eMedicine Specialties > Urology > Cancer, Bladder, Penis, and Urethra
Carcinoma In Situ of the Urinary Bladder
Updated: Oct 9, 2007
Introduction
Bladder cancer is the second most common malignancy of the genitourinary system. Each year, this cancer is diagnosed in approximately 275,000 people worldwide, and about 108,000 die from this disease.
Several types of carcinoma arise on the urothelial surface. The most common type diagnosed in North America, South America, Europe, and Asia is transitional cell carcinoma (TCC), which can arise anywhere in the urinary tract but is usually found in the urinary bladder. In other parts of the world, squamous cell carcinoma is prevalent; its etiology and management differ from those of TCC.
TCC arises from stem cells that are adjacent to the basement membrane of the epithelial surface. Depending on the genetic alterations that occur, these cells may follow different pathways in the expression of their phenotype.
The most common molecular biologic pathway for TCCs involves the development of a papillary tumor that projects into the bladder lumen and, if untreated, eventually penetrates the basement membrane, invades the lamina propria, and then continues into the bladder muscle, where it can metastasize. Nearly 90% of transitional cell bladder tumors exhibit this type of behavior. The remaining 10% follow a different molecular pathway and are called carcinoma in situ (CIS). This is a flat type of tumor that spreads along the surface of the bladder and, over time, may progress to an invasive form of cancer that behaves the same as invasive TCC.
CIS can develop alone or in association with papillary tumors. This type of cancer can be difficult to diagnose because patients may present only with irritative voiding symptoms, which is a common problem in a urology office. Patients usually have microscopic or gross hematuria and are often misdiagnosed with a bladder infection and are treated as such. Cystoscopy may reveal a characteristic red, velvety appearance that resembles an area of inflammation, although, at times, CIS is not visible. Diagnostic tests include a urine cytology test and/or one of several available bladder cancer markers. These tests are highly sensitive in detecting CIS. Bladder biopsies are needed to firmly establish a diagnosis.
Several agents, chemotherapies, and immunotherapies are effective in treating CIS. These are all administered intravesically. Endoscopic surgery, which is the initial treatment for papillary cancers, is not effective for CIS because the disease is often so diffuse and difficult to visualize that surgical removal is not feasible.
The most common intravesical agent used to treat CIS is bacillus Calmette-Guérin (BCG). This is a form of immunotherapy. Serial instillations of this tuberculosis vaccine have been shown to effectively eradicate this disease in 70% of patients and to prevent recurrence and progression. Chemotherapeutic agents such as mitomycin-C (Mutamycin), thiotepa, gemcitabine (Gemzar), and doxorubicin (Adriamycin) can also be instilled into the bladder to treat this disease. Interferon-alfa (IFN-alfa) is another immunotherapeutic agent that is used in conjunction with BCG in some patients.
Zbar et al, while working at the US National Cancer Institute, discovered the principle behind BCG therapy. These investigators conducted a series of experiments that studied the immunomodulating effect of BCG vaccine on various carcinomas in animal models. They found that direct exposure of BCG vaccine to small tumors in immunocompetent hosts could eradicate the tumors. BCG vaccine was tried unsuccessfully in various cancers in humans, but bladder tumors confined to the epithelial layer or lamina propria of the bladder met the postulates that Zbar et al described. These include direct exposure of the cancer cells to BCG, relatively small tumors, repeated exposure, and an immunocompetent host. Small tumors treated repeatedly with intravesical instillations of BCG vaccine eliminated existing tumors and prevented the recurrence of new bladder cancers. This therapeutic strategy is regarded as the most effective form of management for both CIS and papillary bladder tumors.
These intravesical treatments are not effective in the 20% of patients in whom cancer invades the bladder wall; thus, cystectomy or a combination of radiation therapy and chemotherapy is necessary. CIS that invades beyond the lamina propria is considered to be in the same category as a papillary cancer.
Problem
CIS is usually heralded by gross or microscopic hematuria, irritative bladder symptoms, and/or positive cytology or urine tumor marker testing results. More than 30 urinary biomarkers have been reported, but only a few are commercially available; the remainder are still being tested.
Endoscopic biopsies are used to help establish the diagnosis and determine the extent of the cancer.
Multiple biopsy specimens are obtained from suggestive areas and from random sites throughout the bladder. If any evidence indicates invasion into the lamina propria, the CIS is considered to be an invasive TCC and is managed accordingly. A patient with a combination of CIS and TCC is considered to be at high risk for local recurrence and metastatic disease.
Frequency
Each year, bladder cancer is diagnosed in 40,000-50,000 patients in the United States, and most of these patients are men, with a male-to-female ratio of 3:1. CIS represents only 10% of cancers in this population, and, of these 4000-5000 patients with CIS, half have coexisting papillary bladder cancer. Therefore, only about 2500 cases of pure CIS are diagnosed each year. However, many more patients seek the care of urologists because of urinary frequency and urgency that may be accompanied by dysuria. Most of these patients do not have CIS, but the symptoms may be identical. As a result, an evaluation to rule out CIS is warranted in such individuals, and evaluation of these patients can account for a substantial percentage of urologic practice.
Etiology
The development of most bladder cancers, including CIS, is thought to be related to environmental factors. Of patients with bladder cancer, 75% have a history of smoking or exposure to industrial or environmental carcinogens. People who smoke cigarettes are 3 times more likely to develop bladder cancer than those who do not smoke. Secondhand smoke has also been implicated as a risk factor. Even after patients stop smoking, the cancer can still appear 15-20 years later. Patients who continue to smoke after being diagnosed with TCC or CIS and treated have a substantially higher risk of recurrence and development of higher-stage disease.
Patients who are exposed to carcinogenic chemicals because of their occupation are at increased risk of bladder cancer. Petrochemical workers, tire manufacturers, beauticians, leather workers, printers, textile workers, and workers in similar industries are at increased risk. Bladder carcinogens include benzidine, nephelines, aromatic amines, nitrosamines, local radiation therapy, various dyes and solvents, and some chemotherapeutic drugs.
Pathophysiology
CIS is thought to arise because of an early mutation or deletion in the cell cycle regulator TP53. Persons with CIS may also have a mutation or deletion in the 9p arm. If the 9p alteration precedes changes in the TP53 gene, papillary TCC is more likely to develop.
Presentation
CIS has various presentations, including gross hematuria, microscopic hematuria, and irritative bladder symptoms. Diagnosis is often delayed because symptoms are attributed to urinary tract infection. In addition, cystoscopy may not reveal any abnormalities, and no abnormalities are present on imaging studies.
More than 50% of patients with CIS have coexisting papillary cancer. In general, the papillary tumor is diagnosed initially and CIS is discovered during the evaluation and treatment of the papillary tumor.
In cases of pure CIS, urine cytology may lead to the diagnosis. CIS exfoliates cells that have an unusual appearance and are easy to identify via cytologic examination, prompting further evaluation. Unfortunately, even findings from urine cytology may be normal in some patients, in whom the diagnosis is made only when the urologist maintains a high level of suspicion for CIS and obtains random bladder biopsy specimens from patients with worrisome symptoms.
Patients who present with microscopic or gross painless hematuria clearly require urologic evaluation. Urinary frequency, urgency, and dysuria, which are the characteristic symptoms of a urinary tract infection, may also indicate CIS. These symptoms are particularly confusing because they may be intermittent and can resolve with an incidental temporal relationship to the administration of antibiotics, further supporting an erroneous diagnosis of urinary tract infection.
Individuals with persistent bladder irritative symptoms or infections that do not resolve within an appropriate period should undergo urologic evaluation. Investigation includes urine cultures for fungi and tuberculosis and cytology studies.
A physical examination is unlikely to reveal any abnormalities associated with CIS. If a large coexistent bladder cancer is present, a mass may be palpable in the suprapubic area or during a rectal examination.
Indications
The initial surgical procedure involved with carcinoma in situ (CIS) is transurethral biopsy of the bladder. Multiple biopsy specimens are obtained from various locations in the bladder. This disease may not be visible, and a map of the areas where biopsy samples were obtained is helpful for subsequent follow-up examinations.
CIS often coexists with papillary TCC. A transurethral resection of these tumors is performed, and biopsy samples are obtained from areas that appear suspicious for CIS and from areas that appear normal. The biopsy samples are usually obtained with a cup biopsy forceps, which fits inside the cystoscope.
Patients who do not respond to intravesical immunotherapy or chemotherapy are candidates for radical cystectomy. Radiation therapy with or without chemotherapy is of limited benefit in patients with CIS but can be useful in those with TCC.
Relevant Anatomy
Most cases of carcinoma in situ (CIS) occur in the bladder; however, CIS can develop in any portion of the urothelial surface. CIS in the urethra, renal pelvis, or ureters is more difficult to diagnose and treat. Imaging studies are usually obtained, but ureteroscopy, cytology, brushings, and biopsy of the prostatic urethra, ureters, and renal pelvis may be necessary.
Contraindications
Immunocompromised patients (eg, those with HIV infection, on steroid therapy), patients with porcine heart valves in whom a systemic infection from the BCG vaccine could occur, and patients receiving anticoagulants are not good candidates for intravesical BCG vaccine. BCG vaccine administration should be immediately stopped in patients who develop severe systemic reactions such as chills and fever, gross hematuria, hepatitis, or acute arthritis. BCG is not contraindicated in those who have previously been vaccinated or who have already tested positive for purified protein derivative (PPD).
More on Carcinoma In Situ of the Urinary Bladder |
 Overview: Carcinoma In Situ of the Urinary Bladder |
| Workup: Carcinoma In Situ of the Urinary Bladder |
| Treatment: Carcinoma In Situ of the Urinary Bladder |
| Follow-up: Carcinoma In Situ of the Urinary Bladder |
| References |
| Next Page » |
References
Sánchez-Carbayo M, Urrutia M, Silva JM, Romaní R, De Buitrago JM, et al. Comparative predictive values of urinary cytology, urinary bladder cancer antigen, CYFRA 21-1 and NMP22 for evaluating symptomatic patients at risk for bladder cancer. J Urol. May 2001;165(5):1462-7. [Medline].
van Rhijn BW, van der Poel HG, van der Kwast TH. Urine markers for bladder cancer surveillance: a systematic review. Eur Urol. Jun 2005;47(6):736-48. [Medline].
Ikeda N, Honda I, Yano I, Koyama A, Toida I. Bacillus calmette-guerin Tokyo172 substrain for superficial bladder cancer: characterization and antitumor effect. J Urol. May 2005;173(5):1507-12. [Medline].
Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, 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. Apr 2000;163(4):1124-9. [Medline].
Palou J, Laguna P, Millán-Rodríguez F, Hall RR, Salvador-Bayarri J, Vicente-Rodríguez J. Control group and maintenance treatment with bacillus Calmette-Guerin for carcinoma in situ and/or high grade bladder tumors. J Urol. May 2001;165(5):1488-91. [Medline].
Colombo R, Da Pozzo LF, Salonia A, Rigatti P, Leib Z, Baniel J, et al. Multicentric study comparing intravesical chemotherapy alone and with local microwave hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma. J Clin Oncol. Dec 1 2003;21(23):4270-6. [Medline].
Akaza H, Hinotsu S, Aso Y, Kakizoe T, Koiso K. Bacillus Calmette-Guerin treatment of existing papillary bladder cancer and carcinoma in situ of the bladder. Four-year results. The Bladder Cancer BCG Study Group. Cancer. Jan 15 1995;75(2):552-9. [Medline].
Au JL, Badalament RA, Wientjes MG, Young DC, Warner JA, Venema PL, et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst. Apr 18 2001;93(8):597-604. [Medline].
Barghi MR, Rahmani MR, Hosseini Moghaddam SM, Jahanbin M. Immediate intravesical instillation of mitomycin C after transurethral resection of bladder tumor in patients with low-risk superficial transitional cell carcinoma of bladder. Urol J. 2006;3(4):220-4. [Medline].
Bohle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol. Jan 2003;169(1):90-5. [Medline].
Bostwick DG, Ramnani D, Cheng L. Diagnosis and grading of bladder cancer and associated lesions. Urol Clin North Am. Aug 1999;26(3):493-507. [Medline].
Brosman SA. Bacillus Calmette-Guerin immunotherapy. Techniques and results. Urol Clin North Am. Aug 1992;19(3):557-64. [Medline].
Böhle A, Gerdes J, Ulmer AJ, Hofstetter AG, Flad HD. Effects of local bacillus Calmette-Guerin therapy in patients with bladder carcinoma on immunocompetent cells of the bladder wall. J Urol. Jul 1990;144(1):53-8. [Medline].
Casella R, Huber P, Blochlinger A, Stoffel F, Dalquen P, Gasser TC, et al. Urinary level of nuclear matrix protein 22 in the diagnosis of bladder cancer: experience with 130 patients with biopsy confirmed tumor. J Urol. Dec 2000;164(6):1926-8. [Medline].
Cookson MS, Herr HW, Zhang ZF, Soloway S, Sogani PC, Fair WR. The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol. Jul 1997;158(1):62-7. [Medline].
Crawford ED. Diagnosis and treatment of superficial bladder cancer: an update. Semin Urol Oncol. Feb 1996;14(1 Suppl 1):1-9. [Medline].
de Reijke TM, de Boer EC, Kurth KH, Schamhart DH. Urinary cytokines during intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: processing, stability and prognostic value. J Urol. Feb 1996;155(2):477-82. [Medline].
de Reijke TM, Kurth KH, Sylvester RJ, Hall RR, Brausi M, van de Beek K, et al. Bacillus Calmette-Guerin versus epirubicin for primary, secondary or concurrent carcinoma in situ of the bladder: results of a European Organization for the Research and Treatment of Cancer--Genito-Urinary Group Phase III Trial (30906). J Urol. Feb 2005;173(2):405-9. [Medline].
Fernando H, Thota SS, Burtt G, Waterfall N, Husain I. Importance of red patches diagnosed in cystoscopy for haematuria and lower urinary tract symptoms. Postgrad Med J. Jan 2007;83(975):62-3. [Medline].
Foresman WH, Messing EM. Bladder cancer: natural history, tumor markers, and early detection strategies. Semin Surg Oncol. Sep-Oct 1997;13(5):299-306. [Medline].
Garbar C, Mascaux C, Wespes E. Is urinary tract cytology still useful for diagnosis of bladder carcinomas? A large series of 592 bladder washings using a five-category classification of different cytological diagnoses. Cytopathology. Apr 2007;18(2):79-83. [Medline].
Golijanin D, Shapiro A, Pode D. Immunostaining of cytokeratin 20 in cells from voided urine for detection of bladder cancer. J Urol. Dec 2000;164(6):1922-5. [Medline].
Greenberg RE, Bahnson RR, Wood D, Childs SJ, Bellingham C, Edson M, et al. Initial report on intravesical administration of N-trifluoroacetyladriamycin-14-valerate (AD 32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder. Urology. Mar 1997;49(3):471-5. [Medline].
Herr HW. Intravesical therapy. Hematol Oncol Clin North Am. Feb 1992;6(1):117-27. [Medline].
Hudson MA, Herr HW. Carcinoma in situ of the bladder. J Urol. Mar 1995;153(3 Pt 1):564-72. [Medline].
Islam MA, Bhuiyan ZH, Shameem IA. Intravesical adjuvant therapy using mitomycin C. Mymensingh Med J. Jan 2006;15(1):40-4. [Medline].
Kaasinen E, Rintala E, Pere AK, Kallio J, Puolakka VM, Liukkonen T, et al. Weekly mitomycin C followed by monthly bacillus Calmette-Guerin or alternating monthly interferon-alpha2B and bacillus Calmette-Guerin for prophylaxis of recurrent papillary superficial bladder carcinoma. J Urol. Jul 2000;164(1):47-52. [Medline].
Kirollos MM, McDermott S, Bradbrook RA. Bladder tumor markers: need, nature and application. 2. Tumor and tumor- associated antigens. Int Urogynecol J Pelvic Floor Dysfunct. 1998;9(4):228-35. [Medline].
Lamm DL. BCG immunotherapy for transitional-cell carcinoma in situ of the bladder. Oncology (Huntingt). Oct 1995;9(10):947-52, 955, discussion 955-65. [Medline].
Lamm DL. Carcinoma in situ. Urol Clin North Am. Aug 1992;19(3):499-508. [Medline].
Landman J, Chang Y, Kavaler E, Droller MJ, Liu BC. Sensitivity and specificity of NMP-22, telomerase, and BTA in the detection of human bladder cancer. Urology. Sep 1998;52(3):398-402. [Medline].
Laufer M, Ramalingam S, Schoenberg MP, Haisfield-Wolf ME, Zuhowski EG, Trueheart IN, et al. Intravesical gemcitabine therapy for superficial transitional cell carcinoma of the bladder: a phase I and pharmacokinetic study. J Clin Oncol. Feb 15 2003;21(4):697-703. [Medline].
Losa A, Hurle R, Lembo A. Low dose bacillus Calmette-Guerin for carcinoma in situ of the bladder: long-term results. J Urol. Jan 2000;163(1):68-71; discussion 71-2. [Medline].
Orsola A, Palou J, Xavier B, Algaba F, Salvador J, Vicente J. Primary bladder carcinoma in situ: assessment of early BCG response as a prognostic factor. Eur Urol. 1998;33(5):457-63. [Medline].
Serretta V, Galuffo A, Pavone C, Allegro R, Pavone-MacAluso M. Gemcitabine in intravesical treatment of Ta-T1 transitional cell carcinoma of bladder: Phase I-II study on marker lesions. Urology. Jan 2005;65(1):65-9. [Medline].
Smith JA Jr, Labasky RF, Cockett AT, Fracchia JA, Montie JE, Rowland RG. Bladder cancer clinical guidelines panel summary report on the management of nonmuscle invasive bladder cancer (stages Ta, T1 and TIS). The American Urological Association. J Urol. Nov 1999;162(5):1697-701. [Medline].
Stampfer DS, Carpinito GA, Rodriguez-Villanueva J, Willsey LW, Dinney CP, Grossman HB, et al. Evaluation of NMP22 in the detection of transitional cell carcinoma of the bladder. J Urol. Feb 1998;159(2):394-8. [Medline].
Sylvester RJ, van der Meijden AP, 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. Nov 2002;168(5):1964-70. [Medline].
Sylvester RJ, van der Meijden AP, Witjes JA, Kurth K. Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J Urol. Jul 2005;174(1):86-91; discussion 91-2. [Medline].
Sánchez-Carbayo M, Herrero E, Megias J, Mira A, Espasa A, Chinchilla V, et al. Initial evaluation of the diagnostic performance of the new urinary bladder cancer antigen test as a tumor marker for transitional cell carcinoma of the bladder. J Urol. Apr 1999;161(4):1110-5. [Medline].
Thalmann GN, Sermier A, Rentsch C, Mohrle K, Cecchini MG, Studer UE. Urinary Interleukin-8 and 18 predict the response of superficial bladder cancer to intravesical therapy with bacillus Calmette-Guerin. J Urol. Dec 2000;164(6):2129-33. [Medline].
Witjes JA, Hendricksen K. Intravesical Pharmacotherapy for Non-Muscle-Invasive Bladder Cancer: A Critical Analysis of Currently Available Drugs, Treatment Schedules, and Long-Term Results. Eur Urol. Aug 20 2007;[Medline].
Witjes JA, v d Meijden AP, Collette L, Sylvester R, Debruyne FM, van Aubel A, et al. Long-term follow-up of an EORTC randomized prospective trial comparing intravesical bacille Calmette-Guerin-RIVM and mitomycin C in superficial bladder cancer. EORTC GU Group and the Dutch South East Cooperative Urological Group. European Organisation f. Urology. Sep 1998;52(3):403-10. [Medline].
Further Reading
Keywords
carcinoma in situ of the urinary bladder, CIS of the urinary bladder, bladder cancer, flat carcinoma of the urothelium, transitional cell carcinoma, TCC, papillary tumors, cystectomy, bacillus Calmette-Guérin, BCG, gross hematuria, microscopic hematuria, irritative bladder symptoms, bacillus Calmette-Guérin vaccine, BCG vaccine, bladder CIS, CIS of the bladder, urinary CIS, urothelial CIS, transurethral biopsy of the bladder
