Two-hit model for the development of aldosterone-producing adenoma: supporting from two new cases.

Recently, a two-hit model for the development of aldosterone-producing adenoma (APA) was proposed but until now, only two cases supporting the model have been reported. Here, we present two new cases of primary aldosteronism (PA), both of which had large functional adenomas with somatic mutations in aldosterone-driving genes. Furthermore, the first patient, who had a history of colorectal cancer, was found to have a germline and an additional somatic mutation in APC , and APC inactivation was confirmed by immunohistochemistry. The other patient had pathogenic somatic mutation in CTNNB1 . These pro-proliferation mutations resulted in abnormal activation of the Wnt/β-catenin pathway. Two consecutive events apparent in these patients, namely, the first event leading to cell proliferation and the second driving hormonal hypersecretion, supported the two-hit model of APA development. The two-hit model usually occurs in the larger adenomas, and the driving factors of the first hit that promote cell proliferation still require further research and exploration.