["cisplatin","doxorubicin","cyclophosphamide","carboplatin","paclitaxel","imrt-igrt"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Thymomas and Thymic Carcinomas"}},{"setting":"Recurrent thymoma","approach":"Re-resection of pleural or local recurrence; chemotherapy; octreotide + prednisone if octreoscan-positive; everolimus.","refs":["octreotide-lanreotide","everolimus"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Thymomas and Thymic Carcinomas"}},{"setting":"Recurrent thymic carcinoma","approach":"Sunitinib or lenvatinib (REMORA); pembrolizumab (with strict cardiac monitoring, not in thymoma); everolimus; KIT inhibitors for KIT-mutant disease.","refs":["sunitinib","lenvatinib","pembrolizumab","everolimus","imatinib"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Thymomas and Thymic Carcinomas"}}],"stateOfArt":["Surgery cures most thymomas; the ITMIG global database and TNM staging (2017) standardised a field once defined by single-centre series.","Multikinase inhibitors are the only agents with prospective phase 2 evidence in thymic carcinoma.","Immunotherapy is a double-edged sword: responses in thymic carcinoma, but life-threatening myocarditis and myositis, and contraindication in thymoma.","Thymoma's near-absence of mutations and its autoimmune phenotype make it a model for understanding tolerance."],"history":[{"year":1939,"title":"Blalock: thymectomy improves myasthenia gravis","refs":[]},{"year":1981,"title":"Masaoka staging system","note":"Refined by Koga in 1994.","refs":[]},{"year":1999,"title":"WHO histologic classification of thymic epithelial tumours","refs":[]},{"year":2010,"title":"ITMIG founded; global retrospective database","refs":[]},{"year":2014,"title":"GTF2I mutation discovered in thymoma (Petrini, Nat Genet)","refs":[]},{"year":2015,"title":"Sunitinib active in thymic carcinoma (Thomas, Lancet Oncol)","refs":["sunitinib"]},{"year":2017,"title":"TNM 8th edition staging (IASLC/ITMIG)","refs":[]},{"year":2018,"title":"Pembrolizumab in thymic carcinoma: activity with severe irAEs (Giaccone, Lancet Oncol)","refs":["pembrolizumab"]},{"year":2020,"title":"REMORA: lenvatinib in thymic carcinoma","refs":["lenvatinib"]}],"pipeline":["lenvatinib","sunitinib","pembrolizumab","kc1036","eb-car30-nk"],"openProblems":["No randomised trials have ever been completed in thymic epithelial tumours.","Immunotherapy safety in a tumour that disturbs central tolerance.","Thymic carcinoma metastatic disease: median survival ~2-3 years.","Management of paraneoplastic syndromes alongside cancer therapy."]},{"id":"thyroid","kind":"cancer","name":"Thyroid cancer","aka":[],"tldr":"Thyroid cancer is usually curable with surgery and radioactive iodine, the original theranostic. Rare aggressive forms respond to RET and BRAF inhibitors.","summary":"Thyroid cancer is really several diseases. Differentiated thyroid cancer (papillary ~85%, follicular, oncocytic) arises from follicular cells, retains iodine uptake, and has a 10-year survival above 95%; its incidence has tripled in many countries because ultrasound finds tiny tumours that would never have caused harm. Medullary thyroid cancer comes from calcitonin-producing C cells, is driven by RET mutations (hereditary in MEN2), and does not take up iodine. Anaplastic thyroid cancer is rare, dedifferentiated, and historically progressed within months; BRAF/MEK inhibition and immunotherapy have started to change that.\n\nDifferentiated disease is treated by surgery, with radioactive iodine (the first theranostic, 1946) reserved for intermediate and high-risk patients after HiLo, ESTIMABL2, and IoN showed low-risk patients gain nothing from it; active surveillance is accepted for microcarcinomas, and lobectomy suffices for many. When cancer becomes radioiodine-refractory, lenvatinib (SELECT) and sorafenib (DECISION) extend progression-free survival, and genotype directs selective therapy: selpercatinib for RET fusions, larotrectinib for NTRK, dabrafenib-trametinib for BRAF. Medullary cancer moved from vandetanib and cabozantinib to RET-selective selpercatinib after LIBRETTO-531 (2023). Anaplastic cancer with BRAF V600E responds to dabrafenib-trametinib (ROAR), often enabling surgery, and triplets with pembrolizumab are producing multi-year survivors.\n\nThe field's biggest problems are the opposite of most cancers': over-detection and over-treatment of indolent disease, alongside the unsolved lethality of anaplastic and RAI-refractory disease, resistance to RET inhibitors (solvent-front mutations), and the toxicity of long-term multikinase therapy.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Thyroid_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Thyroid_cancer"}],"tags":["endocrine","spike"],"related":["radiopharma-roadmap","braf-mek-neoadjuvant-atc","redifferentiation-rai","theranostics"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","radioligand-therapy","ultrasound","radioiodine-therapy","thyroid-fna-molecular","active-surveillance-thyroid","germline-testing"],"targets":["ret","braf","ntrk","vegf","pd1"],"drugs":["radioactive-iodine","vandetanib","selpercatinib","pralsetinib","dabrafenib-trametinib","afirma","thyrotropin-alfa"],"companies":["eli-lilly","bayer","novartis","sanofi","veracyte","astrazeneca"],"institutions":["gustave-roussy","cruk","md-anderson","mskcc"],"pathways":["ras-mapk","thyroid-cancer-signalling"],"terms":["rai-refractory","low-risk-dtc","bethesda-category","tsh-suppression","tert-promoter","theranostics"],"trials":["nct06860971","nct04940052","nct03690388","select-lenvatinib","decision-sorafenib","libretto-531","arrow-thyroid","estimabl2","ion-trial","hilo","roar-atc","astra"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["endocrine-related-cancer","european-thyroid-journal"],"dependsOn":[],"notes":[],"group":"endocrine","burden":"~820,000 cases per year; most are indolent papillary cancers with >98% survival.","subtypes":["Papillary (~85%; BRAF V600E ~50%, RET/PTC fusions, RAS)","Follicular (RAS, PAX8-PPARG)","Oncocytic (Hürthle cell)","Poorly differentiated","Anaplastic (BRAF V600E ~40%, TP53, TERT)","Medullary (RET germline in MEN2 ~25%; somatic RET M918T)","Papillary microcarcinoma (≤1 cm; surveillance candidate)","Paediatric differentiated thyroid cancer (fusion-driven, often nodal, excellent survival)"],"biomarkers":["BRAF V600E","RET fusion/mutation","NTRK","RAS","TERT","Thyroglobulin and anti-Tg antibodies (surveillance of differentiated cancer)","Calcitonin and CEA (medullary)","Germline RET (MEN2 screening, prophylactic thyroidectomy)","Somatic RET fusion/mutation (selpercatinib)","BRAF V600E (prognosis; anaplastic targeted therapy; redifferentiation)","TERT promoter (aggressiveness)","NTRK, ALK fusions (tumour-agnostic drugs)","Bethesda cytology category and molecular classifier result","Radioiodine avidity on diagnostic scan"],"standardOfCare":[{"setting":"Differentiated","approach":"Thyroidectomy ± radioactive iodine; TSH suppression.","refs":["radioligand-therapy"],"guideline":{"version":"NCCN Guidelines: Thyroid Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1470"}},{"setting":"Advanced/refractory","approach":"Lenvatinib; selpercatinib (RET); BRAF/MEK (anaplastic).","refs":["selpercatinib"],"guideline":{"version":"NCCN Guidelines: Thyroid Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1470"}},{"setting":"Nodule work-up","approach":"Ultrasound with TI-RADS; FNA only for nodules meeting size/appearance thresholds; Bethesda reporting; molecular classifier (Afirma, ThyroSeq) for indeterminate results.","refs":["thyroid-fna-molecular","ultrasound","bethesda-category"],"guideline":{"nccn":"2A","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1470"}},{"setting":"Papillary microcarcinoma (≤1 cm, no spread)","approach":"Active surveillance or lobectomy; total thyroidectomy and radioiodine not indicated.","refs":["active-surveillance-thyroid","idea-thyroid-overdiagnosis-reversal"],"guideline":{"nccn":"2A"}},{"setting":"Low-risk differentiated (pT1-T2 N0)","approach":"Lobectomy or total thyroidectomy; no radioiodine ablation (ESTIMABL2, IoN); modest TSH suppression then normal-range TSH.","refs":["estimabl2","ion-trial","low-risk-dtc","tsh-suppression"],"guideline":{"nccn":"2A"}},{"setting":"Intermediate/high-risk differentiated","approach":"Total thyroidectomy with therapeutic node dissection; radioiodine (1.1-3.7 GBq adjuvant; higher for known metastases) after recombinant TSH; TSH suppression.","refs":["radioactive-iodine","radioiodine-therapy","hilo"],"guideline":{"nccn":"2A"}},{"setting":"Radioiodine-refractory, progressive","approach":"Genotype first: selpercatinib (RET fusion), larotrectinib/entrectinib (NTRK), dabrafenib-trametinib (BRAF V600E); otherwise lenvatinib (or sorafenib); consider MAPK-inhibitor redifferentiation to restore iodine uptake.","refs":["select-lenvatinib","decision-sorafenib","selpercatinib","redifferentiation-rai","rai-refractory"],"guideline":{"nccn":"1 (lenvatinib)","esmoMcbs":"3"}},{"setting":"Medullary, localised","approach":"Total thyroidectomy with central neck dissection; prophylactic thyroidectomy in RET germline carriers by codon-based age; calcitonin surveillance.","refs":["ret","germline-testing"],"guideline":{"nccn":"2A"}},{"setting":"Medullary, advanced progressive RET-mutant","approach":"Selpercatinib first line (LIBRETTO-531); cabozantinib or vandetanib if RET-selective therapy unavailable or failed.","refs":["libretto-531","selpercatinib","vandetanib"],"guideline":{"nccn":"1 (preferred)","esmoMcbs":"3"}},{"setting":"Anaplastic, BRAF V600E","approach":"Rapid BRAF testing; dabrafenib-trametinib (ROAR), often with pembrolizumab, then surgery and radiation if rendered resectable.","refs":["roar-atc","dabrafenib-trametinib","braf-mek-neoadjuvant-atc","idea-atc-triplet-io"],"guideline":{"nccn":"2A"}},{"setting":"Anaplastic, BRAF wild-type","approach":"Multimodal chemoradiation (paclitaxel-based) if feasible; lenvatinib; immunotherapy for PD-L1-high or TMB-high; NTRK/RET/ALK agents if fusion-positive; early palliative care.","refs":["imrt-igrt","pembrolizumab"]},{"setting":"Survivorship","approach":"Lifelong levothyroxine with risk-adapted TSH targets; calcium/PTH monitoring after surgery; salivary care after radioiodine; low-risk patients can be discharged to primary care.","refs":["tsh-suppression","supportive-care"]}],"stateOfArt":["Genotype-directed therapy for aggressive subtypes.","De-escalation is the story: radioiodine omitted for low-risk disease (ESTIMABL2, IoN), low-dose ablation when needed (HiLo), lobectomy and active surveillance for small tumours.","Genotype-directed therapy covers most aggressive disease: RET (selpercatinib beat multikinase inhibitors head to head), BRAF, NTRK, ALK.","Anaplastic thyroid cancer with BRAF V600E has moved from a median survival under six months to 15 months with the doublet and longer with immunotherapy added, and neoadjuvant use enables surgery.","Molecular classifiers on needle biopsies have halved diagnostic surgery for indeterminate nodules.","Redifferentiation with MAPK inhibitors can restore radioiodine uptake in about half of refractory patients."],"history":[{"year":1946,"title":"Radioactive iodine: first theranostic","refs":[]},{"year":1946,"title":"First patient treated with radioactive iodine for metastatic thyroid cancer","note":"Seidlin, Marinelli, and Oshry: the first theranostic.","refs":["radioactive-iodine","radioiodine-therapy"]},{"year":1985,"title":"RET proto-oncogene identified; MEN2 germline RET mutations follow (1993)","refs":["ret"]},{"year":2003,"title":"BRAF V600E found in ~45% of papillary thyroid cancers","refs":["braf"]},{"year":2009,"title":"Bethesda System for thyroid cytology standardises nodule reporting","refs":["bethesda-category","thyroid-fna-molecular"]},{"year":2011,"title":"Vandetanib: first drug for medullary thyroid cancer","refs":["vandetanib"]},{"year":2012,"title":"HiLo and ESTIMABL1: low-dose radioiodine ablation is enough","refs":["hilo"]},{"year":2013,"title":"Sorafenib approved for RAI-refractory disease (DECISION); selumetinib redifferentiation proof of concept","refs":["decision-sorafenib","redifferentiation-rai"]},{"year":2015,"title":"Lenvatinib approved (SELECT); ATA guidelines endorse active surveillance and less radioiodine","refs":["select-lenvatinib","active-surveillance-thyroid"]},{"year":2018,"title":"Dabrafenib-trametinib approved for BRAF V600E anaplastic thyroid cancer (ROAR); larotrectinib tumour-agnostic","refs":["roar-atc","dabrafenib-trametinib","ntrk"]},{"year":2020,"title":"Selpercatinib approved","refs":["selpercatinib"]},{"year":2020,"title":"Selpercatinib and pralsetinib: RET-selective inhibitors approved","refs":["selpercatinib","pralsetinib","arrow-thyroid"]},{"year":2022,"title":"ESTIMABL2: no radioiodine for low-risk disease; ASTRA adjuvant redifferentiation negative","refs":["estimabl2","astra"]},{"year":2023,"title":"LIBRETTO-531: selpercatinib beats cabozantinib/vandetanib in medullary cancer","refs":["libretto-531"]},{"year":2025,"title":"IoN confirms omission of radioiodine in low-risk disease (Lancet)","refs":["ion-trial"]},{"year":2026,"title":"Selpercatinib label update (July 2026)","refs":["selpercatinib"]}],"pipeline":["selpercatinib","al2846","jk08","idea-atc-triplet-io","braf-mek-neoadjuvant-atc","redifferentiation-rai","idea-thyroid-overdiagnosis-reversal","thyroid-fna-molecular","active-surveillance-thyroid","pembrolizumab","cthpv-dna","targeted-alpha-therapy","mrd-testing","dermoscopy-ai"],"openProblems":["Overdiagnosis of microcarcinoma.","Anaplastic thyroid cancer: BRAF V600E cases now respond to dabrafenib-trametinib, often enough to allow surgery; the 60% without the mutation still have few options.","Overdiagnosis: incidence has tripled with no change in mortality; most detected cancers would never have caused harm, yet surveillance uptake outside Japan and Korea remains low.","Anaplastic thyroid cancer without BRAF V600E (about 60%) still has a median survival of a few months.","Resistance to RET-selective inhibitors via solvent-front (G810) mutations has no approved next-generation drug.","Multikinase inhibitors for RAI-refractory disease cause hypertension, weight loss, and fatigue; most patients need dose reductions and quality of life suffers.","No validated way to predict which low-risk patients will be the rare ones to recur, so follow-up intensity is uniform.","Redifferentiation works in about half of refractory patients but predictors and optimal regimens are undefined.","Paediatric and radiation-induced thyroid cancers (Chernobyl, Fukushima cohorts) have distinct fusion-driven biology that is under-studied.","Hereditary MEN2 requires lifelong surveillance and prophylactic surgery in children; long-term outcomes of RET-selective therapy in this group are unknown."]},{"id":"thyrotroph-pitnet","kind":"cancer","name":"Thyrotroph pituitary neuroendocrine tumour (TSH-secreting)","aka":["Thyrotroph tumour","TSHoma","Thyrotropin-secreting pituitary adenoma","TSH-secreting pituitary tumour","Thyrotroph adenoma"],"tldr":"A thyrotroph tumour is a very rare pituitary tumour that secretes TSH, driving the thyroid to overactivity with a TSH level that is not suppressed. It is often mistaken for common hyperthyroidism and wrongly treated by destroying the thyroid, which makes the pituitary tumour grow. Surgery is the treatment of choice; somatostatin analogues control most of the rest.","summary":"The 2022 WHO classification places the thyrotroph tumour in the PIT1 lineage, defined by TSH-beta and GATA3 staining (Asa 2022). The European Thyroid Association guideline notes that TSH-secreting tumours are characterised by high free thyroid hormones with non-suppressed TSH, that failure to recognise them may lead to inappropriate thyroid ablation with a significant increase in pituitary tumour mass, that diagnosis rests on TSH response to T3 suppression and TRH stimulation together with imaging and genetic testing to exclude thyroid hormone resistance, and that surgery is the treatment of choice with somatostatin analogues normalising TSH in most surgical failures (ETA 2013). In 90 consecutive patients operated on between 1991 and 2013 (47 women, median age 42, range 11 to 74), 18 percent were microadenomas and 82 percent macroadenomas, microadenomas becoming more frequent recently, 23 percent invaded the cavernous sinus, 74 percent were firm or hard, and co-secretion of growth hormone or prolactin occurred (J Neurosurg 2014).\n\nHow it differs from its parent: its syndrome mimics Graves disease, so the diagnostic trap is thyroid rather than pituitary; the tumours are often fibrous and invasive, making complete resection harder; and somatostatin analogues are unusually effective medically.\n\nHow common: no incidence figure in the sources read; the rarest functioning pituitary tumour (ETA 2013).\n\nTreatment: transsphenoidal surgery after rendering the patient euthyroid; somatostatin analogues (octreotide, lanreotide) for residual or recurrent disease; radiotherapy where medical control fails (ETA 2013; J Neurosurg 2014).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Thyrotropic_pituitary_adenoma","links":[{"label":"NCI PDQ: pituitary tumours treatment","url":"https://www.cancer.gov/types/pituitary/treatment"},{"label":"Asa 2022, Endocrine Pathology: overview of the 2022 WHO classification of pituitary tumours","url":"https://doi.org/10.1007/s12022-022-09703-7"},{"label":"European Thyroid Journal 2013: ETA guidelines for thyrotropin-secreting pituitary tumours","url":"https://doi.org/10.1159/000351007"},{"label":"J Neurosurg 2014: thyrotropin-secreting pituitary adenomas, 90 cases treated by transsphenoidal surgery","url":"https://doi.org/10.3171/2014.7.jns1471"}],"tags":["subtype-page","wave4","rare"],"related":["pituitary-tumours","somatotroph-pitnet","lactotroph-pitnet","gonadotroph-pitnet","thyroid"],"cancers":[],"sections":[],"technologies":["radiosurgery-srs"],"targets":[],"drugs":["pasireotide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"The rarest functioning pituitary tumour and a very rare cause of hyperthyroidism (ETA 2013); the largest surgical series holds 90 patients, median age 42, 82 percent macroadenomas (J Neurosurg 2014). GLOBOCAN does not count pituitary tumours.","subtypes":["Thyrotroph pituitary macroadenoma (82 percent; often invasive and fibrous)","Thyrotroph pituitary microadenoma (increasingly recognised)","Thyrotroph tumour co-secreting growth hormone or prolactin (PIT1 lineage plurihormonal)"],"biomarkers":["Free T4 and T3 with non-suppressed TSH","TSH response to T3 suppression and TRH stimulation; alpha-subunit","TSH-beta, GATA3 and PIT1 immunostaining","Thyroid hormone receptor beta testing to exclude resistance"],"standardOfCare":[{"setting":"All cases","approach":"Transsphenoidal surgery after achieving euthyroidism; somatostatin analogues for residual disease; radiotherapy where medical control fails (ETA 2013).","refs":["pituitary-tumours","pasireotide","radiosurgery-srs"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"pituitary-tumours"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","aka":["ER negative PR negative HER2 negative","all three receptors negative","receptor negative breast cancer","grade 3 triple negative breast cancer","ER- PR- HER2- breast cancer"],"tldr":"A breast cancer that lacks the three receptors (oestrogen, progesterone, HER2) that other breast cancers can be treated through. It was the hardest subtype for decades; since 2020 immunotherapy and ADCs have changed that.","summary":"TNBC is defined by what it lacks: ER <1%, PR <1%, HER2 0-1+ (or 2+/ISH-negative). It is biologically heterogeneous (basal-like 1 and 2, mesenchymal, luminal androgen receptor, immunomodulatory subtypes), nearly always TP53-mutant, frequently HRD-positive (11 to 17% germline BRCA1/2 by cohort), and has the highest TROP2 expression and the most immune infiltration of any breast subtype. Relapses cluster in the first three years and favour visceral and brain metastases.\n\nThe standard of care changed three times in six years. KEYNOTE-522 (2020-21) made pembrolizumab plus carboplatin-containing chemotherapy before surgery, continued after, the standard for stage II-III disease, with a 4.9-point overall survival gain at five years (86.6% against 81.7%). OlympiA (2021) added adjuvant olaparib for germline BRCA carriers with residual disease. In metastatic disease, pembrolizumab-chemotherapy (CPS ≥10) was joined by the TROP2 ADCs: sacituzumab govitecan (ASCENT, second line 2020; first-line ASCENT-03/04 2026) and datopotamab deruxtecan (TROPION-Breast02, first-line PD-1-ineligible, 2026, with an overall survival benefit), while T-DXd covers the roughly one third of TNBC that is HER2-low (24 to 37% by cohort). The EGFR×HER3 bispecific ADC iza-bren posted the first positive phase 3 for a bispecific ADC in pretreated TNBC in February 2026.\n\nWhat remains unsolved: residual disease after KEYNOTE-522 (RCB II-III) still carries ~40-50% relapse risk; ADC sequencing (TOP1-payload cross-resistance) is unstudied; PD-L1-negative early disease has immunotherapy proven only in KEYNOTE-522's unselected population; brain metastases; and the biology of the mesenchymal/claudin-low subtype resists every class. The most promising directions are ADC + IO first line, de-escalation guided by TILs and pCR, ctDNA-guided escalation, TROP2 PET selection, next-generation ADCs with non-TOP1 or dual payloads, and personalised vaccines in the adjuvant setting.\n\nHow common it is, world and United States. No registry publishes a world count of triple-negative disease; the share has to be applied to breast cancer as a whole. The IARC breast fact sheet, served today with the GLOBOCAN 2024 estimates, gives 2,434,087 new breast cancers a year (the second commonest cancer, age-standardised rate 47.8 per 100,000) and 693,660 deaths (fourth, 12.9 per 100,000), with 45.1 percent of cases in Asia, 22.3 percent in Europe, 13.2 percent in Northern America, 9.3 percent in Africa and 9.0 percent in Latin America and the Caribbean. The triple-negative share in registries with receptor data runs from 8.4 percent of 1,151,724 US cases in 2010 to 2014 (Scott 2019) through 10.8 percent of US cases with a known subtype in SEER 21, 2019 to 2023 (the SEER subtype fact sheet), 12.2 percent of cases with known status in 2010 (Howlader 2014) and 12 percent in 2012 to 2016 (Howard and Olopade 2021), to around 15 percent on the Cancer Research UK patient page and 17 percent of 15,204 women treated at NCCN centres in 2000 to 2006 (Lin 2012). Applied to 2.4 million, a share of 10 to 15 percent would be about 240,000 to 370,000 people a year; that is arithmetic on the figures above, not a published count. In the United States the age-adjusted rate of hormone receptor-negative, HER2-negative breast cancer is 14.3 per 100,000 women a year against 132.5 for all breast cancer (SEER 21, 2019 to 2023), and 321,910 new female breast cancers of all subtypes are projected for 2026.\n\nWho gets it. Age: triple-negative tumours are diagnosed younger than hormone receptor-positive tumours. Women under 40 had 1.53 times the odds of the triple-negative phenotype in the California registry (Bauer 2007) and 1.95 times the odds relative to women aged 50 to 64 in US Cancer Statistics (Scott 2019); Howlader found triple-negative patients 10 to 30 percent less likely to be diagnosed at older ages and 6.4 to 20 times more likely to present with high-grade disease; Cancer Research UK says the type develops more often in women under 40. Ethnicity: in SEER 21 (2019 to 2023) the rate of hormone receptor-negative, HER2-negative disease is 25.7 per 100,000 in non-Hispanic Black women against 13.0 in non-Hispanic White, 12.5 in Hispanic, 11.4 in American Indian and Alaska Native and 10.5 in Asian and Pacific Islander women, roughly a two-fold difference; non-Hispanic Black women had 2.27 times the odds of a triple-negative diagnosis in 2010 to 2014 (Scott 2019); the basal-like subtype was found in 39 percent of premenopausal African American women against 16 percent of non-African American women in the Carolina Breast Cancer Study (Carey 2006); and in 507 women in Nigeria and Senegal, triple-negative disease (basal-like 27 percent plus unclassified 28 percent) predominated, with a mean age of 44.8 (Huo 2009). In the UK, the POSH cohort of women diagnosed at 40 or under found triple-negative tumours in 26.1 percent of Black against 18.6 percent of White patients (Copson 2014), and an analysis of 116,500 women in England (2013 to 2018) found greater adjusted odds of ER-negative, high-grade and high-stage tumours in ethnic minority women, most marked in Black African and Black Caribbean women (Gathani 2021). Even after adjustment for stage, treatment delay and socioeconomic factors, African American women with triple-negative disease remain nearly twice as likely to die of it (Howard and Olopade 2021). Inherited risk: 57.1 percent of breast cancers in BRCA1 carriers were triple-negative against 23.3 percent in BRCA2 carriers and 13.8 percent in non-carriers (Atchley 2008); in 6,893 carriers the triple-negative share fell with age at diagnosis in BRCA1 and rose in BRCA2 carriers, and medullary tumours were BRCA1-related (Mavaddat 2012). Looked at from the other side, 14.6 percent of 1,824 triple-negative patients unselected for family history carried a deleterious mutation in one of 17 genes, 8.5 percent BRCA1, 2.7 percent BRCA2 and 1.2 percent PALB2 (Couch 2015); a prospective US registry found 15.4 percent with BRCA1 or BRCA2 mutations, 27.6 percent among those diagnosed at 50 or under, 11.4 percent at 51 to 60 and 4.9 percent at 61 or over (Sharma 2014); and 12 percent of 2,733 UK women with breast cancer at 40 or under carried a BRCA mutation (Copson 2018). Cancer Research UK puts the lifetime breast cancer risk of a BRCA1 or BRCA2 carrier at 45 to 65 percent by age 70, with about 1 in 450 women carrying a mutation; PALB2 carries a relative risk of 7.18 and a 53 percent risk to age 80 (Yang 2020).\n\nUnited Kingdom (Cancer Research UK, drawing on the four national registries). Breast cancer is the commonest cancer, with 59,413 new cases a year (2019 and 2021 to 2022), about 59,000 in females and 420 in males, 15 percent of all cancers; a quarter are diagnosed at 75 or over; incidence rates have risen 20 percent since the early 1990s and are projected to fall 1 percent by 2038 to 2040 while the count rises to about 70,300 a year; incidence rates are lower in the Asian and Black ethnic groups than the White group in England (2013 to 2017), which sits beside the higher triple-negative share in Black women noted above. There are about 11,200 deaths a year (2022 to 2024), the fourth commonest cause of cancer death and the second in women; mortality rates have fallen 46 percent since the early 1970s. In England in 2022, 85 percent of cases with a known stage were stage I or II; in 2019, 53 percent were diagnosed through an urgent suspected cancer referral, 32 percent through screening and 4 percent after an emergency presentation. About 23 percent of UK breast cancers are judged preventable, 8 percent attributed to alcohol and 1 percent to ionising radiation. Cancer Research UK does not publish a separate UK incidence count for triple-negative disease; the around 15 percent share on its patient page, and the 20 percent share in the young-onset POSH cohort (558 of 2,733), are the UK figures found for this record.\n\nRisk factors that separate triple-negative from other breast cancers. Reproduction runs the other way from hormone receptor-positive disease: in 23,353 cases and 71,072 controls pooled across 31 studies, parous women had a lower risk of every luminal and HER2-enriched-like subtype but a higher risk of triple-negative disease immediately after a birth (odds ratio 3.12 for multiparous women right after their last birth), attenuating over decades (Jung 2022); in African American women parity raised triple-negative risk (odds ratio 1.37) while breastfeeding lowered ER-negative risk (0.81), and ER-negative risk rose with each birth in women who had not breastfed (1.68 for four or more births) (Palmer 2014). Cancer Research UK's summary that triple-negative disease is not associated with parity, from an older meta-analysis, is recorded beside these newer pooled analyses. Obesity: triple-negative cases were more often obese than hormone receptor-positive cases (odds ratio 1.20 case-case, 1.24 case-control), a signal confined to premenopausal women (1.43) in an 11-study meta-analysis (Pierobon 2013), and 1.89 in an Atlanta case series (Trivers 2009); Cancer Research UK notes the postmenopausal body-mass effect is largely limited to ER- and PR-positive tumours (adult weight gain raised ER- and PR-negative risk by 34 percent against 133 percent for positive tumours). Age at first birth and at menarche, and oral contraceptive or HRT use, are associated mainly with hormone receptor-positive tumours (CRUK risk page). A first-degree relative with breast cancer doubles breast cancer risk of any type, and the germline factors above (BRCA1 above all, then PALB2 and BRCA2) are the strongest known triple-negative risk factors. What is shared with all breast cancer: alcohol (8 percent of UK cases), ionising radiation (1 percent) and breast density (3 to 5 times the risk in the most dense breasts).\n\nHow it presents. Symptoms are those of any breast cancer: a lump or thickening in the breast or armpit, a change in size, shape or feel, skin puckering, dimpling, a rash or redness, fluid from the nipple, or a nipple that turns in (Cancer Research UK triple-negative and symptoms pages). What differs is the route and the tempo. Triple-negative tumours are less often found by a screening mammogram (29 percent against 48 percent of hormone receptor-positive, HER2-negative tumours in NCCN centres) and present with a higher tumour category but are less likely to involve the lymph nodes (Lin 2012); they are over-represented among interval cancers, which appear between screens and carry worse prognostic features than screen-detected cancers (Houssami 2017); and they are more often high grade (Howlader 2014). Relapse is early: in 1,601 Toronto patients the triple-negative group had 2.6 times the hazard of distant recurrence and 3.2 times the hazard of death within five years but not afterwards, with the risk of distant recurrence peaking at about three years and falling rapidly (Dent 2007); recurrence and death rates were higher only in the first three years in the MD Anderson neoadjuvant series, which also found more visceral and fewer bone relapses (Liedtke 2008); and in 116 patients with metastatic disease treated in 2000 to 2006, 46 percent developed brain metastases before death and median survival from the metastatic diagnosis was 13.3 months (Lin 2008), a figure that the later trials in the treatment rows have moved. NICE NG12 (1.4) asks GPs to refer on the suspected cancer pathway anyone aged 30 or over with an unexplained breast lump, anyone 50 or over with discharge, retraction or other change in one nipple, and to consider it for skin changes or an unexplained axillary lump at 30 or over.\n\nHow it is diagnosed. In the UK the GP refers to a one-stop breast clinic for triple assessment: examination, mammogram, ultrasound and a needle core (or vacuum-assisted) biopsy, with axillary ultrasound and needle biopsy of any abnormal node (Cancer Research UK tests page). NICE NG101 (1.3.1 to 1.3.4) requires ER, PR and HER2 status to be assessed simultaneously on every invasive breast cancer at the initial histopathological diagnosis, by standardised, quality-assured immunohistochemistry reported quantitatively, and recorded at the preoperative and postoperative multidisciplinary meetings. Triple-negative is then a laboratory definition: ER negative when fewer than 1 percent of tumour nuclei stain, PR likewise, with 1 to 10 percent reported as a new ER Low Positive category on which endocrine benefit is uncertain (ASCO/CAP 2020, Allison); HER2 negative when immunohistochemistry is 0 or 1+, or 2+ with no amplification on in situ hybridisation (ASCO/CAP 2018, Wolff). The 2023 ASCO-CAP update kept those categories but added a reporting comment because the difference between HER2 0 and 1+ now decides eligibility for trastuzumab deruxtecan (Wolff 2023). NG101 defines triple-negative simply as ER, PR and HER2 each scored negative under local multidisciplinary team rules. Where the receptors are low rather than absent the behaviour is the same: ER 1 to 10 percent tumours matched ER-negative tumours for germline BRCA prevalence, response and survival in a US registry (Yoder 2022) and in an Italian series (Dieci 2021), and Sweden treats ER 1 to 9 percent HER2-negative tumours as triple-negative, with 9.9 percent of 5,655 such cancers in 2008 to 2020 falling in that band (Acs 2024). Breast MRI is not routine before surgery but is offered when the extent of disease is unclear, when breast density defeats mammography, or to size an invasive lobular cancer (NG101 1.2). Staging tests beyond the breast and axilla, where the stage or symptoms warrant, are CT, bone scan, liver ultrasound or PET-CT, and blood tests including CA 15-3 which cannot diagnose or direct treatment on its own (Cancer Research UK tests page). NG101 (1.3.6) adds one test that applies to this subtype alone: offer germline BRCA1 and BRCA2 testing to women under 50 with triple-negative breast cancer, including those with no family history.\n\nWhat the pathologist sees. Most triple-negative cancers are invasive carcinomas of no special type (the term the 2019 WHO classification, 5th edition, uses for what was called ductal carcinoma) of grade 3, with a high proliferation index: the Swedish cohort's median Ki-67 was 63 percent in ER-zero and 60 percent in ER-low tumours, and 80.8 percent of ER-zero tumours were grade III (Acs 2024). By gene expression, 78.6 percent of triple-negative tumours are basal-like and 21.4 percent belong to other intrinsic subtypes, while 31.5 percent of basal-like tumours are not triple-negative (Prat 2013); basal-like tumours share many molecular features with high-grade serous ovarian cancer, and TP53 is the mutation that recurs across them (TCGA 2012). Within the triple-negative group, Lehmann's 2011 analysis of 587 cases found six expression subtypes (basal-like 1 and 2, immunomodulatory, mesenchymal, mesenchymal stem-like and luminal androgen receptor), refined in 2016 to four tumour-intrinsic subtypes once the immunomodulatory and stem-like signals were traced to infiltrating lymphocytes and stroma; Burstein's four (luminal androgen receptor, mesenchymal, basal-like immunosuppressed and basal-like immune-activated) overlap them. Each has a page linked from this record. The WHO classification also names special histological types that are usually triple-negative: metaplastic carcinoma (70.3 percent triple-negative in 2,451 US cases, Ong 2018), carcinoma with medullary pattern (no longer a separate type in the 5th edition, Thomas 2023; Cserni 2020), adenoid cystic carcinoma (95 percent localised at diagnosis, 15-year relative survival 91.4 percent, Ghabach 2010), apocrine carcinoma (ER and PR negative, androgen receptor positive, Vranic 2013) and secretory carcinoma (ETV6-NTRK3 fusion in 92 percent, Tognon 2002). Rare subtypes together are 5 to 10 percent of triple-negative cancers (Thomas 2023), and the European Working Group for Breast Screening Pathology concludes that patients with the indolent pure forms (classical adenoid cystic, low-grade adenosquamous, fibromatosis-like metaplastic, secretory, acinic cell, tall cell with reversed polarity) are unlikely to benefit from chemotherapy (Cserni 2021). Stromal tumour-infiltrating lymphocytes are scored on the biopsy, and PD-L1 combined positive score is tested when metastatic treatment is planned (the glossary terms carry the thresholds).\n\nHow it is staged. The TNM 8th edition (2017) is the usual system in the UK, and Cancer Research UK sets it out in plain words. T1 is 2 cm or less (T1mi 0.1 cm or less, T1a to 0.5 cm, T1b to 1 cm, T1c to 2 cm), T2 over 2 to 5 cm, T3 over 5 cm, T4 into the chest wall (a), skin (b), both (c) or inflammatory carcinoma (d). Nodes are staged clinically (cN) before any treatment and pathologically (pN) from the sentinel node or clearance: pN1 one to three axillary nodes (pN1mi micrometastases 0.2 to 2 mm), pN2 four to nine, pN3 ten or more or infraclavicular, or axillary plus internal mammary, or supraclavicular nodes. Stage 1A is T1 N0; 1B adds micrometastases; 2A is T0 to T1 N1 or T2 N0; 2B is T2 N1 or T3 N0; 3A is N2 with T0 to T3 or T3 N1; 3B is T4 with N0 to N2; 3C is any N3; stage 4 is any M1. The American Joint Committee on Cancer's 8th edition kept this anatomic stage but added a prognostic stage that folds grade, ER, PR and HER2 status (and, for some hormone receptor-positive tumours, a low Oncotype DX score) into the stage group (Giuliano 2017); in a 3,327-patient MD Anderson cohort the prognostic stage moved 29.5 percent of patients up and 28.1 percent down, and predicted disease-specific survival better than the anatomic stage (C index 0.84 against 0.74), with the same result in 54,727 Californian patients (Weiss 2018). Because grade 3 and receptor negativity count against a tumour, a triple-negative cancer generally carries a higher prognostic than anatomic stage; the UK pathway pages quote the anatomic stage. When chemotherapy is given before surgery, as it is for most stage II and III triple-negative disease, the response at surgery (pathological complete response or residual cancer burden) becomes the stronger prognostic marker (Cortazar 2014; Symmans 2017; the glossary terms).\n\nScreening and prevention. There is no screening test for triple-negative disease as such. The NHS Breast Screening Programme invites everyone registered as female from age 50 (first invitation between 50 and 53) every three years until their 71st birthday, and women 71 or over can ask for screening (NHS). Because triple-negative tumours arrive younger and grow between rounds, a smaller share is screen-detected (Lin 2012; Houssami 2017), which is one reason the family history pathway matters here. NICE CG164 sets the UK rules: GPs refer to a specialist breast or genetics clinic on defined family patterns, and clinicians should seek genetics advice for families containing triple-negative breast cancer under 40, Jewish ancestry, sarcoma under 45 or glioma; genetic testing is offered when the combined BRCA1 and BRCA2 carrier probability is 10 percent or more (calculated with CanRisk, formerly BOADICEA, or the Manchester score); known BRCA1 or BRCA2 carriers are offered annual MRI from 30 to 49 and annual mammography from 40 to 69, TP53 carriers MRI from 20, and MRI is not offered to carriers aged 50 to 69 unless the breasts are dense. In the UK MARIBS study of 649 women at high familial risk, MRI sensitivity was 77 percent against 40 percent for mammography, 92 against 23 percent in BRCA1 carriers (Leach 2005). Risk-reducing surgery: bilateral mastectomy cut breast cancer risk by about 90 percent in BRCA1 and BRCA2 carriers in PROSE (1.9 percent against 48.7 percent over a mean 6.4 years; Rebbeck 2004) and pooled relative risk 0.114 in a 15-study meta-analysis, with contralateral mastectomy 0.072 and salpingo-oophorectomy 0.552 for breast cancer overall (Li 2016), though a prospective study of 3,722 carriers found oophorectomy did not lower breast cancer risk in BRCA1 carriers (hazard ratio 0.96) (Kotsopoulos 2017). CG164 restricts risk-reducing mastectomy to a small proportion of women from high-risk families, managed by a multidisciplinary team with genetic counselling, verified family history and reconstruction options discussed. Chemoprevention has a gap that matters for this subtype: NICE offers tamoxifen (premenopausal) or anastrozole (postmenopausal) for five years to women at high risk, and considers them at moderate risk, but tamoxifen had no effect on invasive ER-negative breast cancer in IBIS-I (hazard ratio 1.05 over 16 years; Cuzick 2015) or NSABP P-1 (Fisher 1998), and anastrozole's 49 percent reduction in IBIS-II was in ER-positive disease (Cuzick 2020); Cancer Research UK says the trial evidence is unclear for women with gene changes. One observational signal runs the other way: tamoxifen after a first breast cancer was associated with a lower contralateral breast cancer risk in BRCA1 (hazard ratio 0.38) and BRCA2 (0.33) carriers regardless of the first tumour's ER status (Phillips 2013). Breastfeeding is the modifiable factor with a specific ER-negative signal (Palmer 2014), and keeping a healthy weight and being physically active are the general measures Cancer Research UK names.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Triple-negative_breast_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Triple-negative_breast_cancer"},{"label":"SEER Cancer Stat Facts: female breast cancer subtypes (rates, share, survival by stage and by race)","url":"https://seer.cancer.gov/statfacts/html/breast-subtypes.html"},{"label":"GLOBOCAN breast fact sheet (IARC Global Cancer Observatory, 2024 estimates)","url":"https://gco.iarc.who.int/media/globocan/factsheets/cancers/20-breast-fact-sheet.pdf"},{"label":"CRUK: triple negative breast cancer (patient page)","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/types/triple-negative-breast-cancer"},{"label":"CRUK: breast cancer incidence statistics (invasive)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/incidence-invasive"},{"label":"CRUK: breast cancer statistics (stage, routes to diagnosis, treatment)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer"},{"label":"CRUK: breast cancer mortality statistics","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/mortality"},{"label":"CRUK: breast cancer survival statistics (professional)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/survival"},{"label":"CRUK: breast cancer risk factors (professional)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/risk-factors"},{"label":"CRUK: survival for breast cancer (England by stage, 2018 to 2022)","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/survival"},{"label":"CRUK: number stages of breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/stages-grades/number-stages"},{"label":"CRUK: TNM staging of breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/stages-grades/tnm-staging"},{"label":"CRUK: family history and inherited genes in breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/risks-causes/family-history-and-inherited-genes"},{"label":"CRUK: symptoms of breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/symptoms"},{"label":"CRUK: tests to diagnose breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/getting-diagnosed/tests"},{"label":"NHS: who breast screening is for (ages 50 to 71, every 3 years)","url":"https://www.nhs.uk/tests-and-treatments/breast-screening-mammogram/who-breast-screening-is-for/"},{"label":"NICE CG164: familial breast cancer (referral, genetic testing, surveillance, risk-reducing surgery, chemoprevention)","url":"https://www.nice.org.uk/guidance/cg164/chapter/Recommendations"},{"label":"NICE NG101: early and locally advanced breast cancer (receptor testing 1.3, genetic testing 1.3.6, triple-negative section 1.8)","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"},{"label":"NICE NG12: suspected cancer, recommendations by site (breast cancer 1.4)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"},{"label":"Howlader, JNCI 2014: US incidence of breast cancer subtypes by joint hormone receptor and HER2 status","url":"https://doi.org/10.1093/jnci/dju055"},{"label":"Howlader, Cancer Epidemiol Biomarkers Prev 2018: breast cancer survival by molecular subtype in the United States","url":"https://doi.org/10.1158/1055-9965.EPI-17-0627"},{"label":"Scott, Cancer 2019: triple-negative breast cancer disparities, US Cancer Statistics 2010 to 2014","url":"https://doi.org/10.1002/cncr.32207"},{"label":"Bauer, Cancer 2007: the triple-negative phenotype in the California Cancer Registry","url":"https://doi.org/10.1002/cncr.22618"},{"label":"Carey, JAMA 2006: race, breast cancer subtypes and survival in the Carolina Breast Cancer Study","url":"https://doi.org/10.1001/jama.295.21.2492"},{"label":"Huo, J Clin Oncol 2009: over-representation of triple-negative breast cancer in indigenous West African women","url":"https://doi.org/10.1200/jco.2008.19.6873"},{"label":"Howard and Olopade, Cancer J 2021: epidemiology of triple-negative breast cancer, a review","url":"https://doi.org/10.1097/ppo.0000000000000500"},{"label":"Gathani, Br J Cancer 2021: ethnicity and tumour characteristics of invasive breast cancer in 116,500 women in England","url":"https://doi.org/10.1038/s41416-021-01409-7"},{"label":"Copson, Br J Cancer 2014: ethnicity and outcome of young breast cancer patients in the UK (POSH)","url":"https://doi.org/10.1038/bjc.2013.650"},{"label":"Copson, Lancet Oncol 2018: germline BRCA mutation and outcome in young-onset breast cancer (POSH)","url":"https://doi.org/10.1016/s1470-2045(17)30891-4"},{"label":"Mavaddat, Cancer Epidemiol Biomarkers Prev 2012: pathology of breast cancers in BRCA1 and BRCA2 carriers (CIMBA)","url":"https://doi.org/10.1158/1055-9965.epi-11-0775"},{"label":"Atchley, J Clin Oncol 2008: clinical and pathological characteristics of BRCA-positive and BRCA-negative breast cancer","url":"https://doi.org/10.1200/jco.2008.16.6231"},{"label":"Couch, J Clin Oncol 2015: inherited mutations in 17 genes among 1,824 triple-negative breast cancers unselected for family history","url":"https://doi.org/10.1200/jco.2014.57.1414"},{"label":"Sharma, Breast Cancer Res Treat 2014: germline BRCA mutations in a prospective triple-negative breast cancer registry","url":"https://doi.org/10.1007/s10549-014-2980-0"},{"label":"Yang, J Clin Oncol 2020: cancer risks with germline PALB2 pathogenic variants, 524 families","url":"https://doi.org/10.1200/jco.19.01907"},{"label":"Jung, JNCI 2022: reproductive risk profiles for intrinsic-like breast cancer subtypes (Breast Cancer Association Consortium)","url":"https://doi.org/10.1093/jnci/djac117"},{"label":"Palmer, JNCI 2014: parity, lactation and breast cancer subtypes in African American women (AMBER)","url":"https://doi.org/10.1093/jnci/dju237"},{"label":"Pierobon, Breast Cancer Res Treat 2013: obesity as a risk factor for triple-negative breast cancer, meta-analysis","url":"https://doi.org/10.1007/s10549-012-2339-3"},{"label":"Trivers, Cancer Causes Control 2009: the epidemiology of triple-negative breast cancer, including race","url":"https://doi.org/10.1007/s10552-009-9331-1"},{"label":"Dent, Clin Cancer Res 2007: clinical features and patterns of recurrence of triple-negative breast cancer","url":"https://doi.org/10.1158/1078-0432.ccr-06-3045"},{"label":"Lin, Cancer 2012: clinicopathological features, recurrence and survival of triple-negative breast cancer in NCCN centres","url":"https://doi.org/10.1002/cncr.27581"},{"label":"Lin, Cancer 2008: sites of distant recurrence in metastatic triple-negative breast cancer, high incidence of CNS metastases","url":"https://doi.org/10.1002/cncr.23930"},{"label":"Liedtke, J Clin Oncol 2008: response to neoadjuvant therapy and long-term survival in triple-negative breast cancer","url":"https://doi.org/10.1200/jco.2007.14.4147"},{"label":"Houssami and Hunter, NPJ Breast Cancer 2017: interval breast cancers in population mammography screening","url":"https://doi.org/10.1038/s41523-017-0014-x"},{"label":"Monaghan, BJS Open 2024: tumour biology and survival in young women with breast cancer (UK single centre)","url":"https://doi.org/10.1093/bjsopen/zrae138"},{"label":"Allison, J Clin Oncol 2020: ASCO/CAP guideline update on ER and PR testing (1 percent threshold, ER Low Positive)","url":"https://doi.org/10.1200/jco.19.02309"},{"label":"Wolff, J Clin Oncol 2018: ASCO/CAP HER2 testing guideline focused update","url":"https://doi.org/10.1200/jco.2018.77.8738"},{"label":"Wolff, J Clin Oncol 2023: ASCO-CAP HER2 testing update (IHC 0 versus 1+ after DESTINY-Breast04)","url":"https://doi.org/10.1200/jco.22.02864"},{"label":"Yoder, NPJ Breast Cancer 2022: low versus negative ER/PR in HER2-negative breast cancer","url":"https://doi.org/10.1038/s41523-022-00448-4"},{"label":"Acs, Lancet Reg Health Eur 2024: ER-zero and ER-low HER2-negative breast cancer treated as triple-negative, Swedish cohort","url":"https://doi.org/10.1016/j.lanepe.2024.100886"},{"label":"Dieci, NPJ Breast Cancer 2021: ER levels and outcome in non-metastatic triple-negative breast cancer","url":"https://doi.org/10.1038/s41523-021-00308-7"},{"label":"Tan, Histopathology 2020: the 2019 WHO classification of tumours of the breast","url":"https://doi.org/10.1111/his.14091"},{"label":"Thomas, NPJ Breast Cancer 2023: rare subtypes of triple-negative breast cancer","url":"https://doi.org/10.1038/s41523-023-00554-x"},{"label":"Cserni, Cancers 2021: triple-negative breast cancer histological subtypes with a favourable prognosis (European Working Group for Breast Screening Pathology)","url":"https://doi.org/10.3390/cancers13225694"},{"label":"Prat, Oncologist 2013: molecular characterisation of basal-like and non-basal-like triple-negative breast cancer","url":"https://doi.org/10.1634/theoncologist.2012-0397"},{"label":"Cancer Genome Atlas Network, Nature 2012: comprehensive molecular portraits of human breast tumours","url":"https://doi.org/10.1038/nature11412"},{"label":"Lehmann, J Clin Invest 2011: identification of human triple-negative breast cancer subtypes (BL1, BL2, IM, M, MSL, LAR)","url":"https://doi.org/10.1172/jci45014"},{"label":"Lehmann, PLoS One 2016: refinement of triple-negative breast cancer molecular subtypes to four (TNBCtype-4)","url":"https://doi.org/10.1371/journal.pone.0157368"},{"label":"Burstein, Clin Cancer Res 2015: four triple-negative subtypes (LAR, MES, BLIS, BLIA) with distinct prognoses","url":"https://doi.org/10.1158/1078-0432.ccr-14-0432"},{"label":"Giuliano, CA Cancer J Clin 2017: major changes in the AJCC 8th edition breast cancer staging manual","url":"https://doi.org/10.3322/caac.21393"},{"label":"Weiss, JAMA Oncol 2018: validation of the AJCC 8th edition prognostic stage against the anatomic stage","url":"https://doi.org/10.1001/jamaoncol.2017.4298"},{"label":"Leach, Lancet 2005: MRI and mammography screening of a UK population at high familial risk (MARIBS)","url":"https://doi.org/10.1016/s0140-6736(05)66481-1"},{"label":"Rebbeck, J Clin Oncol 2004: bilateral prophylactic mastectomy in BRCA1 and BRCA2 carriers (PROSE)","url":"https://doi.org/10.1200/jco.2004.04.188"},{"label":"Li, Clin Cancer Res 2016: effectiveness of prophylactic surgeries in BRCA1 or BRCA2 carriers, meta-analysis","url":"https://doi.org/10.1158/1078-0432.ccr-15-1465"},{"label":"Kotsopoulos, JNCI 2017: bilateral oophorectomy and breast cancer risk in BRCA1 and BRCA2 carriers","url":"https://doi.org/10.1093/jnci/djw177"},{"label":"Cuzick, Lancet Oncol 2015: IBIS-I tamoxifen prevention trial, extended long-term follow-up","url":"https://doi.org/10.1016/s1470-2045(14)71171-4"},{"label":"Fisher, JNCI 1998: tamoxifen for prevention of breast cancer, NSABP P-1","url":"https://doi.org/10.1093/jnci/90.18.1371"},{"label":"Cuzick, Lancet 2020: anastrozole for breast cancer prevention (IBIS-II), long-term results","url":"https://doi.org/10.1016/s0140-6736(19)32955-1"},{"label":"Phillips, J Clin Oncol 2013: tamoxifen and contralateral breast cancer risk in BRCA1 and BRCA2 carriers","url":"https://doi.org/10.1200/jco.2012.47.8313"},{"label":"NHS: treatment for breast cancer in women","url":"https://www.nhs.uk/conditions/breast-cancer-in-women/treatment-for-breast-cancer-in-women/"},{"label":"NHS: tests and next steps for breast cancer in women","url":"https://www.nhs.uk/conditions/breast-cancer-in-women/tests-and-next-steps-for-breast-cancer-in-women/"},{"label":"NHS: help and support for breast cancer in women","url":"https://www.nhs.uk/conditions/breast-cancer-in-women/help-and-support-for-breast-cancer-in-women/"},{"label":"Macmillan: triple negative breast cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/breast-cancer/triple-negative-breast-cancer"},{"label":"Breast Cancer Now: triple negative breast cancer","url":"https://breastcancernow.org/about-breast-cancer/diagnosis/types-of-breast-cancer/triple-negative-breast-cancer"},{"label":"NICE TA851: pembrolizumab for neoadjuvant and adjuvant treatment of triple-negative early or locally advanced breast cancer","url":"https://www.nice.org.uk/guidance/ta851"},{"label":"NICE TA886: olaparib for adjuvant treatment of BRCA mutation-positive HER2-negative high-risk early breast cancer after chemotherapy","url":"https://www.nice.org.uk/guidance/ta886"},{"label":"NICE TA801: pembrolizumab plus chemotherapy for untreated triple-negative locally recurrent unresectable or metastatic breast cancer","url":"https://www.nice.org.uk/guidance/ta801"},{"label":"NICE TA819: sacituzumab govitecan for unresectable triple-negative advanced breast cancer after 2 or more therapies","url":"https://www.nice.org.uk/guidance/ta819"},{"label":"Triple Negative Breast Cancer Foundation: newly diagnosed","url":"https://tnbcfoundation.org/living-with-tnbc/newly-diagnosed"},{"label":"ESMO: breast cancer, a guide for patients","url":"https://www.esmo.org/for-patients/patient-guides/breast-cancer"},{"label":"Macmillan: carboplatin and paclitaxel, EC and pembrolizumab (the KEYNOTE-522 regimen)","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/carboplatin-paclitaxel-ec-pembrolizumab"},{"label":"Macmillan: questions to ask your healthcare team","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatment/your-treatment-options/questions-to-ask-your-healthcare-team"},{"label":"Cancer Research UK: chemotherapy for breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/treatment/chemotherapy"},{"label":"Cancer Research UK: having radiotherapy for breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/treatment/radiotherapy/radiotherapy-treatment"},{"label":"Macmillan: radiotherapy for breast cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/radiotherapy-for-breast-cancer"},{"label":"Breast Cancer Now: radiotherapy for primary breast cancer","url":"https://breastcancernow.org/about-breast-cancer/treatment/radiotherapy-for-primary-breast-cancer"},{"label":"Cancer Research UK: prehabilitation","url":"https://www.cancerresearchuk.org/about-cancer/treatment/prehabilitation"},{"label":"Macmillan: chemotherapy for breast cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/chemotherapy-for-breast-cancer"},{"label":"Macmillan: surgery to the lymph nodes for breast cancer","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/surgery-to-the-lymph-nodes-for-breast-cancer"},{"label":"Breast Cancer Now: genetic testing for altered breast cancer genes","url":"https://breastcancernow.org/about-breast-cancer/awareness/breast-cancer-in-families/genetic-testing-for-altered-breast-cancer-genes"},{"label":"Macmillan: BRCA1 and BRCA2 genes","url":"https://www.macmillan.org.uk/cancer-information-and-support/worried-about-cancer/causes-and-risk-factors/brca-gene"},{"label":"Macmillan: clinical trials","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/clinical-trials"},{"label":"Schmid et al., overall survival with pembrolizumab in early-stage triple-negative breast cancer, KEYNOTE-522 (NEJM 2024)","url":"https://doi.org/10.1056/NEJMoa2409932"},{"label":"Schmid et al., pembrolizumab for early triple-negative breast cancer, KEYNOTE-522 (NEJM 2020)","url":"https://doi.org/10.1056/NEJMoa1910549"},{"label":"Masuda et al., adjuvant capecitabine after preoperative chemotherapy, CREATE-X (NEJM 2017)","url":"https://doi.org/10.1056/NEJMoa1612645"},{"label":"Tutt et al., adjuvant olaparib for BRCA1- or BRCA2-mutated breast cancer, OlympiA (NEJM 2021)","url":"https://doi.org/10.1056/NEJMoa2105215"},{"label":"Geyer et al., overall survival in OlympiA (Annals of Oncology 2022)","url":"https://doi.org/10.1016/j.annonc.2022.09.159"},{"label":"Symmans et al., long-term prognostic risk after neoadjuvant chemotherapy by residual cancer burden and subtype (JCO 2017)","url":"https://doi.org/10.1200/JCO.2015.63.1010"},{"label":"Yau et al., residual cancer burden and long-term survival, pooled analysis of 5,161 patients (Lancet Oncology 2022)","url":"https://doi.org/10.1016/S1470-2045(21)00589-1"},{"label":"Cortes et al., pembrolizumab plus chemotherapy in advanced triple-negative breast cancer, KEYNOTE-355 (NEJM 2022)","url":"https://doi.org/10.1056/NEJMoa2202809"},{"label":"Murray Brunt et al., FAST-Forward: 1 week versus 3 weeks of breast radiotherapy, 5-year results (Lancet 2020)","url":"https://doi.org/10.1016/S0140-6736(20)30932-6"},{"label":"Haviland et al., START trials of breast radiotherapy hypofractionation, 10-year results (Lancet Oncology 2013)","url":"https://doi.org/10.1016/S1470-2045(13)70386-3"},{"label":"Coles et al., partial-breast radiotherapy after breast conservation, IMPORT LOW (Lancet 2017)","url":"https://doi.org/10.1016/S0140-6736(17)31145-5"},{"label":"Macmillan: olaparib","url":"https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/olaparib"},{"label":"Breast Cancer Now: olaparib (Lynparza)","url":"https://breastcancernow.org/about-breast-cancer/treatment/targeted-therapy/olaparib-lynparza"},{"label":"Breast Cancer Now: pembrolizumab (Keytruda)","url":"https://breastcancernow.org/about-breast-cancer/treatment/targeted-therapy/pembrolizumab-keytruda"},{"label":"NHS: genetic and genomic testing","url":"https://www.nhs.uk/tests-and-treatments/genetic-and-genomic-testing/"},{"label":"NHS: clinical trials","url":"https://www.nhs.uk/tests-and-treatments/clinical-trials/"},{"label":"Macmillan: tiredness (fatigue)","url":"https://www.macmillan.org.uk/cancer-information-and-support/impacts-of-cancer/tiredness"},{"label":"Royal College of Pathologists G148: dataset for histopathological reporting of breast disease in surgical excision specimens of breast cancer, version 3, November 2024 (full review due November 2026)","url":"https://www.rcpath.org/resourceLibrary/g148-dataset-for-histopathological-reporting-of-breast-disease-in-surgical-excision-specimens-of-breast-cancer.html"}],"tags":["spike","breast"],"related":["adc-generations","trop2-adc-roadmap","tnbc-history","platinum-plus-hrd","germline-to-parp","src-tnbc-foundation","breast-her2-positive","breast-hr-positive","her2-low-metastatic-breast-cancer","inflammatory-breast-cancer","tnbc-basal-like-1","tnbc-basal-like-2","tnbc-mesenchymal","tnbc-mesenchymal-stem-like","tnbc-luminal-androgen-receptor","tnbc-immunomodulatory","metaplastic-breast-carcinoma","medullary-pattern-breast-carcinoma","adenoid-cystic-carcinoma-breast","apocrine-carcinoma-breast","secretory-carcinoma-breast","brca-associated-tnbc","breast-cancer","tnbc-roadmap","idea-tnbc-de-escalation-for-exceptional-responders","idea-tnbc-ctdna-guided-adjuvant-decisions","idea-tnbc-disparities-in-access-and-outcomes","idea-tnbc-pd-l1-assay-harmonisation","idea-tnbc-adc-sequencing-trial","idea-tnbc-brain-metastasis-trials","idea-tnbc-her2-ultralow-testing-uptake","idea-tnbc-uk-trial-access-and-germline-testing-audit","idea-tnbc-uk-ethnicity-stratified-outcome-reporting","pd-l1-cps","pd-l1-ic-score","her2-low-ihc","her2-ultralow","brca-germline","brca-somatic","hrd-positive","tmb-high","msi-high","dmmr-ihc","trop2-expression","pten-alteration","pik3ca-hotspot-mutation","akt1-e17k","ctdna-mrd-positive"],"cancers":[],"sections":[],"technologies":["adc","checkpoint-inhibitor","parp-inhibitor","platinum","bispecific-adc","trop2-pet","mrd-testing","germline-testing","digital-pathology-ai","mammography","hypnosis-cancer-care","lymphoedema-decongestive-therapy","ultrasound","mri","ct","pet-ct","histopathology-ihc","chemoprevention","scalp-cooling","fertility-preservation","hypofractionated-radiotherapy","sentinel-node","exercise-during-chemotherapy","cbt-fatigue-distress","palliative-care","prehabilitation","psycho-oncology","peer-support-groups","multidisciplinary-tumour-board","survivorship-care-plan","imrt-igrt","sbrt","acupuncture-chemotherapy-neuropathy","acupuncture-hot-flushes","hrd-testing","hrd-genomic-scar-scores","wes-wgs","liquid-biopsy","tmb-testing","msi-mmr-testing"],"targets":["trop2","pdl1","pd1","brca","parp","her2","her3","egfr","androgen-receptor","tp53","nectin4","folr1","liv1","pik3ca","pten","rb1","palb2","akt","notch1","mmr","myc-gene","atr"],"drugs":["ventana-pd-l1-sp142","lunit-insight-mmg","epirubicin","ixabepilone","dako-pd-l1-22c3-pharmdx","ventana-pd-l1-sp263","her2-testing-assays","bracanalysis-cdx","mychoice-cdx","foundationone-cdx","signatera","guardant-reveal","radar-mrd","ventana-mmr-rxdx","trusight-oncology-comprehensive","tempus-xt-cdx","caris-mi-cancer-seek","bicalutamide","enzalutamide","ipatasertib","capivasertib","veliparib","capecitabine","carboplatin","nab-paclitaxel","avelumab","durvalumab","ceralasertib","docetaxel","eribulin","talazoparib","olaparib","atezolizumab","denosumab","zoledronic-acid","dexamethasone"],"companies":["gilead","astrazeneca","daiichi-sankyo","merck","bms","systimmune","kelun-biotech","mabwell-shanghai-bioscience","nanjing-leads-biolabs","scancell"],"institutions":["breast-cancer-now","royal-marsden","guys-st-thomas","barts-cancer-institute","the-christie","addenbrookes-cambridge"],"pathways":["ddr","p53-cell-cycle","pd1-checkpoint","pi3k-akt-mtor","emt","breast-cancer-signalling","homologous-recombination-repair","myc","notch","rtk-activation","ar-signaling","antigen-presentation-immunoediting","mutagenesis-signatures","mismatch-repair-msi"],"terms":["pcr","rcb","her2-low","tils","cps","hrd","er-pr-negative-threshold","her2-low-and-trop2-adc-eligibility-tnbc","pd-l1-cps-10-tnbc","hrd-in-breast-cancer","germline-brca-testing-criteria-tnbc","ki-67-in-tnbc","basal-like","claudin-low","androgen-receptor-positive-tnbc","ajcc-prognostic-stage-breast","interval-breast-cancer","risk-reducing-surgery-brca-carriers","chemoprevention-and-er-negative-breast-cancer","founder-mutation","idfs","luminal-androgen-receptor","pd-l1-assay-discordance","exceptional-responder","health-disparities","tnm-staging","tumour-grade","germline-vs-somatic","hair-loss-and-scalp-cooling-breast","menopause-after-chemotherapy-breast","body-image-after-breast-surgery","neutropenic-sepsis-breast-chemotherapy","adc-side-effects-breast","urgent-help-tnbc","work-and-money-breast-cancer-uk","carers-breast-cancer-uk","ctdna","mrd","de-escalation","germline-testing","brain-metastases","adc-sequencing","pam50","neoadjuvant-adjuvant","ild","ocular-toxicity","febrile-neutropenia","neutropenia","peripheral-neuropathy","immune-colitis","irae","cancer-related-fatigue","mastectomy","lumpectomy","sentinel-lymph-node-biopsy","lymphadenectomy","stereotactic-radiosurgery","wbrt","hand-foot-syndrome","radiation-dermatitis","deep-inspiration-breath-hold","clinical-trial","informed-consent","placebo","financial-toxicity","emotional-support-cancer-uk","cardiotoxicity","anthracycline","ihc","fish","msi","tmb","ngs","tps","gbrca-mutation","mutational-signature","tumour-agnostic","vus","tumour-informed-assay","gene-amplification","synthetic-lethality","brca-reversion-mutations","tnbc-trials-open-today","tnbc-residual-disease-decision","tnbc-symptom-control-palliation","grade-stage-receptor-breast","nottingham-grade","er-pr-scoring-breast","her2-testing-uk-breast","receptor-conversion-breast","tnm-breast-cancer-editions","who-breast-classification","nottingham-prognostic-index"],"trials":["tmist","nct06419621","nct06732323","nct07544056","nct07533123","nct06519370","start-b","import-low","nsabp-b39","eortc-22922","ma-20","dbcg-82bc","nct06767527","nct06393374","nct07669467","nct03671044","nct07111832","nct06966700","nct05347134","nct04915755","nct07173751","nct07679360","nct06279364","nct03997123","nct06841354","geparsixto","ascent-05","tropion-breast03","tropion-breast05","tnt","partner","fast-forward","impassion130","keynote-355","ascent","destiny-breast04","destiny-breast06","i-spy-2","olympia","create-x","calgb-40603","neotrip","gepardouze","impassion030","a-brave","neopact","sysucc-001","geicam-ciboma","ea1131","bre12-158","c-trak-tn","swog-s1418","phoenix","barbican","keynote-119","ipatunity130","brocade3","diamond","lotus","pakt","scan-b","impassion031","olympiad","embraca","brightness","optimice-pcr","scarlet-s2212","nct06112379","nct03742102"],"people":["jean-abraham","ellen-copson","anne-armstrong"],"bottlenecks":[],"keyPapers":["paper-shah-tnbc-clonal-evolution-nature-2012","paper-tcga-breast-molecular-portraits-nature-2012","paper-lehmann-tnbc-subtype-multiomics-nat-commun-2021","paper-bareche-tnbc-multiomic-heterogeneity-ann-oncol-2018","paper-bareche-tnbc-microenvironment-jnci-2020","paper-jiang-fuscc-tnbc-landscape-cancer-cell-2019","paper-staaf-tnbc-whole-genome-scan-b-nat-med-2019","paper-bertucci-metastatic-breast-genomics-nature-2019","paper-couch-tnbc-germline-17-genes-jco-2015","paper-hahnen-geparsixto-germline-brca-jama-oncol-2017","paper-shimelis-tnbc-risk-genes-jnci-2018","paper-sharma-tnbc-registry-germline-brca-bcrt-2014","paper-telli-hrd-score-platinum-tnbc-ccr-2016","paper-zheng-nigerian-inherited-breast-cancer-jco-2018","paper-huo-tcga-ancestry-breast-jama-oncol-2017","paper-martini-african-ancestry-tnbc-cancer-discov-2022","paper-donenberg-bahamas-brca1-founder-bcrt-2011","paper-villarreal-garza-mexican-tnbc-brca-bcrt-2015","paper-sigurjonsdottir-sp142-22c3-tnbc-bcr-2023","paper-barroso-sousa-breast-tmb-prevalence-ann-oncol-2020","paper-barroso-sousa-tmb-pten-ici-mtnbc-ccr-2020","paper-ren-tnbc-mmr-msi-440-front-oncol-2021","paper-kurata-japanese-tnbc-msi-breast-cancer-2020","paper-loi-tils-pooled-early-tnbc-jco-2019","paper-denkert-tils-neoadjuvant-pooled-lancet-oncol-2018","paper-gruosso-tnbc-spatial-immune-microenvironments-jci-2019","paper-park-tils-untreated-early-tnbc-ann-oncol-2019","paper-denkert-her2-low-pooled-neoadjuvant-lancet-oncol-2021","paper-boissiere-michot-her2-ultralow-tnbc-virchows-arch-2026","paper-bardia-ascent-trop2-biomarker-ann-oncol-2021","paper-gucalp-bicalutamide-ar-positive-tbcrc011-ccr-2013","paper-traina-enzalutamide-ar-tnbc-jco-2018","paper-kim-lotus-ipatasertib-tnbc-lancet-oncol-2017","paper-schmid-pakt-capivasertib-tnbc-jco-2020","paper-stoeck-notch-rearrangements-tnbc-cancer-discov-2014","paper-wang-notch-pest-mutations-tnbc-ccr-2015","paper-horiuchi-myc-tnbc-cdk-synthetic-lethal-jem-2012","paper-herschkowitz-rb1-loss-basal-like-bcr-2008","paper-magbanua-ispy2-ctdna-neoadjuvant-ann-oncol-2021","paper-stecklein-ctdna-rcb-tnbc-residual-disease-npj-2023","paper-garcia-murillas-ctdna-mutation-tracking-stm-2015","paper-garcia-murillas-molecular-relapse-detection-jama-oncol-2019","paper-cavallone-tnbc-ctdna-neoadjuvant-sci-rep-2020","paper-bedrosian-asco-sso-germline-testing-breast-jco-2024","paper-conroy-nhs-r208-mainstream-testing-audit-breast-j-2026","paper-hudson-phillips-expanded-germline-testing-clin-breast-cancer-2026","paper-lehmann-tnbc-subtypes-jci-2011","paper-lehmann-tnbctype-4-refinement-plos-one-2016","paper-burstein-tnbc-genomic-subtypes-ccr-2015","paper-loibl-geparsixto-survival-hrd-ann-oncol-2018","paper-struewing-brca-founder-mutations-ashkenazi-nejm-1997","paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021","paper-schettini-her2-low-features-npj-breast-cancer-2021","paper-radovich-ctdna-ctc-bre12-158-jama-oncol-2020","paper-turner-c-trak-tn-ctdna-pembrolizumab-ann-oncol-2023"],"journals":["breast-cancer-jbcs","breast-cancer-research","breast-cancer-research-and-treatment","clinical-breast-cancer","journal-of-mammary-gland-biology-and-neoplasia","the-breast","the-breast-journal"],"dependsOn":[],"notes":["What does triple-negative actually mean? The cancer cells lack the three receptors other breast cancers are treated through: oestrogen receptor under 1 percent of nuclei, progesterone receptor under 1 percent, and HER2 scored 0 or 1+, or 2+ without gene amplification. Each is measured on the biopsy by immunohistochemistry (ASCO/CAP 2020 and 2018; NICE NG101 1.3). A tumour with ER of 1 to 10 percent is reported as ER Low Positive and behaves like triple-negative disease (Yoder 2022; Acs 2024).","How common is it? About 10.8 percent of US breast cancers with a known subtype (SEER 21, 2019 to 2023) and around 15 percent on Cancer Research UK's page; roughly 12 percent in earlier US series (Howlader 2014). It is diagnosed younger: women under 40 have about 1.5 to 2 times the odds of a triple-negative diagnosis (Bauer 2007; Scott 2019).","Why is it more common in Black women? In the United States the rate is 25.7 per 100,000 non-Hispanic Black women against 13.0 for non-Hispanic White women (SEER 21), and in the UK POSH cohort 26.1 percent of Black against 18.6 percent of White young patients had triple-negative tumours (Copson 2014). Reproductive patterns (parity without breastfeeding raises ER-negative risk in African American women, Palmer 2014), ancestry and access all contribute; the causes are not settled (Howard and Olopade 2021).","Should I have a genetic test? NICE says yes for women under 50 with triple-negative disease even without a family history (NG101 1.3.6), and UK mainstream criteria extend testing to all triple-negative disease under 60 (Evans 2024); about 11 percent of unselected triple-negative patients carry a BRCA1 or BRCA2 mutation and 14.6 percent a mutation in one of 17 genes (Couch 2015). The result changes surgery options, opens olaparib after chemotherapy for high-risk early disease (NICE TA886) and matters for relatives.","Is it more dangerous than other breast cancers? Stage for stage, survival is lower: 78.7 percent five-year relative survival against 95.8 percent for hormone receptor-positive, HER2-negative disease in SEER, but 92.8 percent when found while localised. The risk of relapse is concentrated in the first three to five years and is low afterwards (Dent 2007), and a pathological complete response to chemotherapy before surgery carries an excellent outlook (Liedtke 2008; Cortazar 2014).","Why did my treatment start with chemotherapy rather than surgery? For tumours over 2 cm or with node involvement, chemotherapy with pembrolizumab is given first because the response at surgery predicts relapse and directs what follows, and because it raised five-year survival from 81.7 to 86.6 percent in KEYNOTE-522 (Schmid 2024). NICE recommends a platinum, a taxane and an anthracycline in that setting (NG101 1.8, 2025) and pembrolizumab with it (TA851).","Does hormone therapy or tamoxifen have any role? Not to treat triple-negative disease, which has no oestrogen receptor to block. As prevention, tamoxifen and anastrozole reduced ER-positive but not ER-negative breast cancer in the prevention trials (Cuzick 2015; Fisher 1998; Cuzick 2020), although tamoxifen after a first cancer was associated with fewer contralateral cancers in BRCA carriers (Phillips 2013).","Will screening pick it up? The NHS invites women from 50 to 71 every three years (NHS). Triple-negative cancers are less often screen-detected (29 percent against 48 percent, Lin 2012) because they arise younger and grow between rounds. Known BRCA carriers are offered annual MRI from 30 and mammography from 40 (NICE CG164); anyone with a new breast change should see a GP without waiting for the next screen.","What are the subtypes I might read about? Gene expression divides triple-negative disease into basal-like 1 and 2, mesenchymal and luminal androgen receptor tumours (Lehmann 2016), which respond differently to chemotherapy (pathological complete response 41 percent for basal-like 1, 18 percent for basal-like 2, 29 percent for luminal androgen receptor) but are not used to choose treatment in the NHS. Special histological types such as adenoid cystic and secretory carcinoma are triple-negative but indolent and may need no chemotherapy (Cserni 2021). Each has a page linked from this record.","What is HER2-low and why does it matter if I am HER2-negative? HER2 1+, or 2+ without amplification, is called HER2-low; those tumours (63 of 557 patients in DESTINY-Breast04 had hormone receptor-negative disease) responded to trastuzumab deruxtecan, so the pathologist's distinction between 0 and 1+ now has a treatment consequence (Modi 2022; ASCO-CAP 2023).","Frequencies marked cBioPortal were computed from the public API on 24 September 2026 on receptor-defined triple-negative subsets of brca_tcga_pub (123 samples; the same patients read in brca_tcga_pan_can_atlas_2018), brca_metabric (320) and breast_msk_2018 (176), as sample-level counts of non-synonymous mutation, high-level amplification or deep deletion over the subset; they are not the papers' own percentages, which are quoted alongside.","Metastatic samples in breast_msk_2018 (85 of 176) and the 173-gene METABRIC panel make cross-cohort comparison approximate; TMB on the MSK panel is reported as a mutation count, not a per-megabase rate.","What this page is called on a report, and why grade 3 does not send you anywhere else. Triple-negative means the oestrogen receptor under 1 percent, the progesterone receptor under 1 percent and HER2 scored 0 or 1+, or 2+ without amplification. Most triple-negative cancers are also grade 3, and a grade is not a page: someone told 'grade 3, triple negative' has been told one thing that chooses the page and one thing that does not. Grade 3 is expected here rather than alarming on top of the diagnosis, and the grade still matters, because it feeds the Nottingham Prognostic Index and the American prognostic stage. An oestrogen receptor figure of 1 to 10 percent is not triple-negative on paper but behaves like it, and those patients are excluded from most triple-negative trials."],"group":"breast","burden":"About 10 to 15 percent of breast cancers: 10.8 percent of US cases with a known subtype (SEER 21, 2019 to 2023) and around 15 percent on Cancer Research UK's patient page, against 2.43 million breast cancers a year worldwide (GLOBOCAN 2024). Diagnosed younger, about twice as often in Black women (25.7 against 13.0 per 100,000 in the United States) and in most breast cancers arising in BRCA1 carriers.","subtypes":["Basal-like 1 (BL1, DDR-deficient, platinum/PARP-sensitive)","Basal-like 2 (BL2, growth-factor signalling)","Mesenchymal / claudin-low (EMT, stem-like, chemoresistant)","Luminal androgen receptor (LAR, AR+, PIK3CA-mutant)","Immunomodulatory (high TILs, IO-responsive)","HER2-low TNBC (~35%, eligible for T-DXd)","Mesenchymal stem-like (MSL, 2011; traced to stromal cells and folded into the mesenchymal subtype in 2016)","Metaplastic carcinoma (squamous, spindle cell, matrix-producing, fibromatosis-like, low-grade adenosquamous; about 70 percent triple-negative)","Carcinoma with medullary pattern (a pattern of invasive carcinoma of no special type in the 2019 WHO classification, formerly medullary carcinoma; BRCA1-related)","Adenoid cystic carcinoma of the breast (MYB-NFIB fusion; triple-negative with an excellent outlook)","Apocrine carcinoma (ER and PR negative, androgen receptor positive; HER2 or EGFR expressed)","Secretory carcinoma (ETV6-NTRK3 fusion; indolent, NTRK inhibitors when advanced)","BRCA-associated triple-negative breast cancer (germline BRCA1 above all; PARP inhibitor and surgical decisions)","ER-low (1 to 10 percent) HER2-negative carcinoma, treated as triple-negative in practice and in Sweden by definition"],"biomarkers":["PD-L1 (22C3 CPS ≥10 for metastatic pembrolizumab)","Germline BRCA1/2 and PALB2 (PARP inhibitors, surgery choices)","HRD score","TILs (prognostic; de-escalation trials)","HER2-low status (T-DXd eligibility)","TROP2 (not required for TROP2 ADCs; PET tracers in development)","Ki-67, grade","ctDNA/MRD (Signatera, investigational)","AR (LAR subtype trials)","TMB / MSI (rare, tumour-agnostic IO)","ER and PR by immunohistochemistry: negative under 1 percent of nuclei; 1 to 10 percent reported as ER Low Positive (ASCO/CAP 2020) and behaving like triple-negative disease","HER2 immunohistochemistry 0 versus 1+ or 2+ without amplification (HER2-low), the line that now decides trastuzumab deruxtecan eligibility (ASCO-CAP 2023)","Grade (almost always 3) and Ki-67 (median about 60 percent; prognostic and predictive within triple-negative disease but without a clinical-utility threshold)","Intrinsic subtype (basal-like in about 79 percent) and the Lehmann or Burstein triple-negative subtype, research classifications with different chemotherapy response rates","Special histological type (adenoid cystic, secretory, low-grade adenosquamous, fibromatosis-like metaplastic), which can spare chemotherapy","TP53 mutation: 80% (80% of basal-like tumours in the TCGA breast study (Cancer Genome Atlas 2012))","PIK3CA mutation (amplification in a further tenth): 10-18% (9% of basal-like tumours (Cancer Genome Atlas 2012))","PTEN mutation or deletion (loss): 12-35% (PTEN mutation or loss in 35% of basal-like tumours, with INPP4B loss in 30% (Cancer Genome Atlas 2012))","RB1 mutation or deletion (loss): 15-20% (RB1 mutation or loss in 20% of basal-like tumours (Cancer Genome Atlas 2012))","BRCA1 germline pathogenic variant: 7-11% (8.5% of 1,824 TNBC patients unselected for family history (Couch 2015))","BRCA2 germline pathogenic variant: 3-4% (2.7% of 1,824 unselected patients (Couch 2015))","PALB2 germline or biallelic loss: 1-2% (1.2% of 1,824 unselected patients (Couch 2015))","Homologous recombination deficiency hrd (hrdetect-high, or hrd score 42 or more / tumour brca): 59-71% (HRDetect-high in 58.6% of 237 population-based TNBC whole genomes (35.9% low, 5.5% intermediate))","MYC amplification: 18-35% (cBioPortal: high-level amplification in 34 of 119 triple-negative samples, 28.6%, in brca_tcga_pub and 37 of 119, 31.1%, on the 2018 calls)","PIK3CA / AKT1 / PTEN pi3k-akt pathway alteration (any of the three): 20-27% (28 of 140 first-line metastatic TNBC patients, 20%, in PAKT, where capivasertib gave a progression-free survival hazard ratio of 0.30 in that subgroup (Schmid 2020))","NOTCH1 / NOTCH2 / NOTCH3 activating rearrangement, pest-domain mutation or amplification: 5-9% (NOTCH1 and NOTCH2 rearrangements causing constitutive activation in 6 of 66 TNBCs, 9%, and in no other solid tumour type (Stoeck 2014))","EGFR amplification: 3-6% (EGFR amplified (gains included) in 23% of basal-like tumours, alongside PIK3CA 49%, KRAS 32% and BRAF 30% (Cancer Genome Atlas 2012))","Androgen receptor (LAR subtype) ar expression and luminal androgen receptor subtype: 12-16% (LAR was 16% of tumours by TNBCtype-4 and 9% by the original six-subtype call (Lehmann 2016))","Tumour mutational burden tmb 10 or more mutations per megabase: 4-5% (5% of 3,969 breast cancers of all subtypes were hypermutated, higher in HR-negative/HER2-negative and metastatic samples (8.4% metastatic versus 2.9% primary), with APOBEC (59.2%) and mismatch repair deficiency (36.4%) the dominant processes (Barroso-Sousa 2020, Ann Oncol))","MLH1 / MSH2 / MSH6 / PMS2 microsatellite instability or mismatch repair deficiency: 0-2% (No MSI-high tumour among 195 by PCR and one mismatch-repair-deficient tumour (lost MSH2) among 440 by IHC in Chinese TNBC (Ren 2021))","CD274 (PD-L1), SP142 immune-cell score ic 1% or more (sp142): 41-51% (46.4% of 614 centrally scored IMpassion130 samples (Rugo 2021))","CD274 (PD-L1), 22C3 combined positive score cps 10 or more (22c3): 27-38% (The CPS-10 subgroup of KEYNOTE-355 carried the overall survival benefit, 23.0 versus 16.1 months (Cortes 2022))","TROP2 (TACSTD2) protein expression (h-score) and amplification: 2-4% (Trop-2 expression was assessable in 290 of 468 ASCENT patients and sacituzumab govitecan benefit was seen at high and medium expression (progression-free survival 6.9 and 5.6 versus 2.5 and 2.2 months), with the low group too small to judge (Bardia 2021))","ERBB2 (HER2) her2-low (ihc 1+ or 2+/ish-negative): 24-37% (36.6% of triple-negative against 65.4% of hormone receptor-positive disease among 3,689 HER2-negative patients (Schettini 2021))","ERBB2 (HER2) her2-ultralow (ihc 0 with faint membrane staining in 10% or fewer cells): 38% (37.6% ultralow, 38.4% null and 24.0% low among 367 non-metastatic TNBCs)","Stromal tumour-infiltrating lymphocytes stils (immune infiltration): 21-30% (Mean sTILs 23% with 77% of patients at 1% or more among 2,148 early TNBC patients on anthracycline chemotherapy (Loi 2019))"],"standardOfCare":[{"setting":"Stage I (T1a-b N0)","approach":"Surgery ± radiation; chemotherapy for ≥T1c; TIL-high tumours have >90% 5-year RFS even without chemotherapy (OPTimal, ETNA, TIL-CHOICE cohorts). De-escalation trials ongoing.","refs":["sentinel-node","histopathology-ihc"],"guideline":{"version":"NCCN Guidelines: Breast Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419"}},{"setting":"Stage II-III","approach":"Neoadjuvant pembrolizumab + carboplatin/paclitaxel → AC/EC, surgery, adjuvant pembrolizumab (KEYNOTE-522). Germline BRCA + residual disease: olaparib 1 year (OlympiA). Residual disease without BRCA: capecitabine (CREATE-X). Radiation per stage.","refs":["keynote-522","pembrolizumab","carboplatin","olaparib","olympia"],"guideline":{"nccn":"Category 1, preferred: neoadjuvant pembrolizumab + chemotherapy (KEYNOTE-522); adjuvant olaparib for gBRCA Category 2A, preferred","esmoMcbs":"A (KEYNOTE-522); A (OlympiA)","version":"NCCN Guidelines: Breast Cancer","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13114725/"}},{"setting":"Metastatic, first line, PD-L1 CPS ≥10","approach":"Pembrolizumab + chemotherapy (KEYNOTE-355) or sacituzumab govitecan + pembrolizumab (ASCENT-04, approved 2026).","refs":["keynote-355","ascent-04","sacituzumab-govitecan","pembrolizumab"],"guideline":{"nccn":"Category 1, preferred: sacituzumab govitecan + pembrolizumab (NCCN Breast, February 2026); pembrolizumab + chemotherapy Category 1","esmoMcbs":"4 (KEYNOTE-355)","version":"NCCN Guidelines: Breast Cancer","url":"https://www.pharmacytimes.com/view/a-new-era-in-first-line-metastatic-tnbc-nccn-guidelines-elevate-sacituzumab-govitecan-to-category-1-status"}},{"setting":"Metastatic, first line, PD-L1 negative or PD-1 ineligible","approach":"Datopotamab deruxtecan (TROPION-Breast02, OS benefit) or sacituzumab govitecan (ASCENT-03), both approved 2026; PARP inhibitor if germline BRCA; chemotherapy.","refs":["tropion-breast02","ascent-03","datopotamab-deruxtecan","olaparib"],"guideline":{"nccn":"Category 1, preferred: sacituzumab govitecan monotherapy (NCCN Breast, 2026)","version":"NCCN Guidelines: Breast Cancer","url":"https://www.pharmacytimes.com/view/a-new-era-in-first-line-metastatic-tnbc-nccn-guidelines-elevate-sacituzumab-govitecan-to-category-1-status"}},{"setting":"Metastatic, later lines","approach":"Whichever TROP2 ADC was not used first (cross-resistance uncertain); T-DXd if HER2-low (DESTINY-Breast04); iza-bren where available; chemotherapy (eribulin, capecitabine); clinical trials.","refs":["trastuzumab-deruxtecan","izalontamab-brengitecan","destiny-breast04"],"guideline":{"esmoMcbs":"4 (ASCENT; re-scored 5 in the breast-cancer analysis); 4 (DESTINY-Breast04)","version":"NCCN Guidelines: Breast Cancer","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13114725/"}},{"setting":"Suspected cancer in primary care","approach":"Suspected cancer pathway referral for an unexplained breast lump at 30 or over, or discharge, retraction or other change in one nipple at 50 or over; consider it for skin changes or an unexplained axillary lump at 30 or over; non-urgent referral for a lump under 30 (NICE NG12 1.4). The clinic does triple assessment: examination, mammogram, ultrasound and core biopsy.","refs":["mammography","ultrasound","histopathology-ihc","interval-breast-cancer"],"guideline":{"version":"NICE NG12 (2015, updated)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"}},{"setting":"Receptor testing that defines the subtype","approach":"ER, PR and HER2 assessed together on the diagnostic biopsy by quality-assured immunohistochemistry and reported quantitatively (NG101 1.3.1 to 1.3.4): ER and PR negative under 1 percent, ER 1 to 10 percent reported as low positive, HER2 0 or 1+ or 2+ without amplification. HER2 0 versus 1+ is reported with a comment because HER2-low disease qualifies for trastuzumab deruxtecan.","refs":["histopathology-ihc","er-pr-negative-threshold","her2-low-and-trop2-adc-eligibility-tnbc","her2-low"],"guideline":{"version":"NICE NG101 (2018, updated 2025); ASCO/CAP ER and PR 2020; ASCO-CAP HER2 2018 and 2023","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Germline testing at diagnosis","approach":"Germline BRCA1 and BRCA2 testing for women under 50 with triple-negative breast cancer including those with no family history (NG101 1.3.6); UK mainstream criteria extend to all triple-negative disease under 60 and any breast cancer under 40; CG164's 10 percent carrier-probability rule for everyone else. A pathogenic variant opens adjuvant olaparib (TA886), informs surgery, and starts cascade testing of relatives.","refs":["germline-testing","germline-brca-testing-criteria-tnbc","brca-associated-tnbc","olaparib","olympia"],"guideline":{"version":"NICE NG101 1.3.6; NICE CG164 1.5","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Surveillance and risk reduction for BRCA carriers (before any cancer)","approach":"Annual MRI from 30 to 49 and annual mammography from 40 to 69 for known BRCA1 or BRCA2 carriers (MRI sensitivity 77 percent against 40 percent for mammography in MARIBS); bilateral risk-reducing mastectomy for a small proportion of women from high-risk families after genetic counselling, cutting breast cancer risk by about 90 percent; tamoxifen or anastrozole are offered to women at high risk in general but did not reduce ER-negative breast cancer in the prevention trials.","refs":["mri","mammography","risk-reducing-surgery-brca-carriers","chemoprevention-and-er-negative-breast-cancer","chemoprevention","mastectomy"],"guideline":{"version":"NICE CG164 (2013, updated 2019 and 2023)","url":"https://www.nice.org.uk/guidance/cg164/chapter/Recommendations"}},{"setting":"Staging and the pathology report","approach":"TNM 8th edition with the AJCC prognostic stage note; sentinel node biopsy rather than axillary clearance to stage a clinically node-negative axilla (NG101 1.4); after neoadjuvant treatment the report gives pathological complete response or residual cancer burden, which drive the adjuvant choices in the residual-disease rows.","refs":["tnm-staging","ajcc-prognostic-stage-breast","sentinel-node","pcr","rcb"],"guideline":{"version":"NICE NG101; AJCC 8th edition (2017)","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Chemotherapy before or after surgery","approach":"For most triple-negative cancers larger than 2 cm or with involved nodes, chemotherapy comes first (neoadjuvant): it can shrink the cancer so that breast-conserving surgery replaces a mastectomy, and the pathology report at surgery then shows how well it worked, which guides the treatment given afterwards. NICE NG101 (2025) says where neoadjuvant chemotherapy is indicated for triple-negative disease, offer a regimen containing a platinum, a taxane and an anthracycline, and discuss the trade-off: 85 rather than 81 out of 100 alive at 3 years with a platinum, against more neutropenic sepsis, low blood counts and anaemia. Very small node-negative cancers may go to surgery first, with chemotherapy afterwards decided on the final pathology. Macmillan: people with triple-negative breast cancer are more likely to have chemotherapy before surgery.","refs":["keynote-522","carboplatin","paclitaxel","pcr","rcb","lumpectomy","mastectomy"],"guideline":{"version":"NICE NG101 (2025), recommendation 1.8.1; Macmillan and Cancer Research UK patient pages","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Adding pembrolizumab before surgery: what PD-L1 means here","approach":"NICE TA851 recommends pembrolizumab with chemotherapy before surgery, then pembrolizumab alone for up to nine cycles after surgery, for triple-negative early breast cancer at high risk of recurrence or locally advanced disease (KEYNOTE-522: stage II to III). No PD-L1 test is needed at this stage: the trial's gain in complete responses (64.8% against 51.2%) and in survival (86.6% against 81.7% alive at 5 years) was seen whatever the PD-L1 result. The combined positive score of 10 or more decides pembrolizumab only for cancer that has spread. The cost is immune-related side effects, which can start at any time during or after treatment and occasionally leave a gland permanently underactive; carry the alert card and ring the 24-hour number for the symptoms on it.","refs":["pembrolizumab","keynote-522","checkpoint-inhibitor","cps","tils","irae"],"guideline":{"version":"NICE TA851 (2022); KEYNOTE-522 (NEJM 2020, 2024)","url":"https://www.nice.org.uk/guidance/ta851"}},{"setting":"Residual disease after chemotherapy: capecitabine or olaparib","approach":"The pathology report after neoadjuvant treatment is the strongest guide to what comes next. A pathological complete response (no invasive cancer left in breast or nodes) carries a good outlook and pembrolizumab simply continues. Residual disease is graded by residual cancer burden (RCB I to III); in triple-negative disease 10-year relapse-free survival fell from 86% after a complete response to 81%, 55% and 23% across the classes (Symmans 2017). For residual disease with a germline BRCA1 or BRCA2 variant, NICE TA886 recommends a year of olaparib (OlympiA: 4-year invasive disease-free survival 82.7% against 75.4%, with a survival gain). Without a BRCA variant, six to eight cycles of capecitabine is the usual offer (CREATE-X: 5-year survival 78.8% against 70.3% in triple-negative disease; hand-foot syndrome in 73%). Olaparib and capecitabine were not tested together, and there is no proven way to add both; trials, including ones guided by circulating tumour DNA, are the route beyond. The decision aid at /tools/tnbc-after-chemotherapy/ walks the report through these statements.","refs":["tnbc-residual-disease-decision","capecitabine","olaparib","olympia","create-x","ea1131","bre12-158","ascent-05","tropion-breast03","swog-s1418","rcb","pcr","brca","germline-testing","hand-foot-syndrome"],"guideline":{"nccn":"Category 1: adjuvant olaparib for germline BRCA carriers with residual disease; capecitabine for residual disease without BRCA (CREATE-X)","esmoMcbs":"A (OlympiA)","version":"NICE TA886 (2023); NCCN Guidelines: Breast Cancer","url":"https://www.nice.org.uk/guidance/ta886"}},{"setting":"Mastectomy or breast-conserving surgery, and when to reconstruct","approach":"Breast-conserving surgery (wide local excision) followed by radiotherapy is usually as effective as mastectomy (Macmillan); mastectomy is advised when the cancer is large compared with the breast, there are several areas of cancer, or after earlier chest radiotherapy, and some people choose it. Chemotherapy first often makes conservation possible. Cancer at the margin means further surgery (NICE NG101: re-excise at 0 mm, consider within 1 mm). NICE says offer reconstruction to everyone having a mastectomy, offer both immediate and delayed options whether or not they are available locally, and offer immediate reconstruction even to those who may need radiotherapy; its table lists the trade-offs (implants more affected by radiotherapy than flaps; complications can delay chemotherapy or radiotherapy; more time to decide with delayed reconstruction). Some people prefer no reconstruction. The armpit is staged with a sentinel node biopsy (1 to 3 nodes); removing all the nodes raises the risk of lymphoedema and is reserved for involved nodes that need clearing.","refs":["lumpectomy","mastectomy","sentinel-node","lymphadenectomy","prehabilitation","lymphoedema-decongestive-therapy"],"guideline":{"version":"NICE NG101, sections 1.4 and 1.5 (2018 to 2024); Macmillan and Cancer Research UK surgery pages","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Radiotherapy after surgery: which schedule and where","approach":"After breast-conserving surgery the remaining breast is treated; after mastectomy the chest wall is treated when nodes were involved (macrometastases) or margins were involved, including after neoadjuvant chemotherapy where pretreatment tests showed involved nodes, and considered for node-negative T3 disease. NICE NG101 (2023): offer 26 Gy in 5 fractions over 1 week when the lymph nodes are not being treated (FAST-Forward: non-inferior to 40 Gy in 15 at 5 years), consider 40 Gy in 15 fractions over 3 weeks after implant reconstruction or where 3 weeks suits better, and offer 40 Gy in 15 fractions whenever regional nodes are irradiated (START-B). A boost to the tumour bed is offered where the risk of local recurrence is high. Partial-breast radiotherapy (IMPORT LOW) is reserved for low-risk ER-positive tumours in NICE's wording, so it rarely applies to triple-negative disease. Left-sided treatment often uses breath-hold to protect the heart. Skin reactions peak at the end and settle over 3 to 4 weeks.","refs":["hypofractionated-radiotherapy","fast-forward","start-b","import-low","imrt-igrt","deep-inspiration-breath-hold","radiation-dermatitis"],"guideline":{"version":"NICE NG101, section 1.13 (2023); FAST-Forward (Lancet 2020); START (Lancet Oncology 2013)","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Fertility preservation before chemotherapy","approach":"Triple-negative breast cancer is more common under 40 and chemotherapy usually starts within weeks. NICE NG101 asks teams to advise everyone about options for preserving fertility and cross-refers to the NICE fertility guideline; Cancer Research UK says national guidelines expect the discussion at diagnosis. Options: embryo or egg freezing (about 2 to 3 weeks of ovarian stimulation, with random-start protocols to avoid delay), ovarian tissue freezing at a growing number of UK centres, and contraception during treatment because chemotherapy can damage eggs. NHS funding for freezing varies by area. Because this cancer has no hormone receptors there is no endocrine therapy to interrupt later; the question is protecting eggs before the first cycle, and asking early enough that the referral does not delay chemotherapy.","refs":["fertility-preservation"],"guideline":{"version":"NICE NG101 recommendation 1.1.5 and NICE CG156 (fertility problems); Cancer Research UK and Macmillan fertility pages","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Genetic testing and what a BRCA result means for your family","approach":"NICE NG101 says offer BRCA1 and BRCA2 testing to women under 50 with triple-negative breast cancer even with no family history; Breast Cancer Now says anyone diagnosed under 60 should be offered a referral to discuss testing, and the NHS test directory criteria that NICE points to for PARP inhibitor eligibility (R444.1) may make people over 60 eligible too. Testing is free on the NHS when a hospital specialist refers you, results take about 1 to 3 months, and a genetic counsellor helps with what the result means. A pathogenic variant: opens olaparib after chemotherapy for residual disease (NICE TA886) and a PARP inhibitor in metastatic disease; raises the question of risk-reducing surgery to the other breast and the ovaries, managed by a multidisciplinary team with counselling first (NICE CG164); and means each child has a 1 in 2 chance of carrying it, so relatives can be offered predictive testing. A variant of uncertain significance changes nothing yet. No variant found means relatives are not tested, though a strong family history may still raise risk.","refs":["germline-testing","brca","hrd","olaparib","mastectomy"],"guideline":{"version":"NICE NG101 recommendation 1.3.6 (2017); NICE CG164; Breast Cancer Now genetic testing page","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"First treatment for metastatic disease: the tests that decide","approach":"Three results decide the first treatment for cancer that has spread, so ask that all three are back before the choice is made, ideally on a fresh biopsy because receptors can change: PD-L1 combined positive score (CPS 10 or more opens pembrolizumab with chemotherapy, NICE TA801, or with sacituzumab govitecan), germline BRCA status (a PARP inhibitor, olaparib or talazoparib), and HER2 score (1+ or 2+ without amplification, HER2-low, opens trastuzumab deruxtecan after chemotherapy). The TROP2 antibody-drug conjugates sacituzumab govitecan and datopotamab deruxtecan were approved first line in 2026 with different side-effect profiles; NHS funding follows NICE appraisals (sacituzumab govitecan is funded after two prior therapies under TA819), so ask what applies where you are treated. Ask for the palliative care team from the start, and think about a trial before the first line, because eligibility narrows with each treatment.","refs":["cps","her2-low","brca","germline-testing","keynote-355","pembrolizumab","sacituzumab-govitecan","datopotamab-deruxtecan","olaparib","talazoparib","trastuzumab-deruxtecan","palliative-care"],"guideline":{"version":"NICE TA801 (2022) and TA819 (2022); KEYNOTE-355 (NEJM 2022); NCCN Guidelines: Breast Cancer","url":"https://www.nice.org.uk/guidance/ta801"}},{"setting":"Antibody-drug conjugates: what to expect and the side effects to report","approach":"An antibody-drug conjugate carries chemotherapy into cells that show its target (TROP2 for sacituzumab govitecan and datopotamab deruxtecan, HER2 for trastuzumab deruxtecan), given as a drip in cycles: sacituzumab govitecan on days 1 and 8 of 21. The effects are still chemotherapy-like. Sacituzumab govitecan: low white cells (boxed warning; growth factor injections are sometimes used) and diarrhoea (boxed warning; Macmillan's rule is ring the 24-hour line for 4 or more stools a day, stools at night, or anti-diarrhoea medicine not working within 24 hours), plus sickness, tiredness and hair loss. Datopotamab deruxtecan: mouth soreness, eye problems (the label requires eye examinations) and rarely lung inflammation. Trastuzumab deruxtecan: interstitial lung disease in about 15% (2.2% fatal in the pooled analysis), mostly in the first year, so any new cough, breathlessness or fever is reported immediately; also sickness and low counts. Blood tests before each dose; doses are delayed or reduced rather than pushed through.","refs":["adc","sacituzumab-govitecan","datopotamab-deruxtecan","trastuzumab-deruxtecan","ascent","neutropenia","febrile-neutropenia","ild","ocular-toxicity"],"guideline":{"version":"NICE TA819 (2022); ASCENT (NEJM 2021); US prescribing information (Trodelvy, Datroway, Enhertu); Macmillan and Breast Cancer Now drug pages","url":"https://www.nice.org.uk/guidance/ta819"}},{"setting":"Brain metastases: radiosurgery, whole-brain radiotherapy, surgery and drugs","approach":"Triple-negative breast cancer spreads to the brain more often than other breast subtypes: about 29% of people with metastatic disease in a 433-patient series (25% within two years), and 46% before death in an older 116-patient series. For 1 to 3 metastases of a size suitable for radiosurgery, stereotactic radiosurgery alone is generally preferred: in a randomised trial it caused less cognitive decline at 3 months than radiosurgery plus whole-brain radiotherapy (63.5% against 91.7%) with no difference in survival. Whole-brain radiotherapy is kept for many or widespread metastases, with hippocampal-sparing planning and memantine where possible. Surgery is considered for a single large metastasis causing pressure. Drug treatment for the rest of the body usually continues; activity of the antibody-drug conjugates in the brain is emerging but unproven (the palliation term carries the ASCENT, real-world and DEBBRAH figures). Steroids relieve swelling in the short term. Ask what the plan is for symptoms (headache, seizures, weakness) and who to ring.","refs":["brain-metastases","stereotactic-radiosurgery","wbrt","sbrt","tnbc-symptom-control-palliation","sacituzumab-govitecan","trastuzumab-deruxtecan"],"guideline":{"version":"Brown et al., NCCTG N0574 (JAMA 2016); NCCN Guidelines: Central Nervous System Cancers","url":"https://doi.org/10.1001/jama.2016.9839"}},{"setting":"A clinical trial or standard treatment","approach":"At every stage a trial can be a reasonable choice beside standard treatment: ask what the comparison arm is, whether a placebo is used (the NHS says only where no proven treatment exists; in KEYNOTE-522 the control arm had chemotherapy plus placebo, never placebo alone), what extra visits, tests and travel are involved and whether travel is paid, and that you can leave at any time without it affecting your care. Trials open to triple-negative breast cancer include ones testing less treatment after a complete response (OptimICE-pCR), anthracycline-free chemotherapy (SCARLET), circulating tumour DNA-guided escalation, and new antibody-drug conjugates in metastatic disease; the Triple Negative Breast Cancer Foundation and Cancer Research UK run trial finders. NICE NG101 asks teams to discuss research opportunities and encourage trial entry.","refs":["clinical-trial","informed-consent","placebo","optimice-pcr","scarlet-s2212","mrd-testing"],"guideline":{"version":"NICE NG101 recommendation 1.1.4 (discuss research opportunities and encourage trial entry); NHS: clinical trials","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"}},{"setting":"Choice of neoadjuvant backbone: the platinum debate","approach":"Carboplatin raises pathological complete response in every trial (GeparSixto 53.2 versus 36.9 percent, BrighTNess 58 versus 31, CALGB 40603) and improved disease-free survival in GeparSixto (hazard ratio 0.56) and event-free survival in BrighTNess (0.57) but not long-term outcomes in CALGB 40603 (not powered); it is part of the KEYNOTE-522 regimen and is standard in the UK. Adding veliparib to carboplatin added nothing (BrighTNess). Atezolizumab in place of pembrolizumab has no survival evidence (NeoTRIP, GeparDouze, ALEXANDRA).","refs":["carboplatin","geparsixto","brightness","calgb-40603","veliparib","neotrip","gepardouze","impassion030"],"guideline":{"nccn":"Category 1 (carboplatin within the KEYNOTE-522 regimen)","version":"ESMO early breast cancer guideline 2024","url":"https://doi.org/10.1016/j.annonc.2023.11.016"}},{"setting":"Germline BRCA1 or BRCA2 carriers: early-stage choices","approach":"About one in nine unselected triple-negative patients carries a germline BRCA1 or BRCA2 variant (11.2 percent, Couch 2015; 15.4 percent in a prospective registry, Sharma 2014; 17.2 percent in GeparSixto, Hahnen 2017); the testing rules are in the germline testing row. The result decides adjuvant olaparib (OlympiA, 82 percent triple-negative; NICE TA886), informs risk-reducing surgery, and in the UK offers PARTNER (olaparib with neoadjuvant carboplatin and paclitaxel, 30 sites). Platinum sensitivity is greatest in carriers (TNT: response 68 versus 33 percent with carboplatin versus docetaxel in metastatic disease).","refs":["germline-testing","gbrca-mutation","olympia","olaparib","partner","tnt","carboplatin","brca-associated-tnbc"],"guideline":{"nccn":"Category 1 (adjuvant olaparib)","version":"NICE TA886 (2023); NCCN Breast Cancer","url":"https://www.nice.org.uk/guidance/ta886"}},{"setting":"Metastatic, germline BRCA1 or BRCA2","approach":"Olaparib (OlympiAD: progression-free survival 7.0 versus 4.2 months, hazard ratio 0.58; no overall survival gain overall, hazard ratio 0.51 in patients untreated for metastatic disease; NICE TA1040) or talazoparib (EMBRACA: 8.6 versus 5.6 months, hazard ratio 0.54; final overall survival hazard ratio 0.85; NICE TA952), with the lower-cost option first in England; a platinum doublet is the alternative (BROCADE3 control arm median survival 28.2 months); PARP inhibitor added to chemotherapy (veliparib, BROCADE3) improved progression-free but not overall survival and is not licensed. Sequence relative to PD-1 or TROP2 ADC first-line therapy is untested.","refs":["olaparib","olympiad","talazoparib","embraca","carboplatin","brocade3","veliparib","tnt"],"guideline":{"nccn":"Category 1 (olaparib, talazoparib)","esmoMcbs":"4 (OlympiAD); 4 (EMBRACA)","version":"NICE TA1040 (2025), TA952 (2024); ESMO metastatic breast cancer guideline 2021","url":"https://www.nice.org.uk/guidance/ta1040"}},{"setting":"Metastatic, HER2-low, after one or two lines of chemotherapy","approach":"Trastuzumab deruxtecan 5.4 mg/kg every 3 weeks (DESTINY-Breast04: overall survival 23.4 versus 16.8 months in all patients, hazard ratio 0.64; hormone-receptor-negative cohort of 63, progression-free survival 8.5 versus 2.9 months, hazard ratio 0.46; interstitial lung disease 12.1 percent, 0.8 percent fatal). Licensed in the US (2022) and EU (2023) for HER2-low regardless of hormone receptor status; not recommended by NICE (TA992, 29 July 2024; rapid review in development), so not commissioned in England. HER2-ultralow triple-negative disease has no licensed indication.","refs":["trastuzumab-deruxtecan","destiny-breast04","her2-low","ild"],"guideline":{"nccn":"Category 1, preferred (HER2-low after chemotherapy)","esmoMcbs":"4","version":"NICE TA992 (2024, not recommended); ESMO metastatic breast cancer guideline 2021","url":"https://www.nice.org.uk/guidance/ta992"}},{"setting":"Palliation of symptoms: bone, pleura, skin and end of life","approach":"Single-fraction radiotherapy for painful bone metastases with denosumab or zoledronic acid to reduce skeletal events; urgent radiotherapy or surgery for spinal cord compression; drainage with talc pleurodesis or an indwelling catheter for malignant pleural effusion; radiotherapy and wound care for chest wall recurrence; management of drug toxicities (hand-foot syndrome on capecitabine, neutropenia and diarrhoea on sacituzumab govitecan, stomatitis and eye symptoms on datopotamab deruxtecan, interstitial lung disease on trastuzumab deruxtecan); early integrated palliative care from diagnosis of metastatic disease.","refs":["tnbc-symptom-control-palliation","bone-metastases","denosumab","zoledronic-acid","hypofractionated-radiotherapy","palliative-care","hand-foot-syndrome","neutropenia","ild"],"guideline":{"nccn":"Category 2A","version":"ESMO metastatic breast cancer guideline 2021","url":"https://doi.org/10.1016/j.annonc.2021.09.019"}}],"stateOfArt":["Curative-intent: chemo-immunotherapy (KEYNOTE-522) cures more patients than ever; pCR ~65%. Adjuvant PARP inhibitor for BRCA carriers.","Metastatic: ADCs first line (sacituzumab, Dato-DXd), ADC + IO for PD-L1+ disease; median OS in first-line trials now approaches two years, roughly double the 2015 figure.","HER2-low reclassification gives a third of TNBC patients access to T-DXd.","De-escalation is real: TIL-guided omission of chemotherapy in stage I; anthracycline-free and pembrolizumab-omission trials in stage II-III.","Genomic landscape. TP53 mutation in about 80% (79 to 90% by cohort), PIK3CA 10 to 18%, PTEN loss 12 to 35%, RB1 loss 15 to 20%, MYC amplification 18 to 35%, EGFR amplification 3 to 6%, NOTCH activation 5 to 9%, PI3K-AKT pathway alteration 20 to 27%; germline BRCA1 7 to 11%, BRCA2 3 to 4%, PALB2 1 to 2%, and homologous recombination deficiency in 59 to 71% (mostly BRCA1 promoter methylation and sporadic scars rather than germline mutation). TMB 10 or more in 4 to 5% of early and 18% of pretreated metastatic disease; MSI-high 0 to 2%. Every figure and cohort is in the molecular table; the cBioPortal rows were computed on receptor-defined triple-negative subsets of TCGA, METABRIC and the MSK 2018 cohort.","Subtypes. Lehmann's TNBCtype-4: BL1 35% (TP53 92%, unstable, platinum-sensitive, pCR 41%), BL2 22% (growth-factor signalling, pCR 18%), mesenchymal 25% (EMT, immune-cold, PRC2-silenced MHC-I, lung-tropic) and LAR 16% (AR-driven, PIK3CA 55%, AKT1 13%, bone-tropic, pCR 29%, worst prognosis, modest AR-antagonist benefit); the immunomodulatory signal (21 to 25%) is the lymphocyte infiltrate and carries the best prognosis. Burstein's BLIS and BLIA split basal-like disease by immune state; the FUSCC scheme repeats the four-way logic in 465 Chinese patients. By PAM50, 76% of TNBC is basal-like and 15% HER2-enriched.","Immune biomarkers by assay. SP142 IC 1% or more (IMpassion130): 41 to 51%. 22C3 CPS 10 or more (KEYNOTE-355, ASCENT-04): 27 to 38%. The two agree weakly and are not interchangeable; a 22C3 or SP263 positive does not imply SP142 positivity, and the atezolizumab benefit sat in SP142-positive tumours. Stromal TILs average 23%, are 60% or more in about 30%, and predict chemotherapy response and survival with or without chemotherapy; spatial immune classes (immunoreactive, immune-cold B7-H4-high, stroma-restricted) refine the score.","HER2 and TROP2. HER2-low (IHC 1+ or 2+/ISH-negative) is 24 to 37% of TNBC and on-label for trastuzumab deruxtecan after one line (DESTINY-Breast04, 63 hormone receptor-negative patients); ultralow is a further 38% but unlabelled in TNBC because DESTINY-Breast06 was hormone receptor-positive only. TROP2 is not tested: ASCENT benefit spanned high and medium H-scores and neither TROP2 antibody-drug conjugate requires an assay.","Ancestry and geography. African ancestry carries a 3.8-fold odds of basal-like disease, more TP53 and fewer PIK3CA mutations, with about 44% of the subtype difference heritable and a distinct immune landscape; 46% of Nigerian breast cancers with receptor data are triple-negative and 14.7% carry a germline repair-gene variant. BRCA1 founder mutations dominate in the Bahamas (23% of unselected patients), Mexico (ex9-12del) and Ashkenazi Jews (185delAG); Chinese TNBC carries more PIK3CA; MSI-high is under 1% in China and Japan.","ctDNA and molecular residual disease. Post-neoadjuvant ctDNA positivity (about a third of patients with residual disease, rising with residual cancer burden) carries a two- to four-fold relapse hazard independent of RCB; every pathological complete responder in I-SPY 2 was ctDNA-negative. Prospective surveillance (c-TRAK TN) found ctDNA in 27% by a year but most already had metastases and pembrolizumab cleared none, and brain-only relapse escapes detection. No TNBC approval uses ctDNA; it stratifies ASCENT-05 and the ZEST design.","Testing. Germline BRCA1/2 (and PALB2) for every TNBC diagnosis (ASCO-SSO 2024; NHS R208 and R444.1), with results before surgery where possible; 22C3 CPS on a metastatic biopsy for pembrolizumab combinations; HER2 IHC re-read at the 0 versus 1+ boundary; a comprehensive tumour panel at relapse for TMB, MSI, PIK3CA/AKT1/PTEN and NOTCH; HRD scores and TROP2 IHC are research readouts with no breast label."],"history":[{"year":1987,"title":"HER2 amplification found in 30 percent of breast cancers and tied to early relapse","note":"Slamon and colleagues, 189 tumours. With the oestrogen and progesterone receptor assays it completed the three tests whose absence defines triple-negative disease.","refs":["paper-slamon-her2-amplification-science-1987","her2"]},{"year":1997,"title":"Founder BRCA mutations: 56 percent breast cancer risk by 70 in Ashkenazi carriers","note":"Struewing and colleagues, 5,318 volunteers, three founder variants carried by over 2 percent of the population; Górski described the Polish BRCA1 founder set in 2000.","refs":["paper-struewing-brca-founder-mutations-ashkenazi-nejm-1997","paper-gorski-brca1-founder-mutations-poland-ajhg-2000","brca"]},{"year":2000,"title":"Molecular portraits define the basal-like subtype","note":"Perou and Sørlie's expression profiling separates basal-like from luminal breast cancers.","refs":["rna-seq"]},{"year":2003,"title":"BRCA1 carriers' tumours shown to be basal-like","note":"Sørlie's independent data sets and Foulkes's cytokeratin 5/6 stain (odds ratio 9.0) linked hereditary and basal-like disease; Atchley (2008) found 57 percent of BRCA1 carriers' cancers triple-negative.","refs":["paper-sorlie-repeated-observation-subtypes-brca1-basal-pnas-2003","paper-foulkes-brca1-basal-phenotype-jnci-2003","paper-atchley-brca-status-triple-negative-jco-2008","germline-testing"]},{"year":2006,"title":"Carolina Breast Cancer Study: basal-like tumours in 39 percent of young African American women","note":"Carey and colleagues, 496 cases; 16 percent in other women. California registry data (2007) fixed the wider demography of younger, Black, Hispanic and poorer women with worse survival at every stage.","refs":["paper-carey-race-breast-cancer-subtypes-cbcs-jama-2006","paper-bauer-triple-negative-california-registry-cancer-2007","idea-tnbc-disparities-in-access-and-outcomes"]},{"year":2007,"title":"'Triple-negative' enters clinical vocabulary","note":"Defined by absence of ER, PR, HER2; recognised as the subtype with the fewest treatment options, which set the research agenda that followed.","refs":[]},{"year":2007,"title":"Residual cancer burden score; the relapse curve that peaks at three years","note":"Symmans graded residual disease after neoadjuvant chemotherapy; Dent's Toronto cohort showed distant relapse hazard ratio 2.6 peaking at three years and fading after five.","refs":["paper-symmans-j-clin-oncol","paper-dent-tnbc-clinical-features-recurrence-ccr-2007","rcb"]},{"year":2008,"title":"The residual disease paradox and the brain metastasis rate","note":"Liedtke: pathological complete response 22 vs 11 percent yet worse survival, driven by residual disease. Lin: 46 percent of metastatic patients developed brain metastases; median survival 13.3 months.","refs":["paper-liedtke-neoadjuvant-response-survival-tnbc-jco-2008","paper-lin-tnbc-cns-metastases-dfci-cancer-2008","brain-metastases"]},{"year":2010,"title":"Claudin-low described as a breast cancer subtype","note":"Mostly triple-negative tumours with epithelial-to-mesenchymal transition and stem-cell features (Prat, Breast Cancer Research); re-defined as a phenotype across subtypes in 2020.","refs":["claudin-low"]},{"year":2011,"title":"Six molecular subtypes of triple-negative breast cancer","note":"Lehmann and colleagues, 587 tumours: basal-like 1 and 2, immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor; refined to four in 2016 (Burstein reached a similar four in 2015).","refs":["paper-lehmann-tnbc-subtypes-jci-2011","paper-lehmann-tnbctype-4-refinement-plos-one-2016","paper-burstein-tnbc-genomic-subtypes-ccr-2015"]},{"year":2012,"title":"TCGA basal-like portrait and the first TNBC genomes","note":"TP53 80%, PTEN loss 35%, RB1 loss 20% in basal-like disease and a likeness to serous ovarian cancer (Nature); Shah's 104 TNBC genomes show a continuous spectrum of clonal complexity.","refs":["paper-tcga-breast-molecular-portraits-nature-2012","paper-shah-tnbc-clonal-evolution-nature-2012","tp53"]},{"year":2014,"title":"Carboplatin raises pCR","note":"GeparSixto and CALGB 40603 show platinum increases pathologic complete response.","refs":["carboplatin","platinum"]},{"year":2014,"title":"UK POSH cohort: young Black women have more triple-negative disease and worse survival despite equal access","note":"Copson and colleagues, 2,915 women aged 40 or under: 26.1 vs 18.6 percent triple-negative; five-year survival 71.1 vs 82.4 percent with equal chemotherapy use.","refs":["paper-copson-posh-ethnicity-young-breast-cancer-uk-bjc-2014","idea-tnbc-uk-ethnicity-stratified-outcome-reporting"]},{"year":2015,"title":"Germline testing case made for all triple-negative disease","note":"14.6 percent of 1,824 unselected triple-negative patients carry a predisposition mutation, 11.2 percent in BRCA1 or BRCA2 (Couch, JCO); the same year Burstein's basal-like immunosuppressed and immune-activated subtypes split basal-like disease by immune state.","refs":["germline-brca-testing-criteria-tnbc","brca-associated-tnbc","paper-couch-tnbc-germline-17-genes-jco-2015","paper-burstein-tnbc-genomic-subtypes-ccr-2015","brca"]},{"year":2016,"title":"TNBCtype-4 and the HRD score threshold","note":"Lehmann refines the subtypes to four (BL1 35%, BL2 22%, M 25%, LAR 16%) with pCR 41% versus 18% versus 29%; Telli sets HRD score 42 in neoadjuvant platinum trials.","refs":["paper-lehmann-tnbctype-4-refinement-plos-one-2016","paper-telli-hrd-score-platinum-tnbc-ccr-2016"]},{"year":2017,"title":"AJCC 8th edition adds the prognostic stage","note":"Grade, ER, PR and HER2 enter the stage group alongside TNM (Giuliano, CA); validated in 2018.","refs":["ajcc-prognostic-stage-breast"]},{"year":2017,"title":"CREATE-X: capecitabine after residual disease lengthens survival","note":"910 patients; five-year overall survival 89.2 vs 83.6 percent, and 78.8 vs 70.3 percent in the triple-negative group. The first post-neoadjuvant treatment.","refs":["paper-create-x-adjuvant-capecitabine-nejm-2017","capecitabine"]},{"year":2018,"title":"First immunotherapy signal","note":"IMpassion130: atezolizumab + nab-paclitaxel improves PFS in PD-L1+ metastatic TNBC (approval later withdrawn).","refs":["impassion130","atezolizumab"]},{"year":2018,"title":"PARP inhibitors in BRCA breast cancer","note":"OlympiAD and EMBRACA lead to olaparib and talazoparib approvals.","refs":["olaparib","talazoparib"]},{"year":2018,"title":"TNT: germline BRCA, not the HRD score, predicts platinum benefit","note":"In 376 advanced patients carboplatin doubled the response rate in germline BRCA carriers while the Myriad HRD score and BRCA1 methylation predicted nothing; Bareche maps mutations onto the Lehmann subtypes in 550 tumours.","refs":["paper-tutt-nat-med","paper-bareche-tnbc-multiomic-heterogeneity-ann-oncol-2018","hrd-positive"]},{"year":2019,"title":"WHO classification of breast tumours, 5th edition","note":"Medullary carcinoma becomes a pattern of invasive carcinoma of no special type; metaplastic, adenoid cystic, apocrine and secretory carcinomas keep their special-type status.","refs":["medullary-pattern-breast-carcinoma","metaplastic-breast-carcinoma"]},{"year":2019,"title":"Population whole genomes and TILs","note":"SCAN-B whole-genome sequencing puts HRDetect-high at 59% of TNBC (Nat Med); Loi's pooled 2,148 patients fix TILs as the strongest early prognostic marker.","refs":["paper-staaf-tnbc-whole-genome-scan-b-nat-med-2019","paper-loi-tils-pooled-early-tnbc-jco-2019"]},{"year":2020,"title":"Sacituzumab govitecan approved","note":"ASCENT: OS 12.1 vs 6.7 months in pretreated disease; first ADC for TNBC.","refs":["ascent","sacituzumab-govitecan"]},{"year":2020,"title":"Pembrolizumab + chemotherapy first line","note":"KEYNOTE-355 in CPS ≥10 disease.","refs":["keynote-355"]},{"year":2020,"title":"ASCO/CAP creates the ER Low Positive category","note":"ER 1 to 10 percent is reported separately because endocrine benefit is uncertain; cohorts show these tumours behave like triple-negative disease.","refs":["er-pr-negative-threshold"]},{"year":2020,"title":"Post-neoadjuvant ctDNA triples the relapse hazard","note":"BRE12-158's preplanned analysis of 196 residual-disease patients: distant relapse hazard ratio 2.99 and death hazard ratio 4.16 when ctDNA is detected after chemotherapy.","refs":["paper-radovich-ctdna-ctc-bre12-158-jama-oncol-2020","ctdna-mrd-positive"]},{"year":2021,"title":"KEYNOTE-522 changes early-stage care","note":"Neoadjuvant/adjuvant pembrolizumab approved for stage II-III TNBC; OS benefit confirmed 2024.","refs":["keynote-522","pembrolizumab"]},{"year":2021,"title":"OlympiA: adjuvant olaparib","note":"One year of olaparib after standard therapy improves iDFS and OS in gBRCA carriers.","refs":["olympia"]},{"year":2021,"title":"PD-L1 assays shown not to be interchangeable","note":"Rugo and colleagues on 614 IMpassion130 tumours: SP142, SP263 and 22C3 positive in 46, 75 and 73 percent, concordance 69 percent. Atezolizumab's US breast indication withdrawn the same year.","refs":["paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021","impassion130","idea-tnbc-pd-l1-assay-harmonisation"]},{"year":2021,"title":"HER2-low measured at about a third of TNBC","note":"Schettini (3,689 HER2-negative cancers, 36.6% of triple-negative) and Denkert (34.0% of 1,162 hormone receptor-negative trial patients) fix the share a year before DESTINY-Breast04 gave it a drug.","refs":["paper-schettini-her2-low-features-npj-breast-cancer-2021","paper-denkert-her2-low-pooled-neoadjuvant-lancet-oncol-2021","her2-low-ihc"]},{"year":2022,"title":"HER2-low: T-DXd works in 'HER2-negative' disease","note":"DESTINY-Breast04 includes TNBC patients with HER2-low tumours.","refs":["destiny-breast04","trastuzumab-deruxtecan"]},{"year":2022,"title":"African ancestry linked to the TNBC immune landscape","note":"Martini's RNA sequencing of African American, West and East African tumours finds 613 ancestry-associated genes and distinct tumour-associated immune profiles.","refs":["paper-martini-african-ancestry-tnbc-cancer-discov-2022","paper-huo-tcga-ancestry-breast-jama-oncol-2017"]},{"year":2023,"title":"c-TRAK TN: acting on ctDNA came too late","note":"UK trial, 161 women under surveillance; 27 percent ctDNA-positive by a year, 72 percent of them already metastatic on staging; none of five given pembrolizumab cleared.","refs":["paper-turner-c-trak-tn-ctdna-pembrolizumab-ann-oncol-2023","ctdna","idea-tnbc-ctdna-guided-adjuvant-decisions"]},{"year":2023,"title":"ctDNA and residual cancer burden shown independently prognostic","note":"Stecklein's 80-patient registry: ctDNA positive in a third of residual-disease patients, rising with RCB class, with three-year event-free survival 48% against 82%.","refs":["paper-stecklein-ctdna-rcb-tnbc-residual-disease-npj-2023","ctdna-mrd-positive"]},{"year":2024,"title":"Lymphocyte-rich stage I tumours do well without chemotherapy","note":"Leon-Ferre and colleagues, 1,966 untreated patients: five-year distant recurrence-free survival 94 percent with lymphocytes of 50 percent or more vs 78 percent below 30 percent.","refs":["paper-leon-ferre-tils-tnbc-no-chemotherapy-jama-2024","tils","idea-tnbc-de-escalation-for-exceptional-responders"]},{"year":2024,"title":"Universal germline testing recommended","note":"ASCO-SSO recommends BRCA1/2 testing for all breast cancer diagnosed at 65 or under and for every PARP inhibitor candidate.","refs":["paper-bedrosian-asco-sso-germline-testing-breast-jco-2024","brca-germline"]},{"year":2025,"title":"First-line ADC era begins","note":"ASCENT-03, ASCENT-04, and TROPION-Breast02 all positive; TROPION-Breast02 shows OS benefit.","refs":["ascent-03","ascent-04","tropion-breast02"]},{"year":2026,"title":"Bispecific ADC succeeds; first-line ADC approvals","note":"Iza-bren phase 3 positive (Feb 2026); FDA approves Dato-DXd and sacituzumab govitecan first line (Q2 2026).","refs":["bl-b01d1-307","datopotamab-deruxtecan","sacituzumab-govitecan"]},{"year":2026,"title":"TROPION-Breast02 and OlympiA six-year update published; CAPItello-290 negative","note":"Datopotamab deruxtecan first line: overall survival 23.7 vs 18.7 months. Olaparib: six-year survival 87.5 vs 83.2 percent, no excess leukaemia. Capivasertib plus paclitaxel: no survival gain.","refs":["paper-tropion-breast02-ann-oncol-2026","paper-olympia-6-year-update-ann-oncol-2026","paper-capitello-290-capivasertib-paclitaxel-ann-oncol-2026","tropion-breast02","olympia","nct03997123"]},{"year":2026,"title":"HER2-ultralow share of TNBC measured","note":"Boissiere-Michot reclassifies 367 untreated TNBCs as 38% null, 38% ultralow and 24% low, none prognostic; ultralow stays unlabelled in TNBC.","refs":["paper-boissiere-michot-her2-ultralow-tnbc-virchows-arch-2026","her2-ultralow"]}],"pipeline":["sacituzumab-tirumotecan","izalontamab-brengitecan","tropion-breast05","izabright-breast01","optimice-pcr","scarlet-s2212","trop2-pet","patritumab-deruxtecan","puxitatug-samrotecan","dual-payload-adc","neoantigen-mrna-vaccine","mrd-testing","ivonescimab","ak146d1","pm8002","oleclumab","ak117","ceralasertib","esg401","bebt-209","jskn016","fda018-adc","avzo-021","jk08","lp-184","tenalisib","idea-tnbc-de-escalation-for-exceptional-responders","idea-tnbc-ctdna-guided-adjuvant-decisions","idea-tnbc-disparities-in-access-and-outcomes","idea-tnbc-pd-l1-assay-harmonisation","idea-tnbc-adc-sequencing-trial","idea-tnbc-brain-metastasis-trials","idea-tnbc-her2-ultralow-testing-uptake","idea-tnbc-uk-trial-access-and-germline-testing-audit","idea-tnbc-uk-ethnicity-stratified-outcome-reporting","ascent-05","tropion-breast03","nct06112379","swog-s1418","partner","phoenix","diamond","barbican"],"openProblems":["Residual disease after KEYNOTE-522: no approved escalation beyond capecitabine/olaparib; ctDNA-guided trials needed.","ADC sequencing: does a second TOP1-payload ADC work after the first? SATEEN/BRE-354 suggest limited efficacy; chemotherapy interposition debated.","Patient selection for TROP2 ADCs: IHC does not predict; TROP2 PET and ctDNA are candidates.","PD-L1-negative early disease has immunotherapy proven only in KEYNOTE-522's unselected population, no biomarker that spares anyone pembrolizumab, and no ADC yet in the curative setting.","Brain metastases (up to 30-45% of metastatic TNBC) remain undertreated; ADC CNS activity is emerging but unproven.","Mesenchymal/claudin-low biology (EMT, efflux pumps) resists chemotherapy, ADC payloads, and immunotherapy alike.","Disparities: Black women have twice the TNBC incidence and worse outcomes; trial enrolment does not reflect this.","No UK registry publishes triple-negative incidence or survival as a subtype; the UK share rests on Cancer Research UK's around 15 percent and on cohorts such as POSH, while SEER publishes rates by receptor status every year.","ER 1 to 10 percent tumours behave like triple-negative disease yet are excluded from most triple-negative trials, so the evidence for immunotherapy and ADCs in that band is thin (Yoder 2022; Acs 2024).","Chemoprevention for BRCA1 carriers: tamoxifen and anastrozole prevent ER-positive disease, which is not the cancer BRCA1 carriers mostly get; risk-reducing mastectomy and surveillance are the only proven options.","PD-L1 assays disagree on about a quarter of tumours (SP142 46 percent positive, 22C3 73 percent, concordance 69 percent in IMpassion130; 27 percent CPS 10 or more against 51 percent SP142-positive in the Swedish early cohort); only 22C3 combined positive score of 10 has an approved drug attached, laboratories are not harmonised, and no assay predicts benefit from the first-line antibody-drug conjugate plus pembrolizumab combinations.","Acting on ctDNA after residual disease failed once (c-TRAK TN: detection came after metastases were visible, and ctDNA misses brain-only relapse); the next design needs tumour-informed assays, a sample at surgery and an active drug, and has not been run.","The disparity is measured in the United States and was measured once in the UK (POSH, women under 41, recruited to 2008); NHS statistics do not report triple-negative outcomes by ethnicity, and women of African ancestry, who carry a distinct immune landscape, remain under-represented in the trials that set the biomarker thresholds.","Most homologous recombination deficiency in TNBC is not germline BRCA, yet the PARP inhibitor labels are germline-only and the HRD scores validated in ovarian cancer did not predict carboplatin benefit in advanced TNBC (TNT).","The Lehmann subtypes predict chemotherapy response retrospectively but no prospective subtype-directed trial has changed a guideline; the mesenchymal and LAR subtypes have no approved targeted therapy.","Capecitabine after residual disease (CREATE-X) was proven before pembrolizumab existed; no trial has tested it alongside adjuvant pembrolizumab, and the two ADC trials in that setting (ASCENT-05, TROPION-Breast03) will not report before 2027.","The independent contribution of adjuvant pembrolizumab is unknown: KEYNOTE-522 gave it before and after surgery, OptimICE-pCR asks whether it can be dropped after a complete response, and SWOG S1418 asks whether it helps after residual disease without prior immunotherapy.","Three atezolizumab phase 3 trials in early disease were negative or null while pembrolizumab succeeded; whether that is the drug, the PD-L1 rather than PD-1 target, the backbone or chance is unresolved, and it leaves PD-L1-negative early disease with immunotherapy proven only in KEYNOTE-522's unselected population.","In England HER2-low triple-negative disease cannot receive trastuzumab deruxtecan (NICE TA992 not recommended), the first-line ADC indications await appraisal, and atezolizumab remains commissioned on a licence the United States withdrew; the UK and US pathways for metastatic disease have diverged.","AKT inhibition failed twice in biomarker-selected metastatic disease (IPATunity130, CAPItello-290) despite positive phase 2 trials, so PIK3CA, AKT1 and PTEN alterations, present in a fifth to a quarter of tumours, are not actionable in triple-negative breast cancer today; PTEN loss may also mark immunotherapy resistance."],"basics":{"symptoms":["A new lump or thickening in the breast or armpit; a change in the size, shape or feel of the breast; puckering, dimpling, a rash or redness of the skin; fluid from the nipple when not pregnant or breastfeeding; a nipple that turns in (Cancer Research UK). The symptoms are the same as for other breast cancers, but triple-negative tumours arrive younger, more often between screening rounds, and more often at a higher grade","Redness may look darker or reddish brown on brown or black skin (Cancer Research UK symptoms page)","Less often found by screening: 29 percent of triple-negative cancers against 48 percent of hormone receptor-positive, HER2-negative cancers presented through an abnormal screening mammogram in US cancer centres (Lin 2012)","Referral rules: an unexplained breast lump at 30 or over, or nipple discharge, retraction or other change in one nipple at 50 or over, goes on the suspected cancer pathway; skin changes or an unexplained axillary lump at 30 or over should prompt the same consideration (NICE NG12 1.4)"],"diagnosis":["One-stop breast clinic and triple assessment: examination, mammogram, ultrasound and a needle core or vacuum-assisted biopsy, with ultrasound and needle biopsy of any abnormal axillary node (Cancer Research UK)","ER, PR and HER2 are tested together on the biopsy at diagnosis by quality-assured immunohistochemistry and reported quantitatively (NICE NG101 1.3.1 to 1.3.4); results take about 2 to 4 weeks (Cancer Research UK)","Triple-negative means ER under 1 percent, PR under 1 percent (1 to 10 percent is ER Low Positive and behaves the same way) and HER2 0, 1+ or 2+ without gene amplification (ASCO/CAP 2020 and 2018)","HER2 0 versus 1+ is reported with a comment because the HER2-low category qualifies for trastuzumab deruxtecan later (ASCO-CAP 2023)","Germline BRCA1 and BRCA2 testing is offered to women under 50 with triple-negative disease even without a family history (NICE NG101 1.3.6); the familial cancer guideline adds a 10 percent carrier-probability rule for everyone else (CG164)","Breast MRI only where the extent is unclear, the breasts are dense or the cancer is lobular (NG101 1.2); CT, bone scan or PET-CT for staging when the stage or symptoms call for it; CA 15-3 is not diagnostic (Cancer Research UK)"],"staging":["TNM 8th edition. T1 is 2 cm or less (T1a to 0.5 cm, T1b to 1 cm, T1c to 2 cm), T2 over 2 to 5 cm, T3 over 5 cm, T4 into the chest wall or skin or inflammatory (Cancer Research UK)","Nodes: cN before treatment, pN after surgery; pN1 one to three axillary nodes, pN2 four to nine, pN3 ten or more or infraclavicular, supraclavicular or axillary plus internal mammary nodes (Cancer Research UK)","Stage 1 is T1 N0 (1B with micrometastases); stage 2 is T2 N0, T0 to T2 N1 or T3 N0; stage 3 is N2, T3 N1, T4 or N3; stage 4 is any spread beyond the regional nodes (Cancer Research UK)","The AJCC prognostic stage adds grade, ER, PR and HER2 to the TNM groups; a grade 3 triple-negative tumour is generally placed higher than its anatomic stage (Giuliano 2017; Weiss 2018)","After chemotherapy before surgery, the pathologist reports whether any invasive cancer is left (pathological complete response) and how much (residual cancer burden classes I to III), which predict relapse better than the starting stage in this subtype (Cortazar 2014; Symmans 2017)"],"sources":[{"label":"CRUK: triple negative breast cancer (patient page)","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/types/triple-negative-breast-cancer"},{"label":"CRUK: symptoms of breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/symptoms"},{"label":"CRUK: tests to diagnose breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/getting-diagnosed/tests"},{"label":"CRUK: TNM staging of breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/stages-grades/tnm-staging"},{"label":"CRUK: number stages of breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/stages-grades/number-stages"},{"label":"NICE NG12: suspected cancer, recommendations by site (breast cancer 1.4)","url":"https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer"},{"label":"NICE NG101: early and locally advanced breast cancer (receptor testing 1.3, genetic testing 1.3.6, triple-negative section 1.8)","url":"https://www.nice.org.uk/guidance/ng101/chapter/Recommendations"},{"label":"NICE CG164: familial breast cancer (referral, genetic testing, surveillance, risk-reducing surgery, chemoprevention)","url":"https://www.nice.org.uk/guidance/cg164/chapter/Recommendations"},{"label":"Allison, J Clin Oncol 2020: ASCO/CAP guideline update on ER and PR testing (1 percent threshold, ER Low Positive)","url":"https://doi.org/10.1200/jco.19.02309"},{"label":"Wolff, J Clin Oncol 2018: ASCO/CAP HER2 testing guideline focused update","url":"https://doi.org/10.1200/jco.2018.77.8738"},{"label":"Wolff, J Clin Oncol 2023: ASCO-CAP HER2 testing update (IHC 0 versus 1+ after DESTINY-Breast04)","url":"https://doi.org/10.1200/jco.22.02864"},{"label":"Lin, Cancer 2012: clinicopathological features, recurrence and survival of triple-negative breast cancer in NCCN centres","url":"https://doi.org/10.1002/cncr.27581"},{"label":"Giuliano, CA Cancer J Clin 2017: major changes in the AJCC 8th edition breast cancer staging manual","url":"https://doi.org/10.3322/caac.21393"},{"label":"Weiss, JAMA Oncol 2018: validation of the AJCC 8th edition prognostic stage against the anatomic stage","url":"https://doi.org/10.1001/jamaoncol.2017.4298"},{"label":"Cortazar, Lancet 2014: pathological complete response and long-term benefit, the CTNeoBC pooled analysis","url":"https://doi.org/10.1016/s0140-6736(13)62422-8"},{"label":"Symmans, J Clin Oncol 2017: long-term prognosis by residual cancer burden and breast cancer subtype","url":"https://doi.org/10.1200/jco.2015.63.1010"}]},"prognosis":{"text":"Population figures, quoted with their cohorts; none is a personal prognosis. United States (SEER 21, excluding Illinois, people diagnosed 2016 to 2022): five-year relative survival for hormone receptor-negative, HER2-negative breast cancer is 78.7 percent, against 95.8 percent for hormone receptor-positive, HER2-negative disease and 91.9 percent for all breast cancer; by stage it is 92.8 percent for localised, 68.3 percent for regional and 14.9 percent for distant disease (the same fact sheet). Four-year breast cancer-specific survival was 77.0 percent for the triple-negative subtype in SEER cases diagnosed 2010 to 2013 (Howlader 2018), and in the California registry (1999 to 2003) non-Hispanic Black women with late-stage triple-negative disease had a five-year relative survival of 14 percent, the lowest of any group (Bauer 2007). United Kingdom: no UK registry publishes survival for the triple-negative subtype. For all breast cancer in England (women diagnosed 2018 to 2022) five-year net survival is almost 100 percent at stage 1, 90 percent at stage 2, around 75 percent at stage 3 and more than 30 percent at stage 4 (Cancer Research UK, from NHS England), and 76.6 percent of UK women survive ten years or more (2018). Subtype-specific UK figures come from cohorts: in the POSH study of women diagnosed at 40 or under (2000 to 2008), ten-year overall survival among 558 triple-negative patients was 72 percent in BRCA carriers and 69 percent in non-carriers (Copson 2018), and in a Manchester single-centre series of women aged 40 or under (2010 to 2015) five-year survival was 70.8 percent for triple-negative against 86.3 percent for ER-positive, HER2-negative tumours (Monaghan 2024). What moves the figures: stage at diagnosis above all; response to chemotherapy given before surgery, with ten-year relapse-free survival of 86 percent after a pathological complete response, 81 percent for residual cancer burden class I, 55 percent for class II and 23 percent for class III (Symmans 2017); and the newer regimens, with five-year overall survival of 86.6 percent for stage II and III disease treated with pembrolizumab and chemotherapy against 81.7 percent with chemotherapy alone in KEYNOTE-522 (Schmid 2024). Relapse risk is concentrated in the first three to five years and is low thereafter (Dent 2007).","sources":[{"label":"SEER Cancer Stat Facts: female breast cancer subtypes (rates, share, survival by stage and by race)","url":"https://seer.cancer.gov/statfacts/html/breast-subtypes.html"},{"label":"Howlader, Cancer Epidemiol Biomarkers Prev 2018: breast cancer survival by molecular subtype in the United States","url":"https://doi.org/10.1158/1055-9965.EPI-17-0627"},{"label":"Bauer, Cancer 2007: the triple-negative phenotype in the California Cancer Registry","url":"https://doi.org/10.1002/cncr.22618"},{"label":"CRUK: survival for breast cancer (England by stage, 2018 to 2022)","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/survival"},{"label":"CRUK: breast cancer survival statistics (professional)","url":"https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/survival"},{"label":"Copson, Lancet Oncol 2018: germline BRCA mutation and outcome in young-onset breast cancer (POSH)","url":"https://doi.org/10.1016/s1470-2045(17)30891-4"},{"label":"Monaghan, BJS Open 2024: tumour biology and survival in young women with breast cancer (UK single centre)","url":"https://doi.org/10.1093/bjsopen/zrae138"},{"label":"Symmans, J Clin Oncol 2017: long-term prognosis by residual cancer burden and breast cancer subtype","url":"https://doi.org/10.1200/jco.2015.63.1010"},{"label":"Schmid, N Engl J Med 2024: KEYNOTE-522 overall survival","url":"https://doi.org/10.1056/nejmoa2409932"},{"label":"Dent, Clin Cancer Res 2007: clinical features and patterns of recurrence of triple-negative breast cancer","url":"https://doi.org/10.1158/1078-0432.ccr-06-3045"}]},"parent":"breast-cancer"},{"id":"tubular-carcinoma-breast","kind":"cancer","name":"Tubular carcinoma of the breast","aka":["Tubular carcinoma","Tubular breast cancer","Pure tubular carcinoma"],"tldr":"Tubular carcinoma is a rare, slow-growing type of breast cancer made of small, well-formed tubes, usually found small on a screening mammogram. Its outlook is excellent, better even than other grade 1 breast cancers, and it is treated with surgery, radiotherapy where the breast is kept, and hormone therapy.","summary":"The WHO classification defines tubular carcinoma by well-formed open tubules with a single layer of low-grade cells making up over 90 percent of the tumour (Tan 2020). In the Nottingham series of 2,608 carcinomas, the 102 tubular carcinomas, compared with 212 grade 1 ductal carcinomas, were more often detected by screening, smaller, and less often showed lymphovascular invasion; they had longer disease-free and breast cancer-specific survival, and no patient developed distant metastasis or died of the disease without an intervening recurrence of a different histological type (Rakha 2010). In an earlier series of 44 patients, nodes were involved in 4 of 32 examined (13 percent), tumours under 15 mm had no nodal involvement, ductal carcinoma in situ accompanied 52 percent, second breast cancers developed in 16 percent and overall mortality was 2 percent (Breast Journal 2003).\n\nHow it differs from its parent: it is the special type with the best prognosis, hormone-receptor positive and HER2-negative (luminal A), and its main risk is a second, different breast cancer rather than relapse of the tubular tumour (Rakha 2010).\n\nHow common: 3.9 percent of the Nottingham series (Rakha 2010); no population figure was found in the sources read.\n\nTreatment: as HR-positive breast cancer, generally the minimum the parent page allows: breast-conserving surgery with radiotherapy (local recurrence 1 of 20 without radiotherapy against 0 of 13 with it in the 2003 series), sentinel node biopsy, and endocrine therapy; chemotherapy is rarely indicated.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Tubular_carcinoma","links":[{"label":"Tan 2020, Histopathology: the 2019 WHO classification of tumours of the breast","url":"https://doi.org/10.1111/his.14091"},{"label":"Rakha 2010, JCO: tubular carcinoma of the breast, further evidence for its excellent prognosis","url":"https://doi.org/10.1200/jco.2009.23.5051"},{"label":"Breast Journal 2003: tubular carcinoma of the breast, institutional experience and review","url":"https://doi.org/10.1046/j.1524-4741.2003.09409.x"},{"label":"Cancer Research UK: types of breast cancer","url":"https://www.cancerresearchuk.org/about-cancer/breast-cancer/types"}],"tags":["subtype-page","wave4","breast"],"related":["breast-cancer","breast-hr-positive","invasive-cribriform-carcinoma-breast","invasive-lobular-carcinoma","mucinous-carcinoma-breast"],"cancers":[],"sections":[],"technologies":["endocrine-therapy"],"targets":[],"drugs":["tamoxifen","letrozole"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"breast","burden":"102 of 2,608 carcinomas (3.9 percent) in the Nottingham series that defined its prognosis (Rakha 2010); more often found by screening than other types.","subtypes":["Pure tubular carcinoma (over 90 percent tubules; luminal A)","Mixed tubular carcinoma (tubular with another low-grade component)","Tubular carcinoma with associated ductal carcinoma in situ (about half of cases)"],"biomarkers":["Percentage of tubule formation (over 90 percent)","Oestrogen and progesterone receptor positive, HER2 negative","Node status (usually negative)"],"standardOfCare":[{"setting":"All stages","approach":"Treated as HR-positive breast cancer with the least treatment the parent page allows: surgery, radiotherapy after breast conservation, endocrine therapy; chemotherapy rarely.","refs":["breast-hr-positive","tamoxifen","letrozole","endocrine-therapy"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"breast-cancer"},{"id":"thymoma-type-a-ab","kind":"cancer","name":"Type A and type AB thymoma","aka":["Type A thymoma","Type AB thymoma","Spindle cell thymoma","Mixed thymoma","Atypical type A thymoma","Type A thymoma (spindle cell, indolent, GTF2I mutant)","Type AB thymoma (mixed, indolent, GTF2I mutant)"],"tldr":"Type A and type AB thymoma are the indolent end of thymoma, tumours of the thymus gland made of spindle-shaped epithelial cells (type A) or mixed with lymphocyte-rich areas (type AB), mostly in older adults and driven by a GTF2I mutation. Nine in ten are found at an early stage and almost none come back after complete surgery, so surgery alone is usually the whole treatment.","summary":"The WHO classification of thymic tumours divides thymoma into types A, AB, B1, B2 and B3 (with rare others), and the ITMIG consensus refined the criteria at the A/AB borderland and proposed the term atypical type A thymoma for tumours with increased mitoses or necrosis (Marx 2014). In the worldwide database, type A made up 12 percent and, with type AB, occurred at a higher age (64 and 57 years); 90 percent of type A were stage I or II, and recurrence after resection was 1 to 2 percent for types A and AB against 2 to 7 percent for B1 to B3 (Weis 2015). The GTF2I L424H mutation, characteristic of types A and AB, is recorded on the parent page. Atypical type A components can rarely metastasise, as in a case with lung and brain metastases 10 and 15 years after diagnosis (Journal of Thoracic Disease 2017).\n\nHow it differs from its parent: the parent page covers all thymoma types and their staging; types A and AB are the oldest patients, the earliest stages, the lowest recurrence and the GTF2I-mutant biology, and paraneoplastic myasthenia gravis is less frequent than with the B types.\n\nHow common: about 12 percent (type A) of thymomas, with type AB a further large share (Weis 2015).\n\nTreatment: complete surgical resection; postoperative radiotherapy only for incompletely resected or stage III disease as on the parent page; systemic therapy is rarely needed and follows the parent's platinum-based regimens when it is.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Thymoma","links":[{"label":"NCI PDQ: thymoma and thymic carcinoma treatment","url":"https://www.cancer.gov/types/thymus-cancer/thymoma-thymic-carcinoma"},{"label":"Weis 2015, JTO: the impact of thymoma histotype on prognosis in the ITMIG worldwide database, 4,221 thymomas","url":"https://doi.org/10.1097/jto.0000000000000393"},{"label":"Marx 2014, JTO: ITMIG consensus on the use of the WHO histological classification of thymoma and thymic carcinoma","url":"https://doi.org/10.1097/jto.0000000000000154"},{"label":"Journal of Thoracic Disease 2017: AB thymoma with atypical type A component and delayed lung and brain metastases","url":"https://doi.org/10.21037/jtd.2017.07.95"}],"tags":["subtype-page","wave4","rare"],"related":["thymoma","thymoma-type-b1-b2","thymoma-type-b3","micronodular-thymoma","thymic-epithelial"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"thoracic","burden":"Type A is the least common thymoma at 12 percent of 4,221 thymomas in the ITMIG worldwide database, with type AB also common in Europe and the United States and both rarer in Asia; patients are older (64 and 57 years) than with other thymomas (Weis 2015).","subtypes":["Type A thymoma (spindle or oval cells, few lymphocytes; 90 percent stage I or II)","Atypical type A thymoma (increased mitoses or necrosis; rare metastasis)","Type AB thymoma (type A areas mixed with lymphocyte-rich type B-like areas)"],"biomarkers":["WHO histotype on ITMIG criteria","GTF2I L424H mutation","Masaoka-Koga or TNM stage and resection status","Acetylcholine receptor antibodies (myasthenia gravis)"],"standardOfCare":[{"setting":"All stages","approach":"Complete resection; postoperative radiotherapy for incomplete resection or stage III as on the parent page; systemic therapy rarely needed.","refs":["thymoma","thymic-epithelial"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"thymoma"},{"id":"thymoma-type-b1-b2","kind":"cancer","name":"Type B1 and type B2 thymoma","aka":["Type B1 thymoma","Type B2 thymoma","Lymphocyte-rich thymoma","Cortical thymoma","Type B1 thymoma (lymphocyte-rich)"],"tldr":"Type B1 and type B2 thymoma are thymus gland tumours in which the epithelial tumour cells are mixed with many immature lymphocytes, resembling the normal thymic cortex; B2 is the commonest thymoma of all. They are strongly linked to myasthenia gravis, are usually cured by surgery, and get radiotherapy when they have grown beyond the gland or could not be fully removed.","summary":"Types B1 and B2 sit between the indolent A and AB thymomas and the aggressive B3 in the WHO classification; B1 resembles normal thymic cortex with sparse epithelial cells and B2 has clusters of epithelial cells among the lymphocytes, and the ITMIG consensus set criteria for distinguishing B1, B2 and B3 (Marx 2014). In the worldwide database type B2 was the most common histotype (28 percent), the B types presented at higher stages than A and AB, and recurrence after resection for B1 to B3 was 2 to 7 percent, with age, stage and resection status the multivariate predictors of survival and histology affecting recurrence (Weis 2015). Myasthenia gravis and other paraneoplastic autoimmunity are most frequent with the B types.\n\nHow it differs from its parent: the lymphocyte-rich histology can be mistaken for lymphoma or normal thymus on biopsy, the association with myasthenia gravis shapes perioperative care, and the B types more often present at Masaoka-Koga stage II or III than types A and AB.\n\nHow common: B2 is 28 percent of thymomas, the largest share (Weis 2015).\n\nTreatment: complete resection with or without preoperative therapy for locally advanced disease; postoperative radiotherapy for stage III or incomplete resection; platinum-based chemotherapy (cisplatin, doxorubicin, cyclophosphamide) for unresectable or metastatic disease, as on the parent page; myasthenia gravis managed jointly with neurology.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Thymoma","links":[{"label":"NCI PDQ: thymoma and thymic carcinoma treatment","url":"https://www.cancer.gov/types/thymus-cancer/thymoma-thymic-carcinoma"},{"label":"Weis 2015, JTO: the impact of thymoma histotype on prognosis in the ITMIG worldwide database, 4,221 thymomas","url":"https://doi.org/10.1097/jto.0000000000000393"},{"label":"Marx 2014, JTO: ITMIG consensus on the use of the WHO histological classification of thymoma and thymic carcinoma","url":"https://doi.org/10.1097/jto.0000000000000154"}],"tags":["subtype-page","wave4","rare"],"related":["thymoma","thymoma-type-a-ab","thymoma-type-b3","micronodular-thymoma","thymic-epithelial"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["cisplatin","doxorubicin","cyclophosphamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"thoracic","burden":"Type B2 is the most common thymoma at 28 percent of 4,221 thymomas in the ITMIG worldwide database; B1 and B2 are more frequent in Asia than types A and AB (Weis 2015).","subtypes":["Type B1 thymoma (lymphocyte-rich, organoid; indolent)","Type B2 thymoma (epithelial cell clusters among lymphocytes; the commonest thymoma)","Type B1 or B2 thymoma with myasthenia gravis","Combined B2/B3 thymoma"],"biomarkers":["WHO histotype on ITMIG criteria (epithelial cell density)","Masaoka-Koga or TNM stage and resection status","Acetylcholine receptor antibodies (myasthenia gravis)","Terminal deoxynucleotidyl transferase-positive immature T cells (distinguishes from lymphoma)"],"standardOfCare":[{"setting":"All stages","approach":"Complete resection; postoperative radiotherapy for stage III or incomplete resection; platinum-based chemotherapy for unresectable or metastatic disease, as on the parent page.","refs":["thymoma","cisplatin","doxorubicin","cyclophosphamide"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"thymoma"},{"id":"thymoma-type-b3","kind":"cancer","name":"Type B3 thymoma","aka":["Type B3 thymoma (epithelial-rich, the most aggressive thymoma)","Well-differentiated thymic carcinoma (historical term)","Epithelial thymoma","Atypical thymoma"],"tldr":"Type B3 thymoma is the most aggressive thymoma, a thymus gland tumour made mostly of epithelial cells with few lymphocytes, sitting at the border with thymic carcinoma. More than a third have already grown into the chest structures when found, so it is treated with surgery plus radiotherapy, and chemotherapy before surgery when it is too large to remove at once.","summary":"Type B3 thymoma is the epithelial-rich thymoma of the WHO classification, once called well-differentiated thymic carcinoma; the ITMIG consensus set criteria separating B3 from B2 and from thymic carcinoma, the latter distinguished by frank cytological atypia, loss of thymus-like features and expression of CD5 and CD117 (Marx 2014). In the worldwide database, 38 percent of type B3 thymomas were stage III at diagnosis, the highest of any type, and the B1 to B3 group recurred in 2 to 7 percent after resection against 1 to 2 percent for A and AB (Weis 2015).\n\nHow it differs from its parent: it is the thymoma most likely to invade the pericardium, great vessels and lung and to recur, so it is the one where preoperative chemotherapy, radical surgery with vascular reconstruction and postoperative radiotherapy are most often combined, and the one that must be separated from thymic carcinoma, which has its own page and its own drugs.\n\nHow common: the ITMIG database gives its stage distribution but not its share in the abstract read; it is less common than B2 (Weis 2015).\n\nTreatment: complete resection when feasible with postoperative radiotherapy for stage II to III disease or incomplete resection; induction platinum-based chemotherapy (cisplatin, doxorubicin, cyclophosphamide) for tumours not resectable at presentation, then surgery or radiotherapy; systemic therapy for recurrence as on the parent page.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Thymoma","links":[{"label":"NCI PDQ: thymoma and thymic carcinoma treatment","url":"https://www.cancer.gov/types/thymus-cancer/thymoma-thymic-carcinoma"},{"label":"Weis 2015, JTO: the impact of thymoma histotype on prognosis in the ITMIG worldwide database, 4,221 thymomas","url":"https://doi.org/10.1097/jto.0000000000000393"},{"label":"Marx 2014, JTO: ITMIG consensus on the use of the WHO histological classification of thymoma and thymic carcinoma","url":"https://doi.org/10.1097/jto.0000000000000154"}],"tags":["subtype-page","wave4","rare"],"related":["thymoma","thymoma-type-b1-b2","thymoma-type-a-ab","thymic-carcinoma","thymic-epithelial"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["cisplatin","doxorubicin","cyclophosphamide"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"thoracic","burden":"A minority of thymomas but the one most often advanced: 38 percent of type B3 in the ITMIG worldwide database presented at stage III (Weis 2015).","subtypes":["Type B3 thymoma, encapsulated (stage I to II)","Type B3 thymoma, locally invasive (stage III; 38 percent)","Combined B3 thymoma and thymic carcinoma (classified by the carcinoma component)"],"biomarkers":["WHO histotype on ITMIG criteria; absence of CD5 and CD117 (thymic carcinoma markers)","Masaoka-Koga or TNM stage and resection status","Acetylcholine receptor antibodies (myasthenia gravis)","Ki-67 and mitoses"],"standardOfCare":[{"setting":"All stages","approach":"Resection with postoperative radiotherapy for stage II to III or incomplete resection; induction platinum-based chemotherapy for unresectable tumours; recurrence as on the parent page.","refs":["thymoma","thymic-carcinoma","cisplatin","doxorubicin","cyclophosphamide"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"thymoma"},{"id":"pancreatic-undifferentiated-carcinoma-ogc","kind":"cancer","name":"Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells","aka":["Undifferentiated carcinoma with osteoclast-like giant cells (1.4 percent of resected pancreatic cancers; five-year survival 59 percent)","Osteoclastic giant cell tumour of the pancreas","UC-OGC","Undifferentiated carcinoma with osteoclastic giant cells","Giant cell carcinoma of the pancreas"],"tldr":"Undifferentiated carcinoma with osteoclast-like giant cells is a rare form of pancreatic cancer studded with large bone-eating-type cells that are not themselves cancerous. It grows as a big, well-circumscribed mass, often within a cyst, spreads to nerves and lymph nodes far less often than ordinary pancreatic cancer, and about six in ten patients are alive five years after surgery.","summary":"What it is. A WHO variant of ductal adenocarcinoma (Nagtegaal 2020) in which undifferentiated, often spindled or pleomorphic carcinoma cells are mixed with non-neoplastic osteoclast-like giant cells that express the histiocytic marker CD68; the background spindle and giant carcinoma cells often show p53 and often lack cytokeratin, and osteoid was seen in 12 of 38 tumours (Muraki 2016). A 2021 review sets out its pathology and molecular features and the questions it raises (Luchini 2021). Undifferentiated (anaplastic) carcinoma without giant cells is a separate, aggressive variant that this record does not describe.\n\nHow it differs from its parent. In 38 resected cases against 725 resected ductal adenocarcinomas, the tumours were larger (mean 5.3 against 3.2 cm), nodular with pushing borders, arose in a mucinous cystic or IPMN-type lesion in 8 cases and showed prominent intraductal or intracystic growth in 61 percent; 76 percent also had an invasive ductal or tubular component. Despite their size, perineural invasion (31.6 against 85.5 percent) and nodal metastasis (22.6 against 64.0 percent) were uncommon, and five-year survival was 59.1 percent against 15.7 percent (Muraki 2016).\n\nHow common it is. 1.4 percent of the resected pancreatic cancers reviewed at one centre; no population count is published.\n\nHow it is treated. Resection, with adjuvant chemotherapy by extrapolation from ductal adenocarcinoma; there is no trial. The more protracted course than the literature had assumed is the main lesson of the 2016 series, and it argues for offering surgery even to large tumours.","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Giant-cell_tumor_of_bone","links":[{"label":"Muraki, Am J Surg Pathol 2016: undifferentiated carcinoma with osteoclastic giant cells of the pancreas, 38 cases","url":"https://doi.org/10.1097/pas.0000000000000689"},{"label":"Luchini, Virchows Arch 2021: undifferentiated carcinoma of the pancreas with osteoclast-like giant cells, a review","url":"https://doi.org/10.1007/s00428-021-03021-9"},{"label":"Nagtegaal, Histopathology 2020: the 2019 WHO classification of tumours of the digestive system","url":"https://doi.org/10.1111/his.13975"}],"tags":["gi","pancreatic","subtype-page"],"related":["pancreatic","pancreatic-adenosquamous-carcinoma","mcn-associated-carcinoma","ipmn-associated-carcinoma","undifferentiated-pleomorphic-sarcoma"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","histopathology-ihc"],"targets":["kras","tp53"],"drugs":["folfirinox","gemcitabine-nab-paclitaxel"],"companies":[],"institutions":[],"pathways":["ras-mapk","pancreatic-cancer-signalling","emt"],"terms":["tumour-grade","whipple","resection-margins"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gastrointestinal","burden":"1.4 percent of systematically reviewed resected pancreatic cancers in the largest series (38 of about 2,700 cases); slight female predominance (62.9 percent) and a mean age of 57.9 against 65.0 for ordinary ductal adenocarcinoma.","subtypes":["Undifferentiated carcinoma with osteoclast-like giant cells and an invasive ductal (PDAC) component (76 percent of cases)","Undifferentiated carcinoma with osteoclast-like giant cells arising in a mucinous cystic neoplasm or IPMN","Undifferentiated (anaplastic) carcinoma without giant cells (aggressive; treated as ductal adenocarcinoma)"],"biomarkers":["CD68-positive osteoclast-like giant cells (non-neoplastic) among cytokeratin-poor, p53-positive carcinoma cells","Associated ductal adenocarcinoma component or cystic precursor on histology","KRAS as in ductal adenocarcinoma"],"standardOfCare":[{"setting":"Resectable","approach":"Resection even of large tumours, given the low rates of nodal and perineural spread and the 59 percent five-year survival in the resected series; adjuvant chemotherapy by extrapolation from ductal adenocarcinoma.","refs":["whipple","distal-pancreatectomy","folfirinox"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}},{"setting":"Advanced","approach":"Treated as pancreatic ductal adenocarcinoma: resection with adjuvant chemotherapy when removable, the chemotherapy rows of the parent page when not; the parent record carries the trials.","refs":["folfirinox","gemcitabine-nab-paclitaxel"],"guideline":{"version":"NCCN Guidelines: Pancreatic Adenocarcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455"}}],"stateOfArt":["The 2016 series of 38 cases overturned the assumption that this variant behaves like ductal adenocarcinoma."],"history":[{"year":2016,"title":"Muraki and colleagues report a more protracted course in 38 resected cases","refs":["tumour-grade"]},{"year":2021,"title":"Review of pathology and molecular features (Luchini)","refs":["histopathology-ihc"]}],"pipeline":[],"openProblems":["No trial; adjuvant treatment is extrapolated.","Whether the immune-rich microenvironment makes it a candidate for immunotherapy is unproven."],"parent":"pancreatic"},{"id":"undifferentiated-pleomorphic-sarcoma","kind":"cancer","name":"Undifferentiated pleomorphic sarcoma (UPS)","aka":["UPS","Malignant fibrous histiocytoma (historic)","MFH","Pleomorphic sarcoma, not otherwise specified"],"tldr":"Undifferentiated pleomorphic sarcoma is the diagnosis for a high-grade soft tissue sarcoma whose cells show no recognisable line of differentiation. It is treated with surgery and radiotherapy, with doxorubicin-based chemotherapy for high-risk or spread disease, and it is one of the few sarcomas in which the immunotherapy drug pembrolizumab has clear activity.","summary":"Undifferentiated pleomorphic sarcoma is a diagnosis of exclusion: a genomically complex, high-grade sarcoma with no line of differentiation on histology, immunohistochemistry or molecular testing. It replaced the older label malignant fibrous histiocytoma once many such tumours were reclassified as dedifferentiated liposarcoma, myxofibrosarcoma or pleomorphic leiomyosarcoma. It arises mostly in the deep soft tissues of the limbs in people over 60, less often in the retroperitoneum, and its genome shows widespread copy number change with TP53, RB1, CDKN2A and ATRX loss rather than a driver fusion.\n\nLocalised disease is treated with wide resection and radiotherapy, given preoperatively or postoperatively, following the principles established for extremity sarcoma. In the Italian Sarcoma Group ISG-STS 1001 trial, three cycles of neoadjuvant epirubicin and ifosfamide improved relapse-free and overall survival in high-risk limb and trunk sarcomas, a benefit driven partly by the UPS group, and full-dose anthracycline-ifosfamide is offered to fit patients with large, deep, high-grade tumours. Advanced disease is treated with doxorubicin alone or with ifosfamide, gemcitabine-docetaxel, trabectedin or pazopanib.\n\nUPS stands out among sarcomas for immunotherapy: in the SARC028 phase 2 trial pembrolizumab produced objective responses in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma but almost none in leiomyosarcoma or synovial sarcoma, and the randomised SU2C-SARC032 trial found that pembrolizumab added to preoperative radiotherapy and surgery improved disease-free survival in stage III UPS and dedifferentiated liposarcoma of the limbs. Tertiary lymphoid structures and B-cell-rich immune classes predict who benefits.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Undifferentiated_pleomorphic_sarcoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Undifferentiated_pleomorphic_sarcoma"}],"tags":["subtype-page"],"related":["extremity-soft-tissue-sarcoma","liposarcoma","myxofibrosarcoma","leiomyosarcoma","malignant-peripheral-nerve-sheath-tumour","synovial-sarcoma"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["sarc028"],"people":[],"bottlenecks":[],"keyPapers":["paper-eortc-62012-doxorubicin-ifosfamide-judson-lancet-oncol-2014","paper-esmo-sts-guideline-gronchi-ann-oncol-2021","paper-isg-sts-1001-gronchi-lancet-oncol-2017","paper-sarc028-pembrolizumab-sarcoma-tawbi-lancet-oncol-2017"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"One of the commonest soft tissue sarcomas of older adults, usually a deep, fast-growing mass in the thigh or upper arm; about a third of patients with high-grade limb tumours develop lung metastases despite surgery and radiotherapy.","subtypes":["Undifferentiated pleomorphic sarcoma of the limbs (commonest)","Undifferentiated pleomorphic sarcoma of the trunk and retroperitoneum","Radiation-associated undifferentiated sarcoma","Undifferentiated round cell and spindle cell sarcomas (separate WHO categories, fusion-defined)"],"biomarkers":["FNCLCC grade, size and depth (risk)","Exclusion of specific differentiation by immunohistochemistry and molecular testing","TP53, RB1, CDKN2A and ATRX alterations","Tertiary lymphoid structures and B-cell-rich immune class (immunotherapy response)"],"standardOfCare":[{"setting":"Localised, limb or trunk","approach":"Wide resection with preoperative or postoperative radiotherapy; neoadjuvant anthracycline-ifosfamide for large, deep, high-grade tumours in fit patients (ISG-STS 1001).","refs":["limb-salvage-surgery","imrt-igrt","isg-sts-1001","doxorubicin","ifosfamide","fnclcc-grade"]},{"setting":"Advanced, first line","approach":"Doxorubicin alone or doxorubicin plus ifosfamide (EORTC 62012) when response matters.","refs":["doxorubicin","ifosfamide","eortc-62012"]},{"setting":"Later lines","approach":"Gemcitabine-docetaxel, trabectedin, pazopanib; pembrolizumab in trials or off label after SARC028.","refs":["gemcitabine","docetaxel","trabectedin","pazopanib","pembrolizumab","checkpoint-inhibitor"]}],"stateOfArt":["SARC028 identified UPS as the sarcoma with the clearest response to PD-1 blockade.","SU2C-SARC032 showed pembrolizumab with preoperative radiotherapy improves disease-free survival in stage III limb UPS and dedifferentiated liposarcoma.","Immune classification by B-cell signatures is being tested to select patients for immunotherapy."],"history":[{"year":1964,"title":"O'Brien and Stout describe malignant fibrous histiocytoma","refs":[]},{"year":2002,"title":"WHO abandons malignant fibrous histiocytoma as a diagnosis in favour of undifferentiated pleomorphic sarcoma","refs":[]},{"year":2014,"title":"EORTC 62012: doxorubicin plus ifosfamide improves response and progression-free but not overall survival","refs":["eortc-62012"]},{"year":2017,"title":"ISG-STS 1001: neoadjuvant epirubicin-ifosfamide improves survival in high-risk limb sarcoma","refs":["isg-sts-1001"]},{"year":2017,"title":"SARC028: pembrolizumab responses concentrated in UPS and dedifferentiated liposarcoma","refs":["pembrolizumab"]},{"year":2024,"title":"SU2C-SARC032: pembrolizumab plus preoperative radiotherapy improves disease-free survival","refs":["pembrolizumab","imrt-igrt"]}],"pipeline":["pembrolizumab","checkpoint-inhibitor","isg-sts-1001"],"openProblems":["No molecular driver to target; the diagnosis is defined by what the tumour is not.","A third of high-grade limb tumours still metastasise to the lungs.","Which patients gain from neoadjuvant chemotherapy versus immunotherapy is not settled."],"parent":"sarcoma"},{"id":"stage-iii-unresectable-nsclc","kind":"cancer","name":"Unresectable stage III non-small-cell lung cancer","aka":["Locally advanced non-small-cell lung cancer","Inoperable stage III NSCLC","Stage IIIB and IIIC NSCLC"],"tldr":"Stage III lung cancer that cannot be removed is treated with chemotherapy and radiotherapy together, aiming at cure. A year of the immunotherapy antibody durvalumab afterwards raised five-year survival from a third to over 40 percent, and for EGFR-mutated tumours osimertinib after chemoradiation holds the disease for years.","summary":"Concurrent chemoradiation, platinum-based chemotherapy given during six weeks of thoracic radiotherapy to 60 Gy, became the standard for unresectable stage III disease in the 1990s and 2000s after trials showed it beat radiotherapy alone and sequential treatment, at the cost of oesophagitis and pneumonitis. RTOG 0617 (2015) showed that raising the dose to 74 Gy shortened survival, so 60 Gy with intensity-modulated, image-guided delivery remains the norm, with proton therapy under randomised evaluation. Precise staging by PET-CT, brain MRI and mediastinal sampling matters because the group is heterogeneous: some IIIA tumours are resectable after induction therapy, while IIIB and IIIC are not.\n\nPACIFIC (2017) changed the outcome: 713 patients without progression after chemoradiation were randomised to a year of durvalumab or placebo, and progression-free survival rose from 5.6 to 16.8 months, median overall survival from 29.1 to 47.5 months and five-year survival from 33.4 to 42.9 percent. Durvalumab consolidation was approved in February 2018 and adopted worldwide. PACIFIC-2 (2024), which gave durvalumab concurrently with chemoradiation, did not improve on the sequential approach, and trials of pembrolizumab with or without olaparib (KEYLYNK-012) and of other combinations are testing how to build on PACIFIC.\n\nFor EGFR-mutated stage III disease, where durvalumab works poorly, LAURA (2024) showed that osimertinib after chemoradiation extended progression-free survival from 5.6 to 39.1 months (hazard ratio 0.16) and it was approved in September 2024. Open questions are how to reduce pneumonitis when immunotherapy follows radiotherapy, whether ALK and other driver subtypes should also receive targeted consolidation, how to treat patients too frail for concurrent chemoradiation, and whether proton therapy spares the heart enough to lengthen life.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Chemoradiotherapy","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Chemoradiotherapy"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":["resectable-nsclc","pdl1-high-nsclc","egfr-mutant-nsclc","alk-positive-nsclc"],"cancers":[],"sections":[],"technologies":["imrt-igrt","proton-therapy","checkpoint-inhibitor","kinase-inhibitors","pet-ct","cytotoxic-chemotherapy","platinum","hypofractionated-radiotherapy"],"targets":["pdl1","pd1","egfr"],"drugs":["durvalumab","osimertinib","cisplatin","carboplatin","etoposide","pemetrexed","paclitaxel","vinorelbine"],"companies":["astrazeneca","merck","nrg-oncology"],"institutions":[],"pathways":["pd1-checkpoint"],"terms":["chemoradiation","consolidation-therapy","radiation-pneumonitis","ild","tnm-staging","cancer-stage","mediastinum"],"trials":["pacific","laura","nct04380636","pacific-2"],"people":["scott-antonia","david-planchard","wu-yi-long","suresh-ramalingam"],"bottlenecks":[],"keyPapers":["paper-pacific-nejm-2017"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"About a fifth of non-small-cell lung cancers present at stage III, spread to mediastinal nodes or invading adjacent structures but not metastatic; roughly two thirds of these are not resectable. Before immunotherapy fewer than one in five was alive at five years.","subtypes":["Stage IIIA or IIIB adenocarcinoma, unresectable, without a driver (chemoradiation then durvalumab)","Stage III squamous cell carcinoma, unresectable (chemoradiation then durvalumab)","Stage III EGFR-mutated adenocarcinoma (chemoradiation then osimertinib)","Stage III in patients unfit for concurrent chemoradiation (sequential chemoradiation or radiotherapy alone)","Superior sulcus (Pancoast) tumour (chemoradiation then surgery where possible)"],"biomarkers":["TNM stage by PET-CT, brain MRI and mediastinal sampling","EGFR mutation status (osimertinib consolidation instead of durvalumab)","PD-L1 expression (durvalumab licensed for PD-L1 of 1 percent or more in Europe, regardless of PD-L1 in the United States)","Pulmonary function and radiation dose to lung and heart","Circulating tumour DNA after chemoradiation (under study)"],"standardOfCare":[{"setting":"Unresectable stage III, fit, no EGFR mutation","approach":"Concurrent platinum-based chemoradiation to 60 Gy with intensity-modulated radiotherapy, then durvalumab for up to a year in patients without progression (PACIFIC).","refs":["pacific","durvalumab","chemoradiation","imrt-igrt","cisplatin","carboplatin","etoposide","pemetrexed","paclitaxel","consolidation-therapy"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Unresectable stage III, EGFR-mutated","approach":"Concurrent chemoradiation then osimertinib until progression (LAURA).","refs":["laura","osimertinib","chemoradiation"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Unfit for concurrent treatment","approach":"Sequential chemotherapy then radiotherapy, or radiotherapy alone with a hypofractionated schedule; durvalumab afterwards where tolerated.","refs":["imrt-igrt","hypofractionated-radiotherapy","durvalumab","carboplatin","paclitaxel"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Toxicity","approach":"Grading and steroid treatment of radiation and immune pneumonitis; oesophagitis supportive care; heart dose constraints in planning.","refs":["radiation-pneumonitis","ild","imrt-igrt","proton-therapy"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Durvalumab consolidation after chemoradiation (PACIFIC): five-year survival 42.9 percent versus 33.4 percent.","Osimertinib consolidation for EGFR-mutated disease (LAURA): progression-free survival 39.1 versus 5.6 months.","60 Gy with image-guided intensity-modulated radiotherapy as the dose standard; proton therapy under randomised test.","Concurrent immunotherapy with chemoradiation (PACIFIC-2) did not beat the sequential approach."],"history":[{"year":1990,"title":"CALGB 8433: chemotherapy before radiotherapy beats radiotherapy alone in stage III","refs":["cisplatin","chemoradiation"]},{"year":2011,"title":"RTOG 9410 long-term results: concurrent chemoradiation beats sequential","refs":["chemoradiation","nrg-oncology"]},{"year":2015,"title":"RTOG 0617: 74 Gy is worse than 60 Gy; dose escalation abandoned","refs":["imrt-igrt","nrg-oncology"]},{"year":2017,"title":"PACIFIC: durvalumab after chemoradiation extends progression-free and overall survival","refs":["pacific","durvalumab","scott-antonia","paper-pacific-nejm-2017"]},{"year":2022,"title":"PACIFIC five-year update: 42.9 percent alive versus 33.4 percent","refs":["pacific","durvalumab"]},{"year":2024,"title":"LAURA: osimertinib after chemoradiation for EGFR-mutated stage III; PACIFIC-2 concurrent durvalumab negative","refs":["laura","osimertinib","durvalumab"]}],"pipeline":["nct04380636","proton-therapy","intensity-modulated-proton-therapy","laura","ctdna","mrd-testing"],"openProblems":["Pneumonitis from radiotherapy followed by immunotherapy limits treatment in patients with poor lung function.","Whether ALK, RET, ROS1 or other driver subtypes should receive targeted rather than immune consolidation is untested.","Patients too frail for concurrent chemoradiation, a large share, have no evidence-based route to durvalumab.","Proton therapy's heart-sparing has not yet been shown to improve survival."],"parent":"nsclc"},{"id":"urethral","kind":"cancer","name":"Urethral cancer","aka":["Primary urethral carcinoma","Carcinoma of the urethra"],"tldr":"Urethral cancer grows in the tube that carries urine out of the body, with fewer than one case per million people a year. With no randomised trials, it is treated by borrowing from bladder, anal or vulvar cancer depending on cell type and location; chemotherapy with radiotherapy before or instead of surgery lets more patients keep their organs.","summary":"Primary urethral carcinoma is defined by where in the urethra it starts and by the lining it arises from: urothelial carcinoma in the prostatic and proximal urethra, squamous cell carcinoma in the distal (penile or anterior) urethra, and adenocarcinoma, often of Skene or Littre gland origin or arising in a diverticulum, particularly in women. Risk factors include chronic stricture and inflammation, prior radiotherapy, urethral diverticulum and HPV infection for squamous tumours. Presentation is with bleeding, obstruction or a palpable mass, and diagnosis is frequently delayed because symptoms mimic stricture or infection.\n\nThere are no randomised trials. Distal tumours are treated with organ-sparing surgery (partial urethrectomy or distal penectomy in men; distal urethrectomy in women) or with radiotherapy; proximal and locally advanced tumours have historically required radical cystoprostatectomy or anterior exenteration, but the modern approach favours neoadjuvant or definitive platinum-based chemotherapy with or without radiotherapy, extrapolated from bladder cancer (cisplatin-based combinations for urothelial histology) and anal or vulvar cancer (mitomycin or cisplatin with fluorouracil and radiotherapy for squamous histology). Multi-institutional series such as those from the international collaboration on primary urethral carcinoma show better survival with multimodal therapy than with surgery alone, and the EAU has published a dedicated guideline.\n\nThe practical frontier is applying advances from urothelial cancer (enfortumab vedotin with pembrolizumab, checkpoint inhibitors) and HPV-associated squamous cancers to this tiny population through basket trials and registries.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Urethral_cancer","links":[{"label":"NCI PDQ: urethral cancer","url":"https://www.cancer.gov/types/urethral"},{"label":"EAU Guidelines: Primary Urethral Carcinoma","url":"https://uroweb.org/guidelines/primary-urethral-carcinoma"}],"tags":["nci-coverage","rare","genitourinary"],"related":["urothelial","anal","vulvar","penile"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","imrt-igrt","brachytherapy","checkpoint-inhibitor","adc"],"targets":["pd1","nectin4","fgfr3"],"drugs":["cisplatin","gemcitabine-cisplatin","fluorouracil","mitomycin","enfortumab-vedotin","pembrolizumab"],"companies":[],"institutions":[],"pathways":["oncogenic-viruses"],"terms":["hpv-p16","chemoradiation"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"One of the rarest genitourinary cancers, with fewer than one case per million per year in most registries; it is more common in men and in people over 60.","subtypes":["Urothelial carcinoma (proximal and prostatic urethra)","Squamous cell carcinoma (distal urethra; HPV-associated in some)","Adenocarcinoma (including clear cell adenocarcinoma of the female urethra)","Urethral melanoma (very rare)"],"biomarkers":["Histology and site (drives treatment analogy)","Clinical and MRI stage, nodal status","HPV / p16 in squamous tumours","PD-L1 and FGFR3 in urothelial histology (extrapolated from bladder cancer)","Urine cytology and urethroscopy findings"],"standardOfCare":[{"setting":"Distal, localised","approach":"Organ-sparing surgery (distal urethrectomy, partial penectomy) or radiotherapy including brachytherapy.","refs":["brachytherapy"],"guideline":{"version":"EAU Guidelines on Primary Urethral Carcinoma","url":"https://uroweb.org/guidelines/primary-urethral-carcinoma"}},{"setting":"Proximal or locally advanced","approach":"Neoadjuvant platinum-based chemotherapy (or chemoradiation for squamous histology) followed by surgery; definitive chemoradiation as organ-preserving alternative.","refs":["cisplatin","gemcitabine-cisplatin","fluorouracil","mitomycin","imrt-igrt"],"guideline":{"nccn":"Category 2A (in Bladder Cancer guideline, primary carcinoma of the urethra section)","version":"NCCN Guidelines: Bladder Cancer"}},{"setting":"Metastatic","approach":"Treat by histology: urothelial-type regimens (enfortumab vedotin plus pembrolizumab, gemcitabine-cisplatin) or squamous regimens; clinical trials.","refs":["enfortumab-vedotin","pembrolizumab","gemcitabine-cisplatin"]}],"stateOfArt":["Multimodal therapy (chemotherapy with radiotherapy or surgery) has largely replaced radical surgery alone, based on international retrospective collaborations.","Treatment is chosen by histology, borrowing the best evidence from bladder cancer for urothelial tumours and from anal and vulvar cancer for squamous tumours.","The EAU maintains the only dedicated guideline; registries and basket trials are the path to better evidence."],"history":[{"year":1834,"title":"First reported case of urethral carcinoma","note":"Thiaudierre's description in a woman.","refs":[]},{"year":2013,"title":"International collaboration on primary urethral carcinoma","note":"Gakis and colleagues pool multi-institutional data, showing benefit of perioperative chemotherapy and defining the EAU guideline.","refs":[]},{"year":2023,"title":"Enfortumab vedotin plus pembrolizumab approved for urothelial cancer","note":"Applied by extrapolation to urothelial-type urethral carcinoma.","refs":["enfortumab-vedotin","pembrolizumab"]}],"pipeline":["enfortumab-vedotin","pembrolizumab"],"openProblems":["No prospective trials; international registries and inclusion in urothelial and HPV-squamous basket trials are the response.","Late diagnosis mimicking benign stricture; urethroscopy for unexplained stricture or bleeding is the practical fix.","Balancing organ preservation with cure in proximal tumours; chemoradiation series are growing."]},{"id":"urethral-urothelial-carcinoma","kind":"cancer","name":"Urothelial carcinoma of the urethra","aka":["Urethral urothelial carcinoma","Transitional cell carcinoma of the urethra","Urothelial carcinoma (proximal and prostatic urethra)","Prostatic urethral carcinoma"],"tldr":"Urothelial carcinoma of the urethra is the type of urethral cancer that grows from the same lining as bladder cancer, usually in the part of the urethra nearest the bladder or running through the prostate. It is treated by borrowing from bladder cancer: surgery, and chemotherapy with cisplatin before surgery when the disease is advanced.","summary":"Primary urethral carcinoma is classified by the lining it arises from, and urothelial carcinoma arises in the proximal (bulbomembranous and prostatic) urethra in men and the proximal urethra in women, where the lining is urothelium continuous with the bladder (Gakis 2013). In the international collaboration on primary urethral carcinoma, 154 patients from ten referral centres between 1993 and 2012 had urothelial carcinoma in 47 percent, squamous cell carcinoma in 30 percent, adenocarcinoma in 11 percent and mixed or other histology in the rest; clinical nodal stage was the critical predictor of recurrence and survival (Gakis 2016). Two thirds of the patients in that series were men.\n\nHow it differs from its parent: the parent page covers all urethral cancers; this histology is the one closest to bladder cancer in behaviour and treatment, and it can be a first presentation of urothelial carcinoma of the prostatic ducts, which the EAU guideline treats with cystoprostatectomy pathways. A separate urethral urothelial carcinoma must also be distinguished from recurrence in the urethra after cystectomy for bladder cancer, which is staged as bladder disease.\n\nHow common: fewer than one case per million a year for all urethral cancer (parent page; Derksen 2013 gives 0.7 per million women in the Netherlands), and no registry counts the urothelial type alone.\n\nTreatment follows the EAU guideline for the parent, with no randomised trial in this histology: urethra-sparing surgery for distal and superficial disease, and for locally advanced proximal disease cisplatin-based chemotherapy before surgery, borrowed from bladder cancer, with radiotherapy as an alternative; metastatic disease is treated as urothelial cancer of the bladder, so the enfortumab vedotin and pembrolizumab regimens linked from the parent page apply (EAU Guidelines: primary urethral carcinoma).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Urethral_cancer","links":[{"label":"NCI PDQ: urethral cancer treatment","url":"https://www.cancer.gov/types/urethral/patient/urethral-treatment-pdq"},{"label":"EAU Guidelines: primary urethral carcinoma","url":"https://uroweb.org/guidelines/primary-urethral-carcinoma"},{"label":"Gakis 2013, European Urology: EAU guidelines on primary urethral carcinoma","url":"https://doi.org/10.1016/j.eururo.2013.03.044"},{"label":"Gakis 2016, World J Urol: international collaboration on primary urethral carcinoma, 154 patients","url":"https://doi.org/10.1007/s00345-015-1583-7"},{"label":"Visser 2012, Eur J Cancer: incidence and survival of rare urogenital cancers in Europe (RARECARE)","url":"https://doi.org/10.1016/j.ejca.2011.10.031"}],"tags":["subtype-page","wave4","rare"],"related":["urethral","urethral-squamous-cell-carcinoma","urethral-adenocarcinoma","urothelial","non-muscle-invasive-bladder-cancer","urethral-melanoma"],"cancers":[],"sections":[],"technologies":[],"targets":["nectin4","fgfr3","pd1"],"drugs":["gemcitabine-cisplatin","cisplatin","enfortumab-vedotin","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"The commonest histology of primary urethral carcinoma: 72 of 154 patients (47 percent) in the international collaboration's ten-centre series, median age 66 (Gakis 2016). Urethral cancer as a whole affects about 650 people a year in the European Union (Visser 2012).","subtypes":["Urothelial carcinoma of the prostatic urethra and ducts","Urothelial carcinoma of the bulbomembranous or proximal urethra","Urothelial carcinoma of the female proximal urethra"],"biomarkers":["Clinical nodal stage (the strongest predictor in the international collaboration)","Depth of invasion and location along the urethra","PD-L1, FGFR3 and nectin-4 as in bladder cancer, when systemic therapy is considered"],"standardOfCare":[{"setting":"All stages","approach":"Treated as the parent page describes, borrowing bladder cancer pathways: urethra-sparing surgery when distal, cisplatin-based chemotherapy before surgery or chemoradiation when locally advanced, bladder-cancer systemic therapy when metastatic.","refs":["urethral","urothelial","gemcitabine-cisplatin","enfortumab-vedotin","pembrolizumab"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"urethral"},{"id":"uterine-carcinosarcoma","kind":"cancer","name":"Uterine carcinosarcoma","aka":["Malignant mixed Mullerian tumour","MMMT","Endometrial carcinosarcoma"],"tldr":"Uterine carcinosarcoma is a two-faced cancer with a carcinoma part and a sarcoma-like part that both come from the same faulty epithelial cell. It is treated as a high-grade endometrial cancer, with surgery, carboplatin-paclitaxel and often radiotherapy, and its frequent HER2 expression is opening a route to antibody-drug conjugates.","summary":"Carcinosarcoma contains both a carcinomatous component, usually serous or high-grade endometrioid, and a sarcomatous component, which may resemble fibrosarcoma, leiomyosarcoma or heterologous tissue such as cartilage or skeletal muscle. Sequencing shows that both components share the same TP53, PIK3CA, FBXW7 and PPP2R1A mutations, so the tumour is a carcinoma that has undergone epithelial-to-mesenchymal transition rather than a true sarcoma, and it is classified and staged as an endometrial carcinoma. Almost all are p53-abnormal; a minority are mismatch-repair deficient and a few POLE-ultramutated, and HER2 is expressed or amplified in a substantial minority. Patients are older than average, tamoxifen exposure and prior pelvic radiotherapy are risk factors, and the tumour often presents as a polypoid mass protruding through the cervix.\n\nSurgery with hysterectomy, salpingo-oophorectomy, nodal assessment and omental sampling is followed by chemotherapy for almost every stage. Ifosfamide-paclitaxel had been the standard after GOG-0161, but GOG-0261 showed carboplatin-paclitaxel non-inferior and less toxic, and it is now the regimen of choice. Radiotherapy improves local control and is added for pelvic-confined disease with risk factors, and the ESGO/ESTRO/ESP guideline treats carcinosarcoma as p53-abnormal high-risk disease for adjuvant decisions. RUBY included carcinosarcoma among its histologies, so dostarlimab with chemotherapy is an option in advanced disease, with the largest benefit in the mismatch-repair-deficient minority.\n\nHER2 is the most promising target. The Japanese STATICE trial gave trastuzumab deruxtecan to HER2-expressing carcinosarcoma and reported responses in about half of patients, and DESTINY-PanTumor02 included carcinosarcoma in its endometrial cohort, which underpins the tumour-agnostic approval for HER2 3+ tumours. Trials of WEE1 and ATR inhibitors exploit the p53-null cell cycle, and PARP inhibition is being tested on the same homologous recombination logic as in ovarian cancer. Rarity keeps carcinosarcoma out of most dedicated randomised trials, so its evidence base is borrowed from serous endometrial cancer.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Uterine_carcinosarcoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Uterine_carcinosarcoma"}],"tags":["subtype-page"],"related":["advanced-recurrent-endometrial-cancer","endometrial-nsmp","endometrial-mmr-deficient","endometrial-p53-abnormal","endometrial-pole-ultramutated"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-ruby-nejm-2023","paper-destiny-pantumor02-jco-2024","paper-gog-0261-carcinosarcoma-powell-jco-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"About five percent of uterine cancers but a far larger share of deaths; most patients are older women, half present with disease beyond the uterus, and even stage I tumours recur in a third of cases.","subtypes":["Homologous carcinosarcoma (sarcoma element resembles uterine tissue)","Heterologous carcinosarcoma (cartilage, bone or skeletal muscle elements)","Serous-type carcinoma component (most common, p53-abnormal)","HER2-expressing carcinosarcoma (trastuzumab deruxtecan)","Mismatch-repair-deficient carcinosarcoma (minority, immunotherapy-responsive)","Stage I carcinosarcoma (adjuvant chemotherapy with or without radiotherapy)"],"biomarkers":["p53 immunohistochemistry (abnormal in most)","HER2 immunohistochemistry and in situ hybridisation","MMR immunohistochemistry (deficient in a minority)","POLE (rare, favourable)","Percentage of sarcomatous component and heterologous elements","CA-125"],"standardOfCare":[{"setting":"Surgery","approach":"Hysterectomy with bilateral salpingo-oophorectomy, sentinel node mapping or lymphadenectomy, and omental sampling.","refs":["hysterectomy","sentinel-node","robotic-surgery"]},{"setting":"Adjuvant, all stages","approach":"Carboplatin-paclitaxel (GOG-0261), with pelvic radiotherapy and vaginal brachytherapy for stage I to III disease with risk factors; ifosfamide-paclitaxel is the older alternative.","refs":["carboplatin","paclitaxel","ifosfamide","imrt-igrt","brachytherapy","portec-3"]},{"setting":"Advanced or recurrent","approach":"Carboplatin-paclitaxel with dostarlimab (RUBY included carcinosarcoma); trastuzumab deruxtecan for HER2-expressing disease; lenvatinib-pembrolizumab after platinum.","refs":["dostarlimab","ruby","trastuzumab-deruxtecan","destiny-pantumor02","her2","lenvatinib","pembrolizumab"]}],"stateOfArt":["Genomics reclassified carcinosarcoma from sarcoma to a metaplastic carcinoma, so it follows endometrial cancer guidelines.","GOG-0261 replaced ifosfamide-paclitaxel with carboplatin-paclitaxel.","HER2-directed antibody-drug conjugates are the first targeted therapy to show activity."],"history":[{"year":2007,"title":"GOG-0161: ifosfamide-paclitaxel improves survival over ifosfamide alone","refs":["ifosfamide","paclitaxel"]},{"year":2014,"title":"WHO classifies carcinosarcoma as a metaplastic carcinoma rather than a sarcoma","refs":[]},{"year":2017,"title":"TCGA sequencing confirms a shared clonal origin of both components with frequent TP53 mutation","refs":["tp53"]},{"year":2022,"title":"GOG-0261: carboplatin-paclitaxel non-inferior to ifosfamide-paclitaxel","refs":["carboplatin","paclitaxel"]},{"year":2023,"title":"STATICE: trastuzumab deruxtecan active in HER2-expressing carcinosarcoma","refs":["trastuzumab-deruxtecan"]}],"pipeline":["trastuzumab-deruxtecan","dostarlimab","wee1","atr","idea-her2-adc-serous-endometrial"],"openProblems":["No dedicated randomised trials for a tumour that behaves worse than the serous cancers it is grouped with.","Whether the sarcomatous component needs different drugs.","High relapse rate after apparently complete treatment of stage I disease."],"parent":"endometrial"},{"id":"uterine-sarcoma","kind":"cancer","name":"Uterine sarcoma","aka":["Leiomyosarcoma of the uterus","Endometrial stromal sarcoma","Undifferentiated uterine sarcoma","Uterine LMS","ESS"],"tldr":"Uterine sarcomas are rare cancers of the muscle and supporting tissue of the womb, distinct from the far commoner endometrial cancer. Removing the uterus intact is the main treatment and is followed by observation for stage I disease; low-grade stromal sarcomas respond to hormone-blocking pills, while advanced leiomyosarcoma is treated with doxorubicin and trabectedin.","summary":"Uterine sarcomas comprise leiomyosarcoma (LMS, the majority), low-grade and high-grade endometrial stromal sarcoma (ESS), undifferentiated uterine sarcoma, adenosarcoma, and a growing set of molecularly defined entities: JAZF1-SUZ12 fusions in low-grade ESS, YWHAE-NUTM2 and BCOR alterations in high-grade ESS, and rare NTRK-, ALK- or COL1A1-PDGFB-rearranged uterine sarcomas that have matched targeted drugs. LMS is often diagnosed after hysterectomy or myomectomy for presumed fibroids; power morcellation of an unsuspected LMS disseminates tumour and worsens outcome, which led the FDA to restrict the practice in 2014.\n\nTreatment of localised disease is total hysterectomy with intact removal; oophorectomy is standard for ESS (hormone-sensitive) but optional in premenopausal LMS. Adjuvant chemotherapy did not improve outcomes in the randomised GOG-0277 trial (gemcitabine-docetaxel followed by doxorubicin versus observation, closed early) and adjuvant radiotherapy did not improve survival in EORTC 55874, so observation is standard after complete resection of stage I LMS. For advanced LMS, doxorubicin-based therapy is first line (GeDDiS showed gemcitabine-docetaxel was not superior to doxorubicin; LMS-04 showed doxorubicin plus trabectedin improved progression-free survival over doxorubicin alone), followed by trabectedin, gemcitabine-docetaxel or pazopanib. Low-grade ESS is treated with aromatase inhibitors or progestins, not chemotherapy, and estrogen must be avoided.\n\nThe frontier is molecular: fusion-directed therapy for NTRK and ALK cases, and trials of PARP inhibitors and immunotherapy in the subset of LMS with homologous recombination deficiency or high mutation burden.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Uterine_sarcoma","links":[{"label":"NCI PDQ: uterine sarcoma","url":"https://www.cancer.gov/types/uterine/patient/uterine-sarcoma-treatment-pdq"},{"label":"NCCN Uterine Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1473"},{"label":"LMS-04 (Lancet Oncol 2022)","url":"https://doi.org/10.1016/S1470-2045(22)00380-1"},{"label":"GeDDiS (Lancet Oncol 2017)","url":"https://doi.org/10.1016/S1470-2045(17)30622-8"}],"tags":["nci-coverage","rare","gynaecologic","sarcoma"],"related":["leiomyosarcoma","retroperitoneal-sarcoma","liposarcoma","pecoma"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","endocrine-therapy","kinase-inhibitors","mri"],"targets":["estrogen-receptor","ntrk","alk","parp"],"drugs":["doxorubicin","trabectedin","gemcitabine","docetaxel","pazopanib","eribulin","letrozole","megestrol-progestins","larotrectinib","entrectinib","crizotinib"],"companies":[],"institutions":[],"pathways":["er-signaling","homologous-recombination-repair"],"terms":["hysterectomy","rare-cancers"],"trials":["nct06088290"],"people":[],"bottlenecks":["b-rare-cancers"],"keyPapers":["paper-seddon-lancet-oncol"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"About 3 to 4 percent of uterine cancers; leiomyosarcoma is the most common type, typically diagnosed in women in their fifties, often unexpectedly after surgery for presumed fibroids.","subtypes":["Uterine leiomyosarcoma","Low-grade endometrial stromal sarcoma (JAZF1-SUZ12)","High-grade endometrial stromal sarcoma (YWHAE-NUTM2, BCOR)","Undifferentiated uterine sarcoma","Adenosarcoma","NTRK-, ALK- or PDGFB-rearranged uterine sarcoma"],"biomarkers":["Histological subtype and mitotic count","Estrogen and progesterone receptor status (ESS, some LMS)","Fusion testing: JAZF1, YWHAE, BCOR, NTRK, ALK","Homologous recombination deficiency and BRCA alterations (subset of LMS)","Stage and whether the tumour was morcellated"],"standardOfCare":[{"setting":"Localised, any subtype","approach":"Total hysterectomy with intact removal (no morcellation); bilateral salpingo-oophorectomy for ESS; observation after complete resection of stage I LMS because adjuvant chemotherapy (GOG-0277) and radiotherapy (EORTC 55874) did not improve survival.","refs":["hysterectomy"],"guideline":{"nccn":"Category 2A","version":"NCCN Uterine Neoplasms; ESGO-EURACAN-GCIG guideline","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1473"}},{"setting":"Advanced or recurrent leiomyosarcoma","approach":"Doxorubicin alone or with trabectedin (LMS-04); gemcitabine-docetaxel; trabectedin, pazopanib or eribulin in later lines.","refs":["doxorubicin","trabectedin","gemcitabine","docetaxel","pazopanib","eribulin"],"guideline":{"nccn":"Category 2A","version":"NCCN Uterine Neoplasms"}},{"setting":"Low-grade endometrial stromal sarcoma","approach":"Aromatase inhibitor (letrozole) or progestin; avoid estrogen and tamoxifen; surgery for resectable recurrence.","refs":["letrozole","megestrol-progestins","endocrine-therapy"]},{"setting":"Fusion-driven sarcoma","approach":"Larotrectinib or entrectinib for NTRK fusions, crizotinib or alectinib for ALK, imatinib for COL1A1-PDGFB.","refs":["larotrectinib","entrectinib","crizotinib","imatinib"]}],"stateOfArt":["Molecular reclassification (JAZF1, YWHAE, BCOR, NTRK, ALK) has split what was one histology into entities with different behaviour and, for some, matched drugs.","Two randomised trials showed that adjuvant chemotherapy and radiotherapy do not help after complete resection, sparing patients toxicity: observation is the evidence-based standard.","LMS-04 established doxorubicin plus trabectedin as a first-line option for advanced leiomyosarcoma.","Avoiding morcellation of unsuspected sarcomas changed gynaecological surgery practice worldwide after 2014."],"history":[{"year":2008,"title":"EORTC 55874: adjuvant pelvic radiotherapy does not improve survival in uterine sarcoma","refs":[]},{"year":2012,"title":"JAZF1-SUZ12 and YWHAE-NUTM2 fusions define low- and high-grade ESS","note":"Lee and colleagues; earlier Koontz 2001 for JAZF1.","refs":[]},{"year":2014,"title":"FDA warns against power morcellation","note":"Unsuspected uterine sarcoma disseminated by morcellation during fibroid surgery.","refs":[]},{"year":2017,"title":"GeDDiS: gemcitabine-docetaxel not superior to doxorubicin","note":"Seddon and colleagues, Lancet Oncol; doxorubicin retained as first line.","refs":["doxorubicin"]},{"year":2018,"title":"GOG-0277 closed early","note":"Adjuvant chemotherapy for stage I LMS did not improve outcomes; observation is standard.","refs":["gemcitabine","docetaxel"]},{"year":2022,"title":"LMS-04: doxorubicin plus trabectedin improves progression-free survival","note":"Pautier and colleagues, Lancet Oncol.","refs":["doxorubicin","trabectedin"]}],"pipeline":["trabectedin","larotrectinib","pazopanib"],"openProblems":["Preoperative distinction of leiomyosarcoma from fibroids: MRI and LDH criteria and imaging AI are under study.","Advanced LMS remains chemoresistant after two lines: PARP inhibitors for the HRD subset and antibody-drug conjugates are in trials.","High-grade ESS and undifferentiated sarcoma have no proven standard beyond anthracycline.","Rarity limits randomised evidence: international sarcoma consortia are pooling trials."],"parent":"sarcoma"},{"id":"uveal-melanoma","kind":"cancer","name":"Uveal melanoma","aka":["Ocular melanoma","Choroidal melanoma","Intraocular Melanoma"],"tldr":"A melanoma inside the eye that is biologically unrelated to skin melanoma: different mutations, no response to standard immunotherapy, and a tendency to spread to the liver years later. Tebentafusp is the first drug ever to extend survival in the metastatic disease.","summary":"Uveal melanoma arises from melanocytes of the choroid, ciliary body or iris and is driven by GNAQ/GNA11 (or CYSLTR2/PLCB4) mutations activating Gαq signalling, with metastatic risk set by BAP1 loss and monosomy 3 (gene-expression class 2, PRAME expression) versus SF3B1 and EIF1AX mutations (lower risk). The primary tumour is controlled by plaque brachytherapy or proton beam in most cases (COMS showed equivalence to enucleation), but about half of patients relapse, typically in the liver, with a median survival historically under a year.\n\nUnlike cutaneous melanoma, the tumour mutational burden is low and checkpoint inhibitors give response rates around 5%. Tebentafusp, a gp100×CD3 ImmTAC restricted to HLA-A*02:01, was the first therapy to improve overall survival in metastatic uveal melanoma (IMCgp100-202, 2021; approved 2022). Liver-directed therapy (percutaneous hepatic perfusion with melphalan, approved 2023 as Hepzato; radioembolisation; resection) controls hepatic disease. Darovasertib (PKC inhibitor) with crizotinib is in phase 2/3 in metastatic and neoadjuvant settings.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Uveal_melanoma","links":[{"label":"NCCN Guidelines: Uveal Melanoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1488"},{"label":"Tebentafusp IMCgp100-202 (NEJM 2021)","url":"https://doi.org/10.1056/NEJMoa2103485"},{"label":"Ocular Melanoma Foundation","url":"https://ocularmelanoma.org/"}],"tags":["gap-fill","skin","eye","rare"],"related":["mucosal-melanoma","acral-melanoma","advanced-melanoma"],"cancers":[],"sections":[],"technologies":["t-cell-engager","brachytherapy","proton-therapy","percutaneous-hepatic-perfusion","radioembolisation-tare","mri"],"targets":["gp100","cd3","pd1","ctla4","prame"],"drugs":["tebentafusp","melphalan","ipilimumab","nivolumab","brenetafusp"],"companies":["immunocore","bioinvent-international","aura-biosciences","ionctura"],"institutions":[],"pathways":["ras-mapk"],"terms":["hla-a02-restriction","crs","uveal-melanoma-prognostic-markers","bap1-loss","sf3b1-mutation"],"trials":["nct07804186","nct07015190","nct06581406","nct05022901","nct05987332","nct06007690"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["pigment-cell-and-melanoma-research"],"dependsOn":[],"notes":[],"group":"skin","burden":"About 5-7 per million per year (the most common primary eye cancer in adults); half of patients eventually develop metastases, almost always in the liver.","subtypes":["Choroidal melanoma (~90%)","Ciliary body melanoma","Iris melanoma (best prognosis)","GEP class 1A/1B (low risk) vs class 2 (high risk)","BAP1-mutant / monosomy 3 (high metastatic risk)"],"biomarkers":["GNAQ / GNA11 mutations","BAP1 loss and monosomy 3","SF3B1, EIF1AX (lower risk)","Gene-expression profile (DecisionDx-UM class 1/2) and PRAME","HLA-A*02:01 (tebentafusp eligibility)","Liver MRI surveillance"],"standardOfCare":[{"setting":"Primary tumour","approach":"Plaque brachytherapy (I-125 or Ru-106) or proton beam radiotherapy for most; enucleation for large tumours; prognostic biopsy for GEP/chromosome 3.","refs":["brachytherapy","proton-therapy"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Uveal Melanoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1488"}},{"setting":"Surveillance","approach":"Risk-adapted liver imaging (MRI/ultrasound) every 6-12 months for high-risk GEP class 2 / monosomy 3; no proven adjuvant therapy.","refs":["mri"]},{"setting":"Metastatic, HLA-A*02:01-positive","approach":"Tebentafusp weekly (OS 21.7 vs 16.0 months vs investigator's choice); manage cytokine release and rash.","refs":["tebentafusp"],"guideline":{"nccn":"Category 1","esmoMcbs":"4","version":"NCCN Guidelines: Uveal Melanoma"}},{"setting":"Metastatic, HLA-A*02:01-negative or liver-dominant","approach":"Percutaneous hepatic perfusion with melphalan (FOCUS trial; approved 2023), radioembolisation, hepatic resection; ipilimumab-nivolumab (~15% response); clinical trials (darovasertib-crizotinib).","refs":["percutaneous-hepatic-perfusion","melphalan","radioembolisation-tare","ipilimumab","nivolumab"]}],"stateOfArt":["Tebentafusp is the first TCR-based bispecific approved in any cancer and the first drug to improve survival in metastatic uveal melanoma.","Liver-directed therapy has a randomised trial (FOCUS) behind percutaneous hepatic perfusion.","Gene-expression profiling reliably separates patients who will and will not metastasise, but there is still no adjuvant therapy that helps them.","Gαq-pathway inhibition (darovasertib ± crizotinib) is the leading targeted strategy."],"history":[{"year":2001,"title":"COMS: brachytherapy equals enucleation for medium tumours","refs":["brachytherapy"]},{"year":2004,"title":"Gene-expression classes 1 and 2 predict metastasis (Onken, Harbour)","refs":[]},{"year":2009,"title":"GNAQ mutations discovered (Van Raamsdonk); GNA11 in 2010","refs":[]},{"year":2010,"title":"BAP1 loss drives metastasis (Harbour, Science)","refs":[]},{"year":2021,"title":"Tebentafusp improves overall survival (NEJM)","refs":["tebentafusp"]},{"year":2022,"title":"Tebentafusp approved","note":"FDA January 2022; EMA April 2022.","refs":["tebentafusp"]},{"year":2023,"title":"Percutaneous hepatic perfusion (Hepzato) approved","refs":["percutaneous-hepatic-perfusion","melphalan"]}],"pipeline":["tebentafusp","percutaneous-hepatic-perfusion","brenetafusp","darovasertib"],"openProblems":["Half of patients metastasise with no adjuvant therapy despite accurate prediction.","Tebentafusp only for HLA-A*02:01 (about 45% of white patients, fewer elsewhere) and gives few objective responses despite OS benefit.","Liver-tropic metastasis biology poorly understood.","Vision-preserving local therapy still causes radiation retinopathy."],"parent":"melanoma"},{"id":"vaginal-adenocarcinoma","kind":"cancer","name":"Vaginal adenocarcinoma (including DES-associated clear cell adenocarcinoma)","aka":["Clear cell adenocarcinoma of the vagina","DES-associated vaginal cancer","Vaginal adenocarcinoma","Mesonephric and endometrioid adenocarcinoma of the vagina"],"tldr":"Vaginal adenocarcinoma is a rare glandular form of vaginal cancer, best known through the clear cell type that struck young women whose mothers took the hormone DES in pregnancy. Unlike the common squamous form it is not caused by HPV, it is treated with surgery where possible because it often affects young women, and radiotherapy and platinum chemotherapy are used when it is advanced.","summary":"Adenocarcinoma of the vagina is uncommon and heterogeneous. The clear cell type arises from adenosis, glandular tissue left in the vagina when the Müllerian epithelium fails to be replaced, and in 1971 Arthur Herbst linked a cluster of cases in teenagers and young women in Boston to their mothers' use of diethylstilboestrol (DES) in early pregnancy, the first proof that a drug taken in pregnancy could cause cancer in the child decades later. DES was withdrawn for that use the same year; exposed women carry a lifetime risk of about one in a thousand, most tumours appeared between the ages of 15 and 30, and cases still occur as the cohort ages. Sporadic clear cell, endometrioid, mucinous and mesonephric adenocarcinomas also arise, usually in older women, and any vaginal adenocarcinoma must first be shown not to be a metastasis from the endometrium, cervix, ovary or bowel.\n\nTreatment follows the same stage-based principles as squamous cell carcinoma, but with a greater place for surgery because patients with DES-associated disease were young and fertility and vaginal function mattered: radical vaginectomy or hysterectomy with lymphadenectomy for early upper-vaginal tumours, sometimes with vaginal reconstruction, and radiotherapy with brachytherapy for larger or lower tumours or after surgery. Clear cell tumours spread to lymph nodes early and can recur late, so follow-up is prolonged. Advanced or recurrent disease is treated with platinum-based chemotherapy, extrapolating from clear cell cancers of the ovary and cervix, and immunotherapy is being explored because clear cell carcinomas at other sites respond in a minority. The DES story remains the model for transplacental carcinogenesis and led to lifelong surveillance programmes for exposed daughters.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Vaginal_cancer","links":[{"label":"Herbst 1971 (NEJM)","url":"https://doi.org/10.1056/NEJM197104222841604"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Vaginal_cancer"}],"tags":["subtype-page","gynaecologic"],"related":["vaginal-squamous-cell-carcinoma","vaginal","clear-cell-ovarian-cancer"],"cancers":[],"sections":[],"technologies":["brachytherapy","imrt-igrt","histopathology-ihc","fertility-preservation","colposcopy-excision","mri","pet-ct"],"targets":[],"drugs":["cisplatin","carboplatin","paclitaxel","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":["hpv-status","chemoradiation","lymphadenectomy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-herbst-diethylstilbestrol-vaginal-adenocarcinoma-nejm-1971","paper-figo-cancer-report-cancer-of-the-vagina-ijgo-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"A small minority of vaginal cancers; the clear cell form appeared as an epidemic in young women exposed to diethylstilboestrol before birth between the 1940s and 1971 and is now rare, while adenocarcinomas in older women are usually metastases rather than primaries.","subtypes":["DES-associated clear cell adenocarcinoma of the vagina (young women, adenosis)","Sporadic clear cell adenocarcinoma of the vagina","Endometrioid and mucinous vaginal adenocarcinoma","Mesonephric adenocarcinoma of the vagina","Vaginal metastasis from endometrial, cervical, ovarian or bowel adenocarcinoma (to be excluded)"],"biomarkers":["Prenatal DES exposure history","Vaginal adenosis on examination and biopsy","Immunohistochemistry to separate primary from metastatic adenocarcinoma (PAX8, ER, CDX2, napsin A, HNF1 beta)","HPV and p16 status (usually negative)","FIGO stage (MRI, PET-CT)","Mismatch repair and PD-L1 status (immunotherapy candidacy)"],"standardOfCare":[{"setting":"Diagnosis","approach":"Biopsy with immunohistochemistry to exclude metastasis; MRI and PET-CT staging; DES exposure history.","refs":["histopathology-ihc","mri","pet-ct"],"guideline":{"version":"NCCN Guidelines: Vaginal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1481"}},{"setting":"Early stage","approach":"Radical vaginectomy or radical hysterectomy with lymphadenectomy, with vaginal reconstruction and ovarian preservation where appropriate; adjuvant radiotherapy for close margins or positive nodes.","refs":["lymphadenectomy","fertility-preservation","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Vaginal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1481"}},{"setting":"Locally advanced disease","approach":"External beam radiotherapy with brachytherapy, with concurrent cisplatin by extrapolation from cervical cancer.","refs":["imrt-igrt","brachytherapy","cisplatin","chemoradiation"],"guideline":{"version":"NCCN Guidelines: Vaginal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1481"}},{"setting":"Recurrent or metastatic disease","approach":"Platinum-based chemotherapy (carboplatin and paclitaxel); checkpoint inhibitors for mismatch-repair-deficient or PD-L1-positive tumours; pelvic exenteration for isolated central recurrence.","refs":["carboplatin","paclitaxel","pembrolizumab"],"guideline":{"version":"NCCN Guidelines: Vaginal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1481"}},{"setting":"DES-exposed women","approach":"Lifelong annual gynaecological examination with cytology of the cervix and vagina and colposcopy of adenosis.","refs":["colposcopy-excision"],"guideline":{"version":"NCCN Guidelines: Vaginal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1481"}}],"stateOfArt":["The DES cohort established that prenatal drug exposure can cause cancer decades later and remains under surveillance.","Surgery with reconstruction gives good outcomes in early disease in young women.","Systemic therapy is borrowed from clear cell cancers of other organs."],"history":[{"year":1971,"title":"Herbst links vaginal clear cell adenocarcinoma in young women to prenatal DES exposure; the FDA advises against DES in pregnancy","refs":[]},{"year":1992,"title":"Registry data define the lifetime risk in DES-exposed daughters at about one in a thousand","refs":[]},{"year":2011,"title":"Long-term follow-up of the DES cohort confirms continued excess of clear cell adenocarcinoma and other harms","refs":[]}],"pipeline":["pembrolizumab"],"openProblems":["No trial-based treatment exists; everything is extrapolated from cervical and ovarian cancer.","The natural history of late recurrence in clear cell tumours means decades of follow-up.","DES-exposed women are now in their fifties to seventies and the shape of their late risk is uncertain.","Sporadic adenocarcinomas are so rare that their biology is barely studied."],"parent":"vaginal"},{"id":"vaginal","kind":"cancer","name":"Vaginal cancer","aka":["Vaginal squamous cell carcinoma","Primary vaginal carcinoma","VAIN (vaginal intraepithelial neoplasia; precursor)"],"tldr":"Primary vaginal cancer is rare and mostly caused by HPV, the virus behind cervical cancer. It is treated like cervical cancer, with weekly cisplatin alongside external and internal radiotherapy, which controls most tumours while preserving the organ; HPV vaccination and cervical screening, which also detects vaginal precursors, are steadily reducing it.","summary":"Primary vaginal carcinoma is defined as a tumour confined to the vagina without involvement of the cervix or vulva; tumours touching either are classified as cervical or vulvar. Most are HPV-related squamous cell carcinomas arising from vaginal intraepithelial neoplasia (VAIN), often in women with prior cervical neoplasia or hysterectomy for CIN. Adenocarcinoma is uncommon: clear cell adenocarcinoma in young women was the signature harm of in-utero diethylstilboestrol (DES) exposure between the 1940s and 1971, and the cohort is now ageing out. Melanoma and, in young children, embryonal rhabdomyosarcoma (sarcoma botryoides) complete the differential.\n\nBecause randomised trials are impossible at this rarity, treatment is extrapolated from cervical cancer. Small stage I lesions of the upper vagina can be excised or treated with brachytherapy alone; most patients receive definitive external beam radiotherapy with concurrent weekly cisplatin followed by image-guided brachytherapy, which preserves the vagina and gives local control comparable to cervical cancer series. Radical surgery (vaginectomy, exenteration) is reserved for radiotherapy failures or selected early lesions. Metastatic or recurrent disease is treated with platinum-based chemotherapy and, since 2018 for PD-L1-positive HPV-associated tumours by extension from cervical data, pembrolizumab; the KEYNOTE-A18 chemoradiation-plus-pembrolizumab result in cervical cancer is being extrapolated to locally advanced vaginal cancer. VAIN is treated with laser, topical imiquimod or fluorouracil, or excision, and surveillance after hysterectomy for CIN 3 is recommended.\n\nPrevention rests on HPV vaccination and on cervical screening programmes, which detect VAIN incidentally.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Vaginal_cancer","links":[{"label":"NCI PDQ: vaginal cancer","url":"https://www.cancer.gov/types/vaginal"},{"label":"ESGO / ESTRO / ESP rare gynaecological cancers (vaginal cancer) guidance","url":"https://doi.org/10.1016/j.radonc.2023.109590"},{"label":"NCCN: Vulvar Cancer (includes vaginal cancer principles)","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"},{"label":"SEER: vaginal cancer","url":"https://seer.cancer.gov/statfacts/html/vagina.html"}],"tags":["nci-coverage","rare","gynaecologic","hpv"],"related":["cervical","vulvar","rhabdomyosarcoma","anal"],"cancers":[],"sections":[],"technologies":["brachytherapy","imrt-igrt","cytotoxic-chemotherapy","checkpoint-inhibitor","hpv-vaccine","hpv-testing","colposcopy-excision"],"targets":["pd1","pdl1"],"drugs":["cisplatin","paclitaxel","pembrolizumab","gardasil-9","fluorouracil"],"companies":[],"institutions":[],"pathways":["oncogenic-viruses"],"terms":["hpv-p16","hpv-status","chemoradiation","cin-hsil"],"trials":["keynote-826","keynote-a18","nct04422366","nct05027776"],"people":[],"bottlenecks":["b-rare-cancers","b-prevention-adoption"],"keyPapers":["paper-karius-radiother-oncol"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"About one to two percent of gynaecological cancers; most vaginal tumours are actually spread from the cervix, vulva or endometrium, and true primary vaginal cancer is rare (SEER).","subtypes":["Squamous cell carcinoma (HPV-associated; most)","Adenocarcinoma (including DES-associated clear cell adenocarcinoma)","Vaginal melanoma","Embryonal rhabdomyosarcoma (children; see rhabdomyosarcoma)","VAIN 1 to 3 (precursor)"],"biomarkers":["HPV DNA / p16 IHC","FIGO stage (clinical, MRI and PET-CT)","PD-L1 CPS (checkpoint inhibitor eligibility, extrapolated from cervical cancer)","Prior cervical neoplasia or hysterectomy history","DES exposure history (clear cell adenocarcinoma)"],"standardOfCare":[{"setting":"VAIN 2 to 3","approach":"Laser ablation, topical imiquimod or fluorouracil, or excision; surveillance after treatment of CIN 3 or hysterectomy for CIN.","refs":["hpv-testing","colposcopy-excision","precancer-ablation"],"guideline":{"version":"ASCCP / BSCCP management guidance"}},{"setting":"Stage I, small upper-vaginal lesion","approach":"Wide excision or brachytherapy alone in selected cases.","refs":["brachytherapy"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Vulvar Cancer (vaginal cancer principles) / Cervical Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}},{"setting":"Stage I to IVA, most patients","approach":"External beam radiotherapy with concurrent weekly cisplatin followed by image-guided brachytherapy, extrapolated from cervical cancer.","refs":["cisplatin","imrt-igrt","brachytherapy","chemoradiation"],"guideline":{"version":"ESGO / ESTRO / ESP recommendations; extrapolation from cervical cancer chemoradiation trials","url":"https://doi.org/10.1016/j.radonc.2023.109590"}},{"setting":"Recurrent or metastatic","approach":"Platinum-based chemotherapy; pembrolizumab for PD-L1-positive disease by extension from cervical cancer; salvage exenterative surgery for isolated central recurrence after radiotherapy.","refs":["cisplatin","paclitaxel","pembrolizumab","keynote-826"],"guideline":{"version":"NCCN Guidelines: Cervical Cancer (applied to vaginal cancer)"}}],"stateOfArt":["Chemoradiation with image-guided brachytherapy gives high local control while preserving the vagina; it is the standard by extrapolation from cervical cancer.","Checkpoint inhibitors approved for cervical cancer are being applied to HPV-associated vaginal cancer; dedicated cohorts in HPV-basket trials are recruiting.","HPV vaccination and cervical screening are shrinking the disease; DES-associated clear cell cancers are disappearing as the exposed cohort ages.","Survivorship issues (vaginal stenosis, sexual function, bladder and bowel toxicity) are addressed with dilator programmes and MRI-guided adaptive brachytherapy."],"history":[{"year":1971,"title":"DES linked to vaginal clear cell adenocarcinoma","note":"Herbst and colleagues (NEJM 1971) report the association; DES is withdrawn for pregnancy the same year.","refs":[]},{"year":1999,"title":"Cisplatin chemoradiation becomes the cervical cancer standard","note":"Five randomised trials; the approach is extrapolated to vaginal cancer.","refs":["cisplatin"]},{"year":2006,"title":"HPV vaccine approved","note":"Protects against the HPV types that cause most vaginal, cervical and vulvar cancers.","refs":["hpv-vaccine","gardasil-9"]},{"year":2018,"title":"Pembrolizumab approved for PD-L1-positive cervical cancer","note":"Extended in practice to HPV-associated vaginal cancer.","refs":["pembrolizumab"]},{"year":2023,"title":"ESGO / ESTRO / ESP guidance on rare gynaecological cancers includes vaginal cancer","refs":["brachytherapy"]}],"pipeline":["pembrolizumab","keynote-a18","hpv-vaccine"],"openProblems":["No dedicated randomised trials; HPV-basket immunotherapy trials and international rare-tumour registries are filling the gap.","Optimal brachytherapy technique and dose for vaginal primaries; MRI-guided adaptive brachytherapy series are maturing.","Late toxicity and sexual function after pelvic radiotherapy; survivorship programmes are the response.","Surveillance of women treated for CIN 3 to catch VAIN early."]},{"id":"vaginal-melanoma","kind":"cancer","name":"Vaginal melanoma","aka":["Primary vaginal melanoma","Melanoma of the vagina","Vulvovaginal melanoma (with vulvar melanoma)"],"tldr":"Vaginal melanoma is a very rare, aggressive melanoma of the vaginal lining in older women, usually found late because it is hidden, with the worst outlook of any melanoma site. It is treated with surgery where the tumour can be removed and radiotherapy where it cannot; advanced disease gets the drugs used for mucosal melanoma. Unlike skin melanoma it is as common in black as in white women.","summary":"Vaginal melanoma is a mucosal melanoma listed among the vaginal tumours in the WHO female genital classification and among the vaginal cancer page's types. In SEER data for 1992 to 2005, 125 vaginal melanomas were recorded against 324 vulvar, with age-adjusted incidence of vulvar and vaginal melanoma per million women of 0.87 in black, 0.75 in American Indian, 1.03 in Asian and Pacific Islander, 1.22 in Hispanic and 1.90 in non-Hispanic white women, and a vaginal white to black ratio of 1.02 to 1 (Melanoma Research 2010). Molecular profiling of 14 vaginal and 37 vulvar melanomas found BRAF mutations in 26 percent of vulvovaginal melanomas, more than in other mucosal melanomas, and other targetable alterations (Cancer 2017).\n\nHow it differs from its parent: it is not an HPV-associated carcinoma, so the vaginal cancer page's squamous and adenocarcinoma pathways do not apply; it presents with bleeding or a mass in the lower third of the vagina, spreads early to nodes, lung and liver, and has a five-year survival below that of vulvar melanoma in the literature the sources cite.\n\nHow common: under 1 per million women a year, with no racial gradient (Melanoma Research 2010).\n\nTreatment: wide local excision or, for larger tumours, radical surgery where organ function allows, with radiotherapy as an alternative or adjunct; sentinel node assessment; systemic therapy as on the mucosal melanoma page (checkpoint inhibitors, BRAF and MEK inhibitors for BRAF V600, imatinib for KIT), with trials recommended (Cancer 2017).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Vaginal_cancer","links":[{"label":"NCI PDQ: vaginal cancer treatment","url":"https://www.cancer.gov/types/vaginal/patient/vaginal-treatment-pdq"},{"label":"Melanoma Research 2010: population-based incidence of vulvar and vaginal melanoma by race and ethnicity, SEER 1992 to 2005","url":"https://doi.org/10.1097/cmr.0b013e32833684e8"},{"label":"Cancer 2017: vulvar and vaginal melanoma, molecular analysis of 51 cases against 2,253 non-gynaecological melanomas","url":"https://doi.org/10.1002/cncr.30473"}],"tags":["subtype-page","wave4","rare"],"related":["vaginal","vulvar-melanoma","mucosal-melanoma","melanoma","vaginal-squamous-cell-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":["braf","kit"],"drugs":["nivolumab","pembrolizumab","imatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"Very rare: 125 vaginal melanomas were diagnosed in the US SEER registries over 1992 to 2005, with a white to black incidence ratio of 1.02 to 1, far below the 13 to 17 to 1 of cutaneous melanoma (Melanoma Research 2010).","subtypes":["Vaginal melanoma of the lower third (the usual site; vaginal bleeding)","Vaginal melanoma involving the vulva or urethra (vulvovaginal melanoma)","BRAF-mutated vaginal melanoma","Amelanotic vaginal melanoma (diagnostic pitfall)"],"biomarkers":["Melanocytic markers (S100, SOX10, Melan-A, HMB45)","Tumour thickness and depth of invasion","BRAF, KIT and NRAS mutation testing","Node and distant staging"],"standardOfCare":[{"setting":"All stages","approach":"Excision or radical surgery where feasible, radiotherapy as an alternative or adjunct; systemic therapy as on the mucosal melanoma page; trials recommended.","refs":["vaginal","mucosal-melanoma","nivolumab","pembrolizumab","imatinib"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"vaginal"},{"id":"vaginal-squamous-cell-carcinoma","kind":"cancer","name":"Vaginal squamous cell carcinoma (HPV-associated)","aka":["Primary vaginal squamous cell carcinoma","HPV-related vaginal cancer","Vaginal cancer treated with chemoradiotherapy","VAIN and vaginal squamous carcinoma"],"tldr":"Vaginal squamous cell carcinoma is the commonest form of vaginal cancer, caused by the same HPV infection as cervical cancer and often following earlier cervical disease. It is treated much as cervical cancer is, with radiotherapy, brachytherapy and cisplatin for most stages and surgery only for small upper-vaginal tumours, and it is prevented by HPV vaccination and cervical screening.","summary":"Squamous cell carcinoma makes up most primary vaginal cancers and shares its cause and precursor with cervical cancer: persistent high-risk HPV infection leading to vaginal intraepithelial neoplasia (VAIN), which is commonest at the vaginal vault after hysterectomy for cervical precancer. The strict definition excludes tumours that reach the cervix or vulva, which are classified as cervical or vulvar, and metastases from the cervix, endometrium and bowel outnumber true primaries. Diagnosis is by biopsy at colposcopy, staging is clinical and by MRI and PET-CT under the FIGO system shared with cervical cancer, and p16 confirms HPV association.\n\nBecause the disease is rare, no randomised trial has ever been run in it, and treatment is extrapolated from cervical cancer. High-grade VAIN is treated with laser ablation, excision, topical imiquimod or fluorouracil, or brachytherapy for extensive vault disease. Small stage I tumours of the upper vagina can be removed by radical upper vaginectomy with pelvic lymphadenectomy, but most patients receive external beam radiotherapy to the pelvis and groins followed by brachytherapy, with concurrent weekly cisplatin for stage II and above by analogy with cervical chemoradiotherapy; brachytherapy dose is the strongest determinant of local control. Recurrent or metastatic disease is treated as cervical cancer, with carboplatin and paclitaxel with or without bevacizumab and with pembrolizumab for PD-L1-positive tumours, extrapolating KEYNOTE-826. HPV vaccination and cervical screening prevent the disease, and Chinese vaccine trials list vaginal cancer among their endpoints.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Vaginal_cancer","links":[{"label":"NCCN Vaginal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1481"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Vaginal_cancer"}],"tags":["subtype-page","gynaecologic"],"related":["vaginal-adenocarcinoma","vaginal","locally-advanced-cervical-cancer","hpv-associated-vulvar-cancer"],"cancers":[],"sections":[],"technologies":["brachytherapy","imrt-igrt","checkpoint-inhibitor","hpv-vaccine","hpv-testing","colposcopy-excision","precancer-ablation"],"targets":["pd1","pdl1"],"drugs":["cisplatin","carboplatin","paclitaxel","pembrolizumab","fluorouracil","gardasil-9"],"companies":[],"institutions":[],"pathways":[],"terms":["hpv-p16","hpv-status","chemoradiation","cin-hsil","lymphadenectomy"],"trials":["nct04422366","nct05027776","nct07572396","keynote-826"],"people":[],"bottlenecks":[],"keyPapers":["paper-figo-cancer-report-cancer-of-the-vagina-ijgo-2018","paper-figo-annual-report-carcinoma-of-the-vagina-ijgo-2006"],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"The large majority of primary vaginal cancers, mostly in women over 60, many with a history of cervical precancer or hysterectomy for it; a tumour is called vaginal only when the cervix and vulva are uninvolved.","subtypes":["High-grade vaginal intraepithelial neoplasia (VAIN 2 to 3, precursor, often at the vault after hysterectomy)","Stage I vaginal squamous cell carcinoma (upper vagina, surgery or brachytherapy)","Stage II to IVA vaginal squamous cell carcinoma (chemoradiotherapy with brachytherapy)","HPV-associated vaginal cancer after cervical precancer","Recurrent or metastatic vaginal squamous cell carcinoma (treated as cervical cancer)"],"biomarkers":["HPV DNA and p16 immunohistochemistry","FIGO stage (clinical, MRI, PET-CT)","Prior cervical neoplasia or hysterectomy","PD-L1 combined positive score (pembrolizumab, extrapolated)","Brachytherapy dose delivered (local control)"],"standardOfCare":[{"setting":"Precursor (VAIN)","approach":"Laser ablation or excision; topical imiquimod or fluorouracil; brachytherapy for extensive vault disease; HPV vaccination and screening for prevention.","refs":["colposcopy-excision","precancer-ablation","fluorouracil","brachytherapy","hpv-vaccine","gardasil-9","nct04422366","nct05027776"],"guideline":{"version":"NCCN Guidelines: Vaginal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1481"}},{"setting":"Stage I, upper vagina","approach":"Radical upper vaginectomy with pelvic lymphadenectomy, or brachytherapy with or without external beam radiotherapy.","refs":["brachytherapy","lymphadenectomy"],"guideline":{"version":"NCCN Guidelines: Vaginal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1481"}},{"setting":"Stage II to IVA","approach":"External beam radiotherapy to the pelvis (and groins for lower-third tumours) with concurrent weekly cisplatin, followed by brachytherapy, extrapolating from cervical cancer.","refs":["imrt-igrt","brachytherapy","cisplatin","chemoradiation"],"guideline":{"version":"NCCN Guidelines: Vaginal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1481"}},{"setting":"Recurrent or metastatic disease","approach":"Carboplatin and paclitaxel with or without bevacizumab; pembrolizumab for PD-L1-positive tumours (KEYNOTE-826 extrapolated); pelvic exenteration for isolated central recurrence after radiotherapy.","refs":["carboplatin","paclitaxel","pembrolizumab","keynote-826"],"guideline":{"version":"NCCN Guidelines: Vaginal Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1481"}}],"stateOfArt":["Image-guided brachytherapy gives high local control in stage I and II disease.","Chemoradiotherapy is standard for stage II and above by extrapolation from cervical cancer.","HPV vaccination and cervical screening are preventing the disease in younger cohorts."],"history":[{"year":1933,"title":"Vaginal intraepithelial neoplasia first described","refs":[]},{"year":1999,"title":"Cisplatin chemoradiotherapy becomes standard in cervical cancer and is adopted for vaginal cancer","refs":["cisplatin","chemoradiation"]},{"year":2006,"title":"HPV vaccine approved with protection against vaginal precancer","refs":["hpv-vaccine","gardasil-9"]},{"year":2021,"title":"KEYNOTE-826 adds pembrolizumab to first-line therapy in cervical cancer, extrapolated to vaginal cancer","refs":["pembrolizumab","keynote-826"]}],"pipeline":["pembrolizumab","hpv-vaccine","nct07572396"],"openProblems":["No randomised trial has ever been conducted in vaginal cancer.","Radiotherapy causes vaginal stenosis and sexual morbidity that are poorly addressed.","The role of chemotherapy with radiotherapy is assumed, not proven.","Tumours at the vault after hysterectomy are hard to distinguish from recurrent cervical cancer."],"parent":"vaginal"},{"id":"vascular-tumours","kind":"cancer","name":"Vascular tumours (angiosarcoma, epithelioid haemangioendothelioma, kaposiform haemangioendothelioma)","aka":["Childhood vascular tumours","Angiosarcoma","EHE","KHE","Epithelioid haemangioendothelioma","Kaposiform haemangioendothelioma"],"tldr":"Vascular tumours range from angiosarcoma, an aggressive cancer of blood vessel lining cells, to the slow-growing EHE and the infant tumour KHE. Angiosarcoma responds to paclitaxel and, in the sun-damaged scalp form, to immunotherapy; EHE and KHE depend on growth signals that the mTOR blocker sirolimus quiets, and EHE without symptoms is watched.","summary":"Malignant and intermediate vascular tumours share an endothelial origin but differ sharply in behaviour. Angiosarcoma is a high-grade sarcoma arising in sun-damaged skin of the scalp and face of older adults, in the breast after radiotherapy (with MYC amplification), in lymphoedematous limbs (Stewart-Treves) or in viscera; ultraviolet-signature cutaneous tumours carry a high mutation burden. Epithelioid haemangioendothelioma (EHE) is defined by the WWTR1-CAMTA1 fusion (or YAP1-TFE3 in a minority) that constitutively activates the Hippo pathway effector TAZ; it is multifocal in liver, lung and bone and may stay stable for years. Kaposiform haemangioendothelioma (KHE) is an infantile tumour with lymphatic features that can trigger the Kasabach-Merritt phenomenon, a consumptive coagulopathy. Infantile haemangioma, though benign, is on the same NCI page and is treated with propranolol.\n\nAngiosarcoma is treated with wide resection and radiotherapy when localised; paclitaxel (ANGIOTAX) is the preferred first-line chemotherapy, with doxorubicin and gemcitabine-based regimens as alternatives, and propranolol has been added in some series. Checkpoint inhibitors produce responses particularly in cutaneous head and neck angiosarcoma (DART SWOG S1609 cohort, ipilimumab plus nivolumab), consistent with its UV-driven mutation load. EHE is managed by surveillance when asymptomatic, sirolimus when progressive (mTOR inhibition targets the tumour's dependency on PI3K-mTOR signalling downstream of TAZ), and transplant is considered for isolated hepatic disease. KHE with Kasabach-Merritt is treated with sirolimus, which has replaced vincristine and steroids as first line in many centres.\n\nMechanistic frontiers are TEAD inhibitors that block the TAZ-TEAD transcriptional complex in EHE, and immunotherapy combinations for angiosarcoma.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Angiosarcoma","links":[{"label":"NCI PDQ: childhood vascular tumours","url":"https://www.cancer.gov/types/soft-tissue-sarcoma/patient/child-vascular-tumors-treatment-pdq"},{"label":"NCI PDQ: soft tissue sarcoma","url":"https://www.cancer.gov/types/soft-tissue-sarcoma"},{"label":"EHE consensus (ESMO Open 2021)","url":"https://doi.org/10.1016/j.esmoop.2021.100170"},{"label":"DART S1609 angiosarcoma cohort (J Immunother Cancer 2021)","url":"https://doi.org/10.1136/jitc-2021-002990"}],"tags":["nci-coverage","rare","sarcoma","paediatric"],"related":["kaposi-sarcoma","leiomyosarcoma","undifferentiated-pleomorphic-sarcoma"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","checkpoint-inhibitor","imrt-igrt","active-surveillance","liver-transplant-oncology","antiangiogenic"],"targets":["vegf","pd1","ctla4"],"drugs":["paclitaxel","doxorubicin","pazopanib","nivolumab","ipilimumab","vincristine"],"companies":[],"institutions":[],"pathways":["hippo-yap","pi3k-akt-mtor","vegf-angiogenesis","mutagenesis-signatures"],"terms":["rare-cancers"],"trials":["tappas"],"people":[],"bottlenecks":["b-rare-cancers"],"keyPapers":["paper-wagner-j-immunother-cancer"],"journals":[],"dependsOn":[],"notes":[],"group":"sarcoma","burden":"Angiosarcoma accounts for about 1 to 2 percent of soft tissue sarcomas; EHE and KHE are rarer still, with KHE mostly in infants.","subtypes":["Cutaneous angiosarcoma of scalp and face (UV signature)","Radiation-associated breast angiosarcoma (MYC-amplified)","Visceral and cardiac angiosarcoma","Epithelioid haemangioendothelioma (WWTR1-CAMTA1 or YAP1-TFE3)","Kaposiform haemangioendothelioma (infants; Kasabach-Merritt phenomenon)","Infantile haemangioma (benign)"],"biomarkers":["ERG, CD31, CD34 endothelial markers","MYC amplification (radiation-associated angiosarcoma)","WWTR1-CAMTA1 or YAP1-TFE3 fusion (EHE)","Tumour mutational burden and UV signature (cutaneous angiosarcoma)","Platelet count and fibrinogen (Kasabach-Merritt in KHE)"],"standardOfCare":[{"setting":"Localised angiosarcoma","approach":"Wide excision with radiotherapy; margins are often positive because of field spread in the scalp, and neoadjuvant paclitaxel is used to downstage.","refs":["paclitaxel","imrt-igrt"],"guideline":{"nccn":"Category 2A","version":"NCCN Soft Tissue Sarcoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1464"}},{"setting":"Advanced angiosarcoma","approach":"Weekly paclitaxel (ANGIOTAX) or doxorubicin-based chemotherapy; gemcitabine-docetaxel, pazopanib; checkpoint inhibitors for cutaneous head and neck disease (DART cohort) or in trials.","refs":["paclitaxel","doxorubicin","pazopanib","checkpoint-inhibitor","nivolumab","ipilimumab"]},{"setting":"Epithelioid haemangioendothelioma","approach":"Active surveillance if asymptomatic and stable; sirolimus for progressive or symptomatic disease; surgery or liver transplant for isolated hepatic disease.","refs":["active-surveillance","liver-transplant-oncology"],"guideline":{"version":"EHE consensus (Stacchiotti, ESMO Open 2021)","url":"https://doi.org/10.1016/j.esmoop.2021.100170"}},{"setting":"Kaposiform haemangioendothelioma with Kasabach-Merritt","approach":"Sirolimus, with steroids in the acute phase; vincristine as an alternative; platelet transfusion avoided unless bleeding because it feeds the consumptive process.","refs":["vincristine"]}],"stateOfArt":["Immunotherapy has entered angiosarcoma via the UV-signature cutaneous form, where high mutation burden predicts response to ipilimumab plus nivolumab.","EHE has a single fusion driver, WWTR1-CAMTA1, and TEAD inhibitors that block its transcriptional output are the first fusion-directed drugs in trials for the disease.","Sirolimus repositioned from transplant medicine has become the medical treatment of choice for both EHE and KHE.","Propranolol turned infantile haemangioma management from steroids and surgery into a safe oral therapy after a chance observation in 2008."],"history":[{"year":1940,"title":"Stewart and Treves describe lymphangiosarcoma after mastectomy","refs":[]},{"year":1982,"title":"Weiss and Enzinger define epithelioid haemangioendothelioma","refs":[]},{"year":2008,"title":"Propranolol for infantile haemangioma","note":"Léauté-Labrèze and colleagues, NEJM: serendipitous discovery.","refs":[]},{"year":2008,"title":"ANGIOTAX: weekly paclitaxel in angiosarcoma","note":"Penel and colleagues, JCO, phase 2.","refs":["paclitaxel"]},{"year":2011,"title":"WWTR1-CAMTA1 fusion identified in EHE","note":"Tanas and colleagues, Sci Transl Med; Errani and colleagues.","refs":[]},{"year":2018,"title":"Checkpoint inhibitors in cutaneous angiosarcoma","note":"Florou and colleagues; later confirmed in the DART SWOG S1609 angiosarcoma cohort (2021).","refs":["checkpoint-inhibitor"]},{"year":2021,"title":"EHE international consensus","note":"Surveillance first, sirolimus for progression (ESMO Open).","refs":["active-surveillance"]}],"pipeline":["checkpoint-inhibitor","paclitaxel","pazopanib"],"openProblems":["Angiosarcoma outside the UV-exposed skin remains chemoresistant: immunotherapy combinations and antiangiogenic agents are being tested.","EHE: which patients will progress, and TEAD inhibitors as the first fusion-directed therapy.","Radiation-associated breast angiosarcoma incidence after breast-conserving therapy: hyperfractionated re-irradiation and surgery are being studied.","Paediatric vascular tumours are so rare that the evidence base is largely case series; registries are the response."],"parent":"sarcoma"},{"id":"vestibular-schwannoma","kind":"cancer","name":"Vestibular schwannoma (acoustic neuroma)","aka":["Acoustic neuroma","Vestibular schwannoma","NF2-related schwannomatosis","Eighth nerve tumour"],"tldr":"A vestibular schwannoma is a benign brain tumour, a growth on the balance and hearing nerve, deep in the skull. It is rarely dangerous, so many are simply watched with scans; growing tumours are treated with either an operation or a single precisely focused dose of radiation, and people with the inherited condition NF2, who develop tumours on both sides, can be helped by the drug bevacizumab.","summary":"Vestibular schwannoma is a WHO grade 1 nerve sheath tumour arising from Schwann cells of the vestibular division of the eighth cranial nerve in the internal auditory canal and cerebellopontine angle. Sporadic tumours are unilateral and carry somatic NF2 inactivation; bilateral tumours define NF2-related schwannomatosis, the germline condition renamed in 2022 from neurofibromatosis type 2, which also causes meningiomas, spinal schwannomas and ependymomas. Presentation is progressive unilateral hearing loss, tinnitus and imbalance; large tumours compress the brainstem and cause hydrocephalus. Diagnosis is by MRI; biopsy is not needed.\n\nManagement has three arms. Observation with serial MRI is appropriate for small tumours because many do not grow, and hearing can be followed. Microsurgery through retrosigmoid, translabyrinthine or middle fossa approaches removes the tumour with facial nerve monitoring; it is favoured for large tumours with brainstem compression and in younger patients. Stereotactic radiosurgery at marginal doses of about 12 to 13 Gy controls the great majority of small and medium tumours with low facial nerve risk, and fractionated stereotactic radiotherapy or proton therapy is used for larger lesions. Leksell treated the first acoustic neuroma with the Gamma Knife in 1969, and radiosurgery has since displaced surgery for most small growing tumours. Hearing preservation is the outcome that most separates the options and depends on pre-treatment hearing and tumour size.\n\nIn NF2-related schwannomatosis the aim is to preserve hearing and function over a lifetime of multiple tumours. Bevacizumab produced tumour shrinkage and hearing improvement in progressive NF2 tumours (Plotkin and colleagues, NEJM 2009) and is used off label; brigatinib showed activity across NF2-related tumour types in the INTUITT-NF2 platform trial (2024), and cochlear or auditory brainstem implants restore hearing after bilateral loss. Radiosurgery is used more cautiously in NF2 because control rates are lower and there is a small concern about malignant change in a germline-predisposed nerve.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Vestibular_schwannoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Vestibular_schwannoma"},{"label":"Bevacizumab in NF2 vestibular schwannomas (NEJM 2009)","url":"https://doi.org/10.1056/NEJMoa0902579"}],"tags":["subtype-page","cns"],"related":["brain-tumours","meningioma","spinal-cord-tumours","ependymoma","pituitary-tumours"],"cancers":[],"sections":[],"technologies":["radiosurgery-srs","gamma-knife","cyberknife","imrt-igrt","active-surveillance","mri"],"targets":[],"drugs":["bevacizumab","brigatinib"],"companies":[],"institutions":[],"pathways":[],"terms":["stereotactic-radiosurgery"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-plotkin-bevacizumab-nf2-nejm-2009","paper-carlson-link-vestibular-schwannomas-nejm-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"central nervous system","burden":"A benign tumour found in roughly one in a thousand people over a lifetime, presenting with one-sided hearing loss; sporadic tumours are single, while NF2-related schwannomatosis causes bilateral tumours from young adulthood and is the hard form of the disease.","subtypes":["Sporadic unilateral vestibular schwannoma (somatic NF2 loss)","NF2-related schwannomatosis with bilateral vestibular schwannoma","Intracanalicular schwannoma (confined to the internal auditory canal)","Cerebellopontine angle schwannoma with brainstem compression","Cystic vestibular schwannoma (faster growth, less predictable radiosurgery response)"],"biomarkers":["Tumour size and growth on serial MRI (Koos grade)","Pure-tone audiometry and word recognition (hearing class)","Germline NF2 testing when bilateral, young or with other schwannomas or meningiomas","Facial nerve function (House-Brackmann grade) before and after treatment"],"standardOfCare":[{"setting":"Small tumour, stable or good hearing","approach":"Observation with MRI and audiometry, typically yearly; treatment on documented growth or hearing decline.","refs":["active-surveillance","mri"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Growing small or medium tumour","approach":"Stereotactic radiosurgery (Gamma Knife, CyberKnife or linac) at about 12 to 13 Gy, or fractionated stereotactic radiotherapy; microsurgery in younger patients or by preference.","refs":["radiosurgery-srs","gamma-knife","cyberknife","imrt-igrt"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Large tumour with brainstem compression or hydrocephalus","approach":"Microsurgical resection with facial nerve monitoring, sometimes deliberately subtotal followed by radiosurgery to the remnant; shunting for hydrocephalus.","refs":["radiosurgery-srs","mri"],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"NF2-related schwannomatosis, progressive tumour or falling hearing","approach":"Bevacizumab (off label, phase 2 evidence) to shrink tumours and improve hearing; brigatinib on INTUITT-NF2 evidence; hearing rehabilitation with cochlear or auditory brainstem implants; surgery and radiosurgery used selectively.","refs":["bevacizumab","brigatinib","intuitt-nf2"],"guideline":{"version":"NCI PDQ; NF2 consensus guidance"}}],"stateOfArt":["Radiosurgery controls most small vestibular schwannomas with a single outpatient treatment and has displaced surgery as the default for growing small tumours.","Watchful waiting is legitimate first-line management because a large share of tumours never grow.","Bevacizumab and, more recently, brigatinib are the first drugs to shrink NF2-related tumours, turning a surgical disease into one partly managed medically."],"history":[{"year":1894,"title":"Ballance removes an acoustic neuroma","note":"Among the first successful removals of a cerebellopontine angle tumour.","refs":[]},{"year":1917,"title":"Cushing publishes his monograph on acoustic neuromas","refs":[]},{"year":1961,"title":"House introduces the translabyrinthine microsurgical approach","note":"The operating microscope transforms mortality and facial nerve outcomes.","refs":[]},{"year":1969,"title":"Leksell treats the first acoustic neuroma with the Gamma Knife","refs":["gamma-knife","radiosurgery-srs"]},{"year":1993,"title":"NF2 gene cloned","note":"Trofatter and Rouleau identify the merlin tumour suppressor on chromosome 22.","refs":[]},{"year":2009,"title":"Bevacizumab shrinks NF2 vestibular schwannomas and improves hearing","note":"Plotkin and colleagues (NEJM).","refs":["bevacizumab"]},{"year":2022,"title":"Neurofibromatosis type 2 renamed NF2-related schwannomatosis","refs":[]},{"year":2024,"title":"INTUITT-NF2: brigatinib active across NF2-related tumours","note":"Plotkin and colleagues (NEJM) report the first platform trial in the condition.","refs":["brigatinib"]}],"pipeline":["brigatinib","bevacizumab","radiosurgery-srs"],"openProblems":["No approved drug for NF2-related schwannomatosis; bevacizumab is off label and its effect wanes.","Predicting which small tumours will grow, so that the rest can be left alone.","Preserving hearing: each option trades tumour control against hearing and facial nerve function.","Rare malignant transformation after radiosurgery in NF2 is not well quantified."],"parent":"brain-tumours"},{"id":"vipoma","kind":"cancer","name":"VIPoma","aka":["Vasoactive intestinal peptide-secreting tumour","Verner-Morrison syndrome","Pancreatic cholera","WDHA syndrome (watery diarrhoea, hypokalaemia, achlorhydria)"],"tldr":"VIPoma is a very rare pancreatic neuroendocrine tumour that secretes vasoactive intestinal peptide, causing litres of watery diarrhoea a day with dangerous loss of potassium. Most have spread to the liver by diagnosis. Fluid replacement and somatostatin analogues control the diarrhoea, surgery cures the few caught early, and the usual neuroendocrine tumour treatments are used for spread.","summary":"VIPoma is a functioning pancreatic neuroendocrine tumour secreting vasoactive intestinal peptide, producing the Verner-Morrison syndrome of watery diarrhoea, hypokalaemia and achlorhydria (Pancreatology 2021). In the French GTE series of 22 patients with strictly confirmed diagnoses, tumours were mostly metastatic (77 percent) and grade 2 (83 percent), median follow-up was 78.2 months, surgical excision of non-metastatic tumours controlled the secretory syndrome, and the antisecretory (over 50 percent fall in bowel movements) and antitumour efficacy of each treatment received was recorded (Pancreatology 2021).\n\nHow it differs from its parent: the emergency is metabolic rather than oncological; secretory diarrhoea persists during fasting and can cause renal failure and arrhythmia, so rehydration and octreotide come before any tumour-directed treatment.\n\nHow common: no registry figure in the sources read; the functioning tumours are a minority of pancreatic neuroendocrine tumours.\n\nTreatment: intravenous fluids and potassium; somatostatin analogues for the syndrome; resection for localised disease; the parent page's pathways (everolimus, sunitinib, peptide receptor radionuclide therapy, liver-directed therapy, chemotherapy for grade 3) for metastatic disease, with the GTE series as the evidence on antisecretory efficacy (Pancreatology 2021).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/VIPoma","links":[{"label":"NCI PDQ: pancreatic neuroendocrine (islet cell) tumour treatment","url":"https://www.cancer.gov/types/pancreatic/neuroendocrine-tumors/treatment"},{"label":"Pancreatology 2021: efficacy of treatments for VIPoma, French GTE multicentre series of 22 patients","url":"https://doi.org/10.1016/j.pan.2021.08.001"}],"tags":["subtype-page","wave4","rare"],"related":["pancreatic-net","glucagonoma","somatostatinoma","men1-syndrome","neuroendocrine"],"cancers":[],"sections":[],"technologies":["prrt"],"targets":[],"drugs":["everolimus","sunitinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"Very rare and life-threatening: seven French expert centres treated 22 patients between 1990 and 2016, 77 percent with metastatic disease and 83 percent grade 2 (Pancreatology 2021). No registry figure is in the sources read.","subtypes":["Pancreatic VIPoma, a functioning pancreatic neuroendocrine tumour (the usual site in adults)","Extrapancreatic VIP-secreting tumours (neurogenic tumours in children)","MEN1-associated VIPoma"],"biomarkers":["Plasma vasoactive intestinal peptide","Serum potassium and bicarbonate; stool volume","Chromogranin A; WHO grade (Ki-67)","Somatostatin receptor imaging"],"standardOfCare":[{"setting":"All cases","approach":"Rehydration and potassium; somatostatin analogues for the syndrome; resection when localised; the parent page's pathways for metastatic disease.","refs":["pancreatic-net","everolimus","sunitinib","prrt"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"pancreatic-net"},{"id":"vulvar","kind":"cancer","name":"Vulvar cancer","aka":[],"tldr":"An uncommon cancer of the external genitalia with two distinct causes: HPV infection in younger women and chronic skin inflammation in older women. Surgery is the mainstay, and sentinel-node biopsy has made it far less mutilating.","summary":"Vulvar squamous cell carcinoma has two pathways: HPV-associated (usual-type VIN, p16-positive, younger patients, better prognosis) and HPV-independent (differentiated VIN arising in lichen sclerosus, p53-mutant, older patients, higher recurrence). Rarer histologies include melanoma, Bartholin gland adenocarcinoma, Paget disease and basal cell carcinoma. Nodal status is the dominant prognostic factor.\n\nEarly disease is treated with radical local excision and sentinel lymph node biopsy (GROINSS-V I established safety for tumours <4 cm with unifocal disease, replacing inguinofemoral lymphadenectomy and its lymphoedema in most); GROINSS-V II showed radiotherapy can replace lymphadenectomy for micrometastases ≤2 mm. Locally advanced disease receives chemoradiation (cisplatin-based, GOG 205/279) to avoid exenteration. Metastatic or recurrent disease has limited options: platinum-based chemotherapy, pembrolizumab for PD-L1-positive or TMB-high disease (KEYNOTE-158), cemiplimab in trials, and, for HPV-independent p53-mutant disease, no targeted therapy.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Vulvar_cancer","links":[{"label":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"},{"label":"GROINSS-V II (JCO 2021)","url":"https://doi.org/10.1200/JCO.21.00006"},{"label":"NCI PDQ: vulvar cancer","url":"https://www.cancer.gov/types/vulvar/patient/vulvar-treatment-pdq"}],"tags":["gap-fill","gynaecologic","hpv"],"related":["vaginal"],"cancers":[],"sections":[],"technologies":["sentinel-node","imrt-igrt","checkpoint-inhibitor","hpv-vaccine","platinum"],"targets":["pd1","tp53"],"drugs":["cisplatin","carboplatin","paclitaxel","bevacizumab","pembrolizumab","cemiplimab","gardasil-9"],"companies":["merck","regeneron"],"institutions":[],"pathways":[],"terms":["hpv-p16","cps"],"trials":["nct04422366"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"About 45,000 cases per year worldwide (GLOBOCAN); two peaks: younger women with HPV-related disease and older women with lichen sclerosus-associated disease.","subtypes":["HPV-associated SCC (usual VIN precursor, p16+)","HPV-independent SCC (differentiated VIN, lichen sclerosus, p53-mutant)","Vulvar melanoma","Extramammary Paget disease","Bartholin gland carcinoma","Basal cell carcinoma of the vulva"],"biomarkers":["p16 (HPV) and p53 IHC (molecular subtype)","Sentinel node status and metastasis size (≤2 mm vs >2 mm)","Depth of invasion (>1 mm for nodal assessment)","PD-L1 CPS / TMB / MSI (pembrolizumab)","Margin status"],"standardOfCare":[{"setting":"Early (T1, <4 cm, unifocal)","approach":"Radical local excision with 1 cm margin and sentinel lymph node biopsy (GROINSS-V); radiotherapy for sentinel micrometastases ≤2 mm, lymphadenectomy for macrometastases.","refs":["sentinel-node","imrt-igrt"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Vulvar Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1476"}},{"setting":"Node-positive after surgery","approach":"Adjuvant radiotherapy to groins and pelvis (± concurrent cisplatin) for ≥2 nodes or extracapsular spread (AGO-CaRE-1 supports chemoradiation).","refs":["cisplatin","imrt-igrt"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Vulvar Cancer"}},{"setting":"Locally advanced (T3 / fixed nodes)","approach":"Definitive or neoadjuvant chemoradiation with weekly cisplatin (GOG 279: ~70% complete response), reserving exenterative surgery for residual disease.","refs":["cisplatin","imrt-igrt"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Vulvar Cancer"}},{"setting":"Metastatic or recurrent","approach":"Carboplatin-paclitaxel ± bevacizumab (by cervical analogy); pembrolizumab for PD-L1 CPS ≥1, TMB-H or MSI-H; clinical trials.","refs":["carboplatin","paclitaxel","bevacizumab","pembrolizumab"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Vulvar Cancer"}}],"stateOfArt":["Sentinel-node biopsy and radiotherapy for micrometastases (GROINSS-V I/II) have removed lymphadenectomy morbidity for most early patients.","Molecular classification (HPV/p16 vs p53) is entering staging and predicts recurrence better than stage alone.","Chemoradiation avoids exenteration in most locally advanced disease.","Systemic therapy remains borrowed from cervical cancer; dedicated trials are few."],"history":[{"year":1912,"title":"Basset describes radical vulvectomy with en bloc lymphadenectomy","note":"Cure at the cost of severe morbidity; standard for 70 years.","refs":[]},{"year":1990,"title":"Separate groin incisions replace en bloc dissection","refs":[]},{"year":2008,"title":"GROINSS-V I: sentinel node biopsy safe in early vulvar cancer","refs":["sentinel-node"]},{"year":2016,"title":"HPV-independent vs HPV-associated pathways defined (WHO 2020 adopts)","refs":[]},{"year":2021,"title":"GROINSS-V II: radiotherapy for sentinel micrometastases","refs":["imrt-igrt"]},{"year":2021,"title":"GOG 279: cisplatin-gemcitabine chemoradiation for locally advanced disease","refs":["cisplatin"]}],"pipeline":["pembrolizumab","cemiplimab","lorigerlimab"],"openProblems":["HPV-independent p53-mutant disease recurs often and has no targeted therapy.","Lichen sclerosus surveillance and prevention of malignant transformation.","Few dedicated trials; therapy extrapolated from cervical cancer.","Psychosexual morbidity after treatment."]},{"id":"vulvar-melanoma","kind":"cancer","name":"Vulvar melanoma","aka":["Primary vulvar melanoma","Melanoma of the vulva","Vulvovaginal melanoma (with vaginal melanoma)"],"tldr":"Vulvar melanoma is the second most common vulvar cancer, a melanoma of the mucosal skin of the vulva in older women that is usually found late and has shorter survival than skin melanoma. It is removed with a margin, staged like skin melanoma by thickness, and treated when advanced with the immunotherapy and, for the quarter with a BRAF or KIT mutation, the targeted drugs used for other melanomas.","summary":"Primary vulvar melanoma is the second most common vulvar malignancy and is staged by the American Joint Committee on Cancer system for cutaneous melanoma despite its distinct site and genetics; in 100 patients, older age, greater thickness, higher dermal mitotic rate, ulceration, lymphovascular and perineural invasion, microscopic satellitosis and absence of a precursor naevus were associated with worse survival, and thickness and mitotic rate robustly predicted melanoma-specific survival (Clin Cancer Res 2017). A review of 33 patients found the expected profile of older women with delayed presentation, high stage and shorter survival, lichen sclerosus in 9.1 percent, and c-KIT expression as a prognostic marker (Int J Mol Med 2014). Molecular profiling of 51 vulvar and vaginal melanomas against 2,253 non-gynaecological melanomas found BRAF the most frequently mutated gene (26 percent, against 8.3 percent of other mucosal melanomas), with fewer of the BRAF mutations at the valine 600 codon (Cancer 2017). Incidence differs less by race than cutaneous melanoma, with a white to black ratio of 3.14 to 1 for vulvar melanoma (Melanoma Research 2010).\n\nHow it differs from its parent: it is not a carcinoma, so HPV, p16 and the squamous pathways do not apply; staging follows melanoma thickness rather than FIGO; and systemic therapy follows the mucosal melanoma page.\n\nHow common: about 1 to 2 per million women a year (Melanoma Research 2010).\n\nTreatment: wide local excision with margins by thickness rather than radical vulvectomy, sentinel node biopsy, and adjuvant or metastatic therapy as on the mucosal melanoma page: checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab), BRAF and MEK inhibitors for BRAF V600 mutations and imatinib for KIT mutations (Cancer 2017 for the mutation frequencies).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Vulvar_cancer","links":[{"label":"NCI PDQ: vulvar cancer treatment","url":"https://www.cancer.gov/types/vulvar/treatment"},{"label":"Clin Cancer Res 2017: tumour thickness and mitotic rate predict survival in 100 primary vulvar melanomas","url":"https://doi.org/10.1158/1078-0432.ccr-16-2126"},{"label":"Int J Mol Med 2014: clinicopathological review of 33 vulvar melanomas, c-KIT as a prognostic marker","url":"https://doi.org/10.3892/ijmm.2014.1659"},{"label":"Cancer 2017: vulvar and vaginal melanoma, molecular analysis of 51 cases against 2,253 non-gynaecological melanomas","url":"https://doi.org/10.1002/cncr.30473"},{"label":"Melanoma Research 2010: population-based incidence of vulvar and vaginal melanoma by race and ethnicity, SEER 1992 to 2005","url":"https://doi.org/10.1097/cmr.0b013e32833684e8"}],"tags":["subtype-page","wave4","rare"],"related":["vulvar","vaginal-melanoma","mucosal-melanoma","melanoma","urethral-melanoma","bartholin-gland-carcinoma"],"cancers":[],"sections":[],"technologies":[],"targets":["braf","kit"],"drugs":["nivolumab","pembrolizumab","ipilimumab","imatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"gynaecologic","burden":"The second most common vulvar malignancy (Clin Cancer Res 2017); 324 vulvar melanomas were diagnosed in the US SEER registries over 1992 to 2005, with an annual incidence of 1.90 per million non-Hispanic white women and 0.87 per million black women (Melanoma Research 2010).","subtypes":["Vulvar melanoma of the labia and clitoris (mucosal melanoma)","Vulvar melanoma arising in lichen sclerosus (9 percent in one series)","BRAF-mutated vulvar melanoma (26 percent of vulvovaginal melanomas)","KIT-mutated vulvar melanoma"],"biomarkers":["Breslow thickness and dermal mitotic rate (survival)","Ulceration, lymphovascular and perineural invasion, satellitosis","BRAF, KIT and NRAS mutation testing","Sentinel node status"],"standardOfCare":[{"setting":"All stages","approach":"Wide local excision by thickness with sentinel node biopsy; systemic therapy as on the mucosal melanoma page: checkpoint inhibitors, BRAF and MEK inhibitors for BRAF V600, imatinib for KIT.","refs":["vulvar","mucosal-melanoma","nivolumab","pembrolizumab","ipilimumab","imatinib"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"vulvar"},{"id":"waldenstrom","kind":"cancer","name":"Waldenström macroglobulinaemia","aka":["Lymphoplasmacytic lymphoma","WM","LPL","Non-IgM lymphoplasmacytic lymphoma","IgM lymphoplasmacytic lymphoma","Waldenstrom macroglobulinemia","C88.0"],"tldr":"A slow lymphoma that makes an abnormal IgM antibody, causing thick blood, anaemia and nerve damage. Nearly all cases share one mutation (MYD88 L265P), and BTK inhibitors control it for years.","summary":"Waldenström macroglobulinaemia (WM) is an IgM-secreting lymphoplasmacytic lymphoma with MYD88 L265P in ~95% and CXCR4 WHIM-like mutations in ~30-40%, the latter predicting slower BTK-inhibitor response. Symptoms come from marrow infiltration (cytopenias), IgM (hyperviscosity, neuropathy, cryoglobulinaemia, cold agglutinins) and adenopathy. Asymptomatic WM is observed.\n\nTreatment for symptomatic disease is rituximab-based chemo-immunotherapy (bendamustine-rituximab, DRC) or a covalent BTK inhibitor: ibrutinib (first WM approval 2015, iNNOVATE with rituximab), zanubrutinib (ASPEN 2021, fewer cardiac events than ibrutinib) or acalabrutinib. Plasmapheresis treats hyperviscosity before rituximab, which can transiently raise IgM (flare). Relapse options include the alternative class, proteasome inhibitors (bortezomib, carfilzomib), venetoclax, pirtobrutinib after covalent BTKi, and transplant in young fit patients. Bing-Neel syndrome (CNS involvement) responds to ibrutinib.\n\nOpen problems: fixed-duration versus indefinite therapy, CXCR4-mutant disease (mavorixafor trials), and transformation to DLBCL.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Waldenstr%C3%B6m_macroglobulinemia","links":[{"label":"NCCN Guidelines: WM/LPL","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1475"},{"label":"IWMF (patient foundation)","url":"https://iwmf.com/"},{"label":"ASPEN (Blood 2020)","url":"https://doi.org/10.1182/blood.2020006844"},{"label":"Lymphoma Action: helpline services","url":"https://lymphoma-action.org.uk/information-and-support/support-you/helpline-services"},{"label":"Lymphoma Action: questions to ask your medical team about lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/tests-scans-and-lymphoma-staging/questions-ask-your-medical-team-about-lymphoma"},{"label":"Lymphoma Action: follow-up after lymphoma treatment","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/follow-after-lymphoma-treatment"},{"label":"Lymphoma Action: infections, risk and prevention","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/infections-risk-and-prevention"},{"label":"Lymphoma Action: neutropenia (low neutrophils)","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/neutropenia-low-neutrophils"},{"label":"Lymphoma Action: cancer-related fatigue","url":"https://lymphoma-action.org.uk/information-and-support/side-effects-lymphoma-and-treatment/cancer-related-fatigue"},{"label":"Lymphoma Action: lymphoma, work and you","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/day-day-living/lymphoma-work-and-you"},{"label":"Maggie's: support and information","url":"https://www.maggies.org/support-and-information/"},{"label":"Lymphoma Action: active monitoring (watch and wait)","url":"https://lymphoma-action.org.uk/information-and-support/lymphoma-treatment/active-monitoring-watch-and-wait"},{"label":"Lymphoma Action: the emotional impact of living with lymphoma","url":"https://lymphoma-action.org.uk/information-and-support/living-and-beyond-lymphoma/emotional-impact-living-lymphoma"},{"label":"Macmillan: non-Hodgkin lymphoma","url":"https://www.macmillan.org.uk/cancer-information-and-support/lymphoma/non-hodgkin-lymphoma"},{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"}],"tags":["gap-fill","haematologic"],"related":["marginal-zone-lymphoma","follicular-lymphoma","mantle-cell-lymphoma","myd88-l265p","btk-c481s"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","monoclonal-antibody","autologous-stem-cell-transplant","palliative-care","psycho-oncology","peer-support-groups","survivorship-care-plan","fertility-preservation","financial-navigation","cbt-fatigue-distress","exercise-during-chemotherapy","multidisciplinary-tumour-board","oncology-nutrition","prehabilitation","cgp","flow-cytometry-mrd","clonality-testing"],"targets":["btk","cd20","cxcr4","bcl2","myd88","cd19"],"drugs":["ibrutinib","zanubrutinib","acalabrutinib","rituximab","bendamustine","bortezomib","carfilzomib","venetoclax","pirtobrutinib","mavorixafor"],"companies":["beone","abbvie","johnson-johnson","astrazeneca"],"institutions":[],"pathways":["inflammation-nfkb","bcr-signalling"],"terms":["ighv-status","histologic-transformation","myd88-l265p","m-protein-free-light-chains","lymphoma-tx-watch-and-wait","lymphoma-tx-transplant-role","cancer-related-fatigue","late-effects","febrile-neutropenia","neutropenia","financial-toxicity","central-venous-access","hypogammaglobulinaemia","performance-status","quality-of-life","lymphoma-decision-watch-and-wait","lymphoma-decision-trial","lymphoma-living-indolent-lymphoma","lymphoma-living-infection-years-after","lymphoma-living-fatigue","watchful-waiting","lymphoma-bio-lymphgen","lymphoma-classification-2022","lymphoma-indolent-versus-aggressive"],"trials":["aspen-wm"],"people":["meletios-dimopoulos"],"bottlenecks":[],"keyPapers":["paper-tam-blood"],"journals":[],"dependsOn":[],"notes":["Living with Waldenstrom macroglobulinaemia: This is orientation from public patient pages, guidelines and the trials themselves, not advice for your case: your own team's instructions and the 24-hour number they gave you come first, and no figure here is a prediction about you. The decision records, the question sets, the first 60 days checklist and the red cards on this page were written from the NHS, Lymphoma Action, Macmillan and Cancer Research UK patient pages, from NICE NG52, NG47, CG151 and NG234, from the NHS Breast Screening Programme protocols and the Green Book, and from the trial reports named beside each figure, all read on 1 October 2026.","Taxonomy. The corpus holds one record for lymphoplasmacytic lymphoma and Waldenstrom macroglobulinaemia, because WHO-HAEM5 treats them as one entity with two subtypes and the IgM subtype is the great majority. The International Consensus Classification names the entity \"lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia)\" in the same breath, and adds that the diagnosis may be made on lymphoplasmacytic aggregates filling less than 10 per cent of a trephine biopsy where clonal B cells and plasma cells are demonstrated, and that MYD88 L265P and CXCR4 testing are strongly encouraged in the work-up."],"group":"haematologic","burden":"About 3-4 per million per year; median age ~70; median survival now exceeds 10 years.","subtypes":["MYD88-mutant, CXCR4-wild-type (~55-60%)","MYD88-mutant, CXCR4-mutant (~30-40%)","MYD88-wild-type (~5%, higher transformation risk)","IgM MGUS and smouldering WM (precursors)","Bing-Neel syndrome (CNS)","IgM lymphoplasmacytic lymphoma, which is Waldenstrom macroglobulinaemia and is the great majority of lymphoplasmacytic lymphoma (WHO-HAEM5)","Non-Waldenstrom lymphoplasmacytic lymphoma, about 5 per cent: IgG or IgA paraprotein, non-secretory disease, or IgM disease without bone marrow involvement"],"biomarkers":["MYD88 L265P (AS-PCR/NGS)","CXCR4 mutation (S338X and others)","Serum IgM and viscosity","IPSSWM / rIPSSWM","Anti-MAG antibodies (neuropathy)","Cryoglobulins, cold agglutinins"],"standardOfCare":[{"setting":"Asymptomatic","approach":"Observation; treat on symptoms, cytopenias, hyperviscosity or neuropathy, not on IgM level alone.","refs":["active-surveillance"],"guideline":{"version":"IWWM-11 consensus; NCCN Guidelines: WM/LPL","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1475"}},{"setting":"Symptomatic, first line","approach":"Bendamustine-rituximab or dexamethasone-rituximab-cyclophosphamide for fixed duration; or zanubrutinib / ibrutinib (± rituximab) continuously; plasmapheresis first for hyperviscosity.","refs":["bendamustine","rituximab","zanubrutinib","ibrutinib"],"guideline":{"nccn":"Category 1 (zanubrutinib, ibrutinib ± rituximab; BR)","version":"NCCN Guidelines: WM/LPL"}},{"setting":"Relapsed","approach":"Switch class (BTKi ↔ chemo-immunotherapy); bortezomib- or carfilzomib-based regimens; venetoclax; pirtobrutinib after covalent BTKi; autologous transplant in selected young patients.","refs":["bortezomib","carfilzomib","venetoclax","pirtobrutinib","autologous-stem-cell-transplant"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: WM/LPL"}},{"setting":"Waldenstrom macroglobulinaemia: what to test before treatment, and why the genotype matters","approach":"A lymphoplasmacytic lymphoma that secretes IgM. Two mutations, found by allele-specific PCR on a marrow aspirate, shape the whole plan. MYD88 L265P is present in more than 90 per cent and predicts response to BTK inhibitors; MYD88 wild-type disease responds much less well to them. CXCR4 mutations, present in about a third, predict slower and shallower responses to ibrutinib and a higher risk of a rise in IgM when treatment starts.\n\nTwo complications need to be looked for because they change the urgency. Hyperviscosity, from a very high IgM, causes headache, blurred vision, nosebleeds and confusion, is confirmed on fundoscopy, and is treated with plasma exchange before anything else. IgM-related peripheral neuropathy, often anti-MAG positive, is a reason to treat even when other criteria are not met, because nerve damage does not reverse.\n\nRituximab causes a transient rise in IgM, an IgM flare, in about half of patients, which can precipitate hyperviscosity; it is therefore held back or given after plasma exchange where the IgM is very high.","refs":["paper-treon-blood","rituximab","ibrutinib","zanubrutinib"],"guideline":{"version":"NCCN Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma; ESMO; BSH","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Waldenstrom macroglobulinaemia, first treatment: BTK inhibitor or chemoimmunotherapy","approach":"Treatment is for symptoms, not for a number: anaemia, thrombocytopenia, constitutional symptoms, symptomatic organ or node enlargement, hyperviscosity, neuropathy, cryoglobulinaemia or amyloidosis. An asymptomatic patient is watched.\n\nTwo routes. Fixed-duration chemoimmunotherapy, usually bendamustine with rituximab for four to six cycles, gives deep responses and a treatment-free interval afterwards, and is the preference of many patients and many British units. Continuous BTK inhibition with zanubrutinib or ibrutinib gives high response rates without chemotherapy but is taken indefinitely.\n\nASPEN, the only head-to-head trial, randomised 201 patients with MYD88-mutated disease to zanubrutinib or ibrutinib: the complete or very good partial response rate by independent review was 28.4 against 19.2 per cent, which did not reach statistical significance, but zanubrutinib caused markedly less atrial fibrillation, hypertension, bleeding and diarrhoea. A separate cohort treated MYD88 wild-type disease with zanubrutinib. Where a BTK inhibitor is chosen, zanubrutinib is therefore preferred. Rituximab with cyclophosphamide and dexamethasone is an alternative chemoimmunotherapy for patients in whom bendamustine is unsuitable. Proteasome-inhibitor regimens containing bortezomib are used where a rapid response is needed and neuropathy is absent.","refs":["aspen-wm","zanubrutinib","ibrutinib","bendamustine","rituximab","cyclophosphamide","dexamethasone","bortezomib","lymphoma-tx-watch-and-wait","paper-tam-blood"],"guideline":{"version":"NCCN Waldenstrom Macroglobulinemia; ESMO; ASPEN","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}},{"setting":"Relapsed Waldenstrom macroglobulinaemia","approach":"The choice turns on what was used first and how long the remission lasted. After fixed-duration chemoimmunotherapy with a remission of two years or more, the same regimen can be repeated, or a BTK inhibitor started. After a BTK inhibitor, options are a different BTK inhibitor including the non-covalent pirtobrutinib, venetoclax, which has activity in this disease, proteasome-inhibitor regimens, chemoimmunotherapy if not previously used, and a clinical trial. Autologous transplant is occasionally used in younger patients with chemosensitive disease and multiple relapses. Transformation to diffuse large B-cell lymphoma is treated as aggressive lymphoma. Plasma exchange remains the immediate treatment for symptomatic hyperviscosity at any point.","refs":["zanubrutinib","ibrutinib","pirtobrutinib","venetoclax","bortezomib","bendamustine","rituximab","autologous-stem-cell-transplant","lymphoma-tx-transplant-role"],"guideline":{"version":"NCCN Waldenstrom Macroglobulinemia; ESMO","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}}],"stateOfArt":["MYD88 L265P (2012) turned WM from a descriptive diagnosis into a genotype and made BTK inhibitors the rational therapy.","Zanubrutinib is the best-tolerated BTK inhibitor in head-to-head comparison (ASPEN) and is the preferred agent in many guidelines.","Median survival now exceeds 10 years; death from WM itself is uncommon in patients under 70.","Fixed-duration BTKi-venetoclax and CXCR4 antagonists are the next questions.","This is the lymphoma with the closest thing to a defining point mutation. Whole-genome sequencing of 30 patients found MYD88 L265P in all 10 with paired normal tissue, and Sanger sequencing found it in 49 of 54 patients and in 91% of lymphoplasmacytic lymphoma overall, while it was absent from paired normal tissue, from healthy donor B cells and from most marginal zone lymphoma, myeloma and IgM monoclonal gammopathy of undetermined significance.","The mutation works by assembling an IRAK1 and IRAK4 signalling complex without a receptor signal, driving NF-kB, which is the mechanistic reason BTK inhibition works in this disease.","The genotype that matters clinically is a pair. CXCR4 mutations of the WHIM type occur alongside MYD88 and blunt the response to a BTK inhibitor, so the two genes are read together before first treatment rather than separately."],"history":[{"year":1944,"title":"Waldenström describes the syndrome","note":"Two patients with hyperviscosity, bleeding and a large serum globulin.","refs":[]},{"year":2002,"title":"Consensus diagnostic criteria (IWWM-2)","refs":[]},{"year":2012,"title":"MYD88 L265P discovered","note":"Treon et al. (NEJM): whole-genome sequencing finds the mutation in over 90% of WM.","refs":["btk"]},{"year":2014,"title":"CXCR4 WHIM-like mutations","note":"Present in ~30% and associated with BTKi resistance.","refs":["cxcr4"]},{"year":2015,"title":"Ibrutinib: first drug ever approved for WM","refs":["ibrutinib"]},{"year":2018,"title":"iNNOVATE: ibrutinib-rituximab","refs":["ibrutinib","rituximab"]},{"year":2021,"title":"Zanubrutinib approved (ASPEN)","note":"Fewer atrial fibrillation events than ibrutinib.","refs":["zanubrutinib"]}],"pipeline":["pirtobrutinib","venetoclax","zanubrutinib"],"openProblems":["Indefinite BTKi therapy: cost, toxicity and resistance (BTK C481S).","CXCR4-mutant disease responds slower and shallower.","No approved therapy specific to IgM-related neuropathy.","Transformation to DLBCL (5-10%) is the hardest event to treat."],"parent":"non-hodgkin-lymphoma"},{"id":"wilms-tumor","kind":"cancer","name":"Wilms tumour (nephroblastoma)","aka":[],"tldr":"Wilms tumour is a kidney cancer of young children and one of paediatric oncology's success stories: surgery plus a few months of chemotherapy cures about nine in ten. Today's trials aim to give the lowest-risk children almost no chemotherapy while finding the few with aggressive biology.","summary":"Wilms tumour is an embryonal kidney cancer arising from nephrogenic rests, associated with WT1, CTNNB1, WTX, TP53 (anaplastic), and microRNA-processing gene (DROSHA, DGCR8) mutations, and with predisposition syndromes (WAGR, Denys-Drash, Beckwith-Wiedemann). Two cooperative-group philosophies coexist: COG (upfront nephrectomy, then risk-stratified chemotherapy using stage, histology, 1p/16q loss of heterozygosity and 1q gain) and SIOP (pre-operative vincristine-actinomycin then nephrectomy, with post-operative therapy by histologic response and stage; UMBRELLA protocol).\n\nFavourable-histology stage I-II disease is treated with vincristine and actinomycin D (EE-4A) or, for very low-risk stage I tumours in children under 2 with tumours <550 g, surgery alone; stage III-IV adds doxorubicin and flank/whole-lung radiotherapy, with lung irradiation omitted in rapid complete responders without 1p/16q LOH (AREN0533). Diffuse anaplastic tumours need intensive regimen UH-1/UH-2 with carboplatin, cyclophosphamide and etoposide; bilateral tumours receive neoadjuvant chemotherapy and nephron-sparing surgery. Relapse is treated by risk group (ICE regimens, high-dose chemotherapy in some). Survivorship issues include cardiotoxicity, renal function, second cancers and fertility (radiation).","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Wilms%27_tumor","links":[{"label":"NCI PDQ: Wilms tumour","url":"https://www.cancer.gov/types/kidney/patient/wilms-treatment-pdq"},{"label":"SIOP-RTSG UMBRELLA protocol (Nat Rev Urol 2017)","url":"https://doi.org/10.1038/nrurol.2017.163"},{"label":"Children's Oncology Group","url":"https://childrensoncologygroup.org/"}],"tags":["gap-fill","paediatric"],"related":["paediatric-oncology-roadmap","neuroblastoma","hepatoblastoma","retinoblastoma","pleuropulmonary-blastoma"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","imrt-igrt","robotic-surgery","germline-testing","survivorship-care-plan","ultrasound"],"targets":["tp53"],"drugs":["vincristine","dactinomycin","doxorubicin","cyclophosphamide","carboplatin","etoposide","ifosfamide"],"companies":["childrens-oncology-group"],"institutions":[],"pathways":["wnt","p53-cell-cycle"],"terms":["germline-vs-somatic","nephrectomy","wilms-risk-markers"],"trials":["ccss","aren0532"],"people":["jeffrey-dome"],"bottlenecks":[],"keyPapers":["paper-van-den-heuvel-eibrink-nat-rev-urol"],"journals":["journal-of-pediatric-hematology-oncology","pediatric-hematology-and-oncology"],"dependsOn":[],"notes":[],"group":"paediatric","burden":"The most common childhood kidney cancer: ~1 in 10,000 children, ~650 cases per year in the US, peak age 3-4; overall survival ~90% in high-income countries versus ~50% or lower in much of Africa.","subtypes":["Favourable histology (~90%)","Diffuse anaplastic (TP53-mutant, ~5-10%)","Focal anaplastic","Bilateral Wilms (stage V, ~5%)","Syndromic Wilms (WAGR, Denys-Drash, Beckwith-Wiedemann)","Non-Wilms renal tumours (clear cell sarcoma, rhabdoid, renal cell) are managed separately"],"biomarkers":["Stage (COG or SIOP post-chemotherapy)","Histology: anaplasia; SIOP risk group after pre-op chemotherapy (blastemal-type = high risk)","1p and 16q loss of heterozygosity (COG)","1q gain","TP53 mutation (anaplastic)","Tumour weight and age (surgery-only eligibility)","Germline WT1 / 11p15 testing"],"standardOfCare":[{"setting":"Very low risk (stage I FH, <2 years, <550 g)","approach":"Nephrectomy alone with close surveillance (AREN0532).","refs":["active-surveillance"],"guideline":{"version":"COG AREN0532 (JCO 2019)","url":"https://doi.org/10.1200/JCO.18.02102"}},{"setting":"Stage I-II favourable histology","approach":"Nephrectomy then vincristine + actinomycin D for 18 weeks (EE-4A), or SIOP pre-op VA ×4 weeks then stage-adapted post-op therapy.","refs":["vincristine","dactinomycin"],"guideline":{"version":"COG AREN0532; SIOP-RTSG UMBRELLA"}},{"setting":"Stage III-IV favourable histology","approach":"Vincristine, actinomycin D, doxorubicin (DD-4A) for 24 weeks; flank/abdominal radiotherapy for stage III; whole-lung radiotherapy for lung metastases not in rapid complete response (AREN0533).","refs":["vincristine","dactinomycin","doxorubicin","imrt-igrt"],"guideline":{"version":"COG AREN0533 (JCO 2018)"}},{"setting":"Diffuse anaplastic or relapsed","approach":"Intensive UH-1/UH-2 (vincristine, doxorubicin, cyclophosphamide, carboplatin, etoposide) with radiotherapy; relapse: ICE-type regimens, surgery, RT, high-dose therapy or trials.","refs":["cyclophosphamide","carboplatin","etoposide","doxorubicin","ifosfamide"],"guideline":{"version":"COG AREN0321"}}],"stateOfArt":["Survival ~90% with steadily less therapy: surgery-only for the youngest lowest-risk children, radiation omitted for lung responders.","Molecular markers (1p/16q LOH, 1q gain) already stratify therapy, a rare achievement in paediatric solid tumours.","Two cooperative strategies (COG vs SIOP) reach similar outcomes, giving the field a natural experiment.","The largest gap is geographic: mortality in sub-Saharan Africa is several-fold higher, driven by late presentation, abandonment and supportive-care shortfalls (SIOP PODC adapted regimens)."],"history":[{"year":1899,"title":"Max Wilms's monograph on mixed tumours of the kidney","refs":[]},{"year":1956,"title":"Actinomycin D active in Wilms tumour (Farber)","note":"Combined with surgery and radiation, cure rates begin to climb.","refs":["dactinomycin"]},{"year":1969,"title":"National Wilms Tumor Study (NWTS-1) begins","note":"Cooperative-group model that raised survival from ~30% to ~90% over five trials.","refs":[]},{"year":1990,"title":"WT1 cloned (Call, Gessler)","note":"First Wilms tumour gene; also links to WAGR and Denys-Drash.","refs":[]},{"year":2005,"title":"1p/16q LOH predicts relapse (NWTS-5, Grundy)","refs":[]},{"year":2018,"title":"AREN0533: lung radiotherapy omitted for rapid complete responders","refs":["imrt-igrt"]},{"year":2019,"title":"AREN0532: surgery alone confirmed for very-low-risk stage I","refs":["active-surveillance"]}],"pipeline":["vincristine","dactinomycin"],"openProblems":["Diffuse anaplastic and relapsed disease: survival ~50% or lower.","Global inequity: Wilms is curable, yet most children with it worldwide lack access to the treatment that cures it; adapted regimens (SIOP PODC) are the response.","Late effects of doxorubicin and radiation in 90% survivors.","Bilateral disease: preserving kidney function."],"parent":"childhood-cancers"},{"id":"medulloblastoma-wnt","kind":"cancer","name":"WNT-activated medulloblastoma","aka":["WNT medulloblastoma","WNT-subgroup medulloblastoma","CTNNB1-mutant medulloblastoma"],"tldr":"WNT-activated medulloblastoma is the rarest and most curable of the four molecular groups of medulloblastoma, a brain tumour of the cerebellum. It is driven by a mutation in the beta-catenin gene that switches the WNT growth pathway on. Almost every child is cured with standard therapy, so current trials are asking how much radiotherapy and chemotherapy can be taken away.","summary":"Medulloblastoma was split into four molecular groups by gene-expression studies between 2006 and 2012, and the WHO classification adopted them in 2016. WNT-activated tumours carry an activating CTNNB1 (beta-catenin) mutation in about 90 percent, with monosomy 6 in most and germline APC mutations (Turcot syndrome) in some of the rest; nuclear beta-catenin on immunohistochemistry is the practical marker and DNA methylation profiling the reference test. They arise not from the cerebellar granule cell lineage but from the lower rhombic lip of the brainstem, so they sit in the midline against the brainstem and cerebellar peduncle, have classic histology, occur in children over seven and in adolescents, and are almost never metastatic at diagnosis.\n\nWNT patients treated on the average-risk regimens of the 2000s, 23.4 Gy craniospinal radiotherapy with a posterior fossa or tumour-bed boost followed by cisplatin, vincristine and cyclophosphamide or lomustine, almost all survived: pooled analyses of the SIOP PNET3 and HIT-SIOP PNET4 cohorts and the St Jude SJMB03 trial each found WNT tumours to have the best outcome of any group, with few if any relapses. Because the cost of that therapy in a ten-year-old is intellectual decline, hearing loss, growth and hormone failure and second tumours, both cooperative groups opened de-escalation trials: SJMB12 gives WNT patients 15 Gy craniospinal radiotherapy with a reduced boost and four rather than seven cycles of chemotherapy, and COG ACNS1422 gives 18 Gy craniospinal radiotherapy with reduced chemotherapy for non-metastatic WNT tumours with no residual disease. Both are single-arm studies judged against the historical rate.\n\nThe open questions are whether radiotherapy can be cut further, or omitted in favour of chemotherapy alone in the youngest patients; how to treat the rare metastatic or adult WNT tumour, which may not share the excellent prognosis; and whether the mutant beta-catenin pathway itself can be drugged, since no WNT inhibitor has reached the clinic in this disease. Because WNT tumours invade the brainstem, surgeons are advised against chasing the last few millimetres of tumour: residual disease under 1.5 square centimetres does not worsen outcome and brainstem injury does.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Medulloblastoma","links":[{"label":"Wikipedia: Medulloblastoma","url":"https://en.wikipedia.org/wiki/Medulloblastoma"},{"label":"NCI PDQ: Childhood Medulloblastoma Treatment","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}],"tags":["subtype-page","paediatric","cns"],"related":["medulloblastoma-shh","medulloblastoma-group-3-4"],"cancers":[],"sections":[],"technologies":["proton-therapy","methylation-profiling"],"targets":[],"drugs":[],"companies":["childrens-oncology-group"],"institutions":["st-jude","siop-europe"],"pathways":["wnt"],"terms":["late-effects","medulloblastoma-molecular-groups"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-who-2021-cns-louis-neuro-oncology-2021","paper-taylor-medulloblastoma-consensus-acta-neuropathol-2012","paper-cavalli-medulloblastoma-subtypes-cancer-cell-2017","paper-acns0331-michalski-jco-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About one medulloblastoma in ten is WNT-activated; it affects older children and adolescents and has the best outlook of the four molecular groups, with almost every child cured in trial cohorts.","subtypes":["WNT-activated medulloblastoma, CTNNB1-mutant with monosomy 6 (about 90 percent)","WNT-activated medulloblastoma with germline APC mutation (Turcot syndrome)","Metastatic WNT-activated medulloblastoma (rare; standard high-risk therapy)","WNT-activated medulloblastoma in adults (uncertain whether the childhood prognosis holds)"],"biomarkers":["Nuclear beta-catenin immunohistochemistry","CTNNB1 exon 3 mutation","Monosomy 6","DNA methylation profiling","APC germline testing","Spinal MRI and CSF cytology staging"],"standardOfCare":[{"setting":"Non-metastatic, standard therapy","approach":"Maximal safe resection, 23.4 Gy craniospinal radiotherapy with tumour-bed boost (protons where available), then cisplatin, vincristine and cyclophosphamide or lomustine.","refs":["proton-therapy","imrt-igrt","cisplatin","vincristine","cyclophosphamide","lomustine","methylation-profiling"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"Non-metastatic, de-escalation trials","approach":"15 Gy (SJMB12) or 18 Gy (ACNS1422) craniospinal radiotherapy with reduced boost and fewer chemotherapy cycles, judged against historical survival.","refs":["proton-therapy","cisplatin","vincristine","cyclophosphamide","methylation-profiling","st-jude","childrens-oncology-group","acns1422","sjmb12"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"Metastatic or residual disease","approach":"High-risk therapy: 36 Gy craniospinal radiotherapy with boost and intensified chemotherapy, as for other groups.","refs":["carboplatin","cisplatin","cyclophosphamide","vincristine","imrt-igrt"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"Survivorship","approach":"Neurocognitive, audiological, endocrine and second-tumour follow-up for life.","refs":["late-effects","survivorship-care-plan"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}}],"stateOfArt":["WNT-activated medulloblastoma has the best outcome of any group, with few relapses on average-risk therapy.","SJMB12 and ACNS1422 are testing reduced craniospinal radiotherapy and chemotherapy specifically for WNT patients.","Nuclear beta-catenin and methylation profiling identify the group reliably at diagnosis."],"history":[{"year":2006,"title":"Gene-expression studies first separate a WNT subgroup of medulloblastoma","refs":[]},{"year":2012,"title":"Consensus on four molecular groups: WNT, SHH, group 3 and group 4","refs":[]},{"year":2013,"title":"SJMB12 opens with reduced therapy for WNT patients","refs":["st-jude"]},{"year":2016,"title":"WHO adopts molecular groups; ACNS1422 opens with 18 Gy craniospinal radiotherapy for WNT tumours","refs":["childrens-oncology-group"]},{"year":2021,"title":"WHO 2021 defines medulloblastoma by molecular group with methylation profiling","refs":["methylation-profiling"]}],"pipeline":["proton-therapy","methylation-profiling","germline-testing"],"openProblems":["How far craniospinal radiotherapy can be reduced without losing cures.","Whether adult and metastatic WNT tumours share the childhood prognosis.","No drug targets the mutant beta-catenin pathway."],"parent":"medulloblastoma"},{"id":"yolk-sac-tumour-postpubertal","kind":"cancer","name":"Yolk sac tumour of the testis, postpubertal type","aka":["Yolk sac tumour","Yolk sac tumor","Endodermal sinus tumour","Endodermal sinus tumor","Yolk sac tumour, postpubertal-type","Glandular yolk sac tumour"],"tldr":"Yolk sac tumour is a germ cell tumour whose cells copy the yolk sac of an early embryo and make the protein alpha-fetoprotein, which is measured in the blood to track it. In adults it almost always occurs mixed with other non-seminoma components and is cured with cisplatin chemotherapy; the pure infant form is a different, gentler disease covered on the childhood page.","summary":"The 2016 WHO classification splits yolk sac tumour into a postpubertal type, derived from germ cell neoplasia in situ and almost always part of a mixed non-seminoma, and a prepubertal type, unrelated to GCNIS, that is the commonest malignant testicular tumour of infants (Moch 2016). It grows in reticular, microcystic, endodermal sinus (Schiller-Duval body), papillary, glandular, solid and other patterns, secretes alpha-fetoprotein, and stains for glypican-3 and SALL4. Its importance in adults extends beyond the primary: among 124 somatic-type malignancies arising from testicular germ cell tumours, 7 of 45 adenocarcinomas were reclassified as glandular yolk sac tumour on glypican-3 and alpha-fetoprotein positivity, supporting a frequent yolk sac origin of the glandular tumours that appear in late relapse (Am J Surg Pathol 2014). In 33 pure yolk sac tumours of boys aged 5 to 71 months, 24 were disease-free and 8 developed metastases, with size over 4.5 cm, rete or epididymal invasion and necrosis predicting a poor outcome in stage I (Am J Surg Pathol 2015).\n\nHow it differs from its parent: it is the alpha-fetoprotein-producing component of non-seminoma, so a raised AFP after treatment signals yolk sac elements; it is the usual source of the chemoresistant glandular late relapses; and its prepubertal type belongs on the childhood germ cell page rather than here.\n\nHow common: no separate incidence figure in the sources read.\n\nTreatment: as non-seminoma by stage and risk group with BEP, and resection of residual masses; late relapses with somatic-type or glandular yolk sac elements are treated surgically because they respond poorly to chemotherapy (Am J Surg Pathol 2014).","asOf":"2026-09-24","wikipedia":"https://en.wikipedia.org/wiki/Endodermal_sinus_tumor","links":[{"label":"NCI PDQ: testicular cancer treatment","url":"https://www.cancer.gov/types/testicular/treatment"},{"label":"Moch 2016, European Urology: the 2016 WHO classification of urinary and male genital tumours, part A","url":"https://doi.org/10.1016/j.eururo.2016.02.029"},{"label":"Am J Surg Pathol 2014: somatic-type malignancies from testicular germ cell tumours, 124 cases, frequent yolk sac tumour origin","url":"https://doi.org/10.1097/pas.0000000000000262"},{"label":"Am J Surg Pathol 2015: yolk sac tumour of the testis in infants and children, 33 cases","url":"https://doi.org/10.1097/pas.0000000000000432"},{"label":"Am J Surg Pathol 2004: OCT4 staining in testicular tumours, a marker for seminoma and embryonal carcinoma","url":"https://doi.org/10.1097/00000478-200407000-00014"}],"tags":["subtype-page","wave4","testicular","rare"],"related":["non-seminoma","testicular","embryonal-carcinoma-testis","testicular-choriocarcinoma","paediatric-germ-cell-tumours"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["bleomycin","etoposide","cisplatin"],"companies":[],"institutions":[],"pathways":[],"terms":["afp","tumour-markers"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"genitourinary","burden":"A component of 38 of 64 mixed germ cell tumours in a marker study (Am J Surg Pathol 2004); pure yolk sac tumour is rare in adults and is the usual germ cell tumour of infants, where it has its own biology (Am J Surg Pathol 2015). No registry figure was found in the sources read.","subtypes":["Yolk sac tumour, postpubertal type, in a mixed germ cell tumour (the usual adult form)","Pure yolk sac tumour, postpubertal type (rare)","Glandular yolk sac tumour in late relapse (chemoresistant; surgical)","Yolk sac tumour, prepubertal type (infants; on the childhood germ cell page)"],"biomarkers":["Serum alpha-fetoprotein","Glypican-3, SALL4 and alpha-fetoprotein immunohistochemistry","Schiller-Duval bodies","Isochromosome 12p (postpubertal type only)"],"standardOfCare":[{"setting":"All stages","approach":"Treated as non-seminoma by stage and risk group with BEP and resection of residual masses; late glandular relapses are resected.","refs":["non-seminoma","testicular","bleomycin","etoposide","cisplatin","afp"]}],"stateOfArt":[],"history":[],"pipeline":[],"openProblems":[],"parent":"non-seminoma"}]