Sequential Hepatic Histologic and Histochemical Changes Produced by Diethylnitrosamine in the Rhesus Monkey 2

Abstract

Six young adult male rhesus monkeys were given diethylnitrosamine ip for 3-5 years. Liver biospies were done monthly. After 6 months, biopsy specimens showed individual hepatocytes and small foci of hepatocytes that were intensely positive for glycogen. During the second and later years, larger foci of such cells developed. In sections stained with hematoxylin and eosin, the glycogen-containing hepatocytes generally appeared unusually clear. Some hepatocytes, however, had eosinophilic or basophilic cytoplasm. Nuclear enlargement and atypic developed, particularly outside the foci. The hepatocytes within most foci were uniform in their histochemical features: glycogen was elevated, glucose-6-phosphatase was decreased, and ATPase activity was present not only along the bile canalicular surface but also along the enire cell membrane. After 3-5 years, neoplastic nodules and hepatocarcinomas developed in 5 of 6 animals. Two nodules and particularly the heptocarcinomas differed from the foci in one of more histochemical parameters. The findings suggested that the glycogen-containing, histochemically altered cells of the foci in one or more histochemical parameters. The findings suggested that the glycogen-containing, histochemically altered cells of the foci may be the first step in the development of neoplasia; further steps toward malignancy appeared to be frequently associated with additional alterations, such as loss of sinusoidal ATPase and re-formation of glucose-6-phosphatase.

Liver tumors and possible preneoplastic lesions, induced by a food‐derived heterocyclic amine in cynomolgus monkeys; a study of histology and cytokeratin expression

“…The hepatocytes were characterized by marked increase in cellular size, normal nuclear/ cytoplasmic ratio and sometimes more than one pleomorphic, hyperchromatic nucleus. A similar type of hepatocyte dysplasia has been reported in rhesus monkeys chronically dosed with diethylnitrosamine (24). Liver cell dysplasia, originally described in cirrhotic livers, was considered to be a premalignant lesion (31).…”

“…They were also seen in the majority of the HCC cases at the time of autopsy. Glycogen-rich, clearcell foci were previously described in rhesus monkeys given diethylnitrosamine (24) and in human livers showing micronodular regenerative hyperplasia of alcoholic cirrhosis (25). In rodents treated with N-nitrosomorpholine or N-nitrosodiethylamine, the development of clear-cell foci was shown to precede HCC, but it has been disputed whether they represent preneoplastic lesions (23-28).…”

Correlation between growth rate and cytochemistry in morris hepatomas

“…In the liver of carcinogen-treated rats, biochemical data show that the decrease of glucose-6-phosphatase correlates with the synthesis and storage of glycogen (Bannasch and Muller, 1964;Sylven, 1967;Ruebner et al, 1976). Our cytochemical data reveal that glucose-6-phosphatase is present in moderate amounts in hepatoma 9618A, but is not detectable in hepatoma 3924A.…”

“…Glucose-6-phosphatase, a key enzyme of gluconeogenesis, diminishes in the chemical carcinogen-induced rat hepatomas (Gossner and Friederick-Freksa, 1964;Weber et al, 1972) and in the virus-induced chicken hepatomas . In the liver of carcinogen-treated rats, biochemical data show that the decrease of glucose-6-phosphatase correlates with the synthesis and storage of glycogen (Bannasch and Muller, 1964;Sylven, 1967;Ruebner et al, 1976). Our cytochemical data reveal that glucose-6-phosphatase is present in moderate amounts in hepatoma 9618A, but is not detectable in hepatoma 3924A.…”

Biological markers of preneoplastic foci and neoplastic nodules in rodent liver

“…The findings of many other authors (31,33,79,84,100 and others) and recent results of enzyme-histochemical investigations (38) are in agreement with this concept. Further support is given by observations in mice treated with various hepatocarcinogens (12,47,65,77,104) and results obtained in some other species, such as Mastomys (106) and monkeys (76).…”