Hepatocarcinogenicity of the woodchuck hepatitis virus

During investigations of the evolution of experimental laboratory infections of woodchucks (Marmota monax) with the woodchuck hepatitis virus (WHV), eight hepatocellular carcinomas (HCC) were observed, six in newborns and two in young adult animals, all within 17-36 months after infection. The absence of an external cocarcinogenic effect in the well-monitored woodchucks indicates the carcinogenicity of WHV and suggests the same for the genetically and biologically similar human hepatitis B virus (HBV). Laboratory infections of woodchucks with two strains of WHV, not reported here in detail, resembled human and chimpanzee HBV infections histologically and serologically. In these studies, eight woodchucks became carriers of surface antigen of WHV for greater than 1 year. All eight woodchucks developed HCC, indicating a 100% risk of HCC in experimentally infected chronic WHV antigen carriers, which is analogous to the high risk of HCC in human hepatitis B surface antigen carriers. Histologically, the absence of cirrhosis in the examined pericarcinomatous tissue permits recognition of gradual transition from normal parenchyma to neoplastic nodules to HCC of rising anaplasia, indicating a continuum of increasingly more malignant neoplastic stages, as known for chemical carcinogenesis. The HCC developed in carrier woodchucks infected as newborns with only minor, if any, hepatitic changes but is associated with antigen-carrying hepatocytes and sometimes with hyperplastic nodules. This stage was preceded in infected adults by an early, acute, weeks-long hepatitis coinciding with the appearance of surface antigen. These findings are also analogous to typical HBV infection in human newborns and young adults, respectively. At the time of HCC development in all animals with adequate histologic material, an acute recent necroinflammation appeared around the tumor, associated with abnormal hematopoietic cells around and within the tumor. A promoting role in carcinogenesis of this necroinflammation of yet unestablished pathogenesis is being postulated, to be confirmed by determination of the status of the WHV DNA in the HCC and by prospective histologic study of the inflammatory reaction.