Cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is a highly lethal, epithelial cell malignancy that occurs anywhere along the biliary tree and/or within the hepatic parenchyma. CCA displays features of cholangiocyte differentiation and probably arises predominantly from the epithelial cells lining the bile ducts, which are termed cholangiocytes; however, the cancers may also develop from peribiliary glands and hepatocytes, depending on the underlying liver disease and location [1][2][3][4] . These cancers are heterogeneous and are best classified according to the primary, anatomic subtype as intrahepatic CCA (iCCA), perihilar CCA (pCCA) or distal CCA (dCCA) 5,6 (Fig. 1). 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, and dCCA is confined to the common bile duct below the cystic duct insertion. The true incidence of pCCA and iCCA is unclear owing to the extensive misclassification of pCCA as iCCA in national databases 6,7 . In addition, enhanced diagnostic capabilities have enabled increased clinical distinction between carcinoma of unknown primary and iCCA 8,9 . These factors have, in part, contributed to the reported increase in incidence of iCCA over the past two or three decades. Each of the anatomic subtypes is characterized by unique genetic aberrations, clinical presentations and management options 10 . However, many databases categorize both pCCA and dCCA as extrahepatic CCA. Most CCAs are adenocarcinomas and other histological subtypes, such as adenosquamous carcinoma or clear cell carcinoma, are encountered rarely 11 . These cancers are highly desmoplastic and are enmeshed in dense networks of inflammatory cells and matrix termed the tumour immune microenvironment [12][13][14] .The epidemiology of these cancers varies worldwide. Infections with specific trematodes (flatworm parasites, commonly called flukes) are a major cause of CCA in some regions. For example, in Southeast Asia, the liver fluke Opisthorchis viverrini is the leading cause of CCA 15 . CCA occurring secondary to fluke infestation can arise anywhere within the biliary tree and present as any one of the three anatomic subsets. Fluke-related CCA may have a specific pathogenesis, especially genetic aberrations, but the diagnosis and management are not different from non-fluke-related CCA. In the Western world, most patients with CCA do not have an identifiable risk factor, except for some with primary sclerosing cholangitis (PSC) 7,10 . Further insights into the epidemiology, risk factors and biology of CCA are needed to improve its prevention and therapy.In this Primer, we discuss the epidemiology and pathophysiological mechanisms of liver-fluke-related and non-liver-fluke-related CCA and associated risk factors and summarize diagnosis and management of C holangiocarcinoma

Knockout of liver fluke granulin, Ov-grn-1, impedes malignant transformation during chronic infection with Opisthorchis viverrini

“…The CCA tumors observed ranged in sizes from small neoplasms with multifocal distributions (10/24) to fully developed tumor masses visible to the unaided eye (14/24) (Figure 5). With respect to histological classification, 19 of 24 were of the tubular type (Brindley et al ., 2021). One papillary/cystic CCA was seen in the ΔOv-grn-1 group and as was the mucinous type CCA in one SCR- and three ΔOv-tsp-2 O. viverrini -infected hamsters.…”

“…Tumor protein p53 plays a well-recognized role in cholangiocarcinogenesis and is highly expressed in fluke infection associated CCA cells (Brindley et al ., 2021; Jusakul et al, 2017). Brown nuclear staining pattern presents only in neoplastic biliary cells (Figure 7C).…”

“…Cholangiocarcinoma (CCA) accounts for ∼15% of all primary liver cancers and its incidence rates are increasing (Banales et al, 2020). Infection with the foodborne liver fluke, Opisthorchis viverrini , is the principal risk factor for CCA in the Lower Mekong River Basin countries including Thailand and Laos PDR (Brindley et al ., 2021; Petney et al, 2013; Sripa et al ., 2007). In an earlier report, we exploited this link to explore the role of a growth factor, liver fluke granulin, Ov-GRN-1, secreted by the parasite in tumorigenesis using programmed gene knockout, and reported that the infection was less severe although gene-edited parasites colonized the biliary tract of hamsters and developed into adult flukes (Arunsan et al ., 2019).…”

“…Given the role of Ov -GRN-1 as a virulence factor in opisthorchiasis, interventions that target this growth factor might be beneficial. Indeed, antibodies raised against recombinant Ov -GRN-1 block its ability to drive proliferation of CCA cell lines (Smout et al ., 2009), and vaccination strategies that target Ov -GRN-1 in the GI tract, for example through induction of mucosal IgA and IgG responses (Chaiyarit et al, 2011; Phumrattanaprapin et al, 2021) should be explored, and might form a valuable component of a multivalent, orally administered, anti-infection and anti-cancer vaccine (Brindley et al ., 2021; Phumrattanaprapin et al ., 2021).…”

“…Indeed, the International Agency for Research on Cancer of the World Health Organization classifies infection with O. viverrini as a Group 1 carcinogen, i.e. definitely carcinogenic in humans (Brindley et al ., 2021; Brindley et al, 2015; IARC, 2012).…”