Histopathological features of aldosterone-producing lesions according to their different somatic genetic mutations

Primary aldosteronism (PA) is composed of different aldosterone-producing lesions including aldosterone-producing adenoma (APA), aldosterone-producing micronodules (APM), aldosterone-producing nodules (APN) and aldosterone-producing diffuse hyperplasia (APDH), all of which could result in hypertensive status and electrolyte imbalances. These aldosterone-producing lesions above are frequently accompanied by somatic mutations, including those of KCNJ5, CACNA1D, ATP1A1, and ATP2B3. APA is a neoplasm which frequently harbors KCNJ5 somatic mutations in tumor cells, especially those arising in East Asian patients. Histologically, APAs with KCNJ5 and ATP2B3 mutations presented with more clear cells, whereas those with ATP1A1 and CACNA1D mutations with more compact cells. In addition, the expression levels of steroidogenic enzymes such as aldosterone synthase (CYP11B2) in APAs varied among those with different patterns of somatic mutations, suggesting a potential association between specific mutations and altered aldosterone synthesis in APAs. In contrast, CACNA1D mutation was the most frequent subtype in non-neoplastic lesions including APM and APN, suggesting the possible correlation of KCNJ5 mutation with neoplastic aldosterone-producing lesions. This review provides pivotal insights into the histopathological diversity of aldosterone-producing lesions in PA patients and emphasizes the significance of genetic mutations in constituting the histological landscape of the lesion in order to better understand the detailed pathogenesis of primary aldosteronism.