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Adrenal (Excluding Mineralocorticoids)

SAT-421 - Unmasking the Molecular Landscape of Cortisol-Producing Adenomas: An Immunohistochemistry-Guided Sequencing Approach Reveals Distinct Mutational Profiles in Overt Cushing and Mild Autonomous Cortisol Excess

Saturday, June 13, 2026
9:30 AM - 4:30 PM CT


Introduction: Cushing syndrome (CS) is characterized by cortisol excess and represents a major endocrine cause of cardiometabolic morbidity. Solitary cortisol-producing adenomas (CPAs) account for most cases of adrenocorticotropic hormone (ACTH)-independent CS. The majority of CPAs harbor somatic cortisol-driver variants in genes including PRKACA, CTNNB1, and GNAS.

Objective: To determine the somatic variant spectrum in CPAs from patients with either overt Cushing syndrome (OCS) or mild autonomous cortisol secretion (MACS) using an immunohistochemistry (IHC)-guided next-generation sequencing (NGS) pipeline applied to archival formalin-fixed paraffin-embedded (FFPE) adrenal tissue.

Method: FFPE adrenal tissue from 166 patients (53 men, 113 women) with either OCS (n = 82) or MACS (n = 84) was analyzed for the presence of somatic variants. IHC for 11β-hydroxylase (CYP11B1), 17α-hydroxylase/17,20-lyase (CYP17A1), and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) was performed to identify CPAs and guide tissue capture. DNA isolated from these tumors was subjected to Sanger, targeted NGS, and/or whole exome sequencing for the identification of known cortisol-driver gene variants.

Results: IHC-guided analysis identified 170 CPAs, comprising 84 OCS CPAs (29 men, 55 women) and 86 MACS CPAs (26 men, 60 women). Somatic variants were identified in 67.6% (115/170) of CPAs overall, including 71.4% (60/84) of OCS CPAs and 64% (55/86) of MACS CPAs. PRKACA was the most frequently mutated gene in OCS CPAs (38.1%, 32/84), whereas CTNNB1 variants were predominant in MACS CPAs (44.2%, 38/86). GNAS variants occurred at similar frequencies in OCS (8.3%, 7/84) and MACS (10.5%, 9/86). Additionally, rare somatic variants were also identified in three OCS CPAs involving PRKAR1A (n = 2) and PDE11A (n = 1).

Conclusion: A comprehensive FFPE CPA IHC-guided sequencing approach identified somatic variants in ~68% of CPAs from patients with ACTH-independent adrenal CS. These data confirm the predominance of PRKACA variants in OCS CPAs, consistent with prior studies, and demonstrate a higher prevalence of CTNNB1 variants in MACS CPAs. These findings suggest distinct molecular underpinnings of OCS and MACS, which may have implications for understanding disease pathogenesis and clinical management. Further investigation is warranted to characterize the molecular drivers in ~32% of CPAs without identifiable variants.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*