SECONDARY POLYCYTHEMIA IN MALE B6C3F(1) MICE WITH SPONTANEOUSLY OCCURRING HEPATOCELLULAR CARCINOMAS

The purpose of this study was to investigate che cause of polycythemia occurring in control male B6C3F(1) mice with hepatocellular carcinoma s from 2-yr carcinogenicity studies. Erythrocyte counts and plasma ery thropoietin levels in these mice were significantly increased compared to those in nontumor-bearing mice. Hepatocellular carcinomas in the m ice were well differentiated, and the neoplastic hepatocytes contained either or both of 2 types of intracytoplasmic inclusion bodies; one w as relatively large and weakly eosinophilic (pale inclusion body), whi le the other was relatively small and strongly eosinophilic (globular inclusion body). The pale eosinophilic inclusions but not the globular ones were immunohistochemically positive for erythropoietin. Ultrastr ucturally, the erythropoietin-positive inclusions were characterized b y granular materials in dilated cisternae of rough endoplasmic reticul um, suggesting increased protein synthesis. Erythropoietin-negative in clusions were dense bodies that were not surrounded by a delimiting me mbrane. These findings indicate that polycythemia in hepatocellular ca rcinoma-bearing mice occurs secondary to excess synthesis and secretio n of erythropoietin by neoplastic hepatocytes.