title: An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors: Department of Pathology, Josephine Nefkens Institute, Erasmus MC, University Medical Center, Rotterdam, Netherlands.
authors: Francien H
authors: FH
authors: van Nederveen
authors: José
authors: J
authors: Gaal
authors: Judith
authors: J
authors: Favier
authors: Esther
authors: E
authors: Korpershoek
authors: Rogier A
authors: RA
authors: Oldenburg
authors: Elly M C A
authors: EM
authors: de Bruyn
authors: Hein F B M
authors: HF
authors: Sleddens
authors: Pieter
authors: P
authors: Derkx
authors: Julie
authors: J
authors: Rivière
authors: Hilde
authors: H
authors: Dannenberg
authors: Bart-Jeroen
authors: BJ
authors: Petri
authors: Paul
authors: P
authors: Komminoth
authors: Karel
authors: K
authors: Pacak
authors: Wim C J
authors: WC
authors: Hop
authors: Patrick J
authors: PJ
authors: Pollard
authors: Massimo
authors: M
authors: Mannelli
authors: Jean-Pierre
authors: JP
authors: Bayley
authors: Aurel
authors: A
authors: Perren
authors: Stephan
authors: S
authors: Niemann
authors: Albert A
authors: AA
authors: Verhofstad
authors: Adriaan P
authors: AP
authors: de Bruïne
authors: Eamonn R
authors: ER
authors: Maher
authors: Frédérique
authors: F
authors: Tissier
authors: Tchao
authors: T
authors: Méatchi
authors: Cécile
authors: C
authors: Badoual
authors: Jérôme
authors: J
authors: Bertherat
authors: Laurence
authors: L
authors: Amar
authors: Despoina
authors: D
authors: Alataki
authors: Eric
authors: E
authors: Van Marck
authors: Francesco
authors: F
authors: Ferrau
authors: Jerney
authors: J
authors: François
authors: Wouter W
authors: WW
authors: de Herder
authors: Mark-Paul F M Vrancken
authors: MP
authors: Peeters
authors: Anne
authors: A
authors: van Linge
authors: Jacques W M
authors: JW
authors: Lenders
authors: Anne-Paule
authors: AP
authors: Gimenez-Roqueplo
authors: Ronald R
authors: RR
authors: de Krijger
authors: Winand N M
authors: WN
authors: Dinjens
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000175:diagnosis / Q000235:genetics*; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D010235:Paraganglioma / Q000175:diagnosis / Q000235:genetics*; D010673:Pheochromocytoma / Q000175:diagnosis / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics*; D013577:Syndrome; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C108096:SDHC protein, human; C491545:SDHD protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase