Chapter 21

### Incidence

Bladder cancer is the second most common cancer of the genitourinary tract. It accounts for 7% of new cancer cases in men and 2% of new cancer cases in women. The incidence is higher in whites than in African Americans, and there is a positive social class gradient for bladder cancer in both sexes. The average age at diagnosis is 65 years. At that time, approximately 75% of bladder cancers are localized to the bladder; 25% have spread to regional lymph nodes or distant sites.

### Risk Factors and Pathogenesis

Cigarette smoking accounts for 65% of cases in men and 20–30% in women. In general, smokers have approximately a two- to threefold increased risk of bladder cancer than nonsmokers, and the association appears to be dose related. The causative agents are thought to be alpha- and beta-naphthylamine, which are secreted into the urine of smokers. The risk of bladder appears to decrease after smoking cessation but may not reach the levels of never smokers.

Occupational exposure accounts for 15–35% of cases in men and 1–6% in women (Matanoski and Elliott, 1981). Workers in the chemical, dye, rubber, petroleum, leather, and printing industries are at increased risk. Specific occupational carcinogens include benzidine, beta-naphthylamine, and 4-aminobiphenyl, and the latency period between exposure and tumor development may be prolonged. Patients who have received cyclophosphamide (Cytoxan) for the management of various malignant diseases are also at increased risk (Fairchild et al, 1979). Ingestion of artificial sweeteners has been proposed to be a risk factor, but several studies have failed to confirm any association (Elcock and Morgan, 1993). Physical trauma to the urothelium induced by infection, instrumentation, and calculi increases the risk of malignancy (Hicks, 1982).

The exact genetic events leading to the development of bladder cancer are unknown, but they are likely to be multiple and may involve the activation of oncogenes and inactivation or loss of tumor suppressor genes (Olumi et al, 1990). Loss of genetic material on chromosome 9 appears to be a consistent finding in patients with both low-grade, low-stage and high-grade, high-stage disease (Miyao et al, 1993; Tsai et al, 1990), which suggests that this may be an early event in bladder cancer development. Loss of chromosome 9 in multiple tumors from an individual patient supports the concept that genetic changes in bladder cancer represent a “field defect” that may occur throughout the urothelium. More recent studies examining p53 tumor suppressor gene mutations in primary, recurrent, and upper-tract tumors suggest that these tumors can have a single clonal origin (Dalbagni et al, 2001; Sidransky et al, 1991). Additional genetic changes have been described that are specific for invasive bladder tumors. Chromosome 11p, which contains the c-Ha-ras proto-oncogene, is deleted in approximately 40% of bladder cancers (Olumi et al, 1990). Increased expression of ...

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