title: Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis.
abstract: BACKGROUND
  Tumor stage, histologic grade, and regional lymph node status are currently used to obtain prognostic information about bladder cancers. However, additional prognostic indicators are needed to aid clinicians in selecting patients who would benefit most from specific therapies. A majority of studies assessing the prognostic value of measuring tumor angiogenesis (i.e., measurement of tumor microvessel densities) have found a positive association between increasing microvessel densities and worsening prognosis.
  
  
  OBJECTIVE
  We explored the relationship between established prognostic indicators and the extent of tumor-associated angiogenesis in patients with invasive transitional cell carcinoma (TCC) of the bladder, and we determined whether tumor microvessel density measurement could be used independently to predict bladder tumor behavior.
  
  
  METHODS
  Tumor tissue was obtained from 164 patients with invasive primary TCC of the bladder. The extent of tumor-associated angiogenesis in this tissue was evaluated by immunohistochemical methods using HPCA-1, a mouse monoclonal antibody directed against the endothelial cell antigen, CD34. The number of microvessels in a 200x microscopic high-power field (hpf) containing the area of greatest neovascularization within or immediately adjacent to each tumor was determined. The patient population was then divided into three equivalently sized groups, with tumors containing low (< or = 64), intermediate (65-99), or high (> or = 100) numbers of microvessels per hpf. Kaplan-Meier product limit estimates of overall survival and the complement of cumulative incidence curves for recurrence-free survival were plotted. When analyzing survival or recurrence, the logrank test was used to compare groups of patients with and without stratification according to tumor stage. Analysis of variance was used to test for an association between microvessel density and established prognostic variables. Reported P values are from two-sided tests.
  
  
  RESULTS
  Microvessel density was significantly associated with disease-free (P < .0001) and overall (P = .0007) survival. The estimated probabilities of recurrence at 5 years were 19% (95% confidence interval [CI] = 8-29), 56% (95% CI = 43-69), and 68% (95% CI = 55-81) for patients with lowest, intermediate, and highest microvessel counts, respectively. Overall survival at 5 years was estimated to be 68% (95% CI = 56-81), 44% (95% CI = 30-57), and 34% (95% CI = 21-47) for the same three patient groups. Microvessel density was associated with disease progression in patients with organ-confined tumors, tumors extending through the bladder wall, and tumors that had spread to regional lymph nodes. Tumor angiogenesis was found to be an independent prognostic indicator when evaluated in the presence of histologic grade, pathologic stage, and regional lymph node status.
  
  
  CONCLUSIONS
  Tumor angiogenesis, as determined by microvessel density measurement, is an independent prognostic indicator for patients with invasive TCC of the bladder.
authors.affiliation: Department of Urology, University of Southern California School of Medicine, Kenneth Norris Jr. Comprehensive Cancer Center, Los Angeles 90033, USA.
authors.forename: B H
authors.initials: BH
authors.lastname: Bochner
authors.forename: R J
authors.initials: RJ
authors.lastname: Cote
authors.forename: N
authors.initials: N
authors.lastname: Weidner
authors.forename: S
authors.initials: S
authors.lastname: Groshen
authors.forename: S C
authors.initials: SC
authors.lastname: Chen
authors.forename: D G
authors.initials: DG
authors.lastname: Skinner
authors.forename: P W
authors.initials: PW
authors.lastname: Nichols
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D002295:Carcinoma, Transitional Cell / Q000098:blood supply* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic; D011237:Predictive Value of Tests; D011379:Prognosis; D016019:Survival Analysis; D001749:Urinary Bladder Neoplasms / Q000098:blood supply* / Q000473:pathology