A Nationwide Population-based Study Shows Increasing Incidence of Cholangiocarcinoma
Teng-Yu Lee,1-3 Jaw-Town Lin,4-6 Ken N. Kuo,6 Ming-Shiang Wu,4 Hsiu J. Ho,1 Tzu-Ting Chen,1 and Chun-Ying Wu,1,7-9
1Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital,
Taichung, Taiwan;
2Graduate Institute of Clinical Medical Science, China Medical University, Taichung,
Taiwan;
3Department of Medicine, Chung Shan Medical University, Taichung, Taiwan;
4Division of Gastroenterology, National Taiwan University Hospital, Taipei, Taiwan;
5Department of Internal Medicine, E-Da Hospital and I-Shou University, Kaohsiung, Taiwan;
6Center for Health Policy Research and Development, National Health Research Institutes,
Miaoli, Taiwan;
7Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan;
8Department of Public Health, China Medical University, Taichung, Taiwan;
9Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan
Correspondence: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Dr. Chun-Ying Wu, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. 155, Sec. 2, Linong Street, Taipei 112, Taiwan, Tel: +886-4-23592525 # 3304, Fax: +886-4-23741331, E-mail: [email protected]
Running head: Rising incidence of cholangiocarcinoma 1 2 3 4 5 6 7 8 9 10
Abstract
Purpose An increasing incidence of cholangiocarcinoma (CCA) has been reported in Western
countries, but evidence is lacking in Asia. We investigated the incidence of CCA in a nationwide cohort.
Patients and methods We conducted a nationwide cohort study based on data from the
Taiwan National Health Insurance Research Database (NHIRD) between 1998 and 2008. A total of 6,491 CCA patients were recruited. Adjusted incidences, cumulative incidences, and stratified analyses were used to detect trends regarding CCA incidence in Taiwan.
Results The incidence of CCA increased by 2.01-fold, from 1.79 in 1998 to 3.60 in 2008 per
100,000 persons. For extrahepatic CCA, the incidence increased by 1.5-fold from 0.48 to 0.73 per 100,000. Intrahepatic CCA increased by 3.0-fold from 0.72 to 2.19 per 100,000. The rising incidence of CCA was observed across all sexes and ages, especially in those older than 65 years of age. The proportion of CCA patients who underwent surgery and the overall survival rates remained stable.
Conclusions The incidence of both intrahepatic and extrahepatic CCA increased significantly
between 1998 and 2008. Rising trends were observed among different ages and sexes, especially in the elderly population.
Keywords Liver tumors．Hepatobiliary cancers．Epidemiology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Introduction
Cholangiocarcinoma (CCA) that arises along the biliary tract, excluding the ampulla of Vater and the gall bladder, is the second most common type of primary liver cancer in the world. CCA accounts for an estimated 15% of primary liver cancers [1,2]. Although CCA is a relatively uncommon disease in industrialized countries, the clinical impact of CCA is important due to its high morbidity and mortality rates [3].
CCA is anatomically classified into intrahepatic and extrahepatic CCA, and the incidence of CCA based on different tumor locations have been discussed in previous studies [4-6]. A few studies have reported recent changes in the overall incidence of biliary (intrahepatic and extrahepatic) CCA, with increasing trends in Western countries [7-10].
The incidence of intrahepatic CCA is on the rise in Western countries, with a 1.65-fold increase within the United States and a 12-fold increase in England and Wales [4-9]. There is relatively little data, however, concerning the incidence of extrahepatic CCA and the few reports that exist appear to contradict each other [4,7-11]. In Asia, there is little information regarding either intrahepatic or extrahepatic CCA. We conducted a nationwide cohort study to determine the incidence of CCA based on tumor location.
Most previous cohort studies regarding CCA in Western countries were conducted before the beginning of the 21st century, and the trend toward an increasing incidence of CCA has persisted [4-9]. Furthermore, most of the increases have occurred in the last decade of the 20th century [5,7,10]. The rapidly increasing incidence of CCA in recent years, however, has 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
not been extensively studied, and further updates are needed. In addition, an age-specific increase in incidence of intrahepatic CCA was reported across all age groups with the most significant increase noted among the oldest age groups [5,7,9], but changes in the overall incidence of biliary CCA according to different age groups have been underreported. Although the progressive increase in the incidence of CCA with age has been reported for intrahepatic, extrahepatic, and part-unspecified CCA in a cohort study in Italy [9], an overall increased incidence of biliary CCA in different age groups was not demonstrated. Furthermore, changes in the incidence of CCA in different age groups have not been reported in Asia. We investigated the trends regarding CCA incidence among different ages and sexes, especially in the elderly population in Taiwan.
Patients and methods
Study Population
We conducted a nationwide cohort study based on information retrieved from Taiwan’s National Health Insurance Research Database (NHIRD) [12,13]. The National Health Research Institutes approved the use of the NHIRD in the present study. The NHIRD contains health care data from > 99% of the entire population of 23.74 million in Taiwan. The NHIRD comprises comprehensive information, such as demographic data, dates of clinical visits, diagnostic codes, details of prescriptions, and expenditure amounts, as detailed previously [14,15]. The International Classification of Diseases, 9th Revision (ICD-9) codes 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
were consistently used to define disease during the study period. CCA was defined according to the Registry for Catastrophic Illness Patient Database (RCIPD), a separate subpart of the NHIRD which is associated with CCA qualification for insurance payment and requires strict histological and/or clinical confirmation of CCA.
Study Subjects
Between January 1, 1998, and December 31, 2008, all patients with a diagnosis of CCA were analyzed according to the ICD-9 codes (155.1, 156.1, and 156.9 for intrahepatic CCA, extrahepatic CCA and part-unspecified CCA, respectively). For patients with uncertain ICD codes, the diagnosis of CCA was confirmed by the primary diagnosis at hospitalization. The proportion of patients who underwent surgery on the liver (ICD-9 codes: 50.22 partial hepatectomy, 50.3 lobectomy of the liver, or 50.5 liver transplant) were calculated. In addition, the proportion of patients who had underlying bile duct stones (code 574.5), hepatitis B virus infection (codes 070.2 and 070.3), hepatitis C virus infection (codes 070.44, 070.54 and 070.7), non-alcoholic liver cirrhosis (codes 571.5 and 571.6), alcoholic liver cirrhosis (code 571.2), diabetes mellitus (codes 250 and 648.0), liver fluke infection (codes 121.0 and 121.1), or ulcerative colitis (code 556) before development of CCA during study period were calculated according to ICD codes for risk factor analysis.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Statistical Analysis
The annual incidence of CCA was calculated from the total number of new cases per 100,000 in the population based on information from the NHIRD during study period (1998– 2008), and standardized incidence was further calculated by weighing the age-sex specific rates according to the standard population of Taiwan in 2003. Furthermore, the incidence was analyzed based on different ages (<45, 45-54, 55-64, 65-74, and ≧75 years old) and sex using stratified analyses.
In addition, we examined the annual proportion of patients who underwent surgery throughout the study period, as well as the 1-year, 2-year and 3-year cumulative mortality rates of CCA patients. Case numbers and the proportion of patients who had risk factors before development of CCA were calculated on an annual basis in order to determine the proportion of patients with underlying risk factors for CCA, based on different tumor locations. The incidence was determined using the slope from a simple linear regression analysis with incidence as the dependent variable and observed year as the independent variable. A significant increase in incidence was defined as a positive slope with a p-value < 0.05 as verified by t-test. All data management and SIR analyses were performed using SAS 9.1 software (SAS Institute, Cary, NC). Cumulative incidences were analyzed via the SPSS program for Windows 11.0 (SPSS, Inc., Chicago, IL).
Results 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Incidence
The estimated standardized incidence of overall biliary CCA progressively increased by 2.01-fold, from 1.79 in 1998 to 3.60 in 2008 per 100,000 persons. The incidence of intrahepatic CCA significantly increased by 3.04-fold, from 0.72 in 1998 to 2.19 in 2008 per 100,000 persons, and the incidence of extrahepatic CCA modestly increased by 1.52-fold, from 0.48 in 1998 to 0.73 in 2008 per 100,000 persons (Table 1). In addition, compared with intrahepatic and extrahepatic CCA, the incidence of part-unspecified CCA did not significantly change (from 0.60 in 1998 to 0.69 in 2008 per 100,000 persons).
Sex
The increasing incidence of overall biliary CCA was similar between both sexes from 1998 to 2008. The incidences increased by 2.12- and 1.90-fold, respectively, in males vs. females (Figure 1A & 1B). Among male patients, the incidence of intrahepatic CCA increased by 3.38-fold, from 0.66 in 1998 to 2.23 in 2008 per 100,000 persons, and the incidence of extrahepatic CCA increased by 1.57-fold, from 0.54 in 1998 to 0.84 in 2008 per 100,000 persons (Figure 1A). However, compared with intrahepatic and extrahepatic CCAs, the incidence of part-unspecified CCA did not show significant changes.
Among female patients, the incidence of intrahepatic CCA increased by 2.76-fold, from 0.78 in 1998 to 2.14 in 2008 per 100,000 persons, and the incidence of extrahepatic CCA increased by 1.49-fold, from 0.41 in 1998 to 0.61 in 2008 per 100,000 persons (Figure 1B). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
However, compared with intrahepatic and extrahepatic CCAs, the incidence of part-unspecified CCA did not show significant changes.
Age
The incidence of overall biliary CCA progressively increased across all age groups from 1998 to 2008 (Figure 2), with the greatest increase in incidence (3.01-fold) reported among patients ≧ 75 years old (from 9.07 per 100,000 in 1998 to 27.27 per 100,000 in 2008). In general, the incidence of CCA was higher in older subgroups. For example, in 2008, patients in the 45-54, 55-64, 65-74, and ≧75 years-of-age subgroups showed a 12.11, 43.50, 84.43, and 110.69 fold increase, respectively, compared to their < 45 years-of-age cohorts. Furthermore, the incidence of CCA among patients aged 65 years or more rapidly increased with a significantly steeper slope compared to younger patients. Similar to the trends for total biliary CCA, the incidence of intrahepatic or extrahepatic CCA in different age groups showed similar increases.
Surgery on the Liver
The proportion of patients who had CCA and liver surgery did not significantly change, from 20.76% in 1998 to 21.23% in 2008 (mean standard deviation: 21.22 2.51%) (The operative rates are shown in Supplementary Figure 1 online).
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Mortality Rates
The mortality rates from CCA in this cohort study were still very high and the 1-year, 2-year and 3-2-year cumulative mortality rates of CCA patients did not significantly change (The mortality rates are shown in Supplementary Figure 2 online). The mean 1-year, 2-year and 3-year cumulative mortality rates (expressed as mean standard deviation) were 67.52 2.48%, 77.88 2.64% and 81.88 2.24%, respectively.
Risk Factor Analysis
The annual proportion of patients with underlying risk factors for CCA did not significantly change during the study period. In addition, diabetes, bile duct stones and liver cirrhosis were found in a higher percentage of patients, and they continued to be the top three risk factors regardless of tumor location (Table 2). Viral hepatitis B or C infection could be found in a certain proportion of patients, and the proportion of patients with liver fluke infections or ulcerative colitis continued to be very low.
Discussion
This is the first report to highlight recent changes in the incidence of CCA in Asia. We found that the incidence of both intra- and extrahepatic CCA increased in Taiwan from 1998 to 2008, whereas part-unspecified CCA remained constant. In addition, the increase in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
intrahepatic CCA was greatest among the subgroups based on tumor location. Like their western cohorts, these findings show that intrahepatic CCA is on the rise in the Taiwanese population [4-10]. Although not as dramatic as the 12-fold rise in intrahepatic CCA found in England and Wales during the years 1971 to 2001 [7], the increased incidence in Taiwan was slightly greater (at 3.04-fold in 11 years) compared to other Western countries [4-6,8,9]. In addition, there was a more rapid increase in CCA incidence near the beginning of the 21st century compared to previous studies [5,7], and it is unclear if the same trend is occurring in the West. Further epidemiological studies of CCA in other countries are needed to formulate a more global picture.
Compared to intrahepatic CCA, the incidence of extrahepatic CCA was found to be increasing at a slower but predominantly steady pace in Taiwan. Previously reported incidences of extrahepatic CCA in the West were inconsistent, with decreased [4,7], constant [11], and increased [8,9] incidences reported in Europe and the United States. This inconsistency may be due to misclassification, as hilar CCAs (also known as Klatskin tumors that involve the hepatic ductal bifurcation) are anatomically defined as extrahepatic CCAs but are not assigned a unique ICD code. Therefore, they may not have been coded as extrahepatic CCAs [16]. The incidence of extrahepatic CCA may have been underestimated due to such misclassification, but such errors have had only a minor impact on incidence studies [11]. In this study, the impact of misclassification was small and constant due to simultaneously 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
increased incidences of intra- and extrahepatic CCA and relatively constant incidence of part-unspecified CCA, and, in addition, our ICD classification system has not changed during the study period.
A significant rise in the overall incidence of biliary CCA was found in this study, with a 2.01-fold increase from 1998 to 2008, and similar increasing trends have been reported in Italy, England, Wales, Crete, and Australia [7-10]. Using data from the Japan Autopsy Registry (collected from major hospitals in Japan from 1968 through 1997), Okuda et al. found a nearly two-fold overall rise in biliary CCA [17]. Similar to the Japanese study, an increase in the incidence of CCA has been noted in Asia, and this finding could have a significant impact on public health in the future due to high morbidity and mortality rates associated with CCA.
The incidence of CCA is traditionally considered to be higher in Asian countries, but
varies widely by region [1,18]. The overall incidence of biliary CCA was 3.36 per 100,000 persons in Italy (1996-2005) vs. 3.33 per 100,000 persons in Crete (1998-2000) [8, 9],similar to the incidence in Taiwan (3.60 per 100,000 persons in 2008). Hence, the prevalence of CCA in industrialized Asian countries is not necessarily higher compared to Western countries. Additional epidemiological studies will be needed in the future to support this conclusion.
The possibility that the rising incidence of CCA may be due to improved diagnostic and 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
histological techniques has been raised, but their impact was considered minimal due to stable proportions of patients in different tumor stages over time [11]. CCAs are highly fatal malignancies with a median survival rate for unresectable disease of only 6-12 months, and resectability is the most reliable predictor of a good prognosis [19,20]. Surgery for CCA is usually performed for disease in the earlier stages, and the rate of patients who undergo surgery on the liver may reflect the rate of disease at earlier stages. In our study, the rate of patients who underwent liver surgery did not significantly change during the study period.
In addition, early detection of CCA could increase the rate of disease in the earlier stages, so the mortality rates would be decreased due to effective therapies and longer patient survival. However, the 1-year, 2-year and 3-year mortality rates of CCA patients were unchanged in our study. In summary, early detection did not seem to explain the rising incidence of CCA.
The increasing incidence of CCA was similar in both males and females. In previous studies of intrahepatic CCA [6,8], increased incidences were observed in both sexes, but the incidence was usually higher in males compared to females. However, similar to studies performed in England and Wales [7], we found little difference between males and females regarding the incidence of intrahepatic or extrahepatic CCA in this study. In addition, although changes in the incidence of extrahepatic CCA were not consistent among different countries, the trends were consistent between males and females [7,8]. In our study, although 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
the incidence was usually higher in males compared to females, the differences were small. For example, the incidence of intrahepatic CCA was 2.26 in males compared to 2.14 in females per 100,000 persons in 2008. In summary, although CCAs are considered more common in males than in females, sex did not appear to play a role in the rising incidence of CCA in Taiwan.
CCA is rarely found in patients less than 40 years old, and most CCAs are diagnosed in patients more than 65 years old [16]. The incidence of CCA was found to increase across all age groups in previous studies that mainly focused on intrahepatic CCA, and the incidences were the highest in the oldest age group [4-8]. In this study, increasing incidences of CCA were observed at all ages, however, the incidence of CCA showed the greatest increase among patients more than 65 years old. In addition, the overall incidence of biliary CCA in patients ≧ 75 years old was the highest among all age cohorts, with a incidence of 27.27 per 100,000 in 2008. Our findings were similar to the aforementioned Italian study conducted between 1996 and 2005, in which the incidences for patients aged 75-84 and aged ≧ 85 were 21.75 and 34.58 per 100,000, respectively.
Our study is the first to report changes in the incidence of CCA among different age groups in Asia. We found that the incidence of CCA increased with age, for all age groups. Investigation into the age-related causes contributing to CCA development require further study but may be related to prolonged exposure to certain risk factors [21,22].
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Even though risk factors for CCA (such as parasitic infections, primary sclerosing cholangitis, biliary-duct cysts, hepatolithiasis, and Thorotrast exposure) have been established and other potential risk factors (such as cirrhosis, hepatitis C, hepatitis B, and human immunodeficiency virus infections, diabetes, obesity, alcohol consumption, smoking, and inflammatory bowel disease) have been investigated, the putative mechanisms underlying the increasing incidence of CCA remain ambiguous [19,21-24]. Since the risk factors for CCA usually induce chronic injury and inflammation to the biliary epithelium, a prospective cohort study regarding CCA development is difficult, especially considering the prolonged length of time required for carcinogenesis to develop [3,23]. An increased exposure to risk factors could explain the increasing incidence of CCA, but the current increases in CCA may be caused by exposure to the risk factors that occurred several decades ago [25]. Long-term population-based cohort studies are especially important but are sparse, especially those examining the mechanisms underlying the increasing CCA incidence.
In this nationwide population-based study, we calculated the proportion of patients with various risk factors for CCA and found that diabetes, bile duct stones, and liver cirrhosis continued to be among the top three risk factors. This data may provide useful clues for future longitudinal cohort studies that focus on potential causes for the rise in CCA incidence. Hepatolithiasis is found primarily in Southeast Asia (including Taiwan) [26], but the incidence of bile duct stones wasn’t increased in this study. Furthermore, infestation with 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
hepatobiliary flukes has also been considered a major risk factor for CCA, particularly in Southeast Asia [1.2], but the prevalence of hepatobiliary flukes is very low in Taiwan. In addition, the mechanisms and risk factors for intrahepatic vs. extrahepatic CCA may be different, and the location of CCA development is usually associated with the site of chronic inflammation [3]. Despite inconsistent reports, some risk factors such as viral hepatitis B, hepatitis C, and cirrhosis seemed to have a significant impact on intrahepatic but not on extrahepatic CCA [22-24], and some risk factors such as smoking and alcohol consumption might not show a predilection for a specific location [23]. Compared with extrahepatic CCA, a higher proportion of patients with viral hepatitis B and liver cirrhosis had intrahepatic CCA in this study, and the effect of various risk factors on CCA incidence should be important consideration in future studies.
In conclusion, we found a rising incidence of both intrahepatic and extrahepatic CCA in the Taiwanese, and the increases were observed among different ages and sexes, especially in the elderly population. Furthermore, CCA continues to be associated with poor prognosis, and the survival rate and operative rate of CCA patients remains low. Additional studies that focus on prevention and improving early detection of CCA will be crucial for the future of public health. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
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Acknowledgements
Financial support by Taiwan National Health Research Institutes (Grant number: PH-100-PP54) and Taichung Veterans General Hospital (Grant number: TCVGH-1003303C).
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Figure legends
Figure 1. The standardized incidences of intrahepatic, extrahepatic, and part-unspecified cholangiocarcinomas from 1998 to 2008 for (A) males and (B) females.
Figure 2. The standardized incidences of cholangiocarcinoma for different age groups from 1998 to 2008.
Supplementary Figure 1. The proportion of patients with overall biliary cholangiocarcinoma who received operation (OP) on the liver between 1998 and 2008.
Supplementary Figure 2. The 1-year, 2-year and 3-year cumulative mortality rates of patients with overall biliary cholangiocarcinoma between 1998 and 2008.
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