Primary sclerosing cholangitis (PSC) as one of the most common chronic cholestatic liver diseases is a main predisposing factor for the development of cholangiocarcinoma (CCA). Biliary intraepithelial neoplasia (BilIN) is defined as precancerous bile duct epithelial changes, which can be eventually led to cholangiocarcinoma. There are very few studies about the frequency of BilIN in the patients with PSC and its correlation with paraclinical findings.

In this study, we tried to find the frequency of BilIN in the patients with PSC and correlate its presence with clinicopathologic factors.

During two years (2014 - 15) of investigation, 80 explanted livers with the confirmed diagnosis of PSC were studied through precise inspection and thorough sectioning of the explanted livers. These findings were correlated with paraclinical findings to identify any predictor of these neoplastic epithelial changes.

During the study period of 2 years, among 80 livers with confirmed diagnosis of PSC, there were 43 cases with different types of metaplasia. The frequency of epithelial changes was as below: 29 (35%) for pyloric metaplasia, 9 (10.8%) for mucinous metaplasia, 3 (3.6%) for intestinal metaplasia, 1 (1.2%) for osteoid metaplasia, and 1 (1.2%) for squamous metaplasia. There was no epithelial dysplasia in the study sample; however, according to the most recent reports, mucinous metaplasia is considered as BilIN 1; therefore, there would be 9 cases of BilIN I. There has been no statistically significant difference between PSC cases and those with BilIN in demographic variables, except for bilirubin and CA19-9 which were higher in the PSC cases with BilIN.

This study showed that the frequency of BilIN was low among Iranian patients with PSC. High bilirubin and CA19-9 can be predictors of the development of bile duct epithelial changes in patients with PSC.

Patients with primary sclerosing cholangitis (PSC) are at increased risk for developing cholangiocarcinoma (CCA). However, the morphology of precursor lesions and the prevalence of biliary dysplasia among patients undergoing liver transplantation for PSC are incompletely defined, and the earlier studies using relatively small number of cases have yielded conflicting results. We retrospectively evaluated 100 consecutive formalin-fixed PSC liver explants (including 30 with CCA) by randomly sampling the hilar and large intrahepatic bile ducts (10 additional tissue cassettes submitted per case). The following histologic features were evaluated and quantitated according to the number of ducts involved: mucinous metaplasia, pyloric metaplasia, intestinal metaplasia, pancreatic acinar metaplasia, and biliary dysplasia [low-grade vs. high-grade (biliary intraepithelial neoplasia-2 or neoplasia-3), papillary vs. flat]. Using Fisher exact test and t test, these features were correlated with the presence or absence of CCA and with the following clinical parameters: sex, age, PSC duration, cirrhotic-stage liver disease, and inflammatory bowel disease at the time of transplant. We found high frequencies of mucinous metaplasia (77%), pyloric metaplasia (73%), and pancreatic acinar metaplasia (10%), which did not differ between CCA and non-CCA livers. However, livers with CCA were more likely to harbor intestinal metaplasia (43% vs. 19%, P=0.013), dysplasia (of any grade) (83% vs. 36%, P<0.0001), and high-grade dysplasia (60% vs. 11%, P<0.0001), and also contained greater numbers of dysplastic ducts than non-CCA cases (P<0.0001). The relative frequency of papillary (44%) versus flat (56%) dysplasia did not differ between CCA and non-CCA cases. Overall, intestinal metaplasia was a significant predictor of bile duct dysplasia (P=0.0005) and CCA (P=0.013), low-grade dysplasia predicted high-grade dysplasia (P<0.0001) and CCA (P=0.0004), and high-grade dysplasia predicted CCA (P<0.0001). Among the clinical parameters, there were no significant differences in age, sex, history of inflammatory bowel disease, or PSC duration, but patients transplanted for CCA were less likely to have cirrhosis (60% vs. 86%, P=0.008). These data strongly support a metaplasia-low-grade dysplasia-high-grade dysplasia-carcinoma sequence in PSC-associated CCA, and underscore the known lack of relationship between patient age and PSC duration in the development of CCA. Even in the absence of CCA, bile duct dysplasia is still a relatively frequent finding, seen at least focally in 36% of benign end-stage PSC explants. Dysplasia, however, is generally confined to large and septal-size bile ducts and its presence may not be recognized unless multiple sections specifically targeted to the biliary tree are examined.

Intraductal papillary neoplasm of bile duct (IPNB) is one of the precursor lesions of cholangiocarcinoma. Although hepatolithiasis has been extensively studied in its association with IPNBs, there had been no comprehensive study of IPNBs with Clonorchis sinensis infection. Twelve IPNBs were selected from 20 surgically resected cholangiocarcinomas, positive for C. sinensis tests (60%) and compared with eight IPNBs, selected from 51 resected cholangiocarcinomas, negative for C. sinensis tests (16%), by histologic and immunohistochemical studies of mucin core proteins and cytokeratin panels. The predominant immuno-phenotype of IPNB cases with Clonorchiasis was pancreatobiliary type (MUC1+/MUC2-/CDX2-; 9/12 cases), while that of IPNB cases with negative for C. sinensis was intestinal type (MUC1-/MUC2+/CDX2+; 6/8; p = 0.04). The prevalence of IPNBs was higher when patients with cholangiocarcinoma had Clonorchiasis. IPNBs with Clonorchiasis tended to have a more pancreatobiliary phenotype, which suggests IPNBs with Clonorchiasis may have a different tumorigenesis pathway from IPNBs with other etiologies.