As with most cancers, no cause of bladder cancer is known. However, there is strong circumstantial evidence that environmental exposure to carcinogens plays a major role. Up to 33% of cases may be related to occupational exposures to carcinogenic aromatic amines in dye, textile, rubber, cable, printing, and plastics industries. Four proven bladder carcinogens are (a) 3-naphthylamine, (b) 4-aminobiphenyl (xenylamine), (c) 4-nitrobiphenyl, and (d) 4,4-diaminobiphenyl (benzidine). Significant nonoccupational exposures are cigarette smoking, dietary nitrosamines, Schistosoma haematobium of the bladder, cyclophosphamide chemotherapy, and therapeutic radiation of the prostate or cervix. A latency period of 15 to 30 years from first exposure to carcinogens to diagnosis of a tumor is common.

Urothelial cancer is described as a field defect because the entire urothelium, from the renal pelvis to the bladder, is bathed in the urinary carcinogens. However, most tumors occur on the floor of the bladder where exposure is greatest. These tumors usually grow in a papillary fashion and are often multicentric. Angiolymphatic invasion is a poor prognostic sign.

Urothelial cancers are now categorized into non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC).

MIBCs (20%) are all high-grade tumors (T2 and above). Urothelial dysplasia has abnormal cytologic and nuclear characteristics that are preneoplastic but are insufficient to be classified as CIS. CIS appears as a flat, non-papillary erythematous lesion confined to the urothelial mucosa. Its reddish appearance can be mistaken for inflammatory changes or radiation cystitis. CIS is histologically characterized by severe urothelial dysplasia, is clearly more aggressive, and is associated with a poorer prognosis than papillary lesions. CIS has a high recurrence rate of >80%; most are multifocal; and progression occurs in 50% to 75%. CIS is a precursor lesion for invasive cancer. Tumors labeled PUNLMP are generally considered benign but do have a risk of recurrence. They demonstrate minimal cytologic atypia and are not associated with invasion (<4%) or metastases, but can recur in 35% of cases. True papillary carcinoma of the bladder is now classified as only low grade or high grade. Eighty percent of high-grade papillary carcinomas will invade if left untreated.

Normal histologic anatomy of the bladder includes the inner urothelium, the lamina propria, and the outer muscularis propria. Smooth muscle fibers found in the lamina propria, referred to as the muscularis mucosa, must not be confused with the true muscularis propria which constitutes the detrusor muscle. A muscularis mucosa is difficult to identify. Cancer invasion of the muscularis mucosa can be misinterpreted. Uncertainty can arise particularly in the transurethral resection (TUR) specimens. Urothelial cancer staging requires good communication between the urologist and pathologist. The TNM classification is reviewed in the following table.

Tumor grade refers to the histologic morphology as determined by cellular atypia, nuclear abnormalities, and the number as well as location of mitotic figures. UC is only classified as low grade or high grade.