title: Angiogenesis and proliferation markers in adjacent cirrhotic tissue could predict hepatocellular carcinoma outcome after liver transplantation.
abstract: BACKGROUND
  The current staging systems for hepatocellular carcinoma (HCC) do not sufficiently predict outcomes after liver transplantation (LT). The present study assessed whether some tissue markers related to proliferation and angiogenesis have prognostic value.
  
  
  METHODS
  The expression of CD34, vascular endothelial growth factor (VEGF), VEGFR2, VEGFR1, angiopoietin-1, angiopoietin-2, TIE2, COX-2, and proliferating cell nuclear antigen (PCNA) in tumor and adjacent cirrhotic tissue samples from 36 patients with HCC (n=10 with tumor recurrence after LT) was determined by immunochemistry. Microvessel density was assessed by CD34 staining and the PCNA labeling index calculated as the percentage of positive cells among at least 1000 hepatocyte nuclei studied in each sample using the computer program ContimUZ. VEGF, VEGFR2, VEGFR-1, angiopoietin-1, angiopoietin-2, TIE2, and COX-2 staining were evaluated by two blinded pathologists. The tumor recurrence rate was analyzed after a minimum follow-up of 36 months.
  
  
  RESULTS
  A higher proliferation index in both tumor and adjacent cirrhotic tissue was related to HCC recurrence. The proliferation index in tumor tissue was also related to microvascular invasion. High expression (staining in ≥50% of hepatocytes) of COX2 [P=0.025, odds ratio (OR)=7.5, 95% confidence interval (CI) 1.3-43.4], VEGF (P=0.01, OR=12, 95% CI 1.8-80.4), and its receptor VEGFR-2 (P=0.02, OR=8.5, 95% CI 1.4-49.5) in cirrhotic liver tissue, but not tumor tissue, was related to HCC recurrence after LT.
  
  
  CONCLUSIONS
  A high proliferation index in tumor and cirrhotic tissue and high expression levels of some angiogenic markers in adjacent cirrhotic tissue could be predictive of tumor recurrence after LT.
authors.affiliation: Departments of aGastroenterology and Hepatology bHistopathology cSurgery, University Hospital Lozano Blesa dIIS Aragon, Aragon Institute of Health Sciences eMedical University of Zaragoza, Zaragoza fNetworked Biomedical Research Center Hepatic and Digestive Diseases (CIBERehd), Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Campillo
authors.forename: Estela
authors.initials: E
authors.lastname: Solanas
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Morandeira
authors.forename: Tomas
authors.initials: T
authors.lastname: Castiella
authors.forename: Sara
authors.initials: S
authors.lastname: Lorente
authors.forename: Francisco Agustín
authors.initials: FA
authors.lastname: Garcia-Gil
authors.forename: Elena
authors.initials: E
authors.lastname: Piazuelo
authors.forename: Alba
authors.initials: A
authors.lastname: de Martino
authors.forename: Maria T
authors.initials: MT
authors.lastname: Serrano
mesh_terms: D000368:Aged; D042501:Angiogenic Proteins / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D049109:Cell Proliferation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D016031:Liver Transplantation; D008297:Male; D055806:Microvessels / Q000473:pathology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D042501:Angiogenic Proteins; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D018809:Proliferating Cell Nuclear Antigen