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.

Cellular Senescence in Adrenocortical Biology and Its Disorders

“…The less physiological aldosterone production is possibly due to the shrinkage of the ZG with decreased aldosterone synthase expression during aging, whereas the autonomous or renin-independent aldosterone production in older individuals is possibly due to the increased number of aldosterone-producing micronodules (APMs) [ 76 ]. Notably, APMs were reported to frequently harbor aldosterone-producing adenoma (APA) driving somatic mutations of various ion channels, including potassium inwardly rectifying channel subfamily J member 5 (KCNJ5) , calcium voltage-gated channel subunit alpha1 D (CACNA1D) , ATPase Na + /K + transporting subunit alpha 1 (ATP1A1) and ATPase plasma membrane Ca 2+ transporting 3 (ATP2B3) [ 11 , 12 ]. Another study also revealed the presence of numerous renin independent APMs in normal adrenal glands adjacent to APAs with autonomous aldosterone production [ 37 ].…”

“…APA is the major cause of primary aldosteronism (PA), which accounts for 5–10% of all hypertensive patients [ 123 ]. The formation of APA is caused by somatic mutations of the aldosterone-driver gene, such as KCNJ5 , CACNA1D , ATP1A1 and ATP2B3 [ 12 ]. CPA is the result of abnormal differentiation from ZF cells and is usually caused by somatic mutations of protein kinase cAMP-activated catalytic subunit alpha ( PRKACA ) , GNAS complex locus ( GNAS ) and catenin beta 1 ( CTNNB1 ), resulting in hypercortisolism and clinical Cushing’s syndrome [ 106 ].…”

“…Along with deep exploration in the adrenal field, an age-dependent atrophy of the adrenal cortex has been demonstrated, especially that of the ZR layer [ 5 , 6 , 7 , 8 , 9 , 10 ]. In adrenocortical disorders, cortisol-producing adenomas (CPAs) were reported to produce excessive adrenal steroids, which resulted in in situ or local cellular senescence and more senescent phenotype being harbored than aldosterone-producing adenomas (APAs) [ 11 , 12 , 13 ]. Both APAs and CPAs were demonstrated to consist of two cellular subtypes, namely compact and clear tumor cells, which may harbor different senescent phenotypes reflecting intratumoral heterogeneity [ 11 , 12 , 14 ].…”

“…In adrenocortical disorders, cortisol-producing adenomas (CPAs) were reported to produce excessive adrenal steroids, which resulted in in situ or local cellular senescence and more senescent phenotype being harbored than aldosterone-producing adenomas (APAs) [ 11 , 12 , 13 ]. Both APAs and CPAs were demonstrated to consist of two cellular subtypes, namely compact and clear tumor cells, which may harbor different senescent phenotypes reflecting intratumoral heterogeneity [ 11 , 12 , 14 ]. In addition to the in situ or local effect of adrenal steroids, they were also reported to induce a distant cellular senescence in other tissues such as the brain, kidneys, lungs, liver, bone and colon, as well as in some cancers [ 14 , 15 , 16 , 17 , 18 ].…”

Expression of CYP11B1 and CYP11B2 in adrenal adenoma correlates with clinical characteristics of primary aldosteronism

“…2 In a German cohort of PA, 77.6% of the patients had a positive result for at least one of three screening tests for Cushing's syndrome: a 1 mg overnight dexamethasone suppression test, late-night salivary cortisol and/or 24-h urinary free cortisol. 3 The coexistence of autonomous cortisol secretion was associated with poor clinical outcomes, impaired glucose metabolism and psychological symptoms in patients with PA. [3][4][5] With the development of monoclonal antibodies specific to steroidogenic enzymes, including CYP11B1 (11β-hydroxylase), CYP11B2 (aldosterone synthase) and CYP17A1 (17α-hydroxylase and 17,20-lyase), immunohistochemistry (IHC)-based analyses of adrenal tissues have provided new insights into the pathogenesis of PA. [6][7][8][9] CYP11B1 is expressed mainly in the adrenal zona fasciculata and is responsible for the synthesis of cortisol. The expression of CYP11B1 in adrenal adenoma tissue of patients with PA was positively associated with the excretion of glucocorticoid metabolites.…”