title: The spectrum of neuroendocrine differentiation among gastrointestinal carcinoids: importance of histologic grading, MIB-1, p53, and bcl-2 immunoreactivity.
abstract: BACKGROUND
  The advent of panneuroendocrine markers has helped to better depict the heterogeneity of gastrointestinal carcinoids. Consequently, it has been proposed that these tumors constitute a histologic spectrum that includes well-, moderately, and poorly differentiated carcinoids. However, the reproducibility of this grading system and its prognostic importance have sometimes been called into question.
  
  
  OBJECTIVE
  To investigate the potential utility of cell proliferation and oncoprotein markers in augmenting the histologic classification.
  
  
  METHODS
  Retrospective study; tertiary care teaching hospital.
  
  
  METHODS
  Fifty-eight patients with 41 well-differentiated, 12 moderately differentiated and 5 poorly differentiated carcinoids from various topographic sites of the gastrointestinal tract were selected and immunostained for panneuroendocrine markers, MIB-1, p53, and bcl-2.
  
  
  METHODS
  Degree of association between histologic grading, MIB-1, p53, and bcl-2 immunoreactivity and carcinoid metastatic behavior.
  
  
  RESULTS
  The group comprised 30 males and 28 females whose mean age was 52.7 years (range, 14-81). Mean follow-up time was 85.8 months. All 58 patients tested positive for chromogranin A and/or synaptophysin. The group was divided into nonmetastatic (42/58, or 72.4%) and metastatic (16/58, or 27.6%) cases. Histologic grading tended to be associated with metastatic spread, but this occurrence of metastases did not attain statistical significance (P =.08). Positivity for MIB-1 (P =.004) and p53 (P =.04) was significantly associated with metastatic behavior, whereas bcl-2 was not (P = 0. 63).
  
  
  CONCLUSIONS
  Although an organoid pattern and neuroendocrine immunophenotype help to define the spectrum of gastrotestinal carcinoids, this study suggests that the histologic grading of these tumors has some limitations with respect to predicting metastatic behavior. However, MIB-1 and p53 can compliment histologic grading as prognostic indicators in this regard while bcl-2 appears to be less useful.
authors.affiliation: Departments of Pathology, Royal University Hospital, Saskatoon, Saskatchewan, Canada.
authors.forename: T N
authors.initials: TN
authors.lastname: Moyana
authors.forename: J
authors.initials: J
authors.lastname: Xiang
authors.forename: A
authors.initials: A
authors.lastname: Senthilselvan
authors.forename: A
authors.initials: A
authors.lastname: Kulaga
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D034961:Antigens, Nuclear; D015415:Biomarkers / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis*; D002276:Carcinoid Tumor / Q000473:pathology* / Q000601:surgery; D002454:Cell Differentiation; D053379:Chromogranin A; D002864:Chromogranins / Q000032:analysis; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000473:pathology* / Q000601:surgery; D006784:Hospitals, Teaching; D006801:Humans; D019394:Ki-67 Antigen; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012189:Retrospective Studies; D012525:Saskatchewan; D016708:Synaptophysin / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D034961:Antigens, Nuclear; D015415:Biomarkers; D014408:Biomarkers, Tumor; D053379:Chromogranin A; D002864:Chromogranins; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016708:Synaptophysin; D016159:Tumor Suppressor Protein p53