Hepadnaviral hepatocarcinogenesis: in situ visualization of viral antigens, cytoplasmic compartmentation, enzymic patterns, and cellular proliferation in preneoplastic hepatocellular lineages in woodchucks

Background/Aims: Hepadnaviral hepatocarcinogenesis induced in woodchucks wi th and without dietary aflatoxin B-1 has been established as an appropriate animal model for studying the pathogenesis of human hepatocellular carcino ma in high-risk areas. Our aim in this study was the elucidation of phenoty pic cellular changes in early stages of this process. Methods: Woodchucks were inoculated as newborns with woodchuck hepatitis vi rus (WHV), and partly also exposed to aflatoxin B1. Sequential hepatocellul ar changes in the expression of viral antigens, ultra-structural organizati on, cellular proliferation and apoptosis were studied in situ by electron m icroscopy, enzyme and immunohistochemistry. Results: A characteristic finding in WHV-infected animals (with and without aflatoxin B1) was proliferative areas of minimal structural deviation, whi ch predominated periportally, comprised glycogen-rich, amphophilic, and gro und-glass hepatocytes, and expressed the woodchuck hepatitis core and surfa ce antigens. Two main types of proliferative foci emerged from minimal devi ation areas, glycogenotic clear cell foci and amphophilic cell foci (being poor in glycogen but rich in mitochondria), giving rise to the glycogenotic -basophilic and the amphophilic preneoplastic hepatocellular lineages. A gr adual loss in the expression of viral antigens appeared in both lineages, p articularly early in the glycogenotic-basophilic cell lineage. Whereas glyc ogenosis was associated with an enzymic pattern suggesting an early activat ion of the insulin-signaling pathway amphophilic cells shelved changes in e nzyme activities mimicking a response of the hepatocytes to thyroid hormone , which may also result from early changes in signal transduction. Conclusion: Preneoplastic hepatocellular lineages in hepadnaviral and chemi cal hepatocarcinognesis show striking phenotypic similarities, indicating c oncordant and possibly synergistic early changes in signaling.