Urothelial Carcinoma In Situ and Treatment of Bacillus Calmette-Guérin Failures

  • David D’Andrea
  • Fred Witjes
  • Francesco Soria
  • Shahrokh F. ShariatEmail author
Living reference work entry


Despite its superficial growth, urothelial carcinoma in situ is an aggressive disease with high recurrence and progression rates. Macroscopic as well as microscopic diagnosis is challenging.

Bacillus Calmette-Guérin (BCG) is the most effective therapy for high-risk bladder cancer. In case of failure no other intravesical therapy has shown convincing results to be used in clinical routine. Radical cystectomy remains from an oncologic point of view the most effective therapy.


  1. Arends TJH, Van der Heijden AG, Witjes JA. Combined chemohyperthermia: 10-year single center experience in 160 patients with nonmuscle invasive bladder cancer. J Urol. 2014;192(3):708–13.PubMedCrossRefGoogle Scholar
  2. Arends TJH, et al. Results of a randomised controlled trial comparing intravesical chemohyperthermia with mitomycin C versus bacillus Calmette-Guérin for adjuvant treatment of patients with intermediate- and high-risk non-muscle-invasive bladder cancer. Eur Urol. 2016;69(6):1046–52.PubMedCrossRefGoogle Scholar
  3. Barlow LJ, McKiernan JM, Benson MC. Long-term survival outcomes with intravesical docetaxel for recurrent nonmuscle invasive bladder cancer after previous bacillus Calmette-Guérin therapy. J Urol. 2013;189(3):834–9.PubMedCrossRefGoogle Scholar
  4. Burger M, et al. Hexaminolevulinate is equal to 5-aminolevulinic acid concerning residual tumor and recurrence rate following photodynamic diagnostic assisted transurethral resection of bladder tumors. Urology. 2009;74(6):1282–6.PubMedCrossRefGoogle Scholar
  5. Burger M, et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol. 2013;64(5):846–54.PubMedCrossRefGoogle Scholar
  6. Cambier S, et al. EORTC Nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non-muscle-invasive stage ta-T1 urothelial bladder cancer patients treated with 1-3 years of maintenance bacillus Calmette-Guérin. Eur Urol. 2016;69(1):60–9.PubMedCrossRefGoogle Scholar
  7. Casey RG, et al. Diagnosis and management of urothelial carcinoma in situ of the lower urinary tract: a systematic review. Eur Urol. 2015;67(5):876–88.PubMedCrossRefGoogle Scholar
  8. Catalona WJ, et al. Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol. 1987;137(2):220–4.PubMedCrossRefGoogle Scholar
  9. Chade DC, Shariat SF, Adamy A, et al. Clinical outcome of primary versus secondary bladder carcinoma in situ. J Urol. 2010a;184(2):464–9.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Chade DC, Shariat SF, Godoy G, et al. Clinical outcomes of primary bladder carcinoma in situ in a contemporary series. J Urol. 2010b;184(1):74–80.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Cheng L, et al. Natural history of urothelial dysplasia of the bladder. Am J Surg Pathol. 1999;23(4):443–7.PubMedCrossRefGoogle Scholar
  12. Di Stasi SM, et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol. 2006;7(1):43–51.PubMedCrossRefGoogle Scholar
  13. Dinney CPN, Greenberg RE, Steinberg GD. Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette-Guérin. Urol Oncol. 2013;31(8):1635–42.PubMedCrossRefGoogle Scholar
  14. Epstein JI, et al. 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. 1998;22(12):1435–48.PubMedCrossRefGoogle Scholar
  15. Goebell PJ, Knowles MA. Bladder cancer or bladder cancers? Genetically distinct malignant conditions of the urothelium. Urol Oncol. 2010;28(4):409–28.PubMedCrossRefGoogle Scholar
  16. Hernández S, et al. Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J Clin Oncol. 2006;24(22):3664–71.PubMedCrossRefGoogle Scholar
  17. Herr HW, Dalbagni G. Defining bacillus Calmette-Guerin refractory superficial bladder tumors. J Urol. 2003;169(5):1706–8.PubMedCrossRefGoogle Scholar
  18. Hopman AHN, et al. Identification of chromosome 9 alterations and p53 accumulation in isolated carcinoma in situ of the urinary bladder versus carcinoma in situ associated with carcinoma. Am J Pathol. 2002;161(4):1119–25.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Joudi FN, et al. Contemporary management of superficial bladder cancer in the United States: a pattern of care analysis. Urology. 2003;62(6):1083–8.PubMedCrossRefGoogle Scholar
  20. Joudi FN, et al. Final results from a national multicenter phase II trial of combination bacillus Calmette-Guérin plus interferon alpha-2B for reducing recurrence of superficial bladder cancer. Urol Oncol. 2006;24(4):344–8.PubMedCrossRefGoogle Scholar
  21. Kamat AM, et al. Definitions, end points, and clinical trial designs for non-muscle-invasive bladder cancer: recommendations from the international bladder cancer group. J Clin Oncol. 2016;34(16):1935–44.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Knowles MA. Bladder cancer subtypes defined by genomic alterations. Scand J Urol Nephrol Suppl. 2008;42(218):116–30.CrossRefGoogle Scholar
  23. Lamm D, et al. Updated concepts and treatment of carcinoma in situ. Urol Oncol. 1998;4(4–5):130–8.PubMedCrossRefGoogle Scholar
  24. Lamm DL, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000;163(4):1124–9.PubMedCrossRefGoogle Scholar
  25. Lerner SP, et al. Failure to achieve a complete response to induction BCG therapy is associated with increased risk of disease worsening and death in patients with high risk non-muscle invasive bladder cancer. Urol Oncol. 2009;27(2):155–9.PubMedCrossRefGoogle Scholar
  26. Lopez-Beltran A, et al. Dysplasia and carcinoma in situ of the urinary bladder. Anal Quant Cytopathol Histopathol. 2015;37(1):29–38.Google Scholar
  27. Mallofré C, et al. Immunohistochemical expression of CK20, p53, and Ki-67 as objective markers of urothelial dysplasia. Mod Pathol. 2003;16(3):187–91.PubMedCrossRefGoogle Scholar
  28. Martínez-Piñeiro JA, et al. Bacillus Calmette-Guerin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990;143(3):502–6.PubMedCrossRefGoogle Scholar
  29. McKiernan JM, et al. Phase II trial of intravesical nanoparticle albumin bound paclitaxel for the treatment of nonmuscle invasive urothelial carcinoma of the bladder after bacillus Calmette-Guérin treatment failure. J Urol. 2014;192(6):1633–8.PubMedCrossRefGoogle Scholar
  30. Mhawech-Fauceglia P, Cheney RT, Schwaller J. Genetic alterations in urothelial bladder carcinoma: an updated review. Cancer. 2006;106(6):1205–16.PubMedCrossRefGoogle Scholar
  31. Moch H, et al. WHO classification of tumours of the urinary system and male genital organs. 4th ed. Lyon: International Agency for Research on Cancer; 2016.Google Scholar
  32. Morales A, et al. Efficacy and safety of MCNA in patients with nonmuscle invasive bladder cancer at high risk for recurrence and progression after failed treatment with bacillus Calmette-Guérin. J Urol. 2015;193(4):1135–43.PubMedCrossRefGoogle Scholar
  33. Moschini M, et al. Comparing long-term outcomes of primary and progressive carcinoma invading bladder muscle after radical cystectomy. BJU Int. 2016;117(4):604–10.PubMedCrossRefGoogle Scholar
  34. Mowatt G, et al. Photodynamic diagnosis of bladder cancer compared with white light cystoscopy: systematic review and meta-analysis. Int J Technol Assess Health Care. 2011;27(1):3–10.PubMedCrossRefGoogle Scholar
  35. Murphy WM, Takezawa K, Maruniak NA. Interobserver discrepancy using the 1998 World Health Organization/International Society of Urologic Pathology classification of urothelial neoplasms: practical choices for patient care. J Urol. 2002;168(3):968–72.PubMedCrossRefGoogle Scholar
  36. Nativ O, et al. Combined thermo-chemotherapy for recurrent bladder cancer after bacillus Calmette-Guerin. J Urol. 2009;182(4):1313–7.PubMedCrossRefGoogle Scholar
  37. Palou J, et al. Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Guérin. Eur Urol. 2012;62(1):118–25.PubMedCrossRefGoogle Scholar
  38. Rink M, et al. 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. 2013;64(4):624–38.PubMedCrossRefGoogle Scholar
  39. Robertson AG, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171(3):540–556.e25.PubMedCrossRefGoogle Scholar
  40. Rosevear HM, et al. Factors affecting response to bacillus Calmette-Guérin plus interferon for urothelial carcinoma in situ. J Urol. 2011;186(3):817–23.PubMedCrossRefGoogle Scholar
  41. Sauter G, et al. Tumours of the urinary system: non-invasive urothelial neoplasias. In: Sauter G, Amin M, et al., editors. WHO classification of classification of tumours of the urinary system and male genital organs. IARCC Press: Lyon. 2004.Google Scholar
  42. Shariat SF, et al. E-cadherin expression predicts clinical outcome in carcinoma in situ of the urinary bladder. Urology. 2001;57(1):60–5.PubMedCrossRefGoogle Scholar
  43. Shariat SF, et al. Association of p53 and p21 expression with clinical outcome in patients with carcinoma in situ of the urinary bladder. Urology. 2003;61(6):1140–5.PubMedCrossRefGoogle Scholar
  44. Shariat SF, et al. Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium. J Urol. 2006;176(6 Pt 1):2414–22, discussion 2422PubMedCrossRefGoogle Scholar
  45. Shariat SF, Palapattu GS, Karakiewicz PI, Rogers CG, Vazina A, Bastian PJ, Schoenberg MP, Lerner SP, Sagalowsky AI, Lotan Y. Concomitant carcinoma in situ is a feature of aggressive disease in patients with organ-confined TCC at radical cystectomy. Eur Urol. 2007a;51(1):152–60.PubMedCrossRefGoogle Scholar
  46. Shariat SF, Palapattu GS, Karakiewicz PI, Rogers CG, Vazina A, Bastian PJ, Schoenberg MP, Lerner SP, Sagalowsky AI, Lotan Y. Discrepancy between clinical and pathologic stage: impact on prognosis after radical cystectomy. Eur Urol. 2007b;51(1):137–49, discussion 149–51PubMedCrossRefGoogle Scholar
  47. Sharkey FE, Sarosdy MF. The significance of central pathology review in clinical studies of transitional cell carcinoma in situ. J Urol. 1997;157(1):68–70, discussion 70–1PubMedCrossRefGoogle Scholar
  48. Skinner EC, et al. SWOG S0353: phase II trial of intravesical gemcitabine in patients with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of intravesical bacillus Calmette-Guérin. J Urol. 2013;190(4):1200–4.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Steinberg G, et al. Efficacy and safety of valrubicin for the treatment of bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. J Urol. 2000;163(3):761–7.PubMedCrossRefGoogle Scholar
  50. Steinberg RL, et al. Bacillus Calmette-Guérin (BCG) treatment failures with non-muscle invasive bladder cancer: a data-driven definition for BCG unresponsive disease. Bladder Cancer. 2016;2(2):215–24.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Steinberg RL, et al. Quadruple immunotherapy of bacillus Calmette-Guérin, interferon, interleukin-2, and granulocyte-macrophage colony-stimulating factor as salvage therapy for non-muscle-invasive bladder cancer. Urol Oncol. 2017;35(12):670.e7–14.CrossRefGoogle Scholar
  52. Sylvester RJ, van der Meijden APM, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol. 2002;168(5):1964–70.PubMedCrossRefGoogle Scholar
  53. Sylvester RJ, et al. High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder. Urology. 2005;66(6 Suppl 1):90–107.PubMedCrossRefGoogle Scholar
  54. Takenaka A, et al. Clinical outcomes of bacillus Calmette-Guérin instillation therapy for carcinoma in situ of urinary bladder. Int J Urol. 2008;15(4):309–13.PubMedCrossRefGoogle Scholar
  55. Tilki D, et al. Characteristics and outcomes of patients with clinical carcinoma in situ only treated with radical cystectomy: an international study of 243 patients. J Urol. 2010;183(5):1757–63.PubMedCrossRefGoogle Scholar
  56. Utz DC, Hansh KA, Farrow GM. The plight of the patient with carcinoma in situ of the bladder. Trans Am Assoc Genitourin Surg. 1969;61:90–100.PubMedGoogle Scholar
  57. Wheat JC, et al. Concomitant carcinoma in situ is a feature of aggressive disease in patients with organ confined urothelial carcinoma following radical nephroureterectomy. Urol Oncol. 2012;30(3):252–8.PubMedCrossRefGoogle Scholar
  58. Wo JY, et al. The results of concurrent chemo-radiotherapy for recurrence after treatment with bacillus Calmette-Guérin for non-muscle-invasive bladder cancer: is immediate cystectomy always necessary? BJU Int. 2009;104(2):179–83.PubMedCrossRefGoogle Scholar
  59. Youssef RF, et al. Prognostic effect of urinary bladder carcinoma in situ on clinical outcome of subsequent upper tract urothelial carcinoma. Urology. 2011;77(4):861–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • David D’Andrea
    • 1
  • Fred Witjes
    • 2
  • Francesco Soria
    • 1
  • Shahrokh F. Shariat
    • 1
    Email author
  1. 1.Department of Urology and Comprehensive Cancer CenterMedical University of ViennaViennaAustria
  2. 2.Department of UrologyUniversity Hospital NijmegenNijmegenThe Netherlands

Section editors and affiliations

  • Wolfgang Otto
    • 1
  • Shahrokh F. Shariat
    • 2
  1. 1.der Universität RegensburgOberarzt der Klinik für UrologieRegensburgGermany
  2. 2.Departement of UrologyWeill Cornell Medical CenterNew YorkUSA

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