Best Practice & Research Clinical Gastroenterology 29 (2015) 245e252

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Gastroenterology

Clinical presentation, risk factors and staging

systems of cholangiocarcinoma
Ruben R. Plentz, MD, PD *, Nisar P. Malek, MD, Prof.
Department of Internal Medicine I, Medical University Hospital, Otfried-Mller-Str. 10, 72076 Tbingen,
Germany

a b s t r a c t
Keywords:
Cholangiocarcinoma
Risks
Staging systems
Symptoms

Cholangiocarcinoma (CCA) is the second most common primary

liver tumour. Intra-hepatic CCA develops within the liver parenchyma while extrahepatic CCA involves the biliary tree within the
hepatoduodenal ligament. Hilar CCA are also called Klatskin
tumour. The CCA incidence has increased worldwide over the last
years, but there are also geographic differences, with focus in Asian
countries. Known risk factors are primary sclerosing cholangitis
(PSC), hepatolithiasis, Caroli's disease, hepatitis B and C infection,
liver ukes, cirrhosis, diabetes, obesity, alcohol consumption and
probably tobacco smoking. Patients with early CCA have only little
discomfort, but can later show episodes with jaundice and other
non-specic tumour symptoms. For the staging of the disease
different classications are available, which consider various factors like tumour size, location, regional lymph nodes, metastasis,
vascular involvement and tumour marker.
2015 Elsevier Ltd. All rights reserved.

Cholangiocarcinoma (CCA) represents the second most common primary hepatobiliary cancer [1].
Most CCA tumours are adenocarcinomas arising from epithelial cells lining the intra- and extrahepatic
biliary tract system [2]. Hilar CCA are also called Klatskin tumour and they are located within 2 cm from
the bifurcation of the common duct [3]. Worldwide epidemiological data have shown an increasing
incidence of CCA, most of the increase occurred after 1985, but the reasons for this are only poorly

tsklinik, Department of Internal Medicine I, Otfried-Mller-Str. 10, 72076

* Corresponding author. Medizinische Universita
Tbingen, Germany. Tel.: 49 7071 29 82701; fax: 49 7071 29 2095.
E-mail address: Ruben.Plentz@med.uni-tuebingen.de (R.R. Plentz).

http://dx.doi.org/10.1016/j.bpg.2015.02.001
1521-6918/ 2015 Elsevier Ltd. All rights reserved.

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understood [4]. In the following section we would like to summarize in detail the leading clinical
symptoms of patients with CCA, we will discuss possible risk factors and will give an overview about
the current staging systems for this deadly disease.
Clinical presentation
Patients with early onset of CCA have no or no typical symptoms. However, during the course of the
disease patients with extrahepatic CCA develop jaundice. Often other non-specic symptoms like
weight loss, abdominal pain, night sweats, fatigue, emesis, vomiting, loss of appetite, pruritus and
increase of cholestasis related lab parameters (ALT, AST, GGT, Bilirubin) are recognized [5,6].
Risk factors
Many risk factors have been identied and they are quite variable in different areas of the world, but
nearly 70% of all cases are sporadic [7,8]. One of the most striking risk factors is primary sclerosing
cholangitis (PSC) with or without ulcerative colitis (UC) [9]. PSC is an autoimmune disease which involves both the intra- and extrahepatic bile duct system [10]. PSC can cause bile duct strictures, dilatations and can develop malignancies of the bile duct system [9,10]. In populations based series the
life-time incidence to develop CCA ranges from 6 to 36% and the cumulative incidence is between 7 and
14% [11e15]. In a prospective study by Rosen et al. 70 patients were recorded for 30 months with PSC on
average 42% of the autopsies and thus at least 7% of all patients developed a CCA [16]. Approximately
50% of CCA are diagnosed within the rst year of diagnosis of PSC, but the CCA incidence decreases over
time [12,13,17]. PSC develops mainly tumours in the hilar area of the bile duct system [10]. CCA
complicates PSC in ca. 10% of all cases, possible risk factors for this subgroup are: high bilirubin, variceal
bleeding, smoking, alcohol and inammatory bowel disease like ulcerative colitis (UC) or Crohn's
disease (CD) [9,18]. It still remains unclear how the coexistence of inammatory bowel diseases with
PSC increases the CCA risk compared to PSC alone. CCA occurred nearly twice as frequently in patients
with UC as in CD [17]. Interestingly, persistent biliary candidiasis in patients with PSC was recently
discovered as a new risk factor for CCA development [19]. However, further possible subgroup risk
factors for PSC and CCA are still likely but not identied yet.
More than 50 years ago it was also reported that intrahepatic CCA development is strongly
associated with hepatolithiasis [7,20,21]. Hepatolithiasis are calculi or concretions often located at the
conuence of the right and left hepatic ducts. Hepatolithiasis was found in 5e65% of patients with
CCA, but they are rare in Western countries (incidence to 1.3%) [22,23]. The incidence of intrahepatic
CCA in patients with hepatolithiasis is reported to be 4e11% [24]. CCA development is very likely
caused by chronic inammation of the bile duct system [25]. Studies from Korea and China showed
signicant associations between hepatolithiasis and intrahepatic CCA [26,27]. In addition, Asian patients with hepatolithiasis are co-infected with parasites like Clonorchis sinensis and Ascaris lumbricoides [28]. Liu et al showed that signicant risk factors for developing CCA in hepatolithiasis were
smoking, family history of cancer, appendectomy in childhood and duration of symptoms longer than
ten years [29]. Also patients with gallstones have an increased risk to develop CCA. The risk of
extrahepatic CCA increases with the size of gallstones, calcication of epithelium and duration of
disease [30]. An Italian study group described that, among 161 patients with hepatolithiasis, 23
developed CCA during the observation period of 14 years [23]. Welzel et al showed a signicant
association between choledocholithiasis, cholangitis and intrahepatic CCA development in a Danish
patient cohort [31]. However, this study did not exclude patients with PSC and therefore provides
only incomplete information.
Caroli's disease is a congenital disorder and was rst described 1958 and is characterized by
segmental communicating saccular dilation of the large intrahepatic bile ducts. Caroli's disease
generally starts with bacterial cholangitis and is associated with hepatolithiasis [32,33]. Caroli's
disease must be distinguished from the Caroli-Syndrome. The latter is a combination of cystic bile
duct disease with congenital hepatic brosis [34]. In a German cohort of 33 patients with Caroli's
disease, CCA was detected in three patients [35]. A study from Argentina showed that one patient out
of 24 patients had CCA and Caroli's disease [36]. Besides these, other case reports with a signicant

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247

connection between Caroli's disease and CCA development have been published [37,38]. Additionally
other bile-duct cysts are reported as a risk factor. Depending on their location (extrahepatic vs.
extrahepatic and intrahepatic) the cysts have increasing incidence of CCA transformation [39]. For
this population the lifetime incidence is reported from 6 to 30% [39,40]. However, the total incidence
of CCA is much higher in Asian patients with bile-duct cysts [41e44]. In patients with bile-duct cysts
the incidence of CCA in the rst decade of their life and the risk of malignancy decreases after cyst
excision [41,42,44e46].
Other conrmed risk factors are virus infection with hepatitis B (HBV) and hepatitis C (HCV)
[47e54]. However, the contribution of hepatitis infection differs between Western countries and Asia,
where HBV is endemic. Matsumoto et al found a seroprevalence of HbsAG of 10% in patients with
intrahepatic and 4.2% in extrahepatic CCA [47]. The prevalence of HCV-ab was 20% in intrahepatic and
7.4% in extrahepatic CCA [47]. Li et al found HbsAg to be a risk factor for intrahepatic CCA in a Chinese
patient population [55]. They detected serum total HBV DNA in 104 of 183 cryptogenic intrahepatic CCA
patients (56.83%) using a diagnostic kit for the quantication of HBV DNA. The detection rate for
intrahepatic total HBV DNA in cryptogenic ICC patients was signicantly higher than that in hepatic
cavernous hemangioma patients with seronegative HBsAg (63.64% vs. 18.75%). Yin et al reported that
HCV RNA was isolated from ICC tissue using real-time polymerase chain reaction (RT-PCR) [8], which
suggests a relationship between HCV infection and the development of ICC [56]. Also Tao et al showed a
strong association between HBV and development of intrahepatic CCA [57]. Wu et al postulated that
HBV-associated intrahepatic CCA should be distinguished from those without HBV infection [58]. In
this context it is worth mentioning that cirrhosis of the liver is an independent risk factor regardless of
the underlying aetiology. Some reports only see HBV or HCV as an independent risk factor [59e62].
Wang et al detected HCV RNA in patients with intrahepatic CCA [63]. In general hepatitis is correlated
with CCA development, even though some studies do not conrm a signicant association [26,27,64].
In summary, there is strong epidemiological evidence in support of an association between HBV and
intrahepatic CCA where HBV is endemic. Some evidence exists in support of a link between HBV and
extrahepatic CCA in areas of high disease prevalence. In countries where HCV is more prevalent, evidence also supports a link with intrahepatic CCA, but this is less clear in Asia. There is a lack of
consistent epidemiological evidence in support of an association between HCV and extrahepatic CCA
[65].
In Southeast Asia the parasite infestation with Opisthorchis viverrini and Clonorchis sinensis which
are ingested by eating raw sh are the most important risk factors for CCA development [66]. Liver
ukes inhabit mainly the intra- and extra-hepatic bile ducts and are rarely found in the gallbladder and
pancreatic duct. During the infection process, inammation of the epithelial cells and brosis are
predisposing CCA factors [67]. In the chronic phase, when the parasites develop into the adult stage,
hyperplasia and adenomatous formations of the bile duct epithelium lead to periductal brosis and
scarring, which later become the most prominent feature in the chronic infection stage [68]. The study
by Parkin et al demonstrated that infection with the sh-borne trematode O. viverrini increased the risk
of CCC development ve-fold [69]. Studies from Korea and China conrmed infections with Clonorchis
sinensisas a risk factor for CCA [70e73]. In Thailand, despite treatment strategies, the prevalence of O.
viverrini reaches 70% in some areas [74]. Khon Kaen province in Thailand has the highest C. sinensis
incidence of the world [75]. In addition to liver uke infections, other cofactors like nitrosamine
exposure contribute to the CCA carcinogenesis [76].
There are also associations reported between the former used radiographic contrast agent
Thorotrast and CCA development. The association between Thorotrast and CCA was best shown in a
large Japanese study [77], However, Thorotrast is not used anymore, but exposure to asbestos bres
is discussed to be another toxic determinant [78]. Other possible risk factors are diabetes and
obesity, but the reports are limited and some are even inconsistent [26,27,31,49,64,79]. Grainge
et al showed a signicant association between elevated body mass index and CCA development [80].
Alcohol is another risk factor for intra- and extrahepatic CCA. Patients with alcoholic cirrhosis had an
increased risk in the study of Sorensen et al [81]. So far the inuence of tobacco smoking on CCA
carcinogenesis is not fully studied yet and the ndings are not consistent [27,49,64,79,80]. However,
it is assumed that there are still other risk factors, which were not previously recognized or studied
in detail yet.

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Staging systems
CCAs can be anatomically staged in extrahepatic (80%) and intrahepatic (20%) tumours [82].
Extrahepatic CCA can be divided into perihilar cholangiocarcinomas, which are also called Klatskin
tumours or distal tumors [82]. Besides that, intrahepatic tumours are again separated into nodular,
periductal and intraductal tumours [82]. There are also cases of mixed CCA and hepatocellular carcinoma (HCC), which will not be further discussed in this article. However, in daily practice there are only
a few established staging systems for perihilar CCA available (Table 1).
Bismuth-Corlette System (BCS)
More than 30 years ago, Bismuth and Corlette launched a staging system for CCA, which focused on
the level and extension of the tumour invasion along the biliary tree [83]. In this system, CCA lesions
are classied in different types (I, II, IIIa, IIIb, IV) and considered mainly the local tumour growth.
However, even though BCS is used worldwide, it also had several weak points. BCS is not presenting
any information about vascular encasement, lymph node involvement, and / or metastases. Paul
et al found that the BCS classication had an accuracy rate below 50% for Type IIIA and IIIB tumours
[84]. Hence, the BCS staging system does not yield prognostic value and does not correlate with survival. BCS is also not useful for patients with anatomical abnormalities like trifurcations.
TNM classication for extrahepatic bile duct tumours
The TNM classication system is based on the pathological ndings and is also associated with the
histological classication [85]. T represents the primary tumour, N the regional lymph nodes and M the
metastasis. The TNM classication system also gives additional information about the residual tumour
(R). R0 represents no residual tumour and R1 reects a microscopic residual tumour and R2 denotes a
macroscopic residual tumour. Additionally, the tumour grading (G) is expressed as G1 (well differentiated), G2 (moderately differentiated), G3 (poorly differentiated) and G4 (undifferentiated). Obviously,
such a staging system is mainly used after surgical resection or transplantation and is not established
for preoperative classication. Studies reported that the TNM classication system was not associated
with the overall survival of patients with perihilar CCA undergoing surgery [86].
MSKCC (Memorial Sloan Katering Cancer Center) classication
This system is using three factors for the classication: local extension of the tumour, presence of
portal vein invasion and hepatic lobar atrophy [87]. Compared to the other systems, MSKCC
Table 1
Overview about perihilar CCA staging systems.
Staging systems

BCS

TNM

MSKCC

EHPBA

MCS

Local spread
Tumour location/size
Number of tumours
Lymph nodes
Metastases
Residual tumour
Portal vein invasion
Hepatic artery invasion
Hepatic lobar atrophy
Liver size after surgery
Underlying liver disease
ECOG
CA19-9

X
X

(X)
X

X
X

X
X

(X)
X
X
X
X

X
X
X

X
X
X
X

X
X
X
X
X

X
X

X
X

Abbreviations: BCS: Bismuth-Corlette System; CCA: cholangiocarcinoma; EHPBA: Consensus classication from the European
Hepato-Pancreato-Biliary Association; TNM: Classication for Extrahepatic Bile Duct Tumours; MCS: Mayo Clinic Score; MSKCC:
Memorial Sloan Katering Cancer Center.

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249

classication is useful for any preoperative staging and tries to predict resectability. The classication
does not consider information about nodal or distant metastases and/or involvement of the artery. Per
postoperative analysis the correlation between the T stages and resectability and survival is not uniform. However, this classication is based on single-center data only.
Consensus classication from the European Hepato-Pancreato-Biliary Association (EHPBA)
In 2011 a group of experts published a new staging system for perhilar cholangiocarcinoma [88].
This new classication focused on the tumour size, the extent of the disease in the biliary system, the
involvement of the hepatic artery and portal vein, as well as the involvement of lymph nodes, metastases, liver atrophy and the size of the putative remnant liver after surgery. This classication is also
not used worldwide yet, but combines for the rst time pre-, intra- and post-surgical evaluation.
Adversely, this staging system is somewhat complicated and some included prognostic factors are not
fully established yet and larger studies are necessary for conrmation.
Mayo Clinic Score (MCS)
This score is based on the analysis of 413 patients with perihilar CCA [89]. The staging system reects patient and tumour characteristics. Different parameters were analysed and four tumour stages
(IeIV) were built up by focussing on mass lesion, vascular encasement, metastasis, tumour marker
CA19-9 and Eastern Cooperative Oncology Group (ECOG) status. All parameters are obtained preoperatively at the time of diagnosis. The authors postulate that their score has excellent power to predict
survival of patients. However, this score is also based on experience and data from a US single-center
and a validation cohort was missing due to low patients numbers.

Practice points
-

CCA is the second most common primary liver tumour

The incidence of CCA is increasing worldwide
Clinical symptoms often present late in the course of the disease
70% of all CCA are sporadic; established risk factors are primary sclerosing cholangitis,
hepatolithiasis, Caroli's disease, hepatitis B and C infection, liver flukes, cirrhosis, diabetes,
obesity and alcohol
- Staging systems are limited

Research agenda
- Detailed studies are necessary to find and confirm new risk factors and to better understand
the increase of CCA
- Further standardized staging systems are required.

Conict of interest
No conict of interest has been declared by the authors.

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