Several types of carcinoma arise on the urothelial surface. The most common is transitional cell carcinoma (TCC), which can arise anywhere in the urinary tract but is usually found in the urinary bladder. These cancers arise from the stem cells adjacent to the basement membrane of the epithelial surface. Depending on the genetic alterations that occur, they may follow different pathways in the expression of their phenotype.
The most common pathway leads to the development of a papillary tumor that projects into the bladder lumen and eventually invades into the bladder muscle. Nearly 90% of transitional cell bladder tumors are this type. The remaining 10% are carcinoma in situ (CIS). This is a flat type of tumor that spreads along the surface of the bladder and can progress to a muscle invasive tumor.
CIS can be difficult to diagnose and can coexist with papillary tumors. CIS may have a characteristic red, velvety appearance when viewed endoscopically. At times, CIS is not visible and the diagnosis is made from cytologic examination of the urine or by obtaining random bladder biopsies.
This disease can be effectively treated with the instillation of bacillus Calmette-Guérin (BCG), which is a tuberculosis vaccine. The treatment effectively eradicates the disease in 70% of patients. Some chemotherapeutic agents can be instilled into the bladder to treat this disease. If the cancer invades the bladder wall, these treatments are not effective and cystectomy is necessary.
Frequency: Each year, 40,000-50,000 patients are diagnosed with bladder cancer in the United States, and most of these occur in 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 patients with pure CIS are diagnosed each year. However, many more patients see a urologist because of 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 in these cases 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. A history of smoking is present in 75% of bladder cancer patients. People who smoke cigarettes are 3 times more likely to develop bladder cancer as compared to nonsmokers. Secondhand smoke has also been implicated as a risk factor. Even after patients stop smoking, the cancer can appear 15-20 years later. Patients who continue to smoke after being diagnosed with TCC or CIS have a substantially higher chance of recurrent higher-stage cancer.
Patients who are exposed to chemicals because of their occupation are at increased risk for developing 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, p53. Mutation or deletion in the 9p chromosome arm may also be present in CIS. If the 9p alteration precedes changes in the p53 gene, papillary TCC is more likely to develop.
Clinical: Patients with CIS may present in a variety of ways. They may have gross hematuria, microscopic hematuria, or 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.
Coexisting papillary cancer is present in 50% of patients with CIS. In general, the papillary tumor is diagnosed initially and the presence of 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 by cytologic examination, prompting further evaluation. Unfortunately, even findings on urine cytology may be normal in some patients, in which case the diagnosis is only made when the urologist maintains a high level of suspicion for CIS and obtains random bladder biopsies in any patient with worrisome symptoms.
Patients who present with microscopic or gross painless hematuria clearly require a urologic evaluation. Urinary frequency, urgency, and dysuria, which are the characteristic symptoms of a urinary tract infection, may also indicate the presence of 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 as well as cytology.
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 on rectal examination.
The initial surgical procedure involved with CIS is transurethral biopsy of the bladder. Multiple biopsies are obtained from various locations in the bladder. This disease may not be visible, and a map of the biopsied areas is helpful for subsequent follow-up.
CIS often coexists with papillary TCC. A transurethral resection of these tumors is performed, and biopsies are obtained from areas that appear suspicious for CIS, as well as areas that appear normal. The biopsies 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.
Relevant Anatomy: Most cases of 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 with biopsies from the ureters and renal pelvis is necessary in a few patients.
Contraindications: No general contraindications to therapy exist. A variety of protocols involve intravesical therapy, and most patients respond to this therapy.
When first diagnosed, as many as 20% of patients with CIS may have invasion. CIS is characterized by bizarre, abnormal cells in the epithelial layer. The cells appear to be high-grade cancers; thus, they are readily detected in cytology specimens.
Sometimes the pathologist may have difficulty distinguishing between cellular atypia and CIS. Slides should be reviewed by a consultant if the pathologist is uncertain or makes a diagnosis of atypia. These cases usually prove to be CIS on further review. The distinction is important because CIS requires therapy, and atypia can be observed in CIS.
Some pathologists attempt to grade CIS; however, CIS is currently
considered one grade.
Medical therapy: BCG is the principle immunotherapeutic agent used for the eradication of CIS. Interferon alfa (IFN-alfa) may be used in conjunction with BCG, but it has not been effective as monotherapy. Bropirimine is an oral immunostimulant thought to have properties similar to IFN-alfa. This agent was found to have limited effectiveness and was never approved for commercial use. Keyhole limpet hemocyanin (KLH) is another immune adjuvant that never progressed further than phase 2 testing.
BCG is available in a vial containing a freeze-dried preparation of both live and dead organisms. The preparation is activated by dissolving the powder in 1 cc of sterile water and diluting the mixture with 30-50 cc of saline. Several preparations of BCG are approved by the FDA, and their strength is measured in terms of colony-forming units (CFU). The BCG used in the United States contains 6-9 million CFUs per ampoule. The solution is instilled into the bladder through a catheter. The patient voids the solution after 1-2 hours.
Once in the bladder, the live organisms enter macrophages, where they induce the same type of histologic and immunologic reaction as found in patients with tuberculosis. BCG also has a predilection for entering bladder cancer cells, where the proteins are broken down and fragments are combined with histocompatibility antigens and displayed on the cell surface. This induces a cytokine and direct cell-to-cell cytotoxicity response, which targets these cells for destruction.
In order for BCG to be effective, the host should be immunocompetent, tumor burden should be small, direct contact with the tumor should occur, and the dose should be adequate to incite a reaction.
To induce this reaction, multiple instillations of BCG are required. Typically, 6 weekly instillations comprise the induction phase, although some patients respond with fewer instillations and a few need more. The induction phase is considered complete when the immunologic reaction has occurred. This is evident when the patient has bladder irritative symptoms, WBCs are in the urine without evidence of infection, and microscopic hematuria is present.
When induction is completed, a course of immunoprophylaxis or maintenance therapy is begun. Prolonging the course of therapy has been shown to be beneficial in reducing the frequency of recurrence and progression. These intervals have varied from instillations administered monthly to every 3 months or every 6 months. The optimum frequency and duration of this therapy has not been established. From the immunologic point of view, establishing this interval is difficult and patient variability is great. Antigenic stimulation becomes greater with consecutive instillations but decreases when the stimulation is excessive. In order for this maintenance therapy to be effective, a series of instillations every 3-4 months over a 1- to 2-year period seems to be an effective program.
Data from a small study conducted by Palou et al (2001) indicate that patients who are tumor free after 6 months of therapy are likely to remain so indefinitely and do not need additional maintenance.
Patients often have difficulty completing long-term therapy because of irritative adverse effects in the bladder. Not only is lengthening the interval between instillations necessary but dose modification also may be necessary. Generally, a full ampoule is administered, but some patients respond just as well to half or even one third of a dose and seem to have fewer adverse effects. The dose selection depends on the degree of reaction the patient experiences.
A failure to respond to BCG may be defined as persistent tumor when a BCG reaction is evident. In this situation, 50 million units of IFN-alfa can be instilled into the bladder and BCG is administered an hour later. The IFN-alfa up-regulates the major histocompatibility complex (MHC)–BCG antigen complex that enhances the immunologic response. With this combination, doses of BCG as small as one tenth of a vial have been shown to be effective. IFN-alfa is well tolerated, and the lower doses of BCG are usually associated with decreased adverse effects.
Chemotherapeutic agents that can be administered intravesically to treat CIS include mitomycin C, thiotepa, Adriamycin, cis-platinum, and valrubicin. In randomized studies comparing these agents to BCG, results have been mixed. Several studies from Europe have reported similar responses comparing mitomycin C to BCG, while an American study found BCG to be superior.
Valrubicin is used in patients for whom BCG therapy has failed, and valrubicin induces a response in 20% of these patients. Thiotepa, Adriamycin, and cis-platinum have limited benefit and are rarely employed to treat CIS.
The intravesical instillation of either BCG or chemotherapy is initiated about 2-4 weeks following endoscopic resection of any visible papillary tumors or bladder biopsies. The bladder is usually healed well enough to avoid systemic distribution of the organism.
Contraindications to BCG therapy include immunosuppression, cancer invading into the bladder muscle, large tumor volume, and patients who are on anticoagulants. Reports exist of BCG organisms identified on vascular grafts in patients who have died following BCG sepsis.
Photodynamic therapy has been shown to be effective, but it has limited usefulness because of adverse effects. This treatment involves the intravenous injection of a porphyrin derivative followed 24 hours later with exposure of the bladder surface to laser light, activating the cytotoxic agent, which has preferentially concentrated within the cancer cells. The laser is introduced through a cystoscope. The major adverse effect is severe photosensitivity, which can last for several months.
Surgical therapy: The only surgical treatment for CIS is radical cystectomy. For a more in-depth description of this procedure, please see Cystectomy, Radical. The 10-year survival rate after cystectomy in patients for whom BCG therapy failed approaches 90% if the tumor is confined to the bladder surface.
Eliminating some visible lesions with fulguration or laser therapy is possible, but many of the CIS lesions are not visible.
Bladder biopsies may be performed as a part of the patient's follow-up. These are necessary to determine if the cancer has been eradicated.
Preoperative details: Minimal preoperative care is necessary for cystoscopy and bladder biopsies. When papillary tumors are present, these are resected at the same time. These are usually outpatient procedures and, on occasion, can be performed in the urologist's office.
In contrast, preoperative assessment prior to cystectomy can be quite extensive. Please see Cystectomy, Radical for details.
Intraoperative details: Careful bladder mapping of biopsy sites is helpful in determining the extent of the cancer and allowing better follow-up examinations. Adequate tissue should be obtained to allow the pathologist to determine the depth of penetration of the tumor. Usually, a cold-cup biopsy forceps is used to avoid cautery artifact to the specimen. In general, biopsies are taken from the left lateral wall, right lateral wall, base, dome, and trigone of the bladder, as well as from the prostatic urethra. Obtain biopsies from any areas of suspicious erythema that are not included in these biopsies and label them as an additional site. Following tissue acquisition, cauterization of the biopsy sites can be performed for hemostasis. Take care to avoid damage to the ureteral orifice or intramural tunnel of the ureter. If potential damage to the ureteral orifice is unavoidable because of the location of suspicious lesions, a ureteral stent may be placed.
Retrograde pyelograms are generally discouraged at the time of bladder biopsies to avoid reflux of malignant cells, but they may be performed if the patient has contrast allergies or other issues that prevent other imaging modalities for evaluation of the upper urinary tract. Ureteral washes for cytologic analysis may also be obtained. These should be obtained with saline (not water) and should be collected prior to the instillation of any contrast material, which has been shown to negatively effect cytology results.
Please see Cystectomy, Radical for intraoperative details of this procedure.
Postoperative details: In a few patients, a catheter may be left in place for 1-3 days after bladder biopsies, and it is usually removed in the urology office.
Follow-up care: Following successful treatment of initial or recurrent CIS with intravesical BCG and/or chemotherapy, patients are monitored at regular intervals with cystoscopy and urine cytology. This usually occurs at a frequency of every 3 months for the first 1-2 years and every 6 months thereafter. IVP is usually performed every 6-12 months as well. This follow-up continues for a minimum of 5 years.
Following cystectomy and urinary diversion, cytology is performed every 3 months for the first 1-2 years and every 6 months thereafter. For patients with a urostomy or continent diversion, a catheterized specimen is obtained from the stoma, not the urostomy bag, because contact with the bag and the stagnant nature of urine in the bag confounds the cytologic findings. If the patient did not undergo a urethrectomy, a urethral wash for cytology should also be performed on this schedule. Patients with an intestinal neobladder should provide a voided specimen. An IVP or loopogram should be performed every 6-12 months to evaluate the upper urinary tract, as should a CT scan, chest radiograph, and serum chemistries to rule out metastatic disease. After 2-3 years, a vitamin B-12 level should be checked because many of these patients develop deficiency of this vitamin.
For excellent patient education resources, visit eMedicine's Cancer and Tumors Center and Kidneys and Urinary System Center. Also, see eMedicine's patient education articles Bladder Cancer and Blood in the Urine.
Usually very few adverse effects occur after the first 1-3 instillations of BCG, unless the patient has been previously vaccinated with BCG or has a history of tuberculosis. After the third instillation, patients begin experiencing bladder irritative symptoms and/or flulike symptoms lasting 24-72 hours. These symptoms are usually mild and can be controlled with bladder sedatives and antihistamines, and they are often perceived as favorable immunological responses to the therapy. Nearly 80% of patients can expect to experience this type of reaction.
Patients who experience temperatures higher than 39ºC and those who have gross hematuria, severe irritative symptoms lasting more than 72 hours, a urinary tract infection, or elevated liver enzymes should not receive additional BCG therapy until these findings have resolved. If BCG must be resumed, a half or a quarter dose of BCG can be administered. These are symptoms of a systemic BCG reaction, and further administration is unnecessary, immunosuppressive, and potentially lethal.
With more severe or persistent systemic symptoms, patients may require therapy with isoniazid and/or rifampin. If patients are being monitored carefully, these types of reactions should be rare and are usually predictable.
Severe reactions to BCG, including high-grade fevers (ie, temperature >40ºC), hepatotoxicity, respiratory distress, chills, hemodynamic instability, and mental status changes, are indicative of a life-threatening septicemia. These are emergencies, and patients should be hospitalized. A urine culture should be obtained because many cases of septicemia following BCG instillation are caused by more common uropathogens rather than the BCG organisms. Broad-spectrum antibiotics should be administered intravenously, and the patient should be started on antituberculosis therapy, which includes rifampin, isoniazid, and cycloserine, which is the only antituberculosis drug to reach bacteriocidal levels within 24 hours of administration. Corticosteroids are also recommended for some patients.
When BCG therapy was introduced, several deaths were reported, all of which could be attributed to improper use of this agent. Today, a death is extraordinary because clinicians have learned how to administer this agent and stop therapy before a patient becomes ill.
Currently, BCG therapy is the only agent approved by the FDA as the primary therapy of CIS, supplanting cystectomy as the treatment of choice in the mid 1980s. Approximately 70% of patients have an initial response to BCG. Rates of tumor progression vary according to the particular study, but more than 75% of those who initially have a complete response remain disease free for more than 5 years. This is equivalent to 45-50% of those who initially respond.
Disease-specific survival rates of 63% at 15 years compare favorably to those of patients treated with cystectomy early in the course of their disease.
Results associated with chemotherapy regimens are not as favorable. Mitomycin C can eradicate the cancer in 50% of patients, while the other chemotherapy agents have response rates of 20-30%.
Patients who do not respond to BCG or who are unable to receive this agent were at one time limited to cystectomy as the only alternative therapy. Bladder-sparing protocols involving chemotherapy and radiation are available for patients with papillary bladder cancer but not for CIS. Neither systemic chemotherapy nor radiation therapy has been shown to have any benefit for this disease.
Currently, patients can receive intravesical mitomycin C, valrubicin, and INF-alfa, either alone or in combination with BCG, or they can receive other chemotherapy agents. The availability of these combinations has improved the ability of the urologist to eradicate this disease and retain the patient's bladder. An ongoing debate is related to how long patients should be treated and how to determine if the disease is eradicated.
Improvements in urine cytology and the introduction of a variety of molecular tumor markers enable the clinician to identify the presence of CIS. They also help determine when the disease has recurred, even though it is not visible.