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Mod Pathol. 2015 Jun;28(6):807-21. doi: 10.1038/modpathol.2015.41. Epub 2015 Feb 27.

SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T).

Author information

  • 11] Department of Histopathology, King's College Hospital, London, UK [2] Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
  • 2Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
  • 3Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
  • 41] Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia [2] Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.
  • 5Laboratory for Pathology, PAL Dordrecht, Dordrecht, The Netherlands.
  • 6Department of Pathology and Laboratory Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA.
  • 71] Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Rare Adrenal Cancer Network COMETE, Paris, France [2] Department of Pathology, Hôpital Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France.
  • 8Department of Oncology, University of Turin at San Luigi Hospital, Turin, Italy.
  • 9Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, IRBLLEIDA, University of Lleida, Lleida, Spain.
  • 10Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
  • 111] Paris-Centre de Recherche Cardiovasculaire (PARCC), Inserm UMR970, Hôpital Européen Georges Pompidou, Paris, France [2] Université Paris Descartes, Faculté de Médecine, Paris Cité Sorbonne, France.
  • 12Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
  • 13Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Rare Adrenal Cancer Network COMETE, Paris, France.
  • 14Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 15Department of Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Brussels, Belgium.
  • 16Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • 17Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
  • 18Department of Internal Medicine, Section of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands.
  • 19Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.
  • 20Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.
  • 21Department of Pathomorphology, Jagiellonian University Medical College, Krakow, Poland.
  • 22Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
  • 23Department of Pathology, Technische Universität Dresden, Dresden, Germany.
  • 24Division of Pathological Anatomy, University of Florence, Florence, Italy.
  • 251] Paris-Centre de Recherche Cardiovasculaire (PARCC), Inserm UMR970, Hôpital Européen Georges Pompidou, Paris, France [2] Université Paris Descartes, Faculté de Médecine, Paris Cité Sorbonne, France [3] Service d'Anatomie Pathologique, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France.
  • 26Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III, University Hospital, Technische Universität Dresden, Dresden, Germany.
  • 271] Institut Cochin, Université Paris Descartes, INSERM U1016, CNRS UMR8104, Paris, France [2] Department of Endocrinology, Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.
  • 281] Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy [2] Istituto Toscano Tumori (ITT), Florence, Italy.
  • 291] Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain [2] Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.
  • 301] Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands [2] Department of Pathology, Reinier de Graaf Hospital, Delft, The Netherlands [3] Department of Pathology, University Medical Center Utrecht, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Abstract

Despite the established role of SDHB/SDHA immunohistochemistry as a valuable tool to identify patients at risk for familial succinate dehydrogenase-related pheochromocytoma/paraganglioma syndromes, the reproducibility of the assessment methods has not as yet been determined. The aim of this study was to investigate interobserver variability among seven expert endocrine pathologists using a web-based virtual microscopy approach in a large multicenter pheochromocytoma/paraganglioma cohort (n=351): (1) 73 SDH mutated, (2) 105 non-SDH mutated, (3) 128 samples without identified SDH-x mutations, and (4) 45 with incomplete SDH molecular genetic analysis. Substantial agreement among all the reviewers was observed either with a two-tiered classification (SDHB κ=0.7338; SDHA κ=0.6707) or a three-tiered classification approach (SDHB κ=0.6543; SDHA κ=0.7516). Consensus was achieved in 315 cases (89.74%) for SDHB immunohistochemistry and in 348 cases (99.15%) for SDHA immunohistochemistry. Among the concordant cases, 62 of 69 (~90%) SDHB-/C-/D-/AF2-mutated cases displayed SDHB immunonegativity and SDHA immunopositivity, 3 of 4 (75%) with SDHA mutations showed loss of SDHA/SDHB protein expression, whereas 98 of 105 (93%) non-SDH-x-mutated counterparts demonstrated retention of SDHA/SDHB protein expression. Two SDHD-mutated extra-adrenal paragangliomas were scored as SDHB immunopositive, whereas 9 of 128 (7%) tumors without identified SDH-x mutations, 6 of 37 (~16%) VHL-mutated, as well as 1 of 21 (~5%) NF1-mutated tumors were evaluated as SDHB immunonegative. Although 14 out of those 16 SDHB-immunonegative cases were nonmetastatic, an overall significant correlation between SDHB immunonegativity and malignancy was observed (P=0.00019). We conclude that SDHB/SDHA immunohistochemistry is a reliable tool to identify patients with SDH-x mutations with an additional value in the assessment of genetic variants of unknown significance. If SDH molecular genetic analysis fails to detect a mutation in SDHB-immunonegative tumor, SDHC promoter methylation and/or VHL/NF1 testing with the use of targeted next-generation sequencing is advisable.

PMID:
25720320
DOI:
10.1038/modpathol.2015.41
[PubMed - indexed for MEDLINE]
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