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Muñoz-Martínez et al. Hepatoma Res 2022;8:30 https://dx.doi.org/10.20517/2394-5079.2022.22 Page 3 of 11

surveillance tests are expensive (which clearly impacts on cost-efficacy of any surveillance program
proposal), not widely available, and there is not a validated recall diagnostic strategy upon the suspicion of
[1]
CCA. Finally, only a few proportion of patients may benefit from potential curative therapies , which calls
into question the efficacy of any surveillance program.

PRIMARY SCLEROSING CHOLANGITIS AND CCA: AN OPPORTUNITY FOR
SURVEILLANCE
PSC is recognized as the most important risk factor for CCA development in Western countries. It is
associated with almost a 400-fold increased risk for developing CCA compared to the general population
with a 5.65% risk of developing CCA ten years from PSC diagnosis. Approximately 30%-50% of the patients
will have CCA at the time of PSC diagnosis or within the first year of diagnosis, and CCA is found to be
responsible for almost 30% of PSC-related deaths [12-14] . Anatomically, the majority of CCAs in PSC are
perihilar, though distal (below the cystic duct) or intrahepatic CCA (arising beyond second-order IHDs)
can also occur.

Available epidemiology data from previous studies regarding the PSC-CCA association are heterogeneous,
probably due to: (1) the low frequency of both diseases (PSC prevalence ranges from 0 to 16.2 per
[15]
100,000/inhabitants and CCA age‐standardized incidence rate per 100,000 inhabitants in Western
countries is 0.5-3 ); (2) delayed PSC diagnosis as many patients are asymptomatic for a long-term prior to
[16]
the diagnosis; (3) heterogeneity on the CCA detection time as patients with PSC might develop CCA more
than 4 to 6 years from PSC diagnosis [12,13] , 50% within the first year after PSC diagnosis and approximately
10% present with CCA at the time of PSC diagnosis ; and (4) analysis from previous studies pooling PSC
[17]
with other inflammatory liver diseases by the generic term of “cholangitis”. PSC is a cholestatic idiopathic
liver disease characterized by inflammation and progressive intra and extrahepatic biliary duct fibrosis, so
the term is correct, but other biliary tract diseases that mimic PSC (including IgG4-related cholangitis) can
be confounders. Accordingly, reliable data regarding the actual incidence of CCA in PSC and the risk
factors associated with its occurrence is scarce, which impacts on the design of an effective surveillance
strategy.

Furthermore, it is relevant to tease apart CCA surveillance aimed to achieve an early CCA diagnosis in
asymptomatic patients with PSC who may be potential candidates for curative treatments, from recall
diagnosis of CCA triggered from a change in clinical status, an elevation of biochemical parameters (for
example bilirubin or CA 19.9) or upon the detection of a highly suspicious lesion by an imaging technique,
events usually related to advanced CCA stages.

The scientific evidence supporting the efficacy of CCA surveillance in PSC is scarce. Although the incidence
of CCA is high in patients with PSC, surveillance strategies in asymptomatic patients are not universally
endorsed because of several diagnostic and therapeutic limitations. First, the incidence of CCA in
[18]
asymptomatic PSC patients may not be high enough for recommending surveillance in this population .
Second, diagnosis of CCA in PSC is quite challenging because CCA mimics inflammation-related dominant
biliary strictures. Third, confirmatory diagnosis requires invasive endoscopic procedures, and conventional
cytology or even sophisticated techniques such as fluorescence in situ hybridization (FISH) lack sensitivity.
Finally, potentially curative treatment is only feasible in a minority of cases, depending in part on the
availability of liver transplantation . Despite these limitations, retrospective studies, some of them
[2]
monocentric and including a limited number of patients , suggest that cancer-related mortality decreases
[19]
with surveillance [19-22] . While further prospective studies are warranted, despite the lack of evidence, some
scientific guidelines recommend surveillance for CCA in patients with PSC .
[20]