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

Francien H. van Nederveen, José Gaal, Judith Favier, Esther Korpershoek, Rogier A. Oldenburg, Elly MCA de Bruyn, Hein FBM Sleddens, Pieter Derkx, Julie Rivière, Hilde Dannenberg, Bart Jeroen Petri, Paul Komminoth, Karel Pacak, Wim CJ Hop, Patrick J. Pollard, Massimo Mannelli, Jean Pierre Bayley, Aurel Perren, Stephan Niemann, Albert A. VerhofstadAdriaan P. de Bruïne, Eamonn R. Maher, Frédérique Tissier, Tchao Méatchi, Cécile Badoual, Jérôme Bertherat, Laurence Amar, Despoina Alataki, Eric Van Marck, Francesco Ferrau, Jerney François, Wouter W. de Herder, Mark Paul FM Vrancken Peeters, Anne van Linge, Jacques WM Lenders, Anne Paule Gimenez-Roqueplo, Ronald R. de Krijger, Winand NM Dinjens

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Abstract

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.

Original languageEnglish
Pages (from-to)764-771
Number of pages8
JournalThe Lancet Oncology
Volume10
Issue number8
DOIs
Publication statusPublished - Aug 2009
Externally publishedYes

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