Malignancies in Primary Sclerosing Cholangitis - A Continuing Threat

Abstract

Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease of unknown etiology, primarily targeting cholangiocytes at any portion of the biliary tree. No effective medical treatments are currently available. A unique feature of PSC is its close association (about 80%) with inflammatory bowel disease (IBD), mainly ulcerative colitis (UC). As in many chronic inflammatory conditions, cancer development can complicate PSC, accounting for >40% of deaths. Cholangiocarcinoma (CCA), gallbladder carcinoma (GBC) and colorectal carcinoma (CRC) have been variably associated to PSC, with a prevalence up to 13-14%. The risk of cancer is one of the most challenging issues in the management of PSC; it raises several questions about cancer surveillance, early diagnosis, prevention and treatment. Key Messages: Among the different cancers complicating PSC, CCA is the most relevant, because it is more frequent (incidence of 0.5-1.5%) and because the prognosis is poor (5-year survival <10%). Early diagnosis of CCA in PSC can be difficult because lesions may not be evident in radiological studies. Surgical resection provides disappointing results; liver transplantation combined with neoadjuvant chemoradiotherapy is being proposed, but this approach is limited to a highly selected group of patients and is available only in a few specialized centers. Similar to CCA, GBC carries a dismal prognosis. Since it is difficult to discriminate GBC from other gallbladder abnormalities, cholecystectomy has been proposed in all gallbladder lesions detected in PSC, regardless of their size. CRC is a frequent complication of PSC associated to UC; its incidence steadily increases with time of colitis, reaching up to 20-30% of the patients after 20 years. Colonoscopy with extensive histologic sampling at an annual/biannual interval is an effective surveillance strategy. However, when dysplastic lesions are detected, preemptive proctocolectomy should be considered. Conclusions: PSC may be regarded as paradigmatic of the sequence leading from chronic inflammatory epithelial damage to neoplastic transformation. Understanding the molecular mechanisms regulating this pathogenetic sequence, may improve strategies of disease surveillance and cancer prevention and treatment. PSC is a chronic inflammatory cholangiopathy of unknown etiology but likely immune-mediated, characterized by peribiliary inflammation and fibrosis leading to strictures in any portion (intra- and/or extrahepatic) of the bile duct system. No effective medical treatments are currently available. A unique feature of PSC is the close association (about 80%) with IBD, mainly UC, often diagnosed before PSC (PSC/UC). As in other chronic inflammatory diseases, development of malignancies is a feared complication of PSC.

Primary Hepatic Adenosquamous Carcinoma Associated with Primary Sclerosing Cholangitis

“…As in many chronic inflammatory conditions, PSC may be complicated by cancer development, which accounts for >40% of deaths in patients with PSC [1,2,13] . Cholangiocarcinoma, gallbladder carcinoma, and colorectal carcinoma have been variably associated with PSC, with prevalences of up to 13-14% [14] . ASC is a rare subtype of cholangiocarcinoma with more aggressive clinical and pathological features than other cholangiocarcinomas, and the prognosis of patients with hepatic ASC is extremely poor.…”

An update on cancer risk and surveillance in primary sclerosing cholangitis

“…While high‐quality evidence is lacking for screening of CCA in this population, experts in this area agree with conditional recommendations in a variety of literature reviews and recently published American College of Gastroenterology (ACG) guidelines for PSC that screening should occur. A rational approach for screening PSC patients for CCA is interval radiological assessment with cross‐sectional imaging of the biliary tree with either US or MRI/MRCP in combination with CA 19‐9 every 6‐12 months . Patients who develop a dominant stricture on imaging should undergo ERCP with brush cytology, biopsies, and FISH for further evaluation of CCA .…”

Surveillance for cholangiocarcinoma in patients with primary sclerosing cholangitis: Effective and justified?

“…In addition, more than 30% of patients with PSC with CA 19‐9 ≥129 U/mL are free of cancer long term. CA 19‐9 utility will be influenced by the Lewis blood group phenotype (7% of the population is Lewis‐negative and has the undetectable CA 19‐9 level) and by allelic variants of fucosyltransferases 2 and 3 . Ultrasound sensitivity for CCA detection in PSC is very limited.…”

“…CA 19-9 utility will be influenced by the Lewis blood group phenotype (7% of the population is Lewis-negative and has the undetectable CA 19-9 level) 9 and by allelic variants of fucosyltransferases 2 and 3. 11 Ultrasound sensitivity for CCA detection in PSC is very limited. Traditionally, CCA was thought to be a slowly growing tumor, but its doubling time to guide surveillance intervals is unknown and difficult to define in patients with PSC who most often have non-massforming perihilar CCA.…”