{"entity":{"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."]},"route":"/cancers/pheochromocytoma-paraganglioma/","neighbours":{"technology":[{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/"},{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"},{"id":"mibg-theranostics","kind":"technology","name":"MIBG imaging and 131I-MIBG therapy","route":"/technologies/mibg-theranostics/"},{"id":"prrt","kind":"technology","name":"Peptide receptor radionuclide therapy (PRRT)","route":"/technologies/prrt/"},{"id":"radioligand-therapy","kind":"technology","name":"Radioligand therapy (beta emitters)","route":"/technologies/radioligand-therapy/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"sstr-pet","kind":"technology","name":"Somatostatin receptor PET (68Ga/64Cu-DOTATATE)","route":"/technologies/sstr-pet/"}],"target":[{"id":"hif2a","kind":"target","name":"HIF-2α","route":"/targets/hif2a/"},{"id":"mllt6","kind":"target","name":"MLLT6","route":"/targets/mllt6/"},{"id":"ranbp2","kind":"target","name":"RANBP2","route":"/targets/ranbp2/"},{"id":"ret","kind":"target","name":"RET","route":"/targets/ret/"},{"id":"sstr2","kind":"target","name":"Somatostatin receptor 2","route":"/targets/sstr2/"},{"id":"vegf","kind":"target","name":"VEGF / VEGFR","route":"/targets/vegf/"},{"id":"vhl","kind":"target","name":"VHL","route":"/targets/vhl/"}],"drug":[{"id":"i131-mibg","kind":"drug","name":"131I-MIBG (iobenguane I-131) therapy","route":"/drugs/i131-mibg/"},{"id":"belzutifan","kind":"drug","name":"Belzutifan","route":"/drugs/belzutifan/"},{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"cyclophosphamide","kind":"drug","name":"Cyclophosphamide","route":"/drugs/cyclophosphamide/"},{"id":"lutathera","kind":"drug","name":"Lutetium-177 dotatate","route":"/drugs/lutathera/"},{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"},{"id":"temozolomide","kind":"drug","name":"Temozolomide","route":"/drugs/temozolomide/"},{"id":"vincristine","kind":"drug","name":"Vincristine","route":"/drugs/vincristine/"}],"company":[{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/"},{"id":"novartis","kind":"company","name":"Novartis","route":"/companies/novartis/"},{"id":"pfizer","kind":"company","name":"Pfizer (incl. Seagen)","route":"/companies/pfizer/"}],"pathway":[{"id":"cancer-metabolism","kind":"pathway","name":"Cancer metabolism","route":"/pathways/cancer-metabolism/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"},{"id":"hif-vhl","kind":"pathway","name":"VHL / HIF oxygen sensing","route":"/pathways/hif-vhl/"}],"term":[{"id":"adrenalectomy","kind":"term","name":"Adrenalectomy","route":"/terms/adrenalectomy/"},{"id":"hereditary-cancer-syndromes","kind":"term","name":"Hereditary cancer syndromes","route":"/terms/hereditary-cancer-syndromes/"},{"id":"rare-cancers","kind":"term","name":"Rare cancers","route":"/terms/rare-cancers/"}],"bottleneck":[{"id":"b-hereditary-risk","kind":"bottleneck","name":"Inherited risk is mostly unidentified","route":"/bottlenecks/b-hereditary-risk/"},{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"}],"trial":[{"id":"nct00923481","kind":"trial","name":"A Broad Multi-histology Phase II Study of the Multi-Kinase Inhibitor R935788 (Fostamatinib Disodium) in Advanced Colorectal, Non-small Cell Lung, Head and Neck Hepatocellular and Renal Cell Carcinomas, and Pheochromocytoma and Thyroid Tumors (Multi-H..","route":"/trials/nct00923481/"},{"id":"nct04924075","kind":"trial","name":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL","route":"/trials/nct04924075/"},{"id":"firstmappp","kind":"trial","name":"FIRSTMAPPP","route":"/trials/firstmappp/"},{"id":"nct07282587","kind":"trial","name":"Study of ONC206 (JZP3507) in Advanced Pheochromocytoma and Paraganglioma","route":"/trials/nct07282587/"},{"id":"nct04711135","kind":"trial","name":"Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With GEP-NETs and PPGLs","route":"/trials/nct04711135/"},{"id":"nct05636618","kind":"trial","name":"Targeted Alpha-Particle Therapy for Advanced Somatostatin Receptor Type 2 (SSTR2) Positive Tumors","route":"/trials/nct05636618/"}],"cancer":[{"id":"hereditary-ppgl","kind":"cancer","name":"Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127)","route":"/cancers/hereditary-ppgl/"},{"id":"metastatic-ppgl","kind":"cancer","name":"Metastatic pheochromocytoma and paraganglioma","route":"/cancers/metastatic-ppgl/"},{"id":"multiple-endocrine-neoplasia","kind":"cancer","name":"Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)","route":"/cancers/multiple-endocrine-neoplasia/"},{"id":"men2-syndrome","kind":"cancer","name":"Multiple endocrine neoplasia type 2 (MEN2A and MEN2B)","route":"/cancers/men2-syndrome/"},{"id":"rare-childhood-cancers","kind":"cancer","name":"Rare cancers of childhood (NCI PDQ umbrella)","route":"/cancers/rare-childhood-cancers/"}],"paper":[{"id":"paper-firstmappp-sunitinib-metastatic-ppgl-baudin-lancet-2024","kind":"paper","name":"FIRSTMAPPP: sunitinib for metastatic progressive phaeochromocytomas and paragangliomas","route":"/key-papers/paper-firstmappp-sunitinib-metastatic-ppgl-baudin-lancet-2024/"}]}}