Cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is a highly lethal adenocarcinoma of the hepatobiliary system, which can be classified as intrahepatic, perihilar and distal. Each anatomic subtype has distinct genetic aberrations, clinical presentations and therapeutic approaches. In endemic regions, liver fluke infection is associated with CCA, owing to the oncogenic effect of the associated chronic biliary tract inflammation. In other regions, CCA can be associated with chronic biliary tract inflammation owing to choledocholithiasis, cholelithiasis, or primary sclerosing cholangitis, but most CCAs have no identifiable cause. Administration of the anthelmintic drug praziquantel decreases the risk of CCA from liver flukes, but reinfection is common and future vaccination strategies may be more effective. Some patients with CCA are eligible for potentially curative surgical options, such as resection or liver transplantation. Genetic studies have provided new insights into the pathogenesis of CCA, and two aberrations that drive the pathogenesis of non-fluke-associated intrahepatic CCA, fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase gain-of-function mutations, can be therapeutically targeted. CCA is a highly desmoplastic cancer and targeting the tumour immune microenvironment might be a promising therapeutic approach. CCA remains a highly lethal disease and further scientific and clinical insights are needed to improve patient outcomes.

Fig. 1 |. Anatomic subtypes of CCA.

Cholangiocarcinoma (CCA) is best classified according to the primary, anatomic subtype as intrahepatic CCA (iCCA), perihilar CCA (pCCA) and distal CCA (dCCA). iCCA is located proximally to the second-order bile ducts within the liver parenchyma. pCCA is localized between the second-order bile ducts and the insertion of the cystic duct into the common bile duct. dCCA is confined to the common bile duct below the cystic duct insertion.

Fig. 2 |. Pathophysiology of liver-fluke infection and CCA.

a | Resected liver from a patient with cholangiocarcinoma (CCA) showing numerous adult Opisthorchis viverrini flukes (arrows) in the bile ducts (BD). A CCA tumour mass can be seen in the upper left part of the image. b | Transverse section of an O. viverrini fluke (Ov) attached via its oral sucker (S) to the bile duct epithelium (E) of an experimentally infected hamster. Cellular infiltrate in response to the feeding fluke is evident. c | Proliferating cholangiocytes in the biliary epithelium (BE) producing 8-oxo-deoxyguanosine (arrows, brown stain) as a marker of DNA damage in the bile duct of a hamster infected with an O. viverrini fluke (Ov). d | Uptake of O. viverrini-secreted extracellular vesicles (green dots) by human H69 primary cholangiocytes in culture. e | Thickened and disordered biliary epithelium (BE) in a hamster infected with wild-type O. viverrini flukes (Ov; left panel) compared with the BE in a hamster infected with O. viverrini in which Ov-grn-1, which encodes a secreted granulin-like growth factor, has been edited using CRISPR–Cas9 (right panel); editing of Ov-grn-1 has resulted in substantial reduction of biliary hyperplasia as highlighted by the square brackets. L, liver. Part a courtesy of B. Sripa, Khon Kaen University. Part b reprinted with permission from REF., Royal Society of Chemistry. Part d courtesy of S. Chaiyadet, Khon Kaen University. Part e reprinted from REF., CC BY 4.0.

Fig. 3 |. CCA cells gradually adopt invasive phenotypes to metastasize.

Several pathways are dysregulated to transform phenotypes and functions of cholangiocarcinoma (CCA) cells. Cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs) in the tumour microenvironment produce autocrine and paracrine signals that enhance CCA metastasis. The crosstalk between CCA cells, CAFs and TAMs progressively remodels the tumour stroma to facilitate invasion of tumour cells from the primary site to the secondary site. In addition, dysregulation of intracellular O-GlcNAcylation of proteins by adding or removing N-acetylglucosamine (GlcNAc) influences function, stability and localization of several proteins associated with metastasis. Modulation of extracellular glycosylation, for example, fucosylation and O-GalNAcylation of surface glycoproteins or secretory proteins, has an important role in enhancing the metastatic activity of CCA cells. ER, endoplasmic reticulum.

Fig. 4 |. Histological features of the desmoplastic microenvironment in human iCCA.

a | Masson trichrome staining of a moderately to poorly differentiated small duct type mass-forming intrahepatic cholangiocarcinoma (iCCA) largely comprising prominent desmoplastic stroma strongly stained for collagen (blue staining). Arrows point to representative small clusters of cholangiocarcinoma. b | The vast majority of cancer-associated fibroblasts (CAFs) accumulated within the desmoplastic stroma of CCA are strongly immunoreactive for α-smooth muscle actin (αSMA), a biomarker of myofibroblast differentiation, whereas cholangiocarcinoma cells (CC) do not show αSMA staining. c | Picrosirius red (PR) staining for collagen (orange staining under polarized light) typically reveals the extracellular matrix of desmoplastic CCA to consist of thick collagen fibres (predominantly comprising collagen type I). d | Immunostaining for matricellular periostin (POSTN), produced by αSMA⁺ CAFs, which has a binding site for collagen, is exclusively localized to the desmoplastic stroma of iCCA. It is now generally believed that αSMA⁺ CAFs in iCCA are principally derived from activated portal fibroblasts and hepatic stellate cells and are phenotypically and functionally heterogeneous. High expression levels of αSMA and POSTN, both of which are induced by transforming growth factor-β, have been associated with poor iCCA prognosis following surgical resection. Parts a–d, x33. Parts a, b and d reprinted with permission from REF., Elsevier.

Fig. 5 |. Screening for liver fluke infection and associated hepatobiliary disease including CCA.

a | Egg of Opisthorchis viverrini in human stool (egg dimensions 19–30 μm long and 10–20 μm wide). b | Suspected cholangiocarcinoma (CCA) imaged using abdominal sonography during community screening in liver fluke endemic regions of northeast Thailand; the ultrasonographic image shows a mass (green circle), calcification (thin arrow) and dilated intrahepatic duct (large arrow) c | Immunochromatographic device for the serodiagnosis of opisthorchiasis and clonorchiasis. Part a adapted from REF., CC BY 4.0. Part b reprinted with permission from REF., Elsevier. Part c reprinted with permission from REF., The American Journal of Tropical Medicine and Hygiene.