Apoptosis and proliferation in hepatocarcinogenesis related to cirrhosis

BACKGROUND. Dysplastic nodules (DNs) recently have been identified as prene oplastic lesions of hepatocellular carcinoma (HCC). To test an alternative hypothesis regarding DN development, in which we have suggested that DNs de velop as an infiltrating clonal expansion in advance of, or parallel to cir rhosis, the authors investigated the rates of apoptosis and proliferation i n human hepatocarcinogenesis. METHODS. The authors performed terminal deoxynucleotidyl transferase-mediat ed dUTP-biotin nick end labeling (TUNEL) assay and proliferation cell nucle ar antigen (PCNA) staining in 11 low-grade DNs, 8 high-grade DNs including 3 cases with HCC subnodules, 10 small HCCs, and 29 cases of surrounding cir rhotic nodules. Hepatocellular carcinoma subnodules were present in three c ases of high DNs. They determined TUNEL-labeling indices (LIs) and PCNA-LIs as the percentage of positive hepatocyte nuclei per 500 randomly counted c ells. RESULTS. TUNEL-LIs (mean standard deviation) were 0.8 +/- 0.82 in cirrhotic nodules, 1.0 +/- 0.98 in low-grade DNs, 3.0 +/- 4.33 in high-grade DNs, 8. 7 +/- 7.71 in HCC subnodules of high-grade DNs, and 3.2 +/- 3.58 in small H CCs. The peak values of apoptotic activity were higher in high-grade DNs an d HCCs than in low-grade DNs and cirrhotic nodules. Each case of low-grade DN showed a low to medium level of apoptotic activity when compared with th ose of the four surrounding cirrhotic nodules. The PCNA-LIs were 2.6 +/- 1. 35 in cirrhotic nodules, 4.5 +/- 2.31 in low-grade DNs, 15.3 +/- 10.50 in h igh-grade DNs, 25.4 +/- 5.25 in HCC subnodules of high-grade DNs, and 34.9 +/- 15.70 in small HCCs. The peak values gradually increased, although only HCC showed significantly elevated proliferation activity. The differences of PCNA-LIs and TUNEL-LIs, measured in each case, were 1.7 +/- 1.89 in cirr hotic nodules, 3.6 +/- 2.43 in low-grade DNs, 7.9 +/- 5.69 in high-grade DN s, 16.2 +/- 2.87 in HCC subnodules of high-grade DNs, 28.2 +/- 13.97 in sma ll HCCs. At all stages of hepatocarcinogenesis, the rates of cell prolifera tion were higher than apoptosis, allowing a preferential net gain of (pre)n eoplastic cells, and it was significantly increased in small HCCs. In regen erative cirrhotic nodules, 14% (4 cases) showed higher rates of apoptosis t han proliferation. CONCLUSIONS. The regulation/clysregulation of apoptosis of (pre)neoplastic cells as well as of proliferation may play an important role in the process of hepatocarcinogenesis. Cancer 2001;92:2733-8. (C) 2001 American Cancer S ociety.