MON-478 - Histopathology of Bilateral Macronodular Adrenocortical Disease and Its Association with ARMC5 Variant Status: A 10-Patient Case Series

Background
Bilateral macronodular adrenocortical disease (BMAD), also known as primary bilateral macronodular adrenal hyperplasia (PBMAH), is a rare cause of ACTH-independent hypercortisolism. Germline pathogenic variants in ARMC5, a tumor-suppressor gene involved in adrenal cell survival and proliferation, represent the most common known genetic cause, particularly in familial cases, and are frequently associated with additional somatic second-hit events. However, correlations between histopathological features, genetic background, and clinical or imaging findings in routine practice remain incompletely characterized.
Objective
To describe clinical, imaging, and histopathological features of patients with BMAD and to explore histopathological patterns according to ARMC5 variant status.
Methods
We conducted a descriptive case series of 10 patients with BMAD followed at a tertiary referral center. Clinical phenotype (overt Cushing’s syndrome or mild autonomous cortisol secretion), hormonal evaluation, and adrenal imaging were reviewed. Adrenalectomy specimens were analyzed for nodular architecture, cellular composition (clear, compact eosinophilic, and oncocytic cells), and stromal features. Germline ARMC5 sequencing was performed, and findings were summarized according to variant status.
Results
All patients were female, with a median age of 46 years. Overt Cushing’s syndrome was present in 6 patients, and 4 had mild autonomous cortisol secretion. Imaging revealed bilateral adrenal macronodules in all cases, with marked variability in adrenal size and nodule burden. Pathogenic or likely pathogenic ARMC5 variants were identified in 7 patients. In variant carriers, histology typically demonstrated coalescent yellow macronodules distorting the adrenal parenchyma, with minimal residual non-nodular tissue. Nodules were predominantly composed of clear cells arranged in trabecular patterns, without malignant features. Similar histopathological findings were observed across different degrees of cortisol excess.
Conclusion
This case series supports an association between ARMC5 variants and distinct histopathological features in BMAD. Emerging evidence suggests that somatic second-hit ARMC5 mutations play a key role in disease development and phenotypic expression. These findings highlight the marked morphological heterogeneity of BMAD and emphasize the value of integrating clinical, genetic, and pathological data for comprehensive disease characterization.

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