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

Abstract

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 under prospective surveillance for hepatocellular carcinoma (HCC) with annual abdominal ultrasound (US) and serum ␣-fetoprotein (AFP) determination. Immunostaining for proliferating cell nuclear antigen (PCNA) was employed to assess liver cell proliferative activity in formalin-fixed, paraffin-embedded liver specimens. The percentage of reactive nuclei was calculated by a computer-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 50 patients who developed HCC during 88 ؎ 42 months of follow-up than in the 158 patients who remained cancer-free (3.6% ؎ 2.4% vs. 1.6% ؎ 1.5%; P < .0001). By receiver operating curve (ROC), a 2.0% cut-off value of PCNA-LI discriminated between patients at high and low risk for developing cancer. By multivariate analysis, high histologic grading scores and gender were associated to PCNA LI >2.0%. The yearly incidence of HCC was 5.2% for the 80 patients with PCNA-LI >2.0% compared with 1.1% for the 128 with low PCNA-LI (relative risk, 4.90; 95% CI, 2.63-9.55). By multivariate analysis, PCNA-LI >2.0% was the strongest independent predictor of cancer (hazard ratio, 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 with low proliferative rates (10% vs. 75%; P < .0001). In conclusion, development of HCC in patients with compensated cirrhosis seems to be reliably predicted by liver cell proliferation status. (HEPATOLOGY 2001;34:523-528.)Cirrhosis is the dominant risk factor for hepatocellular carcinoma (HCC), worldwide. 1 Prospective surveillance programs based on repeat ultrasound (US) examinations of the liver have shown that HCC risk is particularly high in cirrhotic men older than age 50 who have either advanced liver disease or increased serum ␣-fetoprotein (AFP) levels. [2][3][4][5][6][7][8] To improve the effectiveness and cost-benefit ratio of HCC surveillance programs, close monitoring focused on patients with cirrhosis who have this particularly high risk for developing HCC has been considered. 9,10 However, the use of epidemiologic and clinical predictors for the selection of patients to be surveyed would result in an inappropriate loss of target population, because each of these predictors identifies nonoverlapping HCC risk groups. Conversely, assessment of liver cell proliferation, which is a critical step in cancer development, 11,12 might help to better estimate HCC risk at the individual level. Bromodeoxyuridine uptake assay, 13 silver staining of nucleolar organizer region proteins (AgNOR), 14,15 immunostaining of Ki67, 16 and proliferating cell nuclear antigen (PCNA) 17 have been employed for assessing liver cell proliferation in patients with chronic liver diseases, beca...

Prospective Analysis of Risk Factors for Hepatocellular Carcinoma in Patients With Liver Cirrhosis

“…45,46 More recently, methods to determine the hepatocyte proliferation rate, such as immunostaining of proliferating cell nuclear antigen and flow cytometry, have been applied in cirrhotic patients and could be useful to select a subset of patients at high risk for HCC. [46][47][48] These methods are limited by the fact that they need liver tissue to be applied. In this sense, a liver biopsy had only been performed in 40% of our patients; it could be argued that patients without liver biopsy could not have cirrhosis and consequently the risk for HCC would be lower.…”

Patients with cirrhosis and bare‐stent TIPS may have increased risk of hepatocellular carcinoma†

“…Patients with cirrhosis present an elevation of this index, 21 and this elevation is known to be higher in those that develop HCC. 22 In addition, a higher proliferating cell nuclear antigen-labeling index before TIPS insertion has been associated with a longer survival after TIPS insertion. 23 Placement of a TIPS could select a group of patients with a longer survival and therefore with a higher risk of developing HCC after the procedure.…”

Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress

“…The 5-year cumulative HCC incidence in cirrhosis is between 10% and 30% in HBV and HCV infection, depending on the geographic region, approximately 20% in hereditary hemochromatosis and 8% in alcoholic cirrhosis (Fattovich et al, 2004). Predictors of HCC in cirrhosis include the severity of liver disease determined by the ChildPugh score (Bolondi et al, 2001), the disease activity, reflected by serum transaminase activities (Benvegnu et al, 1994;Tarao et al, 1999), and some histological criteria, such as the presence of large cell changes (LCC) (Borzio et al, 1995;Ganne-Carrié et al, 1996), macronodules (Borzio et al, 2003) and markers for hyperregeneration (Donato et al, 2001;Trerè et al, 2003).…”