Etiology of Bladder Bancer

Up to 80% of bladder cancer cases are associated with environmental exposure. Tobacco use is by far the most common cause of bladder cancer in the United States and is increasing in importance in some developing countries. Smoking duration and intensity are directly related to increased risk. Compared with nonsmokers, smokers have a 2-6 times increased risk of developing bladder carcinoma. The risk appears to be similar between men and women.Nitrosamine, 2-naphthylamine, and 4-aminobiphenyl are possible carcinogenic agents found in cigarette smoke.

Occupational exposure to aromatic amines or aniline dyes is presumed to be the cause of bladder cancer in up to 25% of cases. Numerous occupations associated with diesel exhaust, petroleum products, and solvents (eg, auto work, truck driving, plumbing, leather and apparel work, rubber and metal work) have been associated with an increased risk of bladder cancer. Increased risk has also been reported in persons who work with organic chemicals and dyes, such as beauticians, dry cleaners, painters, paper production workers, rope and twine industry workers, dental workers, physicians, and barbers.

People living in urban areas are more likely to develop bladder cancer. The etiology is thought to be multifactorial, potentially involving exposure to numerous carcinogens.

Several medical risk factors are associated with bladder cancer. Patients who have undergone radiation treatment of the pelvis have an increased risk of bladder cancer. Chemotherapy with cyclophosphamide increases the risk of bladder cancer via exposure to acrolein, a urinary metabolite of cyclophosphamide.[12] Patients with spinal cord injuries who have long-term indwelling catheters have a 16- to 20-fold increased risk of developing SCC of the bladder.

In many underdeveloped countries, particularly in the Middle East, Schistosoma haematobium infection causes most cases of squamous cell carcinoma. In one study from Egypt, 82% of patients with bladder carcinoma harbored S haematobium eggs in the bladder wall.[13] In egg-positive cases, the tumor developed in younger age groups, with predominantly squamous cell carcinoma, relative to egg-negative persons. A higher degree of adenocarcinoma has also been reported in schistosomal-associated bladder carcinomas.[13]

Three pathogenic species responsible for the disease in humans are S haematobium, S mansoni, and S japonicum. The eggs reside in the pelvic and mesenteric venous plexus. In the bladder, a severe inflammatory response and fibrosis secondary to the deposition of Schistosoma eggs is common.

The eggs are found embedded in the lamina propria and muscularis propria of the bladder wall. Many of the eggs are destroyed by host reaction and calcified, resulting in a lesion commonly known as sandy patch, which appears as a granular, yellow-tan surface lesion. It has been reported that S haematobium total antigen induces increased proliferation, migration, and invasion and decreases apoptosis of normal epithelial cells.[14]

Keratinous squamous metaplasia has been associated with the increased risk of developing squamous cell carcinoma, with approximately one half of the cases arising subsequent to the metaplasia.[15, 16] The majority of the cases will arise in the setting of chronic cystitis. Chronic irritation secondary to lithiasis, urinary retention, and indwelling catheters has also been linked to the development of squamous cell carcinoma.

Having bladder diverticula may render an increased chance of developing squamous cell carcinoma in individuals.[18] Rarely, bacillus Calmette-Guerin (BCG) treatment for carcinoma in situ has been reported to lead to development of squamous cell carcinoma.[19] Development of bladder cancer at a younger age has been associated with bladder exstrophy. Squamous cell carcinoma has also been described in urachal remnants.

Coffee consumption does not increase the risk of developing bladder cancer. Early studies of rodents and a minority of human studies suggested a weak connection between artificial sweeteners (eg, saccharin, cyclamate) and bladder cancer; however, most recent studies show no significant correlation.

Although no convincing evidence exists for a hereditary factor in the development of bladder cancer, familial clusters of bladder cancer have been reported. Several genetic mutations have been identified in bladder cancer. Mutations of the tumor suppressor gene p53, found on chromosome 17, are associated with high-grade bladder cancer and CIS. Mutations of the tumor suppressor genes p15 and p16, found on chromosome 9, are associated with low-grade and superficial tumors. Retinoblastoma (Rb) tumor suppressor gene mutations are also noted. Bladder cancer is associated with increased expression of the epidermal growth factor gene and the erb- b2 oncogene and mutations of the oncogenes p21-ras, c-myc, and c-jun.