# Adrenocortical carcinoma

Source: https://onco.cc/cancers/adrenocortical/  
OnCo record `adrenocortical` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

Complete 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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-08
- Also known as: ACC
- Tags: gap-fill; endocrine; rare
- 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)

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/adrenocortical/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/adrenocortical/#overview [2 subtypes, 4 state-of-the-art points]
- What it is (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/adrenocortical/#what-it-is [7 subtypes]
- Finding it (on the hub): How it shows itself, how it is confirmed, what screening exists, and the biomarkers clinicians test for. https://onco.cc/cancers/adrenocortical/#finding-it [6 biomarkers]
- Treating it (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/adrenocortical/#treating-it [4 settings, 4 decisions with options]
- Evidence (on the hub): Trials recruiting now, the landmark trials, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/adrenocortical/#evidence [2 trials, 1 key paper, 8 milestones]
- The science (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/adrenocortical/#science [14 targets, 2 pathways]
- Where you are (own page): Cases by country, the UK and NHS pathway and other country lenses, and the expert centres with trials on record. https://onco.cc/cancers/adrenocortical/where-you-are/ [1 centre]
- Living with it (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/adrenocortical/#living-with-it [17 questions, 6 red cards]
- What is coming (own page): Everything in development, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/adrenocortical/coming/ [7 medicines, 2 trials, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/adrenocortical/data/ [51 connected records]

## Standard of care

- Localised (ENSAT I-III): 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. ([Mitotane](https://onco.cc/drugs/mitotane/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/))
- Advanced, aggressive: EDP-M (etoposide, doxorubicin, cisplatin + mitotane) ×6-8 with surgery for responders; streptozocin-mitotane second line. ([Etoposide](https://onco.cc/drugs/etoposide/), [Doxorubicin](https://onco.cc/drugs/doxorubicin/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Mitotane](https://onco.cc/drugs/mitotane/))
- Advanced, indolent: Mitotane monotherapy (target level 14-20 mg/L) with glucocorticoid replacement; local therapies (ablation, radiotherapy) for oligometastases. ([Mitotane](https://onco.cc/drugs/mitotane/), [Thermal ablation (RFA, microwave, cryo)](https://onco.cc/technologies/thermal-ablation/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/))
- Progressive after chemotherapy: Pembrolizumab, cabozantinib, gemcitabine-capecitabine; control hormone excess; clinical trials. ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Cabozantinib](https://onco.cc/drugs/cabozantinib/))

## State of the art

- 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.

## Open problems

- 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.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Adrenocortical_carcinoma
- ESE/ENSAT ACC guideline 2018: https://doi.org/10.1530/EJE-18-0608
- FIRM-ACT (NEJM 2012): https://doi.org/10.1056/NEJMoa1200966
- NCI PDQ: adrenocortical carcinoma: https://www.cancer.gov/types/adrenocortical/patient/adrenocortical-treatment-pdq

## Connected records

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

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JSON: https://onco.cc/api/v1/entities/adrenocortical.json