Aldosterone-Producing Adenomas

Unilateral primary aldosteronism (PA) is a common surgically curable cause of secondary hypertension. Adrenal glands removed for unilateral PA display histological heterogeneity. Recently, gain-of-function somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 have been found in 50% to 80% of aldosterone-producing adenomas (APAs). These gain-of-function mutations provide plausible mechanistic bases for excessive aldosterone production by APAs, but whether they are also responsible for adenoma formation has yet to be clarified. KCNJ5 mutant APAs, the commonest, have been shown to have an explicit genotype–phenotype relationship, exhibiting large diameters, having zona fasciculata (ZF)–like cell composition, and having low protein expression of KCNJ5 relative to their peritumoral zona glomerulosa (ZG). Conversely, for the other genes, controversy arises on whether they have a similar or opposite genotype–phenotype correlation. We, along with a few others, had shown through post hoc analysis that mutations in the ATP1A1, ATP2B3, CACNA1D, and CTNNB1 frequently occurred in APAs that were smaller and had a ZG-like cell composition. These findings, however, were not replicated in 2 other studies as they found these genes to have Abstract—Mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 are thought to cause the excessive autonomous aldosterone secretion of aldosterone-producing adenomas (APAs). The histopathology of KCNJ5 mutant APAs, the most common and largest, has been thoroughly investigated and shown to have a zona fasciculata–like composition. This study aims to characterize the histopathologic spectrum of the other genotypes and document the proliferation rate of the different sized APAs. Adrenals from 39 primary aldosteronism patients were immunohistochemically stained for CYP11B2 to confirm diagnosis of an APA. Twenty-eight adenomas had sufficient material for further analysis and were target sequenced at hot spots in the 5 causal genes. Ten adenomas had a KCNJ5 mutation (35.7%), 7 adenomas had an ATP1A1 mutation (25%), and 4 adenomas had a CACNA1D mutation (14.3%). One novel mutation in exon 28 of CACNA1D (V1153G) was identified. The mutation caused a hyperpolarizing shift of the voltage-dependent activation and inactivation and slowed the channel’s inactivation kinetics. Immunohistochemical stainings of CYP17A1 as a zona fasciculata cell marker and Ki67 as a proliferation marker were used. KCNJ5 mutant adenomas showed a strong expression of CYP17A1, whereas ATP1A1/CACNA1D mutant adenomas had a predominantly negative expression (P value =1.20×10). ATP1A1/CACNA1D mutant adenomas had twice the nuclei with intense staining of Ki67 than KCNJ5 mutant adenomas (0.7% [0.5%–1.9%] versus 0.4% [0.3%–0.7%]; P value =0.04). Further, 3 adenomas with either an ATP1A1 mutation or a CACNA1D mutation had >30% nuclei with moderate Ki67 staining. In summary, similar to KCNJ5 mutant APAs, ATP1A1 and CACNA1D mutant adenomas have a seemingly specific histopathologic phenotype. (Hypertension. 2017;70:129-136. DOI: 10.1161/HYPERTENSIONAHA.117.09057.) • Online Data Supplement