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Page 2 of 16 Cadamuro et al. Hepatoma Res 2022;8:11 https://dx.doi.org/10.20517/2394-5079.2021.140

[1,2]
to the area between the origin of the cystic duct and the ampulla of Vater . Despite recent progresses, the
prognosis of CCAs has not substantially improved and five-year survival remains very low (5%-20%) with
[3]
high post-surgical recurrence rates .

CCA incidence shows a strong geographical variation, ranging from 0.4:100,000 inhabitants in Canada to
85:100,000 in the northeast of Thailand . Furthermore, in the United States, distinct ethnic groups show
[3]
different incidences with higher rates among Asians and Hispanics (2.8:100,000 and 3.3:100,000,
respectively) and lower ones in Caucasians and African Americans (1.4:100,000 and 1.7:100,000) . The
[4]
most significant known risk factor for the development of CCA in East Asia is parasitic infestations of
Opisthorchis viverrini or Clonorchis sinensis. After their encystation in the biliary network, these parasites
[5]
cause chronic irritation, leading to neoplasm development . In Western countries, the most prominent risk
factor for CCA development is the primary sclerosing cholangitis (PSC) with an odds ratio (OR) of 164 (CI:
73.3-369, P < 0.001) . PSC is an inflammatory disease affecting both the intra- and extra-hepatic biliary
[6]
tract, causing inflammation of the biliary epithelium, periductal fibrosis, and biliary stenosis . Other
[5]
additional risk factors, particularly for iCCA, are HBV- and HCV-related cirrhosis, choledochal cysts,
cholelithiasis, type 2 diabetes mellitus, obesity, non-alcoholic fatty liver disease, smoking, and
hypertension . It is worth noting that all these conditions are associated with liver inflammation.
[7,8]

Genetically, CCA is a heterogeneous tumor. CCAs originating from large ducts show a high mutation
frequency of oncogenes and of tumor suppressor genes, such as Kirsten rat sarcoma virus (15%-30%) and
tumor protein P53 (TP53) (10%-40%) They may also harbor mutations of BRAF, BRCA1 associated protein
1 (BAP1), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), guanine
nucleotide binding protein GNAS, AT-rich interaction domain 1A (ARID1A), SMAD family member 4
(SMAD4), phosphatase and tensin homolog (PTEN), mouse double minute 2 homolog (MDM2), epidermal
growth factor receptor (EGFR), and Erb-B2 receptor tyrosine kinase 2 (ERBB2), among others.
Microsatellite instability is another prognostically and therapeutically relevant marker for CCA, as it has
been shown that tumors with deficiency of mismatch DNA repair mechanisms (e.g., those associated with
liver fluke infestation) are significantly more sensitive to immune checkpoint blockade . In contrast, small
[9]
duct type CCA exhibits a mass-forming growth pattern and exhibits isocitrate dehydrogenase 1/2 mutations
(10%-30%) and fibroblast growth factor receptor 2 (FGFR2) fusions (10%-25%), among others [10,11] .

REACTIVE TUMOR STROMA
Similar to other cancers, such as pancreatic or breast adenocarcinoma, CCA is characterized by an intense
desmoplastic reaction [tumor reactive stroma (TRS)] supported by a rich cellular microenvironment and by
modifications of the matrix composition. This tumor microenvironment (TME) has a structural
[2]
component, the extracellular matrix (ECM), and a cellular component with a plethora of infiltrating cells.
The matrix of the TME is significantly different from the normal one, in both quantity and quality. The TRS
within the tumor is in fact continuously modified by the interaction between neoplastic and infiltrating
cells. The cellular component of TME is variably composed of neoplastic epithelial cells, endothelial cells of
the blood and lymphatic vessels, cancer-associated fibroblasts (CAFs), and cells of the innate [tumor-
associated macrophages (TAM), tumor-associated neutrophils (TAN), dendritic cells (DC), natural killer
(NK), and myeloid-derived suppressor cells (MDSC)] and adaptive immunity [tumor-infiltrating
lymphocytes (TIL)] [12,13] [Figure 1]. The structural component provides a dense and rigid scaffolding, which
confers the characteristic desmoplasia to the tumor. This is composed of numerous and specific
extracellular matrix proteins (see below). It is believed that the stroma does not have a simple passive
function, but it actively participates in the intense communication between cells in the microenvironment
[2]
and supports these interactions [Figure 2] and could be the target of therapeutic interventions [Table 1] .