Toxic and nontoxic changes induced in the urothelium by xenobiotics

Urothelial carcinogenesis progresses through several morphologically identifiable stages from simple hyperplasia, to nodular and papillary hyperplasia, to papilloma, and to noninvasive and invasive carcinoma. Unfortunately, no specific identifiable markers on any of the early lesions are available to distinguish those which will become neoplasms from those that are potentially reversible. Urothelial toxicity secondary to cyclophosphamide injection also progresses through several phases, beginning with vacuolization of the epithelium, to necrosis and ulceration, followed by an inflammatory infiltrate, granulation tissue formation, and marked regenerative hyperplasia of the epithelium, with ultimate repair and return to normal. Numerous changes related to toxicity are similar to those seen during carcinogenesis. In addition, several apparent morphologic "changes" occurring in the adult bladder can be mistaken for evidence of toxicity, and more importantly, many of the changes seen during regenerative repair and during carcinogenesis occur in the normal fetal urothelial development.