Ruben R. Plentz, MD, PD , NisDepartment of Internal Medicine I, Medical UniversitGermany

Keywords:CholangiocarcinomaRisksStaging systemsSymptoms

tors like tumour size, location, regional lymph nodes, metastasis,

All rights reserved.

biliary cancer [1].- and extrahepatic

the bifurcation of the common duct [3]. Worldwide epidemiological data have shown an increasingincidence of CCA, most of the increase occurred after 1985, but the reasons for this are only poorly

* Corresponding author. Medizinische Universitatsklinik, Department of Internal Medicine I, Otfried-Mller-Str. 10, 72076Tbingen, Germany. Tel.: 49 7071 29 82701; fax: 49 7071 29 2095.

E-mail address: Ruben.Plentz@med.uni-tuebingen.de (R.R. Plentz).

Contents lists available at ScienceDirect

Best Practice & Research ClinicalGastroenterology

Best Practice & Research Clinical Gastroenterology 29 (2015) 245e252biliary tract system [2]. Hilar CCA are also called Klatskin tumour and they are located within 2 cm fromvascular involvement and tumour marker. 2015 Elsevier Ltd.

Cholangiocarcinoma (CCA) represents the second most common primary hepatoMost CCA tumours are adenocarcinomas arising from epithelial cells lining the intranon-specic tumour symptoms. For the staging of the diseasedifferent classications are available, which consider various fac-http://dx.doi.org/10.1016/j.bpg.2015.02.0011521-6918/ 2015 Elsevier Ltd. All rights reservedar P. Malek, MD, Prof.y Hospital, Otfried-Mller-Str. 10, 72076 Tbingen,

a b s t r a c t

Cholangiocarcinoma (CCA) is the second most common primaryliver tumour. Intra-hepatic CCA develops within the liver paren-chyma while extrahepatic CCA involves the biliary tree within thehepatoduodenal ligament. Hilar CCA are also called Klatskintumour. The CCA incidence has increased worldwide over the lastyears, but there are also geographic differences, with focus in Asiancountries. Known risk factors are primary sclerosing cholangitis(PSC), hepatolithiasis, Caroli's disease, hepatitis B and C infection,liver ukes, cirrhosis, diabetes, obesity, alcohol consumption andprobably tobacco smoking. Patients with early CCA have only littlediscomfort, but can later show episodes with jaundice and other*3

Clinical presentation, risk factors and stagingsystems of cholangiocarcinoma.

understood [4]. In the following section we would like to summarize in detail the leading clinicalsymptoms of patients with CCA, we will discuss possible risk factors and will give an overview aboutthe 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 thedisease patients with extrahepatic CCA develop jaundice. Often other non-specic symptoms likeweight loss, abdominal pain, night sweats, fatigue, emesis, vomiting, loss of appetite, pruritus andincrease 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 theworld, butnearly 70% of all cases are sporadic [7,8]. One of the most striking risk factors is primary sclerosingcholangitis (PSC) with or without ulcerative colitis (UC) [9]. PSC is an autoimmune disease which in-volves both the intra- and extrahepatic bile duct system [10]. PSC can cause bile duct strictures, di-latations and can develop malignancies of the bile duct system [9,10]. In populations based series thelife-time incidence to develop CCA ranges from 6 to 36% and the cumulative incidence is between 7 and14% [11e15]. In a prospective study by Rosen et al. 70 patients were recorded for 30monthswith PSC onaverage 42% of the autopsies and thus at least 7% of all patients developed a CCA [16]. Approximately50% of CCA are diagnosed within the rst year of diagnosis of PSC, but the CCA incidence decreases overtime [12,13,17]. PSC develops mainly tumours in the hilar area of the bile duct system [10]. CCAcomplicates PSC in ca.10% of all cases, possible risk factors for this subgroup are: high bilirubin, varicealbleeding, smoking, alcohol and inammatory bowel disease like ulcerative colitis (UC) or Crohn'sdisease (CD) [9,18]. It still remains unclear how the coexistence of inammatory bowel diseases withPSC increases the CCA risk compared to PSC alone. CCA occurred nearly twice as frequently in patientswith UC as in CD [17]. Interestingly, persistent biliary candidiasis in patients with PSC was recentlydiscovered as a new risk factor for CCA development [19]. However, further possible subgroup riskfactors 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 stronglyassociated with hepatolithiasis [7,20,21]. Hepatolithiasis are calculi or concretions often located at theconuence of the right and left hepatic ducts. Hepatolithiasis was found in 5e65% of patients withCCA, but they are rare in Western countries (incidence to 1.3%) [22,23]. The incidence of intrahepaticCCA in patients with hepatolithiasis is reported to be 4e11% [24]. CCA development is very likelycaused by chronic inammation of the bile duct system [25]. Studies from Korea and China showedsignicant associations between hepatolithiasis and intrahepatic CCA [26,27]. In addition, Asian pa-tients with hepatolithiasis are co-infected with parasites like Clonorchis sinensis and Ascaris lum-bricoides [28]. Liu et al showed that signicant risk factors for developing CCA in hepatolithiasis weresmoking, family history of cancer, appendectomy in childhood and duration of symptoms longer thanten years [29]. Also patients with gallstones have an increased risk to develop CCA. The risk ofextrahepatic CCA increases with the size of gallstones, calcication of epithelium and duration ofdisease [30]. An Italian study group described that, among 161 patients with hepatolithiasis, 23developed CCA during the observation period of 14 years [23]. Welzel et al showed a signicantassociation between choledocholithiasis, cholangitis and intrahepatic CCA development in a Danishpatient cohort [31]. However, this study did not exclude patients with PSC and therefore providesonly incomplete information.

Caroli's disease is a congenital disorder and was rst described 1958 and is characterized bysegmental communicating saccular dilation of the large intrahepatic bile ducts. Caroli's diseasegenerally starts with bacterial cholangitis and is associated with hepatolithiasis [32,33]. Caroli'sdisease must be distinguished from the Caroli-Syndrome. The latter is a combination of cystic bileduct disease with congenital hepatic brosis [34]. In a German cohort of 33 patients with Caroli'sdisease, CCA was detected in three patients [35]. A study from Argentina showed that one patient out

R.R. Plentz, N.P. Malek / Best Practice & Research Clinical Gastroenterology 29 (2015) 245e252246of 24 patients had CCA and Caroli's disease [36]. Besides these, other case reports with a signicant

R.R. Plentz, N.P. Malek / Best Practice & Research Clinical Gastroenterology 29 (2015) 245e252 247connection between Caroli's disease and CCA development have been published [37,38]. Additionallyother 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]. Forthis population the lifetime incidence is reported from 6 to 30% [39,40]. However, the total incidenceof CCA is much higher in Asian patients with bile-duct cysts [41e44]. In patients with bile-duct cyststhe incidence of CCA in the rst decade of their life and the risk of malignancy decreases after cystexcision [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 withintrahepatic and 4.2% in extrahepatic CCA [47]. The prevalence of HCV-ab was 20% in intrahepatic and7.4% in extrahepatic CCA [47]. Li et al found HbsAg to be a risk factor for intrahepatic CCA in a Chinesepatient population [55]. They detected serum total HBV DNA in 104 of 183 cryptogenic intrahepatic CCApatients (56.83%) using a diagnostic kit for the quantication of HBV DNA. The detection rate forintrahepatic total HBV DNA in cryptogenic ICC patients was signicantly higher than that in hepaticcavernous hemangioma patients with seronegative HBsAg (63.64% vs. 18.75%). Yin et al reported thatHCV RNA was isolated from ICC tissue using real-time polymerase chain reaction (RT-PCR) [8], whichsuggests a relationship between HCV infection and the development of ICC [56]. AlsoTao et al showed astrong association between HBV and development of intrahepatic CCA [57]. Wu et al postulated thatHBV-associated intrahepatic CCA should be distinguished from those without HBV infection [58]. Inthis context it is worth mentioning that cirrhosis of the liver is an independent risk factor regardless ofthe 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 correlatedwith 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 andintrahepatic CCA where HBV is endemic. Some evidence exists in support of a link between HBV andextrahepatic CCA in areas of high disease prevalence. In countries where HCV is more prevalent, evi-dence also supports a link with intrahepatic CCA, but this is less clear in Asia. There is a lack ofconsistent 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 whichare ingested by eating raw sh are the most important risk factors for CCA development [66]. Liverukes inhabit mainly the intra- and extra-hepatic bile ducts and are rarely found in the gallbladder andpancreatic duct. During the infection process, inammation of the epithelial cells and brosis arepredisposing 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 andscarring, which later become the most prominent feature in the chronic infection stage [68]. The studyby Parkin et al demonstrated that infectionwith the sh-borne trematodeO. viverrini increased the riskof CCC development ve-fold [69]. Studies from Korea and China conrmed infections with Clonorchissinensisas 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. sinensisincidence of the world [75]. In addition to liver uke infections, other cofactors like nitrosamineexposure contribute to the CCA carcinogenesis [76].

There are also associations reported between the former used radiographic contrast agentThorotrast and CCA development. The association between Thorotrast and CCA was best shown in alarge Japanese study [77], However, Thorotrast is not used anymore, but exposure to asbestos bresis discussed to be another toxic determinant [78]. Other possible risk factors are diabetes andobesity, but the reports are limited and some are even inconsistent [26,27,31,49,64,79]. Graingeet 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 anincreased risk in the study of Sorensen et al [81]. So far the inuence of tobacco smoking on CCAcarcinogenesis 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.

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 Klatskintumours 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 carci-noma (HCC), whichwill not be further discussed in this article. However, in daily practice there are onlya 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 onthe level and extension of the tumour invasion along the biliary tree [83]. In this system, CCA lesionsare 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 presentingany information about vascular encasement, lymph node involvement, and / or metastases. Paulet al found that the BCS classication had an accuracy rate below 50% for Type IIIA and IIIB tumours

R.R. Plentz, N.P. Malek / Best Practice & Research Clinical Gastroenterology 29 (2015) 245e252248[84]. Hence, the BCS staging system does not yield prognostic value and does not correlate with sur-vival. 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 thehistological classication [85]. T represents the primary tumour, N the regional lymph nodes andM themetastasis. 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 amacroscopic residual tumour. Additionally, the tumour grading (G) is expressed as G1 (well differen-tiated), 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 establishedfor preoperative classication. Studies reported that the TNM classication systemwas not associatedwith 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 ofportal vein invasion and hepatic lobar atrophy [87]. Compared to the other systems, MSKCC

Table 1Overview about perihilar CCA staging systems.

Staging systems BCS TNM MSKCC EHPBA MCS

Local spread X (X) X X (X)Tumour location/size X X X X XNumber of tumours XLymph nodes X X XMetastases X X XResidual tumour XPortal vein invasion X X XHepatic artery invasion X XHepatic lobar atrophy X XLiver size after surgery XUnderlying liver disease XECOG XCA19-9 X

Abbreviations: BCS: Bismuth-Corlette System; CCA: cholangiocarcinoma; EHPBA: Consensus classication from the EuropeanHepato-Pancreato-Biliary Association; TNM: Classication for Extrahepatic Bile Duct Tumours; MCS: Mayo Clinic Score; MSKCC:

Memorial Sloan Katering Cancer Center.

form. 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, theinvolvement of the hepatic artery and portal vein, as well as the involvement of lymph nodes, me-tastases, liver atrophy and the size of the putative remnant liver after surgery. This classication is alsonot 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 notfully 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 re-ects 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 markerCA19-9 and Eastern Cooperative Oncology Group (ECOG) status. All parameters are obtained preop-eratively at the time of diagnosis. The authors postulate that their score has excellent power to predictsurvival of patients. However, this score is also based on experience and data from a US single-centerand a validation cohort was missing due to low patients numbers.

Practice points

R.R. Plentz, N.P. Malek / Best Practice & Research Clinical Gastroenterology 29 (2015) 245e252 249Conict of interest

No conict of interest has been declared by the authors.

- 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.classication is useful for any preoperative staging and tries to predict resectability. The classicationdoes not consider information about nodal or distant metastases and/or involvement of the artery. Perpostoperative analysis the correlation between the T stages and resectability and survival is not uni-

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R.R. Plentz, N.P. Malek / Best Practice & Research Clinical Gastroenterology 29 (2015) 245e252252

Clinical presentation, risk factors and staging systems of cholangiocarcinomaClinical presentationRisk factorsStaging systemsBismuth-Corlette System (BCS)TNM classification for extrahepatic bile duct tumoursMSKCC (Memorial Sloan Katering Cancer Center) classificationConsensus classification from the European Hepato-Pancreato-Biliary Association (EHPBA)Mayo Clinic Score (MCS)

Conflict of interestReferences