Cholelithiasis, Cholecystectomy, and Cancer: A Case-Control Study in Sweden

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1 GASTROENTEROLOGY 1982;83:672-6 Cholelithiasis, Cholecystectomy, and Cancer: A Case-Control Study in Sweden ALBERT B. LOWENFELS, LENNART DOMELLOF, CLAS G. LINDSTROM, FRANK BERGMAN, MARY A. MONK, and NILS H. STERNBY Department of Surgery and Preventive Medicine, New York Medical College; Departments of Surgery and Pathology, Umea University, Sweden; Department of Pathology, University of Lund, Malmo General Hospital, Sweden To study the relationship between gallstone disease (cholelithiasis and cholecystectomy) and cancer, a case-control study was performed in two Swedish hospitals comparing the prevalence of gallstone disease discovered at necropsy in 1422 subjects who died of cancer and 1205 subjects who did not die of cancer. Gallstone disease was more prevalent in the group of 131 women <50 yr of age who died of various cancers: odds ratio = 2.2, P < When the analysis was restricted to 89 younger women who died of cancers that have been suggested to be related to diet (breast, reproductive system, gastrointestinal), the results became more significant: odds ratio = 3.3, P < No such relationship was detected in older women or in men of any age. It seems likely that gallstone disease and several common cancers in younger Swedish women share similar epidemiologic and perhaps metabolic features. Gallstones share similar epidemiologic features with large bowel, breast, and female reproductive cancers, and it seems reasonable that these common diseases may be related through diet. However, it has been difficult to establish this association within individual population groups, perhaps because of selection of inappropriate controls, or because the groups studied were too small to detect important subgroup differences. Received November 13,1981. Accepted April 27, Address requests for reprints to: Albert B. Lowenfels, M.D., Department of Surgery, New York Medical College, Munger Pavilion, Valhalla, New York This study was supported in part by a grant to Albert B. Lowenfels, M.D., from the University of Umea, Sweden while he was a Visiting Professor of Surgery. The authors are indebted to Sven Dahlgren for facilitating the work in Umea, Dr. Calum Muir for valuable ideas, and Stephen Shev and Gert Lindell for their help in examining the records by the American Gastroenterological Association /82/ $02.50 The objectives of this study were: (a) to look for an association between gallstone disease and large bowel cancer as suggested in several previous reports (1-3), (b) to search for an association between gallstones and other "diet" cancers as we have previously suggested (4), (c) to look particularly at the association between various cancers and gallstones in younger subjects since in a preliminary report we found a possible excess of gallstones in younger but not older subjects with cancer (5). The relationship between gallstones, cholecystectomy, and various common cancers was examined using available necropsy records of a large number of Swedish subjects. Subjects selected for study were mainly individuals who died as a result of gastrointestinal, female reproductive, or breast cancers because these tumors have been suggested to be dietrelated (6-8). We have included additional patients who died of other cancers, such as lung, kidney, brain, and malignant lymphoma, to determine whether or not the association between gallstones and cancer might be a general one. Methods The method chosen was a case-control study comparing the prevalence of gallstones or previous cholecystectomy discovered at necropsy in subjects who died of cancer and those who did not die of cancer from 1970 to We selected Sweden as a suitable country because it has a homogeneous, stable population, high quality medical records, and a strong tradition of necropsy examination for nearly every hospital death. The study was performed in two university hospitals Umea Hospital in the north of Sweden and Malmo General Hospital in the south. Umea Hospital, the sole hospital responsible for medical care for the surrounding region of 140,000 people, performed 7569 necropsies during the 10- yr study period, representing 80% of all hospital deaths. Malmo General Hospital is the only hospital supplying

2 September 1982 GALLSTONES AND CANCER 673 Table 1. Types of Tumors and Prevalence of Gallstone Disease in Subjects Fifty Years of Age or Older Men Women of sub- GSDb % of sub- GSp % Type of tumor jects present GSD jects present GSD Colorectal Stomach Breast Reprod ucti ve Lung Bladder, prostate Other si tes O Total Control subjects a Brain, kidney, thyroid, malignant lymphoma, melanoma. b GSD = Gallstone disease. general medical care for the 248,000 inhabitants of Malmo, and during the study period 14,612 necropsies were performed, representiqg 93% of all hospital deaths. Selectiop of Cancer Cases During the years , 7654 deaths from cancer were recorded for the two centers. Tables 1 and 2 list the numbers and types of cancers selected for review. In Umea we included all male and female subjects (749 cases) dying between 1970 and 1979 with any of the tumors listed in the tables. In Malmo we included all women <60 yr old and all men <50 yr old who died between 1970 and 1979 of cancers listed in Tables 1 and 2; all men and women who died of large bowel cancer between 1977 and 1979; 58 randomly selected men aged yr who died of cancers of the lung, brain, kidney, or malignant lymphoma (total Malmo cases = 673). Of the 1422 cancer subjects who were reviewed, 228 were <50 yr old and 1194 were 50 yr or older. Selection of Controls Controls were subjects who did not have cancer and who were chosen from lists in each institution that gave the year and date of death, age at death, sex, and cause of death. The most common ca4ses for death of control subjects < 50 yr old were accidents, lesions of the central nervous system, renal disease, and pulmonary disorders. Cardiovascular diseases accounted for < 10% of deaths in younger women and 31 % of deaths in younger men. In contrast, control subjects aged 50 yr and older had cardiovascular disorders such ' as myocardial infarction and stroke that accounted for the majority of deaths. Exclusions Subjects who were <20 yr old were not included in the study, nor were individuals with cancers of the gall- bladder, liver, biliary tract, and pancreas. After selection, we excluded 125 (9%) subjects who had cancer: 42 individuals with multiple tumors, 27 individuals lacking information about the gallbladder, 56 individuals who died as a result of cancer but with autopsy evidence of a disease that might increase the risk of gallstone disease such as alcoholic cirrhosis, cholecystitis, pancreatitis, or hemolytic disorders. Thirteen excluded cancer patients were < 50 yr old. One hundred fifty-seven control subjects (13%) were excluded, 48 individuals lacking information about the gallbladder and 109 subjects with diseases that might increase the risk of gallstone disease as listed above. Twenty-one excluded control subjects were <50 yr old. Matching Procedure For each cancer subject <50 yr old a control of the same sex who did not have cancer at death and who was autopsied in the same hospital was selected. Age at death was matched exactly, if possible, using a control subject who died within the same year as the cancer subject. If this was impossible, then the 3 yr preceding or following the year of death of the cancer subject were searched. If this did not result in a match, then the age range from which a matched control could be selected was expanded to include the year on either side of the age of the cancer subject. If this did not yield a match, then the acceptable age range for the control subject was expanded an addi- Table 2. Matched-Pair Comparison of Gallstone Disease in Subjects Less Than Fifty Years of Age Who Died of Cancer or of Other Causes Concordant pairs Discordant pairs Patients Controls of GSDO GSD with with Odds Type of tumor tumors present absent GSDO GSDO ratio Men Large bowel Stomach Lung Other types b All tumors Women Gr, breast, reproductive Large bowel Stomach CXl Breast Reprod ucti ve Subtotal c Lung Other types d All tumors " a GSD = Gallstone disease. b Lymphoma = 17, brain = 11, kidney = 9, genitourinary = 3, miscellaneous = 3. c X 2 = 11.26; p < 0.001; 95% confidence intervalfor odds ratio = d Lymphoma = 6, brain = 12, kidney = 3, miscellaneous = 8. e X2 = 6.94; p < 0.01; 95% confidence interval for odds ratio =

3 674 LOWENFELS ET AL. GASTROENTEROLOGY Vol. 83, No.3 tional year and the search continued, using, if necessary, control subjects from the entire study decade. In this fashion all cancer subjects <50 yr old were matched within 2 yr of age; 80% were matched for the same year. Cancer subjects aged 50 yr or older were stratified by age (decade), hospital, and sex and were then compared with a group of patients who died without cancer. In each hospital this control group was constructed by selecting every 15tp. patient who did not have cancer at death, for a total of 977 control subjects aged 50 yr or older. After selection of cases and controls, individual necropsy protocols were then inspected to determine whether or not the gallbladder was present or absent, and whether or not gallstones were present in the gallbladder or bile ducts. An absent gallbladder was presumed to indicate previous cholecystectomy; both cholelithiasis and cholecystectomy were considered indicative of gallstone disease. Statistical Methods For subjects <50 yr old we used McNemar's method to analyze discordant pairs after eliminating those pairs where gallstone disease was either present or absent in both cancer subject and control. Ninety-five percent confidence intervals for the resulting odds ratios that differed significantly from unity were calculated after first estimating the lower and upper limits for the proportion of cancer subjects with gallstone disease (9). For patients aged 50 yr and over X 2 determinations were performed comparing various categories of cancer subjects with control subjects after stratifying them by decade, sex, and hospital. Results In both institutions the records were of a very high quality so that the presence or absence of gallstone disease could be determined in 98% of the chosen cancer cases. In both cancer subjects and control subjects aged 50 yr or over, gallstone disease was extremely frequent, resembling a previous recent report from Sweden (10) (Table 1). However, when cancer subjects aged 50 yr or older were stratified by age, sex, type of tumor, and hospital, no significant differences (p > 0.10) could be found when compared with control subjects without cancer (data not shown). In both centers there were 97 men <50 yr old who died as a result of cancer who were selected for review. When compared with individually matched controls, there was no difference in the prevalence of gallstone disease as noted at necropsy: odds ratio = 0.64, X 2 = 0.70, P > 0.30 (Table 2). Cholecystectomy had been performed on 5 of the cancer subjects and 3 control subjects. There were 131 records available for women <50 yr old who died as a result of cancer between 1970 and 1979 in the two hospitals; this group of younger women showed a significant incidence of gallstone disease compared with matched noncancer controls: 52 discordant pairs, odds ratio = 2.2, X2 = 6.94, P < When we restricted the analysis to those 88 younger women who died of cancers of the gastrointestinal tract, breast, or reproductive organs, the results became highly significant: 43 discordant pairs, odds ratio = 3.3, X2 = 11.26, P < (Table 2). In contrast, there was no significant excess of gallstone disease in the group of WOmen <50 yr old who died as a result of cancer of the lung, kidney, brain, lymphoma, or miscellaneous tumors: 9 discordant pairs, odds ratio = 0.5, X2 = 0.44, P > Necropsy disclosed gallstone disease in 43 of the 131 women who died at <50 yr of age and who had cancer. In 16 individuals, cholecystectomy had been performed with an average interval of 11 yr between cholecystectomy and death from cancer. In the remaining 27 subjects, gallstones were present at necropsy. Table 3 contrasts cholecystectomy with cholelithiasis (discordant pairs only) in this group of younger women who died of cancer as compared with matched noncancer control subjects. The resulting odds ratios were similar for both cholecystectomy and cholelithiasis, but attained statistically significant levels only for cholelithiasis. Discussion The results show an association between gallstone disease and several common cancers in Swedish women <50 yr old; similar results were obtained in a smaller study conducted in the United States (5). We recognize the dangers in drawing conclusions from autopsy material. In this study, however, nearly all hospital deaths were autopsied. In addition, Table 3. Presence or Absence of Gallstone Disease in Matched Discordant Pairs of Female Subjects Less Than Fifty Years of Age Who Died of Cancer or of Other Causes; Cholecystectomy Compared With Cholelithiasis Patients Controls with with Odds Type of tumor GSD GSD ratio Cholecystectomy GI, breast, reproductive Lung, kidney, lymphoma, miscellaneous All tumors Cholelithiasis GI, breast, reproductive b Lung, kidney, lymphoma, miscellaneous All tumors " a GSD = Gallstone disease. b X 2 = 6.76; P < 0.01; 95% confidence interval = "X2 = 4.36; P < 0.05; 95% confidence interval =

4 September 1982 GALLSTONES AND CANCER 675 among women <50 yr old who died outside of hospital, more than one-half were autopsied under the medical-legal system; review of these records disclosed few cancer cases. One-fourth of the control subjects who were women <50 yr old died of accidental causes; the percentage of gallstone disease was similar to the other younger female control subjects (18% vs. 17%). There are of course other biases in an autopsy study, such as different case fatality rates for cancer subjects and controls. We believe, though, that most of these biases would have operated to underestimate the true difference in gallstone disease prevalence between cancer patients and controls. Another flaw could be closer attention to the gallbladder in autopsies of cancer subjects than of noncancer subjects. No evidence of such a bias could be detected; the records of both cancer and noncancer subjects revealed the same careful examination of the biliary tract in both groups. Observer bias in selecting and matching cancer subjects and controls might introduce an error. Again, this seems unlikely, since we reviewed a large number of cancers of every major type, including nearly all cancer subjects who died at <50 yr of age. Moreover, the status of the gallbladder was ascertained only after selecting cancer subjects and controls. In our study, the prevalence of gallstones in younger control subjects who were women was 17.6% nearly identical to the figure of 18.6% found by Lindstrom (10) in Sweden in unselected women in the same age group who died. Thus, we consider it unlikely that a significant bias has been introduced by excluding younger female control subjects who might have had gallstones or by improper selection procedures. Furthermore, if we compare the 42 younger female subjects who died of nondiet cancers to the 89 younger women who died with diet cancers, the results again show that subjects who died with diet cancers had an excess of gallstones (relative risk = 3.4, corrected x 2 = 6.28, P < 0.02). The average age of all of the younger women who died of cancer was 43.2 ± 5.0 yr; there was no difference in age in subjects who died of any of the various types of cancer. Of the 131 women who were <50 yr old, 30 died in Umea Hospital and 101 in Malmo General Hospital. These two groups were similar with respect to distribution of various types of tumors, proportion of cancer subjects and controls with gallstone disease, and average age. Furthermore, necropsy procedures at the two hospitals were comparable, including an equally detailed description of the biliary tract in both institutions. In this study, deaths from cardiovascular disease were common in male control subjects of all ages and in female control subjects >50 yr old. Gallstones are known to be more prevalent with cardiovascular disorders (11,12), perhaps explaining why we observed positive findings only in younger women. We found a positive association between cancer and gallstone disease in younger women who died of gastrointestinal, reproductive, or breast cancer-tumors that have been suggested to be diet-related. An association between gallstone disease and large bowel cancer has been observed in most (1-3), but not all (13), previous reports. Gallstone disease has been reported to be associated with female reproductive cancers (6,14) but not with breast cancer. Obesity could be a common link, since it is a major risk factor for gallstones (15) and since a greater incidence of breast and reproductive cancers have been observed in obese women (16). Duodenogastric reflux, a possible risk factor in gastric cancer, is thought to be more frequent in patients with gallstone disease (17,18); this could explain why we found a greater incidence of gallstone disease in younger women with gastric cancer. Our results imply that younger Swedish women who died as a result of gastrointestinal, breast, or reproductive tumors are 3-4 times more likely to have cholelithiasis or previous cholecystectomy than matched controls without cancer. However, because of the various problems inherent in a casecontrol study, the association we have reported between gallstones and certain tumors in younger women may be weaker than we think or may only be an apparent one. To clarify and extend these findings we have initiated a prospective study of the incidence of cancer in Sweden after cholecystectomy. References 1. Capron JP, Delamarre J, Canarelli JP, et al. La cholecystectomie favorise-t-elle l'apparition due cancer rectocolique. Gastroenterol Clin BioI 1978;2: Linos DA, Beard CM, O'Fallon WM, et al. Cholecystectomy and carcinoma of the colon. Lancet 1981;ii: Vernick LJ, Kuller LH. Cholecystectomy and right-sided colon cancer: an epidemiologic study. Lancet 1981;ii: Lowenfels AB. Gallstones and the risk of cancer. Gut 1980;21: Lowenfels AB, Schwartz R, Pitchumoni C. Cholelithiasis and cancer. Gastroenterology 1981;80: Casagrande JT, Pike MC, Ross RK, et al. Incessant ovulation and ovarian cancer. Lancet 1979;ii: Berg JW. Can nutrition explain the pattern of international epidemiology of hormone-dependent cancers? Cancer Res 1975;35: Reddy BS, Cohen LA, McCoy GD, et al. Nutrition and its relationship to cancer. Adv Cancer Res 1980;32: Fleiss JL. Statistical methods for rates and proportions. 2nd ed. New York: John Wiley and Sons, 1981: Lindstrom CG. Frequency of gallstone disease in a well-

5 676 LOWENFELS ET AL. GASTROENTEROLOGY Vol. 83, No.3 defined Swedish population. Scand J Gastroenterol 1977; 12: Bergman F, Van der Linden W, Soderstrom J. The connexion between myocardial infarction and gallstones in an autopsy series. Acta Pathol Microbiol Scand 1968;73: Breyfogle HS. The frequency of coexisting gallbladder and coronary artery disease: a statistical analysis and biometric evaluation of 1493 necropsies. JAMA 1940;114: Castled en WM, Doouss TW, Jennings KP, Leighton M. Gallstones, carcinoma of the colon and diverticular disease. Clin Oncol 1978;4: Mack TM, Pike Me, Henderson BE, et al. Estrogens and endometrial cancer in a retirement community. N Engl J Med 1976;294: Bennion LJ, Grundy SM. Risk factors for the development of cholelithiasis in man. N Engl J Med1978;299: Lew EA, Garfinkel L. Variations in mortality by weight among 750,000 men and women. J Chronic Dis 1979;32: Rees WEW, Rhodes J. Bile reflux in gastro-oesophageal disease. Clin GastroenteroI1977;6: Kalima T, Sjoberg J. Bile reflux after cholecystectomy. Scand J GastroenteroI1981;16(Suppl 67):153-6.