Histological Characterization of Aldosterone-producing Adrenocortical Adenomas with Different Somatic Mutations

Abstract

Context Aldosterone-producing adrenocortical adenomas (APAs) are mainly composed of clear (lipid rich) and compact (eosinophilic) tumor cells. The detailed association between these histological features and somatic mutations (KCNJ5, ATP1A1, ATP2B3, and CACNA1D) in APAs is unknown. Objective To examine the association between histological features and individual genotypes in APAs. Methods Examination of 39 APAs subjected to targeted next-generation sequencing (11 KCNJ5, 10 ATP1A1, 10 ATP2B3, and 8 CACNA1D) and quantitative morphological and immunohistochemical (CYP11B2 and CYP17A1) analyses using digital imaging software. Results KCNJ5- and ATP2B3-mutated APAs had clear cell dominant features (KCNJ5: clear 59.8% [54.4–64.6%] vs compact 40.2% (35.4–45.6%), P = .0022; ATP2B3: clear 54.3% [48.2–62.4 %] vs compact 45.7% (37.6–51.8 %), P = .0696). ATP1A1- and CACNA1D-mutated APAs presented with marked intratumoral heterogeneity. A significantly positive correlation of immunoreactivity was detected between CYP11B2 and CYP17A1 in tumor cells of KCNJ5-mutated APAs (P = .0112; ρ = 0.7237), in contrast, significantly inverse correlation was detected in ATP1A1-mutated APAs (P = .0025; ρ = −0.8667). Conclusion KCNJ5-mutated APAs, coexpressing CYP11B2 and CYP17A1, were more deviated in terms of zonation-specific differentiation of adrenocortical cells than ATP1A1- and ATP2B3-mutated APAs.

The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease

“…Moreover, the peripheral steroid profiles and histologic features (including APA, hyperplasia and APCC) of unilateral PA patients who underwent adrenalectomy contributed to the predicted postoperative biochemical outcome [60]. APA harboring KCNJ5 mutations principally display a lipid rich clear cell (ZF-like) histology, whereas APA with CACNA1D, ATP1A1, and ATP2B3 mutations predominantly show a compact cell (ZG-like) predominate histology [63][64][65][66][67]. The histologic features of KCNJ5-mutated APA are also associated with the higher expression of the cortisol biosynthetic enzymes, CYP11B1 and CYP17A1 [63,65,66].…”

“…APA harboring KCNJ5 mutations principally display a lipid rich clear cell (ZF-like) histology, whereas APA with CACNA1D, ATP1A1, and ATP2B3 mutations predominantly show a compact cell (ZG-like) predominate histology [63][64][65][66][67]. The histologic features of KCNJ5-mutated APA are also associated with the higher expression of the cortisol biosynthetic enzymes, CYP11B1 and CYP17A1 [63,65,66]. Both 18-oxocortisol and 18-hydroxycortisol are synthesized from cortisol by CYP11B2, while only the latter can be produced by CYP11B1 (▶ Fig.…”

Immunohistochemistry of the Human Adrenal CYP11B2 in Normal Individuals and in Patients with Primary Aldosteronism

“…Visual characterization of adenomas from patients suggested that tumors with KCNJ5 mutations were larger than other aldosterone-producing adenomas and had lipid-laden ZF-like cells [48]. Subsequent digital microscopic analysis of these adenomas demonstrated that they comprised almost 60 % ZF-like clear cells with the rest being compact ZG-like cells [49]. Immunohistochemistry demonstrated that some tumors with KCNJ5 mutations comprise cells expressing only CYP11B2 with those co-expressing CYP11B2 and 17α-hydroxylase and, less frequently, cells co-expressing CYP11B2, 17α-hydroxylase and CYP11B1 [49][50][51].…”

“…Subsequent digital microscopic analysis of these adenomas demonstrated that they comprised almost 60 % ZF-like clear cells with the rest being compact ZG-like cells [49]. Immunohistochemistry demonstrated that some tumors with KCNJ5 mutations comprise cells expressing only CYP11B2 with those co-expressing CYP11B2 and 17α-hydroxylase and, less frequently, cells co-expressing CYP11B2, 17α-hydroxylase and CYP11B1 [49][50][51]. The co-expression of these enzymes explains the marked increase in the hybrid steroids 18-hydroxycortisol and 18-oxocortisol that distinguish patients with KCNJ5 mutations from those with other mutations [52,53].…”

“…The co-expression of these enzymes explains the marked increase in the hybrid steroids 18-hydroxycortisol and 18-oxocortisol that distinguish patients with KCNJ5 mutations from those with other mutations [52,53]. Adenomas with the ATP2B3 mutations also comprise almost equal numbers of clear and compact cells [49]. Adenomas with the ATP1A1, and CACNA1D mutations are more histologically heterogeneous [49].…”