Francesco Fallo1, Isabella Castellano2, Celso E Gomez-Sanchez3, Yara Rhayem4, Catia Pilon5, Valentina Vicennati6, Donatella Santini7, Valeria Maffeis8, Ambrogio Fassina8, Paolo Mulatero9, Felix Beuschlein4, Martin Reincke4. 1. Clinica Medica 3, Department of Medicine, University of Padova, Padova, Italy. francesco.fallo@unipd.it. 2. Division of Pathology, Department of Medical Sciences, University of Torino, Torino, Italy. 3. Endocrine Section, G.V. (Sonny) Montgomery VA Medical Center and University of Mississipi Medical Center, Jackson, MS, USA. 4. Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany. 5. Clinica Medica 3, Department of Medicine, University of Padova, Padova, Italy. 6. Endocrinology Unit, University of Bologna, Bologna, Italy. 7. Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy. 8. Cytopathology Unit, Department of Medicine, University of Padova, Padova, Italy. 9. Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Torino, Torino, Italy.
Abstract
PURPOSE: Aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion are reported in an increasing number of patients. Five aldosterone-producing adenomas from patients with primary aldosteronism and subclinical hypercortisolism were examined. THE AIMS OF OUR STUDY WERE: (1) to analyze pathological features and immunohistochemical expression of CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) in these tumors; (2) to investigate somatic mutations involved in adrenal steroid hypersecretion and/or tumor growth. METHODS: Archival micro-dissected paraffin-embedded slides from tumor specimens were used for histological and molecular studies. Immunohistochemistry was performed using monoclonal anti-CYP11B1 and anti-CYP11B2 antibodies. Cellular composition was determined by examining for known features of zona fasciculata and zona glomerulosa, and immunoreactivity for CYP11B1 and CYP11B2 by McCarty H-score. Spot regions for mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, PRKACA, and CTNNB1 gene sequences were evaluated. RESULTS: Four APAs showed a predominant (≥50%) zona fasciculata-like cell pattern: one tumor had CYP11B1 H-score = 150, no detectable CYP11B2 expression, and harbored a PRKACA p.Leu206Arg mutation (that we have reported previously elsewhere), one had no CYP11B1 expression, CYP11B2 H-score = 40, and no mutations; the remaining two adenomas had high CYP11B1 H-score (160 and 240, respectively) and low CYP11B2 H-score (30 and 15, respectively), with the latter harboring a CTNNB1 p.Ser45Phe activating mutation. One of five aldosterone-producing adenomas had a predominant zona glomerulosa-like pattern, CYP11B1 H-score = 15, CYP11B2 H-score = 180, and no mutations. CONCLUSIONS: The majority of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion were composed mainly of zona fasciculata-like cells, while CYP11B1 and CYP11B2 immunostaining demonstrated clear heterogeneity. In a subset of cases, different somatic mutations may be involved in hormone excess and tumor formation.
PURPOSE:Aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion are reported in an increasing number of patients. Five aldosterone-producing adenomas from patients with primary aldosteronism and subclinical hypercortisolism were examined. THE AIMS OF OUR STUDY WERE: (1) to analyze pathological features and immunohistochemical expression of CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) in these tumors; (2) to investigate somatic mutations involved in adrenal steroid hypersecretion and/or tumor growth. METHODS: Archival micro-dissected paraffin-embedded slides from tumor specimens were used for histological and molecular studies. Immunohistochemistry was performed using monoclonal anti-CYP11B1 and anti-CYP11B2 antibodies. Cellular composition was determined by examining for known features of zona fasciculata and zona glomerulosa, and immunoreactivity for CYP11B1 and CYP11B2 by McCarty H-score. Spot regions for mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, PRKACA, and CTNNB1 gene sequences were evaluated. RESULTS: Four APAs showed a predominant (≥50%) zona fasciculata-like cell pattern: one tumor had CYP11B1 H-score = 150, no detectable CYP11B2 expression, and harbored a PRKACAp.Leu206Arg mutation (that we have reported previously elsewhere), one had no CYP11B1 expression, CYP11B2 H-score = 40, and no mutations; the remaining two adenomas had high CYP11B1 H-score (160 and 240, respectively) and low CYP11B2 H-score (30 and 15, respectively), with the latter harboring a CTNNB1p.Ser45Phe activating mutation. One of five aldosterone-producing adenomas had a predominant zona glomerulosa-like pattern, CYP11B1 H-score = 15, CYP11B2 H-score = 180, and no mutations. CONCLUSIONS: The majority of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion were composed mainly of zona fasciculata-like cells, while CYP11B1 and CYP11B2 immunostaining demonstrated clear heterogeneity. In a subset of cases, different somatic mutations may be involved in hormone excess and tumor formation.
Authors: T Dekkers; M ter Meer; J W M Lenders; A R M Hermus; L Schultze Kool; J F Langenhuijsen; K Nishimoto; T Ogishima; K Mukai; E A B Azizan; B Tops; J Deinum; B Küsters Journal: J Clin Endocrinol Metab Date: 2014-04-23 Impact factor: 5.958
Authors: Yara Rhayem; Luis G Perez-Rivas; Anna Dietz; Kerstin Bathon; Christian Gebhard; Anna Riester; Brigitte Mauracher; Celso Gomez-Sanchez; Graeme Eisenhofer; Thomas Schwarzmayr; Davide Calebiro; Tim M Strom; Martin Reincke; Felix Beuschlein Journal: J Clin Endocrinol Metab Date: 2016-06-07 Impact factor: 5.958
Authors: Ute I Scholl; James M Healy; Anne Thiel; Annabelle L Fonseca; Taylor C Brown; John W Kunstman; Matthew J Horne; Dimo Dietrich; Jasmin Riemer; Seher Kücükköylü; Esther N Reimer; Anna-Carinna Reis; Gerald Goh; Glen Kristiansen; Amit Mahajan; Reju Korah; Richard P Lifton; Manju L Prasad; Tobias Carling Journal: Clin Endocrinol (Oxf) Date: 2015-09-23 Impact factor: 3.478
Authors: Livia Lenzini; Teresa M Seccia; Enrico Aldighieri; Anna S Belloni; Paolo Bernante; Luisa Giuliani; Gastone G Nussdorfer; Achille C Pessina; Gian Paolo Rossi Journal: Hypertension Date: 2007-10-15 Impact factor: 10.190
Authors: Ada E D Teo; Sumedha Garg; Lalarukh Haris Shaikh; Junhua Zhou; Fiona E Karet Frankl; Mark Gurnell; Lisa Happerfield; Alison Marker; Mariann Bienz; Elena A B Azizan; Morris J Brown Journal: N Engl J Med Date: 2015-09-23 Impact factor: 91.245
Authors: Jing Xie; Cui Zhang; Xuefeng Wang; Yiran Jiang; Luming Wu; Lei Ye; Xuan Wang; Wen Xie; Haimin Xu; Weiqing Wang Journal: Front Med (Lausanne) Date: 2022-04-12
Authors: Martina Tetti; Siyuan Gong; Franco Veglio; Martin Reincke; Tracy Ann Williams Journal: Front Endocrinol (Lausanne) Date: 2022-08-08 Impact factor: 6.055