Large cell change of hepatocytes in chronic viral hepatitis represents a senescent-related lesion

Abstract

Large cell change involves the clustering of hepatocytes with hyperchromatism and cellular enlargement without an increase in the nuclear/cytoplasmic ratio. This study investigated whether large cell change in chronic viral hepatitis reflects cellular senescence because of morphological similarities between the 2 conditions. The expression of markers of senescence such as senescence-associated beta-galactosidase, senescence-associated heterochromatic foci, and p21, as well as markers of cell kinetics such as Ki-67, was examined in 26 frozen and 82 formalin-fixed liver specimens. Large cell change was frequently detected in chronic hepatitis B cases with advanced histologic staging, particularly those with hepatocellular carcinoma. Senescence-associated beta-galactosidase activity, senescence-associated heterochromatic foci, and p21 were frequently detected in areas of large cell change. Hepatocytes with large cell change showed no proliferative or apoptotic activity. The frequent expression of senescent features and the absence of proliferative or apoptotic activity suggest that large cell change represents senescence. The parallel increase in large cell change and hepatocellular carcinoma in chronic hepatitis B raises the possibility that cellular senescence develops as a safeguard against malignant transformation rather than as a precursor of hepatocellular carcinoma.