Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.

Cholangiocarcinomas (CCAs) are hepatobiliary cancers with features of cholangiocyte differentiation; they can be classified anatomically as intrahepatic CCA (iCCA), perihilar CCA (pCCA), or distal CCA. These subtypes differ not only in their anatomic location, but in epidemiology, origin, etiology, pathogenesis, and treatment. The incidence and mortality of iCCA has been increasing over the past 3 decades, and only a low percentage of patients survive until 5 years after diagnosis. Geographic variations in the incidence of CCA are related to variations in risk factors. Changes in oncogene and inflammatory signaling pathways, as well as genetic and epigenetic alterations and chromosome aberrations, have been shown to contribute to the development of CCA. Furthermore, CCAs are surrounded by a dense stroma that contains many cancer-associated fibroblasts, which promotes their progression. We have gained a better understanding of the imaging characteristics of iCCAs and have developed advanced cytologic techniques to detect pCCAs. Patients with iCCAs usually are treated surgically, whereas liver transplantation after neoadjuvant chemoradiation is an option for a subset of patients with pCCAs. We review recent developments in our understanding of the epidemiology and pathogenesis of CCA, along with advances in classification, diagnosis, and treatment.