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liver condition characterized by inflammation of the biliary
epithelium lining the biliary tree (Rodrigues et al. 2018). This
inflammatory process in the bile ducts is also known as cholangitis. Chronic inflammation of the ducts leads to fibrosis and
stricturing of the bile ducts. During the disease arc, when the
inflammation settles, the lining of the epithelium develops
scarring which is the sclerosing aspect of the condition.
Blockage in the biliary tree can lead to infections and to the
accumulation of toxic bile acids. This repetitive disease process
increases the risk of GBCs and BTCs. PSC is strongly associated with inflammatory bowel disease, usually ulcerative colitis
(Banales et al. 2020). In Western countries PSC is the main risk
factor leading to CCA (incidence 10 per 100,000 people versus
1 per 100,000 in Eastern countries). PSC is more common in
men than in women, accounting for almost 66% of the cases,
and the mean age at diagnosis is 30–40 years (Song et al. 2020).
PSC patients have 150–400 times higher risk of BTC compared
to the general population (Tan et al. 2022). Patients who have
PSC-associated CCA are unsuitable candidates for surgical
resection due to the potential of multifocal severe disease causing severe hepatic dysfunction (Saffioti and Mavroeidis 2021).
Genetic Polymorphisms
Genome profiling of BTCs has given us a better understanding
of the carcinogenesis of these types of cancers and highlights
the importance of the genetic component in the multifactorial
pathogenesis of such complex heterogeneous diseases (Wardell
et al. 2018). Genomic sequencing of BTC tissue samples has
allowed the identification of somatic and germline drivers and
the pathogenic germline variants of cancer-predisposing genes
which allow clinicians to facilitate the classification of tumors
and determine treatment strategy (Clark et al. 2019). Results
from genomic sequencing showed that the most common
mutated genes were identified as TP53, KRAS, SMAD4, NF1,
ARID1A (chromatin remodeling), CDKN2A/B (cell cycle regu-
lator), PBRM1 (chromatin modulation), and ATR which were
related to poor outcomes regarding patient survival. FGFR2
fusions are almost exclusive to iCCA, which also features
IDH1/2 and BRAF substitutions, and MET amplifications with
a low KRAS mutational frequency. ERBB2 amplification and
PIK3CA/mTOR pathway aberrations are more frequent in
CCAs and GBC (Bekaii-Saab et al. 2021; Bridgewater et al.
2016).
Some new studies have highlighted that a novel deletion of
MUC17 at 7q22.1 has severely negatively impacted patients’
prognosis (Casadio et al. 2021). Sequencing methods have also
highlighted deleterious germline mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1, or
MSH2 in patients with BTC (Hu et al. 2018; Wardell et al.
2018). This highlights the importance of understanding the
marked heterogeneity of BTC and identifying it as a key factor
of the difficulty in the management of BTC Hence why the genetic findings can be useful in establishing diagnostic strategies
and targeted treatment for BTCs (Athauda et al. 2020).
Environmental and Lifestyle
Toxins
Certain biological and chemical toxins have been linked to the
pathogenesis of BTCs. Aflatoxin is a key toxin heavily associated with the development of cancers of the biliary system.
Aflatoxin is a mycotoxin produced by Aspergillus bacterium,
which is documented to often be located usually in warm,
humid regions and can be found in common food types
including cereals, nuts, milk, and certain meats (Benkerroum
2020). The hypothesis of aflatoxin in BTC carcinogenesis is
down to recurrent exposure of the metabolites of aflatoxin
stored within the bile and is in direct contact with the biliary
epithelium of the biliary system (Awuchi et al. 2022). A casecontrol study found significantly more circulating aflatoxin
metabolites in patients with GBC compared to population controls (OR: 13.0; 95% CI: 3.0–52.5) (Koshiol et al. 2017).
Ochratoxin A (OTA), is similar to aflatoxin and has also been
indicated in BTC pathogenesis (Heussner and Bingle 2015).
OTA is primarily produced by Penicillium and Aspergillus
bacteria, and is found in similar food types to aflatoxins. A
Japanese study established a link between a large proportion of
young patients (25–45 years) diagnosed with CCA (specifically
iCCA lesions originating in the large intrahepatic bile ducts) to
their employment in proof-printing plants (Kumagai et al.
2013). The causative link was due to their chronically high level
of exposure to organic solvents like dichloromethane (DCM)
and 1,2-dicholoropropane (1,2-DCP) used in the printing process. Patients presented with regional dilation of the bile ducts
and high serum γ-glutamyl transpeptidase activity (Kubo et al.
2018). Studies have also shown that exposure to toxins like
nitrosamines and other chemicals used in the rubber and dye
industries (including tetramethyl thiuram disulfide and zincdiethyldithiocarbamate) have been implicated in the
development of GBC and CCA (Gobbi et al. 2020).
Lifestyle
Diabetes, obesity, smoking, and alcohol consumption are
increasingly recognized as risk factors for BTCs, however with
some controversy as studies on their effects have been inconclusive (Baidoun et al. 2022; Makiuchi et al. 2019; McGee et al.
2019). Different studies have reported a positive association
between type II diabetes and iCCA as well as eCCA (Khan et al.
2019). It has been difficult to assess the specific contribution of
each factor with BTC, for example, among diabetes, obesity,
and gallstones, due to their strong intrinsic association.
Whether the potential association between diabetes and CCA
may be direct or mediated by other risk factors, such as obesity,
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chronic liver disease, or non-alcoholic fatty liver disease
(NAFLD), remains unclear.
Alcohol
Heavy drinkers (average alcohol consumption ≥ 50 grams
alcohol/day) have a marked increased risk of BTCs, as well as
cases of alcoholic cirrhosis, because they cause scarring, longlasting irritation of the biliary tissue, as well as formation of
gallstones (Kirstein and Vogel 2016; Makiuchi et al. 2019).
Alcohol consumption was only associated with iCCA. In a
study performed by McGee et al. ever, former, and current
smoking were associated with an increased risk for eCCA and
ampulla of Vater (e.g. current vs never smokers HR = 1.69, 95%
CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively)
(McGee et al. 2019). Current smoking and smoking intensity
were also associated with iCCA (>40 cigarettes per day vs never
smokers HR = 2.15, 95% CI = 1.15 to 4.00). The association
between smoking and GBC was not determinant. There was
high heterogeneity among the studies performed to study the
causal role of smoking and alcohol abuse in determining the
risk of BTC. Findings highlight the elevated heterogeneity
across BTCs and further studies are warranted.
Obesity
As observed for other GI malignancies, there is a positive
association between high body mass index (BMI; Obese BMI ≥
30 kg/m
still needs to be elucidated (Osataphan et al. 2021). Thus, the
role of obesity on BTCs remains controversial, particularly for
CCA. It seems to be a link with changes in microbiome composition, lipid levels, blood sugar, poor diet (e.g. elevated red and
processed meat intake, raw fish, low intake of fruits and vegetables), or inflammation (Wang et al. 2022). As for all cancers,
there is a correlation among age and BTCs. Although BTCs are
common in older age-groups, CCA risk increases after the age
of 45 and for GBC, age-specific incidence rates rise steeply
from age 50. However, the average is over the age of 65. Patients
aged ≥75 years had 5–10 times higher mortality rates than the
overall BTC rate in all countries.
2
) and elevated risk for BTCs, but the exact mechanism
Prevention
Prevention is pivotal in endemic regions for parasites and HBV.
Prevention of liver fluke infection includes health education
regarding food handling, cooking procedures, and consumption. For example, in northeast Thailand, the Lawa model (a
liver fluke control program), has been implemented to modify
food (raw fish) consumption (Brindley et al. 2021). It includes
reduction in raw fish consumption (which are part of the traditional culture), vaccination, antiviral therapies, as well as avoiding exposure to toxins and hazardous chemicals, or minimizing
smoking and alcohol consumption (Brindley et al. 2021).
Screening and Surveillance
Around 20–25% of iCCA are diagnosed incidentally (i.e. during surveillance of cirrhotic livers) (Alvaro et al. 2011). eCCAs
(distal or perihilar) on the other hand, remain undetectable
until advanced stages where biliary obstruction manifests as
jaundice – the most common form of presentation of this
tumor type. GBCs are often found incidentally following surgical removal of the gallbladder (García et al. 2020).
Surveillance is the optimal way in which clinicians are able to
identify any early signs of disease, including cancer, through
the means of repeated applications of investigations (blood
analysis, biomarker analysis, imaging etc.) in order to limit
patient mortality and to increase and improve patient survival
and outcome respectively (Vithayathil and Khan 2022).
However, principles for implementation of screening programs
require the condition to pose an important health issue with
high morbidity and mortality rates, adequate understanding of
its pathophysiology (development and course), a latency
period, and early symptoms which offer a window of opportunity for detection as well as substantial clinical benefit to those
diagnosed early. Moreover, target (at high-risk) cohorts should
be clearly defined, sufficiently accurate, and acceptable tests
which are cost effective for healthcare systems compared to the
expenditure incurred as part of its management, should be
available (Shieh et al. 2016). With respect to BTCs, these
requirements remain largely unmet. Considering a higher incidence in certain populations and their association with certain
conditions (PSC), identification of risk factors and cohorts in
which screening could potentially be performed is pivotal
(Muñoz-Martínez et al. 2022).
High-risk groups include patients with primary sclerosing
cholangitis (PSC), who have a 40 fold risk for HPB malignancies, an annual incidence of CCA estimated at 0.5–1.5%,
and a reported lifetime incidence of 20% (Card et al. 2008; Patel
2011).
Other large high-risk groups include patients who are from
endemic regions with liver flukes infestations (O. viverrini and
C. sinensis), and/or the consumption of under-cooked cyprinoid fish consumption, patients with recurrent cholangitis or
cholecystitis, and patients with significant occupational risk
factors (rubber and dyes industry, and agriculture and pesticide
use) (Brindley et al. 2021).
Patients with Occupational Risk
For screening and surveillance in patients with occupational
hazards for the development of biliary tract cancers, a study
determined that routine health checks with a number of blood
analysis including serum γ-glutamyl transpeptidase (γ-GT),
serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), carbohydrate antigen 19–9 (CA 19–9),
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and carcinoembryonic antigen (CEA) levels in tandem with
abdominal ultrasonography (USS) were beneficial for this
screening and surveillance process (Sombattheera et al. 2015).
In the presence and/or at the time of diagnosis of a biliary tract
malignancy, these serum factors increase. The abdominal
ultrasonography prior to confirmatory diagnosis often depicts
regions of biliary duct dilatation in the region of suspected
malignancy. This regional biliary duct dilatation is often due to
tumor-induced stenosis, parenchymal space-occupying lesions,
and/or an associated lymph node swelling causing regional
duct occlusion and proximal and/or distal biliary duct dilatation (Kubo et al. 2016).
Liver Fluke Endemic Regions
Endemic regions including northern Thailand and South-East
Asia have implemented large-scale screening and surveillance
for liver fluke infection and also biliary tract cancers. They have
introduced extensive testing of stool and blood samples, specifically investigating for fluke ova serological assay respectively,
attempting to the diagnosis of Opisthorchiasis and Clonorchiasis
infections (Siripongsakun et al. 2018). Screening initiatives in
this region have also coupled these tests with abdominal ultrasonography (USS) with follow up imaging (computed tomography (CT) or magnetic resonance imaging (MRI)) upon any
preliminary positive findings from surveillance, although USS
surveillance has shown to have positive benefits in areas highly
endemic for CCA by reducing CCA patient mortality, due to
high surveillance pick up-rate of premalignant lesions and
early-stage diseases (Olthof et al. 2016). A five-year populationbased study by Sungkasubun et al. implemented a six-monthly
screening program comprised of blood testing, stool examination, and serial abdominal USS. The study enrolled 4,255 eligible individuals within the first three years of the study and
BTCs were detected in 32 patients (mean age of 51.9 years (41–
62 years)). There were 21 out of 32 cases of BTCs, which were
detected at a curative resectable stage. The 1- and 2-year overall
survival rates of CCA patients were 90.9% and 61.5%, respectively. The screening programmed improved prognosis in these
resectable cases with 100% survival at 1-year and 77.8% survival
at 2-years. This highlights the fact that the surveillance and
detection of premalignant BTC lesions and/or early-stage
resectable CCA by USS resulted in improved clinical outcomes
(Sungkasubun et al. 2016).
have concomitant PSC (Rabiee and Silveira 2021). As described
prior, PSC tends to pre-dominantly affect the distal bile ducts
and also intrahepatic ducts, which is where we primarily see
biliary tract lesions, including CCA. With the increased risk
driving CCA development, it is imperative to establish appropriate surveillance strategies in asymptomatic PSC patient
cohorts (Fung et al. 2019). The combination of serological
assays and non-invasive surveillance imaging including CT,
USS, and/or MRCP (magnetic resonance imaging cholangiopancreatography) imaging techniques. MRI is often deemed a
superior modality compared to USS for surveillance and the
detection of early-stage perihilar CCA in patients with PSC
(Satiya et al. 2020). Upon high suspicion of malignancy, confirmatory diagnosis often requires invasive endoscopic procedures (cholangioscopy) with or without tissue sampling
(biopsy), or conventional cytology, or fluorescence in situ
hybridization (FISH) analysis (Figure 3). However in the event
of low pre-test probability for CCA (i.e. low to normal CA 19–9
levels, absent jaundice, and no recorded weight loss) these techniques and resultant biopsies can lack sensitivity and provide
indeterminate histopathological results (Rizvi et al. 2018).
Biomarkers
Diagnosis of biliary tract cancers relies on a combination of
clinical findings, imaging (ultrasonography, computerized
tomography, and magnetic resonance imaging), and serum
biomarkers (Macias et al. 2018, 2019). Confirmation by histopathology or cytology is often required, as the combination of
different techniques increases individual test diagnostic performances. While the diagnostic workup and management are
reviewed in Chapter 20 here we will discuss clinically applied
and novel biomarkers described in the diagnosis of BTCs.
Serum Biomarkers
Circulating biomarkers used in clinic to diagnose biliary tract
cancers are carbohydrate antigen 19–9 (CA19-9), carcinoembryonic antigen (CEA) and, in some cases, carbohydrate
antigen 125 (CA125). Despite their wide application, their
diagnostic accuracy remains suboptimal, and they are mostly
used for confirmation of diagnosis, monitoring of disease and
prediction of risk of tumor relapse (Banales et al. 2016;
Srivastava and Creek 2019).
Primary Sclerosing Cholangitis
Primary Sclerosing Cholangitis (PSC) is recognized as one of
the most important risk factors for CCA development, with an
increased lifetime incidence of 20% and ~ 500 fold increase in
the relative risk for developing CCA compared to the general
population. A high proportion (up to 50%) of CCA patients
CA19-9
CA19-9 (also known as Lewis Antigen A) is a sialylated tetrasaccharide found on the surface of cells. Under normal conditions, CA19-9 plays a role in cellular recognition, but it is also
found over-expressed in cancers of the biliary tract. CA19-9 is
the primary serological biomarker used in CCA and GBC diagnosis, with levels higher than 100 U/mL indicating the presence
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Figure 3 Cholangiocarcinoma surveillance algorithm is patients with Primary Sclerosing Cholangitis (PSC). MRI – Magnetic Resonance Imaging; MRCP –
Magnetic Resonance Cholangio-pancreatography; USS – Ultrasound Scan; EUS – Endoscopic Ultrasound; MDT – Multi-disciplinary Team.
of malignancy (Patel et al. 2000). The sensitivity and specificity
of this marker for the detection of CCA varies among studies
and groups of comparison, ranging between 50–80% and
40–70%, respectively, with increasing performance in late-stage
tumors (Khan et al. 2012). A study led by Levy showed that the
sensitivity and specificity of CA19-9 in a subgroup of CCA
patients with a background of PSC increased to 79 and 98% for
CCA diagnosis (Levy et al. 2005). Regarding GBC, the diagnostic accuracy of CA19-9 has not yet been validated (Li et al.
2019). Wang et al. reported a sensitivity and specificity of 71.7%
and 96.1% in differentiation of GBC patients from those with
benign disease and healthy individuals (Wang et al. 2014). In a
more recent study, CA19-9 has been proposed as a predictor of
resectability in GBC at a cut-off of 98.91 U/mL for R0 resection
(76.3% sensitivity and 70.8% specificity) (Liu et al. 2019).
One of the reasons for its limited diagnostic value is that
levels of CA19-9 are also raised in cases of benign biliary
obstruction (i.e., jaundice) and in patients with pancreatic cancer. Furthermore, it is important to take into consideration
during study design, and accuracy estimation, that around 7%
of the general population do not express one of the main precursors of CA19-9, the fucosyltransferase 3 (FUT3) (RahnemaiAzar et al. 2017). Lewis (A) negative patients do not show any
increase in the serum levels of CA19-9 even in the presence of
histologically confirmed cancer.
Carcino-Embryonic Antigen A (CEA)
CEA, a cell-surface anchored cell adhesion glycoprotein was
first described as a marker of colorectal cancer. CEA is found to
be elevated in serum (CEA > 5 ng/mL) of around 30% of
patients with biliary tract cancer (Fang et al. 2019). CEA is
highly expressed during fetal development but its levels in
adults are reduced to typically between 2–4 ng/mL. An increase
in CEA may also indicate presence of other cancers like
pancreatic or bowel cancer; or even some benign conditions
such as inflammatory bowel disease, cholangitis, hepatitis, or
cirrhosis (Rule et al. 1973).
Carbohydrate Antigen 125 (CA125)
CA125, also known as mucin (MUC) 16, is a glycoprotein
found in the epithelium of ovaries, cornea, and the respiratory
tract. First described as a biomarker of ovarian cancer, CA125
overexpression has also been linked to other types of cancers
including CCA (as well as pancreatic cancer). Although around
65% of patients with CCA express higher than normal levels of
CA125 (cut-off value of 37 U/mL), similarly to CEA, CA125 a
non-specific marker of BTCs as it is overexpressed by multiple
cancers (Felder et al. 2014). Abnormal serum levels of this
marker are observed in ovarian, breast, colorectal, pancreatic,
or lung cancers, and in some cases of cirrhosis (Moss et al.
2005).
Histological Biomarkers of BTCs
Histological diagnosis of BTCs involve immunohistochemistry
for specific markers as part of confirmation of site of tumor
origin. Cytokeratins (CK) 7 and 19 are epithelial structural proteins that are used in CCA diagnosis. CK7 and CK9 however,
are non-specific markers as they are also expressed by other
adenocarcinomas as well as by HCCs (Takahashi et al. 2021;
Yang et al. 2021).
One of the main challenges in the diagnosis of iCCAs is their
differentiation from poorly differentiated HCC. Applying a
combination of histological markers including hepatocyte
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paraffin 1 (HepPar-1), arginase-1 (Arg1), CD10, alpha-fetoprotein (AFP), and CEA is useful. In some cases, the expression
pattern of glutamine synthetase (GS), glypican 3 (GPC3), or
heat shock protein 70 (HSP70), are also informative. The epithelial cell adhesion molecule (EpCAM) was also considered
for the differentiation of HCC from iCCA but it also shows
expression in some poorly differentiated HCC and other carcinomas, limiting its diagnostic potential (Proca et al. 2000).
The current diagnosis of GBC is based on CK7 positive staining. Additionally, immunohistochemistry of HepPar-1 and
AFP can be performed in rare cases of hepatoid adenocarcinoma variant of GBC. Moreover, claudins, which are transmembrane proteins present in the tight junctions between
epithelial cells, have been proposed for the differential diagnosis of iCCA/eCCA and GBC, although their expression
pattern can be similar to PDAC, compromising its specificity
(Lodi et al. 2006).
Mucins, a group of highly glycosylated proteins secreted by
epithelial cells, can be analyzed during routine histological
staining of resected tumors, as they have been linked with
prognosis (Kasprzak and Adamek 2019). iCCA with highmucin content show shorter survival rates than low-mucin
content (Chi et al. 2018; Komuta et al. 2012). Similarly, Lu et al.
found that pCCAs with high mucin expression are indicative of
worse prognosis compared to low mucin expressing tumors
(Lu et al. 2019).
Emerging Biomarkers
The limited diagnostic accuracy of the circulating biomarkers
currently used in clinic (i.e. CA19-9, CEA, CA125) motivates
the search for novel non-invasive biomolecules with improved
sensitivity and specificity for BTCs. An evolving multi-omics
era (genomics, transcriptomics, proteomics, epigenomics, and
metabolomics), enabled the discovery of biomolecules which
can be obtained using minimally invasive techniques from a
variety of body fluids including serum, plasma, bile, or urine.
Although numerous reports of novel biomarkers have emerged
in recent years (Figure 4), a detailed review of the field is
beyond the scope of this chapter. Here we will discuss a few key
diagnostic and prognostic biomarkers for detection and prognosis of BTCs. Variations in circulating levels of nucleic acids,
proteins, metabolites, or even whole cells which are diagnostic
and/or prognostic in the context of BTCs, are increasingly
described.
Targeted next-generation sequencing (NGS) identifies mutations in CCA biopsies, enabling characterization of BTCs and
highlight potential therapeutic targets (Qin 2019). Studies have
shown these assays have been able to even decipher biological
causative links from the biopsies being tested (Lu and Zhan
2018). One study has described a profile of genes (7 overexpressed and 3 under expressed) in patients with Opisthorchis
viverrini-related CCA (Subrungruanga et al. 2013).
Circulating Tumor DNA (CtDNA)
ctDNA are small fragments of DNA (typically between 150–
200 base pairs) that are released into the bloodstream when
cancer cells undergo cell death (Chakrabarti et al. 2020). The
presence of ctDNA can also been detected in bile (Shen et al.
2019). They have proven to be of extraordinary value as they
are reflective of tumor size, aggressiveness, and of the mutational landscapes of primary tumors. The identification of
commonly mutated genes in BTC (i.e. KRAS, NRAS, BRAF,
and PIK3CA) is possible through their isolation and genomic
analysis (Andersen and Jakobsen 2016). ctDNA sampling can
be of potential interest in the diagnosis of BTCs, where adequate sampling of tissue from a heterogeneous tumor can be
challenging.
MicroRNAs (miRs)
Cell-free RNAs of small size or microRNAs (miRs) are also
abundant in body fluids (blood, bile, and urine). miRNAs act to
repress the target mRNA and as a result, are an important biomarker for diagnostic and prognostic purposes (Condrat et al.
2020). Studies have highlighted around 70 miRNAs that can
affect the genetic expression of genes that mediate signaling
pathways involving cell proliferation, cell exhaustion, cell
senescence, angiogenesis, evasion of the immune response, dissemination, and metastases (Rajasegaran et al. 2021). miRNAs
can be attained from liquid and solid biopsies and are relatively
easy to acquire and meta-analyses concluded that miRNAs
have a high diagnostic accuracy (Sun et al. 2018). miRs are
resistant to degradation and they can easily be detected by
RT-PCR at a low cost (Afonso et al. 2016). In two large metaanalysis, the diagnostic potential of miRs for biliary tract cancer detection was evaluated, reporting the highest performance
in bile (AUC = 0.950) (Liang et al. 2016; Zhou et al. 2017).
Serum miRs reached an AUC of 0.913 and urine miRs of 0.745,
highlighting the strong diagnostic potential of these biomolecules (Liang et al. 2016; Zhou et al. 2017).
There are a few miRNAs that are used in assessing patients
with suspected BTCs. miRNA-21 is an oncogenic miRNA that
is upregulated in a significant subset of cholangiocarcinoma
and is an accurate diagnostic biomarker (area under the curve
(AUC) of 0.89) (Wang et al. 2015). Wang et al. reported that
serum levels of miR-21 differentiated iCCA patients (n = 74)
from healthy controls (n = 74) with test performance (AUC) of
0.908 (Wang et al. 2015). Similarly, Correa-Gallego and collaborators reported an AUC of 0.940 for miR-21 (Correa-Gallego
et al. 2016). Silakit reported that the combined levels of miR-21
and miR-192 in urine differentiated CCA patients from healthy
controls (AUC of 0.849) (Silakit et al. 2017).
miR-412, miR-640, miR-1537, and miR-3189 had a high
accuracy to detect PSC-related CCA PSC disease and clinicians’ use of miRNA described above, in conjunction with
CA19-9 can lead to an accurate CCA diagnosis (Voigtländer et
al. 2015). Although promising, validation studies combining
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Figure 4 Evolving biomarkers for detection, prognostication, and surveillance of Biliary Tract Cancers (BTCs). An evolving multi-omics era (genomics,
transcriptomics, proteomics, epigenomics, and metabolomics), enabled the discovery of biomolecules which can be obtained using minimally invasive
techniques (Lang et al. 2021; Lin et al. 2021; Macias et al. 2019; Rahnemai-Azar et al. 2017).
information of large cohort of patients from different geographic locations are still needed before these markers can be
translated into the clinical practice.
bone tissue, has been proposed as a marker of CCA, being elevated in the serum of a cohort of 80 cancer cases compared to
healthy individuals (AUC = 0.964) (Loosen et al. 2017). The
pro-inflammatory cytokine interleukin 6 (IL-6), was found ele-
Proteins
Proteomic studies have identified some circulating proteins
with, potentially, better diagnostic value for BTCs than the ones
currently used in clinic. CYFRA 21–1, a soluble fragment of
CK19 was also found elevated in the serum of BTC patients
(n = 134) compared to benign biliary disease (n = 52), generating an AUC of 0.851 (Huang et al. 2015). The matrix metal-
vated in BTC cases versus healthy (AUC = 0.875), and making
it a promising marker for further analysis (Cheon et al. 2007).
CA242 (a sialylated carbohydrate antigen) showed great specificity for GBC (98.7%), performing better than CA19–9 and
CEA alone. The combination of this marker with CA19–9 and
CA125 reached a specificity of 100%, although it did not
improve its sensitivity (Rana et al. 2012).
loproteinase-7 (MMP7), an enzyme with a role of degradation
of components of the extracellular matrix, is also upregulated
in the blood of patients with CCA compared with benign biliary disease (AUC = 0.840) (Leelawat et al. 2010). Similarly,
osteopontin (OPN), a structural protein typically found in
Extracellular Vesicles (EVs)
EVs are heterogeneous lipid bilayer spheres released by cells as
part of inter-cellular communication processes. Within their
core, DNA, RNA, proteins, or metabolites are carried as cargo.
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EVs can be found in blood, bile, saliva, urine, and ascitic fluid,
and the number of EVs, cargo, and surface markers can correlate with the cell of origin, highlighting their potential for cancer detection (Lapitz et al. 2018). Arbelaiz and co-workers
analyzed the protein content of EVs isolated from the serum of
CCA patients (n = 43) (Arbelaiz et al. 2017). They found
increased levels of aminopeptidase N (AMPN), pantetheinase
(VNN1) and polymeric immunoglobulin receptor (PIGR)
compared to healthy controls (n = 32), with AUC ranging from
0.844 to 0.878. When they compared CCA with PSC cases (n =
30), the proteins with best performance were fibrinogen gamma
chain (FIBG, AUC = 0.796), alpha-1-acid glycoprotein
(A1AG1, AUC = 0.794) and protein S100A8 (AUC = 0.759).
A different study by Lapitz et al. looking into the RNA
content in serum EVs found a panel of 3 RNAs (i.e. CMIP,
NME1, CKS1B) with the best performance (AUC = 1.00)
when comparing CCA patients with a control group formed
by patients with PSC, UC, and healthy individuals (Lapitz et
al. 2020). The same group also reported that in urine, the
combination of two RNAs (UBE2C and SERPINB1) were able
to achieve an AUC of 0.812. However, the small nuclear RNA
RNU11 was the biomarker with single best performance in
urine EVs of the study (AUC = 0.830). Lastly, Li and collaborators described a panel of miRs present in bile EVs of CCA
(n = 46) patients compared to individuals with benign biliary
diseases (n = 50) (Li et al. 2014). The panel formed by miR191, -486-3p, -1274b, -16, and -484 was able to differentiate
the two groups with a specificity and sensitivity of 96% and
67% respectively.
Circulating Tumor Cells (CTCs)
Circulating tumor cells are cancer cells released to the bloodstream. They can be found at low concentrations in the blood
of cancer patients (> 10 cells/mL) and have recently been
studied for the detection of biliary tract cancers. In a large study
by Yang et al., CTCs were found in 26% of patients with BTC
using an enrichment platform based on the expression of
EpCAM marker on their surface (Yang et al. 2016). They
reported that CTCs correlated with prognosis especially in
metastatic cases, and also with overall survival. Moreover, these
cells can also be used to study the mutation pattern of the
source tumor and be able to select therapies for personalized
medicine.
• International protocols for screening and surveillance in
high-risk patients with pre-malignant cysts, genetic predisposition, and new-onset diabetes are under development yet screening for pancreatic cancer is mostly done in research settings.
• Patients over 50 years of age and diabetes of less than 1-year
duration have a high relative risk for pancreatic cancer. This
cohort represents an attractive target for screening in primary
care.
• High risk groups for BTCs include patients with primary
sclerosing cholangitis and subjects exposed to occupational
hazard or living in liver fluke (O. viverrini and C. sinensis)
endemic areas. The diagnosis of pancreatic and biliary tract cancers requires a multi-modal approach including clinical findings,
imaging and tumor marker levels yet the diagnostic performance
of clinically applied tests (such as CA19-9) is lacking. Similarly to
pancreatic cancer, CA19-9 is mostly used for confirmation of
diagnosis, monitoring of disease progression, and recurrence.
Areas for Further Research
• Screening of High-Risk individuals is beneficial yet requires
understanding of tumor biology, identification of target
cohorts, and the development of accurate and minimally invasive tests.
• Owing to advances in omics technologies, novel biomarkers
(proteins, miRs, circulating cell free DNA and tumor cells) and
panels for detection and prognostication of tumors, are increasingly reported. These, however, will require large scale validations prior to clinical implementation.
• Guidance and protocols for prevention, screening, and surveillance in high-risk cohorts for BTC is evolving.
Trusted Websites for Further Reading
Suggested resources for early detection and screening in
pancreatic and BTC:
• https://lctc.org.uk/affiliates/ukedi
• https://www.europactrial.com
• https://www.cancerresearchuk.org/about-cancer/find-a-clinical-
trial/a-study-looking-blood-urine-tissue-samples-help-diagnosepancreatric-cancer-neuroendo
crine-tumour-pancreas-adepts
• http://www.enscca.org
• https://ammf.org.uk/cca-uk
Key Take Home Messages
• The low five-year survival rates associated with pancreatic
and biliary tract cancers are explained by a most often nonspecific clinical course and late-stage diagnosis.
• Early tumor detection is key for improved outcomes. Due to
a low incidence and lifetime risk, and a relatively low
performance of current diagnostics, screening for pancreatic
cancer in the general population is not feasible.
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