Cholangiocarcinoma: Advances in pathogenesis, diagnosis, and treatment†

Abstract

Cholangiocarcinoma (CCA) is an epithelial cancer originating from the bile ducts with features of cholangiocyte differentiation.1 CCA is the second most common primary hepatic malignancy, and epidemiologic studies suggest its incidence is increasing in Western countries.2 Advanced CCA has a devastating prognosis, with a median survival of <24 months.3 The only curative therapy is surgical extirpation or liver transplantation, but unfortunately the majority of patients present with advanced stage disease, which is not amenable to surgical therapies. Anatomically, CCA is classified into extrahepatic and intrahepatic forms of the disease. The extrahepatic form is more common, accounting for 80% to 90% of CCAs. It is further divided into proximal or perihilar and distal subsets depending on the location of the cancer within the extrahepatic biliary system. Perihilar disease is also frequently referred to as a Klatskin tumor. Three different growth patterns of extrahepatic CCA can be observed: (1) periductal infiltrating, (2) papillary or intraductal, and (3) mass forming.4 Intrahepatic CCA typically presents as an intrahepatic mass. In addition to their distinct morphology and clinical presentations, intrahepatic and extrahepatic CCAs differ in etiopathogenesis, molecular signatures, and management. In the last several years there have been significant new insights into the molecular pathogenesis of CCA. New diagnostic and therapeutic modalities have also been developed, resulting in improved detection rates and outcomes. In addition, we have now entered the era of targeted therapies for human cancers. Therefore, it is timely and topical to review these advances with a focus on promising targeted therapies for this disease. An additional goal is to stimulate further interest in this disease with the hope of improving outcomes for this still highly lethal malignancy. Hepatobiliary malignancies account for 13% of the 7.6 million annual cancer-related deaths worldwide and for 3% of the 560,000 annual cancer-related deaths in the United States. CCA accounts for 10% to 20% of the deaths from hepatobiliary malignancies. The prevalence of CCA shows a wide geographic variability, with the highest rates in Asia and the lowest in Australia.5 In the United States, the incidence of CCA has been reported to be 0.95/100,000 for intrahepatic forms and 0.82/100,000 for extrahepatic forms of the disease.5 Its prevalence in different racial and ethnic groups is heterogeneously distributed, with the highest age-adjusted prevalence in Hispanics (1.22/100,000) and the lowest in African Americans (0.17-0.5/100,000).6 In the last 4 decades, United States incidence rates of intrahepatic CCA have increased by 165%, whereas the extrahepatic CCA incidence has remained stable.7, 8 The significant increase in age-adjusted incidence of intrahepatic CCA was confirmed after correction for a prior misclassification of hilar CCA as intrahepatic CCA.2 Similarly, increasing incidence rates of intrahepatic CCA have also been reported in Western Europe and Japan.9, 10 The cause for the increasing incidence has not been identified. We speculate that increased lipid mediators such as oxysterols may contribute to the current increased incidence in Western societies.11 In Western nations, the median age at presentation is >65 years, and it is only rarely diagnosed in patients <40 years of age except in patients with primary sclerosing cholangitis (PSC).5 There is a slight male predominance for CCA. CCA, cholangiocarcinoma; CT, computed tomography; DIA, digital image analysis; EGFR, epidermal growth factor receptor; ERCP, endoscopic retrograde cholangiopancreatography; FISH, fluorescence in situ hybridization; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; MAPK, mitogen-activated protein kinase; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; PDT, photodynamic therapy; PET, positron emission tomography; PSC, primary sclerosing cholangitis; PTC, percutaneous transhepatic cholangiography; RNOS, reactive nitrogen oxide species; TRAIL, tumor necrosis factor–related apoptosis-inducing ligand. In the majority of cases, the etiology of CCA remains obscure. However, several conditions associated with inflammation and cholestasis have been identified as risk factors for CCA (Table 1). PSC is a common risk factor. The prevalence of CCA in this condition is 5% to 15%, and the annual incidence rate is 0.6% to 1.5%.12, 13 The majority of PSC patients who develop CCA do so within the first 2.5 years following the diagnosis of PSC.12, 13 Thus, the symptomatic patient who presents with their first diagnosis of PSC should be carefully screened for CCA. Hepatobiliary flukes—especially the species Opisthorchis viverrini and Clonorchis sinenesis—are risk factors for CCA.14 They are endemic in portions of East Asia, where ingesting undercooked fish is common. Several case–control studies as well as animal models have confirme