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Page 2 of 5 Hou et al. Hepatoma Res 2023;9:35 https://dx.doi.org/10.20517/2394-5079.2023.40

INTRODUCTION
Intrahepatic cholangiocarcinoma (ICC) has emerged as a growing concern worldwide due to its increasing
incidence and high mortality rates over the past few decades. Intrahepatic lithiasis, primary sclerosing
cholangitis (PSC), chronic liver disease, congenital abnormalities of the bile ducts, parasite infection, and
[1]
toxic exposures have all been associated with an increased risk of ICC . However, the pathogenic factors
contributing to ICC differ significantly by region. PSC is prevalent in the West, while hepatitis B and
intrahepatic lithiasis (IHL) are more commonly implicated in the Asia Pacific region. It is important to note
that the clinical manifestations and prognosis of ICC can vary greatly depending on the underlying cause.
Recent evidence , coupled with our clinical experience, suggests that ICC caused by IHL (IHL-ICC) has
[2-4]
the worst prognosis due to the heterogeneity of tumors. Therefore, I would like to explore how to improve
the treatment of IHL-ICC here.

Pathogenic factors should be one of the important approaches in the classification of ICC
In all clinical practice guidelines for ICC , etiology is considered solely as a risk factor of ICC, rather than
[5-7]
a basis for classification. However, there are significant differences in clinical characteristics and prognosis
among ICC of various causes. For example, ICC caused by hepatitis B is predominantly of mass-forming
[8]
type, and its clinical manifestations are similar to hepatocellular carcinoma (HCC) , which rarely
metastasizes to the hilar lymph node. However, distinguished from HCC and ICC caused by hepatitis B, the
majority of ICC are prone to lymph node metastasis. Furthermore, the prognosis of IHL-ICC patients was
[2-4]
significantly worse than those of conventional ICC and HBV-ICC in many recent studies , including a
Chinese study of 448 ICC patients and a multi-institutional study . However, these are all retrospective
[3]
[2]
studies, and we need large-scale prospective cohort studies to further confirm the worse prognosis of IHL-
ICC and the possible causes.

Previous studies have shown that cholangiocytic differentiation can divide ICC into two types with different
etiologies, clinical manifestations, and molecular pathogeneses . Moreover, integrated systems biology,
[9]
which includes combinations of genomic, transcriptome, metabolome, protein, epigenetic, and
chromosomal analyses, has been recommended for classifying heterogenous ICC subtypes .
[10]
These pieces of evidence all show that the heterogeneity of ICC is highly significant. Therefore, I suggest
incorporating the factor of etiology into the classification of ICC.

To explore every possible avenue to improve the early diagnosis of IHL-ICC
As we all know, early diagnosis of tumors is crucial for improving their prognosis, especially for fatal tumors
such as ICC. Previous studies have reported that about 2.3% to 13.0% of hepatolithiasis patients eventually
[11]
developed cholangiocarcinoma . The progression of cholangitis to ICC is a long process, and detecting
IHL-ICC in its early stages is challenging. Liver enhancement imaging, serum carcinoembryonic antigen
(CEA), and cancer antigen 19-9 (CA 19-9) are commonly used to detect the cholangiocarcinoma in
hepatolithiasis patients. However, despite the use of Positron Emission Tomography (PET) imaging, the
preoperative diagnostic accuracy of IHL-ICC is still low, ranging from 30% to 65%, due to concomitant
chronic inflammation and necrosis caused by the presence of calculi. In my latest research , several
[11]
commonly used clinical indicators were screened by using machine learning algorithms. Clinical physicians
can conveniently use the tool to predict early IHL-ICC via a web page at http://www.bioinformatics.com.cn/
calculate_7_factor_nomogram_total_points_for_zeng. The accuracy of the tool in predicting ICC is more
than 82%. More research methodologies and specimens are being explored to uncover diagnostic indicators
for ICC, such as oncogenes, tumor-suppressor genes, microRNAs, DNA methylation, protein and metabolic
chemicals in bile, bile extracellular vesicles, and volatile organic compounds [12,13] . These new detection