SAT-470 Histological Fingerprint of Bilateral Macronodular Adrenocortical Disease (BMAD) Associated with ARMC5

Abstract Disclosure: H.L. Charchar: None. F. Ledesma: None. A.W. Kuhn: None. B.M. Mariani: None. M.Y. Nishi: None. M.Q. Almeida: None. V. Victor Srougi: None. F.Y. Tanno: None. J. Chambô: None. A. Latronico: None. M.A. Pereira: None. B.B. Mendonca: None. M.B. Fragoso: None. Introduction: Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing’s syndrome. Recent discoveries of clonal molecular alterations have highlighted the neoplastic nature of the disease, leading to the proposed term bilateral macronodular adrenocortical disease (BMAD). BMAD is characterized by the presence of functional adrenal macronodules with variable cortisol secretion. It can occur in association with genetic syndromes or present in isolated forms, such as familial or apparently sporadic cases. Since 2013, mutations in the ARMC5 gene have been recognized as a major genetic cause of BMAD. Objective: This study aims to investigate the histological features that enhance our understanding of patients with BMAD. Methods: A total of 19 patients who underwent surgery for BMAD at HCFMUSP between 2006 and 2021 were included in this study, all of whom were sequenced for ARMC5 germline pathogenic variants. Macroscopic photographs and H&E-stained slides were reviewed by a pathologist (FL), who was blinded to the clinical and genetic data. Results: Twelve patients (63.2%) carried germline pathogenic variants in ARMC5. Among them, three were apparently sporadic cases, while nine were familial cases, comprising six unrelated index cases and three relatives. A total of 11 distinct ARMC5 germline variants were identified, including 8 previously reported (p.Arg654; p.Leu365Pro; Ile58Asnfs45; p.His808Pro; p.Pro662Hist; p.Leu318Val; p.Gly323Asp) and 3 novel variants (p.Leu900Serfs12; p.Leu131Phefs7; p.Ser94Valfs8). In addition, nine different somatic alterations were described (p.Glu442Glyfs19; p.Arg366Leufs7; p.Leu526Alafs9; p.Cys657Trp; p.Leu685del; p.Ala854_Val855del; p.Ala83Argfs51; p.Pro695Serfs20; p.Arg271Glyfs7). Patients carrying ARMC5 germline pathogenic variants (Group 1) exhibited distinct microscopic features, including extensive areas of extracapsular extravasation; trabecular and pseudoglandular patterns; reverse polarity with nuclei positioned away from the basement membrane; and absence of adjacent adrenal parenchyma. In contrast, the seven patients without ARMC5 germline pathogenic variants (Group 2; 36.8%) displayed a slight predominance of clear cells interspersed with compact cells, occasionally showing moderate cytoplasm and lightly eosinophilic nodular outlines. Other findings included areas of adipose metaplasia and frequent lymphoid aggregates, which were sometimes confluent. Conclusion: This study presents a cohort of index and relative patients, proposing a histological fingerprint classification for BMAD associated with ARMC5 germline pathogenic variants. Remarkably, blinded pathologists accurately identified patients with ARMC5 germline pathogenic variants with 100% accuracy, highlighting the distinct histological features linked to this genetic alteration. Presentation: Saturday, July 12, 2025