Adrenocortical carcinoma: current state of the art, ongoing controversies, and future directions in diagnosis and treatment

Abstract

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with an annual incidence of ~1 case per million population. Differentiating between ACC and benign adrenocortical tumors can be challenging in patients who present with an incidentally discovered adrenal mass, due to the limited specificity of standard diagnostic imaging. Recently, urine steroid metabolite profiling has been prospectively validated as a novel diagnostic tool for the detection of malignancy with improved accuracy over current modalities. Surgery represents the only curative treatment for ACC, although local recurrence and metastases are common, even after a margin-negative resection is performed. Unlike other intra-abdominal cancers, the role of minimally invasive surgery and lymphadenectomy in ACC is controversial. Adjuvant therapy with the adrenolytic drug mitotane is used to reduce the risk of recurrence after surgery, although evidence supporting its efficacy is limited; it is also currently unclear whether all patients or a subset with the highest risk of recurrence should receive this treatment. Large-scale pan-genomic studies have yielded insights into the pathogenesis of ACC and have defined distinct molecular signatures associated with clinical outcomes that may be used to improve prognostication. For patients with advanced ACC, palliative combination chemotherapy with mitotane is the current standard of care; however, this is associated with poor response rates (RR). Knowledge from molecular profiling studies has been used to guide the development of novel targeted therapies; however, these have shown limited efficacy in early phase trials. As a result, there is an urgent unmet need for more effective therapies for patients with this devastating disease.

Keywords: adrenal incidentaloma; adrenalectomy; adrenocortical carcinoma; diagnosis; mitotane; treatment.

Figure 1.

CT imaging in a patient with advanced ACC. (a) Axial CT image showing a heterogeneously enhancing right adrenal mass (red arrow) measuring 9.9 × 6.0 × 8.0 cm with possible invasion into the liver. (b) Coronal CT image from the same patient showing tumor thrombus within the inferior vena cava (yellow arrow). ACC, Adrenocortical carcinoma; CT, computed tomography.

Figure 2.

Gross pathology of a resected right-sided ACC. (a) Gross image showing a 10 cm brown mass with an attached rim of liver tissue that was resected en bloc. (b) Cut surface of the resected ACC showing a variegated appearance with focal areas of hemorrhage. ACC, adrenocortical carcinoma.

Figure 3.

Timeline of important studies in the pathogenesis, diagnosis, treatment, and prognostication of ACC over the past 20 years. ACC, adrenocortical carcinoma; ADIUVO, Efficacy of Adjuvant Mitotane Treatment; EDP, etoposide, doxorubicin, and cisplatin; ENS@T, European Network for the Study of Adrenal Tumors; EURINE-ACT, Evaluation of Urine Steroid Metabolomics in the Differential Diagnosis of Adrenocortical Tumours; FFPE, formalin-fixed paraffin-embedded; FIRM-ACT, First International Randomized Trial in Locally Advanced and Metastatic ACC Treatment; GALACCTIC, A Study of OSI-906 in Patients with Locally Advanced or Metastatic Adrenocortical Carcinoma; JAVELIN, Avelumab in Metastatic or Locally Advanced Solid Tumors; OS, overall survival; PFS, progression-free survival; TCGA-ACC, The Cancer Genome Atlas ACC Study.