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Cardinale et al. Hepatoma Res 2018;4:20 I http://dx.doi.org/10.20517/2394-5079.2018.46 Page 7 of 16

epigenetic has been suggested by the demonstration of promoter hypermethylation in a handful of target genes
in a large cohort of iCCA (n = 102) associated with liver fluke infection .
[105]

CCA genetic susceptibility has been investigated in geographic areas where liver flukes are endemic. In these
studies, specific haplotypes of COX2-coding gene (PTGS2) or IL8RB have been recently associated with a
significant risk of CCA development .
[106]
As far as CCA emerging in PSC, different molecular signatures of the high oncogenic risk were described in
PSC patients. KRAS mutations were found in 30% of bile fluid of PSC patients without evidence of CCA .
[107]
Since KRAS mutations are frequently observed in CCA, and since the mutational profiling can be performed
in cell-free DNA of bile supernatant, this early mutagenic event into the bile duct carcinogenesis could be
evaluated for screening purposes in PSC patients . The inflammatory microenvironment has also been
[108]
associated with an aberrant DNA methylation profile in CCA emergence in PSC patients, which provides
survival signals for the tumor . Even, an inherited increase in the risk of CCA development in PSC patients
[109]
was demonstrated by studies concerning the natural killer cell receptor G2D receptor, where specific genetic
variants have been described in PSC patients .
[110]
Heterogeneity of molecular profile of CCA provides a demonstration of how somatic mutagenesis and epigenome
features are highly cell/lineage type-specific, and are largely driven by the pre-neoplastic tissue pathologic
milieu (see inflammation). Indeed, at a molecular level, distinct patterns of genetic mutations, methylation,
and expression profiling may differentiate iCCA from pCCA. iCCAs were significantly more frequently bcl-2+
and p16+, whereas pCCAs were more often p53+ . Miller et al. revealed 545 genes with altered expression
[112]
[111]
in p/dCCA and 2354 in iCCA. Mutations in IDH1 and IDH2 were found only in iCCA (n = 9), but in none
of the examined p/dCCA (n = 22) and gallbladder cancer (n = 75) . Recent papers confirmed liver fluke
[113]
negative iCCAs are enriched for IDH mutants [14,28] . A cross-platform comparison of iCCA with pancreatic
cancer and HCC further emphasizes the presence of distinct tumor subsets, suggesting similarities of the
IDH mutants CCAs with the HCCs rather than pancreatic cancers . Conversely, mutations in KRAS by
[28]
tumor site demonstrated predominance in pCCAs (53.3% of hilar vs. 6.7% of peripheral type) . As far as
[7]
epigenetic abnormalities are concerned, methylation of RASSF1A was more common in pCCA than in iCCA,
while the opposite was demonstrated for methylation of GSTP gene . Other reported alterations uniquely
[114]
associated with iCCA, comprised fibroblast growth factor receptor (FGFR) pathways and ephrin type-A
receptor 2 mutations .
[115]

Finally, the histopathological distinction of cholangiolocellular differentiation of iCCA has been correlated with
molecular features . iCCA with cholangiolocellular differentiation resembling an inflammation-related subtype
[115]
revealed less aggressive histopathological features compared to iCCA without cholangiolocellular differentiation
resembling a proliferation subtype. Accordingly, the former showed more favorable clinical outcomes, including
[116]
overall survival, than iCCA without cholangiolocellular differentiation . The emerging therapeutic approaches
based on the molecular targets in CCA have been recently reviewed by Rizvi and Gores .
[117]

VARIABLE CLINICAL PRESENTATIONS AND DIAGNOSTIC FEATURES
Clinical presentation of CCA is largely influenced by anatomic location and pattern of growth, which
ultimately belong from the cells of the origin. Accordingly, emerging concepts into CCA origins
demonstrated that it comprises at least two separate entities which a distinct histology, progression and
risk factors. These sub-types have been recently classified in large bile duct (mucinous) type CCAs and the
small bile ducts or mixed-CCAs. According to different observations, pCCAs are more likely associated
with pre-neoplastic lesions emerging in surface epithelium and PBGs . On the other hand, iCCAs show
[118]
[2,3]
inter-tumor heterogeneity leading to the classification into two main different histological subtypes [4,119] ,
with likely different cells of origin : the CCAs of the small bile ducts or mixed-CCAs and the large bile duct
[4]