title: An investigation into the prognostic significance of necrosis and hypoxia in high grade and invasive bladder cancer.
abstract: OBJECTIVE
  We investigated hypoxia and necrosis in high grade and invasive bladder cancer, and related this to prognosis.
  
  
  METHODS
  We performed a retrospective observational study of 98 primary cystectomy specimens scored for necrosis, and the hypoxia associated markers carbonic anhydrase IX, hypoxia-inducible factor 1 alpha and 2 alpha, and Bcl2/adenovirus EIB 19 kDa interacting protein 3. Tumor tissue array was used with cores taken from representative and perinecrotic tumor regions. Necrosis was scored on whole sections as absent, less than 5 mm (comedo) or more than 5 mm (gross).
  
  
  RESULTS
  Of the 98 cases analyzed followup data were available on 91. Median followup was 22 months (IQR 8-35). Stage was T0/1 to T4 in 18, 20, 41 and 12 cases, respectively. The prevalence of necrosis in bladder cancer was high and it increased with stage (17%, 30%, 70% and 71% at stages T0/1 to T4, respectively). Necrosis was significantly associated with stage (p = 0.0001) and nodal status (p = 0.016). Hypoxia-inducible factor 1 alpha showed no association with stage, grade or nodal status. Hypoxia-inducible factor 1 alpha and carbonic anhydrase IX showed a significant association with necrosis, whereas hypoxia-inducible factor 2 alpha and Bcl2/adenovirus EIB 19 kDa interacting protein 3 did not. Stage (p <0.0001), necrosis (p <0.0001) and intense hypoxia-inducible factor 1 positivity (p = 0.048) were the only significant prognostic factors on univariate analysis. Stage (HR 3.29, 95% CI 1.80-6.04, p <0.001) and necrosis (HR 1.92, 95% CI 1.05-3.51, p = 0.04) were independent prognostic factors on multivariate analysis, while hypoxia-inducible factor 1 lost significance (HR 1.36, 95% CI 0.98-1.88, p = 0.07). Node status was only reported in 45% of cases.
  
  
  CONCLUSIONS
  Necrosis (the presence and amount) in high grade and invasive bladder cancer is an independent prognostic risk factor.
authors.affiliation: Department of Urology, Churchill Hospital, Oxford, United Kingdom. jord@doctors.org.uk
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Ord
authors.forename: Sachin
authors.initials: S
authors.lastname: Agrawal
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Thamboo
authors.forename: Ian
authors.initials: I
authors.lastname: Roberts
authors.forename: Leticia
authors.initials: L
authors.lastname: Campo
authors.forename: Helen
authors.initials: H
authors.lastname: Turley
authors.forename: Cheng
authors.initials: C
authors.lastname: Han
authors.forename: Derek W
authors.initials: DW
authors.lastname: Fawcett
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Kulkarni
authors.forename: David
authors.initials: D
authors.lastname: Cranston
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000032:analysis; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000032:analysis; D002295:Carcinoma, Transitional Cell / Q000473:pathology* / Q000601:surgery; D015687:Cell Hypoxia / Q000502:physiology*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D009336:Necrosis; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D012189:Retrospective Studies; D046888:Tissue Array Analysis; D001743:Urinary Bladder / Q000473:pathology*; D001749:Urinary Bladder Neoplasms / Q000473:pathology* / Q000601:surgery; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000951:Antigens, Neoplasm; D051792:Basic Helix-Loop-Helix Proteins; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C090121:BNIP3 protein, human; C089226:CA9 protein, human