Morphomolecular Pathology and Genomic Insights into the Cells of Origin of Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma

Cholangiocarcinomas are a highly heterogeneous group of malignancies that, despite recent progress in the understanding of their molecular pathogenesis and clinical management, continue to pose a major challenge to public health. The traditional view posits that cholangiocarcinomas derive from the neoplastic transformation of cholangiocytes lining the biliary tree. However, increasing genetic and experimental evidence has recently pointed to a more complex, and nuanced, scenario for the potential cell of origin of cholangiocarcinomas. Hepatocytes as well as hepatic stem/progenitor cells are being considered as additional potential sources, depending on microenvironmental contexts, including liver injury. The hypothesis of potentially diverse cells of origin for cholangiocarcinoma, albeit controversial, is certainly not surprising given the plasticity of the cells populating the liver as well as the existence of liver cancer subtypes with mixed histologic and molecular features. This review carefully examines the current pathologic, genomic, and experimental evidence supporting the existence of multiple cells of origin of liver and biliary tract cancers, with particular focus on cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma.

Primary liver cancers (PLCs) represent a major health problem, with >900,000 new cases and 830,000 deaths annually worldwide.1 Liver cancer currently ranks among the top three causes of cancer death in 46 countries, and the number of new cases and deaths is expected to rise by 55% between 2020 and 2040, with a possible 1.4 million people diagnosed and a predicted 1.3 million deaths in 2040.

PLCs include hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), the most common forms, followed by combined hepatocellular-cholangiocarcinoma (HCC-CCA), a rare tumor that exhibits unequivocal or mixed phenotypical characteristics of both HCC and CCA.3 Although HCC and iCCA have traditionally been viewed as independent tumors deriving from hepatocytes and cholangiocytes, respectively, the existence of combined HCC-CCA has long suggested a more complex reality in which PLCs should be considered as a continuum spectrum of diseases, with HCC and iCCA at the extremities of such spectrum and a range of tumors in between showing variable degrees of HCC or iCCA differentiation. To complicate the scenario, CCAs can also affect the large bile ducts outside of the liver, the so-called extrahepatic CCA (eCCA), which includes both distal (dCCA) and perihilar (pCCA) CCA.

Despite some common features, all these liver and biliary tract cancers exhibit fundamental differences in epidemiology, risk factors, management, and prognosis. The differences are even more remarkable among CCA subtypes, with important inter-tumor and intra-tumor genetic and molecular heterogeneity that can affect both management and outcome. In this regard, the existence of two different stem cell niches (the canals of Hering and the peribiliary glands), which refurbish the intrahepatic and extrahepatic parenchyma,6–13 respectively, is suggestive evidence of a different cell of origin. Identifying the true tumor-initiating cells in CCA will not only help characterize the full heterogeneity of these tumors but also help understand the differences in response/resistance to treatment. Compelling genomic analyses of large human patient cohorts and in vivo lineage tracing studies in clinically relevant animal models have recently challenged the traditional view of HCC and iCCA deriving from hepatocytes and cholangiocytes; they also support the controversial hypothesis of multiple cells of origin. Despite recent advances, existing evidence is still insufficient to reach any conclusion, and the debate remains open. Herein, we provide an overview of the histologic and molecular differences across all liver and biliary tract cancers, and we carefully review what has been learned from precursor lesions in patients with CCA, lineage tracing studies in rodents, and the application of next-generation sequencing (NGS) technologies to human liver and biliary tract cancers.