Aldosterone-Producing Cell Clusters in Normal and Pathological States

Abstract

Primary aldosteronism (PA) significantly increases the risk of cardiovascular complications, and early diagnosis and targeted treatment based on its pathophysiology is warranted. Next-generation sequencing (NGS) has revealed recurrent somatic mutations in aldosterone-driving genes in aldosterone-producing adenoma (APA). By applying CYP11B2 (aldosterone synthase) immunohistochemistry and NGS to adrenal glands from normal subjects and PA patients, we and others have shown that CYP11B2-positive cells make small clusters, termed aldosterone-producing cell clusters (APCC), beneath the adrenal capsule, and that APCC harbor somatic mutations in genes mutated in APA. We have shown that APCC are increased in CT-negative PA adrenals, while others showed potential progression from APCC to micro APA through mutations. These results suggest that APCC are a key factor for understanding the origin of PA, and further investigation on the relation between APCC and PA is highly needed.

Figure 1. Somatic mutation prevalence in aldosterone-producing adenoma (APA) and aldosterone-producing cell clusters (APCC)

The distinct mutation pattern in APA (European cohorts) and APCC is shown. KCNJ5 is the most commonly mutated gene in APA, whereas CACNA1D mutations are more common in APCC (22/84, 26%). CTNNB1 mutations are also described in APA, while no APCC harbor them. APA chart was adapted from references and , in which all four genes (KCNJ5, CACNA1D, ATP1A1 and ATP2B3) were analyzed in independent cohorts. Note that CTNNB1 was not examined in reference , therefore the prevalence is 10/198. APCC chart was adapted from references and . Mutations in APCC include both reported and unreported ones in APA.

Figure 2. Histology and IHC of a representative aldosterone-producing cell cluster (APCC)

A representative APCC from a normotensive patient is shown in A–D. A. Hematoxylin and eosin (H&E) staining shows zona glomerulosa (ZG) and zona fasciculata (ZF) cells in APCC are not distinguishable from surrounding ZG and ZF cells, and adrenal zonation is preserved with no obvious cellular atypia or capsulization. B. CYP11B2 immunohistochemistry (IHC) shows distinct positive cluster of cells (APCC). C–D. APCC negative staining for CYP17A and CYP11B1. Adapted from Supplemental Figure 1 in reference .