TCC arises from the transitional epithelium, a tissue lining the inner surface of these hollow organs.^[1]

When the term "urothelial" is used, it specifically refers to a carcinoma of the urothelium, meaning a TCC of the urinary system.

Urothelial carcinoma is a prototypical example of a malignancy arising from environmental carcinogenic influences. By far the important cause is cigarette smoking, which contributes to approximately half of the disease burden. Chemical exposures such as those sustained by workers in the petroleum industry, the manufacture of paints and pigments (prototypically aniline dyes), and agrochemicals are known to predispose to urothelial cancer. Interestingly, risk is lowered by increased liquid consumption, presumably as a consequence of increased urine production and thus less "dwell time" on the urothelial surface. Conversely, risk is increased among long-haul truck drivers and others in whom long urine dwell-times are encountered. As with most epithelial cancers, physical irritation has been associated with increased risk of malignant transformation of the urothelium. Thus, urothelial carcinomas are more common in the context of chronic urinary stone disease, chronic catheterization (as in patients with paraplegia or multiple sclerosis), and chronic infections. Some particular examples are listed below:

1. certain drugs such as cyclophosphamide via the metabolite acrolein, and phenacetin are known to predispose to TCC (the latter especially with respect to the upper urinary tract).^[2]
2. radiation exposure
3. somatic mutation such as deletion of Chromosome 9p,9q,11p,17p,13q,14q and over expression of RAS (oncogene) and epidermal growth factor receptor (EGFR)