title: Histopathological Classification of Cross-Sectional Image-Negative Hyperaldosteronism.
abstract: 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.
  
  
  
  To examine histopathology, steroidogenic enzyme expression, and aldosterone-driver gene somatic mutation status in cross-sectional image-negative hyperaldosteronism.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pathology, and.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Department of Pathology, and.|Division of Pathology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Division of Clinical Hypertension, Endocrinology and Metabolism, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.|Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Hospital, Sendai 980-8577, Japan.|Division of Endocrinology, Department of Medicine, The University of Mississippi Medical Center, Jackson, Mississippi 39216.|Research and Medicine Services, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, Mississippi 39216.|Departments of Pathology.|Michigan Center for Translational Pathology, and.
authors.forename: Kei
authors.initials: K
authors.lastname: Omata
authors.affiliation: Department of Pathology, and.|Division of Pathology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Ise
authors.affiliation: Division of Clinical Hypertension, Endocrinology and Metabolism, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.|Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Hospital, Sendai 980-8577, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Tezuka
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Hospital, Sendai 980-8577, Japan.
authors.forename: Yoshikiyo
authors.initials: Y
authors.lastname: Ono
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Hospital, Sendai 980-8577, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Morimoto
authors.affiliation: Division of Cardiology, Asahikawa Red Cross Hospital, Hokkaido 070-0061, Japan.
authors.forename: Yukinaga
authors.initials: Y
authors.lastname: Nozawa
authors.affiliation: Division of Endocrinology, Department of Medicine, The University of Mississippi Medical Center, Jackson, Mississippi 39216.|Research and Medicine Services, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, Mississippi 39216.
authors.forename: Celso E
authors.initials: CE
authors.lastname: Gomez-Sanchez
authors.affiliation: Departments of Pathology.|Urology.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.affiliation: Molecular and Integrative Physiology, and Internal Medicine.
authors.forename: William E
authors.initials: WE
authors.lastname: Rainey
authors.affiliation: Division of Clinical Hypertension, Endocrinology and Metabolism, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.|Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Hospital, Sendai 980-8577, Japan.
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
authors.affiliation: Division of Pathology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan.|Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Hospital, Sendai 980-8577, Japan.
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Satoh
authors.affiliation: Department of Pathology, and.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000096:biosynthesis*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism
chemical_list: C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D000450:Aldosterone; C499076:ATP1A1 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases; C506962:ATP2B3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase