{"entity":{"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."]},"route":"/cancers/adrenocortical/","neighbours":{"technology":[{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/"},{"id":"dual-energy-spectral-ct","kind":"technology","name":"Dual-energy and spectral CT","route":"/technologies/dual-energy-spectral-ct/"},{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"imrt-igrt","kind":"technology","name":"IMRT / IGRT (modern external beam)","route":"/technologies/imrt-igrt/"},{"id":"robotic-surgery","kind":"technology","name":"Robotic & minimally invasive surgery","route":"/technologies/robotic-surgery/"},{"id":"sbrt","kind":"technology","name":"SBRT / SABR (stereotactic radiotherapy)","route":"/technologies/sbrt/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"thermal-ablation","kind":"technology","name":"Thermal ablation (RFA, microwave, cryo)","route":"/technologies/thermal-ablation/"}],"target":[{"id":"atrx","kind":"target","name":"ATRX","route":"/targets/atrx/"},{"id":"bcor","kind":"target","name":"BCOR","route":"/targets/bcor/"},{"id":"ctnnb1","kind":"target","name":"CTNNB1","route":"/targets/ctnnb1/"},{"id":"daxx","kind":"target","name":"DAXX","route":"/targets/daxx/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"prkar1a","kind":"target","name":"PRKAR1A","route":"/targets/prkar1a/"},{"id":"setbp1","kind":"target","name":"SETBP1","route":"/targets/setbp1/"},{"id":"tnc","kind":"target","name":"TNC","route":"/targets/tnc/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"},{"id":"vegf","kind":"target","name":"VEGF / VEGFR","route":"/targets/vegf/"},{"id":"znrf3","kind":"target","name":"ZNRF3","route":"/targets/znrf3/"}],"drug":[{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"cisplatin","kind":"drug","name":"Cisplatin","route":"/drugs/cisplatin/"},{"id":"doxorubicin","kind":"drug","name":"Doxorubicin","route":"/drugs/doxorubicin/"},{"id":"etoposide","kind":"drug","name":"Etoposide","route":"/drugs/etoposide/"},{"id":"mitotane","kind":"drug","name":"Mitotane","route":"/drugs/mitotane/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"relacorilant","kind":"drug","name":"Relacorilant","route":"/drugs/relacorilant/"}],"company":[{"id":"corcept","kind":"company","name":"Corcept Therapeutics","route":"/companies/corcept/"},{"id":"exelixis","kind":"company","name":"Exelixis","route":"/companies/exelixis/"},{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/"}],"pathway":[{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"term":[{"id":"germline-vs-somatic","kind":"term","name":"Germline vs somatic mutations","route":"/terms/germline-vs-somatic/"},{"id":"hereditary-cancer-syndromes","kind":"term","name":"Hereditary cancer syndromes","route":"/terms/hereditary-cancer-syndromes/"},{"id":"li-fraumeni","kind":"term","name":"Li-Fraumeni syndrome (germline TP53)","route":"/terms/li-fraumeni/"},{"id":"rare-cancers","kind":"term","name":"Rare cancers","route":"/terms/rare-cancers/"}],"institution":[{"id":"rutgers-cinj","kind":"institution","name":"Rutgers Cancer Institute of New Jersey","route":"/institutions/rutgers-cinj/"}],"cancer":[{"id":"advanced-adrenocortical-carcinoma","kind":"cancer","name":"Advanced and metastatic adrenocortical carcinoma (ENSAT stage IV or unresectable)","route":"/cancers/advanced-adrenocortical-carcinoma/"},{"id":"choroid-plexus-carcinoma","kind":"cancer","name":"Choroid plexus carcinoma","route":"/cancers/choroid-plexus-carcinoma/"},{"id":"corticotroph-pitnet","kind":"cancer","name":"Corticotroph pituitary neuroendocrine tumour (Cushing disease and silent corticotroph tumour)","route":"/cancers/corticotroph-pitnet/"},{"id":"localised-adrenocortical-carcinoma","kind":"cancer","name":"Localised adrenocortical carcinoma (ENSAT stage I to III, resectable)","route":"/cancers/localised-adrenocortical-carcinoma/"},{"id":"rare-childhood-cancers","kind":"cancer","name":"Rare cancers of childhood (NCI PDQ umbrella)","route":"/cancers/rare-childhood-cancers/"}],"journal":[{"id":"endocrine-related-cancer","kind":"journal","name":"Endocrine-related cancer","route":"/journals/endocrine-related-cancer/"}],"trial":[{"id":"adiuvo","kind":"trial","name":"ADIUVO","route":"/trials/adiuvo/"},{"id":"adiuvo-2","kind":"trial","name":"ADIUVO-2","route":"/trials/adiuvo-2/"}],"paper":[{"id":"paper-adiuvo-adjuvant-mitotane-low-grade-acc-terzolo-lancet-diabetes-endocrinol-2023","kind":"paper","name":"ADIUVO: adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma","route":"/key-papers/paper-adiuvo-adjuvant-mitotane-low-grade-acc-terzolo-lancet-diabetes-endocrinol-2023/"}]}}