Biology of hepatocellular neoplasia in the mouse. I. Histogenesis of safrole-induced hepatocellular carcinoma.

A sequential, histologic analysis of the livers of male BALB/c mice chronically fed the hepatocarcinogen safrole (4,000 ppm) was performed at 2, 4, 8, 16, 24, 36, 52, and 75 weeks. The transplantability of selected lesions to syngeneic hosts was also assessed. Histopathologic liver alterations at 2, 4, 8, and 16 weeks induced hypertrophy of centrolobular hepatocytes, oval cell proliferation, fatty change in periportal hepatocytes, including basophilic, acidophilic, and clear cell, were noted. At 36 and 52 weeks, hepatocellular adenomas occurred in 4 of 10 and 7 of 10 mice, respectively. At 75 weeks they occurred in 5 of 5 mice. Adenomas were larger than a lobule in diameter compressed the adjacent parenchyma, and distorted the hepatic architecture. Individual adenomas were composed of a mixture of basophilic, acidophilic, clear, and lipid-laden cells, arranged in disorganized cords, one to three cells in thickness. None of the 10 adenomas tested grew upon subcutaneous transplantation into syngeneic hosts. Hepatocellular carcinomas (HPC) developed in 2 of 10 safrole-exposed mice at 52 weeks and 3 of 5 mice at 75 weeks. These lesions were large, multilobed and, unlike adenomas, seemed to invade adjacent parenchyma. The HPC were heterogeneous in cell composition. Their architecture was disorganized with trabeculae of 1-10 or more cells in thickness. No central veins or portal tracts were seen. All HPC proliferated when transplanted into syngeneic hosts. The results of this study demonstrated a sequential development of altered hepatocyte populations leading to HPC in safrole-treated mice. The transplantability of HPC indicated their malignant nature.