Adrenocortical Carcinoma

Epidemiology & Impact

Adrenocortical carcinoma (ACC) is an extremely rare and aggressive malignancy arising from the adrenal cortex, with an estimated annual incidence of 0.7 to 2.0 cases per million population. In the United States, approximately 600 new cases are diagnosed each year. The disease shows a bimodal age distribution, with peaks in children under age 5 and adults between ages 40 and 50, and a slight female predominance. In southern Brazil, the incidence in children is 10 to 15 times higher than the global average due to a founder mutation in TP53 (R337H). Approximately 60% of ACCs are functional tumors that produce excess hormones, most commonly cortisol (causing Cushing syndrome) or androgens (causing virilization), which may lead to earlier diagnosis. Despite this, many tumors are discovered incidentally on abdominal imaging or present at advanced stages, contributing to a generally poor prognosis with overall 5-year survival rates of 35-50%.

Molecular Biology & Biomarkers

The molecular biology of ACC is characterized by a high frequency of TP53 mutations and alterations in the Wnt/β-catenin signaling pathway, including activating mutations in CTNNB1 (present in approximately 15-40% of cases). Comprehensive genomic profiling has identified two main molecular subtypes: a hypermutated cluster with frequent mutations in MSH2 and other mismatch repair genes (associated with better prognosis), and a chromosomally unstable cluster with widespread copy number alterations (associated with poor outcomes). Overexpression of IGF-2 through loss of imprinting at 11p15 is found in approximately 90% of ACCs and has been a target of therapeutic investigation. ZNRF3, an inhibitor of the Wnt pathway, is frequently inactivated. The Ki-67 proliferation index is one of the most important prognostic markers, with values above 10% associated with significantly worse outcomes. The Weiss scoring system, based on histological features, remains the standard for distinguishing benign adrenal adenomas from carcinomas.

Evolving Treatment Landscape

Surgery remains the cornerstone of potentially curative treatment for ACC, with complete resection (R0) representing the most important prognostic factor. Adjuvant mitotane, an adrenolytic drug derived from the insecticide DDT, is recommended for patients with high-risk features (R1 resection, Ki-67 >10%, stage III) and has been shown to improve recurrence-free survival. For advanced or metastatic disease, the EDP-M regimen (etoposide, doxorubicin, cisplatin plus mitotane) is the established first-line combination based on the FIRM-ACT trial. Unfortunately, response rates remain modest and durable responses are uncommon. Immunotherapy with checkpoint inhibitors has shown limited but promising activity in selected ACC patients, particularly those with microsatellite instability or high tumor mutational burden. Clinical trials investigating combination immunotherapy approaches and novel targeted agents remain critically important for this rare disease with limited treatment options.

Note: Mitotane is the only FDA-approved drug specifically indicated for adrenocortical carcinoma. Combination chemotherapy (EDP-M: etoposide, doxorubicin, cisplatin plus mitotane) is used for advanced disease based on the FIRM-ACT trial. Pembrolizumab is available via MSI-H/TMB-H tumor-agnostic indication.

EMA-Approved Therapies for Adrenocortical Carcinoma

The European Medicines Agency (EMA) regulates drug approvals across the European Union. Below are key therapies with comparative information to FDA approvals.

For complete European drug information, visit ema.europa.eu ↗