Impact of intravesical therapy for non-muscle invasive bladder cancer on the accuracy of urine cytology

  • Mohit GuptaEmail author
  • Niv Milbar
  • Giorgia Tema
  • Filippo Pederzoli
  • Meera Chappidi
  • Max Kates
  • Christopher J. VandenBussche
  • Trinity J. Bivalacqua
Topic Paper



Urine cytology remains an essential diagnostic tool in the surveillance of patients with non-muscle invasive bladder cancer (NMIBC). The correlation of urine cytology with biopsy specimens to determine its accuracy following induction intravesical therapy has not been investigated.


A retrospective review was performed of patients who underwent intravesical therapy for biopsy-proven non-muscle invasive disease between 2013 and 2016 at our institution. All patients uniformly underwent cytology and systematic bladder biopsies in the operating room within 12 weeks following intravesical therapy. The accuracy of urinary cytology in predicting high-grade disease recurrence following intravesical therapy was confirmed by correlating cytology results to post-treatment systematic biopsies, regardless of endoscopic findings. Only patients with complete information regarding urine cytology and pathologic biopsy results, both pre- and post-intravesical therapy, were included.


90 cytology samples following intravesical therapy were analyzed from 76 patients who met inclusion criteria. 72 (80.0%) and 18 (20.0%) of the samples were collected from patients initially treated for high- and low-grade disease, respectively. Fifty-six (62.2%) specimens were obtained from patients following induction of bacillus Calmette–Guerin (BCG) therapy; the remainder were from patients treated with intravesical gemcitabine/docetaxel, mitomycin, or BCG/interferon. For patients treated with BCG, cytology was positive for high-grade disease in 8/15 patients with high-grade pathology on follow-up biopsy, thus demonstrating a sensitivity of 53% (95% CI 27–79%), specificity of 95% (95% CI 84–99%), positive predictive value of 80% (95% CI 44–98%), and negative predictive value of 85% (95% CI 71–94%). If cytologic interpretation was broadened to include high-grade and “suspicious for high-grade” findings, sensitivity increased to 67% (95% CI 38–88%) and specificity decreased to 88% (95% CI 74–96%).


While urinary cytology maintains a high specificity following intravesical therapy, it demonstrates a low sensitivity for potentially aggressive high-grade urothelial carcinoma. Further evaluation of more effective, clinic-based enhanced cystoscopy techniques and biomarkers is warranted to better identify patients at risk for disease recurrence following BCG therapy.


Urinary bladder neoplasms Urine cytology Urothelial carcinoma Bacillus Calmette–Guerin 


Author contributions

MG: data collection or management, data analysis, and manuscript writing/editing. NM: data collection or management, data analysis, and manuscript writing/editing. GT: data collection or management. FP: data collection or management. MC: data collection or management. MK: protocol/project development. CJV: manuscript writing/editing. TJB: manuscript writing/editing, protocol/project development.



Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Nepple KG, O’Donnell MA (2009) The optimal management of T1 high-grade bladder cancer. Can Urol Assoc J 3:S188–S192CrossRefGoogle Scholar
  2. 2.
    Jones JS (2016) Non-muscle invasive bladder cancers (Ta, T1, and CIS). In: Scott W, McDougal AJW, Kavoussi LR, Novick AC, Partin AW, Peters CA, Ramchandani P (eds) Campbell-Walsh urology, 11th edn. Elsevier, Philadelphia, pp 2205–2222Google Scholar
  3. 3.
    Chang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR et al (2016) Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J Urol 196:1021–1029CrossRefGoogle Scholar
  4. 4.
    Kaufman DS, Shipley WU, Feldman AS (2009) Bladder cancer. Lancet 374:239–249CrossRefGoogle Scholar
  5. 5.
    Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L et al (2006) Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49:466 (discussion 75–77) CrossRefGoogle Scholar
  6. 6.
    Lokeshwar VB, Habuchi T, Grossman HB, Murphy WM, Hautmann SH, Hemstreet GP 3rd et al (2005) Bladder tumor markers beyond cytology: International Consensus Panel on bladder tumor markers. Urology 66:35–63CrossRefGoogle Scholar
  7. 7.
    Gupta M, VandenBussche CJ, Bivalacqua TJ (2018) Urinary cytology and the Paris system for reporting urinary cytology: implications for urological management. Cytopathology 29(4):368–370CrossRefGoogle Scholar
  8. 8.
    Savic S, Zlobec I, Thalmann GN, Engeler D, Schmauss M, Lehmann K et al (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 124:2899–2904CrossRefGoogle Scholar
  9. 9.
    Maier U, Simak R, Neuhold N (1995) The clinical value of urinary cytology: 12 years of experience with 615 patients. J Clin Pathol 48:314–317CrossRefGoogle Scholar
  10. 10.
    Sobin LH, Fleming ID (1997) TNM Classification of malignant tumors, 5th edn. Springer, BerlinGoogle Scholar
  11. 11.
    Storkel S, Eble JN, Adlakha K, Amin M, Blute ML, Bortwick DG (1997) Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer 80:1803–1804CrossRefGoogle Scholar
  12. 12.
    Epstein JI, Amin MB, Reuter VR, Mostofi FK (1998) The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol 22:1435–1448CrossRefGoogle Scholar
  13. 13.
    Rosenthal DL, Wojcik EM, Kurtycz DF (2016) The Paris system for reporting urinary cytology, 1st edn. Springer, New YorkCrossRefGoogle Scholar
  14. 14.
    Rosenthal DL, Vandenbussche CJ, Burroughs FH, Sathiyamoorthy S, Guan H, Owens C (2013) The Johns Hopkins Hospital template for urologic cytology samples: part I-creating the template. Cancer Cytopathol 121:15–20CrossRefGoogle Scholar
  15. 15.
    VandenBussche CJ, Sathiyamoorthy S, Owens CL, Burroughs FH, Rosenthal DL, Guan H (2013) The Johns Hopkins Hospital template for urologic cytology samples: parts II and III: improving the predictability of indeterminate results in urinary cytologic samples: an outcomes and cytomorphologic study. Cancer Cytopathol 121:21–28CrossRefGoogle Scholar
  16. 16.
    Wiener HG, Vooijs GP, vant’t Hof-Grootenboer B (1993) Accuracy of urinary cytology in the diagnosis of primary and recurrent bladder cancer. Acta Cytol 37:163–169Google Scholar
  17. 17.
    Grossman HB, Messing E, Soloway M, Tomera K, Katz G, Berger Y et al (2005) Detection of bladder cancer using a point-of-care proteomic assay. JAMA 293:810–816CrossRefGoogle Scholar
  18. 18.
    Halling KC, King W, Sokolova IA, Meyer RG, Burkhardt HM, Halling AC et al (2000) A comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma. J Urol 164:1768–1775CrossRefGoogle Scholar
  19. 19.
    Karakiewicz PI, Benayoun S, Zippe C, Lüdecke G, Boman H, Sanchez-Carbayo M et al (2006) Institutional variability in the accuracy of urinary cytology for predicting recurrence of transitional cell carcinoma of the bladder. BJU Int 97:997–1001CrossRefGoogle Scholar
  20. 20.
    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 61:109–118 (discussion 18) CrossRefGoogle Scholar
  21. 21.
    Yafi FA, Brimo F, Steinberg J, Aprikian AG, Tanguay S, Kassouf W (2015) Prospective analysis of sensitivity and specificity of urinary cytology and other urinary biomarkers for bladder cancer. Urol Oncol 33(66):e25–e31Google Scholar
  22. 22.
    Tetu B (2009) Diagnosis of urothelial carcinoma from urine. Mod Pathol 22(Suppl 2):S53–S59CrossRefGoogle Scholar
  23. 23.
    Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM et al (2017) EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol 71:447–461CrossRefGoogle Scholar
  24. 24.
    VandenBussche CJ (2016) A review of the Paris system for reporting urinary cytology. Cytopathology 27:153–156CrossRefGoogle Scholar
  25. 25.
    Cowan ML, Rosenthal DL, VandenBussche CJ (2017) Improved risk stratification for patients with high-grade urothelial carcinoma following application of the Paris system for reporting urinary cytology. Cancer Cytopathol 125:427–434CrossRefGoogle Scholar
  26. 26.
    Chou R, Buckley D, Fu R, Gore JL, Gustafson K, Griffin J (2015) AHRQ comparative effectiveness reviews. Emerging approaches to diagnosis and treatment of non-muscle-invasive bladder cancer. Agency for Healthcare Research and Quality (US), RockvilleGoogle Scholar
  27. 27.
    Tomasini JM, Konety BR (2013) Urinary markers/cytology: what and when should a urologist use. Urol Clin N Am 40:165–173CrossRefGoogle Scholar
  28. 28.
    Schmidbauer J, Witjes F, Schmeller N, Donat R, Susani M, Marberger M (2004) Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol 171:135–138CrossRefGoogle Scholar
  29. 29.
    Burger M, Grossman HB, Droller M, Schmidbauer J, Hermann G, Dragoescu O et al (2013) Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol 64:846–854CrossRefGoogle Scholar
  30. 30.
    Rink M, Babjuk M, Catto JW, Jichlinski P, Shariat SF, Stenzl A et al (2013) Hexyl aminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: a critical review of the current literature. Eur Urol 64:624–638CrossRefGoogle Scholar
  31. 31.
    Jichlinski P, Guillou L, Karlsen SJ, Malmstrom PU, Jocham D, Brennhovd B et al (2003) Hexyl aminolevulinate fluorescence cystoscopy: new diagnostic tool for photodiagnosis of superficial bladder cancer—a multicenter study. J Urol 170:226–229CrossRefGoogle Scholar
  32. 32.
    Fradet Y, Grossman HB, Gomella L, Lerner S, Cookson M, Albala D et al (2007) A comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase III, multicenter study. J Urol 178:68–73 (discussion)CrossRefGoogle Scholar
  33. 33.
    Jocham D, Witjes F, Wagner S, Zeylemaker B, van Moorselaar J, Grimm MO et al (2005) Improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a prospective, phase III multicenter study. J Urol 174:862–866 discussion 6 CrossRefGoogle Scholar
  34. 34.
    Witjes JA, Babjuk M, Gontero P, Jacqmin D, Karl A, Kruck S et al (2014) Clinical and cost effectiveness of hexaminolevulinate-guided blue-light cystoscopy: evidence review and updated expert recommendations. Eur Urol 66:863–871CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Mohit Gupta
    • 1
    Email author
  • Niv Milbar
    • 1
  • Giorgia Tema
    • 1
  • Filippo Pederzoli
    • 1
  • Meera Chappidi
    • 1
  • Max Kates
    • 1
  • Christopher J. VandenBussche
    • 2
  • Trinity J. Bivalacqua
    • 1
  1. 1.Department of Urology, James Buchanan Brady Urological InstituteJohns Hopkins Medical Institutions, The Johns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Pathology and OncologyJohns Hopkins Medical InstitutionsBaltimoreUSA

Personalised recommendations