Proliferating cell nuclear antigen expression in peribiliary glands of stone-containing intrahepatic bile ducts

All cases of hepatolithiasis showed features of chronic proliferative cholangitis, and it has been speculated that the atypical glandular proliferation might be a precursor to overt cholangiocarcinoma. Proliferative cell nuclear antigen (PCNA) is a nuclear protein synthesized in the G1/S phase of the cell cycle and therefore is related to cell proliferative activity. In an attempt to assess the activity of cell proliferation of stone-containing intrahepatic bile ducts, we conducted a study using immunohistochemical staining with monoclonal antibody to score PCNA in intrahepatic bile ducts. Thirty patients (10 men, 20 women; mean age 52.4 years) having hepatolithiasis surgically resected were studied. Ten stone-free patients served as controls. All 40 specimens were immunostained for PCNA using PC 10 monoclonal antibody. PCNA of both stone-containing and stone-free intrahepatic bile ducts were assessed by counting positive staining nuclei per 500 cells and expressed as labeling index (LI), ie, percentage of positive nuclei to the total number of nuclei. The PCNA LI in stone-free intrahepatic bile ducts was generally low: 10.0+/-13.2%, 10.4+/-10.7% and 7.9+/-9.6% for extramural glands, intramural glands, and epithelial lining, respectively. In contrast, the PCNA LI for stone-containing intrahepatic bile ducts were significantly higher than those of controls (P < 0.001): 49.4+/-8.3%, 40.6+/-7.0% and 34.1+/-6.8% for extramural glands, intramural glands, and epithelial lining, respectively. The extramural glands had a significantly higher PCNA LI (P < 0.001) than the intramural glands and controls. Hyperplasia was found in all specimens, while dysplasia was found in six of 30 cases with hepatolithiasis. The dysplastic cells also had a higher PCNA LI (P < 0.001) than the hyperplastic cells and normal epithelium. Our findings showed that there is marked increase of activity of cell proliferation in stone-containing intrahepatic bile ducts. It is well known that genetic mutations are facilitated in proliferating cells. Therefore, our results suggest that the high epithelial turnover in dysplastic cells and extramural glands had higher potential for proliferation and neoplastic transformation in long-standing untreated hepatolithiasis.