title: Nuclear survivin is a powerful novel prognostic marker in gastroenteropancreatic neuroendocrine tumor disease.
abstract: Gastroenteropancreatic neuroendocrine tumors represent a heterogeneous tumor entity. The growth pattern ranges from very slowly to fast growing, aggressive types of tumors. Survivin, a member of the family of apoptosis inhibitors, is a bifunctional protein that suppresses apoptosis and regulates cell division. In this study we determined the prognostic value of survivin in this tumor entity. Tumor specimens from 104 patients (38 foregut, 53 midgut, 13 hindgut) were studied immunohistochemically for cytoplasmic and nuclear survivin expression as well as for ki-67 antigen expression. 5-year-follow-up was complete in 89 patients. 29 patients with localized, well-differentiated gastroenteropancreatic neuroendocrine tumors (WDET, WHO class 1) had been curatively treated by surgical or endoscopic tumor resection. 50 patients suffered from well-differentiated endocrine carcinomas (WDEC, WHO class 2), 10 patients were diagnosed with poorly differentiated neuroendocrine carcinomas (PDEC, WHO class 3). Survivin expression was correlated with survival for the 50 patients with metastatic WDEC disease. All 29 WDETs were negative for nuclear survivin, whereas all 10 PDECs stained positive for nuclear survivin. In the 50 patients with metastatic WDECs, 5/50 (10%) tumors were nuclear survivin positive. Those 5 patients had a statistically significant worse prognosis (survival of 41 vs. 103 months, p=0.01). ki-67 was not a prognostic factor in this subgroup of patients. Nuclear survivin expression thus appears to be upregulated during progression of gastroenteropancreatic neuroendocrine tumors. The analysis of nuclear survivin expression identifies subgroups in metastatic disease (WHO class 2) with good (survivin-) or with less favorable prognosis (survivin+). We propose that the determination of nuclear survivin expression could be used to individualize therapeutic strategies in this tumor entity in the future.
authors.affiliation: Medical Clinic I, Gastroenterology/Infectious Diseases/Rheumatology, Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Grabowski
authors.forename: Sonja
authors.initials: S
authors.lastname: Griss
authors.forename: Christian N
authors.initials: CN
authors.lastname: Arnold
authors.forename: Dieter
authors.initials: D
authors.lastname: Hörsch
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Göke
authors.forename: Rudolf
authors.initials: R
authors.lastname: Arnold
authors.forename: Berhard
authors.initials: B
authors.lastname: Heine
authors.forename: Harald
authors.initials: H
authors.lastname: Stein
authors.forename: Martin
authors.initials: M
authors.lastname: Zeitz
authors.forename: Hans
authors.initials: H
authors.lastname: Scherübl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D005770:Gastrointestinal Neoplasms / Q000145:classification / Q000175:diagnosis* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051034:Inhibitor of Apoptosis Proteins; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins; D018358:Neuroendocrine Tumors / Q000145:classification / Q000175:diagnosis* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D011379:Prognosis; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin