Friday, May 9, 2014

Carcinoma In Situ of the Bladder: Beware of this Non-Invasive Cancer

Approximately 75,000 people are diagnosed with urothelial cancer of the bladder each year.[1]  It is estimated that nearly 300,000 people are walking around right now with bladder cancer in a variety of stages.  Fortunately, most people -- approximately 70% -- have non-invasive urothelial cancers or cancers that do not invade the detrusor muscle of the bladder.[2]  In general, non-invasive urothelial cancers are, in their own right, not dangerous.  However, even non-invasive high-grade cancers can progress to invasive disease and therefore have the potential to be fatal.
Bladder Cancer Staging.

Non-invasive cancers are stratified into stage Ta (70%) or confined to the lining of the bladder (i.e. urothelium), T1 (20%) invading the lamina propria (superficial layer of the bladder) or carcinoma in situ (CIS, 10%).[2]  CIS is a high-grade urothelial malignancy that is confined to the superficial-most layers of the bladder.  Although CIS is considered a non-invasive malignancy, it should not be considered a benign or indolent cancer.

Here we review some of the data regarding CIS.


While many bladder cancers (13-34%) present with gross hematuria (visible blood in the urine);[3,4] CIS is notorious for presenting with irritative voiding symptoms.[5]  Upwards of 80% of patients with CIS will present with irritative voiding symptoms.[6]


In many cancers, CIS is considered a "pre-malignant" lesion.  This is NOT true for bladder cancer.  In fact, CIS of the bladder should be thought of as a flat, high-grade cancer and a precursor to invasive disease.  This is supported by a number of studies and findings:

  • The subsequent risk of CIS to progress to muscle-invasive or metastatic urothelial cancer is 40% or greater, especially if concomitant papillary tumors are present.[7,8]  
  • Of patients who undergo cystectomy for CIS alone, upwards of 20% will be found to have invasive cancer at final pathology.[9]  
  • Patients with T1 disease who undergo cystectomy have a 6% risk of upstaging at final pathology; however patients with T1 disease and concomitant CIS have a 55% risk of upstaging.[10]
  • In a number of surgical series, CIS is one of the most important prognostic characteristics after tumor grade.[11,12]
  • 20% of patients with CIS alone will die at 10 years.[13]


CIS can be difficult to manage as it cannot be resected in the same sense as a papillary tumor as CIS is often flat, difficult to visualize and multifocal.  In addition, CIS can be very difficult to find.  In patients with irritative symptoms and/or positive high-grade cytology, a number of strategies can be employed to evaluate the bladder for the presence of CIS including (1) random, cold-cup bladder biopsies or (2) fluorescence cystoscopy.

Once diagnosed, CIS is best treated with intravesical BCG (please see prior blog entries BCG For Bladder Cancer: Why it Works, How it Works and Success Rates for Intravesical BCG Treatments for Bladder Cancer).  BCG is approved by the FDA (Food & Drug Administration) for the treatment of CIS and is the preferred initial intravesical treatment for CIS according to the AUA (American Urological Association) Guideline for the Management of Nonmuscle Invasive Bladder Cancer.

  • The initial tumor-free response after induction BCG is as high as 84%.[14,15]
  • Approximately 50% of patients experience a durable response for 4 years or longer.
    • Approximately 30% of patients experience a response for 10 years.[16]

However, patients who do not respond to BCG have an incredibly high rate of progression; 95% of patients who do not respond to an induction course of BCG will progress to worse disease.[17,18]

There are a number of other chemotherapies that can be used for the treatment of CIS including adriamycin, gemcitabine and thiotepa.  In North America, BCG is used most frequently due to a higher response rate (68% complete response for CIS vs. 49% for other chemotherapies) in a number of studies.[19,20]

Many patients with CIS will be refractory to an initial course of intravesical treatment.  If first-line treatment fails, especially if the first line was chemotherapy, a second course of BCG can be given as 30-50% of patients will respond to this second course.[21,22]  More than two courses of any medication are not recommended as 80% of patients who fail two courses will fail a third, and can be a harbinger of rapidly progressive, dangerous disease.

Patients with CIS who fail BCG should strongly consider an "early" cystectomy.  While removal of the bladder for non-invasive disease can be considered drastic:

  • 50% of patients with non-muscle invasive disease will be found to have muscle-invasion at cystectomy
    • 15% of muscle-invasive cancers will have micrometastatic disease [23]
  • The long-term survival for patients with non-muscle invasive disease approaches 90%, which is significantly higher than patients with muscle-invasive cancers.[24,25]


  • Carcinoma in situ (CIS) is a high-grade, flat cancer of the bladder with potentially aggressive behavior
  • The first line treatment for CIS in intravesical BCG treatment
  • Patients who do not respond to intravesical treatment should strongly consider cystectomy due to the high rates of progression to advanced disease.

For additional information regarding BCG treatments check out the following blog entries:
BCG For Bladder Cancer: Why it Works, How it Works
Success Rates for Intravesical BCG Treatments for Bladder Cancer

This blog was written by Phillip M. Pierorazio, MD, Assistant Professor of Urology and Oncology at the Brady Urological Institute at Johns Hopkins.

[1] American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.
[2] Ro JY, Staerkel GA, Ayala AG,et al: Cytologic and histologic features of superficial bladder cancer. Urol Clin North Am 1992; 19: 435-453
[3] Lee LW, Davis E: Gross urinary hemorrhage: a symptom, not a disease. JAMA 1953; 153: 782-784
[4] Varkarakis MJ, Gaeta J, Moore RH,et al: Superficial bladder tumor: aspects of clinical progression. Urology 1974; 4: 414-420
[5] Mohr DN, Offord KP, Owen RA,et al: Asymptomatic microhematuria and urologic disease: a population-based study. JAMA 1986; 256: 224-229
[6] Zincke H, Utz DC, Farrow GM,et al: Review of Mayo Clinic experience with carcinoma in situ. Urology 1985; 26: 39-46
[7] Donat SM. Evaluation and follow-up strategies for superficial bladder cancer. Urol Clin North Am 2003;30:765–6.
[8] Althausen AF, Prout GR, Daly JJ,et al: Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 1976; 116: 575-580
[9] Farrow GM, Utz DC, Rife CC,et al: Morphological and clinical observations of patients with early bladder cancer treated with total cystectomy. Cancer Res 1976; 36: 2495-2501
[10] Masood S, Sriprasad S, Palmer JH,et al: T1G3 bladder cancer—indications for early cystectomy. Int Urol Nephrol 2004; 36: 41-44
[11] Koch MO, Smith JA: Natural history and surgical management of superficial bladder cancer (stages Ta/T1/Tis). In Vogelzang N, Miles BJ(eds)Comprehensive textbook of genitourinary oncology. Baltimore: Lippincott Williams & Wilkins, 1996, pp.405-415
[12] Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J,et al: Multivariate analysis of the prognostic factors of primary superficial bladder cancer. J Urol 2000; 163: 73-78
[13] Herr HW, Badalament RA, Amato DA,et al: Superficial bladder cancer treated with bacillus Calmette-Guérin: a multivariate analysis of factors affecting tumor progression. J Urol 1989; 141: 22-29
[14] Lamm DL, Blumenstein BA, Crissman JD,et al: Maintenance bacillus Calmette-Guérin immunotherapy for recurrent Ta,T1 and carcinoma in situ TCC of the bladder: a randomized SWOG study. J Urol 2000; 163: 1124-1129
[15] Lamm DL, Riggs DR, Bugaj M,et al: Prophylaxis in bladder cancer: a meta-analysis. J Urol 2000; 163: 151
[16] Herr HW, Wartinger DD, Fair WR,et al: Bacillus Calmette-Guérin therapy for superficial bladder cancer: a 10-year follow-up. J Urol 1992; 147: 1020-1023
[17] Coplen DE, Marcus MD, Myers JA,et al: Long-term follow-up of patients treated with 1 or 2, 6-week courses of intravesical bacillus Calmette-Guérin: analysis of possible predictors of response free of tumor. J Urol 1990; 144: 652-657
[18] Harland SJ, Charig CR, Highman W,et al: Outcome in carcinoma in situ of bladder treatment with intravesical bacille Calmette-Guérin. Br J Urol 1992; 70: 271
[19] O'Donnell MA: Advances in the management of superficial bladder cancer. Semin Oncol 2007; 34: 85-97
[20] Sylvester RJ, van der Meijden A, Witjes JA,et al: High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder. Urology 2005; 66: 90-107
[21] Brake M, Loertzer H, Horsch R,et al: Long-term results of intravesical bacillus Calmette-Guérin therapy for stage T1 superficial bladder cancer. Urology 2000; 55: 673-678
[22] Pansadoro V, De Paula F: Intravesical bacillus Calmette-Guérin in the treatment of superficial transitional cell carcinoma of the bladder. J Urol 1987; 138: 299-301
[23] Chang SS, Cookson MS: Radical cystectomy for bladder cancer: the case for early intervention. Urol Clin North Am 2005; 32: 147-155
[24] Amling C, Thraser J, Frazier H,et al: Radical cystectomy for stages Ta, Tis, and T1 transitional cell carcinoma of the bladder. J Urol 1994; 151: 31
[25] Freeman JA, Esrig D, Stein JP,et al: Radical cystectomy for high-risk patients with superficial bladder cancer in the era of orthotopic urinary reconstruction. Cancer 1995; 76: 833-839


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