Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic [iCCA], perihilar [pCCA], and distal [dCCA]) in a pan-European cohort. The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed. Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors. CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis remains dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality. This is, to date, the largest international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of cholangiocarcinoma has been investigated, comparing the 3 subtypes based on the latest International Classification of Diseases 11^th Edition (ICD-11) (i.e., intrahepatic [2C12], perihilar [2C18], or distal [2C15] affected bile ducts), which come into effect in 2022. General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, are presented and compared, outlining the current clinical state of cholangiocarcinoma in Europe.

Background and Aims: Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which pharmacological treatment options are currently unavailable. PSC is strongly associated with colitis and a disruption of the gut-liver axis, and macrophages are involved in the pathogenesis of PSC. However, how gut-liver interactions and specific macrophage populations contribute to PSC is incompletely understood. Approach and Results: We investigated the impact of cholestasis and colitis on the hepatic and colonic microenvironment, and performed an in-depth characterization of hepatic macrophage dynamics and function in models of concomitant cholangitis and colitis. Cholestasis-induced fibrosis was characterized by depletion of resident KCs, and enrichment of monocytes and monocyte-derived macrophages (MoMFs) in the liver. These MoMFs highly express triggering-receptor-expressed-on-myeloid-cells-2 (Trem2) and osteopontin (Spp1), markers assigned to hepatic bile duct-associated macrophages, and were enriched around the portal triad, which was confirmed in human PSC. Colitis induced monocyte/macrophage infiltration in the gut and liver, and enhanced cholestasis-induced MoMF-Trem2 and Spp1 upregulation, yet did not exacerbate liver fibrosis. Bone marrow chimeras showed that knockout of Spp1 in infiltrated MoMFs exacerbates inflammation in vivo and in vitro, while monoclonal antibody–mediated neutralization of SPP1 conferred protection in experimental PSC. In human PSC patients, serum osteopontin levels are elevated compared to control, and significantly increased in advanced stage PSC and might serve as a prognostic biomarker for liver transplant-free survival. Conclusions: Our data shed light on gut-liver axis perturbations and macrophage dynamics and function in PSC and highlight SPP1/OPN as a prognostic marker and future therapeutic target in PSC.

Background: Lymph node metastasis and positive resection margins have been reported to be major determinants of overall survival (OS) and poor recurrence-free survival (RFS) for patients who underwent resection for perihilar cholangiocarcinoma (pCCA). However, the prognostic value of positive lymph nodes independently from resection margin status on OS has not been evaluated. Methods: From the European Cholangiocarcinoma (ENSCCA) registry, patients who underwent resection for pCCA between 1994 and 2021 were included in this retrospective cohort study. The primary outcome was OS stratified for resection margin and lymph node status. The secondary outcome was recurrence-free survival. Results: A total of 325 patients from 11 different centers and six European countries were included. Of these, 194 (59.7%) patients had negative resection margins. In 113 (34.8%) patients, positive lymph nodes were found. Lymph node status, histological grade, and ECOG performance status were independent prognostic factors for survival. The median OS for N0R0, N0R1, N+R0, and N+R1 was 38, 30, 18, and 12 months, respectively (p < 0.001). Conclusion: These data indicate that in the presence of positive regional lymph nodes, resection margin status does not determine OS or RFS in patients with pCCA. Achieving negative margins in patients with positive nodes should not come at the expense of more extensive surgery and associated higher mortality.

Patients with primary sclerosing cholangitis (PSC) confer a high risk of cholangiocarcinoma (CCA). The molecular mechanisms of CCA development in PSC are incompletely understood, but pro‐oncogenic processes resulting from chronic biliary inflammation are presumably of central importance. Distinguishing benign from malignant biliary strictures in PSC patients is challenging and accurately diagnosing CCA in PSC often requires a multifaceted approach involving imaging, serological testing, biliary brush cytology and fluorescence in situ hybridization (FISH). Lack of early detection tools leads to a late diagnosis in the majority of cases. Surgical resection or liver transplantation represent the only curative intent treatments in PSC‐CCA, but is only an option for the small subset of patients where CCA is detected at an early stage. Current palliative treatment modalities result in only a modest increase in survival. Overall, PSC‐CCA carries a dismal prognosis with a 5‐year survival less than 20%. Advances aiming at improving strategies for early detection, treatment and surveillance of CCA will be essential to provide better future patient care for PSC patients. Herein, we review the pathogenetic mechanisms for PSC‐CCA as well as strategies for diagnosing and managing premalignant and malignant stages of CCA in PSC.

Cholangiocarcinoma (CCA) is a highly fatal malignancy of the bile ducts that arises in up to 20% of patients with primary sclerosing cholangitis (PSC). Current detection methods for CCA display suboptimal sensitivity and/or specificity, and there is no evidence-based screening strategy for CCA in patients with PSC. Consequently, CCA is often detected too late for surgical resection, contributing to the high mortality associated with this malignancy. Recently, biomarkers have emerged with potential to complement current detection methods, and/or be used for cancer surveillance in high-risk patient groups, including patients with PSC. Aberrant DNA methylation patterns represent promising biomarkers with great potential for CCA detection. Such aberrations are frequent in CCA, often occur early, and can be detected in liquid biopsies, including blood, bile and urine. This review summarises and highlights the most promising DNA methylation biomarkers identified for CCA detection so far, focusing on patients with PSC. Other promising molecular biomarkers for detection of PSC-associated CCA in liquid biopsies will also be briefly covered.

Data on the management of primary sclerosing cholangitis (PSC) in European expert centres are sparse. In this study, a PSC group from the ERN RARE-LIVER surveyed European hepatologists to uncover differences in real-life clinical practices. In April 2020 a survey questionnaire was sent to members of the International PSC Study Group and ERN RARE-LIVER. Participants were asked about the size of their PSC cohort, use of medical treatments including ursodeoxycholic acid (UDCA) and surveillance for cholangiocarcinoma, gallbladder polyps and inflammatory bowel disease (IBD). Data were presented descriptively. Eighty-two of 278 members responded. Fifty percent of physicians prescribed UDCA routinely to all their patients with PSC, whereas 12% never prescribed UDCA. UDCA was used for one or more indications including: alkaline phosphatase >1.5x the upper limit of normal, severe PSC changes, pruritus, PSC-IBD or patient demand. Few physicians offered other medical treatments than UDCA. The use of medical treatments was generally comparable in small (<99 patients) and large (≥99 patients) cohorts, as well as for adult and paediatric physicians. Most physicians routinely screened for cholangiocarcinoma and the most frequent modalities used were MRI and ultrasound. At detection of a gallbladder polyp of 6 mm, 46% of physicians recommended repeated ultrasound after 3-6 months, whereas 44% of physicians recommended immediate cholecystectomy. In patients with PSC without IBD at PSC diagnosis, 68% of physicians repeated colonoscopy within 3-5 years whereas 27% referred only patients who developed symptoms of IBD. Substantial variations in treatment and monitoring of European patients with PSC were discovered. Harmonisation of strategies is desirable to enable improved interpretation of outcome data and to optimise clinical patient care. In this study, we explored how different centres in Europe manage primary sclerosing cholangitis (PSC), a rare inflammatory disease of the bile ducts. We collected information through a questionnaire sent to specialist physicians who were part of a European network for rare liver diseases. We found several differences in how patients with PSC were monitored and treated. This includes differences in surveillance for bile duct cancer, gallbladder polyps and inflammatory bowel disease. By pointing out these differences, we hope that management of PSC will be standardized, which could aid clinical research and benefit patients.