Evolution of hepatocellular carcinoma associated with chronic hepatitis B virus infection in Alaskan Eskimos

Hepatocellular carcinoma (HCC) associated with chronic hepatitis B virus (HBV) infection in Yupik Eskimos in southwestern Alaska, detected in early stages as a result of screening, appears to be more frequently associated with variants of chronic portal inflammation in the noninvolved liver than with fully developed cirrhosis, otherwise common in HBV-associated HCC from other geographic areas. Of 38 patients diagnosed with HCC since 1969, adequate tissue was available from both the tumor and nontumorous liver in 17. Of the 17 specimens, 14 had chronic portal inflammation and three had advanced cirrhosis; 12 of the 14 were from hepatitis B surface antigen carriers. These 12 cases were studied in detail to examine the features accompanying the development of HCC unobscured by cirrhotic transformation. In the noninvolved parenchyma they included hepatocytic nodules as apparent precursors to HCC and, as markers of phenotypic alterations, dysplastic hepatocytes and hepatitis B surface antigen-laden ground-glass hepatocytes. The latter were observed in eight instances and often accumulated in nodules. Parenchyma within 1 mm of the HCC exhibited increased confluent hyperplasia and frequently conspicuous necroinflammation associated with pericellular and periductular fibrosis, which contributed, in addition to fibrous connections between displaced and heavily inflamed portal tracts, to the capsule that was forming in all cases to varying degrees in the pericarcinomatous region. The HCC was uniformly trabecular and in a few specimens, a continuous transition from hyperplasia and dysplasia near the periphery of the tumor to increasing anaplasia in the center could be made out in addition to pressure effects of the HCC. The pericarcinomatous changes, including hyperplasia progressing to neoplasia and necroinflammation, are also observed in experimental models, particularly the woodchuck HCC induced by a hepadna virus related to HBV. Coordinated morphologic and molecular biologic studies on such animal models and on human HCC detected by screening, as for instance in Eskimos, neither complicated by cirrhosis, should elucidate the direction of the evolution of the HCC and the postulated promoting role of the inflammation.