The Genotype-Based Morphology of Aldosterone-Producing Adrenocortical Disorders and Their Association with Aging

Abstract

Primary aldosteronism (PA) is the most common cause of secondary hypertension, and is associated with an increased incidence of cardiovascular events. PA itself is clinically classified into the following two types: unilateral PA, mostly composed of aldosteroneproducing adenoma (APA); and bilateral hyperaldosteronism, consisting of multiple aldosterone-producing micronodules (APMs) and aldosterone-producing diffuse hyperplasia. Histopathologically, those disorders above are all composed of compact and clear cells. The cellular morphology in the above-mentioned aldosterone-producing disorders has been recently reported to be closely correlated with patterns of somatic mutations of ion channels including KCNJ5, CACNA1D, ATP1A1, ATP2B3, and others. In addition, in non-pathological adrenal glands, APMs are frequently detected regardless of the status of the renin-angiotensin-aldosterone system (RAAS). Aldosterone-producing nodules have been also proposed as non-neoplastic nodules that can be identified by hematoxylin and eosin staining. These non-neoplastic CYP11B2-positive nodules could represent possible precursors of APAs possibly due to the presence of somatic mutations. On the other hand, aging itself also plays a pivotal role in the development of aldosterone-producing lesions. For instance, the number of APMs was also reported to increase with aging. Therefore, recent studies indicated the novel classification of PA into normotensive PA (RAAS-independent APM) and clinically overt PA.

Keywords: Adenoma; Adrenal glands; Aldosterone; Pathology.

Fig. 1

Histopathological entities of aldosterone-producing lesions. Aldosterone-producing lesions are initially classified into neoplastic (microaldosterone-producing adenoma [microAPA] and APA) and non-neoplastic lesions (aldosterone-producing micronodule [APM], previously termed as aldosterone-producing cluster cell [APCC] and aldosterone-producing nodule [APN]). APMs could physiologically exist in the normal adrenal gland and pathologically in bilateral hyperaldosteronism. Both APMs and APNs are considered to harbor both compact and clear cells with polarity of cytochrome P450 family 11 subfamily B member 2 (CYP11B2) expression pattern and no cortisol-synthesizing capability. APMs frequently harbor predominant calcium voltage-gated channel subunit alpha1 D (CACNA1D) mutations. APA, including microAPA, has frequent potassium inwardly rectifying channel subfamily J member 5 (KCNJ5) mutations and consists of predominant clear cells. Both autonomous aldosterone and cortisol overproduction are more pronounced in KCNJ5-mutated APAs. ATP2B3, ATPase plasma membrane Ca²⁺ transporting 3; ATP1A1, ATPase Na⁺/K⁺ transporting subunit alpha 1; CTNNB1, catenin beta 1; CLCN2, chloride voltage-gated channel 2; WT, wild-type.

Fig. 2

Representative microscopic images of H&E, cytochrome P450 family 11 subfamily B member 2 (CYP11B2) immunohistochemistry (IHC), and cytochrome P450 family 17 subfamily A member 1 (CYP17A1) IHC. (A) Aldosterone-producing micronodules, previously termed aldosterone-producing cluster cells. (B) Aldosterone-producing diffuse hyperplasia. (C) Aldosterone-producing adenoma.

Fig. 3

Development of aldosterone-producing lesions along with aging. Aldosterone-producing micronodule (APM) develops from adrenal precursor cells or progenitor ZG cells. Along with aging, APM contributing to normal renin-angiotensin-aldosterone system (RAAS) has the potential of developing to APM that is independent of RAAS and accounts for normotensive primary aldosteronism (PA). APM may continue to develop with aging, which clinically accounts for many cases of PA, but its association with APA remains unclear. In addition, aging could play a pivotal role in the formation of aldosterone-producing micronodules.