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An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis - 11/08/11

Doi : 10.1016/S1470-2045(09)70164-0 
Francien H van Nederveen, MD a, *, José Gaal, MD a, *, Judith Favier, PhD h, *, Esther Korpershoek, BSc a, Rogier A Oldenburg, MD b, Elly MCA de Bruyn, BSc a, Hein FBM Sleddens, BSc a, Pieter Derkx, BSc a, Julie Rivière, BSc h, Hilde Dannenberg, MD a, Bart-Jeroen Petri, MD a, Paul Komminoth, ProfMD g, Karel Pacak, ProfMD i, Wim CJ Hop, PhD c, Patrick J Pollard, MD j, Massimo Mannelli, ProfMD k, Jean-Pierre Bayley, PhD l, Aurel Perren, MD m, Stephan Niemann, PhD n, Albert A Verhofstad, MD p, †, Adriaan P de Bruïne, ProfMD q, Eamonn R Maher, ProfMD r, Frédérique Tissier, MD s, w, Tchao Méatchi, MD t, Cécile Badoual, MD t, Jérôme Bertherat, ProfMD x, Laurence Amar, MD u, Despoina Alataki, MD y, Eric Van Marck, ProfMD z, Francesco Ferrau, MD a, Jerney François, BSc a, Wouter W de Herder, MD d, Mark-Paul FM Vrancken Peeters, MD e, Anne van Linge, MD f, Jacques WM Lenders, ProfMD o, aa, Anne-Paule Gimenez-Roqueplo, ProfMD h, v, Ronald R de Krijger, MD a, ‡, Winand NM Dinjens, DrPhD a, ‡, ⁎
a Department of Pathology, Josephine Nefkens Institute, Erasmus MC, University Medical Center, Rotterdam, Netherlands 
b Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, Netherlands 
c Department of Biostatistics, Erasmus MC, University Medical Center, Rotterdam, Netherlands 
d Department of Internal Medicine, Sector of Endocrinology, Erasmus MC, University Medical Center, Rotterdam, Netherlands 
e Department of Surgery, Erasmus MC, University Medical Center, Rotterdam, Netherlands 
f Department of Otolaryngology, Erasmus MC, University Medical Center, Rotterdam, Netherlands 
g Institut für Pathologie, Stadtspital Triemli, Zürich, Switzerland 
h INSERM, U970, Paris, France, and Université Paris Descartes, Faculté de Médecine, Paris, France, and Collège de France, Paris, France 
i Reproductive and Adult Endocrinology Program, National Institutes of Health, Bethesda, MD, USA 
j Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK 
k Department of Clinical Physiopathology, University of Florence, Florence, Italy 
l Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands 
m Department of Pathology, Klinikum Rechts der Isar, Munich, Germany 
n Institut für Humangenetik, Justus-Liebig-Universität, Giessen, Germany 
o Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands 
p Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands 
q Department of Pathology, GROW–School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands 
r Department of Medical and Molecular Genetics, Institute of Biomedical Research, University of Birmingham, and West Midlands Region Genetics Service, Birmingham Women’s Hospital, Edgbaston, Birmingham, UK 
s Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service d’Anatomie Pathologie 
t Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d’Anatomo-Pathologie, Paris, France 
u Service d’Hypertension Artérielle, Paris, France 
v Service de Génétique, Paris, France 
w Université Paris Decartes, Faculté de Médecine Paris Descartes, INSERM, U567, Institut Cochin, Paris, France 
x Centre de Reference Maladies Rares de la Surrénale, Hôpital Cochin, Paris, France 
y Department of Pathology, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece 
z Laboratory of Pathology, University of Antwerp, Antwerp University Hospital, Edegem, Belgium 
aa Department of Internal Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany 

*Correspondence to: Dr Winand N M Dinjens, Department of Pathology, Josephine Nefkens Institute, Room Be320a, Erasmus MC, University Medical Center, Rotterdam, Netherlands

Summary

Background

Phaeochromocytomas and paragangliomas are neuro-endocrine tumours that occur sporadically and in several hereditary tumour syndromes, including the phaeochromocytoma–paraganglioma syndrome. This syndrome is caused by germline mutations in succinate dehydrogenase B (SDHB), C (SDHC), or D (SDHD) genes. Clinically, the phaeochromocytoma–paraganglioma syndrome is often unrecognised, although 10–30% of apparently sporadic phaeochromocytomas and paragangliomas harbour germline SDH-gene mutations. Despite these figures, the screening of phaeochromocytomas and paragangliomas for mutations in the SDH genes to detect phaeochromocytoma–paraganglioma syndrome is rarely done because of time and financial constraints. We investigated whether SDHB immunohistochemistry could effectively discriminate between SDH-related and non-SDH-related phaeochromocytomas and paragangliomas in large retrospective and prospective tumour series.

Methods

Immunohistochemistry for SDHB was done on 220 tumours. Two retrospective series of 175 phaeochromocytomas and paragangliomas with known germline mutation status for phaeochromocytoma-susceptibility or paraganglioma-susceptibility genes were investigated. Additionally, a prospective series of 45 phaeochromocytomas and paragangliomas was investigated for SDHB immunostaining followed by SDHB, SDHC, and SDHD mutation testing.

Findings

SDHB protein expression was absent in all 102 phaeochromocytomas and paragangliomas with an SDHB, SDHC, or SDHD mutation, but was present in all 65 paraganglionic tumours related to multiple endocrine neoplasia type 2, von Hippel–Lindau disease, and neurofibromatosis type 1. 47 (89%) of the 53 phaeochromocytomas and paragangliomas with no syndromic germline mutation showed SDHB expression. The sensitivity and specificity of the SDHB immunohistochemistry to detect the presence of an SDH mutation in the prospective series were 100% (95% CI 87–100) and 84% (60–97), respectively.

Interpretation

Phaeochromocytoma–paraganglioma syndrome can be diagnosed reliably by an immunohistochemical procedure. SDHB, SDHC, and SDHD germline mutation testing is indicated only in patients with SDHB-negative tumours. SDHB immunohistochemistry on phaeochromocytomas and paragangliomas could improve the diagnosis of phaeochromocytoma–paraganglioma syndrome.

Funding

The Netherlands Organisation for Scientific Research, Dutch Cancer Society, Vanderes Foundation, Association pour la Recherche contre le Cancer, Institut National de la Santé et de la Recherche Médicale, and a PHRC grant COMETE 3 for the COMETE network.

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© 2009  Elsevier Ltd. Tous droits réservés.
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Vol 10 - N° 8

P. 764-771 - août 2009 Retour au numéro
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