title: Necrosis related HIF-1alpha expression predicts prognosis in patients with endometrioid endometrial carcinoma.
abstract: BACKGROUND
  Hypoxia inducible factor 1alpha (HIF-1alpha) plays an essential role in the adaptive response of cells to hypoxia and is associated with aggressive tumour behaviour. We have shown p27kip1, which is generally reduced in endometrial cancer, to be re-expressed in hypoxic regions. This possibly contributes to survival of cancer cells. The aim of this study was to evaluate the prognostic value of HIF-1alpha and p27kip expression in patients with endometrioid endometrial cancer.
  
  
  METHODS
  Expression levels of HIF-1alpha, CAIX, Glut-1, and p27kip1 were analyzed by immunohistochemistry. Percentage of positive cells, staining pattern (perinecrotic, diffuse, or mixed) and presence of necrosis were noted.
  
  
  RESULTS
  Necrosis was correlated with shortened disease free survival (DFS) (p = 0.008) and overall survival (OS) (p = 0.045). For DFS, perinecrotic HIF-1alpha expression was also prognostic (p = 0.044). Moreover, high p27kip1 expression was an additional prognostic factor for these patients with perinecrotic HIF-1alpha expression. In multivariate Cox regression, perinecrotic HIF-expression emerged as an independent prognostic factor. Perinecrotic HIF-1alpha expression was significantly associated with CAIX and Glut-1 expression, pointing towards functional HIF-1.
  
  
  CONCLUSIONS
  In patients with endometrioid endometrial cancer, necrosis and necrosis-related expression of HIF-1alpha are important prognostic factors. More aggressive adjuvant treatment might be necessary to improve the outcome of patients with these characteristics.
authors.affiliation: Department of Gynaecological Oncology, University Medical Centre Utrecht, The Netherlands.
authors.forename: Laura M S
authors.initials: LM
authors.lastname: Seeber
authors.forename: Nicole
authors.initials: N
authors.lastname: Horrée
authors.forename: Petra
authors.initials: P
authors.lastname: van der Groep
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.forename: René H M
authors.initials: RH
authors.lastname: Verheijen
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D018269:Carcinoma, Endometrioid / Q000378:metabolism* / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008875:Middle Aged; D009336:Necrosis; D015996:Survival Rate
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C436291:CDKN1B protein, human; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases