title: Prediction of progression of non-muscle-invasive bladder cancer by WHO 1973 and 2004 grading and by FGFR3 mutation status: a prospective study.
abstract: OBJECTIVE
  The clinical management of non-muscle-invasive urothelial cell carcinoma of the bladder (UCC) is challenging, as it has a marked tendency to recur and to progress. Aim of this study was to investigate the prognostic value of the WHO 1973 and 2004 grading systems and biomarkers FGFR3, CK20 and Ki-67.
  
  
  METHODS
  In a prospective study, tumours from 221 patients were studied for the expression of CK20 and Ki-67 by immunohistochemistry, and FGFR3 status by SNaPshot mutation detection. Staging and grading were performed according to the WHO classification systems of 1973 and 2004.
  
  
  RESULTS
  : Median follow-up was 35 mo. Recurrence occurred in 72 of 221 patients. None of the parameters was able to predict disease recurrence. CK20, Ki-67, FGFR3 mutation, molecular grade using FGFR3 mutation analysis and Ki-67, and histological grading and staging were significantly associated with disease progression in stage. In multivariable analyses, WHO 1973 and 2004 grading systems remained statistically significant and independent predictors of progression, with p=0.005 for WHO 1973 and p=0.004 for 2004. FGFR3 status was able to discriminate progressors from nonprogressors in a subset of patients with high-grade UCC (p=0.009).
  
  
  CONCLUSIONS
  This is the first prospective study comparing the WHO 1973 and 2004 grading systems. We show that both grading systems contribute valuable independent information. Therefore, it should be considered whether a better grading system could be developed that incorporates essential elements from both. The combination of WHO 2004 grading with FGFR3 status allows a better risk stratification for patients with high-grade non-muscle-invasive UCC.
authors.affiliation: Department of Urology, University of Regensburg, Regensburg, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Burger
authors.forename: Madelon N M
authors.initials: MN
authors.lastname: van der Aa
authors.forename: Johanna M M
authors.initials: JM
authors.lastname: van Oers
authors.forename: Anke
authors.initials: A
authors.lastname: Brinkmann
authors.forename: Theodorus H
authors.initials: TH
authors.lastname: van der Kwast
authors.forename: Ewout C
authors.initials: EC
authors.lastname: Steyerberg
authors.forename: Robert
authors.initials: R
authors.lastname: Stoehr
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Kirkels
authors.forename: Stefan
authors.initials: S
authors.lastname: Denzinger
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.forename: Wolf F
authors.initials: WF
authors.lastname: Wieland
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Hofstaedter
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Zwarthoff
mesh_terms: D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D011379:Prognosis; D011446:Prospective Studies; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3