Localized hepatocarcinogenesis: the response of the liver and kidney to implanted carcinogens

Summary

Attempts by early workers to induce liver tumours by the local implantation of carcinogens had by and large not been successful, so that the liver came to be viewed as being “resistant” to tumourigenesis by this means. A review of these early studies showed not only that fibrosarcomas could be easily induced by the local application of 3-methylcholanthrene (3-M.C.), but that there were also reasons why the apparently low susceptibility of the liver to the localised induction of hepatocellular tumours should not be accepted as established dogma. In an attempt to re-investigate this problem pellets made of chlolesterol (CHOL), anthracene (ANT), α-naphthylisothiocyanate (ANIT), 3-M.C. or 4-dimethylaminoazobenzene (DAB) were implanted into the livers of male litter-mate weanling rats. The evolution of the response was studied by histological examination of the implantation site at varying intervals. In each instance the liver responded with the formation of a firm, complete connective tissue capsule which, however, did not prevent the gradual degradation of the implants. No tumours or other significant changes were observed with the control implants of CHOL or ANT. ANIT, known to damage biliary ducts, elicited what appeared to be an intense serous exudation which was separated from the adjacent parenchyma by a shell-like deposition of calcium in the connective tissue capsule. No significant biliary changes were observed, however, and no tumours were produced. Attention should be drawn to this reproducible, regularly occurring, in vivo model of extra-osseous calcification. The 3-M.C. induced a high incidence of large solitary bosselated tumours associated with the carcinogenic pellet which was found embedded in the tumour mass. The architectural arrangement and bizzare cytological appearance of the tumours led to the currently widely used diagnosis of malignant fibrous histiocytoma (M. F. H.) rather than the fibrosarcoma or rhabdomyosarcoma of the early workers. Some tumours produced large numbers of implantation metastases in the peritoneal cavity, but no distant metastases were observed in this series. Of particular interest is the fact that it was not possible to determine the site of origin of these tumours despite histological sampling at intervals of the site of implantation of the pellets. In contrast to these pleomorphic, clearly mesenchymal tumours reliably produced by 3-M.C., the implantation of pellets of DAB produced fewer tumours which were classified as large, singly occurring hepatocellular carcinomas (H. C. C.). They did not differ in their histological appearance from the description of tumours induced by feeding the carcinogen. Metastases occurred again by implantation in the abdominal cavity. It appears that this is the first experiment in which the reproducible induction of localised H. C. C.s in the liver of the rat has been reported, the only previously reported instance of the induction of H. C. C. by this means having been described some considerable time ago in mice prone to the occurrence of “sponanteous” hepatocellular tumours. This report was disregarded for that reason. The rather low numbers of H. C. C.s induced by DAB implants in the experiments reported here, and their long latency period, suggests a need for further experimental manipulation. None of the usually described associated or precursor phenomena—oval cell proliferation, fasting-resistant glycogen accumulation, nodule formation—were seen either in the parenchyma immediately adjacent to the pellet or in more distant areas. The advantages of this model for further experimentation, and its position in the light of current views of hepatocarcinogenesis, are indicated, while some unsolved problems are underlined. The response of the kidney differed to some extent from that seen in the liver. The implanted pellets of DAB were encapsulated and grdually degraded, but no tumours were induced either in the kidney or, at a distance, in the liver. With pellets of 3-M. C., however, large hydronephrotic cysts with squamous cell metaplasia of the transitional pelvic epithelium progressing to invasive and locally metastasizing squamous cell carcinoma were produced in the kidney of some rats, whereas in others M. F. H.s were the outcome; one of the rats also presented with a mixed tumour. The similarity of the appearance of the 3-M. C.-induced tumours in liver and kidney suggests that the implantation of pellets of 3-M. C. is a reliable tool for the experimental study of M. F. H.s in internal organs.