Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Abstract

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.

Fig. 1. Anatomical classification of cholangiocarcinoma.

On the basis of the anatomical site of origin, cholangiocarcinoma (CCA) is classified into intrahepatic CCA (iCCA), perihilar CCA (pCCA) and distal CCA (dCCA). iCCA is defined as a malignancy located in the periphery of the second-order bile ducts, pCCA arises in the right and/or left hepatic duct and/or at their junction, and dCCA involves the common bile duct (that is, the choledochus). Grossly, CCA can show three main patterns of growth: mass-forming, periductal-infiltrating, and intraductal-growing. Mass-forming CCA is a mass lesion in the hepatic parenchyma. Periductal-infiltrating iCCA grows inside the duct wall and spreads longitudinally along the wall. Intraductal-growing CCA is a polypoid or papillary tumour growing towards the duct lumen.

Fig. 2. Mortality of cholangiocarcinoma worldwide.

Global age-standardized annual mortality rates for cholangiocarcinoma (CCA) (deaths per 100,000 inhabitants, including intrahepatic CCA, perihilar CCA and distal CCA) obtained from Bertuccio et al.. Data refer to the periods 2000–2004 (2002), 2005–2009 (2007) and 2010–2014 (2012). Yellow indicates countries/regions with low mortality (<2 deaths per 100,000 people), orange indicates countries/regions with mortality between 2 and 4 deaths per 100,000 people, and red indicates countries/regions with high mortality (>4 deaths per 100,000 people). Mortality in eastern countries/regions in which CCA is highly prevalent (that is, Thailand, China, Taiwan and South Korea) have not yet been reported and, therefore, CCA incidence is shown for these countries.

Fig. 3. Histological classification and putative cells of origin in cholangiocarcinoma.

Based on the duct size, the intrahepatic biliary tree can be further subdivided into small and large intrahepatic bile ducts (iBDs). Small iBDs are lined by small cuboidal cholangiocytes whereas columnar and mucous cholangiocytes line large iBDs. Typically, large iBDs contain peribiliary glands within their wall. The extrahepatic biliary tree shares anatomical features with large iBDs. Histological cholangiocarcinoma (CCA) variants reflect the phenotype of the involved duct and the putative cell of origin. Conventional intrahepatic CCA (iCCA) has two main variants: small duct-type iCCA arises in small iBDs with cuboidal cholangiocytes representing the putative cell of origin, and large duct-type iCCA involves large iBDs and is considered to be derived from columnar cholangiocytes and peribiliary glands (seromucous glands; mucous acini are shown in light pink, serous acini are shown in green). Cholangiolocarcinoma (CLC) is a frequent histological variant of iCCA and its phenotype suggests the origin from bile ductules or ductular reaction (DR) that occurs in chronic liver diseases. The vast majority of perihilar CCA (pCCA) and distal CCA (dCCA) are considered to originate from the lining epithelium and peribiliary glands. This histological subtyping underlies distinct clinicopathological and molecular features as summarized in Table 2. eBD, extrahepatic bile duct; HpSC, human pluripotent stem cell.

Fig. 4. Non-coding RNAs in cholangiocarcinoma and their relationship with different tumorigenic processes.

Non-coding RNAs (ncRNAs) that have been found to be dysregulated (up or down) in cholangiocarcinoma and that have key roles in the regulation of cellular processes, such as proliferation, cell cycle, ciliogenesis, epigenetics, inflammation, chemoresistance, survival, epithelial to mesenchymal transition (EMT), migration and invasion are shown.

Fig. 5. Signalling pathways involved in cholangiocarcinoma development and progression.

The process of cholangiocarcinogenesis, and further tumour evolution and growth, involves complex and heterogeneous processes that include the interplay of extracellular ligands (such as pro-inflammatory cytokines, growth factors and bile acids, among others), which are present in the tumour microenvironment, and increased expression and/or aberrant activation of cell surface receptors and the deregulation of intracellular signalling pathways, finally leading to cell proliferation, survival and migration or invasion. The most common genes that might be mutated or amplified resulting in the overactivation of some of these pathways are KRAS, BRAF, ARID1, PBRM1, BAP1, IDH1 and IDH2. The activation of these signalling pathways might also occur as a result of the interaction between the tumour epithelia and the tumour reactive stroma. 2-HG, 2-hydroxyglutarate; ECM, extracellular matrix; RTK, receptor tyrosine kinase.

Fig. 6. Central role of cancer-associated fibroblasts in promoting tumour growth and metastasis of cholangiocarcinoma.

Cancer-associated fibroblasts (CAFs) are recruited and persistently activated by cholangiocarcinoma (CCA) cells, in response to the effects of PDGF-D, and of FGF and TGFβ1, also released by tumour-associated macrophages (TAMs). In turn, CAFs enhance cell proliferation and the invasive ability of CCA cells directly, or by influencing the activity of other cells in the tumour microenvironment. CAFs stimulate tumour-associated lymphangiogenesis (lymphatic endothelial cell (LEC)), support M2 polarization of TAMs and the activation of regulatory T (T_reg) cells, while dampening the activity of CD8⁺ T cells, natural killer (NK) and dendritic cells. CAFs also induce heavy remodelling of the extracellular matrix (ECM), which becomes stiffer and affects mechanotransduction of CCA cells, leading to activation of intracellular pathways, including YAP–TAZ. Soluble factors mediating each cell–cell interplay are shown in boxes of different colours according to their origin (orange from CAFs, green from CCA cells, light blue from TAMs, red from ECM). Mediators in bold are those with proven effects, the rest are putative signalling molecules. CAF-derived short-range (Hedgehog (Hh)) and direct (NOTCH3) cell–cell developmental cues also underlie interactions with CCA cells (lower right corner).T_H2 cell, T helper 2 cell.

Fig. 7. Current decisions and management of patients with cholangiocarcinoma.

Flow chart of the presentation, management and outcome of patients with cholangiocarcinoma (CCA) according to current formal guidelines (Supplementary Table 1). BSC, best supportive care; CAR, chimeric antigen receptor; EBRT, external beam radiation therapy; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; FOLFOX, folinic acid, 5-fluorouracil and oxaliplatin; MMR, DNA mismatch repair; OS, overall survival; PFS, progression-free survival; RFS, relapse-free survival; SBRT, stereotactic body radiation therapy.

Fig. 8. Mechanisms of chemoresistance in cholangiocarcinoma.

Relevant genes and proteins involved in each type of mechanism of chemoresistance (MOC-1 to MOC-7) in cholangiocarcinoma (CCA) are shown, either because they are upregulated or downregulated or their function is enhanced or impaired. Drugs whose efficacy is affected by these changes in the resistome are shown. 5-FU, 5-fluorouracil; TKI, tyrosine-kinase inhibitor.