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Cholangiocarcinoma is the second most common primary hepatic malignancy after hepatocellular cancer. It accounts for approximately 10–25 % of all hepatobiliary malignancies. Hilar cholangiocarcinoma is identified based on anatomic location, but the epidemiology is typically aggregated with all cholangiocarcinomas. There are considerable geographic and demographic variations in the incidence of cholangiocarcinoma. These variations are related to risk factors, some of which are established (parasitic infections, primary sclerosing cholangitis, biliary-duct cysts, hepatolithiasis, toxins) and others that are less-established or potential risk factors (inflammatory bowel disease, hepatitis C virus, hepatitis B virus, cirrhosis, diabetes, obesity, alcohol, smoking, host genetic polymorphisms).

2.1 Introduction

Cholangiocarcinoma (CC) accounts for approximately 3 % of gastrointestinal tumors [1–3]. It is the second most common primary hepatic malignancy, representing 10–25 % of primary hepatic malignancies worldwide [1, 4, 5]. Hilar cholangiocarcinoma known as Klatskin tumors, are typically considered extrahepatic (ECC). They are frequently reported to comprise 40–60 % of all CC, but this estimate is derived from a limited number of hospital-based studies, with other hospital and population-based data suggesting a lower ­proportion of hilar cholangiocarcinomas (5–40 %) [2, 6–8].

There are no population-based studies examining the epidemiology of hilar CC specifically. The epidemiology of hilar CC in terms of incidence and risk factors is aggregated with the epidemiology of CC overall, intrahepatic (ICC) or extrahepatic [9–20].

CC rarely occurs before the age of 40; the typical age at presentation is in the seventh decade of life [3, 4]. There is a higher incidence of CC in men than women, with men to women ratios of 1: (1.2–1.5) [3, 4, 21–25]. The incidence of CC varies greatly by geographic region secondary to variations in risk factors among different regions [3, 5]. The prognosis of CC is poor and, therefore, the mortality and incidence rates are similar.

Population-based CC incidence data are sparse. Most cancer registries tend to combine cases of CC with other liver and biliary malignancies, such as hepatocellular carcinoma and gallbladder cancer [22, 24]. Worldwide the incidence of CC varies greatly (Fig. 2.1) [3, 24]. Thailand has the highest incidence of CC with 113 per 100,000 in men and 50 per 100,000 in women; while in western countries such as Australia the incidence is low at 0.2 per 100,000 in men and 0.1 per 100,000 in women [3, 5]. Differing exposure to risk factors is thought to account for the varying geographic incidences, with parasitic infections and hepatolithiasis being more prevalent in Asia [3, 5]. Studies of temporal trends reported increased incidence of ICC and decreased incidence of ECC [22, 24]. The role of misclassification and reclassification may be substantial as recent data from the United States (US) shows that the incidence of ICC has declined from 0.85 per 100,000 persons in 1995–1999 to 0.58 per 100,000 in 2000–2005, and that of ECC has increased from 0.82 per 100,000 persons in 1998 to 0.88 per 100,000 in 2000–2005 [21].

Fig. 2.1
figure 00021

(a) The age-adjusted incidence rates of cholangiocarcinoma (CC) in men in 20 different geographic regions. CC has been calculated as primary liver cancer that is not HCC. The frequency of cases is shown to the right of each bar. (b) The age-adjusted incidence rates of CC in women in 20 different geographic regions. CC has been calculated as primary liver cancer that is not HCC. The frequency of cases is shown to the right of each bar (Figures obtained from the 1997 publication of the International Agency for Cancer Research)

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Differences among studies, registries, and classification of ICC and ECC may account for some of the temporal variations observed in CC (ICC and ECC). For example, hilar cholangiocarcinoma was not given a unique code in Version 1 of the ICD-O (International Classification of Diseases for Oncology) (1973–1991); therefore, it could have been characterized topographically as ICC or ECC. In Version 2 of the ICD-O (1992–2000), hilar CC was given a unique histology code that could be linked to ICC rather than ECC. In Version 3 of the ICD-O (2001–present), the histological code for hilar CC could be linked to either ICC or ECC [26].

2.2 Risk Factors for Cholangiocarcinoma

The established risk factors include parasitic infections, biliary-duct cysts, primary sclerosing cholangitis, hepatolithiasis, and toxins. However, most patients do not have identifiable specific risk factors [1, 4]. Other less-­established, potential risk factors include inflammatory bowel disease (IBD), hepatitis C virus (HCV), hepatitis B virus (HBV), ­cirrhosis, diabetes, obesity, alcohol, smoking, and host genetic polymorphisms (Table 2.1). In studies where the distinction between ICC and ECC was used, some potential risk factors seem to have differential effect on CC depending on site. It is unclear how hilar CC factors into these considerations. It is therefore possible that the consistent use of a more refined classification would allow better understanding of risk ­factors for cholangiocarcinoma.

Table 2.1 Risk factors for cholangiocarcinoma
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2.2.1 Established Risk Factors for Cholangiocarcinoma

2.2.1.1 Parasitic Infections

The hepatobiliary flukes Opisthorchis viverrini (O. viverrini) and Clonorchis sinensis (C. sinensis) are associated with the development of CC irrespective of site, particularly in Southeast Asia. They are trematodes that inhabit the bile ducts and, occasionally, the gallbladder and pancreatic duct of mammals. Eggs laid by the adult worms are passed in feces, which may be ingested by snails, where they hatch and then mature into cercariae and subsequently penetrate the flesh of freshwater fish, where they develop into metacercariae. Infestation in humans occurs via ingestion of raw, pickled or undercooked fish [27, 28].

Both parasites increase the susceptibility of cholangiocytes to endogenous and exogenous carcinogens via chronic irritation and increased cellular turnover. Immunopathologic mechanisms, including inflammation and periductal fibrosis combined with proliferative responses, including epithelial hyperplasia, goblet-cell metaplasia, and adenomatous hyperplasia, may enhance susceptibility to carcinogens [27, 28].

One of the early epidemiological studies (1987–1988) to show a relationship between O. viverrini and CC was a hospital-based, case-control study conducted in Thailand in which 103 patients with CC were compared with an equal number of age- and sex-matched controls. A strong association was found between elevated O. viverrini antibody titers and increased risk of CC (OR 5.0; 95 % CI 2.3–11.0) [29]. A more recent (1999–2001) population-based, case-control study from Thailand compared 129 cases of CC with an equal number of age- and sex-matched controls. Elevated O. viverrini antibody levels were again strongly associated with CC (OR 27.09; CI 6.30–116.57) [30]. Based on this study, the population attributable risk due to O. viverrini was as high as 88 %.

A case-control study from Korea compared 41 patients with CC with 406 controls and reported a strong association between the presence of C. sinensis in the stool and CC (RR 2.7; 95 % CI 1.1–6.3) [31]. A subsequent meta-analysis pooled 912 cases and 4,909 controls and confirmed the strong association between C. sinensis and CC (OR 4.7; CI 2.2–9.8). In endemic areas, the population attributable risk based on this study was as high as 27.9 % for men and 16.2 % for women [18].

2.2.1.2 Biliary-Tract Disorders

2.2.1.2.1 Bile-Duct Cysts

Bile (choledochal)-duct cysts are rare congenital disorders characterized by cystic dilatation of the extrahepatic and/or intrahepatic bile ducts. There are several types of bile-duct cysts, which include the more commonly known choledochocele (extrahepatic biliary cyst) and Caroli’s disease (intrahepatic biliary cysts) [32].

Bile-duct cysts are an established risk factor for CC. It has been postulated that the reflux of pancreatic enzymes, bile stasis, and increased concentration of intraductal bile acids contribute to the formation of malignant cells in patients with bile-duct cysts [32]. The lifetime incidence of CC in these patients ranges from 6 to 30 % [4, 32]. The prevalence of bile-duct cysts is higher in Asian than Western countries [14, 32–35]. The incidence of CC is also higher in Asians with bile-duct cysts, at approximately 18 %, with the US incidence closer to 6 % [19, 33–36]. Patients with bile-duct cysts are reported to have at least 10- to 50-fold increased risk of developing CC compared with the general population [20, 32, 37]. There is an increase in incidence of CC in patients with ­bile-duct cysts from 0.7 % in the first decade of life to >14 % after the age of 20 [38]. The average age at malignancy detection has been reported to be 32 years, which is younger than the age at presentation of CC in the general population [32, 36]. The risk of malignancy decreases in patients undergoing complete choledochal cyst excision; however, these patients are still at a significantly increased risk of developing CC compared with the general population [14, 19, 32–34].

2.2.1.2.2 Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC), an autoimmune disease that results in stricturing of extrahepatic and/or intrahepatic bile ducts, is an established risk factor for CC. Chronic inflammation, proliferation of biliary epithelium, production of endogenous bile mutagens, and bile stasis are postulated mechanisms of carcinogenesis [2]. The lifetime incidence of CC among PSC patients ranges from 6 to 36 % [39, 40]. Although PSC is known to be a strong risk factor for CC, no more than 10 % of CC is attributed to PSC [40].

A hospital-based, retrospective cohort study from the Mayo Clinic followed 161 patients with PSC for a median of 11.5 years; 11 patients (6.8 %) developed CC with an incidence rate of 0.6 % per year. The median time from diagnosis of PSC to diagnosis of CC was 4.1 years (range 0.8–15.0 years), and no association was found between the duration of PSC and the risk of CC [41]. Another hospital-based, retrospective cohort from the Netherlands followed 211 patients with PSC for a median of 9 years; 15 patients (7 %) developed CC with a 10 and 20 year incidence of 7 %. Again there was no association between duration of PSC and the risk of CC; nearly all the cases of CC presented within 3 years of PSC diagnosis [39]. It is unclear whether duration of PSC or underlying IBD correlates with the risk of developing CC, in fact most cases present relatively soon after PSC diagnosis. Cohort studies suggest that CC develops within the first 1–2 years of PSC diagnosis. A European cohort study found that 48 of 394 (12.2 %) PSC patients developed CC, with 24 (50 %) of them being diagnosed within 1 year of the diagnosis of PSC [42]. In a Swedish cohort study 14 of 125 (11.2 %) PSC patients developed CC. Eleven of the 14 (∼78 %) were diagnosed with CC within 2 years of the diagnosis of PSC [43].

Two large population-based US studies showed a strong positive association of CC with choledocholithiasis and cholangitis [16, 20]. However, these studies could not definitively exclude PSC-associated cholangitis; therefore, it is unclear if choledocholithiasis and/or cholangitis are independent risk factors for ICC or ECC.

2.2.1.2.3 Hepatolithiasis

Hepatolithiasis are calculi or concretions located proximal to the confluence of the right and left hepatic ducts and/or their tributaries. Hepatolithiasis are found mainly in Southeast Asia (e.g., up to 20 % in Taiwan) and are rare in the West (1–2 %). It has been postulated that prolonged irritation and inflammation of the biliary epithelium by the calculi, bile stasis, and bacterial infections predispose to malignancy [44, 45]. Additionally, infestation with parasites such as Clonorchis sinensis and Ascaris lumbricoides has been shown in up to 30 % of patients with hepatolithiasis [46].

Hepatolithiasis is an established risk factor for ICC in Asian countries, with 2–10 % of patients with hepatolithiasis developing ICC [4, 44, 45]. A Korean, hospital-based, case-control study found a strong association between hepatolithiasis and ICC, with an OR of 50.0 (95 % CI 21.2–117.3) [37]. A Chinese, hospital-based, case-control study also showed a significant association, with the OR at 5.8 (95 % CI 1.97–16.9) [47]. There is less data on the relationship between hepatolithiasis and ICC in Western countries; but an Italian, hospital-based case-control study also showed a significant association between hepatolithiasis and ICC, with an OR of 6.7 (95 % CI 1.3–33.4) [48].

2.2.1.3 Toxins

The currently banned carcinogenic agent Thorotrast, a radiographic contrast agent used primarily from 1930 to 1960, has been strongly associated with an increased risk of developing CC. Several large studies from Japan, Germany and Denmark have also shown a significantly increased risk of CC among patients exposed to Thorotrast [49–52]. The estimated latency period between exposure and malignancy diagnosis ranges between 16 and 45 years; this is because the biological half-life of Thorotrast is 400 years [51].

2.2.2 Possible Risk Factors for Cholangiocarcinoma

2.2.2.1 Chronic Viral Hepatitis and Cirrhosis

Hepatitis C virus (HCV), hepatitis B virus (HBV) and liver cirrhosis, regardless of etiology, have been postulated as risk factors for CC.

2.2.2.1.1 Asian Studies

Hospital based studies including one cohort study and several case-control studies examined viral hepatitis in relation to CC. A prospective cohort study from Japan followed 600 patients with HCV-related cirrhosis for a median of 7.2 years. Fourteen patients (2.3 %) developed CC during the observation period, resulting in incidence rates at 5 and 10 years of 1.6 and 3.5 %, respectively. These rates were 1,000 times higher than in the general Japanese population [13]. A Korean case-control study compared 41 cases of CC with 406 non-cancer controls did not find a significant association between HBV or HCV seropositivity and CC. However, having a history of hepatitis was associated with CC, with an RR of 22.4 (95 % CI 3.4–146.2) [31]. In another Korean case-control study that compared 622 cases of ICC with 2,488 controls, there was a significant association between ICC and HBV (OR 2.3; 95 % CI 1.6–3.3) as well as cirrhosis of any etiology (OR 13.6; 95 % CI 6.5–28.5). There was no significant association between HCV seropositivity and ICC [37]. A case-control study from China compared 312 ICC cases with 438 controls and reported a strong association between ICC and HBV seropositivity, with an OR of 8.9 (95 % CI 5.97–13.2) but no significant association with HCV seropositivity [47]. Lastly, a case-control study from Japan reported that HCV was a significant risk factor for ICC, with an OR of 6.02 (95 % CI 1.51–24.1). The presence of cirrhosis merely trended towards significance, whereas HBV infection was not a significant risk factor for ICC [53].

2.2.2.1.2 European Studies

Few Western European studies reported an association between CC and both HCV and cirrhosis. A large, population-based cohort study from Denmark examined cancer risk in 11,605 patients with cirrhosis over a mean follow-up period of 6 years, and reported a tenfold increased risk of CC among patients with cirrhosis compared with the expected cancer cases in the general population (standardized incidence ratio of 21 versus 2) [54]. A hospital-based, case-control study in Italy compared 26 ICC cases with 824 controls. Both HCV and HBV ­seropositivity was analyzed, but only HCV was significantly associated with ICC; OR 9.7 (95 % CI 1.6–58.9) [48].

2.2.2.1.3 US Studies

Several US studies have shown an association between the presence of HCV and/or cirrhosis and increased risk of ICC. A hospital-based, case-control study compared 83 patients with ICC and 163 with ECC to 236 controls. HCV was a significant risk factor for ICC with an OR of 7.9 (95 % CI 1.3–84.5). Cirrhosis was not analyzed as a separate variable, but 80 % of HCV-positive patients had cirrhosis. For ECC, neither HCV nor HBV status was a significant risk factor [17]. A large, population-based, case-control study compared 625 cases of ICC with 90,834 controls. In multivariate analysis, HCV was significantly associated with ICC, with an OR of 5.2 (95 % CI 2.1–12.8). It was unclear if patients with HCV also had a recorded diagnostic code for cirrhosis. However, nonspecific cirrhosis was strongly associated with ICC, with an OR of 27.2 (95 % CI 19.9–37.1). In the same study, the prevalence of HBV infection was similar in cases and controls (0.2 %) [16]. A similar population-based, case-control study examined risk factors for both ICC and ECC. There were 549 cases of ECC and 535 cases of ICC compared with 102,782 controls. Similar to the findings of the previous population-based study, significant risk factors for ICC included HCV and nonspecific cirrhosis. Regarding ECC, nonspecific cirrhosis was also a risk factor, but HCV infection was not significant [20]. A large cohort study of US veterans examined the association between HCV and both ICC and ECC in a cohort of 146,394 HCV-infected veterans and 572,293 uninfected controls. The risk for ICC in the HCV-infected cohort, though low at 4 per 100,000 person-years, was more than double that in the controls (HR 2.55; 95 % CI 1.31–4.95). The risk of ECC did not differ between the HCV-infected and uninfected veterans (4.3 vs. 4.2 per 100,000 person-years) [10].

The association of these risk factors with CC is not entirely clear, as studies have differing conclusions; and there is a paucity of population-based or prospective cohort studies. In countries such as Korea and Thailand where both HBV and CC are endemic, data show HBV but not HCV as a risk factor for ICC. On the other hand, countries such as Japan and Western nations, including the United States, where HCV is more prevalent, were more likely to show an association between HCV and ICC [37, 55].

2.2.2.2 Diabetes and Obesity

Population-based case-control studies from the United States and United Kingdom report a significant, but modest association between diabetes and CC (Table 2.2). For example, two large US studies showed a significant positive association between diabetes and CC. The first study looked specifically at ICC and reported an OR of 2.0 (95 % CI 1.6–2.4) with diabetes [16]. The second study found diabetes to be a significant risk factor for both ICC and ECC, with ORs of 1.8 (95 % CI 1.5–2.1) and 1.5 (95 % CI 1.3–1.8), respectively [20]. Another large, population-based, case-control study from the United Kingdom also found a significant association between diabetes and CC, with an OR of 1.48 (95 % CI 1.0–2.2) [57]. Conversely, a population-based study from Denmark did not find a significant association between diabetes and ICC [56]. Additionally, at least three hospital-based, case-control studies failed to show a significant association between diabetes and CC (Table 2.2) [17, 47, 53]. These associations could be confounded by the presence of underlying liver disease which predisposes to diabetes. Case-control studies are typically non informative to this crucial temporal sequence. Given the absence of data from longitudinal cohort studies, the association between diabetes and CC can only be regarded as preliminary.

Table 2.2 Diabetes as a potential risk factor for cholangiocarcinoma. All studies shown in the table were case-control in design
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Obesity was reported as a significant, but weak, risk factor for CC in two population-based, case-control studies. In the UK a BMI  ≥  30 was significantly associated with CC, type not specified, with an OR of 1.52 (95 % CI 1.0–2.2) [57]. The US study reported a significant association between obesity and ICC, with an OR of 1.7 (95 % CI 1.1–2.6), but not between obesity and ECC [20]. However, in the Danish, population-based study there was no significant association between obesity and ICC [56]. The data available on obesity are too limited to make any conclusions.

2.2.2.3 Alcohol Drinking

Several cohort studies and case-control studies have reported a strong association between heavy alcohol use, typically >80 g/day, and CC (Table 2.3). The cohort study from Denmark that examined 11,605 patients with cirrhosis found a significantly increased CC risk, with an RR of 15.3 (95 % CI 8.9–24.5) in individuals with alcoholic cirrhosis [54]. The two US population-based case-control studies also found alcoholic liver disease to be significantly associated with CC. In the first study of ICC, the OR was 7.4 (95 % CI 4.3–12.8) [16]. In the second study of both ICC and ECC, there was an OR of 3.1 (95 % CI 1.3–7.5) and an OR of 4.5 (95 % CI 2.2–9.1), respectively [20]. However, the UK population-based, case-control study did not find alcohol use to be a risk factor for CC [57]. Few hospital-based, case-control studies have shown a significant association between alcohol intake and CC [17, 31, 37]; while others have not (Table 2.3) [47, 48, 53]. Based on the strong magnitude of association (risk estimate range from 2 to 15) and studies with different designs, heavy alcohol use is likely to be a risk factor for CC.

Table 2.3 Alcohol drinking and tobacco smoking as potential risk factors for cholangiocarcinoma. All studies were case–control in design except for Sorensen et al. which was a retrospective cohort
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2.2.2.4 Tobacco Smoking

The data on a possible association between tobacco smoking and CC are not consistent (Table 2.3). Three large, population-based case-control studies found reported history of tobacco smoking to be weakly associated with CC, with risk estimates from 1.38 to 1.80 [16, 20, 57]; the frequency and duration of smoking was not quantified in these studies. Several other hospital-based case-control studies reported no significant association between smoking and CC [17, 31, 37, 47, 53]. Smoking may be a weak risk factor for CC; but given the conflicting data, a firm conclusion cannot be made.

2.2.2.5 Genetic Factors

Several hospital-based, case-control studies reported that polymorphisms in genes coding for enzymes responsible for metabolism of carcinogens, DNA repair, and inflammation were associated with increased as well as decreased risk of developing CC [12, 58–63]. However, given the varying study populations and lack of study replication in ­independent cohorts, it is difficult to draw firm conclusions regarding the relevance of genetic polymorphisms.

2.3 Summary

There is limited information of the epidemiology of hilar CC specifically; instead incidence and risk factors data are reported on CC overall or based on ICC and ECC. CC is a rare malignancy in Western countries, but more common in some parts of Asia. This difference is mostly attributed to the higher prevalence of established risk factors like parasitic infestations, bile-duct cysts and hepatolithiasis. However, most cases of CC especially in Western countries are not associated with established risk factors for CC which include parasitic infestations, biliary-duct cysts, primary sclerosing cholangitis, hepatolithiasis and toxins. Less-established risk factors include IBD, HCV, HBV, cirrhosis, obesity, diabetes, alcohol, smoking and genetic polymorphisms. There are not enough consistent data to support that obesity, smoking, or specific genetic polymorphisms confer an increased risk for CC. The available data suggest that diabetes and heavy alcohol drinking may confer an increased risk for CC. The data also suggest that in Western countries HCV is consistently associated with ICC and not ECC. In Asian countries it appears that HBV may be associated with ICC. Cirrhosis is the most consistently illustrated risk factor for ICC, but not ECC. In studies where the distinction between ICC and ECC was used, some potential risk factors seem to have differential effect on CC depending on site.