Primary Sclerosing Cholangitis as a Premalignant Biliary Tract Disease: Surveillance and Management

Abstract

Primary sclerosing cholangitis (PSC) is a premalignant biliary tract disease that confers a significant risk for the development of cholangiocarcinoma (CCA). The chronic biliary tract inflammation of PSC promotes pro-oncogenic processes such as cellular proliferation, induction of DNA damage, alterations of the extracellular matrix, and cholestasis. The diagnosis of malignancy in PSC can be challenging because inflammation-related changes in PSC may produce dominant biliary tract strictures mimicking CCA. Biomarkers such as detection of methylated genes in biliary specimens represent noninvasive techniques that may discriminate malignant biliary ductal changes from PSC strictures. However, conventional cytology and advanced cytologic techniques such as fluorescence in situ hybridization for polysomy remain the practice standard for diagnosing CCA in PSC. Curative treatment options of malignancy arising in PSC are limited. For a subset of patients selected by using stringent criteria, liver transplantation after neoadjuvant chemoradiation is a potential curative therapy. However, most patients have advanced malignancy at the time of diagnosis. Advances directed at identifying high-risk patients, early cancer detection, and development of chemopreventive strategies will be essential to better manage the cancer risk in this premalignant disease. A better understanding of dysplasia definition and especially its natural history is also needed in this disease. Herein, we review recent developments in our understanding of the risk factors, pathogenic mechanisms of PSC associated with CCA, as well as advances in early detection and therapies.

Keywords: Biliary Dysplasia; Chemoprevention; Interleukin-6; Perihilar Cholangiocarcinoma.

Figure 1. Imaging features of pCCA in PSC

(A) ERC image of a dominant common hepatic duct stricture (indicated by white arrow) in a PSC patient with periductal infiltrating pCCA. (B) MRI image of a perihilar mass (indicated by white arrow) with resultant biliary obstruction. ERC, endoscopic retrograde cholangiography; MRI, magnetic resonance imaging; PSC, primary sclerosing cholangitis; pCCA, perihilar cholangiocarcinoma.

Figure 2. Screening and Surveillance in CCA

Approach to cholangiocarcinoma screening and surveillance among adults with large duct primary sclerosing cholangitis. CCA, cholangiocarcinoma. Modified from Eaton et al. ^aNormal FISH, trisomy/tetrasomy are considered a negative FISH study. ^bIf FISH positive for polysomy, repeat ERC in 3–4 months and follow polysomy algorithm ^cEstimated proportion of patients with cancer 3 years after diagnosis of multifocal polysomy or serial polysomy was 83% and 75%, respectively Abbreviations: CCA (cholangiocarcinoma); FISH (fluorescence in situ hybridization); MRI (magnetic resonance imaging); MRC (magnetic resonance cholangiogram); ERC (endoscopic retrograde cholangiogram); UFP (unifocal polysomy); MFP (multifocal polysomy).

Figure 3

Criteria for Liver Transplantation in PSC Patients with pCCA.

Figure 4

Kaplan-Meier curve for overall survival in PSC patients with pCCA undergoing neoadjuvant chemoradiation followed by liver transplantation.