Revisiting the Pathology of Bilateral Macronodular Adrenocortical Disease in Light of Recent Discoveries

Abstract

Bilateral Macronodular Adrenocortical Disease (BMAD) is a rare cause of ACTH-pituitary-independent Cushing’s syndrome. The recent discovery of a relationship with pathogenic variants of ARMC5, a putative tumor suppressor gene, suggests that genetic determination of the disease is more common than previously thought. In view of apparently sporadic and familial cases from a single tertiary center, we carried out a detailed morphologic review of 22 surgical specimens excised from patients with BMAD, comparing those with pathogenic variants of ARMC5 (PV+, n = 14) and those without (PV−, n = 8), as well as comparing those groups with a control group (n = 11). We also evaluated the expression of Ki-67, BCL-2, BAX, p53, ACTH, and ARMC5 protein. We observed that capsular extrusion, and trabecular and pseudoglandular architectural patterns, were more common in the PV+ group than in the PV− group, suggesting that the boundaries between hyperplastic and neoplastic processes are unclear in BMAD. The disorganized adrenal growth in BMAD was found to be unrelated to increased cell proliferation evaluated by Ki-67 or to changes in the expression of apoptosis-regulating proteins (BCL2 and BAX). In all cases, the ACTH immunoexpression was observed only in the adrenal medulla, suggesting that disruption of the corticomedullary architecture due to large confluent cortical nodules causes an imbalance in ACTH regulation in this intricate morphofunctional relationship. These data open new possibilities for comprehension of this heterogeneous adrenal disorder and further studies can clarify the role of cross-talking of the ACTH in BMAD nodules.