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Aldosterone-producing adenomas (APAs) harbor marked intratumoral heterogeneity in terms of morphology, steroidogenesis, and genetics. However, an association of biological significance of morphologically identified tumor cell subtypes and genotypes is virtually unknown.KCNJ5 mutation is most frequently detected and generally considered a curable phenotype by adrenalectomy. Therefore, to explore the biological significance ofKCNJ5 mutation in APA based on intracellular hormonal activities, 35 consecutively selected APAs (n=18;KCNJ5 mutated, n=17; wild type) were quantitatively examined in the whole tumor areas by newly developed digital image analysis incorporating their histological and ultrastructural features (14 cells from 2KCNJ5 -mutated APAs and 15 cells from 1 wild type) and CYP11B2 immunoreactivity. Results demonstrated thatKCNJ5 -mutated APAs had significantly lower nuclear/cytoplasm ratio and more abundant clear cells than wild type. CYP11B2 immunoreactivity was not significantly different between these genotypes, but a significant correlation was detected between the proportion of clear cells and CYP11B2 immunoreactivity in all of the APAs examined. CYP11B2 was predominantly immunolocalized in clear cells inKCNJ5 -mutated APAs. Quantitative ultrastructural analysis revealed thatKCNJ5 -mutated APAs had significantly more abundant and smaller-sized mitochondria with well-developed cristae than wild type, whereas wild type had more abundant lipid droplets per unit area despite the small number of the cases examined. Our results did provide the novel insights into the morphological features of APA based on their biological significance.KCNJ5 -mutated APAs were characterized by predominance of enlarged lipid-rich clear cells possibly resulting in increased neoplastic aldosterone biosynthesis.

Tumor Cell Subtypes Based on the Intracellular Hormonal Activity in KCNJ5 -Mutated Aldosterone-Producing Adenoma