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Page 2 of 11 Muñoz-Martínez et al. Hepatoma Res 2022;8:30 https://dx.doi.org/10.20517/2394-5079.2022.22

INTRODUCTION
Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy after hepatocellular
carcinoma (HCC), comprising approximately 15% of all primary liver tumors and 3% of gastrointestinal
cancers. Its incidence has been increasing in the past decades worldwide, and despite significant
advancements in the knowledge of CCA mechanisms, diagnosis, and management, survival has not
[1,2]
substantially improved in the past decade .
Since CCAs are usually asymptomatic in early stages, the diagnosis is established when the disease is already
[3,4]
at advanced stages , which highly compromises treatment options, resulting in a dismal outcome.
Therefore, prevention and early diagnosis remain the cornerstone for improving the survival of this
devasting disease. Furthermore, identifying preventable risk factors and patients at risk of CCA are keys to
decreasing the disease-related mortality of this highly lethal neoplasia . In this review, we provide a
[2]
comprehensive and critical overview of the current knowledge and future directions for the early diagnosis
of CCA.

SURVEILLANCE IN CANCER: ANY CHANCE FOR CCA?
Surveillance in cancer is defined as the repeated application of a test over time with the aim of reducing
[5,6]
mortality from a disease . It is critical to tease apart between mortality (measured as the number of deaths
per unit of time) and survival (duration of life after the diagnosis of the disease). Decreasing cancer-related
mortality should be the sole objective of surveillance programs since survival is a surrogate endpoint that is
subject to multiple biases that do not impact mortality . The most common biases in studies evaluating the
[7]
efficacy of cancer surveillance are lead-time (refers to the phenomenon where early diagnosis of a disease
falsely makes it look like people are surviving longer), length bias (surveillance is more likely to detect slow-
growing cancers than rapidly growing cancers), and healthy-volunteer bias (those individuals willing to
participate in early detection efforts may be more attuned to health messages, more predisposed to adhere
to health providers’ recommendations and they may also be from a higher socioeconomic group and have
better access to quality healthcare). The ability of surveillance to detect the disease at an earlier stage is a
required outcome of surveillance programs, but the mere finding of early-stage disease is not sufficient as
proof of efficacy. In addition, treatment at an early stage should impact on survival in most patients.
Otherwise, its effect on mortality will not be evident.

The World Health Organization (WHO) has suggested some principles for recommending surveillance in
cancer [5,8,9] : The condition should be an important health problem with high mortality and/or morbidity,
there should be an accepted treatment for patients with recognized disease, treatment should be better at an
earlier stage, facilities for diagnosis and treatment should be available, there should be a recognizable latent
or early symptomatic stage, a suitable test or examination acceptable for the population should be available,
the natural history of the condition, including development from latent to declared disease, should be
adequately understood, the target population for surveillance should be clearly identified, the cost of case-
finding (including diagnosis and treatment of patients diagnosed) should be economically balanced, and
finally, case-finding should be a continuous process. Unfortunately, most of these criteria are not met in
CCA. Although several risk factors are linked to CCA, most CCA cases remain sporadic, without any
identifiable risk factor, limiting the applicability of any surveillance program. Only patients with primary
sclerosing cholangitis (PSC), the most well-known risk factor for CCA, can be identified as a target
population for surveillance since the cumulative incidence of CCA at 20 years is 20%-25% , and its
[10]
[11]
occurrence constitutes one of the most important causes of death in this population . Furthermore, the
natural history of the disease, including development from latent to declared disease, is not adequately
understood despite recent advancements in the knowledge of CCA mechanisms. In addition, recommended