title: Loss of succinate dehydrogenase subunit B (SDHB) as a prognostic factor in advanced ileal well-differentiated neuroendocrine tumors.
abstract: OBJECTIVE
  Abnormal expression of succinate dehydrogenase, (SDH), in particular of the B subunit (SDHB), is implicated in the pathogenesis of neuroendocrine tumors. This study evaluates the distribution of SDHB in WHO grading G1 and G2 intestinal, well-differentiated neuroendocrine tumors and corresponding lymph node or liver metastases.
  
  
  METHODS
  We collected ileal well-differentiated neuroendocrine tumors specimens from consecutive patients with prior primary resection and distant synchronous or metachronous liver metastases. We obtained 195 specimens from primary tumors (n = 106) and metastases (n = 89). The expression (E) of SDHB and the immunostaining intensity (I) were evaluated semiquantitatively and combined into a single score. SDHB score was evaluated in primitive tumor and metastatic specimens.
  
  
  RESULTS
  SDHB was found in all tumor cells. Mean SDHB expression was 72.7 % ± 17.1 % in primitive specimens and 27.9 % ± 24.6 % in metastatic specimens (p < 0.0001). SDH intensity was higher in primitive specimens (p < 0.0001). SDHB score was 9-12 in 96 specimens of the primitive group and 2 metastatic specimens (p < 0.0001). None of the analyzed parameters was predictive of overall survival in the primitive subset. In the metastatic subset, loss of SDHB expression, intensity, and score were prognostic factors for survival. Lower expression and intensity of SDHB in metastatic lesions were associated with longer overall survival. When combining SDHB score and Ki-67 % in the metastatic subset, a lower SDHB score was associated with prolonged overall survival, independently from Ki-67 %.
  
  
  CONCLUSIONS
  SDHB score was different in primitive and metastatic specimens. The combination of SDHB score and Ki-67 % was a stronger predictor of overall survival than Ki-67 % alone. This stratification might help predict survival.
authors.affiliation: 1st Division of Pathology, Department of Pathology and Laboratory Medicine, IRCCS, Milan, Italy. Massimo.milione@istitutotumori.mi.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Milione
authors.affiliation: Division of Epidemiology and Biostatistics, European Institute of oncology (IEO), Milan, Italy.
authors.forename: Patrick
authors.initials: P
authors.lastname: Maisonneuve
authors.affiliation: 1st Division of Pathology, Department of Pathology and Laboratory Medicine, IRCCS, Milan, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Pellegrinelli
authors.affiliation: Departement of Medical Oncology, IRCCS Foundation National Cancer Institute, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pusceddu
authors.affiliation: 1st Division of Pathology, Department of Pathology and Laboratory Medicine, IRCCS, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Centonze
authors.affiliation: 1st Division of Pathology, Department of Pathology and Laboratory Medicine, IRCCS, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Dominoni
authors.affiliation: 1st Division of Pathology, Department of Pathology and Laboratory Medicine, IRCCS, Milan, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Brambilla
authors.affiliation: Istituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Manila
authors.initials: M
authors.lastname: Rubino
authors.affiliation: Istituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Antongiulio
authors.initials: A
authors.lastname: Faggiano
authors.affiliation: Departement of Medical Oncology, IRCCS Foundation National Cancer Institute, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Buzzoni
authors.affiliation: Departement of Medical Oncology, IRCCS Foundation National Cancer Institute, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Concas
authors.affiliation: University of Genoa, Genoa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Giacomelli
authors.affiliation: Department of Surgery, G.I. Surgery and Liver Transplantation, Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy.
authors.forename: Jorgelina
authors.initials: J
authors.lastname: Coppa
authors.affiliation: Department of Surgery, G.I. Surgery and Liver Transplantation, Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mazzaferro
authors.affiliation: Departement of Medical Oncology, IRCCS Foundation National Cancer Institute, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007078:Ileal Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000378:metabolism*; D018358:Neuroendocrine Tumors / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D011379:Prognosis; D013385:Succinate Dehydrogenase / Q000378:metabolism*; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D009363:Neoplasm Proteins; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase
keywords: Ileal NET; Immunochemistry; Prognosis; SDHB