Histopathological classification of cross-sectional image negative hyperaldosteronism.

CONTEXT: Approximately half of primary aldosteronism (PA) have clinically evident disease according to clinical (hypertension) and/or laboratory (aldosterone and renin levels) findings but do not have nodules detectable in routine cross-sectional imaging. However, the detailed histopathologic, steroidogenic and pathobiological features of cross-sectional image negative PA have not been well characterized.

OBJECTIVE: Examine histopathology, steroidogenic enzyme expression and somatic mutation status of aldosterone-driver genes in adrenals from cross-sectional image negative hyperaldosteronism.

METHODS: 25 cross-sectional image negative cases were retrospectively reviewed. In situ adrenal aldosterone production capacity was determined using immunohistochemistry (IHC) of steroidogenic enzymes. Somatic mutation status of aldosterone-driver genes (ATP1A1, ATP2B3, CACNA1D and KCNJ5) was determined in the CYP11B2 immunopositive areas (n=35, micronodule: n=32, ZG: n=3) using next-generation sequencing (NGS) after macrodissection.

RESULTS: 25 cases were classified as multiple adrenocortical micronodules (MN, n=13) or diffuse hyperplasia of zona glomerulosa (DH, n=12) based upon histopathological evaluation and CYP11B2 IHC. Somatic mutations in aldosterone-driver genes were detected in 21 of 26 (81%) of CYP11B2-positive cortical micronodules in MN, with 17 (65%) mutations in CACNA1D, two (8%) in KCNJ5, and one each (4% each) in ATP1A1 and ATP2B). One of six (17%) of nodules in DH harbored somatic aldosterone-driver gene mutations (in CACNA1D), however no mutations were detected in CYP11B2-positive non-nodular DH areas.

CONCLUSION: Morphologic evaluation and CYP11B2 IHC enabled the classification of cross-sectional image negative hyperaldosteronism into MN and DH. Somatic mutations driving renin-independent aldosterone production are common in micronodules of MN, suggesting the novel histological entity possibly related to APCC development.