International Histopathology Consensus for Unilateral Primary Aldosteronism

Abstract

Objective Develop a consensus for the nomenclature and definition of adrenal histopathologic features in unilateral primary aldosteronism (PA) Context Unilateral PA is the most common surgically-treated form of hypertension. Morphologic examination combined with CYP11B2 (aldosterone synthase) immunostaining reveals diverse histopathologic features of lesions in the resected adrenals. Patients and Methods Surgically removed adrenals (n= 37) from 90 patients operated from 2015 to 2018 in Munich, Germany, were selected to represent the broad histologic spectrum of unilateral PA. Five pathologists (Group 1 from Germany, Italy and Japan) evaluated the histopathology of haematoxylin-eosin and CYP11B2 immunostained sections and a consensus was established to define the identifiable features. The consensus was subsequently used by six additional pathologists (Group 2 from Australia, Brazil, Canada, Japan, UK, USA) for the assessment of all adrenals with disagreement for histopathologic diagnoses among group 1 pathologists. Results Consensus was achieved to define histopathologic features associated with PA. Use of CYP11B2 immunostaining resulted in a change of the original haematoxylin-eosin morphology-driven diagnosis in 5 (14%) of 37 cases. Using the consensus criteria, group 2 pathologists agreed for the evaluation of 11 of the 12 cases of disagreement among group 1 pathologists. Conclusion The HISTALDO (histopathology of primary aldosteronism) consensus is useful to standardize nomenclature and achieve consistency among pathologists for the histopathologic diagnosis of unilateral PA. CYP11B2 immunohistochemistry should be incorporated into the routine clinical diagnostic workup to localize the likely source of aldosterone production.

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

“…Based on the statement of international consensus on PA histopathology, aldosterone-producing non-neoplastic nodules are further classified into APMs and aldosterone-producing nodules www.e-enm.org 17 (APNs) according to whether the nodule is visible (detected) by H&E section (APN was defined as visible nodules) or not, although both types preserve the polarity of zonation, including the gradient of the pattern of CYP11B2 immunoreactivity from the outer to inner part [6]. The previously proposed classifications of "APCC" and/or "micronodule" have been reported to be difficult to distinguish from each other by histopathological findings including CYP11B2 immunohistochemistry alone, and required relevant clinical information such as the presence or absence of hypertension and/or PA.…”

“…APAs are solitary neoplasms usually measuring more than 10 mm in their greatest dimension and histologically composed of both compact and clear cells with immense intratumoral heterogeneity in their morphological features. The definition of APAs should be based upon both clinical information and histopathological features, including CYP11B2-positive immunoreactivity [ 6 ]. We previously reported that KCNJ5 mutated APAs mostly consisted of clear cells [ 38 ].…”

“…In contrast to the diffuse CYP11B2-positive cells in ZG, CYP11B2-positive and cytochrome P450 family 11 subfamily B member 1 (CYP11B1)- and cytochrome P450 family 17 subfamily A member 1 (CYP17A1)-negative adrenocortical cells were identified as clusters of CYP11B2-positive cells in the subcapsular areas previously termed as aldosterone-producing cluster cells (APCCs). Various nomenclature systems for the histopathological classification of aldosterone-producing lesions have been proposed at this juncture, but the international consensus of PA histopathology was very recently published, and the terms were re-defined and integrated [ 6 ].…”

“…PA is clinically classified into two subtypes, unilateral hyperaldosteronism (UHA) and bilateral hyperaldosteronism (BHA), according to the results of adrenal vein sampling [ 7 , 8 ]. In addition, UHA is histologically classified into aldosterone-producing adenoma (APA) and aldosterone-producing micronodules (APMs) using CYP11B2 immunohistochemistry [ 6 , 9 ]. BHA includes multiple APMs and aldosterone-producing diffuse hyperplasia (APDH) and occasionally bilateral APAs [ 6 , 10 ].…”

“…In addition, UHA is histologically classified into aldosterone-producing adenoma (APA) and aldosterone-producing micronodules (APMs) using CYP11B2 immunohistochemistry [ 6 , 9 ]. BHA includes multiple APMs and aldosterone-producing diffuse hyperplasia (APDH) and occasionally bilateral APAs [ 6 , 10 ]. Those non-neoplastic nodules involved in aldosterone overproduction were also recently reported to harbor APA-driver 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 ), which indicated that APM could represent the precursor lesion of APA [ 11 , 12 ].…”