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Can urinary biomarkers replace cystoscopy?

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Abstract

Purpose

Diagnosis and follow-up in patients with non-muscle invasive bladder cancer (NMIBC) rely on cystoscopy and urine cytology. The aim of this review paper is to give an update on urinary biomarkers and their diagnosis and surveillance potential. Besides FDA-approved markers, recent approaches like DNA methylation assays, mRNA gene expression assays and cell-free DNA (cfDNA) are evaluated to assess whether replacing cystoscopy with urine markers is a potential scenario for the future.

Methods

We performed a non-systematic review of current literature without time period restriction using the National Library of Medicine database (http://ww.pubmed.gov). The search included the following key words in different combinations: “urothelial carcinoma”, “urinary marker”, “hematuria”, “cytology” and “bladder cancer”. Further, references were extracted from identified articles. The results were evaluated regarding their clinical relevance and study quality.

Results

Currently, replacing cystoscopy with available urine markers is not recommended by international guidelines. For FDA-approved markers, prospective randomized trials are lacking. Newer approaches focusing on molecular, genomic and transcriptomic aberrations are promising with good accuracies. Furthermore, these assays may provide additional molecular information to guide individualized surveillance strategies and therapy. Currently ongoing prospective trials will determine if cystoscopy reduction is feasible.

Conclusion

Urinary markers represent a non-invasive approach for molecular characterization of the disease. Although fully replacing cystoscopy seems unrealistic in the near future, enhancing the current gold standard by additional molecular information is feasible. A reliable classification and differentiation between aggressive and nonaggressive tumors by applying DNA, mRNA, and cfDNA assays may change surveillance to help reduce cystoscopies.

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References

  1. Chang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR, Pruthi R, Quale DZ, Ritch CR, Seigne JD, Skinner EC, Smith ND, McKiernan JM (2016) Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J Urol 196(4):1021–1029. https://doi.org/10.1016/j.juro.2016.06.049

    Article  PubMed  Google Scholar 

  2. Schmitz-Drager BJ, Kuckuck EC, Zuiverloon TC, Zwarthoff EC, Saltzman A, Srivastava A, Hudson MA, Seiler R, Todenhofer T, Vlahou A, Grossman HB, Schoenberg MP, Sanchez-Carbayo M, Brunn LA, van Rhijn BW, Goebell PJ, Kamat AM, Roupret M, Shariat SF, Kiemeney LA (2016) Microhematuria assessment an IBCN consensus-Based upon a critical review of current guidelines. Urol Oncol 34(10):437–451. https://doi.org/10.1016/j.urolonc.2016.05.030

    Article  PubMed  Google Scholar 

  3. Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, Hernandez V, Kaasinen E, Palou J, Roupret M, van Rhijn BW, Shariat SF, Soukup V, Sylvester RJ, Zigeuner R (2017) EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol 71(3):447–461. https://doi.org/10.1016/j.eururo.2016.05.041

    Article  PubMed  Google Scholar 

  4. van der Aa MN, Steyerberg EW, Bangma C, van Rhijn BW, Zwarthoff EC, van der Kwast TH (2010) Cystoscopy revisited as the gold standard for detecting bladder cancer recurrence: diagnostic review bias in the randomized, prospective CEFUB trial. J Urol 183(1):76–80. https://doi.org/10.1016/j.juro.2009.08.150

    Article  PubMed  Google Scholar 

  5. Schmitz-Drager C, Bonberg N, Pesch B, Todenhofer T, Sahin S, Behrens T, Bruning T, Schmitz-Drager BJ (2016) Replacing cystoscopy by urine markers in the follow-up of patients with low-risk non-muscle-invasive bladder cancer?—an International Bladder Cancer Network project. Urol Oncol 34(10):452–459. https://doi.org/10.1016/j.urolonc.2016.06.001

    Article  PubMed  Google Scholar 

  6. Kamat AM, Dickstein RJ, Messetti F, Anderson R, Pretzsch SM, Gonzalez GN, Katz RL, Khanna A, Zaidi T, Wu X, Grossman HB, Dinney CP (2012) Use of fluorescence in situ hybridization to predict response to bacillus Calmette-Guerin therapy for bladder cancer: results of a prospective trial. J Urol 187(3):862–867. https://doi.org/10.1016/j.juro.2011.10.144

    Article  PubMed  PubMed Central  Google Scholar 

  7. Alfred Witjes J, Lebret T, Comperat EM, Cowan NC, De Santis M, Bruins HM, Hernandez V, Espinos EL, Dunn J, Rouanne M, Neuzillet Y, Veskimae E, van der Heijden AG, Gakis G, Ribal MJ (2017) Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol 71(3):462–475. https://doi.org/10.1016/j.eururo.2016.06.020

    Article  CAS  PubMed  Google Scholar 

  8. Yousef PG, Gabril MY (2018) An update on the molecular pathology of urinary bladder tumors. Pathol Res Pract 214(1):1–6. https://doi.org/10.1016/j.prp.2017.11.003

    Article  CAS  PubMed  Google Scholar 

  9. Lotan Y, Roehrborn CG (2003) Sensitivity and specificity of commonly available bladder tumor markers versus cytology: results of a comprehensive literature review and meta-analyses. Urology 61(1):109–118 (discussion 118)

    Article  PubMed  Google Scholar 

  10. Barkan GA, Wojcik EM, Nayar R, Savic-Prince S, Quek ML, Kurtycz DF, Rosenthal DL (2016) The Paris system for reporting urinary cytology: the quest to develop a standardized terminology. Acta Cytol 60(3):185–197. https://doi.org/10.1159/000446270

    Article  PubMed  Google Scholar 

  11. Mowatt G, Zhu S, Kilonzo M, Boachie C, Fraser C, Griffiths TR, N’Dow J, Nabi G, Cook J, Vale L (2010) Systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer. Health technology assessment (Winchester, England). Health Technol Assess 14(4):1–331. https://doi.org/10.3310/hta14040 (iii–iv)

    Article  CAS  PubMed  Google Scholar 

  12. Todenhofer T, Hennenlotter J, Guttenberg P, Mohrhardt S, Kuehs U, Esser M, Aufderklamm S, Bier S, Harland N, Rausch S, Gakis G, Stenzl A, Schwentner C (2015) Prognostic relevance of positive urine markers in patients with negative cystoscopy during surveillance of bladder cancer. BMC Cancer 15:155. https://doi.org/10.1186/s12885-015-1089-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Seideman C, Canter D, Kim P, Cordon B, Weizer A, Oliva I, Rao J, Inman BA, Posch M, Herr H, Lotan Y (2015) Multicenter evaluation of the role of UroVysion FISH assay in surveillance of patients with bladder cancer: does FISH positivity anticipate recurrence? World J Urol 33(9):1309–1313. https://doi.org/10.1007/s00345-014-1452-9

    Article  CAS  PubMed  Google Scholar 

  14. Schmitz-Drager BJ, Droller M, Lokeshwar VB, Lotan Y, Hudson MA, van Rhijn BW, Marberger MJ, Fradet Y, Hemstreet GP, Malmstrom PU, Ogawa O, Karakiewicz PI, Shariat SF (2015) Molecular markers for bladder cancer screening, early diagnosis, and surveillance: the WHO/ICUD consensus. Urol Int 94(1):1–24. https://doi.org/10.1159/000369357

    Article  CAS  PubMed  Google Scholar 

  15. Moatamed NA, Apple SK, Bennett CJ, Aronson WJ, Klisak I, Shirley BJ, Moatamed F (2013) Exclusion of the uniform tetraploid cells significantly improves specificity of the urine FISH assay. Diagn Cytopathol 41(3):218–225. https://doi.org/10.1002/dc.21831

    Article  PubMed  Google Scholar 

  16. Chou R, Gore JL, Buckley D, Fu R, Gustafson K, Griffin JC, Grusing S, Selph S (2015) Urinary biomarkers for diagnosis of bladder cancer: a systematic review and meta-analysis. Ann Intern Med 163(12):922–931. https://doi.org/10.7326/m15-0997

    Article  PubMed  Google Scholar 

  17. Comploj E, Mian C, Ambrosini-Spaltro A, Dechet C, Palermo S, Trenti E, Lodde M, Horninger W, Pycha A (2013) uCyt+/ImmunoCyt and cytology in the detection of urothelial carcinoma: an update on 7422 analyses. Cancer Cytopathol 121(7):392–397. https://doi.org/10.1002/cncy.21287

    Article  PubMed  Google Scholar 

  18. Todenhofer T, Hennenlotter J, Aufderklamm S, Kuhs U, Gakis G, Germann M, Stenzl A, Schwentner C (2013) Individual risk assessment in bladder cancer patients based on a multi-marker panel. J Cancer Res Clin Oncol 139(1):49–56. https://doi.org/10.1007/s00432-012-1297-9

    Article  PubMed  Google Scholar 

  19. Todenhofer T, Hennenlotter J, Kuhs U, Tews V, Gakis G, Aufderklamm S, Stenzl A, Schwentner C (2012) Influence of urinary tract instrumentation and inflammation on the performance of urine markers for the detection of bladder cancer. Urology 79(3):620–624. https://doi.org/10.1016/j.urology.2011.10.067

    Article  PubMed  Google Scholar 

  20. Huang YL, Chen J, Yan W, Zang D, Qin Q, Deng AM (2015) Diagnostic accuracy of cytokeratin-19 fragment (CYFRA 21-1) for bladder cancer: a systematic review and meta-analysis. Tumour Biol 36(5):3137–3145. https://doi.org/10.1007/s13277-015-3352-z

    Article  CAS  PubMed  Google Scholar 

  21. Konety BR, Nguyen TS, Dhir R, Day RS, Becich MJ, Stadler WM, Getzenberg RH (2000) Detection of bladder cancer using a novel nuclear matrix protein, BLCA-4. Clin Cancer Res 6(7):2618–2625

    CAS  PubMed  Google Scholar 

  22. Cai Q, Wu Y, Guo Z, Gong R, Tang Y, Yang K, Li X, Guo X, Niu Y, Zhao Y (2015) Urine BLCA-4 exerts potential role in detecting patients with bladder cancers: a pooled analysis of individual studies. Oncotarget 6(35):37500–37510. https://doi.org/10.18632/oncotarget.6061

    Article  PubMed  PubMed Central  Google Scholar 

  23. Shariat SF, Casella R, Khoddami SM, Hernandez G, Sulser T, Gasser TC, Lerner SP (2004) Urine detection of survivin is a sensitive marker for the noninvasive diagnosis of bladder cancer. J Urol 171(2 Pt 1):626–630. https://doi.org/10.1097/01.ju.0000107826.78479.90

    Article  CAS  PubMed  Google Scholar 

  24. Svatek RS, Herman MP, Lotan Y, Casella R, Hsieh JT, Sagalowsky AI, Shariat SF (2006) Soluble Fas—a promising novel urinary marker for the detection of recurrent superficial bladder cancer. Cancer 106(8):1701–1707. https://doi.org/10.1002/cncr.21795

    Article  CAS  PubMed  Google Scholar 

  25. Lokeshwar VB, Schroeder GL, Selzer MG, Hautmann SH, Posey JT, Duncan RC, Watson R, Rose L, Markowitz S, Soloway MS (2002) Bladder tumor markers for monitoring recurrence and screening comparison of hyaluronic acid-hyaluronidase and BTA-Stat tests. Cancer 95(1):61–72. https://doi.org/10.1002/cncr.10652

    Article  PubMed  Google Scholar 

  26. Brems-Eskildsen AS, Zieger K, Toldbod H, Holcomb C, Higuchi R, Mansilla F, Munksgaard PP, Borre M, Orntoft TF, Dyrskjot L (2010) Prediction and diagnosis of bladder cancer recurrence based on urinary content of hTERT, SENP1, PPP1CA, and MCM5 transcripts. BMC Cancer 10:646. https://doi.org/10.1186/1471-2407-10-646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Soria F, Droller MJ, Lotan Y, Gontero P, D’Andrea D, Gust KM, Roupret M, Babjuk M, Palou J, Shariat SF (2018) An up-to-date catalog of available urinary biomarkers for the surveillance of non-muscle invasive bladder cancer. World J Urol. https://doi.org/10.1007/s00345-018-2380-x

    Article  PubMed  PubMed Central  Google Scholar 

  28. Savic S, Zlobec I, Thalmann GN, Engeler D, Schmauss M, Lehmann K, Mattarelli G, Eichenberger T, Dalquen P, Spieler P, Schoenegg R, Gasser TC, Sulser T, Forster T, Zellweger T, Casella R, Bubendorf L (2009) The prognostic value of cytology and fluorescence in situ hybridization in the follow-up of nonmuscle-invasive bladder cancer after intravesical Bacillus Calmette-Guerin therapy. Int J Cancer 124(12):2899–2904. https://doi.org/10.1002/ijc.24258

    Article  CAS  PubMed  Google Scholar 

  29. Kamat AM, Briggman J, Urbauer DL, Svatek R, Nogueras Gonzalez GM, Anderson R, Grossman HB, Prat F, Dinney CP (2016) Cytokine Panel for Response to Intravesical Therapy (CyPRIT): nomogram of changes in urinary cytokine levels predicts patient response to bacillus Calmette-Guerin. Eur Urol 69(2):197–200. https://doi.org/10.1016/j.eururo.2015.06.023

    Article  CAS  PubMed  Google Scholar 

  30. Aly MS, Khaled HM, Emara M, Hussein TD (2012) Cytogenetic profile of locally advanced and metastatic schistosoma-related bladder cancer and response to chemotherapy. Cancer Genet 205(4):156–162. https://doi.org/10.1016/j.cancergen.2012.01.011

    Article  CAS  PubMed  Google Scholar 

  31. van Kessel KE, Beukers W, Lurkin I, Ziel-van der Made A, van der Keur KA, Boormans JL, Dyrskjot L, Marquez M, Orntoft TF, Real FX, Segersten U, Malats N, Malmstrom PU, Van Criekinge W, Zwarthoff EC (2017) Validation of a DNA methylation-mutation urine assay to select patients with hematuria for cystoscopy. J Urol 197(3 Pt 1):590–595. https://doi.org/10.1016/j.juro.2016.09.118

    Article  CAS  PubMed  Google Scholar 

  32. Beukers W, van der Keur KA, Kandimalla R, Vergouwe Y, Steyerberg EW, Boormans JL, Jensen JB, Lorente JA, Real FX, Segersten U, Orntoft TF, Malats N, Malmstrom PU, Dyrskjot L, Zwarthoff EC (2017) FGFR3, TERT and OTX1 as a urinary biomarker combination for surveillance of patients with bladder cancer in a large prospective multicenter study. J Urol 197(6):1410–1418. https://doi.org/10.1016/j.juro.2016.12.096

    Article  CAS  PubMed  Google Scholar 

  33. Kavalieris L, O’Sullivan PJ, Suttie JM, Pownall BK, Gilling PJ, Chemasle C, Darling DG (2015) A segregation index combining phenotypic (clinical characteristics) and genotypic (gene expression) biomarkers from a urine sample to triage out patients presenting with hematuria who have a low probability of urothelial carcinoma. BMC Urol 15:23. https://doi.org/10.1186/s12894-015-0018-5

    Article  PubMed  PubMed Central  Google Scholar 

  34. O’Sullivan P, Sharples K, Dalphin M, Davidson P, Gilling P, Cambridge L, Harvey J, Toro T, Giles N, Luxmanan C, Alves CF, Yoon HS, Hinder V, Masters J, Kennedy-Smith A, Beaven T, Guilford PJ (2012) A multigene urine test for the detection and stratification of bladder cancer in patients presenting with hematuria. J Urol 188(3):741–747. https://doi.org/10.1016/j.juro.2012.05.003

    Article  PubMed  Google Scholar 

  35. Kavalieris L, O’Sullivan P, Frampton C, Guilford P, Darling D, Jacobson E, Suttie J, Raman JD, Shariat SF, Lotan Y (2017) Performance characteristics of a multigene urine biomarker test for monitoring for recurrent urothelial carcinoma in a multicenter study. J Urol 197(6):1419–1426. https://doi.org/10.1016/j.juro.2016.12.010

    Article  PubMed  Google Scholar 

  36. Wallace E, Higuchi R, Satya M, McCann L, Sin MLY, Bridge JA, Wei H, Zhang J, Wong E, Hiar A, Mach KE, Scherr D, Egerdie RB, Ohta S, Sexton WJ, Meng MV, Weizer AZ, Woods M, Jansz GK, Zadra J, Lotan Y, Goldfarb B, Liao JC (2017) Development of a 90-minute integrated noninvasive urinary assay for bladder cancer detection. J Urol. https://doi.org/10.1016/j.juro.2017.09.141

    Article  PubMed  PubMed Central  Google Scholar 

  37. Pichler R, Fritz J, Tulchiner G, Klinglmair G, Soleiman A, Horninger W, Klocker H, Heidegger I (2018) Increased accuracy of a novel mRNA-based urine test for bladder cancer surveillance. BJU Int 121(1):29–37. https://doi.org/10.1111/bju.14019

    Article  CAS  PubMed  Google Scholar 

  38. Mengual L, Burset M, Ribal MJ, Ars E, Marin-Aguilera M, Fernandez M, Ingelmo-Torres M, Villavicencio H, Alcaraz A (2010) Gene expression signature in urine for diagnosing and assessing aggressiveness of bladder urothelial carcinoma. Clin Cancer Res 16(9):2624–2633. https://doi.org/10.1158/1078-0432.ccr-09-3373

    Article  CAS  PubMed  Google Scholar 

  39. Mengual L, Ribal MJ, Lozano JJ, Ingelmo-Torres M, Burset M, Fernandez PL, Alcaraz A (2014) Validation study of a noninvasive urine test for diagnosis and prognosis assessment of bladder cancer: evidence for improved models. J Urol 191(1):261–269. https://doi.org/10.1016/j.juro.2013.06.083

    Article  PubMed  Google Scholar 

  40. Ribal MJ, Mengual L, Lozano JJ, Ingelmo-Torres M, Palou J, Rodriguez-Faba O, Witjes JA, Van der Heijden AG, Medina R, Conde JM, Marberger M, Schmidbauer J, Fernandez PL, Alcaraz A (2016) Gene expression test for the non-invasive diagnosis of bladder cancer: a prospective, blinded, international and multicenter validation study. Eur J Cancer (Oxford, England, 1990) 54:131–138. https://doi.org/10.1016/j.ejca.2015.11.003

    Article  CAS  Google Scholar 

  41. Olsson E, Winter C, George A, Chen Y, Howlin J, Tang MH, Dahlgren M, Schulz R, Grabau D, van Westen D, Ferno M, Ingvar C, Rose C, Bendahl PO, Ryden L, Borg A, Gruvberger-Saal SK, Jernstrom H, Saal LH (2015) Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med 7(8):1034–1047. https://doi.org/10.15252/emmm.201404913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Todenhofer T, Struss WJ, Seiler R, Wyatt AW, Black PC (2018) Liquid biopsy-analysis of circulating tumor DNA (ctDNA) in bladder cancer. Bladder Cancer (Amsterdam, Netherlands) 4(1):19–29. https://doi.org/10.3233/blc-170140

    Article  PubMed Central  Google Scholar 

  43. Birkenkamp-Demtroder K, Nordentoft I, Christensen E, Hoyer S, Reinert T, Vang S, Borre M, Agerbaek M, Jensen JB, Orntoft TF, Dyrskjot L (2016) Genomic alterations in liquid biopsies from patients with bladder cancer. Eur Urol 70(1):75–82. https://doi.org/10.1016/j.eururo.2016.01.007

    Article  CAS  PubMed  Google Scholar 

  44. Christensen E, Birkenkamp-Demtroder K, Nordentoft I, Hoyer S, van der Keur K, van Kessel K, Zwarthoff E, Agerbaek M, Orntoft TF, Jensen JB, Dyrskjot L (2017) Liquid biopsy analysis of FGFR3 and PIK3CA hotspot mutations for disease surveillance in bladder cancer. Eur Urol 71(6):961–969. https://doi.org/10.1016/j.eururo.2016.12.016

    Article  CAS  PubMed  Google Scholar 

  45. Birkenkamp-Demtroder K, Christensen E, Nordentoft I, Knudsen M, Taber A, Hoyer S, Lamy P, Agerbaek M, Jensen JB, Dyrskjot L (2018) Monitoring treatment response and metastatic relapse in advanced bladder cancer by liquid biopsy analysis. Eur Urol 73(4):535–540. https://doi.org/10.1016/j.eururo.2017.09.011

    Article  PubMed  Google Scholar 

  46. Aravanis AM, Lee M, Klausner RD (2017) Next-generation sequencing of circulating tumor DNA for early cancer detection. Cell 168(4):571–574. https://doi.org/10.1016/j.cell.2017.01.030

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Tilman Todenhöfer.

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T Todenhöfer serves as a consultant for Ipsen and has scientific cooperations with IDL and Qiagen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Maas, M., Bedke, J., Stenzl, A. et al. Can urinary biomarkers replace cystoscopy?. World J Urol 37, 1741–1749 (2019). https://doi.org/10.1007/s00345-018-2505-2

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