High rates of hepatocellular carcinoma in cirrhotic patients with high liver cell proliferative activity

The prevalence, risk factors, and clinical significance of high liver cell proliferative activity were investigated in 208 well-compensated cirrhotic patients (150 men; 50 years; 135 with chronic hepatitis C) who had been und er prospective surveillance for hepatocellular carcinoma (HCC) with annual abdominal ultrasound (US) and serum a-fetoprotein (AFP) determination. Immu nostaining for proliferating cell nuclear antigen (PCNA) was employed to as sess liver cell proliferative activity in formalin-fixed, paraffin-embedded liver specimens. The percentage of reactive nuclei was calculated by a com puter-assisted image analysis system. The overall PCNA labeling index (LI) ranged from 0.1% to 12.5% (mean, 2.1%), being significantly higher in the 5 0 patients who developed HCC during 88 +/- 42 months of follow-up than in t he 158 patients who remained cancer-free (3.6% +/- 72.4% vs. 1.6% +/- 1.5%; P < .0001). By receiver operating curve (ROC), a 2.0% cut-off value of PCN A-LI discriminated between patients at high and low risk for developing can cer. By multivariate analysis, high histologic grading scores and gender we re associated to PCNA LI >2.0%. The yearly incidence of HCC was 5.2% for th e 80 patients with PCNA-LI >2.0% compared with 1.1% for the 128 with low PC NA-LI (relative risk, 4.90; 95% CI, 2.63-9.55). By multivariate analysis, P CNA-LI >2.0% was the strongest independent predictor of cancer (hazard rati o, 5.49; 95% CI, 2.90-10.37). Overall, survival was significantly lower in patients with high liver cell proliferative activity rates than in those wi th low proliferative rates (10% vs. 75%; P < .0001). In conclusion, develop ment of HCC in patients with compensated cirrhosis seems to be reliably pre dicted by liver cell proliferation status.