Epidemiology and Molecular Pathology of Gallbladder Cancer

CA Cancer J Clin 2001;51:349-364
Epidemiology and Molecular Pathology

of Gallbladder Cancer
Eduardo C. Lazcano-Ponce, MD, PhD; J. F. Miquel, MD; Nubia Muoz, MD;
Rolando Herrero, MD, PhD; Catterina Ferrecio, MD; Ignacio I.Wistuba, MD;
Patricia Alonso de Ruiz, MD; Gerardo Aristi Urista, MD; Flavio Nervi, MD
ABSTRACT Gallbladder cancer is usually associated with gallstone disease, late diagnosis,
unsatisfactory treatment, and poor prognosis. We report here the worldwide geographical
distribution of gallbladder cancer, review the main etiologic hypotheses, and provide some
comments on perspectives for prevention. The highest incidence rate of gallbladder cancer is
found among populations of the Andean area, North American Indians, and Mexican
Americans. Gallbladder cancer is up to three times higher among women than men in all
populations. The highest incidence rates in Europe are found in Poland, the Czech Republic,
and Slovakia. Incidence rates in other regions of the world are relatively low. The highest
mortality rates are also reported from South America, 3.5-15.5 per 100,000 among Chilean
Mapuche Indians, Bolivians, and Chilean Hispanics. Intermediate rates, 3.7 to 9.1 per
100,000, are reported from Peru, Ecuador, Colombia, and Brazil. Mortality rates are low in
North America, with the exception of high rates among American Indians in New Mexico (11.3
per 100,000) and among Mexican Americans.
The main associated risk factors identified so far include cholelithiasis (especially untreated
chronic symptomatic gallstones), obesity, reproductive factors, chronic infections of the
gallbladder, and environmental exposure to specific chemicals. These suspected factors likely
represent promoters of carcinogenesis. The main limitations of epidemiologic studies on
gallbladder cancer are the small sample sizes and specific problems in quantifying exposure
to putative risk factors. The natural history of gallbladder disease should be characterized to
support the allocation of more resources for early treatment of symptomatic gallbladder
disease in high-risk populations. Secondary prevention of gallbladder cancer could be
effective if supported by cost-effective studies of prophylactic cholecystectomy among
asymptomatic gallstone patients in high-risk areas.
INTRODUCTION
Gallbladder cancer was first described in 1777.1 More than 200 years later, late
diagnosis and absence of effective treatment for many patients remain typical
features of this disease.1,2 The prognosis is pooronly about a 32 percent five-year
survival rate for lesions confined to the gallbladder mucosa and a 10 percent oneyear survival rate for more advanced stages.3-6 The highest frequency of the disease
is found among females over the age of 65.7 There is a marked regional and ethnic
Dr. Lazcano-Ponce is Director,

Epidemiology Department, Population Health Research Center, National
Institute of Public Health,
Cuernavaca, Morelos, Mexico.
Dr. Miquel is Associate Professor,
Gastroenterology Department, Catholic University of Chile, Santiago,
Chile.
Dr. Muoz is Consultant, International Agency for Research on
Cancer, Lyon, France.
Dr. Herrero is Consultant, International Agency for Research on
Cancer, Lyon, France, and Costa Rica
Cancer Institute, San Jos, Costa
Rica.
Dr. Ferrecio is Assistant Professor,
Public Health Department, Catholic
University of Chile, Santiago, Chile.
Dr. Wistuba is Associate Professor,
Pathology Department, Catholic
Dr. Alonso de Ruiz is Head of
Cytopathology Laboratory, Autonomous National University of
Mexico, Mexico General Hospital,
Mexico City, DF.
Dr. Aristi Urista is Assistant
Professor, Cytopathology Laboratory,
Autonomous National University of
Mexico, Mexico General Hospital,
Mexico City, DF.
Dr. Nervi is Professor Titular,
Gastroenterology, Public Health and
Pathology Departments, Catholic
Original studies performed in Chile
and referenced herein were supported by a grant from Elliot Marcus, and
institutional grants number 1000739
from the Fondo Nacional Cientfico y
Tecnolgico (FONDECYT), and
1091/G224/ICU/CHILE from the
Italian Ministry of Foreign Affairs.
This study was partially funded by
the Mexican National Council of
Science and Technology and the
Mexican National Institute of Public
Health. The preparation of this manuscript was undertaken during the
period when Dr. Eduardo LazcanoPonce was a visiting scientist at the
International Agency for Research on
Cancer in Lyon, France.
This article is also available at
www.cancer.org.
Volume 51 Number 6 November/December 2001
349
Epidemiology and Molecular Pathology of Gallbladder Cancer
variation in the incidence of gallbladder

cancer. The highest mortality rates have been
reported among Chilean Mapuche Indians
and Hispanics,8,9 among Bolivians,10 North
American Indians,11 and Mexican Americans.12
Incidence rates are much lower in Europe13 and
India.14
There is a clear worldwide association
between chronic cholelithiasis and gallbladder
cancer. Aside from gallstones and female
gender, a number of associated risk factors
appear to favor the development of gallbladder
cancer either as neoplastic initiators, such as
unknown endo- and exobiotic mutagens, or
as neoplastic promoters, including chronic
inflammation and infection. Among the latter
factors, a link has been specifically proposed
between chronic bacterial infection of the
gallbladder with Salmonella typhi. In this
review, we analyze the worldwide geographical
distribution of gallbladder cancer and the
main etiologic hypotheses. We also provide
comments on molecular pathology, associated
risk factors, and potential for prevention
particularly in high-risk populations.
DESCRIPTIVE EPIDEMIOLOGY
Source of Data for the Estimation of
Incidence Rates
Specific age-adjusted incidence rates

(standardized for the world population) were
obtained from some countries from Volume
VII of Cancer Incidence in Five Continents15
and from selected reports where pertinent.
According to the Ninth Revision of the International Classification of Diseases (ICD-9),16
cancers of the biliary tract include tumors of
the gallbladder (156.0), extrahepatic bile ducts
(156.1), the ampulla of Vater (156.2), other and
biliary tract, part unspecified (156.8-9). There
is little geographical variation in the incidence
of tumors of the extrahepatic bile ducts and the
350
CA A Cancer Journal for Clinicians
ampulla of Vater. Greater geographical variation is observed for gallbladder cancer and for
other tumors as well as biliary tract cancer not
otherwise specified (NOS), which are classified
together.
In autopsy studies throughout the world,
gallbladder cancer represents 80 to 95 percent
of cancers of the biliary tree.We combine rates
for tumors of the biliary tract NOS (156.8156.9) with those of gallbladder cancer
(156.0), since it is likely that a significant
fraction of NOS cases were indeed gallbladder
cancer.
The cancer registries fulfilling the following
criteria were included in the present review:
1) availability of incidence rates in the period
under study (1988 to 1992); 2) a minimum of
10 cases reported; and 3) representation of the
highest rates for a given country. The selected
registries as were listed in rank order for
gallbladder cancer in various regions of the
world based on the incidence among females.
A total of approximately 30 areas from five
continents were assessed. Unpublished data
provided by the Cancer Registries in La Paz,
Bolivia, and Asuncion, Paraguay were included
with the permission of the corresponding
registries, as were data published from
Northern India.14 There were no incidence
rates of gallbladder cancer registered in Chile
the country with the highest mortality rate of
gallbladder cancer in the world.8,9 Pooled agespecific incidence rates for Latin America were
calculated using data from six cancer registries:
Trujillo, Peru; Quito, Ecuador; Cali, Colombia;
Porto Alegre, Brazil; Costa Rica; and
Montevideo, Uruguay. Data from 10 registries
from the SEER program in the US and from
12 Canadian Registries included in Volume VII
of Cancer Incidence in Five Continents were
included for North America.15
There is substantial geographic variability of
gallbladder cancer incidence as shown in
Figure 1. The rates for gallbladder cancer are
higher among women than men in all
FIGURE 1
Age-Standardized Incidence Rates of Gallbladder Cancer per 100,000 (World Population) for Selected
Areas Worldwide, 19881992
Females
Males
La Paz, Bolivia1
US, New Mexico, American Indians
Setif, Algeria
Trujillo, Peru
Quito, Ecuador
Cali, Colombia
Kracow, Poland
Porto Alegre, Brazil
North India2
Czech Republic
Slovakia
Latina, Italy
Nagasaki, Japan
Costa Rica
Granada, Spain
Canada, Northwest Territories
Asuncion, Paraguay1
Montevideo, Uruguay
US, Central California, Hispanics
Sweden
Haut Rhin, France
Graubunden, Switzerland
Croatia
Shanghai, China
South Australia
Israel, All Jews
Canada
US SEER, Whites
US SEER, Blacks
UK (England, Wales)
20
15
10
Rate per 100,000
10
15
20
Rate per 100,000
Source: Parkin DM, Whelan SL, Ferlay J, Raymond L, and Young J. Eds. Cancer Incidence in Five Continents, Vol VII
(IARC Scientific Publications No. 143) Lyon, IARC, 1997.
1
Unpublished data from La Paz, Bolivia and Asuncion, Paraguay are shown with permission of the corresponding
registries.
2
Dhir V, Mohandas KM. Epidemiology of Digestive Tract Cancers in India IV. Gall bladder and pancreas. Indian J
Gastroenterol 1999;18(1):24-28.
populations included in the analysis. The rates

are highest in women from La Paz, Bolivia
(15.5 per 100,000). Intermediate rates (from
3.7 to 9.1 per 100,000) are reported in Trujillo,
Peru; Quito, Ecuador; Cali, Colombia; Porto
Alegre, Brazil; Asuncion, Paraguay; and
Montevideo, Uruguay. In North America, low
rates predominate, with the exception of high
rates reported among Indians in New Mexico
(11.3 per 100,000) and intermediate rates
among female immigrants from Latin America.
In Europe, the highest incidence is found in
the countries of Eastern Europe: Poland

(Kracow), the Czech Republic, and Slovakia.13
Likewise, population-based data indicate that
the incidence of gallbladder cancer is relatively
high in northern Indian cities14 (Uttar, Pradesh,
Bihar, Orissa,West Bengal, and Assam). Except
for some high-risk areas such as Nagasaki,
Japan, the rates in other regions of the world
are relatively low.
In males, the highest incidence rates of
gallbladder cancer are reported from La Paz,
Bolivia (7.5 per 100,000) and Quito, Ecuador
351
(4.1 per 100,000). The highest female/male

ratios ( 3) were seen in Porto Alegre, Brazil
(4.69), in Israel (3.6), and among Hispanics in
Central California (3.0). The female
predominance was less marked in Nagasaki,
Japan, the UK (England and Wales), and among
black people in the US. The incidence
increases progressively with age, both in males
and females, in all populations included in the
survey. The increase in males is more marked
after 50 years of age in Latin America.
In summary, there is prominent geographic
variability of gallbladder cancer incidence,
which correlates with the prevalence of
gallstones. The populations with the highest
incidence are Chileans,17 Bolivians,10 North
American Indians,11 Mexican-Americans,12,18
and Central Europeans,13 all of whom also have
high prevalence of cholelithiasis.The high rates
observed in Latin America are primarily in
populations with high levels of Indian
mixture,10,17 supporting the concept that
increased susceptibility depends on genetic
factors that predispose people to gallbladder
cancer either as primary factors, or secondarily
as promoters by favoring the development of
cholesterol gallstones.
TRENDS IN AGE-ADJUSTED MORTALITY RATES
Mortality trends in the age-adjusted rates

(standardized using the world population) over a
16-year period (1980 to 1995) were evaluated in
twelve countries included in the World Health
Organization (WHO) database (US, Canada,
Hungary, United Kingdom, Italy, Austria, France,
Spain, Japan, and Australia),19 and over a 10-yearperiod in Chile (1982 to 1991, standardized by
the Chilean population of 1985).9
In Trujillo, Peru; Quito, Ecuador; Cali,
Colombia; Porto Alegre, Brazil; Latina, Italy;
and Costa Rica, approximately 20 percent of
gallbladder cancer and biliary tract tumors in
352
women were classified as NOS. In contrast, in

Nagasaki, Japan; among Hispanics of Central
California; in Haut Rhin, France; Graubunden,
Switzerland; Croatia; Shanghai, China; and in
the UK (England and Wales) this proportion
was less than five percent (Table 1). In Chile, 80
percent of adenocarcinoma of the biliary tree
originates in the gallbladder, as assessed by
pathological criteria.8
These gross differences probably reflect
variations in the clinical or pathological
criteria used to identify the exact origin of the
adenocarcinoma of the biliary tree, which in
the majority of the cases can only be diagnosed
through laparotomy or necropsy. In spite of
these difficulties, there is general agreement
in the literature that the majority of
adenocarcinoma of the biliary tree originates
in the gallbladder mucosa.
The highest mortality rate of gallbladder
cancer in the world, 35 per 100,000
inhabitants, is found in Southern Chile (the
region of the Araucania), which is inhabited by
Chilean Hispanics and Mapuche Indians. This
high mortality rate contrasts with the mean of
the whole country, which had an age-adjusted
mortality rate of 16.2 for women and 5.4 per
100,000 for men in 1991. These rates have
been inversely correlated with the rates of
cholecystectomy during the 1980s and early
1990s.20 Whereas the cholecystectomy rate was
44 percent among Chilean Hispanics with
gallbladder disease (including cholelithiasis and
cholecystectomy); the cholecystectomy rate for
Mapuche Indians from Southern Chile with
gallstones was only 8.6 percent.17
Analysis of mortality trends of a series of
nine countries is shown in Figures 2 and 3. In
the US, Canada, and Australia, mortality rates
for both men and women decreased over the
16-year period under study; while in areas with
high risksuch as in Japanan increase is
observed. Trends in mortality from gallbladder
cancer for four European countries are
TABLE 1
International Variation in Cancer of the Gallbladder and of the Biliary Tract Not Otherwise Specified
World Age-Adjusted Incidence Rates per 100,000
Cancer Registry
Gallbladder Cancer
Males
156.0
Females
Other and not

specified
156.8-9
Males
Females
Total
Female/Male Ratio
156.0 + 156.8-9
Males
Females
New Mexico, US,

American Indians
3.8
10.3
1.0
3.8
11.3
2.97
Setif, Algeria
3.6
9.8
0.3
0.8
3.9
10.6
2.71
Trujillo, Peru
2.3
6.9
1.0
2.2
3.3
9.1
2.75
Quito, Ecuador
2.1
5.5
2.0
2.2
4.1
7.7
1.80
Cali, Colombia
1.2
4.9
1.6
2.6
2.8
7.5
2.67
Kracow, Poland
3.1
5.9
0.6
0.6
3.7
6.5
1.75
Porto Alegre, Brazil
0.7
3.9
0.6
2.2
1.3
6.1
4.69
Czech Republic
2.6
5.1
0.4
0.6
3.0
5.7
1.90
Slovakia
1.8
5.0
0.3
0.3
2.1
5.3
2.52
Latina, Italy
1.8
3.9
0.6
1.0
2.4
4.9
2.04
Nagasaki, Japan
2.7
4.4
0.3
0.2
3.0
4.6
1.53
Costa Rica
1.0
3.2
1.0
1.3
2.0
4.5
2.25
Granada, Spain
1.7
3.5
0.5
0.6
2.2
4.1
1.86
Northwest Territories,
Canada
2.1
4.0
2.1
4.0
1.90
Montevideo, Uruguay
1.2
3.0
0.6
0.7
1.8
3.7
2.05
Central California, US,

Hispanics
1.0
3.5
0.2
0.1
1.2
3.6
3.00
Sweden
1.2
2.9
0.3
0.4
1.5
3.3
2.20
Haut Rhin, France
1.4
2.9
0.1
1.5
2.9
1.93
Graubunden, Switzerland
0.9
2.5
0.1
1.0
2.5
2.50
Croatia
1.0
2.3
0.1
1.0
2.4
2.40
Shanghai, China
1.2
2.2
0.1
0.1
1.3
2.3
1.77
South Australia
0.7
2.0
0.2
0.2
0.9
2.2
2.44
Israel, All Jews
0.4
1.7
0.1
0.1
0.5
1.8
3.60
Canada
0.7
1.2
0.1
0.1
0.8
1.3
1.62
US SEER, Whites
0.4
1.0
0.1
0.1
0.5
1.1
2.20
US SEER, Blacks
0.6
0.8
0.1
0.1
0.7
0.9
1.28
UK (England, Wales)
0.4
0.6
0.1
0.5
0.6
1.20
Source: Parkin DM, Whelan SL, Ferlay J, Raymond L, and Young J. Eds. Cancer Incidence in Five Continents, Vol. VII. (IARC Scientific
Publications No. 143). International Agency for Research on Cancer, Lyon, France, 1997.
353
FIGURE 2
Trends in Mortality Rates for Gallbladder Cancer in US, Canada, Europe, Japan, and Australia,* 19801995
*Age-standardized rate per 100,000.
summarized in Figure 2. In countries with the

highest rates (Hungary) and with the lowest
rates (United Kingdom), a marked decline
(especially in females) is observed. In Italy and
Spain, two other countries with low rates, little
variation is observed.
On the other hand, one of the higher
mortality rates in the world was observed in
Chile (10.8 per 100,000 in 1991) with a
marked increase during the period from 1982
to 1991 as shown in Figure 3, a trend
concurrent with declining cholecystectomy
rates during the same period.20 This last factor
was probably a consequence of the health
policy that reallocated resources from the
treatment of adult chronic diseases to pediatric
and obstetrical health care.17
354
MORPHOLOGY AND PATHOGENESIS
Although it has been established that

dysplasia and carcinoma in situ21 precede most
gallbladder carcinomas, relatively little is
known about the natural history of these
precursor lesions. Most dysplasias and
carcinomas in situ are diagnosed after
cholecystectomy when the entire lesion is
removed.22 However, there is indirect evidence
that progression could occur from precursor
lesions to infiltrating carcinoma. Dysplasia and
carcinoma in situ are found in the mucosa
adjacent to most carcinomas of the gallbladder,
sometimes separated by histologically normal
epithelium.22,23
FIGURE 3
Trends in Mortality Rates for Gallbladder Cancer in Chile,* 19821991
*Age-standardized rate per 100,000.

Source: Ferrecio C, Chianalae J, Gonzalez C, Nervi F. Epidemiologia descriptiva del cancer digestivo en Chile (19821991):
Una approximacion desde la mortalidad. 1995 Ed. Alfa Beta, Santiago, Chile.
Patients with dysplasia24 and carcinoma in

situ22 are 15 and 5 years younger, respectively,
than those with invasive carcinoma. If multiple
sections of gallbladders removed for
cholelithiasis are examined, dysplasia and
carcinoma in situ are detected in 13.5 percent
and 3.5 percent of the cases, respectively.22
There is consensus that if dysplasia and
carcinoma in situ are found, multiple additional
sections of the gallbladder should be examined
to rule out invasive cancer.
Over 90 percent of gallbladder carcinomas
are adenocarcinoma.24,25 On gross examination,
approximately 10 to 37 percent of the
gallbladder carcinomas cannot be identified
with certainty,24 and their macroscopic findings
are similar to those of chronic cholecystitis.
Gallstones are found in almost all cases of
gallbladder cancer (78 percent to 85

percent).8,22,26 Most carcinomas (60 percent)
originate in the fundus of the gallbladder, 30
percent in the body, and 10 percent in the
neck.22 The prevalence of gallbladder cancer
associated with diffuse calcification of the
gallbladder (so-called porcelain gallbladder) is
12 to 21 percent.26 Most gallbladder cancers are
well-to-moderately differentiated adenocarcinomas. Some of these are papillary lesions
that grow predominantly into the lumen of the
gallbladder.
The main prognostic factor for gallbladder
carcinoma is the clinical or pathologic stage.27
Two staging systems for gallbladder carcinoma
have been widely used. In 1976, Nevin et al.1
proposed a staging system in which Stage I
cancer is limited to the mucosa; Stage II to the
355
muscular layer; and Stage III to the perimuscular layer. Stage IV shows metastases in
the lymph nodes; and Stage V has hepatic or
other distant metastases. There is a correlation
between level of tumor invasion in the
gallbladder wall and the presence of lymph
node metastases.24,27
In a large series of patients with gallbladder
carcinoma,24 no lymph node metastases were
detected in gallbladder tumors invading the
muscularis only, whereas 62 percent of the
tumors invading the serosa showed regional
lymph node metastasis. Patients with localized
stage disease have much better survival rates
(Stages I to III, five-year survival rate of 41.9
percent) than those with regional (Stage IV, 3.8
percent) or distant (Stage V, 0.7 percent)
metastasis.27,28 Similar results have been
obtained using the TNM staging system of the
International Union Against Cancer (UICC)
and American Joint Committee on Cancer
(AJCC), which has proven to be a good system
for comparison of surgical results and
prediction of patient outcome.29,30
Briefly, under the TNM classification: Stage I is
a tumor limited to the mucosa or muscular layers;
Stage II tumors invade the peri-muscular tissue;
Stage III tumors invade serosa, liver less than two
centimeters, or have regional (hepato-duodenal
ligament) lymph node metastasis; and Stage IV
shows liver invasion greater than two centimeters
(Stage IVA), or metastasis to nonregional lymph
nodes and/or distant organs (Stage IVB).
The gallbladders very thin wall and the
discontinuous muscular layer are believed to
facilitate tumor invasion and contribute to the
advanced local and regional disease usually
present at the time of diagnosis.25
Tsukada et al.31 reported that the five-year
survival rate in patients with TNM Stage I
tumors was 91 percent; 85 percent in patients
with Stage II tumors; 40 percent in patients
with Stage III tumors; and 19 percent in
patients with Stage IV tumors. In the same
study, in patients with TNM Stage III and
356
Stage IV tumors the five-year survival rate was

52 percent after curative resection. This was
significantly better than the five percent fiveyear survival rate after a noncurative resection.
MOLECULAR PATHOLOGY
While considerable progress has been made

in understanding the molecular pathogenesis of
several human neoplasms, information about
the genetic changes involved in gallbladder
carcinogenesis is more limited.32 Most of these
studies have focused on ras,33 TP53, and
p16Ink4/CDKN2 34 gene abnormalities and
deletions (loss of heterozygosity) at several
chromosomal regions harboring known or
putative tumor suppressor genes.32,34-35
The reported prevalence rates of ras gene
mutations in series of gallbladder carcinomas is
quite variable.7,34,36-37 While ras mutations were
not detected in some small series,7 two other
groups reported greater of K-ras mutations in
39 to 59 percent of patients.34,38 All the
mutations occurred at codon 12 of the K-ras
gene.7,34,36-37 However, this site has been the
most intensively analyzed ras gene region. A
greater frequency (50 to 83 percent) of K-ras
gene mutations has been reported in
gallbladder carcinomas from patients having
anomalous junction of the pancreatico-biliary
duct39-42 suggesting that reflux of pancreatic
juice might contribute to the carcinogenic
process.
TP53 gene abnormalities are frequent in
gallbladder cancers.43 Although the frequency
of p53 immunostaining in gallbladder
carcinoma varies widely (ranging from 35 to
92 percent), two thirds of the studies show a
frequency greater than 50 percent.39,44-60 Most
of the TP53 mutation studies on gallbladder
carcinoma have confirmed the immunohistochemical findings.39,50,56,59,60 Analyses of
exon 5 to 8 of TP53 have demonstrated point
mutations in 31 to 70 percent of gallbladder
carcinomas,39,50,56,59-61 and no particular hot

spot has been identified.
In addition, deletions at the TP53 locus
(17p13) have been frequently (58 to 92
percent) reported in gallbladder carcinomas,34,35
indicating that the inactivation of the TP53
plays an important role in the pathogenesis of
this neoplasm.Yokoyama et al.60 compared the
TP53 mutations in gallbladder carcinomas
from two high-prevalence areas, Japan and
Chile. No differences in the frequencies of
TP53 mutations between both groups were
detected. However, mutations from Japanese
cases comprised transversions in 31 percent of
cases with 46 percent of all mutations taking
place at the A:T pair.
Whereas, in contrast, the TP53 mutation
spectrum for Chilean cases demonstrated a
very high incidence of transitions (100
percent) and of mutations at G:C pairs. While
no Japanese cases showed G:C to A:T
transitions at CpG sites, these were relatively
frequent (33 percent) in Chilean cases.
Frequent transitions, especially at CpG sites, are
features of mutational spectra found in cancers
not strongly linked to specific exogenous
carcinogens.62,63 There are a few studies that
suggest that CDKN2 gene, also known as
MTS1 or p16INK4, may play a role in gallbladder
carcinogenesis.43 Deletions at the CDKN2
region (9p21) have been reported in half of
gallbladder cancers.40 However, there are no
comprehensive studies at present on the
CDKN2 gene status and the mechanism
of inactivation in gallbladder carcinoma,
including deletion, mutation, methylation,
homozygous deletions, and protein expression
analysis.
Although no comprehensive genome-wide
allelotyping of gallbladder carcinoma has been
published, two reports34,35 suggest that several
chromosomal regions harboring known or
putative tumor suppressor genes may undergo
deletion in this neoplasm. These chromosomal
regions, other than TP53 and CDKN2 gene
loci, are 3p (20 to 52 percent); 5q21 (APCMCC genes, 6 to 66 percent); 8p22-24 (22 to
44 percent); 13q14 (RB gene, 20 to 30
percent); and 18q22 (DCC gene, 18 to 31
percent).35
The exact sequence of molecular changes
that lead to neoplastic transformation in the
gallbladder epithelium remains uncertain.
More detailed understanding of the earliest
molecular abnormalities may eventually
provide methods for risk assessment and early
detection of gallbladder carcinoma.The excess
accumulation of p53 protein in gallbladder
dysplasia (0 to 32 percent) and carcinoma in
situ lesions (45 to 86 percent)44,46,51,54 suggests
that TP53 abnormality is an early event. The
presence of deletions at the TP53 locus
in histologically normal epithelium near
gallbladder carcinoma,34 and of TP53 mutations in precursor lesions, (Miquel et al., in
preparation), indicate an early and important
role of TP53 inactivation.
Other early genetic changes include loss of
heterozygosity at 9p21 (CDKN2 gene) and
18q21 (DCC gene) regions.34 Data regarding
K-ras gene mutations in precursor lesions are
controversial.44,46,51,54 While some studies fail to
demonstrate K-ras mutation in precursor
gallbladder lesions,34,36 others report a relatively
high prevalence (22 to 44 percent) in precursor
lesions accompanying invasive tumors.1,34,42
Interestingly, no differences in the frequency
and spectrum of K-ras gene mutations were
detected in nonmalignant gallbladder
epithelium of patients with anomalous
junction of the pancreato-biliary duct, with
and without gallbladder carcinoma in Japan.40,42
The role of adenomas as precursors of
gallbladder carcinoma is still unclear and
controversial. Molecular analyses of gallbladder
adenomas failed to detect the genetic changes
frequently found in gallbladder carcinomas and
their known precursor lesions,32 suggesting that
adenomas might not be precursors of this
neoplasm.
357
RISK FACTORS
Among other risk factors, a number of

genetic, dietary factors, endo- and exobiotics,
and chronic gallbladder infections, have been
associated with the development of gallbladder
cancer. However, the primary risk factor of
gallbladder cancer as reported in all studies is
gallstone disease.1-6,8-14 Gallbladder cancer has
also been associated with multiple familial
polyposis/Gardner syndrome,64 Peutz-Jeghers
syndrome,65 porcelain gallbladder,66 and
anomalous pancreato-biliary ductal union.67
There has also been a consistently higher risk
in women than in men, independent of
cholelithiasis.3,4,8,12
Gallbladder Cancer and Gallstones
The association between cholelithiasis and

gallbladder cancer has been known since
186168-69 and is supported by autopsy studies,
screening surveys, and hospital-based casecontrol studies (Table 2).1-6,8-14,70-79 Cholelithiasis
is more frequent in gallbladder cancer than in
extrahepatic bile ducts cancer. In a recent casecontrol study performed in Australia, Canada,
Holland, and Poland, a history of gallbladder
symptoms requiring medical attention was
identified as one of the major risk factors for
gallbladder cancer.73
This association was described in patients
who had shown clinically symptomatic
gallbladder disease for at least 20 years prior to
gallbladder cancer diagnosis.70,71,73 The
theoretical basis for this phenomenon is that
the inflammation, chronic trauma, and
infection in approximately one third of
gallstone patients promotes epithelial dysplasia
and adenocarcinoma formation.79 For this
reason, it has been suggested that larger stones
have a greater impact on the risk of developing
gallbladder cancer, possibly reflecting greater
duration and intensity of epithelial irritation.
Diehl reported that in subjects with gallstones
358
larger than three centimeters, the risk of

gallbladder cancer is 10 times greater than in
subjects with gallstones smaller than one
centimeter.80 Warren et al.81 reported a larger
mean stone diameter among 19 subjects with
gallbladder cancer (20.3 mm) when compared
with 883 subjects undergoing surgery for
gallstones (11.9 mm). In contrast, Moerman et
al.82 found no association between stone size
and gallbladder cancer.
Cholesterol gallstones represent approximately 80 to 90 percent of all gallstone cases
in the Western world and are considered to be
a promoting factor. There is little available
information as to whether pigment or
cholesterol stones have a different activity as
promoters of gallbladder cancer development.
Some constituents of bile might be
endogenous carcinogens.83 It has been
postulated that mutagenic endobiotic derivatives, presumably from sterol bacterial
metabolites, might be the putative initiators.
Mutagenic factors were isolated from stone
extracts of a patient with a symptomatic
choledochal cyst (a high-risk precancerous
condition) with chronic bacterial infection of
the biliary tree.84
Only a small fraction (less than one percent)
of patients with cholelithiasis develop
gallbladder cancer,85 and approximately 20
percent of gallbladder cancer patients show no
evidence of previous cholelithiasis.86 However
in high-risk areas, this figure is certainly higher
and increases markedly with age.8-12
Gallstone Predisposition
The etiology of cholesterol cholelithiasis, like

any other chronic disease, is thought to involve
the interaction of genetic and environmental
factors.17,20,87 The risk factors for cholesterol
gallstones have been mainly associated with
hypersecretion of biliary cholesterol, gallbladder
hypomotility, and stasis.88 These conditions are
positively correlated with age, female sex, genetic
TABLE 2
Summary of Studies of Gallstones Disease and Gallbladder Cancer
Cohort Studies
Site and Author
Population
Risk Factors
OR (CI 95%)
Denmark
Chow et al. 199975
60,176
Danish Cancer Registry
Gallstones
Years of follow-up
1-4 years 4.6 (3.0-6.7)
> 4 years 2.7 (1.5-4.4)
Case-Control Studies
Site and Author
Population
Risk Factors
OR (CI 95%)
New York, US
Khan et al. 199973
69 cases
138 controls
Cholelithiasis and
biliary tract cancer
19.5 (6.4-59.4)
Australia, Canada,
Netherlands, and Poland
Zatonski et al. 199776
196 cases
1515 controls
History of gallbladder symptoms

Symptoms 20 years earlier
4.4 (2.6-7.5)
6.2 (2.8-13.4)
Bolivia and Mexico

Strom et al. 19959
84 cases
126 controls without gallstones
264 controls with colelithiasis
Family history of gallstones
3.6 (1.3-11.4)
WHO Collaborative
Study 198980
58 cases
355 controls
Gallstones
2.3 (1.2-4.4)
Cross-Sectional Studies
Site and Author
Population
Risk Factors
OR
Kofu, Japan
Okamoto et al. 199974
194,767
Screening surveys
Gallstones
Increased risk
p < .01
Tokyo, Japan
Kimura et al. 198968
4,482 autopsy surveys
Gallstones
Increased risk
p < .01
Chile
Nervi et al.8 1988
14,768 autopsy surveys
Gallstones
7
p < .05
Rochester, Minnesota
Maringhini et al. 198781
2,583 screening surveys
Gallstones
Increased risk in men

p < .05
factors, obesity, multiple pregnancies, a family

history of gallstones, and low levels of physical
activity.89-101 Obesity and high-energy intake have
been positively associated with the risk of
gallstones in cohort102 and case-control103 studies.
Conversely, coffee99 and alcohol91,97,101 were
associated with a decreased risk of gallstones
in some studies. There is evidence that
endogenous104 and exogenous estrogens105 and

pregnancy increase the risk of cholelithiasis.106
Most environmental factors, including diet,
have been considered a consequence of the
westernization of modern societies.87,99 The
association of diet and gallbladder cancer
remains unclear. Most likely, dietary factors
might influence the production of gallbladder
359
cancer through potential effects on cholesterol

gallstone formation.The principal independent
factors associated with gallstone disease in
several studies were female sex, greater age,
high BMI, slightly higher serum glucose,
increasing parity, and low plasma HDL
cholesterol.17,18,107-109
Genetic Epidemiology of Gallbladder Diseases
There are some reports of familial

tendencies toward gallbladder cancer, although
they are based on a very small number of
patients.110 A potential relationship between
genetic predisposition and gallbladder cancer
incidence has been suggested by population
studies of gallstone prevalence in different
latitudes.108-110 A recent study including three
ethnic groups (Mapuche Indians and Hispanics
from Chile and Maoris from Easter Island)17
concluded that cholesterol lithogenic genes are
highly prevalent among Chilean Indians and
Hispanicspopulations with the highest
mortality rates of gallbladder cancer.9
These studies strongly supported the thesis
that genetic factors play a major role in some
specific populations by favoring the production
of lithogenic bile.88 The genetic hypothesis of
cholesterol gallstone formation has also been
supported by family studies.111 Specific
polymorphisms of apoproteins and plasma
cholesterol ester transfer proteins seem to be
correlated with cholesterol cholelithiasis.112
Chronic Gallbladder Infection
During the last two decades, epidemiological evidence has linked chronic infections
with several cancers; examples include hepatitis
B and hepatitis C viruses with liver cancer;
H. pylori and gastric cancer; and liver flukes
with cholangiocarcinoma.113,114 Chronic
infection by Salmonella typhi has been
associated with an increased risk of gallbladder
cancer. Caygill et al.115,116 hypothesized that
360
typhoid and paratyphoid chronic carriage with

concomitant gallstone formation favors mixed
bacterial infection and higher risks of gallbladder carcinogenesis. Singh et al.117 proposed
that the Salmonella carrier state has a significant association with gallbladder cancer
independent of gallstones.
However, the possible carcinogenic
mechanism involved has not yet been clarified.
It is important to note that Salmonella sp. have
-glucuronidase activity, therefore hepatic
inactivation of exogenous carcinogenic
xenobiotics by glucuronidation could be
reversed after bacterial hydrolysis of glucuronides.118 Strom et al.10 reported from
Bolivia and Mexico a 12-fold increase in risk
of gallbladder cancer in subjects with a history
of typhoid fever (CI 95 percent 1.5-598),
which unfortunately could not be corroborated with serological assays. Additionally, Nath et al.,119 in cultures of bile samples,
found Salmonella typhi more frequently in
patients with gallbladder cancer than in
subjects with gallstones and free of biliary
neoplasia.
Occupation
Increased risk of gallbladder cancer has been

related among workers in the oil, paper,
chemical, shoe, textile, and cellulose acetate
fiber manufacturing industries suggesting
occupational exposure to carcinogens.120,121
A higher risk of gallbladder cancer was also
found among miners exposed to radon.122
PREVENTION AND FUTURE TRENDS
Primary prevention of gallbladder cancer is

unlikely in the near future, since many
etiologic factors remain unknown. However,
prevention of cholesterol gallstone formation is
an important intervention that would certainly
have a great impact in decreasing the incidence
of gallbladder cancer, particularly in high-risk

areas. Availability of adequate and prompt
laparoscopic cholecystectomy for symptomatic
gallstone patients should be effective for
secondary prevention.
Relationship between Cholecystectomy Rates and
Gallbladder Cancer Incidence Rates
Cholecystectomy is the most frequent of all

intra-abdominal operations. It is estimated that
in the US more than 550,000 cholecystectomies are performed yearly within an
estimated population of 20,000,000 at-risk
patients with asymptomatic gallstones.123 The
US cholecystectomy rate was 47.6 per 1000
inhabitants in 1993, whereas the rate was only
25.1 per 1000 inhabitants in 1992 in Chile, in
spite of a three to four times higher prevalence
of cholelithiasis.9,20,124 The incidence of
gallbladder cancer has diminished considerably, in an inverse correlation to the
increase in cholecystectomies in developed
countries.125-127
In
Chile,
while
the
reported
cholecystectomy rates decreased in the 1980s,
time trends revealed an increase in the
incidence of gallbladder cancer. 9,20,124 In
addition, the extremely low frequency of
cholecystectomies found among Mapuche
Indians with gallstones compared with
Chilean Hispanics and Maoris 17 might
explain the high mortality rates of gallbladder
cancer in Southern Chile in areas inhabited
by Mapuche Indians. A descriptive survey
published in 19959 showed that gallbladder
cancer mortality rates were over four times
higher in towns with a high proportion of
Mapuche Indians (35 per 100,000 inhabitants
in the region of the Araucania, Southern
Chile), compared with towns with a
predominantly Hispanic population (8 per
100,000 inhabitants in the municipality of La
Florida, Santiago).9
Elective Laparoscopic Cholecystectomy for

Secondary Prevention of Gallbladder Cancer
Three studies have analyzed the potential

benefits of prophylactic cholecystectomy for
low-risk populations. Based on decision
analysis models, it was concluded that the
benefits of prophylactic cholecystectomy were
irrelevant when compared with expectant
management of gallstone disease.128-130 The role
of prophylactic cholecystectomy in high-risk
populations, including North American
Indians, Mexican Americans, Chileans, and
Bolivians, has yet to be reported. A recent
cost-effectiveness analysis of screening and
treatment among Chilean women under 40
years old with asymptomatic cholelithiasis,
showed that prophylactic laparoscopic cholecystectomy can significantly benefit the
population at a very low incremental cost
(Puschel et al., personal communication,
Santiago, 2000).
CONCLUSIONS AND PERSPECTIVES
Little is still known about the etiology of

gallbladder cancer.This overview of gallbladder
cancer and the annual incidence of gallbladder
cancer in various countries offers a
comparative picture of the descriptive
epidemiology of the disease, a summary of
etiologic studies, and a discussion of associated
risk factors, especially cholesterol gallstone
diseasethe major risk factor of gallbladder
cancer. It is important that several remaining
points be elucidated. Further investigation for
this extremely lethal cancer is urgently needed.
What do we really know for sure and what
needs to be done?
1) The process of gallbladder carcinogenesis
is usually related to a history of cholelithiasis,
which is frequently present for at least 20 years
before the tumor appears.
2) Although several risk factors have been
361
identified for cholesterol stones (obesity, multiple pregnancies, low plasma HDL, female
hormones, and insulin resistance), they do not
explain the full picture. Genetic susceptibility
is likely to play an important role.
3) Because only a small fraction of patients
with cholesterol gallstones develop gallbladder
cancer, it is important to identify the factors
that induce progression from cholelitiasis to
gallbladder cancer. This may allow the
identification and early treatment of gallstones
of susceptible individuals within high-risk
populations.
4) The role of chronic infection in the
development of gallbladder cancer deserves
further research. It is likely that aside from
chronic Salmonella carriers, a number of other
bacterial species chronically inhabiting the
gallbladder might be important etiologic
factors.
5) The limitations of epidemiologic gallbladder cancer studies have included the small
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Epidemiology and Molecular Pathology of Gallbladder Cancer

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CA Cancer J Clin 2001;51:349-364