New insights into cholangiocarcinoma: multiple stems and related cell lineages of origin

Abstract

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that may develop at any level of the biliary tree. CCA is currently classified into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) on the basis of its anatomical location. Notably, although these three CCA subtypes have common features, they also have important inter- and intra-tumor differences that can affect their pathogenesis and outcome. A unique feature of CCA is that it manifests in the hepatic parenchyma or large intrahepatic and extrahepatic bile ducts, furnished by two distinct stem cell niches: the canals of Hering and the peribiliary glands, respectively. The complexity of CCA pathogenesis highlights the need for a multidisciplinary, translational, and systemic approach to this malignancy. This review focuses on advances in the knowledge of CCA histomorphology, risk factors, molecular pathogenesis, and subsets of CCA.

Keywords: Cholangiocarcinoma; cells of origin; classifications; inflammation; molecular profiling; stem cells.

Figure 1

Worldwide incidence (cases/100,000) of cholangiocarcinoma (CCA). Data refer to the period 1971-2009. Green color identifies areas with lower incidence (<6/100,000 cases, rare cancer), while pink color indicates countries where CCA is not a rare cancer (>6/100,000 cases). Diagnoses have been classified according to the International Classification of Diseases (ICD-O-1, ICD-O-2, ICD-O-3, ICD-10, ICD-V9, ICD-V10, ICD-O). Where available, the more incident form (intrahepatic [IH] vs. extrahepatic [EH] CCA) and the temporal trend of incidence (↑increasing trend; ↕stable trend; ↓decreasing trend) have been reported Modified from Banales et al. Nat Rev Gastroenterol Hepatol [ref. 3].

Figure 2

Classification of cholangiocarcinoma based on cell lineages of origin. Based on the grade of maturation of the cell of origin within the two lineages, one constituted by the hepatic stem cells and non mucin-producing cuboidal cholangiocytes in Hering canals and bile ductules/interlobular bile ducts (see red points), the other constituted by peribiliary glands (PBGs) and surface epithelium of corresponding bile ducts (see blue points), our suggestion is that CCAs could be reclassified as: • primary liver parenchymal CCA comprising combined HCC-CCA, cholangiolo-carcinoma, and small-bile-duct type (mixed) CCA • primary biliary CCA comprising dCCA, pCCA, and large-bile-duct (mucinous) type iCCA Modified from Cardinale et al. [119].

Figure 3

We suggest a model of cholangiocarcinogenesis in which the interplay among the lineage of origin, the pathologic conditions, and the cell-etiopathology-specific somatic mutations and epigenetic modifications (+/- shared mutations) determines multiple patterns of cholangiocarcinogenesis

Figure 4

Origin and multilevel repercussions of the CCA heterogeneity. (A) The anatomical-functional heterogeneity of the biliary tree may explain the intertumoral heterogeneity observed at any level in CCA. Somatic mutagenesis and epigenetic features are cell/lineage type-specific, and largely driven by the preneoplastic tissue pathologic milieu (see inflammation). These are tissue-specific. Indeed, pathologic conditions targeting liver parenchyma are chronic hepatitis, nonalcoholic steatohepatitis, and primary biliary cholangitis, while pathologic conditions targeting the bile ducts are primary sclerosing cholangitis and liver flukes. (B) Cells arising from a hHpSC lineage (left) or from a biliary tree stem/progenitor cell (hBTSC) lineage (right) are considered cells of origin of different intrahepatic (i)- and perihilar (p)-cholangiocarcinoma (CCA) subtypes that were recently described. In the boxes, clinicopathological features, histology, gross and clinical features, associated diseases, management, prominent somatic mutations and candidate experimental models of the CCA subtypes arising within the two cell lineages are shown HCC, hepatocellular carcinoma; CLC, cholangiolo-carcinoma.