Review Article| Volume 50, ISSUE 1, P53-67, February 2023

Urine-Based Markers for Detection of Urothelial Cancer and for the Management of Non–muscle-Invasive Bladder Cancer


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.


      Subscribe to Urologic Clinics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Siegel R.L.
        • Miller K.D.
        • Fuchs H.E.
        • et al.
        Cancer statistics, 2022.
        CA Cancer J Clin. 2022; 72: 7-33
      1. Evaluation of the New American Urological Association Guidelines Risk Classification for Hematuria | J Urol.
        (Available at:) (Accessed April 25, 2022)
        • Barocas D.A.
        • Boorjian S.A.
        • Alvarez R.D.
        • et al.
        Microhematuria: AUA/SUFU Guideline.
        J Urol. 2020; 204: 778-786
        • Chang S.S.
        • Boorjian S.A.
        • Chou R.
        • et al.
        Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline.
        J Urol. 2016; 196: 1021-1029
      2. Optimal Trial Design for Studying Urinary Markers ...: Find It! Options.
        (Available at:) (Accessed April 25, 2022)
        • Woldu S.L.
        • Souter L.
        • Boorjian S.A.
        • et al.
        Urinary-based tumor markers enhance microhematuria risk stratification according to baseline bladder cancer prevalence.
        Urol Oncol Semin Orig Investig. 2021; 39: 787.e1-787.e7
        • Miyanaga N.
        • Akaza H.
        • Tsukamoto T.
        • et al.
        Urinary nuclear matrix protein 22 as a new marker for the screening of urothelial cancer in patients with microscopic hematuria.
        Int J Urol. 1999; 6: 173-177
        • Wang Z.
        • Que H.
        • Suo C.
        • et al.
        Evaluation of the NMP22 BladderChek test for detecting bladder cancer: a systematic review and meta-analysis.
        Oncotarget. 2017; 8: 100648-100656
        • Grossman H.B.
        • Messing E.
        • Soloway M.
        • et al.
        Detection of Bladder Cancer Using a Point-of-Care Proteomic Assay.
        JAMA. 2005; 293: 810-816
        • Chou R.
        • Gore J.L.
        • Buckley D.
        • et al.
        Urinary Biomarkers for Diagnosis of Bladder Cancer: A Systematic Review and Meta-analysis.
        Ann Intern Med. 2015; 163: 922-931
        • Lotan Y.
        • Elias K.
        • Svatek R.S.
        • et al.
        Bladder cancer screening in a high risk asymptomatic population using a point of care urine based protein tumor marker.
        J Urol. 2009; 182 ([discussion: 58]): 52-57
        • Huang Y.L.
        • Chen J.
        • Yan W.
        • et al.
        Diagnostic accuracy of cytokeratin-19 fragment (CYFRA 21-1) for bladder cancer: a systematic review and meta-analysis.
        Tumour Biol J Int Soc Oncodevelopmental Biol Med. 2015; 36: 3137-3145
        • Schmitz-Dräger B.J.
        • Droller M.
        • Lokeshwar V.B.
        • et al.
        Molecular markers for bladder cancer screening, early diagnosis, and surveillance: the WHO/ICUD consensus.
        Urol Int. 2015; 94: 1-24
        • Hajdinjak T.
        UroVysion FISH test for detecting urothelial cancers: Meta-analysis of diagnostic accuracy and comparison with urinary cytology testing.
        Urol Oncol Semin Orig Investig. 2008; 26: 646-651
        • Maas M.
        • Bedke J.
        • Stenzl A.
        • et al.
        Can urinary biomarkers replace cystoscopy?.
        World J Urol. 2019; 37: 1741-1749
        • O’Sullivan P.
        • Sharples K.
        • Dalphin M.
        • et al.
        A multigene urine test for the detection and stratification of bladder cancer in patients presenting with hematuria.
        J Urol. 2012; 188: 741-747
        • Raman J.D.
        • Kavalieris L.
        • Konety B.
        • et al.
        The Diagnostic Performance of Cxbladder Resolve, Alone and in Combination with Other Cxbladder Tests, in the Identification and Priority Evaluation of Patients at Risk for Urothelial Carcinoma.
        J Urol. 2021; 206: 1380-1389
        • van Valenberg F.J.P.
        • Hiar A.M.
        • Wallace E.
        • et al.
        Validation of an mRNA-based Urine Test for the Detection of Bladder Cancer in Patients with Haematuria.
        Eur Urol Oncol. 2021; 4: 93-101
        • Robertson A.G.
        • Kim J.
        • Al-Ahmadie H.
        • et al.
        Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.
        Cell. 2017; 171 (e25): 540-556
        • Casadio V.
        • Calistri D.
        • Tebaldi M.
        • et al.
        Urine cell-free DNA integrity as a marker for early bladder cancer diagnosis: preliminary data.
        Urol Oncol. 2013; 31: 1744-1750
        • Tomlinson D.C.
        • Baldo O.
        • Harnden P.
        • et al.
        FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer.
        J Pathol. 2007; 213: 91-98
        • Allory Y.
        • Beukers W.
        • Sagrera A.
        • et al.
        Telomerase reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome.
        Eur Urol. 2014; 65: 360-366
        • Piatti P.
        • Chew Y.C.
        • Suwoto M.
        • et al.
        Clinical evaluation of Bladder CARE, a new epigenetic test for bladder cancer detection in urine samples.
        Clin Epigenetics. 2021; 13: 84
        • Hentschel A.E.
        • Beijert I.J.
        • Bosschieter J.
        • et al.
        Bladder cancer detection in urine using DNA methylation markers: a technical and prospective preclinical validation.
        Clin Epigenetics. 2022; 14: 19
      3. Gene expression signature in urine for diagnosing and assessing aggressiveness of bladder urothelial carcinoma - PubMed.
        (Available at:) (Accessed May 7, 2022)
      4. Carbonic anhydrase IX in bladder cancer: a diagnostic, prognostic, and therapeutic molecular marker - PubMed.
        (Available at:) (Accessed May 7, 2022)
      5. Urinary carbonic anhydrase IX splicing messenger RNA variants in urogenital cancers - PubMed.
        (Available at:) (Accessed May 7, 2022)
      6. Carbonic anhydrase IX as a diagnostic urinary marker for urothelial bladder cancer - PubMed.
        (Available at:) (Accessed May 7, 2022)
        • Ku J.H.
        • Godoy G.
        • Amiel G.E.
        • et al.
        Urine survivin as a diagnostic biomarker for bladder cancer: a systematic review.
        BJU Int. 2012; 110: 630-636
        • Shariat S.F.
        • Casella R.
        • Khoddami S.M.
        • et al.
        Urine detection of survivin is a sensitive marker for the noninvasive diagnosis of bladder cancer.
        J Urol. 2004; 171: 626-630
        • Horstmann M.
        • Bontrup H.
        • Hennenlotter J.
        • et al.
        Clinical experience with survivin as a biomarker for urothelial bladder cancer.
        World J Urol. 2010; 28: 399-404
      7. A urinary microRNA signature can predict the presence of bladder urothelial carcinoma in patients undergoing surveillance | British Journal of Cancer.
        (Available at:) (Accessed May 7, 2022)
        • Kutwin P.
        • Konecki T.
        • Borkowska E.M.
        • et al.
        Urine miRNA as a potential biomarker for bladder cancer detection – a meta-analysis.
        Cent Eur J Urol. 2018; 71: 177-185
        • Roperch J.P.
        • Grandchamp B.
        • Desgrandchamps F.
        • et al.
        Promoter hypermethylation of HS3ST2, SEPTIN9 and SLIT2 combined with FGFR3 mutations as a sensitive/specific urinary assay for diagnosis and surveillance in patients with low or high-risk non-muscle-invasive bladder cancer.
        BMC Cancer. 2016; 16: 704
        • Dahmcke C.M.
        • Steven K.E.
        • Larsen L.K.
        • et al.
        A Prospective Blinded Evaluation of Urine-DNA Testing for Detection of Urothelial Bladder Carcinoma in Patients with Gross Hematuria.
        Eur Urol. 2016; 70: 916-919
      8. Evaluation of an Epigenetic Profile for the Detection of Bladder Cancer in Patients with Hematuria | J Urol.
        (Available at:) (Accessed May 7, 2022)
        • Grossman H.B.
        • Soloway M.
        • Messing E.
        • et al.
        Surveillance for Recurrent Bladder Cancer Using a Point-of-Care Proteomic Assay.
        JAMA. 2006; 295: 299-305
        • Lotan Y.
        • OʼSullivan P.
        • Raman J.D.
        • et al.
        Clinical comparison of noninvasive urine tests for ruling out recurrent urothelial carcinoma.
        Urol Oncol Semin Orig Investig. 2017; 35: 531.e15-531.e22
        • Raitanen M.P.
        • FinnBladder Group
        The role of BTA stat Test in follow-up of patients with bladder cancer: results from FinnBladder studies.
        World J Urol. 2008; 26: 45-50
        • Guo A.
        • Wang X.
        • Gao L.
        • et al.
        Bladder tumour antigen (BTA stat) test compared to the urine cytology in the diagnosis of bladder cancer: A meta-analysis.
        Can Urol Assoc J. 2014; 8: E347-E352
      9. Urine Sediment Smears as a Diagnostic Procedure in Cancers of the Urinary Tract.
        (Available at:) (Accessed May 8, 2022)
        • Yafi F.A.
        • Brimo F.
        • Auger M.
        • et al.
        Is the performance of urinary cytology as high as reported historically? A contemporary analysis in the detection and surveillance of bladder cancer.
        Urol Oncol Semin Orig Investig. 2014; 32: 27.e1-27.e6
        • Gudjónsson S.
        • Isfoss B.L.
        • Hansson K.
        • et al.
        The Value of the UroVysion® Assay for Surveillance of Non–Muscle-Invasive Bladder Cancer.
        Eur Urol. 2008; 54: 402-408
        • Davis N.
        • Shtabsky A.
        • Lew S.
        • et al.
        A Novel Urine-Based Assay for Bladder Cancer Diagnosis: Multi-Institutional Validation Study.
        Eur Urol Focus. 2018; 4: 388-394
      10. Performance Characteristics of a Multigene Urine Biomarker Test for Monitoring for Recurrent Urothelial Carcinoma in a Multicenter Study | J Urol.
        (Available at:) (Accessed May 7, 2022)
        • Yun S.J.
        • Jeong P.
        • Kim W.T.
        • et al.
        Cell-free microRNAs in urine as diagnostic and prognostic biomarkers of bladder cancer.
        Int J Oncol. 2012; 41: 1871-1878
        • Critelli R.
        • Fasanelli F.
        • Oderda M.
        • et al.
        Detection of multiple mutations in urinary exfoliated cells from male bladder cancer patients at diagnosis and during follow-up.
        Oncotarget. 2016; 7: 67435-67448
        • Wasserstrom A.
        • Frumkin D.
        • Dotan Z.
        • et al.
        Mp13-15 molecular urine cytology – bladder epicheck is a novel molecular diagnostic tool for monitoring of bladder cancer patients.
        J Urol. 2016; 195: e140
        • Su S.F.
        • de Castro Abreu A.L.
        • Chihara Y.
        • et al.
        A Panel of Three Markers Hyper- and Hypomethylated in Urine Sediments Accurately Predicts Bladder Cancer Recurrence.
        Clin Cancer Res. 2014; 20: 1978-1989
        • Beukers W.
        • van der Keur K.A.
        • Kandimalla R.
        • et al.
        FGFR3, TERT and OTX1 as a Urinary Biomarker Combination for Surveillance of Patients with Bladder Cancer in a Large Prospective Multicenter Study.
        J Urol. 2017; 197: 1410-1418
        • Mengual L.
        • Marín-Aguilera M.
        • Ribal M.J.
        • et al.
        Clinical Utility of Fluorescent in situ Hybridization for the Surveillance of Bladder Cancer Patients Treated with Bacillus Calmette-Guérin Therapy.
        Eur Urol. 2007; 52: 752-759
        • Kipp B.R.
        • Karnes R.J.
        • Brankley S.M.
        • et al.
        Monitoring intravesical therapy for superficial bladder cancer using fluorescence in situ hybridization.
        J Urol. 2005; 173: 401-404
        • Kamat A.M.
        • Dickstein R.J.
        • Messetti F.
        • et al.
        Use of Fluorescence In Situ Hybridization to Predict Response to Bacillus Calmette-Guérin Therapy for Bladder Cancer: Results of a Prospective Trial.
        J Urol. 2012; 187: 862-867
        • Lotan Y.
        • Inman B.A.
        • Davis L.G.
        • et al.
        Evaluation of the Fluorescence In Situ Hybridization Test to Predict Recurrence and/or Progression of Disease after bacillus Calmette-Guérin for Primary High Grade Nonmuscle Invasive Bladder Cancer: Results from a Prospective Multicenter Trial.
        J Urol. 2019; 202: 920-926
        • Odisho A.Y.
        • Berry A.B.
        • Ahmad A.E.
        • et al.
        Reflex ImmunoCyt Testing for the Diagnosis of Bladder Cancer in Patients with Atypical Urine Cytology.
        Eur Urol. 2013; 63: 936-940
      11. Prospective Evaluation of the Clinical Usefulness of Reflex Fluorescence In Situ Hybridization Assay in Patients With Atypical Cytology for the Detection of Urothelial Carcinoma of the Bladder | J Urol.
        (Available at:) (Accessed May 25, 2022)
        • Schlomer B.J.
        • Ho R.
        • Sagalowsky A.
        • et al.
        Prospective Validation of the Clinical Usefulness of Reflex Fluorescence In Situ Hybridization Assay in Patients With Atypical Cytology for the Detection of Urothelial Carcinoma of the Bladder.
        J Urol. 2010; 183: 62-67
        • Badrinath K.
        • Neal S.
        • Andrew K.K.
        • et al.
        Yair Lotan. Evaluation of Cxbladder and Adjudication of Atypical Cytology and Equivocal Cystoscopy.
        Eur Urol. 2019; 76: 238-243
        • Zuiverloon T.C.M.
        • Tjin S.S.
        • Busstra M.
        • et al.
        Optimization of Nonmuscle Invasive Bladder Cancer Recurrence Detection Using a Urine Based FGFR3 Mutation Assay.
        J Urol. 2011; 186: 707-712
        • Christensen E.
        • Birkenkamp-Demtröder K.
        • Nordentoft I.
        • et al.
        Liquid Biopsy Analysis of FGFR3 and PIK3CA Hotspot Mutations for Disease Surveillance in Bladder Cancer.
        Eur Urol. 2017; 71: 961-969
        • Kamat A.M.
        • Briggman J.
        • Urbauer D.L.
        • et al.
        Cytokine Panel for Response to Intravesical Therapy (CyPRIT): Nomogram of Changes in Urinary Cytokine Levels Predicts Patient Response to Bacillus Calmette-Guérin.
        Eur Urol. 2016; 69: 197-200
        • Rosser C.J.
        • Chang M.
        • Dai Y.
        • et al.
        Urinary Protein Biomarker Panel for the Detection of Recurrent Bladder Cancer.
        Cancer Epidemiol Biomarkers Prev. 2014; 23: 1340-1345
        • Edge Limited Pacific
        Use of a Multiplexed Molecular Biomarker Test Cxbladder.
        in: Real World Decision making to provide clinical utility using a randomized Design., 2022 (Available at:) (Accessed May 5, 2022)