Biliary dysplasia, cell proliferation and nuclear DNA-fragmentation in primary sclerosing cholangitis with and without cholangiocarcinoma

Objectives. To study the extent of biliary dysplasia, and the degree of cell proliferation and apoptosis in bile duct cells (BDC) from patients with primary sclerosing cholangitis (PSC), with and without cholangiocarcinoma (CC). Methods. Specimens of liver tissue from 16 patients suffering from PSC and CC, and 16 patients with endstage PSC without cancer, were investigated. Histological evaluation of presence of biliary dysplasia and bile duct proliferation was made. Immunohistochemistry, applying antibodies against Ki-67, p53 and bcl-2, was used. Nuclear DNA fragmentation was assessed by in situ DNA labelling (ApopTag). The numbers of positive cells expressed as a percentage of the total number of BDCs constituted the labelling index (LI). Results. Bile duct dysplasia was significantly more frequent in nontumorous liner tissue from patients with PSC and CC than from patients having end-stage PSC without cancer (P < 0.05). Patients with biliary dysplasia had a higher frequency of marked bile duct proliferation (P < 0.01) than patients without dysplasia. In tumour tissue, the LI for Ki-67 positive nuclei was more than four times the LI of nuclear DNA fragmentation (P < 0.01). Ki-67, bcl-2, p53 or DNA fragmentation were not significantly different in nontumorous liver tissue from patients with and without CC. Immunohistochemical staining for p53 was positive in 75% of the tumours, whilst in nontumorous tissue no such overexpression was found. Conclusion. PSC patients with CC more often display biliary dysplasia than those with end-stage PSC, indicating that biliary dysplasia may be a precancerous stage in PSC. Additionally, p53 mutation seems to be a late event in tumour development, since no p53 expression was found in the premalignant areas with nontumorous BDC.