Accepted Manuscript Clinical presentation, risk factors and staging systems of cholangiocarcinoma Ruben R. Plentz, MD, Nisar P. Malek

PII:

S1521-6918(15)00017-7

DOI:

10.1016/j.bpg.2015.02.001

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To appear in:

Best Practice & Research Clinical Gastroenterology

Received Date: 14 November 2014 Revised Date:

18 January 2015

Accepted Date: 7 February 2015

Please cite this article as: Plentz RR, Malek NP, Clinical presentation, risk factors and staging systems of cholangiocarcinoma, Best Practice & Research Clinical Gastroenterology (2015), doi: 10.1016/ j.bpg.2015.02.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Clinical presentation, risk factors and staging systems of cholangiocarcinoma

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Ruben R. Plentz*, Nisar P. Malek

Corresponding author:

Ruben R. Plentz, MD

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Department of Internal Medicine I, Medical University Hospital, Otfried-Müller-Str. 10, 72076 Tübingen, Germany

Medizinische Universitätsklinik, Department of Internal Medicine I

72076 Tübingen Germany Tel: +49-7071-29-82701

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Otfried-Müller-Str. 10

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Fax: +49-7071-29-2095

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Email: [email protected]

ACCEPTED MANUSCRIPT Cholangiocarcinoma (CCA) is the second most common primary liver tumor. Intrahepatic CCA develops within the liver parenchyma while extrahepatic CCA involves the biliary tree within the hepatoduodenal ligament. Hilar CCA are also called Klatskin

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tumor. 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

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and C infection, liver flukes, cirrhosis, diabetes, obesity, alcohol consumption and probably tobacco smoking. Patients with early CCA have only little discomfort, but

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can later show episodes with jaundice and other non-specific tumor symptoms. For the staging of the disease different classifications are available, which consider various factors like tumor size, location, regional lymph nodes, metastasis, vascular

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involvement and tumor marker.

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Keywords: Cholangiocarcinoma; Risks; Staging systems; Symptoms

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Cholangiocarcinoma

(CCA)

represents

the

second

most

common

primary

hepatobiliary cancer [1]. Most CCA tumors are adenocarcinomas arising from epithelial cells lining the intra- and extrahepatic biliary tract system [2]. Hilar CCA are

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also called Klatskin tumor and they are located within 2cm 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

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are only poorly 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

deadly disease.

Clinical presentation

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risk factors and will give an overview about the current staging systems for this

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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-specific symptoms like weight loss, abdominal pain, night sweats, fatigue,

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emesis, vomiting, loss of appetite, pruritus and increase of cholestasis related lab

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parameters (ALT, AST, GGT, Bilirubin) are recognized [5,6].

Risk factors

Many risk factors have been identified 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

ACCEPTED MANUSCRIPT incidence to develop CCA ranges from 6 – 36% and the cumulative incidence is between 7-14% [11-15]. 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

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within the first year of diagnosis of PSC, but the CCA incidence decreases over time [12,13,17]. PSC develops mainly tumors 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

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are: high bilirubin, variceal bleeding, smoking, alcohol and inflammatory bowel disease like ulcerative colitis (UC) or Crohn’s disease (CD) [9,18]. It still remains

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unclear how the coexistence of inflammatory 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].

not identified yet.

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However, further possible subgroup risk factors for PSC and CCA are still likely but

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More than 50 years ago it was also reported that intrahepatic CCA development is strongly associated with hepatolithiasis [20-22]. Hepatolithiasis are calculi or

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concretions often located at the confluence of the right and left hepatic ducts. Hepatolithiasis was found in 5-65% of patients with CCA, but they are rare in Western countries (incidence to 1,3%) [23,24]. The incidence of intrahepatic CCA in patients with hepatolithiasis is reported to be 4-11% [25]. CCA development is very likely caused by chronic inflammation of the bile duct system [26]. Studies from Korea and China showed significant associations between hepatolithiasis and intrahepatic CCA [27,28]. In addition, Asian patients with hepatolithiasis are co-infected with parasites like Clonorchis sinensis and Ascaris lumbricoides [29]. Liu et al showed that

ACCEPTED MANUSCRIPT significant risk factors for developing CCA in hepatolithiasis were smoking, family history of cancer, appendectomy in childhood and duration of symptoms longer than 10 years [30]. Also patients with gallstones have an increased risk to develop CCA. The risk of extrahepatic CCA increases with the size of gallstones, calcification of

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epithelium and duration of disease [31]. An Italian study group described that, among 161 patients with hepatolithiasis, 23 developed CCA during the observation period of 14

years

[24]. Welzel

et

al.

showed

a

significant

association

between

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choledocholithiasis, cholangitis and intrahepatic CCA development in a Danish patient cohort [32]. However, this study did not exclude patients with PSC and

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therefore provides only incomplete information.

Caroli´s disease is a congenital disorder and was first described 1958 and is characterized by segmental communicating saccular dilation of the large intrahepatic

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bile ducts. Caroli´s disease generally starts with bacterial cholangitis and is associated with hepatolithiasis [33,34]. Caroli's disease must be distinguished from the Caroli-Syndrome. The latter is a combination of cystic bile duct disease with

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congenital hepatic fibrosis [35]. In a German cohort of 33 patients with Caroli´s disease, CCA was detected in 3 patients [36]. A study from Argentina showed that 1

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patient out of 24 patients had CCA and Caroli's disease [37]. Besides these, other case reports with a significant connection between Caroli's disease and CCA development have been published [38, 39]. 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 [40]. For this population the lifetime incidence is reported from 6 to 30% [40,41]. However, the total incidence of CCA is much higher in Asian patients with bile-duct cysts [42-45]. In

ACCEPTED MANUSCRIPT patients with bile-duct cysts the incidence of CCA in the first decade of their life and the risk of malignancy decreases after cyst excision [42,43,45-47]. Other confirmed risk factors are virus infection with hepatitis B (HBV) and hepatitis C (HCV) [48] [49-55]. However, the contribution of hepatitis infection differs between

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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 [48]. The prevalence of HCV-ab was 20% in intrahepatic and 7.4%

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in extrahepatic CCA [48]. Li et al. found HbsAg to be a risk factor for intrahepatic CCA in a Chinese patient population [56]. They detected serum total HBV DNA in

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104 of 183 cryptogenic intrahepatic CCA patients (56.83%) using a diagnostic kit for the quantification of HBV DNA. The detection rate for intrahepatic total HBV DNA in cryptogenic ICC patients was significantly higher than that in hepatic cavernous hemangioma patients with seronegative HBsAg (63.64% vs. 18.75%). Yin et al.

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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 [57]. Also Tao et al showed a strong association

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between HBV and development of intrahepatic CCA [58]. Wu et al. postulated that HBV-associated intrahepatic CCA should be distinguished from those without HBV

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infection [59]. In this context it is worth mentioning that cirrhosis of the liver is an independent risk factor regardless of the underlying etiology. Some reports only see HBV or HCV as an independent risk factor [60-63]. Wang et al. detected HCV RNA in patients with intrahepatic CCA [64]. In general hepatitis is correlated with CCA development, even though some studies do not confirm a significant association [27,28,65]. 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

ACCEPTED MANUSCRIPT 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

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extrahepatic CCA. [66].

In Southeast Asia the parasite infestation with Opisthorchis viverrini and Clonorchis sinensis which are ingested by eating raw fish are the most important risk factors for

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CCA development [67]. Liver flukes inhabit mainly the intra- and extra-hepatic bile ducts and are rarely found in the gallbladder and pancreatic duct. During the infection

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process, inflammation of the epithelial cells and fibrosis are predisposing CCA factors [68]. In the chronic phase, when the parasites develop into the adult stage, hyperplasia and adenomatous formations of the bile duct epithelium lead to periductal fibrosis and scarring, which later become the most prominent feature in the

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chronic infection stage [69]. The study by Parkin et al. demonstrated that infection with the fish-borne trematode O. viverrini increased the risk of CCC development five-fold [70]. Studies from Korea and China confirmed infections with Clonorchis

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sinensisas a risk factor for CCA [71-74]. In Thailand, despite treatment strategies, the prevalence of O. viverrini reaches 70% in some areas [75]. Khon Kaen province in

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Thailand has the highest C. sinensis incidence of the world [76]. In addition to liver fluke infections, other cofactors like nitrosamine exposure contribute to the CCA carcinogenesis [77].

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 [78], However, Thorotrast is not used anymore, but exposure to asbestos fibers is discussed to be another toxic

ACCEPTED MANUSCRIPT determinant [79]. Other possible risk factors are diabetes and obesity, but the reports are limited and some are even inconsistent [27,28,32,50,65,80]. Grainge et al. showed a significant association between elevated body mass index and CCA development [81]. Alcohol is another risk factor for intra- and extrahepatic CCA.

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Patients with alcoholic cirrhosis had an increased risk in the study of Sorensen et al. [82]. So far the influence of tobacco smoking on CCA carcinogenesis is not fully studied yet and the findings are not consistent [28,50,65,80,81]. However, it is

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assumed that there are still other risk factors, which were not previously recognized

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or studied in detail yet.

Staging systems

CCAs can be anatomically staged in extrahepatic (80%) and intrahepatic (20%) tumors [83]. Extrahepatic CCA can be divided into perihilar cholangiocarcinomas,

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which are also called Klatskin tumors or distal tumors [83]. Besides that, intrahepatic tumors are again separated into nodular, periductal and intraductal tumors [83]. There are also cases of mixed CCA and hepatocellular carcinoma (HCC), which will

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not be further discussed in this article. However, in daily practice there are only a few

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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 tumor invasion along the biliary tree [84]. In this system, CCA lesions are classified in different types (I, II, IIIa, IIIb, IV) and considered mainly the local tumor growth. However, even though BCS is used worldwide, it also had several weak points. BCS is not presenting any information

ACCEPTED MANUSCRIPT about vascular encasement, lymph node involvement, and / or metastases. Paul et al. found that the BCS classification had an accuracy rate below 50% for Type IIIA and IIIB tumors [85]. Hence, the BCS staging system does not yield prognostic value

anatomical abnormalities like trifurcations.

TNM Classification for Extrahepatic Bile Duct Tumors

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and does not correlate with survival. BCS is also not useful for patients with

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The TNM classification system is based on the pathological findings and is also

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associated with the histological classification [86]. T represents the primary tumor, N the regional lymph nodes and M the metastasis. The TNM classification system also gives additional information about the residual tumor (R). R0 represents no residual tumor and R1 reflects a microscopic residual tumor and R2 denotes a macroscopic residual tumor. Additionally, the tumor grading (G) is expressed as G1 (well

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differentiated), G2 (moderately differentiated), G3 (poorly differentiated) and G4 (undifferentiated). Obviously, such a staging system is mainly used after surgical

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resection or transplantation and is not established for preoperative classification. Studies reported that the TNM classification system was not associated with the

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overall survival of patients with perihilar CCA undergoing surgery [87]. MSKCC (Memorial Sloan Katering Cancer Center) Classification This system is using three factors for the classification: local extension of the tumor, presence of portal vein invasion and hepatic lobar atrophy [88]. Compared to the other systems, MSKCC classification is useful for any preoperative staging and tries to predict resectability. The classification does not consider information about nodal or distant metastases and/or involvement of the artery. Per postoperative analysis the

ACCEPTED MANUSCRIPT correlation between the T stages and resectability and survival is not uniform. However, this classification is based on single-center data only. Consensus classification from the European Hepato-Pancreato-Biliary Association (EHPBA)

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In 2011 a group of experts published a new staging system for perhilar cholangiocarcinoma [89]. This new classification focused on the tumor size, the extent of the disease in the biliary system, the involvement of the hepatic artery and

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portal vein, as well as the involvement of lymph nodes, metastases, liver atrophy and the size of the putative remnant liver after surgery. This classification is also not used

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worldwide yet, but combines for the first 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

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confirmation.

Mayo Clinic Score (MCS)

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This score is based on the analysis of 413 patients with perihilar CCA [90]. The staging system reflects patient and tumor characteristics. Different parameters were

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analyzed and four tumor stages (I-IV) were built up by focusing on mass lesion, vascular encasement, metastasis, tumor 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.

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- CCA is the second most common primary liver tumor - The incidence of CCA is increasing worldwide

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Practice points

- Clinical symptoms often present late in the course of the disease

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- 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

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- 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

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Conflict of interest

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- Further standardized staging systems are required.

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No conflict of interest has been declared by the authors.

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ACCEPTED MANUSCRIPT Table 1: Overview about perihilar CCA staging systems MSKCC

EHPBA

MCS

X X

(X) X

X X

X X

(X) X X X X

X X X

RI PT

TNM

X X

X

X X X X X

SC

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

BCS

X

M AN U

Staging systems

X X

X X

AC C

EP

TE D

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

Clinical presentation, risk factors and staging systems of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is the second most common primary liver tumour. Intra-hepatic CCA develops within the liver parenchyma while extrahepatic CCA...
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