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Page 8 of 11 Muñoz-Martínez et al. Hepatoma Res 2022;8:30 https://dx.doi.org/10.20517/2394-5079.2022.22

population makes any attempt of surveillance no cost-effective. Only in those patients with cirrhosis,
[50]
surveillance of HCC by biannual US may allow incidental early iCCA diagnosis .
Infections with specific trematodes such as Opisthorchis viverrini and Clonorchis sinensis are a leading
[51]
cause of CCA in East and Southeast Asia . Infection can cause recurrent inflammation, leading to
disorders of the biliary system, including cholangitis, obstructive jaundice, hepatomegaly, fibrosis of the
[52]
periportal system, cholecystitis, and cholelithiasis . Given the high prevalence of liver fluke infection in
those regions, large-scale screening with stool examination for fluke ova supplemented with serological
assay for the diagnosis of opisthorchiasis and clonorchiasis coupled with abdominal ultrasonography or
other radiological imaging is performed [53,54] . Retrospective studies indicate that US-screening is an effective
tool for detecting early-stage, operable CCA in high incidence areas [53,54] , and when associated with
prevention of infection by educational campaigns and the use of medications (praziquantel) to treat liver
fluke infection, both measures can decerase incidence and mortality of CCA in highly prevalent areas [51,52] .

FUTURE PERSPECTIVES
Major efforts should be directed in identifying those patients at high risk of CCA. Although there are several
[55]
risk factors, most CCA cases remain sporadic . Only patients with PSC can be identified as a target
population for surveillance, but the actual risk of CCA development is not well-known, hindering the
recognition of those patients in whom the expected risk of CCA supports the surveillance recommendation.
In addition, major improvements need to be implemented in the current diagnostic tools. Although
MRI/MRCP is considered the best diagnostic imaging modality, distinguishing between malignant and
benign strictures is challenging. In recent years, artificial intelligence (AI) techniques applied to healthcare
[56]
are evolving and are used in many biomedical areas, in particular oncology . In the field of radiology, the
implementation of AI through machine-learning techniques has allowed the development of radiomics as a
new field of medical research. That said, radiomic studies in CCA are scarce and most of them include a
relatively small number of patients and lack from external validation. In addition, there has been little
standardization and generalization of radiomic findings, which limit the use of this methodology into the
clinical practice [57,58] . Finally, the differential diagnosis of DS is frequently challenging, and the current
techniques are invasive and impaired by low sensitivity. Liquid biopsy may become a reliable tool for
improving the diagnostic accuracy. Recently, a prospective study including patients with suspicious biliary
strictures (n = 68) showed that the mutational analysis of bile cell-free DNA (cfDNA) by next-generation
sequencing (NGS) in bile showed a sensitivity and specificity of 96.4% and 69.2%, respectively. More
interestingly, 22 out of 35 patients initially categorized as having a benign/indeterminate stricture were
finally diagnosed of malignancy during the follow-up and in them, the NGS assay showed a 100% sensitivity
[59]
for malignancy diagnosis . Validation studies including patients with PSC are eagerly awaited. Finally,
refinements in the selection of patients in whom liver transplantation may be effective and improvement
[60]
in the current medical therapy, with the implementation of targeted therapies [61,62] or immunotherapy will
[63]
change the outcome of this lethal disease.

DECLARATIONS
Authors’ contributions
Contributed on the conception of the manuscript, the data management organization, wrote the
manuscript, and gave the final approval of the manuscript: Forner A
Substantially contributed to the writing of the manuscript and gave the final approval before submission:
Muñoz-Martínez S, Rimola J, Londoño MC, Cárdenas A