Biliary tract cancer and stones in relation to chronic liver conditions:
A population-based study in Shanghai, China
Ann W. Hsing1*, Yu-Tang Gao2, Katherine A. McGlynn1, Shelley Niwa3, Mingdong Zhang1,4, Tian-Quan Han5,
Bing-Sheng Wang6, Jinbo Chen1,7, Lori C. Sakoda1, Ming-Chang Shen8, Bai-He Zhang9, Jie Deng2and Asif Rashid10
1Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
2Shanghai Cancer Institute, Shanghai, China
3Health Studies Sector, Westat, Rockville, MD
4Center for Emerging Infectious Diseases, Chinese University of Hong Kong, Hong Kong, China
5Department of Surgery, Raijin Hospital, Shanghai, China
6Department of Surgery, Zhongshan Hospital, Shanghai Medical University, Shanghai, China
7Department of Epidemiology and Biostatistics, School of Medicine, Philadelphia, PA
8Department of Pathology, Shanghai Tumor Hospital, Shanghai, China
9Department of Surgery, Second Military Hospital, Shanghai, China
10Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX
Biliary tract cancers are relatively rare but fatal tumors. Apart
from a close link with gallstones and cholangitis, risk factors for
biliary tract cancer are obscure. Chronic liver conditions, includ-
ing liver cirrhosis, have been linked to a higher risk of biliary tract
cancer. In a population-based case-control study conducted in
Shanghai, China, we investigated the relationships of a history of
chronic hepatitis and liver cirrhosis as well as a family history of
liver cancer with biliary tract cancer risk. The study included 627
patients with biliary tract cancers (368 gallbladder, 191 bile duct
and 68 ampulla of Vater), 1,037 patients with biliary stones (774
gallbladder stones and 263 bile duct stones) and 959 healthy sub-
jects randomly selected from the population. Bile duct cancer was
associated with self-reports of chronic liver conditions, including a
history of chronic hepatitis (OR 5 2.0, 95% CI 0.9–4.4), liver cir-
rhosis (OR 5 4.7, 95% CI 1.9–11.7) and a family history of pri-
mary liver cancer (OR 5 2.0, 95% CI 1.0–3.9). The excess risk
persisted after adjustment for gallstones and were more pro-
nounced among subjects without gallstones (OR 5 5.0, 95% CI
1.3–20.0 and OR 5 4.9, 95% 2.0–12.2, respectively). History of
liver conditions was also associated with an excess of biliary stones
(OR 5 1.9, 95% CI 1.2–3.0). No association was found for cancers
of the gallbladder and ampulla of Vater. A history of chronic hep-
atitis and cirrhosis may be risk factors for extraheptic bile duct
cancer. Given that chronic infection with hepatitis B virus (HBV)
is the most common cause of liver disease in China, serologic
markers of HBV need to be measured in future studies to examine
the link between HBV and bile duct cancer.
' 2007 Wiley-Liss, Inc.
Key words: biliary tract cancer; family history; viral hepatitis; liver
cirrhosis; family history of liver cancer; China
Cancers of the biliary tract encompass tumors arising from the
gallbladder, extrahepatic bile ducts and ampulla of Vater. Biliary
tract cancer is relatively uncommon in most parts of the world,
although high-risk populations and upward incidence trends have
been reported in certain areas.1,2From 1972 to 1994, biliary tract
cancer incidence rose the most rapidly of any malignancy in
Shanghai, China, with an increase of 119% in men and 124% in
women,3although the absolute rates were modest, less than 5 per
100,000 person-years. Higher rates of biliary tract cancer are
reported from populations such as Japan, Korea, India, Eastern
Europeans, Hispanics and native Americans in the U.S.,1with
rates ranging from 5 to 10 per 100,000 person-years. Gallbladder
cancer is one of the few cancers with a female excess, while bile
duct cancer is more likely to occur in men.1
Other than gallstones, the risk factors for biliary tract cancer are
poorly understood.1,4–8Although gallstones are common risk fac-
tors for all three subsites of biliary tract cancer, data from descrip-
tive epidemiology and molecular studies suggest that these three
subsites have distinct etiologic pathways, with cancer of the extra-
hepatic bile duct more closely linked to infection.1Chronic liver
conditions, including viral hepatitis and liver cirrhosis, have been
associated with a higher risk of biliary tract cancer,9–13although
the mechanism is unclear. Bacterial infection, such as the typhoid
carrier state and Helicobacter sp. and pylori, may also play a
To provide further clues to the etiology of biliary tract cancer,
we examined the associations of a personal history of hepatitis or
liver cirrhosis and a family history of hepatitis or liver cancer with
biliary tract cancer in a large population-based case-control study
conducted in Shanghai, China.
Materials and methods
Details of the study have been reported elsewhere.17–22Briefly,
patients with primary biliary tract cancer (ICD9 156) newly diag-
nosed between 1997 and 2000 were identified through a rapid-
reporting system established between the Shanghai Cancer Insti-
tute (SCI) and 42 collaborating hospitals in 10 urban districts of
Shanghai (henceforth referred to as urban Shanghai). This report-
ing system captured over 95% of biliary tract cancer patients in
Shanghai. Cases for the study were permanent residents of urban
Shanghai who had no history of any other cancer. In addition,
patients with gallstones undergoing cholecystectomy or nonsurgi-
cal interventions and patients with bile duct stones undergoing a
surgical intervention were selected for comparison. These patients
were selected from the same hospitals as the cancer cases and
were frequency-matched by age and sex. Healthy subjects, without
a history of cancer, were randomly selected from the population of
6.5 million permanent residents of Shanghai, based on the per-
sonal registry cards of all adults aged above 18 residing in urban
Shanghai and were frequency-matched to the expected age distri-
bution (by 5-year category) of biliary tract cancer cases.
The diagnoses of the cancer cases and gallstone patients were
confirmed by a review of pathology slides conducted independ-
ently by two pathologists. Clinical data and imaging studies, such
Grant sponsors: National Institute of Health, National Cancer Institute.
*Correspondence to: Division of Cancer Epidemiology and Genetics,
National Cancer Institute, EPS 5024, MSC 7234, 6120 Executive Blvd.,
Bethesda, MD 20852-7234, USA. Fax: 1301-402-0916.
Received 12 May 2006; Accepted after revision 22 August 2006
Published online 2 February 2007 in Wiley InterScience (www.interscience.
Int. J. Cancer: 120, 1981–1985 (2007)
' 2007 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
as ultrasonography, CT scan and endoscopic retrograde cholangio-
pancreatography, were used to confirm the diagnoses of cancer
cases without histologic materials and gallstone controls without a
surgery. Abdominal ultrasound was performed on all population
controls to assess the status of gallstones (including silent gall-
stones). The primary site of cancer was obtained from the surgi-
cal/pathological report of the local hospital and was confirmed by
imaging studies and/or histopathology.
Information on potential risk factors, including smoking, use of
alcohol, body size, diet, reproductive history, family history of
cancer, medical history, occupation and physical activity, was eli-
cited from all study subjects through an in-person interview con-
ducted by trained interviewers using a structured questionnaire.
Response rates for interview were over 95% for eligible cases and
83% for controls. Each interview was tape-recorded and verified
by a study supervisor. In addition, 5% of the subjects were ran-
domly selected for a second interview several months after the
original interview to assess the reproducibility of the information.
Concordance between the two interviews was more than 90%.
Hepatitis-related information obtained by interview included self-
reports of a personal history of acute and chronic hepatitis, a per-
sonal history of liver cirrhosis as well as a family history of
chronic hepatitis and primary liver cancer among first-degree rela-
tives. Information about the age at diagnosis was also collected.
For cancer and biliary stone cases, medical records were
abstracted to collect information on gallstones, diabetes, hyperten-
sion and heart disease.
The response rates for in-person interviews were over 90% for
cases and controls. For all study subjects, informed consent was
obtained and clearance for human subjects was approved by the
Institution Review Boards at both the National Cancer Institute
(NCI) and SCI.
Fisher’s exact test was used to detect differences between cases
and controls for selected characteristics. To make the appropriate
case control comparisons, gallbladder cancer cases were compared
to controls without a history of cholecystectomy; bile duct cancer
cases and ampulla of Vater cancer cases were compared to all con-
trols; and biliary stone cases were compared to population controls
without biliary stones. Factors, including education, body mass
index, gallstones and diabetes, with statistically significant differ-
ences (p < 0.05) were considered potential confounders for biliary
tract cancers or stones. Unconditional logistic regression analyses
were used to compute the odds ratios (ORs) and 95% confidence
intervals (CIs) for biliary tract cancer in relation to personal and
family history of hepatitis, liver cirrhosis or primary liver can-
cer.23ORs were estimated for biliary tract cancer and subse-
quently for each anatomic subsite separately. We further analyzed
the family history in parents, siblings and offspring separately. In
all the analyses, ORs were adjusted for age and subsequently
adjusted for education, body mass index (BMI) [(weight (kg)/
height (m2)], diabetes and other potential confounding factors.
The study included a total of 627 patients with biliary tract can-
cers (368 gallbladder, 191 bile duct and 68 ampulla of Vater),
1,037 patients with biliary stones (774 gallbladder stones and 263
bile duct stones) and 959 healthy controls randomly selected from
the population (Table I). Age at diagnosis ranged from 35 to 75
(median 67) for cancer cases. Compared with controls, gallbladder
cancer cases had less education and were less likely to be smokers
or alcohol drinkers, while bile duct and ampulla of Vater cases
were more likely to be smokers. Diabetes was more common
among gallbladder cancer patients. Gallbladder cancer patients
and biliary stone patients were more likely to have hypertension
and a higher BMI, relative to population controls. The prevalence
TABLE I – SELECTED CHARACTERISTICS OF CASES AND CONTROLS
Biliary tract cancer casesBiliary stone cases
GallbladderBile ductAmpulla of vaterGallbladder
Bile duct stones
Alcohol use (%)
Body mass index
*Fisher’s exact test, p < 0.05.
HSING ET AL.
of gallstones in cancer patients was significantly higher than that
in population controls.
The prevalence of liver conditions was relatively low, with 3%
in controls, 6% in biliary stone patients, and 7% in bile duct can-
cer cases (Table II). A history of chronic livier conditions, includ-
ing a history of chronic hepatitis or liver cirrhosis, was associated
with a 2.3-fold risk (95% CI 1.2–4.6) of bile duct cancer, a 2.7-
fold risk (95% CI 1.0–7.3) of ampulla of Vater cancer, and a 1.9-
fold risk (95% CI 1.2–3.0) for biliary stones (2.9-fold for bile duct
stones). Bile duct cancer was associated with a history of hepatitis
(OR 5 2.0, 95% CI 0.9–4.4) and a history of liver cirrhosis (OR
5 4.7, 95% CI 1.9–11.7). In addition, a family history of primary
liver cancer was associated with a 2-fold risk of bile duct cancer
(95% CI 1.0–3.9), but not with cancers of the gallbladder or
ampulla of Vater or biliary stones. Further adjustments for educa-
tion, gallstones, BMI, smoking, and drinking, and diabetes did not
materially change the risk estimates.
Table III shows the risk of bile duct cancer associated with
chronic liver conditions by gallstone status among study subjects.
As shown, the risk imposed by certain liver conditions was more
pronounced in the absence of gallstones, with those reporting a
history of liver cirrhosis having a 5-fold risk (95% CI 1.3–20.0)
and those reporting a family history of primary liver cancer having
a 4.9-fold risk (95% CI 2.0–12.2).
Results from our large population-based case-control study
show that a history of chronic liver conditions, including chronic
hepatitis or liver cirrhosis and a family history of primary liver
cancer is associated with a 2-fold risk of gallstones and a signifi-
cantly increased risk of extrahepatic bile duct cancer but not of
cancers of the gallbladder or ampulla of Vater.
The observed 2-fold risk of gallstones associated with a history
of liver conditions is consistent with previous reports of a higher
prevalence and incidence of gallstones among patients with liver
cirrhosis,24–33with higher risk associated with a longer duration
and the severity of liver cirrhosis. The high incidence of gallstones
in cirrhotic patients has been attributed mainly to metabolic
changes, including increased unconjugated bilirubin in bile and
TABLE II – ODDS RATIOS (ORS) AND 95% CONFIDENCE INTERVALS FOR BILIARY TRACT CANCER AND BILIRY STONES IN RELATION TO HISTORY
OF CHRONIC HEPATITIS, AND LIVER CIRRHOSIS, AND TO FAMILY HISTORY OF HEPATITIS AND LIVER CANCER, SHANGHAI, CHINA
Biliary tract cancer cases
Biliary stone cases
GallbladderExtrahepatic bile ductAmpulla of vater
History of liver conditions2
History of hepatitis
History of liver cirrhosis
Family history of liver conditions3
Family history of hepatitis3
Family history of primary liver cancer3
1Adjusted for age.–2Includes a history of hepatitis or liver cirrhosis.–3Family history among first-degree relatives, i.e., parent, sibling, or child.
TABLE III – ODDS RATIOS (ORS) AND 95% CONFIDENCE INTERVALS (CIS) FOR BILE DUCT CANCER IN RELATION TO HISTORY OF CHRONIC HEPATITIS,
LIVER CIRRHOSIS, FAMILY HISTORY OF HEPATITIS, AND FAMILY HISTORY OF LIVER CANCER, BY GALLSTONE STATUS, SHANGHAI, CHINA
Bile duct cancer with stones
Bile duct cancer without stones
History of liver conditions2
History of hepatitis
History of liver cirrhosis2
Family history of liver conditions3
Family history of hepatitis3
Family history of primary liver cancer3
1Adjusted for age.–2Includes a history of hepatitis or liver cirrhosis.–3Family history among first-degree relatives, i.e., parent, sibling, or
BILIARY TRACT CANCER AND CHRONIC LIVER CONDITIONS
decreased secretion of cholesterol, bile acid and apolipoprotein
secretion,32,33all of these are lithogenic factors that increase the
risk of gallstone formation. Cirrhotic patients also have impaired
gallbladder motility because of higher serum estrogen levels.31
Although a history of gallstones is associated with both bile
duct cancer and liver cirrhosis, the observed associations between
a history of liver cirrhosis and bile duct cancer cannot be
explained entirely by the confounding effect of gallstones. This
excess risk persisted after adjustment for gallstone status among
study subjects. Furthermore, among subjects without gallstones,
those with a history of liver cirrhosis had a 5-fold risk of bile duct
cancer, further supporting the hypothesis that the effect of liver
cirrhosis on bile duct cancer is not mediated entirely by gallstones.
Despite small numbers, the finding of a 5-fold risk of bile duct
cancer associated with a history of liver cirrhosis among subjects
without gallstones suggests that a certain fraction of the bile duct
cancer cases may develop through a non-gallstone mechanism. In
fact, although gallstones alone were associated with an 8-fold risk
of bile duct cancer in our study, nearly 45% of the bile duct cancer
cases did not have gallstones. Chronic infection with the Hepatitis
B virus (HBV) is the most likely explanation for the observed
association between bile duct cancer and a history of chronic liver
conditions, since chronic HBV infection accounts for most of the
hepatitis, liver cirrhosis and primary liver cancer in China.34–37
This hypothesis is further supported by recent clinical surveys in
China that detected HBV DNA in tissue specimens from both in-
trahepatic bile duct cancer (this is considered primary liver cancer)
and hilar cholangiocarcinoma (extrahepatic bile duct cancer).17–19
Factors other than HBV, such as primary sclerosing cholangitis or
parasitic infection, may also be involved in the pathogenesis of
bile duct cancer,1,38–40but their prevalence is extremely low and
they are not the major cause of hepatitis, liver cirrhosis and liver
cancer in China.
Misreporting of jaundice, a complication of bile duct obstruc-
tion as a result of tumor growth or stones, for hepatitis, by subjects
due to similar symptoms, especially among cancer cases, is possi-
ble but is unlikely to explain entirely the 2-fold risk associated
with bile duct cancer. In fact, this positive association persisted af-
ter excluding from the analysis subjects reporting having hepatitis
within 2 years of cancer diagnosis. In addition, the observation
that a history of liver cirrhosis and a family history of primary
liver cancer are associated with bile duct cancer further supports
the notion that misclassification by jaundice reported by the sub-
jects is minimal, since reporting of a family history of cancer is
unlikely to be affected by jaundice in study subjects.
Our study has several strengths. First, selection bias is minimal,
because of the relatively complete case ascertainment and high
response rates in study subjects. Second, misclassification of can-
cer should be minimal, since rigorous procedures, including imag-
ing studies, were implemented for pathological and clinical
review. Third, the location of tumors was reviewed carefully to
minimize misclassification of anatomic subsites of tumors. Fourth,
the assessment of gallstone status was nearly complete, as a result
of careful review of medical records for cases and ultrasound ex-
amination of population control subjects.
Limitations of the study should be noted. We did not validate
the reporting of family history of primary liver cancer against
medical records. However, it is likely that misreporting, if any, is
small, since liver cancer is 10 times more common than biliary
tract cancer in China41and the Chinese names for liver and bile
duct cancer are distinctively different. Chronic HBV infection is
the most likely explanation for the observed association between
bile duct cancer and a history of chronic liver conditions, but we
were unable to differentiate different types of viral hepatitis in our
study because the histories (either personal or family) of hepatitis
and related conditions were based on self-report. Hepatitis C virus
(HCV) infection is a major risk factor for primary liver cancer and
extrahepatic bile duct cancer in Japan, but it is a less important
risk factor for liver and extrahepatic bile duct cancer in Shanghai,
since the prevalence of HCV infection is low (about 2%) in the
general population. Misreporting of acute hepatitis for chronic
hepatitis is possible but should be minimal, since hepatitis is quite
common in China and most subjects should have been able to dis-
tinguish chronic from acute hepatitis. We could not assess the
association between a family history of biliary tract cancer and the
risk of biliary tract cancer in this report since only 2 cancer cases
and none of the controls reported a family history of biliary tract
In summary, results from this population-based study suggest
that a history of liver conditions, in particular liver cirrhosis, is a
risk factor for gallstones and extrahepatic bile duct cancer in
China, although the specific type of viral hepatitis could not be
determined. Although biliary tract cancer has a low incidence in
most populations (other than in American Indians, Hispanics and
some eastern Europeans), its fatality rate is among the highest for
any cancer. It is estimated that there are 350 million chronic car-
riers of HBV worldwide and that 50 million new cases of HBV
infection occur annually. Of the 50 million individuals with inci-
dent infections every year, 5–10% of adults and 90% of infants
will become chronic carriers.42–47Given the global prevalence of
HBV infection and the increasing number of HCV-infected sub-
jects in western populations, future studies should measure sero-
logic markers of HBV and HCV in cases and controls to clarify
further the role of HBV/HCV in extrahepatic bile duct cancer.
We thank Ms. Jiarong Cheng, Ms. Lu Sun, Mr. Kai Wu, and the
staff at the Shanghai Cancer Institute for data collection, specimen
collection and processing; collaborating hospitals and surgeons for
data collection; local pathologists for pathology review; Ms. Lisa
McFarland, Ms. Kathy Hurt-Mullen, Ms. Sara Glashofer,
Ms. Nancy Odaka, Mr. John Heinrich and Ms. Linda Lannom of
Westat for data preparation and management; and Ms. Janis Koci
of the Scientific Applications International Corporation for man-
agement of the biological samples.
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