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Keywords:

  • gallbladder;
  • cancer;
  • incidence;
  • worldwide;
  • aetiology;
  • risk factors

Abstract

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
  9. Appendix
  10. Appendix
  11. Supporting Information

Gallbladder cancer is a relatively rare neoplasm that shows, however, high incidence rates in certain world populations. The interplay of genetic susceptibility, lifestyle factors and infections in gallbladder carcinogenesis is still poorly understood. Age-adjusted rates were calculated by cancer registry-based data. Epidemiological studies on gallbladder cancer were selected through searches of literature, and relative risks were abstracted for major risk factors. The highest gallbladder cancer incidence rates worldwide were reported for women in Delhi, India (21.5/100,000), South Karachi, Pakistan (13.8/100,000) and Quito, Ecuador (12.9/100,000). High incidence was found in Korea and Japan and some central and eastern European countries. Female-to-male incidence ratios were generally around 3, but ranged from 1 in Far East Asia to over 5 in Spain and Colombia. History of gallstones was the strongest risk factor for gallbladder cancer, with a pooled relative risk (RR) of 4.9 [95% confidence interval (CI): 3.3–7.4]. Consistent associations were also present with obesity, multiparity and chronic infections like Salmonella typhi and S. paratyphi [pooled RR 4.8 (95% CI: 1.4–17.3)] and Helicobacter bilis and H. pylori [pooled RR 4.3 (95% CI: 2.1–8.8)]. Differences in incidence ratios point to variations in gallbladder cancer aetiology in different populations. Diagnosis of gallstones and removal of gallbladder currently represent the keystone to gallbladder cancer prevention, but interventions able to prevent obesity, cholecystitis and gallstone formation should be assessed. © 2006 Wiley-Liss, Inc.

Gallbladder cancer (GC) is a relatively rare neoplasm that differs from other cancers of the digestive tract, as being several-fold more common in women than in men.1 Symptoms and signs of GC are not specific and often appear late in the clinical course of the disease.2 For this reason, diagnosis is generally made when the cancer is already in advanced stages, and prognosis for survival is less than 5 years in 90% of cases.2

GC shows a marked geographic and ethnic variation.1, 2, 3 In several European countries and the United States of America (USA), GC is rare, but relatively high incidence and mortality rates were observed in selected central European countries,4 and very high rates were found in the American–Indian and Chilean–Mapuche populations, as well as in the North of India.2 GC has been reported to be the first cause of cancer death among women in some areas of South America.5

These differences can have several interpretations, but they refer particularly to the worldwide distribution of gallstones, which are the most important risk factor for GC.4, 6 However, only a small proportion (1–3%) of patients with gallstones develop GC,2 and other risk factors have been proposed to play a role.

This review includes an update of the worldwide distribution of GC incidence, as well as a systematic review of published findings on the association between GC risk and gallstones, obesity, reproductive variables, use of female hormones and infectious agents.

Material and methods

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
  9. Appendix
  10. Appendix
  11. Supporting Information

Descriptive epidemiology

Cancer registry based data from the series “Cancer Incidence in Five Continents”7, 8, 9, 10, 11, 12 were used to assess age-adjusted and sex-specific incidence rates truncated for individuals aged 35–74 years, and standardized on the basis of the world standard population for 40 cancer registries worldwide. Cancer registries were selected if they met the following criteria: (1) data available in Cancer Incidence in Five Continents, volume 8 and (2) more than 50 female cases reported in the 35–74 year age group. In countries where several registries were available, the registries with the highest number of cases were used.

Variability among age-standardized rates within ethnic groups in the USA was also evaluated for 35–74-year-old subjects in the cancer registries of Los Angeles (California), New Mexico and Surveillance, Epidemiology and End Results (SEER) areas: these registries included all the available ethnic groups inside the USA.

Time trends of GC incidence rates between 1962 and 1997 were evaluated in 4 selected registries that had published incidence rates over 20 years or more7, 8, 9, 10, 11, 12 as representatives of different situations worldwide. During the calendar period considered, 4 different revisions of the International Classification of Diseases (ICD) were used [revision 7 (ICD-7),13 8 (ICD-8),14 9 (ICD-9)15 and 10 (ICD-10)16]. Only in ICD-10 has GC (ICD-10 = C23) been classified separately from “other unspecified” parts of the biliary tract (ICD-10 = C24). Therefore, to obtain the comparability of incidence rates over time, we combined all cancers of the biliary tract, including gallbladder, extrahepatic bile ducts, Ampulla of Vater and other unspecified parts of biliary tract cancers (ICD-7 = 155.1, ICD-8 = 156, ICD-9 = 156, ICD-10 = C23 and C24). This broad definition should not hamper the evaluation of trends of GC since, in the populations considered, GC was the most frequent cancer in the extra-hepatic biliary tract.

Search strategy, selection criteria and statistical methods

Case-control and cohort studies on GC were selected through search of Medline via Pubmed (keywords included gallbladder neoplasm, biliary tract neoplasm, gallbladder, cancer, risk factors, cholelithiasis, gallstone, salmonella, typhoid, diet, reproductive factors, oral contraceptive, hormone replacement therapy, infection, obesity, overweight, body mass index, family history), and from references cited in selected papers. The search was restricted to human studies in English or Spanish published between 1980 and March 2005. For each study included in the review, the following information was abstracted: country and year of data collection, study design (cohort, population- or hospital-based case-control) and potential risk factors for GC examined. Corresponding relative risks (RRs) with 95% confidence intervals (CIs) and adjustment for confounding variables were also extracted or, in a few instances, computed from published data.

If study findings had been reported in more than one article, only the most recent publication for each type of risk factor was considered. Detailed information on all the studies5, 6, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 included is given in Appendix 1.

We decided not to systematically collect RRs for diet (including macronutrients, micronutrients or food items), given the heterogeneity of available information.

For selected risk factors (history of benign gallbladder diseases, family history of benign gallbladder diseases and of GC, oral contraceptive use, menopausal status, hormone replacement therapy and history of infection of Salmonellatyphi or S. paratyphi and Helicobacter bilis and H.pylori), we calculated the summary RRs (and corresponding 95% CI) as a weighted average of the study-specific RRs, by giving each study a weight inversely related to the variance of the log RR.51 Where possible, the summary RRs for each study type (case-control and cohort study) were also computed. Heterogeneity between studies was evaluated according to the method described by Greenland.51

Results

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
  9. Appendix
  10. Appendix
  11. Supporting Information

Descriptive epidemiology

Sex-specific incidence rates of GC and female-to-male (F/M) ratios for the most recent years available (generally mid-1990s) are shown in Figure 1 and Appendix 2. The highest incidence rate worldwide was shown by women from Delhi, India (21.5/100,000), followed by South Karachi, Pakistan (13.8/100,000) and Quito, Ecuador (12.9/100,000). High GC incidence rates were also found in cancer registries from Far East Asia (Korea and Japan), Eastern Europe (Slovakia, Poland, Czech Republic and Yugoslavia) and South America (Colombia). In Western Europe, elevated incidence rates were seen in Granada, Spain. High incidence rates (ranging between 4.4 and 8.0) among men were found in some areas of Asia and Eastern Europe. Low incidence rates (below 3/100,000 women and 1.5/100,000 men) emerged for most registries from Northern Europe, with the partial exception of Sweden, and from the USA (SEER) and Canada.

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Figure 1. Age-standardized incidence rates (truncated for individuals aged 35–74 years) per 100,000 (world standard population) and female-to-male ratio (F/M) for gallbladder cancer in 40 selected areas of the world.

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The F/M ratio of GC incidence rates also varied greatly: it exceeded 5 in several high-risk areas (e.g., Pakistan, Colombia and Spain) as well as in low-risk areas (e.g., Denmark), but was typically between 2 and 3. F/M ratio was close to unity in Korea, Japan and some parts of China (Fig. 1).

The variation of GC incidence among ethnic groups in the USA is shown in Figure 2 and Appendix 3. Hispanic white women in California (8.2/100,000) and New Mexico (5.4/100,000) had higher incidence rates than any other ethnic group. Hispanic white women showed 3- to 5-fold higher incidence rates than Non-Hispanic white women in the same areas. Very high incidence was also reported by American Indians in New Mexico. Variation by ethnicity among men was not as pronounced as that among women, with the exception of American Indians. The F/M ratio was high among Hispanic whites (2.9 in Los Angeles, California and 4.4 in New Mexico), and close to unity among blacks. Koreans, Filipinos, Japanese and Chinese in California showed GC incidence rates similar to Whites but their F/M ratios suggested no female excess risk, in agreement with the ones observed in the countries of origin.

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Figure 2. Age-standardized incidence rates (truncated for individuals aged 35–74 years) per 100,000 (world standard population) and female-to-male (F/M) ratio for gallbladder cancer in selected ethnic groups of the USA.

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Trends in age-adjusted incidence rates for cancer of the biliary tract over the last 3 or 4 decades are shown in Figure 3. Former Czechoslovakia (currently the Czech Republic and Slovakia) did not show any marked change between 1978 and 1997. Incidence rates in Connecticut, USA were already low in 1968–1972, but further declined later on. Upward incidence curves emerged in Osaka, Japan, especially between 1970–1971 and 1983–1987, the overall increase being 44.6% for women and 55.2% for men. A different pattern was observed in Cali, Colombia, where female incidence rates rose steadily until 1981 and then declined by about 31%, while incidence rates in men were fairly stable.

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Figure 3. Trends in male and female age-standardized rates (truncated for individuals aged 35–74 years) per 100,000 (world standard population) of gallbladder and extrahepatic bile duct cancer in selected areas.

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Risk factors

The association between history of benign gallbladder diseases (mainly gallstones) and GC risk was evaluated in 10 studies (Table I). A cohort study33 conducted in the USA reported an increased risk of GC, notably among men (RR 8.3, 95% CI: 1.0–30.3), but the estimate was based on 5 cases only. After adjustment for age and sex, a population-based cohort study20 reported a RR of 3.6 based on 42 cases over a population of 60,176 patients with a hospital discharge diagnosis of gallstones. No association was found in the cohort study conducted in Japan by Yagyu et al.50 either in men or in women. RRs from case-control studies varied between 2.3 (95% CI: 1.2–4.4)49 and 34.4 (95% CI: 4.5–266).27 This variation most likely depends on differences in study design and on methods and definitions used to collect information on gallstones. Summary RR for history of gallstones was 4.9 (95% CI: 3.3–7.4), and was 2.2 (95% CI: 1.2–4.2) among cohort studies and 7.1 (95% CI: 4.5–11.2) among case-control studies. Heterogeneity was significant among all studies (p < 0.001).

Table I. Relative Risks (RR) with Corresponding 95% Confidence Intervals (CI) of Gallbladder Cancer for History of Selected Diseases
StudyParticipantsRR (95% CI)AdjustmentReference
  • 1

    Summary RR for all studies was 4.9 (95% CI: 3.3–7.4) and heterogeneity test between studies was χmath image = 57.361, p < 0.001.

  • 2

    Summary RR for cohort studies was 2.2 (95% CI: 1.2–4.2) and heterogeneity test between studies was χmath image = 6.918, p = 0.075.

  • 3

    Not included in the summary estimates.

  • 4

    Summary RR for case-control studies was 7.1 (95% CI: 4.5–11.2) and heterogeneity test between studies was χmath image = 28.540, p < 0.001.

  • 5

    Chile, China, Colombia, Israel, Kenya, Mexico.

  • 6

    Australia, Canada, Netherlands, Poland.

  • 7

    Estimated from available data.

  • 8

    Summary RR for case-control studies was 3.2 (95% CI: 1.7–6.1) and heterogeneity test between studies was χmath image = 0.007, p = 0.791.

  • 9

    Summary RR for all studies was 4.8 (95% CI: 2.6–8.9) and heterogeneity test between studies was χmath image = 1.647, p = 0.439.

  • 10

    Summary RR for cohort studies was 4.5 (95% CI: 2.4–8.5) and heterogeneity test between studies was χmath image = 0.895, p = 0.344.

History of benign gallbladder diseases1
 Cohort studies2
  Maringhini, 1987 (USA) 2.8 (0.9–6.6)Age and sex33
 Men8.3 (1.0–30.0)3Age and sex 
 Women2.0 (0.4–5.7)3Age and sex 
  Chow, 1999 (Denmark) 3.6 (2.6–4.9)Age and sex20
  Yagyu, 2004 (Japan)Men1.2 (0.3–4.7)Age50
 Women1.1 (0.4–2.9)Age 
 Case-control studies4
  Lowenfels, 1985 (USA)Non-Indians4.4 (2.6–7.3)Age, sex, centre, alcohol, smoking,education and response status31
 Indians20.9 (8.1–54.0)Age, sex, centre, alcohol, smoking,education and response status 
  Nervi, 1988 (Chile) 7.0 (5.9–8.3)Age, sex, country40
  WHO, 19895 2.3 (1.2–4.4)None reported49
  Kato, 1989 (Japan) 34.4 (4.51–266.0)None reported27
  Zatonski, 19976 4.4 (2.6–7.5)Age and sex6
  Okamoto, 1999 (Japan) 10.8 (4.1–28.4)7 41
  Khan, 1999 (USA) 26.6 (7.0–101.4)Sex, age, ethnicity, smoking and socioeconomic status28
 Women28.9 (4.7–173.0)3Age, ethnicity, socioeconomic status, hysterectomy, menopause, parity, diabetes and smoking 
Family history of benign gallbladder diseases
 Case-control studies8
  Kato, 1989 (Japan) 3.0 (1.3–6.5)None reported27
  Strom, 1995 (Bolivia, Mexico) 3.6 (1.3–11.4)Age, sex and hospital47
Family history of gallbladder cancer9
 Cohort studies10
  Goldgar, 1994 (USA)First-degree relatives2.1 (0.2–6.1)Age at diagnosis25
  Hemminki, 2003 (Sweden)Parents5.1 (2.4–9.3)Age, sex, region, period and socioeconomic status26
 Offspring4.1 (2.0–7.6)3Age, sex, region, period and socioeconomic status 
 Case-control studies
  Fernandez, 1994 (Italy)First degree relatives13.9 (1.2–163.9)Age, sex, residence and education23

Family history of gallbladder disease was associated with an increased risk of GC in 2 studies that reported RRs of 3.0 (95% CI: 1.3–6.5)27 and 3.6 (95% CI: 1.3–11.4).47 The summary RR was 3.2 (95% CI: 1.7–6.1) with no heterogeneity between studies (p = 0.791). Elevated RRs were found also for family history of GC in 3 studies. A case-control study conducted in Italy on 58 cases reported increased risk for GC family history among first degree relatives (RR 13.9, 95% CI: 1.2–163.9).23 Two cohort studies in the USA and Sweden also found an association among first degree relatives (RR 2.1, 95% CI: 0.2–6.1),25 and specifically among parents (RR 5.1, 95% CI: 2.4–9.3)26 or offspring (RR 4.1, 95% CI: 2.0–7.6).26 The summary RR for family history of GC was 4.8 (95% CI: 2.6–8.9), and corresponding value among cohort studies was 4.5 (95% CI: 2.4–8.5). No heterogeneity was found among all studies (p = 0.439).

Three studies analyzed the association between GC risk and gallstone size. Two of these21, 32 found a particularly strong association between large gallstones (>3 cm) and GC risk (RRs 10.1 and 9.2, respectively), but another study35 did not find a variation in GC risk according to gallstone size (RR 0.9).

Body mass index (BMI) was also related to GC risk in 8 studies (Table II). A cohort study18 conducted in the USA recorded 484 GC deaths over more than 900,000 people and showed a RR close to 2 for men and women for BMI between 30 and 35 compared with that of BMI between 18.5 and 25. The association of GC with obesity was the second strongest among all cancer sites after that with cancer of the corpus uteri among women and liver cancer among men. Another large cohort study from the USA43 reported a RR of 1.7 (95% CI: 1.1–2.6) for obese white men. Two additional cohort studies from Denmark37 and Japan29 showed an increased GC risk among obese women (RRs 1.4 and 4.5). Case-control studies reported RRs that varied between 0.9 (95% CI: 0.4–1.8)44 and 2.6 (95% CI: 0.5–18.6)47 for obese men and women. In a large multicenter international case-control study, Zatonski et al.6 showed a RR of 2.1 (95% CI: 1.2–3.8) among women for the highest versus the lowest BMI quartile after adjustment for age and some lifestyle covariates.

Table II. Relative Risks (RR) with Corresponding 95% Confidence Intervals (CI) of Gallbladder Cancer for Highest vs. Lowest Category of Body Mass Index
StudyReference categoryHighest categoryParticipantsRR (95% CI)AdjustmentReference
  • 1

    Estimated from available data.

  • 2

    Australia, Canada, Netherlands, Poland.

Cohort studies
 Moller, 1994 (Denmark)Non obeseObeseMen0.5 (0.1–1.8)None reported37
 Non obeseObeseWomen1.4 (0.9–2.1)None reported
 Calle, 2003 (USA)18.5–24.930.0–34.9Men1.8 (1.1–2.9)Age, race, educationand many (8) lifestyle variables18
 18.5–24.930.0–34.9Women2.1 (1.6–2.9)Age, race, education and many (8) lifestyle variables
 Samanic, 2004 (USA)Non obeseObeseWhite men1.7 (1.1–2.6)Age and calendar year43
 Non obeseObeseBlack men0.9 (0.2–3.9)Age and calendar year
 Kuriyama, 2005 (Japan)18.5–24.925.0–27.4Men0.5 (0.1–3.9)Age and many (11) lifestyle and reproductive variables29
 18.5–24.9≥30Women4.5 (1.4–14.2)Age and many (11) lifestyle and reproductive variables
Case-control studies
 Moerman, 1994  (Netherlands)<27≥27Women1.4 (0.7–2.6)1Subjects frequently matched for age and sex36
 Strom, 1995  (Bolivia, Mexico)<24>28BMI average1.6 (0.4–6.1)Age and sex47
 <25>29BMI maximum2.6 (0.5–18.6)Age and sex
 Zatonski, 19972I quartileIV quartileMen1.0 (0.3–2.8)Age, center, alcohol, smoking, education and response status6
 I quartileIV quartileWomen2.1 (1.2–3.8)Age, centre, alcohol, smoking, education and response status
 Serra, 2002 (Chile)<24.9>30 0.9 (0.4–1.8)Age, sex, gallstone disease44

High parity and number of pregnancies, again recognized risk factors for gallstones, were related to increased GC risk in the majority of the 10 studies dealing with this association. The RRs ranged between 1.3 and 4.2, and between 1.0 and 6.7, respectively (Table III), depending on the level of parity and gravidity considered. Among parous women, older age at first birth or pregnancy tended to be associated with reduced risk of GC, but the 95% CIs were broad. A recent study52 conducted in Pakistan, based on 80 cases, confirmed young age at first birth and high parity as risk factors for GC, but no RR was given (data not shown).

Table III. Relative Risks (RR) with Corresponding 95% Confidence Intervals (CI) of Gallbladder Cancer for Highest vs. Lowest Category of the Selected Reproductive and Lifestyle Factors
StudyReference categoryHighest categoryRR (95% CI)AdjustmentReference
  • 1

    Australia, Canada, Netherlands, Poland.

  • 2

    Summary RR for all studies was 0.9 (95% CI: 0.5–1.3) and heterogeneity test between studies was χmath image = 1.501, p = 0.472.

  • 3

    Chile, China, Colombia, Israel, Kenya, Mexico.

  • 4

    Summary RR for all studies was 0.9 (95% CI: 0.3–2.6) and heterogeneity test between studies was χmath image = 7.566, p = 0.056.

  • 5

    Summary RR for all studies was 0.9 (95% CI: 0.3–3.3) and heterogeneity test between studies was χmath image = 8.127, p = 0017.

Parity – number of births
 Lambe, 1993 (Sweden)0≥63.0 (1.1–8.0)Age30
 1≥61.7 (0.6–4.7)Age and age at first birth
 de Aretxabata, 1995 (Chile)<5≥54.2 (1.5–12.8)Subjects matched for age5
 Tavani, 1996 (Italy)0≥11.3 (0.5–3.4)Age and cholelithiasis48
 0≥42.9 (0.9–9.6)Age and cholelithiasis
 Pandey, 2003 (India)≤3>33.9 (1.4–10.3)None reported42
Number of pregnancies
 Moerman, 1994 (Netherlands)0≥12.2 (0.7–6.7)Age36
 1-2≥51.7 (0.7–4.1)Age
 1-2≥51.5 (0.6–3.7)Age and age at first pregnancy
 de Aretxabata, 1995 (Chile)<5≥53.4 (1.2–9.9)Subjects matched for age5
 Zatonski, 199711≥32.2 (0.9–5.4)Age, sex, centre, alcohol, smoking, education and response status6
 Khan, 1999 (USA)0≥11.0 (0.6–1.6)Age, ethnicity, socioecomic status, cholelithiasis, hysterectomy and postmenopause28
 Serra, 2002 (Chile)≤5>51.5 (0.8–2.7)Age, sex, gallstone disease44
 Pandey, 2003 (India)≤3>36.7 (1.8–23.4)None reported42
Age at first childbirth
 Lambe, 1993 (Sweden)<20≥350.5 (0.2–1.4)Age and number of births30
 Tavani, 1996 (Italy)<20>300.9 (0.2–4.0)Age and cholelithiasis48
Zatonski, 19971<20≥200.5 (0.3–1.0)Age, centre, alcohol, smoking, schooling, parity and response status6
 Pandey, 2003 (India)≤20>200.8 (0.4–1.6)None reported42
Oral contraceptive use2
 WHO, 19893NeverEver0.6 (0.3–1.3)History of gallbladder disease, age, centre and year of interview49
 Moerman, 1994 (Netherlands)NeverEver1.2 (0.4–3.2)Age at diagnosis36
 Zatonski, 19971NeverEver1.0 (0.5–2.0)Age, sex, centre, alcohol, smoking, education and response status6
Menopausal status4
 Moerman, 1994 (Netherlands)PreNatural post1.3 (0.3–5.4)Age at diagnosis/interview36
 Tavani, 1996 (Italy)Pre/periNatural post0.2 (0.03–0.9)Age and cholelithiasis48
 Khan, 1999 (USA)PrePost21.3 (1.1–500)Age, ethnicity, socioecomic status, cholelithiasis, hysterectomy and ever-pregnant28
 Pandey, 2003 (India)PrePost0.7 (0.5–0.8)None reported42
Hormone replacement therapy use5
 Moerman, 1994 (Netherlands)NeverEver0.5 (0.1–1.7)Age and BMI36
 Zatonski, 1997 (1)NeverEver0.5 (0.2–1.0)Age, sex, centre, alcohol, smoking, education, and response status6
 Gallus, 2002 (Italy)NeverEver3.2 (1.1–9.3)Age, year of interview, education, smoking, drinking, BMI, parity, type and age at menopause24

A late age at last birth was also associated with increased GC risk in 2 studies, one48 from Italy (RR 2.5, 95% CI: 0.8–7.9 for age ≥35 compared with nulliparae) and another42 from India (RR 3.0, 95% CI: 1.0–8.5 for age >25 compared with ≤25).

Oral contraceptive use was not materially related to GC risk in the 3 reported studies (Table III) and the summary RR was 0.9 (95% CI: 0.5–1.3). Duration of use and time since first and last use were also analyzed in the study of the World Health Organisation (WHO) conducted in Chile, China, Colombia, Israel, Kenya and Mexico, and showed no association with GC risk.49 Inconsistent results were obtained for the association of GC risk with menopausal status and HRT use (Table III). The summary RRs were 0.9 (95% CI: 0.3–2.6) and 0.9 (95% CI: 0.3–3.3), respectively. A significant positive association with HRT use was reported in a case-control study after allowance for reproductive and lifestyle covariants (RR 3.2, 95% CI: 1.1–9.3),24 but not in 2 other studies.6, 36

Eleven epidemiological studies concerning the relation between S. typhi and S. paratyphi and GC are shown in Table IV. All studies based on biological markers, such as serum Vi antigen or the presence of the bacteria in bile specimens, found a significant positive association between carrier state of S. typhi and S. paratyphi and GC risk. The RRs in case-control studies ranged between 7.9 (95% CI: 1.7–37.1),45 and 14 (95% CI: 1.8–92).22 A cohort study by Caygill et al.19 showed a RR of 167 (95% CI: 54.1–389) among chronic carriers of the bacteria, but this finding was based on only 5 GC cases. No association was found for self-reported history of typhoid fever in 3 other studies.42, 44, 50 The summary RR for typhoid infection was 4.8 (95% CI: 1.4–17.3) that became 10.2 (95% CI: 2.0–50.9) after exclusion of studies based on self-reported diagnosis of infection. Statistically significant heterogeneity was found between all the studies (p < 0.001). The summary RR for case-control studies was 2.6 (95% CI: 1.1–6.1), but became 5.2 (95% CI: 2.1–12.7) after exclusion of studies based on self-reported diagnosis of infection.

Table IV. Relative Risks (RR) with Corresponding 95% Confidence Intervals (CI) of Gallbladder Cancer by Presence of Markers or History of Selected Infections
StudyInfecting organismMethod and markerExposed cases/exposed controlsUnexposed cases/unexposed controlsParticipantsRR (95% CI)AdjustmentReference
  • 1

    Summary RR for all studies was 4.8 (95% CI: 1.4–17.3) and heterogeneity test between studies was χmath image = 102.129, p < 0.001, without self-reported information studies was 10.2 (95% CI: 2.0–50.9) and heterogeneity test between studies was χmath image = 38.06, p < 0.001.

  • 2

    Summary RR for cohort studies was 19.3 (95% CI: 0.3–407.7) and heterogeneity test between studies was χmath image = 24.417, p < 0.001.

  • 3

    Summary RR for case-control studies was 2.6 (95% CI: 1.2–6.1) and heterogeneity test between studies was χmath image = 22.464, p = 0.002, without self-reported information studies was 5.2 (95% CI: 2.1–12.7) and heterogeneity test between studies was χmath image = 6.846, p = 0.232.

  • 4

    Estimated from available data.

  • 5

    Summary RR for all studies was 4.3 (95% CI: 2.1–8.8) and heterogeneity test between studies was χmath image = 2.010, p = 0.570.

Salmonella typhi and S. paratyphi1
 Cohort studies2
  Caygill, 1994 (UK)Different typhoid and paratyphoid phagetypesChronic carriers (stillexcreting 2 yearsafter infection)5/83  167 (54.1-389)Sex, age and age at infection19
  Yagyu, 2004 (Japan)Typhoid feverSelf-reported2/63431/37,974Men2.1 (0.5-8.7)Age50
Case-control studies3
  Strom, 1995  (Bolivia, Mexico)Salmonella typhiPhysician-diagnosedtyphoidNone reportedNone reported 12.7 (1.5-598)Age, sex and hospital47
 Salmonella typhiCarriers and past-exposure (serological tests)7/48/4 0.9 (0.2-4.3)4 
  Singh, 1996 (India)Salmonella typhiand paratyphiSalmonella in bilespecimens5/233/65 4.9 (0.9-26.8)4Controls with gallstones46
  Nath, 1997 (India)Salmonella typhiand paratyphi-ASalmonella in bilespecimens4/124/57 9.2 (1.0-86.4)4Controls with gallstones39
  Shukla, 2000 (India)Salmonella typhiCarriers (polysaccharideantigen -Vi- concentration)15/236/38 7.9 (1.7-37.1)None reported45
  Dutta, 2000 (India)Salmonella typhiCarriers (polysaccharideantigen -Vi-concentration)6/231/78 14 (1.8-92)Smoking, age, socioeconomic status22
  Serra, 2002 (Chile)Typhoid feverSelf-reported11/9103/105 0.5 (0.2-1.2)Age, sex, gallstone disease44
  Pandey, 2003 (India)Typhoid feverSelf-reported14/1360/88 1.3 (0.9-2.0)None reported42
Helicobacter bilis and H. pylori
 Case-control studies5
  Matsukura, 2002 (Japan)Helicobacter bilisPCR – Urease A geneand 16S gene13/82/8Japanese6.5 (1.1–38.6)Unadjusted/Controls with gallstones34
 Helicobacter bilisPCR – Urease A geneand 16S gene11/103/16Thai5.9 (1.3–26.3)Unadjusted/Controls with gallstones
  Bulajic, 2002 (Yugoslavia)Helicobacter pyloriPCR – H. pylori DNA12/33/8 9.9 (1.4–70.5)Age and sex17
  Murata, 2004 (Japan)Helicobacter bilisPCR – H. bilis DNA3/28/14 2.6 (0.6–4.6)4Controls with gallstones37

H. bilis and H. pylori have been identified in bile specimens and associated with risk of biliary tract cancer (Table IV). One study34 conducted in Japanese and Thai populations showed that patients positive for H. bilis had an ∼6-fold higher risk of biliary tract carcinoma than the negative ones. H. pylori infection was also identified as a risk factor for biliary tract cancer and the corresponding RR was 9.9 (95% CI: 1.4–70.5) after adjustment for age and sex.17 Another study38 found a positive association between H. bilis and GC and the crude RR was 2.6 (95% CI: 0.6–4.6). The summary RR was 4.3 (95% CI: 2.1–8.8) based on not heterogeneous study-specific estimates (p = 0.570).

Discussion

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
  9. Appendix
  10. Appendix
  11. Supporting Information

The main findings of our present review include: (1) the wide variation of GC incidence worldwide with the identification of 2 major groups of high-risk populations in Latin America and in Asia; (2) the presence in Asia of 2 distinct patterns in respect to the F/M ratio, i.e., one in northern India and Pakistan that showed a high F/M ratio, similar to the one seen elsewhere in the world, and one in Korea and Japan where almost no female excess was present; and (3) the predominance of history of gallstones and cholecystitis among risk factors for GC, with the possible exception of Korean and Japanese populations.

Incidence rates of GC in various ethnic groups in the USA confirmed the worldwide pattern, as GC was substantially more frequent among Hispanic than non-Hispanic white women and men but remarkably elevated incidence rates were also found among Korean and Chinese men. Interestingly, compared to non-Hispanic whites an excess of GC was also reported among American Indians in New Mexico, in agreement with the excess in incidence rates reported for American Indians and Alaskan Natives in 12 of the SEER areas (2.6-fold among women and 4.1-fold among men).53

The worldwide distribution of gallstone prevalence shows a strong positive correlation with the incidence rates of GC. Gallstone prevalence equals to 50% or more among women was found for American Indians in USA,54 and Mapuche Indians in Chile,55 both populations presenting very high GC incidence rates. Other areas reporting high or medium prevalence of gallstones were identified in South America (Chile,55 Argentina,56 Mexico,57 Peru58 and Bolivia59), in Eastern and Western Europe (Austria,60 France,61 Norway,60 Finland,62 the UK,63 Sweden,64 Poland60 and Romania65) and in Australia.66 Very little is known about some countries like India where high incidence of symptomatic gallstones was reported in 1964 for the North-East of the country (91.6/100,000 women),67 but results from ultrasound-based studies are not available. Low-risk areas for gallstones (i.e., prevalence lower than 10% in women) included African countries,60, 68 but also some other countries in Far East Asia as Thailand,60 China,60 Korea68 and Japan41 that reported high GC incidence rates.

Obesity and overweight are major risk factors for gallstones,69 and large cohort studies showed that the association of GC with obesity is one of the strongest seen for any cancer sites. The influence of obesity, however, like the influence of belonging to certain ethnic groups, seemed to be at least in part mediated by an increased predisposition to develop gallstones. In a case-control study from Chile, where GC cases and controls were matched for history of gallstones, no strong association was found between obesity, high parity and history of typhoid fever and GC risk.44

It thus seems that 2 main pathways to GC exist worldwide.70 The predominant pathway involves gallstones and resultant cholecystitis and affects women to a greater extent than men. The other pathway involves an anomalous pancreatobiliary duct junction (APBDJ), a congenital malformation of the biliary tract that is more frequent in Japan, Korea, and possibly China, than in Western countries.70

In APBDJ, the premature junction of common bile and pancreatic ducts results in regurgitation of pancreatic juice into the gallbladder, and consequent irritation and bile stasis that lead to an inflammation status, though usually less severe than that resulting from gallstones.70

APBDJ seems specifically related to papillary carcinoma of the gallbladder, rarer in Western countries than in Japan, less invasive and fatal than other carcinomas of the gallbladder.71 Japanese patients with GC associated with APBDJ are younger and have lower incidence of gallstones than those with GC and without APBDJ.72 No accurate estimate of the prevalence of APBDJ in different populations and corresponding relative risks for GC is available, but its importance in the aetiology of GC in Japan is indirectly supported by the cohort study of 113,394 Japanese, among whom 116 deaths from GC were identified.50 History of gallstones and cholecystitis, diabetes mellitus and typhoid fever were not associated with GC risk in that study, the only 2 significant risk factors being history of constipation and hepatic disease.

In respect to the predominant pathway of GC onset, cholesterol and mixed gallstones account for 80% of the total and pigment stones (composed largely of calcium bilirubinate) account for the remaining fraction.70 Cholesterol gallstones are caused by bile supersaturation with cholesterol or by abnormal motor function with consequent cholestasis. Cholesterol hypersecretion is related to increased cholesterol synthesis in the liver and associated with female gender, obesity and Western lifestyle. Constipation, that has been related to increased GC risk, may facilitate the re-absorption into the bile of secondary bile acids formed in large quantities in the colon via enterohepatic circulation.50 The risk of developing gallstones in response to environmental factors is genetically determined, as shown by the marked tendency of gallstones to cluster in families.27, 47

Cholesterol gallstone formation is, however, a multifactorial process including many metabolic pathways that are not considered in the present review. Several polymorphisms possibly implicated in the aetiology of gallstones and GC have been reported. Modifications of MDR3, a gene involved in the bile formation, and of CYP7A1, which regulates cholesterol metabolism in the liver, seem to play a role in the genetic background of gallstone formation, as well as ApoE and CETP polymorphisms.73 Other genes such as Lith (gallstone) genes are under study.73

Chronic infection of the gallbladder may contribute to the onset of GC, per se or via gallstone formation. Most available evidence implicates S. typhi and S. paratyphi and Helicobacter species. Unfortunately, most studies of infection and GC to date have been small (no more than 15 exposed cases), have lacked well matched controls (with or without gallstones) and have been hampered by the lack of standardized and non invasive methods (from self-reported diagnosis to PCR) for the detection of these infectious agents in large epidemiological studies.

Notably, chlonorchiasis is associated with cholangiocarcinoma,74 cholelithiasis and cholecistitis,75 and, hence, also this infection may be related to GC, although no relative risk estimate is available.

In respect to dietary factors, in the multinational collaborative study from the SEARCH program including 169 cases and 1,515 controls, the strongest direct associations with GC risk were for total carbohydrate intake (RR 11.3 for the highest quartile versus the lowest quartile) and total energy intake (RR 2.0), and the inverse one were for fibers, vitamin V6, E and C (RRs from 0.4 to 0.5).6 However, apart from obesity, there is no nutritional nor dietary factor consistently related to gallbladder cancer risk.

For the time being, diagnosis of gallstones and removal of the gallbladder currently represent the keystone to gallbladder cancer prevention in the majority of the population at high risk. Indeed, a strong inverse association between number of cholecystectomies and GC incidence and mortality rates can be found in many countries. The increase of GC mortality reported in Chile in the 1980s was related to the decrease of the number of cholecystectomies,76 while increased rates of cholecystectomy led to the removal of a substantial amount of gallbladders at risk, and to a reduction of GC incidence and mortality in several countries in Europe,77, 78 the USA and Canada.78 The detection of gallstones and the removal of gallbladder is currently facilitated by the availability of non-invasive and relatively inexpensive diagnostic techniques (e.g., endoscopic ultrasonography) and the possibility of laparoscopic cholecystectomy.

Behavioral interventions meant to prevent overweight and obesity are difficult to implement, but have the added benefit of preventing diabetes mellitus, cardiovascular diseases and a range of cancer sites in addition to GC, especially among women. If the aetiologic role of S. typhi and S. paratyphi, Helicobacter species or other agents were better demonstrated, the benefits of prevention and treatment of these infections may be substantial.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
  9. Appendix
  10. Appendix
  11. Supporting Information

The authors thank Dr Paola Pisani for helping with the design of the descriptive section of this review and Mrs Helene Lorenzen-Augros, Mrs Trudy Perdrix-Thoma and Mrs Ivana Garimoldi for editorial assistance.

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  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
  9. Appendix
  10. Appendix
  11. Supporting Information
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Appendix

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
  9. Appendix
  10. Appendix
  11. Supporting Information
Table 1. Epidemiological studies that have published data on the association between gallbladder cancer and Several risk factors
Study, yearRefCountryCancerStudy designPopulationYear of data collectionNumbers of cases/controlsMean age of cases/controls
  1. GC Gallbladder cancer BTC Biliary tract cancer ∼ Median value” Estimated # Publication year NR None reported * GC incidence and death cases.

Case-control studies
Bulajic, 200217YugoslaviaBTCHosp 2002 #15/1163/52
de Aretxabala, 19955ChileGCHosp 1991–199350/5053/52.8
Diehl, 198321USAGCHosp 1976–198081/80 + 6669/69.5
Dutta, 200022IndiaGCHosp 1994–199537/8053.4/43.5
Fernandez, 199423ItalyGCHosp 1983–199258/1,40861/56 ∼
Gallus, 200224ItalyGCHospWomen1985–199731/3,70264/60 ∼
Kato, 198927JapanGCPop 1982–1986109/21865.9/NR
Khan, 199928USABTCHosp 1980–199438/1,38NR/NR
Lambe, 199330SwedenGCPopWomen1958–1984257/1,28548.3/48.3”
Lowenfels, 198531Louisiana, Arizona, SwedenGCHosp 1963–1983131/2,39970.2/67.8
Lowenfels, 198932Louisiana, ArizonaGCHosp 1979–198515/1,66159.7/61.7
Matsukura, 200234JapanBTCHosp 2002 #53/60NR/59.8
Moerman, 199335NetherlandsGCHosp 1983–198943/9867.2/65.6
Moerman, 199436NetherlandsBTCPopWomen1984–198748/18465.4/65.7
Murata, 200437       
Nath, 199739IndiaGCHosp 1997 #28/56 + 17NR/NR
Nervi, 198840ChileGCAutopsy 1970–197977/14,76864.9/NR
Okamoto, 199941JapanGCScreening 1986–199319/66,13966.2/NR
Pandey, 200342IndiaGCHosp 2003 #64/10151/40.9
Serra, 200244ChileGCHosp 1992–1995114/11463.4/61.9”
Shukla, 200045IndiaGCNR 2000 #51/56 + 4049.9/46.6 + 51.1
Singh, 199646IndiaGCHosp 1996 #38/67NR/NR
Strom, 199547Bolivia, MexicoGCHosp 1984–198884/126 + 26457.3/55.7 + 56.2”
Tavani, 199648ItalyBTCHospWomen1983–199331/37762/59 ∼
Who, 198949Chile, China, Colombia, Israel, Kenya, MexicoGCHosp 1979–198658/35547.6/NR
Zatonski, 19976Australia, Canada, Netherlands, PolandGCPop 1983–1988196/1,515NR/NR
Cohort studies
Calle, 200318USAGC deathPop 1982–1998484/900,053NR/57
Caygill, 199419UKGCCarriers 1967–19945/83NR/49
Chow, 199920DenmarkGCPop 1977–199342/60,17662.1/NR
Goldgar, 199425USAGC deathPop 1952–1992253/399,786NR
Hemminki, 200326SwedenGC*Pop 1961–19987,096/10,200,000NR
Kuriyama, 200529JapanGCPop 1984–199233/27,539NR/56.5
Maringhini, 198733USAGCPop 1950–19705/2,58378.6/NR∼
Moller, 199437DenmarkGC*Hosp 1977–198728/43,965NR/55.0”
Samanic, 200443USAGCHosp 1969–1996338/4,500,70065.7/50
Yagyu, 200450JapanGC deathPop 1988–1999116/113,394NR/59.3”

Appendix

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
  9. Appendix
  10. Appendix
  11. Supporting Information
Table 2. Age-standardized incidence rates (ASR) (truncated for individuals aged 35–74 years) per 100,000 (world standard population) of gallbladder cancer in 40 selected areas of the world, 1992–1997
RegistryFemale incidenceMale incidence
ASRN. of casesASRN. of cases
AMERICAS AND AUSTRALIA
Ecuador, Quito (1993–1997)12.9993.7725
Colombia, Cali (1992–1996)9.5981.5714
Uruguay, Montevideo (1993–1995)6.22743.8133
Australia, New South Wales (1993–1997)2.561861.2990
Canada (1993–1997)2.137441.22385
USA, SEER (1993–1997)1.785131.03254
ASIA
India, Delhi (1993–1996)21.57747.09300
Pakistan, South Karachi (1995–1997)13.83512.5712
Korea, Busan (1996–1997)10.511357.9881
Japan, Nagasaki Prefecture (1993–1997)7.582175.49124
Korea, Seoul (1993–1997)6.75205.31331
Japan, Osaka Prefecture (1993–1997)5.857424.4484
Thailand, Chiang Mai (1993–1997)5.8711.4518
China, Shanghai (1993–1997)5.474892.22203
India, Mumbai (Bombay) (1993–1997)5.082672.41150
Israel (1993–1997)2.761540.7837
China, Tianjin (1993–1997)1.53711.562
China, Taiwan (1997)1.41510.9842
EASTERN EUROPE
Slovakia (1993–1997)10.217264.03217
Poland, Lower Silesia (1993–1997)10.154314.54139
Czech Republic (1993–1997)10.0115675.46662
Poland, Warsaw city (1993–1997)8.422383.9785
Yugoslavia, Vojvodina (1993–1997)7.822662.9486
Slovenia (1993–1997)5.21641.6937
Croatia (1993–1997)4.113001.98106
Lithuania (1993–1997)3.51961.2345
Russia, St Petersburg (1994–1997)3.492411.7869
Estonia (1993–1997)2.55651.3521
Latvia (1993–1997)1.44630.8623
SOUTHERN AND CENTRAL EUROPE
Spain, Granada (1993–1997)7.91881.4514
Germany, Saarland (1993–1997)5.551142.6341
France, Bas-Rhin (1993–1997)3.85541.1713
Italy, Varese Province (1993–1997)3.85541.8121
NORTHERN EUROPE
Sweden (1993–1997)4.185231.77216
The Netherlands (1993–1997)2.154420.89159
Ireland (1994–1997)2.04650.9327
Denmark (1993–1997)1.411040.2819
UK, Scotland (1993–1997)1.411020.638
UK, England (1993–1997)1.117740.48297
Norway (1993–1997)0.9530.2814

Appendix

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
  9. Appendix
  10. Appendix
  11. Supporting Information
Table 3. Age-staNdardized incidence rates (ASR) (truncated for individuals aged 35–74 years) per 100,000 (world standard population) of gallbladder cancer in selected ethnic groups in the USA, 1993–1997
Registry in USAFemale incidenceMale incidence
ASRN. of casesASRN. of cases
USA, California, Los Angeles: Hispanic White (1993–1997)8.251292.8235
USA, New Mexico: American Indian (1993–1997)7.0776.935
USA, New Mexico: Hispanic White (1993–1997)5.35291.226
USA, California, Los Angeles: Korean (1993–1997)2.352.994
USA, California, Los Angeles: Black (1993–1997)2.28231.4912
USA, SEER: Black (1993–1997)1.87461.5231
USA, SEER: White (1993–1997)1.734130.87178
USA, New Mexico: Non-Hispanic White (1993–1997)1.64210.738
USA, California, Los Angeles: Filipino (1993–1997)1.6351.162
USA, California, Los Angeles: Japanese (1993–1997)1.5631.432
USA, California, Los Angeles: Non-Hispanic White (1993–1997)1.54770.627
USA, California, Los Angeles: Chinese (1993–1997)0.9632.267

Supporting Information

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
  9. Appendix
  10. Appendix
  11. Supporting Information

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