title: Detection of urothelial bladder cancer cells in voided urine can be improved by a combination of cytology and standardized microsatellite analysis.
abstract: OBJECTIVE
  To evaluate molecular and immunohistochemical markers to develop a molecular grading of urothelial bladder cancer and to test these markers in voided urine samples.
  
  
  METHODS
  255 consecutive biopsies from primary bladder cancer patients were evaluated on a tissue microarray. The clinical parameters gender, age, adjacent carcinoma in situ, and multifocality were collected. UroVysion fluorescence in situ hybridization (FISH) was done. Expression of cytokeratin 20, MIB1, and TP53 was analyzed by immunohistochemistry. Fibroblast growth factor receptor 3 (FGFR3) status was studied by SNaPshot mutation detection. Results were correlated with clinical outcome by Cox regression analysis. To assess the predictive power of different predictor subsets to detect high grade and tumor invasion, logistic regression models were learned. Additionally, voided urine samples of 119 patients were investigated. After cytologic examination, urine samples were matched with their biopsies and analyzed for loss of heterozygosity (LOH), FGFR3 mutation, polysomy, and p16 deletion using UroVysion FISH. Receiver operator characteristic curves for various predictor subsets were plotted.
  
  
  RESULTS
  In biopsies, high grade and solid growth pattern were independent prognostic factors for overall survival. A model consisting of UroVysion FISH and FGFR3 status (FISH + FGFR3) predicted high grade significantly better compared with a recently proposed molecular grade (MIB1 + FGFR3). In voided urine, the combination of cytology with LOH analysis (CYTO + LOH) reached the highest diagnostic accuracy for the detection of bladder cancer cells and performed better than cytology alone (sensitivity of 88.2% and specificity of 97.1%).
  
  
  CONCLUSIONS
  The combination of cytology with LOH analysis could reduce unpleasant cystoscopies for bladder cancer patients.
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. peter.wild@usz.ch
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.forename: Thomas
authors.initials: T
authors.lastname: Fuchs
authors.forename: Robert
authors.initials: R
authors.lastname: Stoehr
authors.forename: Dieter
authors.initials: D
authors.lastname: Zimmermann
authors.forename: Simona
authors.initials: S
authors.lastname: Frigerio
authors.forename: Barbara
authors.initials: B
authors.lastname: Padberg
authors.forename: Inbal
authors.initials: I
authors.lastname: Steiner
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Zwarthoff
authors.forename: Maximilian
authors.initials: M
authors.lastname: Burger
authors.forename: Stefan
authors.initials: S
authors.lastname: Denzinger
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Hofstaedter
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.forename: Thomas
authors.initials: T
authors.lastname: Hermanns
authors.forename: Hans-Helge
authors.initials: HH
authors.lastname: Seifert
authors.forename: Maurizio
authors.initials: M
authors.lastname: Provenzano
authors.forename: Tullio
authors.initials: T
authors.lastname: Sulser
authors.forename: Volker
authors.initials: V
authors.lastname: Roth
authors.forename: Joachim M
authors.initials: JM
authors.lastname: Buhmann
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000652:urine*; D003584:Cytological Techniques; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000096:biosynthesis / Q000235:genetics; D012680:Sensitivity and Specificity; D046888:Tissue Array Analysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000652:urine*
chemical_list: D014408:Biomarkers, Tumor; C513496:MIB1 ligase, human; D044767:Ubiquitin-Protein Ligases; D051498:Receptor, Fibroblast Growth Factor, Type 3