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Page 2 of 11 Calderon Novoa et al. Hepatoma Res 2023;9:33 https://dx.doi.org/10.20517/2394-5079.2023.36

INTRODUCTION
Intrahepatic cholangiocarcinoma (iCCA) is a rare entity, corresponding to less than 5% of all
[1]
gastrointestinal malignancies worldwide . It accounts for approximately 10% of all hepatobiliary
malignancies, and its clinical course is quite distinct from hilar or distal cholangiocarcinoma (CCA). Its
[2]
usual presentation is that of a mass-forming tumor in 65% of cases , and other subtypes include periductal
[3,4]
infiltrating type and intraductal papillary infiltrating type . As of the latest AJCC edition, early iCCA is
considered to be < 5 cm with no vascular invasion, while that with vascular invasion of a larger size is
[3]
considered advanced . Global iCCA trends of incidence and mortality have been rising during the last
decades, as shown by numerous studies [5-13] . A 2019 study from 32 countries using World Health
Organization and Pan American Health Organization registries from 1995 to 2016 showed that mortality
from iCCA reached its peak from 2010 to 2014, with rates of 1.5-2.5/100.000 in men and 1.2-1.7/100.000 in
women . A recent analysis of the SEER database revealed an increase in the incidence of iCCA from 0,6
[10]
per 100.000 in the year 2000 to 1.3 per 100.000 in 2018 . This rise in incidence and mortality is explained
[13]
by several reasons, including diagnostic tool improvements, and a concomitant increase in risk factors
associated with iCCA, such as viral hepatitis, obesity and metabolic syndrome [9-13] , predominantly in
Western countries. Hepatitis B virus remains a significant risk factor for the development of iCCA. Several
meta-analyses consistently show that the pooled risk of developing iCCA in HBV patients is over three
times higher when compared to the HBV-negative population (HR 3.17-3.42) [14,15] . Other recent studies have
identified primary sclerosis cholangitis as a risk factor for iCCA, with as high as a 30-fold increase in the risk
of developing any type of CCA compared to the general population [16,17] . Most cases of iCCA are diagnosed
at advanced stages, with only 10 to 35% of patients being amenable to curative treatment upon
diagnosis [18,19] . Furthermore, only 5% of all patients are alive at 5 years , due to this tumor 's high
[20]
aggressiveness. Of those patients who are suitable candidates for liver resection (LR), 60% will relapse at 5
years, and only 10% of patients will be completely cured [20,21] .

The high number of patients diagnosed at advanced stages, and the considerable amount of reports showing
iCCA in liver specimens preoperatively interpreted as HCC show that correctly diagnosing iCCA remains
challenging, to say the least. It remains an unfrequent tumor, even in high-risk cohorts, such as patients
with liver disease, and non-invasive methods have discrete success rates. Conventional diagnosis of iCCA
relies primarily on imaging, such as US, computed tomography and magnetic resonance imaging, preferably
with contrast. Imaging features vary significantly between subtypes, and may present with either
hypoatenuation or hyperatenuation, perilesional bile duct dilation and infiltrative contour [22-25] . Recent
studies suggest morphologically distinct features for HBV-related iCCA such as capsule, frequent washout
pattern, smaller size and homogeneous tumor signals, and are usually characterized as LR-M in the
LI-RADS classification . However, due to the shared risk factors between HCC and iCCA and the context
[26]
[22]
of liver disease, the distinction between both entities may be a hardship .
CA 19-9 antigen, a commonly employed biomarker for biliary tract malignancies, has been reviewed in a
meta-analysis of 31 studies with over 3,100 individuals, having a sensitivity of 0.72 and a specificity of 0.84
for cholangiocarcinoma , and is not currently recommended for either screening or diagnosis. Micro-
[27]
RNAs have been presented as a promising tool as biomarkers in several cancers, including CCA, and several
[28]
studies have found the predictive value of different mi-RNA markers in iCCA, such as m6A . A meta-
analysis of 11 studies and 430 CCA revealed that mi-RNA had a pooled specificity of 91.4% and a
[29]
sensitivity of 75.6% with an AUC of 0.90 for the detection of CCA. However, mi-RNA assessment continues
to be limited by costs, sample collection, and applicability.