From hyperplasia to carcinoma: a molecular driven adrenal disease

Abstract

Bilateral Macronodular Adrenocortical Disease (BMAD) is characterized by bilateral benign macronodules and, frequently, autonomous cortisol secretion. Germline molecular alterations of tumor suppressor genes are identified in around 30% of cases, the most frequent being ARMC5. Even if adrenocortical nodular disease often occurs with tumor suppressor gene pathogenic variant, the association with adrenal cortical carcinoma (ACC) is rare and no functional studies have proven a link between these two diseases. We reported the case of a woman with an adrenal Cushing's syndrome developed on BMAD. Over 20 years later, ACC was diagnosed, developed inside a benign nodule of macronodular adrenal gland. Germline genotyping showed no alteration in CDKN1B, KDM1A, PRKACA, PRKAR1A, MEN1, APC, ARMC5, or TP53 genes. Next-generation sequencing has been performed in the ACC and the adjacent macronodular tissue, showing a progressive accumulation of somatic protumoral molecular alterations between the benign nodular part of the adrenal gland and the ACC. Therefore, we hypothesize that BMAD could be an early event of ACC development and may beneficiated from more systematic radiological monitoring.

Keywords: Cushing's syndrome; adrenal cortical carcinoma; bilateral macronodular adrenocortical disease; mutational burden.