Syrian hamsters were treated with ethinylestradiol and maintained on a diet containing
alpha-naphthoflavone (alpha NF), a regimen that produces a high incidence of liver
tumors. Morphologic analyses (light microscopy, immunoperoxidase studies, and electron microscopy) were performed on livers of these animals. After 4 months of
hormone plus alpha NF treatment, marked hepatocyte cell changes were already present, as demonstrated by loss of eosinophilic staining of hepatocyte cytoplasm. Large multinucleated hepatocytes exhibiting frequent mitoses were observed around central veins. After 5 months of treatment, there was proliferation of bile ducts, and small cells with eosinophilic cytoplasm resembling hepatocytes appeared surrounding these bile ducts. At 7 to 8 months, the first
tumor nodules (foci) were seen.
Tumor foci in the portal area consisted of small clusters of large cells resembling hepatocytes with irregular nuclei. At the same time, dysplastic glands were identified among proliferating bile ducts. By 8 to 10 months, large
tumors were present. These were trabecular
hepatocellular carcinomas with widely varying individual cell morphology. Compared with adjacent liver, dysplastic glands in the portal areas, microcarcinomas, and large
tumors all showed intense immunostaining for
cytokeratin. Rats treated with the same regimen also developed hepatic
tumors, but the light and electron microscopy results and immunohistochemical profiles were very different. Altered hepatic foci composed of small hepatocytes were typically prominent; however, malignant
tumors did not arise from the portal area. Neither altered foci nor
tumors stained significantly for
cytokeratin. These data suggest that the biochemical events giving rise to these liver
tumors differ between the species studied, despite the animals being exposed to the same treatment regimens.