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 hematoxylin-eosin (HE) and CYP11B2 immunostained sections, and a consensus was established to define the identifiable features. The consensus was subsequently used by 6 additional pathologists (Group 2 from Australia, Brazil, Canada, Japan, United Kingdom, United States) 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 HE 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.

Keywords: CYP11B2; adrenal gland; diagnostic histopathology; immunohistochemistry; primary aldosteronism.

Figure 1.

HISTALDO consensus procedure. Paraffin-embedded adrenals were selected from HE staining and CYP11B2 immunohistochemistry to cover the wide spectrum of adrenal histopathology observed in surgically treated patients for unilateral PA (37 of 90 adrenals). Whole slide images of the 37 HE-stained adrenals were assessed by 5 pathologists (group 1 pathologists, round A) for histopathology associated with “classical” or “nonclassical” unilateral PA. Group 1 pathologists subsequently assessed the same adrenals based on HE and CYP11B2 (aldosterone synthase) immunostaining (round B) to evaluate the utility of CYP11B2 IHC in the diagnostic pathology of unilateral PA. Diverse features associated with unilateral PA for the consensus-building phase were identified from histopathologic findings. Consensus was achieved by 2 rounds of questionnaires comprising an open questionnaire, a dichotomous questionnaire (agree or disagree) and a face-to-face meeting (see Methods for further details). The consensus criteria were provided to a group of 6 additional pathologists (group 2 pathologists) as a guide for HE and CYP11B2 IHC-based examination of 18 of the 37 adrenals assessed by the group 1 pathologists. The 18 adrenals comprised 6 adrenals for which group 1 pathologists showed agreement (3 cases of agreement for classical and 3 cases of agreement for nonclassical histology of unilateral PA (, adrenals #1-#6) and all 12 adrenals for which group 1 pathologists showed a high level of disagreement (, adrenals #7-#18).

Figure 2.

Agreement between group 1 and group 2 pathologists for the histopathologic diagnosis of unilateral primary aldosteronism. Agreement was defined as at least 4 of the 5 group 1 pathologists or at least 4 of the 6 group 2 pathologists reaching the same histopathologic diagnosis. Classical, indicates “classical” histopathology associated with unilateral PA of a solitary APA or APN; nonclassical, indicates “nonclassical” histopathology of multiple APMs or multiple APNs (or multiple APMs and multiple APNs together) or aldosterone-producing diffuse hyperplasia.

Figure 3.

Histopathologic features in surgically removed adrenals from patients with unilateral primary aldosteronism. Paraffin-embedded adrenal sections (3 µm) were processed and stained for HE and immunostained for CYP11B2 (aldosterone synthase) using the mouse monoclonal antihuman CYP11B2 antibody (clone 17B) (10). APAs are shown with homogeneous (A) and heterogeneous (B) CYP11B2 immunostaining. The CYP11B2 positive immunostaining in tumor cells distinguishes an APA from a nonfunctioning adenoma (C). APNs = are morphologically visible with HE staining (D) whereas APMs are morphologically indistinct from adjacent adrenocortical cells (E). Black scale bar, 2 mm; white scale bar, 200 µm.