Histopathological classification of cross-sectional image-negative hyperaldosteronism

Yuto Yamazaki, Yasuhiro Nakamura, Kei Omata, Kazue Ise, Yuta Tezuka, Yoshikiyo Ono, Ryo Morimoto, Yukinaga Nozawa, Celso E. Gomez-Sanchez, Scott A. Tomlins, William E. Rainey, Sadayoshi Ito, Fumitoshi Satoh, Hironobu Sasano

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51 Citations (Scopus)


Context: Approximately half of patients with 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 are controversial. Objective: To examine histopathology, steroidogenic enzyme expression, and aldosterone-driver gene somatic mutation status in cross-sectional image-negative hyperaldosteronism. Methods: Twenty-five cross-sectional image-negative cases were retrospectively reviewed. In situ adrenal aldosterone production capacity was determined using immunohistochemistry (IHC) of steroidogenic enzymes. Aldosterone-driver gene somatic mutation status (ATP1A1, ATP2B3, CACNA1D, and KCNJ5) was determined in the CYP11B2 immunopositive areas [n = 35; micronodule, n = 32; zona glomerulosa (ZG), n = 3] using next-generation sequencing after macrodissection. Results: Cases were classified as multiple adrenocortical micronodules (MN; n = 13) or diffuse hyperplasia (DH) of ZG (n = 12) based upon histopathological evaluation and CYP11B2 IHC.Aldosterone-driver gene somatic mutations were detected in 21 of 26 (81%) of CYP11B2-positive cortical micronodules in MN; 17 (65%) mutations were in CACNA1D, 2 (8%) in KCNJ5, and 1 each (4% each) in ATP1A1 and ATP2B. One of 6 (17%) of nodules in DH harbored somatic aldosterone-driver gene mutations (CACNA1D); however, no mutations were detected in CYP11B2-positive nonnodular DH areas. Conclusion: Morphologic evaluation and CYP11B2 IHC enabled the classification of cross-sectional image-negative hyperaldosteronism into MN and DH. Somatic mutations driving aldosterone overproduction are common in micronodules of MN, suggesting a histological entity possibly related to aldosterone-producing cell cluster development.

Original languageEnglish
Pages (from-to)1182-1192
Number of pages11
JournalJournal of Clinical Endocrinology and Metabolism
Issue number4
Publication statusPublished - 2017 Apr 1

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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    Yamazaki, Y., Nakamura, Y., Omata, K., Ise, K., Tezuka, Y., Ono, Y., Morimoto, R., Nozawa, Y., Gomez-Sanchez, C. E., Tomlins, S. A., Rainey, W. E., Ito, S., Satoh, F., & Sasano, H. (2017). Histopathological classification of cross-sectional image-negative hyperaldosteronism. Journal of Clinical Endocrinology and Metabolism, 102(4), 1182-1192. https://doi.org/10.1210/jc.2016-2986