Ferrecio, Ignacio I. Wistuba, Patricia Alonso de Ruiz, Gerardo Aristi Urista and Eduardo C. Lazcano-Ponce, J. F. Miquel, Nubia Muñoz, Rolando Herrero, Catterina
Epidemiology and Molecular Pathology of Gallbladder Cancer
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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, latediagnosis and absence of effective treatment for many patients remain typicalfeatures of this disease.1,2 The prognosis is poor—only about a 32 percent five-yearsurvival rate for lesions confined to the gallbladder mucosa and a 10 percent one-year survival rate for more advanced stages.3-6 The highest frequency of the diseaseis found among females over the age of 65.7 There is a marked regional and ethnic
Epidemiology and Molecular Pathologyof Gallbladder CancerEduardo C. Lazcano-Ponce, MD, PhD; J. F. Miquel, MD; Nubia Muñoz, MD;Rolando Herrero, MD, PhD; Catterina Ferrecio, MD; Ignacio I.Wistuba, MD;Patricia Alonso de Ruiz, MD; Gerardo Aristi Urista, MD; Flavio Nervi, MD
Dr. Lazcano-Ponce is Director,Epidemiology Department, Popula-tion Health Research Center, NationalInstitute of Public Health,Cuernavaca, Morelos, Mexico.
Dr. Miquel is Associate Professor,Gastroenterology Department, Cath-olic University of Chile, Santiago,Chile.
Dr. Muñoz is Consultant, Inter-national Agency for Research onCancer, Lyon, France.
Dr. Herrero is Consultant, Inter-national Agency for Research onCancer, Lyon, France, and Costa RicaCancer Institute, San José, CostaRica.
Dr. Ferrecio is Assistant Professor,Public Health Department, CatholicUniversity of Chile, Santiago, Chile.
Dr. Wistuba is Associate Professor,Pathology Department, CatholicUniversity of Chile, Santiago, Chile.
Dr. Alonso de Ruiz is Head ofCytopathology Laboratory, Auto-nomous National University ofMexico, Mexico General Hospital,Mexico City, DF.
Dr. Aristi Urista is AssistantProfessor, Cytopathology Laboratory,Autonomous National University ofMexico, Mexico General Hospital,Mexico City, DF.
Dr. Nervi is Professor Titular,Gastroenterology, Public Health andPathology Departments, CatholicUniversity of Chile, Santiago, Chile.
Original studies performed in Chileand referenced herein were support-ed by a grant from Elliot Marcus, andinstitutional grants number 1000739from the Fondo Nacional Científico yTecnológico (FONDECYT), and1091/G224/ICU/CHILE from theItalian Ministry of Foreign Affairs.
This study was partially funded bythe Mexican National Council ofScience and Technology and theMexican National Institute of PublicHealth. The preparation of this man-uscript was undertaken during theperiod when Dr. Eduardo Lazcano-Ponce was a visiting scientist at theInternational Agency for Research onCancer in Lyon, France.
variation in the incidence of gallbladdercancer. The highest mortality rates have beenreported among Chilean Mapuche Indians and Hispanics,8,9 among Bolivians,10 NorthAmerican Indians,11 and Mexican Americans.12
Incidence rates are much lower in Europe13 andIndia.14
There is a clear worldwide associationbetween chronic cholelithiasis and gallbladdercancer. Aside from gallstones and femalegender, a number of associated risk factorsappear to favor the development of gallbladdercancer either as neoplastic initiators, such asunknown endo- and exobiotic mutagens, or as neoplastic promoters, including chronicinflammation and infection. Among the latterfactors, a link has been specifically proposedbetween chronic bacterial infection of thegallbladder with Salmonella typhi. In thisreview, we analyze the worldwide geographicaldistribution of gallbladder cancer and the main etiologic hypotheses. We also providecomments on molecular pathology, associatedrisk 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) wereobtained 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 Inter-national Classification of Diseases (ICD-9),16
cancers of the biliary tract include tumors ofthe gallbladder (156.0), extrahepatic bile ducts(156.1), the ampulla of Vater (156.2), other andbiliary tract, part unspecified (156.8-9). Thereis little geographical variation in the incidenceof tumors of the extrahepatic bile ducts and the
ampulla of Vater. Greater geographical vari-ation is observed for gallbladder cancer and forother tumors as well as biliary tract cancer nototherwise specified (NOS), which are classifiedtogether.
In autopsy studies throughout the world,gallbladder cancer represents 80 to 95 percentof cancers of the biliary tree.We combine ratesfor tumors of the biliary tract NOS (156.8-156.9) with those of gallbladder cancer(156.0), since it is likely that a significantfraction of NOS cases were indeed gallbladdercancer.
The cancer registries fulfilling the followingcriteria were included in the present review:1) availability of incidence rates in the periodunder study (1988 to 1992); 2) a minimum of10 cases reported; and 3) representation of thehighest rates for a given country.The selectedregistries as were listed in rank order forgallbladder cancer in various regions of theworld based on the incidence among females.
A total of approximately 30 areas from fivecontinents were assessed. Unpublished dataprovided by the Cancer Registries in La Paz,Bolivia, and Asuncion, Paraguay were includedwith the permission of the correspondingregistries, as were data published fromNorthern India.14 There were no incidencerates of gallbladder cancer registered in Chile—the country with the highest mortality rate ofgallbladder cancer in the world.8,9 Pooled age-specific incidence rates for Latin America werecalculated using data from six cancer registries:Trujillo, Peru; Quito, Ecuador; Cali, Colombia;Porto Alegre, Brazil; Costa Rica; andMontevideo, Uruguay. Data from 10 registriesfrom the SEER program in the US and from12 Canadian Registries included in Volume VIIof Cancer Incidence in Five Continents wereincluded for North America.15
There is substantial geographic variability ofgallbladder cancer incidence as shown inFigure 1. The rates for gallbladder cancer arehigher among women than men in all
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Epidemiology and Molecular Pathology of Gallbladder Cancer
populations included in the analysis.The ratesare highest in women from La Paz, Bolivia(15.5 per 100,000). Intermediate rates (from3.7 to 9.1 per 100,000) are reported in Trujillo,Peru; Quito, Ecuador; Cali, Colombia; PortoAlegre, Brazil; Asuncion, Paraguay; andMontevideo, Uruguay. In North America, lowrates predominate, with the exception of highrates reported among Indians in New Mexico(11.3 per 100,000) and intermediate ratesamong 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 thatthe incidence of gallbladder cancer is relativelyhigh in northern Indian cities14 (Uttar, Pradesh,Bihar, Orissa,West Bengal, and Assam). Exceptfor some high-risk areas such as Nagasaki,Japan, the rates in other regions of the worldare relatively low.
In males, the highest incidence rates ofgallbladder cancer are reported from La Paz,Bolivia (7.5 per 100,000) and Quito, Ecuador
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20 15 10 5 0 0 5 10 15 20
Rate per 100,000 Rate per 100,000
Females MalesLa Paz, Bolivia1
US, New Mexico, American IndiansSetif, AlgeriaTrujillo, Peru
Quito, EcuadorCali, ColombiaKracow, Poland
Porto Alegre, BrazilNorth India2
Czech RepublicSlovakia
Latina, ItalyNagasaki, Japan
Costa RicaGranada, Spain
Canada, Northwest TerritoriesAsuncion, Paraguay1
Montevideo, UruguayUS, Central California, Hispanics
SwedenHaut Rhin, France
Graubunden, SwitzerlandCroatia
Shanghai, ChinaSouth AustraliaIsrael, All Jews
CanadaUS SEER, WhitesUS SEER, Blacks
UK (England, Wales)
FIGURE 1
Age-Standardized Incidence Rates of Gallbladder Cancer per 100,000 (World Population) for Selected Areas Worldwide, 1988–1992
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, 1997.1Unpublished data from La Paz, Bolivia and Asuncion, Paraguay are shown with permission of the corresponding registries.2Dhir V, Mohandas KM. Epidemiology of Digestive Tract Cancers in India IV. Gall bladder and pancreas. Indian JGastroenterol 1999;18(1):24-28.
(4.1 per 100,000). The highest female/maleratios (≥ 3) were seen in Porto Alegre, Brazil(4.69), in Israel (3.6), and among Hispanics inCentral California (3.0). The femalepredominance was less marked in Nagasaki,Japan, the UK (England and Wales), and amongblack people in the US. The incidenceincreases progressively with age, both in malesand females, in all populations included in thesurvey. The increase in males is more markedafter 50 years of age in Latin America.
In summary, there is prominent geographicvariability of gallbladder cancer incidence,which correlates with the prevalence ofgallstones. The populations with the highestincidence are Chileans,17 Bolivians,10 NorthAmerican Indians,11 Mexican-Americans,12,18
and Central Europeans,13 all of whom also havehigh prevalence of cholelithiasis.The high ratesobserved in Latin America are primarily inpopulations with high levels of Indianmixture,10,17 supporting the concept thatincreased susceptibility depends on geneticfactors that predispose people to gallbladdercancer either as primary factors, or secondarilyas promoters by favoring the development ofcholesterol gallstones.
TRENDS IN AGE-ADJUSTED MORTALITY RATES
Mortality trends in the age-adjusted rates(standardized using the world population) over a16-year period (1980 to 1995) were evaluated intwelve countries included in the World HealthOrganization (WHO) database (US, Canada,Hungary, United Kingdom, Italy, Austria, France,Spain, Japan, and Australia),19 and over a 10-year-period in Chile (1982 to 1991, standardized bythe Chilean population of 1985).9
In Trujillo, Peru; Quito, Ecuador; Cali,Colombia; Porto Alegre, Brazil; Latina, Italy;and Costa Rica, approximately 20 percent ofgallbladder cancer and biliary tract tumors in
women were classified as NOS. In contrast, inNagasaki, Japan; among Hispanics of CentralCalifornia; in Haut Rhin, France; Graubunden,Switzerland; Croatia; Shanghai, China; and inthe UK (England and Wales) this proportionwas less than five percent (Table 1). In Chile, 80percent of adenocarcinoma of the biliary treeoriginates in the gallbladder, as assessed bypathological criteria.8
These gross differences probably reflectvariations in the clinical or pathologicalcriteria used to identify the exact origin of theadenocarcinoma of the biliary tree, which inthe majority of the cases can only be diagnosedthrough laparotomy or necropsy. In spite ofthese difficulties, there is general agreement in the literature that the majority ofadenocarcinoma of the biliary tree originatesin the gallbladder mucosa.
The highest mortality rate of gallbladdercancer in the world, 35 per 100,000inhabitants, is found in Southern Chile (theregion of the Araucania), which is inhabited byChilean Hispanics and Mapuche Indians. Thishigh mortality rate contrasts with the mean ofthe whole country, which had an age-adjustedmortality rate of 16.2 for women and 5.4 per100,000 for men in 1991. These rates havebeen inversely correlated with the rates ofcholecystectomy during the 1980s and early1990s.20 Whereas the cholecystectomy rate was44 percent among Chilean Hispanics withgallbladder disease (including cholelithiasis andcholecystectomy); the cholecystectomy rate forMapuche Indians from Southern Chile withgallstones was only 8.6 percent.17
Analysis of mortality trends of a series ofnine countries is shown in Figures 2 and 3. Inthe US, Canada, and Australia, mortality ratesfor both men and women decreased over the16-year period under study; while in areas withhigh risk—such as in Japan—an increase isobserved.Trends in mortality from gallbladdercancer for four European countries are
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Epidemiology and Molecular Pathology of Gallbladder Cancer
Source: Parkin DM, Whelan SL, Ferlay J, Raymond L, and Young J. Eds. Cancer Incidence in Five Continents, Vol. VII. (IARC ScientificPublications No. 143). International Agency for Research on Cancer, Lyon, France, 1997.
summarized in Figure 2. In countries with thehighest rates (Hungary) and with the lowestrates (United Kingdom), a marked decline(especially in females) is observed. In Italy andSpain, two other countries with low rates, littlevariation is observed.
On the other hand, one of the highermortality rates in the world was observed inChile (10.8 per 100,000 in 1991) with amarked increase during the period from 1982to 1991 as shown in Figure 3, a trendconcurrent with declining cholecystectomyrates during the same period.20 This last factorwas probably a consequence of the healthpolicy that reallocated resources from thetreatment of adult chronic diseases to pediatricand obstetrical health care.17
MORPHOLOGY AND PATHOGENESIS
Although it has been established thatdysplasia and carcinoma in situ21 precede mostgallbladder carcinomas, relatively little isknown about the natural history of theseprecursor lesions. Most dysplasias andcarcinomas in situ are diagnosed aftercholecystectomy when the entire lesion isremoved.22 However, there is indirect evidencethat progression could occur from precursorlesions to infiltrating carcinoma. Dysplasia andcarcinoma in situ are found in the mucosaadjacent to most carcinomas of the gallbladder,sometimes separated by histologically normalepithelium.22,23
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Epidemiology and Molecular Pathology of Gallbladder Cancer
FIGURE 2
Trends in Mortality Rates for Gallbladder Cancer in US, Canada, Europe, Japan, and Australia,* 1980–1995
Patients with dysplasia24 and carcinoma insitu22 are 15 and 5 years younger, respectively,than those with invasive carcinoma. If multiplesections of gallbladders removed forcholelithiasis are examined, dysplasia andcarcinoma in situ are detected in 13.5 percentand 3.5 percent of the cases, respectively.22
There is consensus that if dysplasia andcarcinoma in situ are found, multiple additionalsections of the gallbladder should be examinedto rule out invasive cancer.
Over 90 percent of gallbladder carcinomasare adenocarcinoma.24,25 On gross examination,approximately 10 to 37 percent of thegallbladder carcinomas cannot be identifiedwith certainty,24 and their macroscopic findingsare similar to those of chronic cholecystitis.Gallstones are found in almost all cases of
gallbladder cancer (78 percent to 85percent).8,22,26 Most carcinomas (60 percent)originate in the fundus of the gallbladder, 30percent in the body, and 10 percent in theneck.22 The prevalence of gallbladder cancerassociated with diffuse calcification of thegallbladder (so-called porcelain gallbladder) is12 to 21 percent.26 Most gallbladder cancers arewell-to-moderately differentiated adeno-carcinomas. Some of these are papillary lesionsthat grow predominantly into the lumen of thegallbladder.
The main prognostic factor for gallbladdercarcinoma is the clinical or pathologic stage.27
Two staging systems for gallbladder carcinomahave been widely used. In 1976, Nevin et al.1
proposed a staging system in which Stage Icancer is limited to the mucosa; Stage II to the
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FIGURE 3
Trends in Mortality Rates for Gallbladder Cancer in Chile,* 1982–1991
*Age-standardized rate per 100,000.Source: Ferrecio C, Chianalae J, Gonzalez C, Nervi F. Epidemiologia descriptiva del cancer digestivo en Chile (1982–1991):Una approximacion desde la mortalidad. 1995 Ed. Alfa Beta, Santiago, Chile.
muscular layer; and Stage III to the peri-muscular layer. Stage IV shows metastases inthe lymph nodes; and Stage V has hepatic orother distant metastases.There is a correlationbetween level of tumor invasion in thegallbladder wall and the presence of lymphnode metastases.24,27
In a large series of patients with gallbladdercarcinoma,24 no lymph node metastases weredetected in gallbladder tumors invading themuscularis only, whereas 62 percent of thetumors invading the serosa showed regionallymph node metastasis. Patients with localizedstage disease have much better survival rates(Stages I to III, five-year survival rate of 41.9percent) than those with regional (Stage IV, 3.8percent) or distant (Stage V, 0.7 percent)metastasis.27,28 Similar results have beenobtained using the TNM staging system of theInternational Union Against Cancer (UICC)and American Joint Committee on Cancer(AJCC), which has proven to be a good systemfor comparison of surgical results andprediction of patient outcome.29,30
Briefly,under the TNM classification:Stage I isa tumor limited to the mucosa or muscular layers;Stage II tumors invade the peri-muscular tissue;Stage III tumors invade serosa, liver less than twocentimeters, or have regional (hepato-duodenalligament) lymph node metastasis; and Stage IVshows liver invasion greater than two centimeters(Stage IVA), or metastasis to nonregional lymphnodes and/or distant organs (Stage IVB).
The gallbladder’s very thin wall and thediscontinuous muscular layer are believed tofacilitate tumor invasion and contribute to theadvanced local and regional disease usuallypresent at the time of diagnosis.25
Tsukada et al.31 reported that the five-yearsurvival rate in patients with TNM Stage Itumors was 91 percent; 85 percent in patientswith Stage II tumors; 40 percent in patientswith Stage III tumors; and 19 percent inpatients with Stage IV tumors. In the samestudy, in patients with TNM Stage III and
Stage IV tumors the five-year survival rate was52 percent after curative resection. This wassignificantly better than the five percent five-year survival rate after a noncurative resection.
MOLECULAR PATHOLOGY
While considerable progress has been madein understanding the molecular pathogenesis ofseveral human neoplasms, information aboutthe genetic changes involved in gallbladdercarcinogenesis is more limited.32 Most of thesestudies have focused on ras,33 TP53, andp16Ink4/CDKN234 gene abnormalities anddeletions (“loss of heterozygosity”) at severalchromosomal regions harboring known orputative tumor suppressor genes.32,34-35
The reported prevalence rates of ras genemutations in series of gallbladder carcinomas isquite variable.7,34,36-37 While ras mutations werenot detected in some small series,7 two othergroups reported greater of K-ras mutations in39 to 59 percent of patients.34,38 All themutations occurred at codon 12 of the K-rasgene.7,34,36-37 However, this site has been themost intensively analyzed ras gene region. Agreater frequency (50 to 83 percent) of K-rasgene mutations has been reported ingallbladder carcinomas from patients havinganomalous junction of the pancreatico-biliaryduct39-42 suggesting that reflux of pancreaticjuice might contribute to the carcinogenicprocess.
TP53 gene abnormalities are frequent ingallbladder cancers.43 Although the frequencyof p53 immunostaining in gallbladdercarcinoma varies widely (ranging from 35 to92 percent), two thirds of the studies show afrequency greater than 50 percent.39,44-60 Mostof the TP53 mutation studies on gallbladdercarcinoma have confirmed the immuno-histochemical findings.39,50,56,59,60 Analyses ofexon 5 to 8 of TP53 have demonstrated pointmutations in 31 to 70 percent of gallbladder
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Epidemiology and Molecular Pathology of Gallbladder Cancer
carcinomas,39,50,56,59-61 and no particular “hotspot” has been identified.
In addition, deletions at the TP53 locus(17p13) have been frequently (58 to 92percent) reported in gallbladder carcinomas,34,35
indicating that the inactivation of the TP53plays an important role in the pathogenesis ofthis neoplasm.Yokoyama et al.60 compared theTP53 mutations in gallbladder carcinomasfrom two high-prevalence areas, Japan andChile. No differences in the frequencies ofTP53 mutations between both groups weredetected. However, mutations from Japanesecases comprised transversions in 31 percent ofcases with 46 percent of all mutations takingplace at the A:T pair.
Whereas, in contrast, the TP53 mutationspectrum for Chilean cases demonstrated avery high incidence of transitions (100percent) and of mutations at G:C pairs.Whileno Japanese cases showed G:C to A:Ttransitions at CpG sites, these were relativelyfrequent (33 percent) in Chilean cases.Frequent transitions, especially at CpG sites, arefeatures of mutational spectra found in cancersnot strongly linked to specific exogenouscarcinogens.62,63 There are a few studies thatsuggest that CDKN2 gene, also known asMTS1 or p16INK4, may play a role in gallbladdercarcinogenesis.43 Deletions at the CDKN2region (9p21) have been reported in half ofgallbladder cancers.40 However, there are nocomprehensive studies at present on theCDKN2 gene status and the mechanism of inactivation in gallbladder carcinoma,including deletion, mutation, methylation,homozygous deletions, and protein expressionanalysis.
Although no comprehensive genome-wideallelotyping of gallbladder carcinoma has beenpublished, two reports34,35 suggest that severalchromosomal regions harboring known orputative tumor suppressor genes may undergodeletion in this neoplasm.These chromosomalregions, other than TP53 and CDKN2 gene
loci, are 3p (20 to 52 percent); 5q21 (APC-MCC genes, 6 to 66 percent); 8p22-24 (22 to44 percent); 13q14 (RB gene, 20 to 30percent); and 18q22 (DCC gene, 18 to 31percent).35
The exact sequence of molecular changesthat lead to neoplastic transformation in thegallbladder epithelium remains uncertain.More detailed understanding of the earliestmolecular abnormalities may eventuallyprovide methods for risk assessment and earlydetection of gallbladder carcinoma.The excessaccumulation of p53 protein in gallbladderdysplasia (0 to 32 percent) and carcinoma insitu lesions (45 to 86 percent)44,46,51,54 suggeststhat TP53 abnormality is an early event. Thepresence of deletions at the TP53 locus in histologically normal epithelium neargallbladder carcinoma,34 and of TP53 muta-tions in precursor lesions, (Miquel et al., inpreparation), indicate an early and importantrole of TP53 inactivation.
Other early genetic changes include loss ofheterozygosity at 9p21 (CDKN2 gene) and18q21 (DCC gene) regions.34 Data regardingK-ras gene mutations in precursor lesions arecontroversial.44,46,51,54 While some studies fail todemonstrate K-ras mutation in precursorgallbladder lesions,34,36 others report a relativelyhigh prevalence (22 to 44 percent) in precursorlesions accompanying invasive tumors.1,34,42
Interestingly, no differences in the frequencyand spectrum of K-ras gene mutations weredetected in nonmalignant gallbladderepithelium of patients with anomalousjunction of the pancreato-biliary duct, withand without gallbladder carcinoma in Japan.40,42
The role of adenomas as precursors ofgallbladder carcinoma is still unclear andcontroversial. Molecular analyses of gallbladderadenomas failed to detect the genetic changesfrequently found in gallbladder carcinomas andtheir known precursor lesions,32 suggesting thatadenomas might not be precursors of thisneoplasm.
Among other risk factors, a number ofgenetic, dietary factors, endo- and exobiotics,and chronic gallbladder infections, have beenassociated with the development of gallbladdercancer. However, the primary risk factor ofgallbladder cancer as reported in all studies isgallstone disease.1-6,8-14 Gallbladder cancer hasalso been associated with multiple familialpolyposis/Gardner syndrome,64 Peutz-Jegherssyndrome,65 “porcelain” gallbladder,66 andanomalous pancreato-biliary ductal union.67
There has also been a consistently higher riskin women than in men, independent ofcholelithiasis.3,4,8,12
Gallbladder Cancer and Gallstones
The association between cholelithiasis andgallbladder cancer has been known since186168-69 and is supported by autopsy studies,screening surveys, and hospital-based case-control studies (Table 2).1-6,8-14,70-79 Cholelithiasisis more frequent in gallbladder cancer than inextrahepatic bile ducts cancer. In a recent case-control study performed in Australia, Canada,Holland, and Poland, a history of gallbladdersymptoms requiring medical attention wasidentified as one of the major risk factors forgallbladder cancer.73
This association was described in patientswho had shown clinically symptomaticgallbladder disease for at least 20 years prior togallbladder cancer diagnosis.70,71,73 Thetheoretical basis for this phenomenon is thatthe inflammation, chronic trauma, andinfection in approximately one third ofgallstone patients promotes epithelial dysplasiaand adenocarcinoma formation.79 For thisreason, it has been suggested that larger stoneshave a greater impact on the risk of developinggallbladder cancer, possibly reflecting greaterduration and intensity of epithelial irritation.Diehl reported that in subjects with gallstones
larger than three centimeters, the risk ofgallbladder cancer is 10 times greater than insubjects with gallstones smaller than onecentimeter.80 Warren et al.81 reported a largermean stone diameter among 19 subjects withgallbladder cancer (20.3 mm) when comparedwith 883 subjects undergoing surgery forgallstones (11.9 mm). In contrast, Moerman etal.82 found no association between stone sizeand gallbladder cancer.
Cholesterol gallstones represent approx-imately 80 to 90 percent of all gallstone casesin the Western world and are considered to bea promoting factor. There is little availableinformation as to whether pigment orcholesterol stones have a different activity aspromoters of gallbladder cancer development.
Some constituents of bile might beendogenous carcinogens.83 It has beenpostulated that mutagenic endobiotic der-ivatives, presumably from sterol bacterialmetabolites, might be the putative initiators.Mutagenic factors were isolated from stoneextracts of a patient with a symptomaticcholedochal cyst (a high-risk precancerouscondition) with chronic bacterial infection ofthe biliary tree.84
Only a small fraction (less than one percent)of patients with cholelithiasis developgallbladder cancer,85 and approximately 20percent of gallbladder cancer patients show noevidence of previous cholelithiasis.86 Howeverin high-risk areas, this figure is certainly higherand increases markedly with age.8-12
Gallstone Predisposition
The etiology of cholesterol cholelithiasis, likeany other chronic disease, is thought to involvethe interaction of genetic and environmentalfactors.17,20,87 The risk factors for cholesterolgallstones have been mainly associated withhypersecretion of biliary cholesterol, gallbladderhypomotility, and stasis.88 These conditions arepositively correlated with age, female sex,genetic
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factors, obesity, multiple pregnancies, a familyhistory of gallstones, and low levels of physicalactivity.89-101 Obesity and high-energy intake havebeen positively associated with the risk ofgallstones in cohort102 and case-control103 studies.
Conversely, coffee99 and alcohol91,97,101 wereassociated with a decreased risk of gallstones in some studies. There is evidence that
endogenous104 and exogenous estrogens105 andpregnancy increase the risk of cholelithiasis.106
Most environmental factors, including diet,have been considered a consequence of thewesternization of modern societies.87,99 Theassociation of diet and gallbladder cancerremains unclear. Most likely, dietary factorsmight influence the production of gallbladder
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Summary of Studies of Gallstones Disease and Gallbladder Cancer
Cohort Studies
Site and Author Population Risk Factors OR (CI 95%)
Denmark 60,176 Gallstones Years of follow-upChow et al. 199975 Danish Cancer Registry 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 69 cases Cholelithiasis and Khan et al. 199973 138 controls biliary tract cancer 19.5 (6.4-59.4)
Australia, Canada, 196 cases History of gallbladder symptoms 4.4 (2.6-7.5)Netherlands, and Poland 1515 controls Symptoms 20 years earlier 6.2 (2.8-13.4)
Zatonski et al. 199776
Bolivia and Mexico 84 cases Family history of gallstones 3.6 (1.3-11.4)Strom et al. 19959 126 controls without gallstones
264 controls with colelithiasis
WHO Collaborative 58 cases Gallstones 2.3 (1.2-4.4)Study 198980 355 controls
Cross-Sectional Studies
Site and Author Population Risk Factors OR
Kofu, Japan 194,767 Gallstones Increased riskOkamoto et al. 199974 Screening surveys p < .01
Tokyo, Japan 4,482 autopsy surveys Gallstones Increased riskKimura et al. 198968 p < .01
Chile 14,768 autopsy surveys Gallstones 7 Nervi et al.8 1988 p < .05
Rochester, Minnesota 2,583 screening surveys Gallstones Increased risk in men Maringhini et al. 198781 p < .05
cancer through potential effects on cholesterolgallstone formation.The principal independentfactors associated with gallstone disease inseveral studies were female sex, greater age,high BMI, slightly higher serum glucose,increasing parity, and low plasma HDLcholesterol.17,18,107-109
Genetic Epidemiology of Gallbladder Diseases
There are some reports of familialtendencies toward gallbladder cancer, althoughthey are based on a very small number ofpatients.110 A potential relationship betweengenetic predisposition and gallbladder cancerincidence has been suggested by populationstudies of gallstone prevalence in differentlatitudes.108-110 A recent study including threeethnic groups (Mapuche Indians and Hispanicsfrom Chile and Maoris from Easter Island)17
concluded that cholesterol lithogenic genes arehighly prevalent among Chilean Indians andHispanics—populations with the highestmortality rates of gallbladder cancer.9
These studies strongly supported the thesisthat genetic factors play a major role in somespecific populations by favoring the productionof lithogenic bile.88 The genetic hypothesis ofcholesterol gallstone formation has also beensupported by family studies.111 Specificpolymorphisms of apoproteins and plasmacholesterol ester transfer proteins seem to becorrelated with cholesterol cholelithiasis.112
Chronic Gallbladder Infection
During the last two decades, epidemi-ological evidence has linked chronic infectionswith several cancers; examples include hepatitisB and hepatitis C viruses with liver cancer;H. pylori and gastric cancer; and liver flukeswith cholangiocarcinoma.113,114 Chronicinfection by Salmonella typhi has beenassociated with an increased risk of gallbladdercancer. Caygill et al.115,116 hypothesized that
typhoid and paratyphoid chronic carriage withconcomitant gallstone formation favors mixedbacterial infection and higher risks of gall-bladder carcinogenesis. Singh et al.117 proposedthat the Salmonella carrier state has a sig-nificant association with gallbladder cancerindependent of gallstones.
However, the possible carcinogenicmechanism involved has not yet been clarified.It is important to note that Salmonella sp. have ß-glucuronidase activity, therefore hepaticinactivation of exogenous carcinogenicxenobiotics by glucuronidation could bereversed after bacterial hydrolysis of ß-glucuronides.118 Strom et al.10 reported fromBolivia and Mexico a 12-fold increase in riskof gallbladder cancer in subjects with a historyof typhoid fever (CI 95 percent 1.5-598),which unfortunately could not be cor-roborated with serological assays. Addition-ally, Nath et al.,119 in cultures of bile samples,found Salmonella typhi more frequently inpatients with gallbladder cancer than insubjects with gallstones and free of biliaryneoplasia.
Occupation
Increased risk of gallbladder cancer has beenrelated among workers in the oil, paper,chemical, shoe, textile, and cellulose acetatefiber manufacturing industries suggestingoccupational exposure to carcinogens.120,121
A higher risk of gallbladder cancer was alsofound among miners exposed to radon.122
PREVENTION AND FUTURE TRENDS
Primary prevention of gallbladder cancer isunlikely in the near future, since manyetiologic factors remain unknown. However,prevention of cholesterol gallstone formation isan important intervention that would certainlyhave a great impact in decreasing the incidence
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Epidemiology and Molecular Pathology of Gallbladder Cancer
of gallbladder cancer, particularly in high-riskareas. Availability of adequate and promptlaparoscopic cholecystectomy for symptomaticgallstone patients should be effective forsecondary prevention.
Relationship between Cholecystectomy Rates and
Gallbladder Cancer Incidence Rates
Cholecystectomy is the most frequent of allintra-abdominal operations. It is estimated thatin the US more than 550,000 chol-ecystectomies are performed yearly within anestimated population of 20,000,000 at-riskpatients with asymptomatic gallstones.123 TheUS cholecystectomy rate was 47.6 per 1000inhabitants in 1993, whereas the rate was only25.1 per 1000 inhabitants in 1992 in Chile, inspite of a three to four times higher prevalenceof cholelithiasis.9,20,124 The incidence ofgallbladder cancer has diminished con-siderably, in an inverse correlation to theincrease in cholecystectomies in developedcountries.125-127
In Chile, while the reportedcholecystectomy rates decreased in the 1980s,time trends revealed an increase in theincidence of gallbladder cancer.9,20,124 Inaddition, the extremely low frequency ofcholecystectomies found among MapucheIndians with gallstones compared withChilean Hispanics and Maoris17 mightexplain the high mortality rates of gallbladdercancer in Southern Chile in areas inhabitedby Mapuche Indians. A descriptive surveypublished in 19959 showed that gallbladdercancer mortality rates were over four timeshigher in towns with a high proportion ofMapuche Indians (35 per 100,000 inhabitantsin the region of the Araucania, SouthernChile), compared with towns with apredominantly Hispanic population (8 per100,000 inhabitants in the municipality of LaFlorida, Santiago).9
Elective Laparoscopic Cholecystectomy for
Secondary Prevention of Gallbladder Cancer
Three studies have analyzed the potentialbenefits of prophylactic cholecystectomy forlow-risk populations. Based on decisionanalysis models, it was concluded that thebenefits of prophylactic cholecystectomy wereirrelevant when compared with expectantmanagement of gallstone disease.128-130 The roleof prophylactic cholecystectomy in high-riskpopulations, including North AmericanIndians, Mexican Americans, Chileans, andBolivians, has yet to be reported. A recent cost-effectiveness analysis of screening andtreatment among Chilean women under 40years old with asymptomatic cholelithiasis,showed that prophylactic laparoscopic chol-ecystectomy can significantly benefit thepopulation at a very low incremental cost(Puschel et al., personal communication,Santiago, 2000).
CONCLUSIONS AND PERSPECTIVES
Little is still known about the etiology ofgallbladder cancer.This overview of gallbladdercancer and the annual incidence of gallbladdercancer in various countries offers acomparative picture of the descriptiveepidemiology of the disease, a summary ofetiologic studies, and a discussion of associatedrisk factors, especially cholesterol gallstonedisease—the major risk factor of gallbladdercancer. It is important that several remainingpoints be elucidated. Further investigation forthis extremely lethal cancer is urgently needed.What do we really know for sure and whatneeds to be done?
1) The process of gallbladder carcinogenesisis usually related to a history of cholelithiasis,which is frequently present for at least 20 yearsbefore the tumor appears.
identified for cholesterol stones (obesity, mul-tiple pregnancies, low plasma HDL, femalehormones, and insulin resistance), they do notexplain the full picture. Genetic susceptibility is likely to play an important role.
3) Because only a small fraction of patientswith cholesterol gallstones develop gallbladdercancer, it is important to identify the factorsthat induce progression from cholelitiasis togallbladder cancer. This may allow theidentification and early treatment of gallstonesof susceptible individuals within high-riskpopulations.
4) The role of chronic infection in thedevelopment of gallbladder cancer deservesfurther research. It is likely that aside fromchronic Salmonella carriers, a number of otherbacterial species chronically inhabiting thegallbladder might be important etiologicfactors.
5) The limitations of epidemiologic gall-bladder cancer studies have included the small
size of populations studied and problems inquantifying exposure to putative exogenousrisk factors, particularly potential carcinogenicxenobiotics. Multicenter case-control studies in high-risk populations in which accuratebiomarkers of exposure to various risk factorsare used and the genetic factors are assessedwill be of great value in answering several ofthe questions raised in this review.
6) Primary prevention of gallbladder canceris not expected in the near future. However,secondary prevention, primarily oriented totreatment of symptomatic gallstones, must be emphasized in endemic areas wherecholelithiasis is highly prevalent. Prophylacticlaparoscopic cholecystectomy might be costeffective. It is apparent that interventionalprograms are urgently needed to decrease thenumber of gallbladders at risk for gallbladdercancer development in high-risk areas,particularly in the Andean region. CA
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