title: Combined application of cytology and molecular urine markers to improve the detection of urothelial carcinoma.
abstract: BACKGROUND
  The sensitivity of cytology for the detection of urothelial carcinoma (UC) is limited. Newer methods such as fluorescence in situ hybridization (FISH), immunocytology (uCyt+), and protein markers have been developed to improve urine-based detection of UC. As only little is known regarding the combined application of these markers, we investigated whether combinations of 4 of the most broadly available tests (cytology, FISH, uCyt+, and nuclear matrix protein 22 [NMP22-ELISA]) may improve their diagnostic performance.
  
  
  METHODS
  The study was comprised of 808 patients who were suspected of having UC. All patients underwent urethrocystoscopy and upper urinary tract imaging and, in the case of positive findings, transurethral resection/biopsy. FISH, uCyt+, cytology, and NMP22-ELISA were performed in all patients.
  
  
  RESULTS
  UC was diagnosed in 115 patients (14.2%). Cytology and FISH were found to be the single tests with the best overall performance (area under the curve [AUC], 0.78/0.79). Combinations of 2, 3, and 4 markers were found to increase the AUC to various extents compared with the use of single markers. Combining cytology and FISH improved the sensitivity and performance (AUC, 0.83) compared with the single tests and identified 12 tumors that were not detected by cytology alone. The percentage of WHO grade 3/carcinoma in situ tumors not detected by cytology was reduced by 62.5% when FISH was performed in cytology-negative patients. The addition of uCyt+ as a third test further improved performance (AUC, 0.86), whereas the addition of NMP22-ELISA was not found to have any additional influence on the performance of the test combination.
  
  
  CONCLUSIONS
  The results of the current study support the combined use of urine markers and may form the basis of further studies investigating whether risk stratification based on urine marker combinations may individualize diagnostic algorithms and the surveillance of patients suspected of having UC.
authors.affiliation: Department of Urology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Todenhöfer
authors.forename: Jörg
authors.initials: J
authors.lastname: Hennenlotter
authors.forename: Michael
authors.initials: M
authors.lastname: Esser
authors.forename: Sarah
authors.initials: S
authors.lastname: Mohrhardt
authors.forename: Veronika
authors.initials: V
authors.lastname: Tews
authors.forename: Stefan
authors.initials: S
authors.lastname: Aufderklamm
authors.forename: Georgios
authors.initials: G
authors.lastname: Gakis
authors.forename: Ursula
authors.initials: U
authors.lastname: Kuehs
authors.forename: Arnulf
authors.initials: A
authors.lastname: Stenzl
authors.forename: Christian
authors.initials: C
authors.lastname: Schwentner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell / Q000175:diagnosis* / Q000235:genetics / Q000652:urine; D003581:Cytodiagnosis / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000032:analysis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000652:urine; D014556:Urine / Q000166:cytology*; D055815:Young Adult
chemical_list: D009687:Nuclear Proteins; C100379:nuclear matrix protein 22