title: Immunohistochemical, genetic and clinical characterization of sporadic aldosterone-producing adenomas.
abstract: Adrenal glands removed for unilateral primary aldosteronism (PA) display marked histological heterogeneity. Recently reported somatic mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D can partially account for these differences. In this study we aimed at combining phenotypic and genotypic characteristics, integrating genetic and immunohistochemistry correlates in sporadic PA. Seventy-one adrenal glands have been included in the study and analyzed for mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D. Histological examination and immunohistochemical staining for CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) were performed on aldosterone-producing adenomas (APAs) and adjacent adrenal cortex. In our cohort, the final histopathological diagnosis was multinodular hyperplasia in 22.5% of the patients and single nodule in 77.5%. Forty-five percent of the removed adrenals displayed extra-APA CYP11B2-positive cell nests (B2-CN). Among adrenal vein sampling parameters the suppression of contralateral adrenal was more frequent and the lateralization index was higher in the subgroup of patients without extra-APA B2-CN compared to the subgroup with extra-APA B2-CN. KCNJ5-mutated APAs were composed mainly of zona fasciculata-like cells with high expression of CYP11B1, while ATP1A1, ATP2B3 and CACNA1D-mutated APAs presented more frequently a zona-glomerulosa-like phenotype with high expression of CYP11B2. We observed a significant inverse correlation between CYP11B2 expression and the size of the nodules and, if CYP11B2 expression was corrected for tumor volume, a significant correlation with plasma aldosterone and aldosterone to renin ratio. Our findings indicate that combination of genotyping and immunohistochemistry improves the final histopathological diagnosis between single nodule and multinodular hyperplasia of the assessed adrenals.
authors.affiliation: Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Torino, Torino, Italy. Electronic address: smv.monticone@gmail.com.
authors.forename: Silvia
authors.initials: S
authors.lastname: Monticone
authors.affiliation: Division of Pathology, Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Castellano
authors.affiliation: Division of Radiology, University of Torino, Torino, Italy.
authors.forename: Karine
authors.initials: K
authors.lastname: Versace
authors.affiliation: Division of Endocrinology, Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lucatello
authors.affiliation: Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Veglio
authors.affiliation: Division of Endocrinology, G.V. (Sonny) Montgomery VA Medical Center and University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Celso E
authors.initials: CE
authors.lastname: Gomez-Sanchez
authors.affiliation: Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Williams
authors.affiliation: Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Torino, Torino, Italy. Electronic address: paolo.mulatero@libero.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mulatero
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000302:Adrenal Cortex / Q000378:metabolism* / Q000473:pathology; D018246:Adrenocortical Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000450:Aldosterone / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D019405:Cytochrome P-450 CYP11B2 / Q000378:metabolism; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D013252:Steroid 11-beta-Hydroxylase / 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; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; C499076:ATP1A1 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases; C506962:ATP2B3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase
keywords: ATP1A1; Aldosterone producing adenoma; CACNA1D; CYP11B1 immunohistochemistry; CYP11B2 immunohistochemistry; KCNJ5