A HISTOPATHOLOGICAL MAPPING STUDY OF THE URINARY-BLADDER TUMORS INDUCED BY N-BUTYL-N-(4-HYDROXYBUTYL)NITROSAMINE IN DOGS

Bladder tumors were induced by N-butyl-N-(4-hydroxybutyl)nitrosamine ( BBN) in five Beagles and four mongrel dogs. The tumors were observed f or long periods and the tumor progression was traced using histopathol ogical mapping. The results indicated (1) that low-dose BBN over a lon g period induced multiple low-grade (G1-2) and low-stage (pTa-1) papil lary tumors, resembling superficial bladder cancer in humans; (2) that high-dose BBN over a short period induced high-grade (G2-3) and high- stage (pT3b) nonpapillary tumors and carcinoma in situ (CIS) resemblin g invasive cancer and CIS in humans; (3) that beagle dogs required lon ger periods and higher total doses of BBN as compared with mongrel dog s; (4) that the tumors induced by low-dose BBN in beagles were observe d without BBN as long as the animals lived, and neither increasing num bers of tumors nor malignant features such as deep infiltration and me tastasis was observed; and (5) that low-dose BBN seems to induce mild dysplasia, which is followed by Brunn's nest-like proliferation in the lamina propria and nodular change, eventually leading to the developm ent of papillary noninvasive transitional cell carcinoma (TCC); and th at high-dose BBN seems to induce severe dysplasia which leads to CIS a nd nonpapillary invasive TCC. These results may contribute to clarifyi ng the natural history of human bladder cancer.