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Genomic and immunohistochemical analysis in human adrenal cortical neoplasia reveal beta-catenin mutations as potential prognostic biomarker.

Evaluation for malignancy of the adrenal cortex, adrenal cortical carcinoma (ACC), is a challenge in surgical pathology due to its relative rarity and histologic overlap with its benign counterpart, adrenocortical adenoma (ACA). We characterized a cohort of human ACC and ACA, including a molecular screen, with a goal of identifying potential diagnostic adjuncts. Thirty-six cases of ACC underwent histologic and clinical review. In the 31 ACC cases with available material and a cohort of 10 ACA cases, a multiplex nucleotide amplification molecular screen from formalin-fixed, paraffin-embedded tissue was peformed. ACCs demonstrated a wide variety of clinical and histologic characteristics with overall poor but unpredictable survival for subjects with ACC. By mutational screen, 12/31 (38.7%) carcinomas harbored CTNNB1 mutations, 1 with an additional TP53 mutation; 1 case each had isolated APC and TP53 mutations; 16 were wild-type for all tested loci; and 1 case demonstrated repeated assay failures. Two of the 10 ACA (20%) demonstrated CTNNB1 mutations by mutational screen, with no additional mutations. Immunohistochemistry for beta-catenin was performed and compared with the results of the molecular screen. Strong nuclear beta-catenin immunopositivity corresponded to the presence of CTNNB1 mutation by genotyping in 10 of 12 cases (83% sensitivity); the mismatched case(s) demonstrated strong membranous staining by immunohistochemistry. Seventeen of the 18 cases without CTNNB1 mutation showed membranous staining or did not stain (94% specificity); the mismatched case demonstrated scattered (<10%) positive nuclei. Both mutations in ACA were corroborated with immunohistochemistry for beta-catenin. No histomorphologic parameter appeared dominant in lesions with a particular mutational status. Based on these results, mutational status of CTNNB1 in adrenal cortical neoplasms can be predicted with reasonable accuracy by immunohistochemical cellular localization. Nuclear localization of beta-catenin by immunostain may be helpful in analysis of select lesions of the adrenal cortex whose biological behavior is uncertain from clinical and histologic information; a larger cohort is required to test this hypothesis.