Absence of a complete carcinogenic effect of phenacetin on the quiescent and proliferating urothelium stimulated by partial cystectomy. A 2-year feeding study in rats.

It was the object of the present animal experiments to test whether phenacetin (PH) exerts a complete solitary carcinogenic effect on the quiescent and rapidly proliferating urothelium of the lower urinary tract of the rat. In order to stimulate proliferative activity resection of one-third of the urinary bladder was performed which is known to induce intensive reparative regeneration in the stump. PH was administered either continuously with the diet or by gavage in three single doses when proliferative activity was highest. After an experimental period of 2 years 74-83% of the animals receiving PH continuously and 49-52% of the rats after limited gavage feeding had developed uni- and bilateral hyperplasia of the epithelium of the renal papilla. Histologically, the papillary hyperplasia exhibited urothelial differentiation and a typical endophytic growth pattern. It was always associated with healed or, rarely, fresh micronecroses of the subjacent papillary tissue. The urothelial hyperplasia of the renal papilla has to be considered not a true preneoplastic, but rather a reactive proliferative lesion in the sense of a reparative hyperregeneration due to toxic necroses. There was no evidence for a complete solitary carcinogenic action of PH on the urothelium of the entire lower urinary tract. It seems most likely that a metabolite of PH realizes tumor growth only as cocarcinogen with initiation-stimulating and/or initiation-promoting effects acting together with other causative factors during multifactorial multistage carcinogenesis. Based upon the experimental findings reported here, the concept of PH as a solitary complete urothelial carcinogen for man should be reassessed.