Bladder Cancer

The annual incidence of bladder cancer in the USA is 20 new cases/100,000 persons > 40 years, and the male:female ratio among whites is at least 2:1 (29.6 vs. 7.6 cases/100,000). Racial predisposition is variable and probably geographic.

Various risk factors have been identified (see Table 101-2). The strongest risk factor is exposure to heterocyclic organic compounds, particularly arylamines. Bladder cancer was one of the first occupational-related diseases; aniline dye workers contracted bladder cancer at alarmingly high rates. Smoking also confers a significant risk for bladder cancer. Genetic polymorphisms detected at loci of genes whose products are associated with carcinogen metabolism may constitute an additional risk factor. However, there are no strong familial risk factors nor syndromes with a high risk of concurrent bladder cancer. The rare congenital anomaly of bladder exstrophy is associated with development of bladder cancer later in life. In Northern Africa, development of squamous cell carcinoma of the bladder is associated with long-standing schistosomiasis.

Pathology

The vast majority of bladder tumors in the elderly are of epithelial (or urothelial) cell origin, and in the USA and Europe, most are transitional cell carcinomas (TCCs). Bladder tumors can be low grade (noninvasive papillary tumors that grow exophytically within the bladder lumen) or high grade (more insidious sessile [broad-based] tumors that have the propensity for early invasion and metastasis). Bladder cancer often metastasizes to the lymph nodes, lungs, liver, and bone.

Carcinoma in situ (CIS) of the bladder, an unfortunate nomenclature because of the common inference with other organ sites of relative benignity, is a very aggressive, usually multifocal, high-grade cancer that commonly becomes frankly invasive.

Symptoms and Signs

Two clinical presentations are common: gross hematuria and irritated voiding (frequency, dysuria). Painless gross hematuria is an important symptom that should not be ignored even in a patient taking aspirin or warfarin; indeed, a therapeutic anticoagulated state can unmask urinary tract tumors, particularly the ominous, invasive tumors less prone to bleed.

Papillary tumors tend to bleed grossly. Sessile tumors are less prone to manifest as gross hematuria but are still likely to be detectable as microhematuria. Bladder CIS commonly manifests with microhematuria and modest pyuria in patients complaining of urgency, frequency, dysuria, and strangury (pain referred to the urethral meatus at the end of voiding). Bladder tumors should always be considered in patients with urine culture-negative pyuria, especially with concurrent microhematuria.

Diagnosis and Staging

The diagnosis of bladder cancer is made primarily by visual confirmation of proliferative lesions within the bladder during cystoscopy; every patient with gross hematuria, unexplained microhematuria, or persistent irritative voiding symptoms should undergo this procedure. CIS is not a visible proliferation but often appears as epithelial erythema (the result of submucosal neoangiogenesis) and can be diagnosed by endoscopic biopsy.

Urine cytology can be helpful but is inadequate as a screening tool because exfoliated cells from lower-grade tumors are difficult to differentiate from benign epithelia. Mass screening of high-risk patients is controversial because of the low specificity of available laboratory tests. Radiographically, an occasional large tumor can create a filling defect seen on imaging studies using IV contrast, but contrast studies also are insensitive as screening tools for cancer.

Most tumors recognized at the time of office cystoscopy are best staged and treated initially with endoscopic resection (transurethral resection). The tumor is resected to its base; then an additional resection of the base with contained bladder wall muscle is performed to stage the tumor for the possible presence of invasive disease. Biopsy of adjacent suspicious mucosa for CIS is obtained. For low-grade, noninvasive lesions, endoscopic resection is sufficient for staging and treatment. For high-grade (particularly invasive) disease, further staging is needed. Bone scan, abdominal and pelvic CT, and chest x-rays are used to evaluate disease stage. When observed, ureteral obstruction (usually the result of locally invasive cancer at or near the ureteral orifice) is often an ominous sign of locally advanced disease.

Prognosis and Treatment

Recurrent, low-grade disease: Although endoscopic resection is definitive, new lesions subsequently develop within the bladder in > 40% of patients. Monitoring for these new lesions is performed by surveillance cystoscopy every 3 to 6 months. Only a small percentage of patients have gradual worsening of their disease (upgrading and concomitant invasion), thus placing them at some disease-specific risk of death.

Intravesical therapy is used for patients with CIS, and adjuvant postresection intravesical therapy is valuable for patients with multiply recurrent low-grade tumors. Antineoplastic cytotoxic drugs (eg, mitomycin C, thiotepa, doxorubicin) have been used effectively in this setting. An immunotherapeutic approach using intravesical bacille Calmette-Guérin (BCG) is highly effective, particularly for CIS, although it has a higher toxicity profile.

Invasive disease: Mortality rates have decreased substantially for whites and blacks of both sexes with invasive disease--about 24% overall from 1973 to 1996. Early diagnosis and aggressive surgical intervention account for this improvement. The standard of care for invasive, high-grade bladder cancer is complete removal of the bladder and adjacent organs (prostate and seminal vesicles in males; uterus and adnexa in females). Partial cystectomy is rarely appropriate because of the high propensity for multifocal disease throughout the bladder.

Urine excretion is managed by the construction of urinary reservoirs from the intestine. The simplest is the ileal conduit. The ureters are anastomosed to a resected piece of the small bowel, which then tunnels through the abdominal wall to form a stoma; an external appliance is applied ("glued" to the skin) around the stoma. More complex reservoirs provide substantial improvement in quality of life, particularly for patients who object to an external urostomy. A continent reservoir has no external appliance; the patient catheterizes a continent stoma to drain the urine. Another option is construction of an orthotopic reservoir anastomosed to the urethra.

Surgical mortality from cystectomy is now only about 2%. However, for patients who are poor surgical risks, external beam radiation therapy is an option, although it is considered inferior to cystectomy, particularly in patients with concurrent CIS. Complications of radiation therapy include radiation cystitis, bladder contracture, and radiation proctitis; preservation of the bladder has been attempted with systemic IV cisplatin, a chemotherapeutic drug used in this case as a radiosensitizer to improve the therapeutic effect.

Multimodal approaches for invasive bladder cancer are increasingly used, although their effect on survival is still controversial. Treatment with induction (ie, neoadjuvant or presurgical) or adjuvant (ie, immediately postsurgical) chemotherapy is now commonplace.

Metastatic disease: Advanced disease is treated with systemic multiagent chemotherapy. Use of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) or cisplatin, methotrexate, and vinblastine (CMV) IV combination therapy is standard. However, although response rates exceed 60%, the responses are not durable, and the cure rate is only about 10%. Prolongation of survival has been enhanced by surgical resection, when applicable, after chemotherapy, although this role for surgery is controversial. The increased survival obviously is limited to the subset of patients with potentially resectable disease. Newer combination drug therapies are being explored. Radiation therapy is reserved for palliation, particularly for patients with symptomatic bony metastases; radiation to a neobladder risks serious complications.