Cortisol‐Producing Oncocytic Adrenocortical Carcinoma Harboring a GNAS Mutation: An Integrated Histologic, Ultrastructural, and Genomic Analysis

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Abstract
Oncocytic adrenal neoplasms are rare adrenocortical tumors characterized by abundant eosinophilic cytoplasm due to massive mitochondrial accumulation. Their biological behavior is often difficult to predict, and various diagnostic systems—including the Lin–Weiss–Bisceglia system, the Helsinki score, and the reticulin algorithm—are used to assess their malignant potential. We report a case of an oncocytic adrenocortical carcinoma associated with Cushing's syndrome and hyperandrogenemia in a 34‐year‐old woman. Histologically, the tumor showed diffuse growth of eosinophilic cells with marked pleomorphism and focal capsular invasion. Immunohistochemistry confirmed adrenocortical origin and cortisol production, with a Ki‐67 labeling index of 25%. Ultrastructural examination revealed densely packed mitochondria with lamellar and tubulovesicular cristae, accompanied by numerous whorled smooth endoplasmic reticulum formations, suggesting active remodeling of the endoplasmic reticulum. Whole‐exome sequencing identified a pathogenic GNAS R201S mutation, together with copy number losses of ARID1A , CDKN2A , and ZNRF3 with widespread copy number alteration. Despite multiple adverse prognostic indicators, the patient has remained disease‐free for over 5 years following adrenalectomy and adjuvant low‐dose mitotane therapy. These findings suggest that GNAS activation may drive steroidogenesis while attenuating malignant progression, as demonstrated by integrated morphologic and genomic assessment in this case.

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