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

Abstract

Six young adult male rhesus monkeys were given diethylnitrosamine ip for 3–5 years. Liver biopsies 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 atypia 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 entire cell membrane. After 3–5 years, neoplastic nodules and hepatocarcinomas developed in 5 of 6 animals. Two nodules and 1 hepatocarcinoma had a histochemical reaction pattern identical to that of the foci. However, most of the nodules and particularly the heptocarcinomas differed from 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.