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The association between biliary tract cancers and cancers of other sites
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 1999 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 94, No. 8, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00358-5
The Association Between Biliary Tract Cancers and Cancers of Other Sites Yun Su, M.D., M.P.H., Habibul Ahsan, M.D., MMed.Sc., and Alfred I. Neugut, M.D., Ph.D. Division of Epidemiology, Joseph L. Mailman School of Public Health; Division of Oncology, Department of Medicine; and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York
OBJECTIVE: Cancers of the biliary tract, including cancers of the gallbladder and bile duct, generally carry a very poor prognosis. Little is known about their etiology. The pattern of co-occurrence of two cancers may give clues to shared etiological risk factors. We therefore investigated the association of biliary tract cancer with other cancers, especially with estrogen- and tobacco-related cancers. METHODS: We used data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Associations between biliary tract cancer and other cancers were evaluated using the standardized incidence ratio as an estimate of the relative risk of a second primary malignancy. RESULTS: Estrogen-related cancers of the breast and uterine corpus and smoking-related upper aerodigestive tract cancers were not associated with biliary tract cancer. The risk of gallbladder cancer was inversely related to the risk of prostate cancer in men, but positively related to the risk of cervical cancer in women. CONCLUSIONS: This study suggests that smoking and estrogen exposure have minimal roles in the pathogenesis of biliary tract cancer. Our finding of an inverse relationship between prostate cancer and gallbladder cancer requires confirmation by further studies. (Am J Gastroenterol 1999; 94:2256 –2262. © 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION Cancers of the biliary tract, including cancers of the gallbladder, extrahepatic bile duct, and ampulla of Vater, are uncommon but fatal, with about 4300 deaths per year in the United States (1). Each of them has a distinct demographic distribution (1). Although gallbladder cancer occurs more frequently among women than among men, bile duct and ampullary cancers occur more frequently among men. Their racial and geographical variations also follow different patterns. These epidemiological variations and the different physiological functions of the different subsites of the biliary tract suggest that biliary tract cancers of different subsites could have different etiologies (2). Little is known about the etiology of biliary tract cancers (1, 3), except for a close relationship with gallstones. Other
factors suspected to be associated with biliary tract cancers, either directly or indirectly through cholelithiasis, include reproductive and hormonal factors, obesity, dietary factors, tobacco and alcohol use, ulcerative colitis, and genetic predisposition. Few analytical epidemiological studies have been done to clarify the roles these factors may play in the pathogenesis of biliary tract cancers (1). Multiple primary neoplasms are a fairly common clinical occurrence (4). Although some cancers may co-occur by chance, a greater-than-chance association between two cancers can provide clues to a shared etiology (4, 5). A unidirectional, significantly altered risk of one primary cancer following another, but not vice versa, usually suggests surveillance bias, cancer effects, or treatment effects. A bidirectional, mutually altered risk of two cancers following each other suggests shared environmental, genetic, or immunological predisposing risk factors. In the past, biliary tract cancers have been found to co-occur with cancers of the prostate (6, 7), ovary (8), breast (9), esophagus (10), rectum (10), pancreas (10, 11), liver (11, 12), stomach (12–14), and colorectum (15–18). These findings, however, are mostly from individual case reports, with only a few systematic studies of very limited sample size, making it impossible to draw meaningful inferences (6 –10). Additionally, liver cancer and biliary tract cancer were sometimes considered as one disease entity (7–10), which makes interpretation of these studies difficult. Finally, none of the previous epidemiological studies adjusted for race in their risk estimates. Given the widely varying incidence rates of biliary tract cancer among different ethnic groups (1), race is a likely confounding variable, which should be taken into account in assessing epidemiological associations. In the present study, we investigated the associations of biliary tract cancers with cancers of other sites using a large population-based cancer registry. Separate analyses were conducted for biliary tract cancers of different subsites. Race was controlled for in the risk estimates. Hypotheses regarding the effects of smoking and estrogen were tested in particular by assessing the associations of biliary tract cancers with tobacco/alcohol-related upper aerodigestive tract cancers, and with female sex hormone-related cancers of the
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Table 1. Person-Years of Follow-up for Second Biliary Tract Cancers Following Cancers of Other Sites 2nd Primary All Biliary Tract 1st Primary Men UAT Lung Colorectum Prostate Bladder Kidney Women UAT Lung Colorectum Breast Ovary Corpus Uteri Cervix Bladder Kidney
Persons at Risk
Person-Years of Follow-up
Gallbladder Persons at Risk
Bile Duct
Person-Years of Follow-up
Persons at Risk
Person-Years of Follow-up
99,509 79,677 82,966 163,121 45,556 12,976
245,290 159,708 381,749 668,679 255,836 60,474
99,509 79,677 79,677 79,677 79,677 79,677
245,315 159,718 159,718 159,718 159,718 159,718
99,510 79,678 82,978 163,125 45,556 12,977
245,299 159,715 381,732 688,704 255,841 60,496
48,636 43,352 81,243 204,266 24,796 51,289 21,181 15,064 7573
120,731 100,534 404,440 1,227,786 106,170 410,906 137,483 86,214 36,905
48,637 43,353 81,246 204,273 24,796 51,290 21,181 15,064 7573
120,739 100,542 404,485 1,227,868 106,173 410,950 137,483 86,215 36,915
48,637 43,542 81,260 204,269 24,799 51,292 21,181 15,065 7573
120,736 100,540 404,533 1,227,834 106,176 410,943 137,486 86,216 36,905
UAT ⫽ upper aerodigestive tract; follow-up ⫽ begins at the sixth month after the diagnosis of the first primary cancer.
breast, ovary, and uterine corpus. In addition to being implicated by previous studies in the etiology of biliary tract cancers (1), tobacco/alcohol and female reproductive hormones are two of the major shared risk factors underlying multiple primary malignancies (5).
MATERIALS AND METHODS SEER Database Data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, for the period 1973 through 1993 (19), were used in this study. The SEER data are drawn from population-based cancer registries in nine major U.S. areas, covering approximately 10% of the U.S. population. The populations included are rea-
sonably representative of the entire U.S. population (20). Cancer registration is generally considered rather complete and of high quality, with 95% of the diagnoses confirmed microscopically (21). Among other variables, information contained in the SEER cancer data for each incidence case includes identification numbers for each patient; demography; the type of reporting source; the date of diagnosis; the length of survival; primary site; morphology; stage; and sequence number indicating the presence or absence of multiple primary cancers and the order of occurrence of each. Cases In this study, as shown in Tables 1 and 2, a primary cancer of each site was defined by either its International Classifi-
Table 2. Person-Years of Follow-up for Second Cancers of Other Sites Following Biliary Tract Cancers 1st Primary All Biliary Tract ICD-O 239–249 2nd Primary Men UAT Colorectum Prostate Women UAT Colorectum Breast Ovary Corpus Uteri Cervix
Gallbladder ICD-O 239, 249
Bile Duct ICD-O 240–248
Persons at Risk
Person-Years of Follow-up
Persons at Risk
Person-Years of Follow-up
Persons at Risk
Person-Years of Follow-up
2035 2033 2033
4602 4598 4554
618 617 618
1288 1280 1281
1417 1416 1415
3314 3318 3273
2935 2930 2928 2934 2934 2935
6271 6229 6199 6266 6254 6273
1703 1699 1700 1702 1702 1703
3650 3620 3616 3646 3629 3651
1232 1231 1228 1232 1232 1232
2621 2610 2583 2620 2624 2623
UAT ⫽ upper aerodigestive tract; ICD-O 1976 ⫽ International Classification of Disease for Oncology, 1976. Follow-up ⫽ begins at the sixth month after the diagnosis of the first primary cancer.
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cation of Disease for Oncology (ICD-O), 1976 topography codes, or its ICD-O, 1976 morphology codes, or both, as they are used in the SEER database. Biliary tract cancers that were not otherwise specified (NOS, ICD-O topography code 249) were grouped with gallbladder cancer, as it is the most common type (1), constituting about 30% of biliary tract cancers. Because of their many similarities, extrahepatic bile duct cancer and ampulla of Vater cancer were combined for analytic purposes (referred to as bile duct cancer). Included in the upper aerodigestive tract cancer category according to Schottenfeld (5) were cancers of the lip, oral cavity, pharynx, esophagus, larynx, lung, and bronchus; primary cancers occurring after a second primary cancer were excluded. Also excluded were those second primary cancers diagnosed within 6 months after the diagnosis of a first primary cancer. First and second primary cancers occurring in the same person were linked by the same SEER participant number and case number, which together identifies each patient. To fulfill the criteria of multiple primary cancers described by Schottenfeld (5), only malignant tumors were included, i.e., noninvasive in situ neoplasms were excluded. Also excluded were those cancers that were reported by autopsy or death certificate only. The first primary cancers chosen for analysis were the more common cancers, to allow sufficient statistical power for analysis. Cases with unknown race and cases with unknown dates of diagnosis, for whom person-years of follow-up could not be calculated, were excluded also. The excluded cases were a small fraction of all cases available for each cancer site, at most fewer than 2% (data not shown). Analyses We used a retrospective cohort design. The standardized incidence ratio (SIR) uses the general population incidence rates rather than the incidence rates in an unexposed group. The comparison group was used in calculating the relative risk (RR). If the general population differs systematically from the unexposed population with respect to the risk factors, then bias may arise. The SIR was used as an estimate of the RR for developing a second primary cancer after a first primary cancer of another site. SIR is the ratio of the gender-specific observed to expected number of cases of a second primary cancer. The gender-specific observed number of cases was determined directly from the database. The gender-specific expected number of cases was adjusted for age, time period, and race, and was calculated by multiplying the gender-, race-, age-, and period-specific standard population incidence rates by the corresponding stratumspecific person-years of follow-up for the first primary cancer, and then summing by gender. Race was specific for white, black, and others; age and period were specific for each 5-yr age group (0 – 85⫹), and each 3-calendar year (1973–1993), respectively. The gender-, race-, age-, and period-specific person-years of follow-up began at the sixth month after the diagnosis of the first primary cancer; and
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was censored at the diagnosis of the second primary cancer, or at the end of the survival time as defined in the SEER database, whichever was first. The 95% confidence interval (CI) around the RR was calculated using Byar’s limits, assuming a Poisson distribution (22). The RRs of biliary tract cancers occurring as second malignancies after first primary cancers of other sites were determined. For those first primary cancers with significant findings or that were important for our hypothesis testing, their RRs as second primary cancers after first primary biliary tract cancers were also estimated. Gallbladder cancer and bile duct cancer were first combined and analyzed as one entity, biliary tract cancer, and then analyzed separately, as the available numbers of cases allowed.
RESULTS Tables 1 and 2 show the persons at risk, and person-years of follow-up starting at the sixth month after the diagnosis of the first primary cancer. The RRs of second primary biliary tract cancer after other cancers are shown in Table 3 and the RRs of selected second primary cancers of other sites after biliary tract cancers are shown in Table 4. Associations of Gallbladder Cancer With Other Cancers As seen in Table 3, there is a significantly reduced risk of gallbladder cancer after colorectal cancer in both men and women. The risk of gallbladder cancer is also significantly or almost significantly altered after two gender-related tumors: reduced after prostate cancer in men, but elevated after cervical cancer in women. Although with very high statistical power, the reduction in risk for gallbladder cancer after breast cancer was only close to significance. The risk of gallbladder cancer was not significantly altered after either uterine corpus cancer or ovarian cancer. In light of these findings, important associations were tested in the reverse direction, with biliary tract cancers as the first primary cancer, followed by other cancers (Table 4). The statistical power for such analyses was generally low, due to small numbers of cases and poor survival of biliary tract cancer patients. Not surprisingly, although the risks of prostate cancer and cervical cancer seemed to be altered similarly after gallbladder cancer as they were in the reverse direction, neither was significant. Moreover, unlike what was found in the reverse direction, the risk of second primary colorectal cancer was elevated, not reduced, in both men and women. On the other hand, a significant, greatly elevated risk of ovarian cancer was found after gallbladder cancer in the absence of a reciprocal finding. Association Between Bile Duct Cancer and Other Cancers As shown in Table 3, the most important finding is a significantly elevated risk of bile duct cancer after colorectal cancer in both men and women. Among the trio of female gender-related cancers, almost significantly elevated risk of
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Table 3. Relative Risks of Second Biliary Tract Cancers Following Cancers of Other Sites 2nd Primary All Biliary Tract 1st Primary Men UAT Lung Colorectum Prostate Bladder Kidney Women UAT Lung Colorectum Breast Ovary Corpus Uteri Cervix Bladder Kidney
Gallbladder
Bile Duct
Ob
Ex
RR (95% CI)
Ob
Ex
RR (95% CI)
Ob
Ex
RR (95% CI)
25 13 51 68 25 5
18.7 12.6 39.1 86.6 24.1 3.9
1.34 (0.86–1.97) 1.03 (0.55–1.76) 1.30 (0.97–1.71) 0.79 (0.61–1.00)* 1.04 (0.67–1.53) 1.29 (0.42–3.02)
12 6 7 22 14 2
7.7 5.2 16.7 37.3 10.2 1.6
1.56 (0.81–2.73) 1.15 (0.42–2.51) 0.42 (0.17–0.86)* 0.59 (0.37–0.89)* 1.38 (0.75–2.31) 1.27 (0.14–4.57)
13 7 44 46 11 3
11.0 7.4 22.5 49.2 14.0 2.3
1.18 (0.63–2.02) 0.94 (0.38–1.94) 1.96 (1.42–2.63)* 0.93 (0.68–1.25) 0.79 (0.39–1.41) 1.31 (0.26–3.83)
10 9 47 97 7 41 11 11 4
10.0 8.5 53.0 99.1 6.0 32.1 5.4 10.5 2.8
1.00 (0.48–1.83) 1.06 (0.49–2.02) 0.89 (0.65–1.18) 0.98 (0.79–1.19) 1.16 (0.46–2.39) 1.28 (0.92–1.73) 2.04 (1.02–3.64)* 1.05 (0.52–1.88) 1.41 (0.38–3.60)
7 7 19 54 4 23 8 8 3
6.6 5.6 35.4 65.7 4.0 21.3 3.5 7.0 1.9
1.06 (0.43–2.19) 1.26 (0.50–2.59) 0.54 (0.32–0.84)* 0.82 (0.62–1.07) 1.00 (0.27–2.57) 1.08 (0.69–1.62) 2.26 (0.97–4.46) 1.14 (0.49–2.26) 1.60 (0.32–4.67)
3 2 28 43 3 18 3 3 1
3.4 2.9 17.6 33.4 2.1 10.9 1.9 3.5 1.0
0.87 (0.18–2.55) 0.69 (0.08–2.48) 1.59 (1.06–2.30)* 1.29 (0.93–1.74) 1.46 (0.29–4.26) 1.66 (0.98–2.62) 1.61 (0.32–4.71) 0.86 (0.17–2.52) 1.03 (0.01–5.75)
Prim ⫽ primary; Ob ⫽ Observed number of cases; Ex ⫽ expected number of cases; RR ⫽ relative risk; CI ⫽ confidence interval; UAT ⫽ upper aerodigestive tract. * Significant result.
bile duct cancer was seen after uterine corpus cancer, but not after breast or ovarian cancer. No significant association was found with upper aerodigestive tract cancers, with low statistical power again clouding the picture. On analyses in the reverse direction (Table 4), corresponding to the earlier-stated finding, a significantly elevated risk of colorectal cancer was found in women after bile duct cancer. However, the elevated risk was not significant in men. Probably due to inadequate statistical power, the risk for uterine corpus cancer was not elevated after bile duct cancer. Comparable to the finding with gallbladder cancer and far exceeding what was found in the reverse direction, there is an increased risk of ovarian cancer, nearly significant in this case, after bile duct cancer.
DISCUSSION This retrospective cohort study was large and populationbased. It gave us the opportunity to comprehensively and systematically examine the associations between biliary tract cancers and other cancers, and shed some new light on the etiology of biliary tract cancers. This study had some limitations. It was unable to adjust for many potential confounding variables for which information was lacking in the database (22), e.g., patients’ history of cholelithiasis, other noncancerous comorbid conditions, smoking, and their basic physiological characteristics, such as weight. This might be of particular importance, for example, in the context of colorectal cancer, where gall
Table 4. Relative Risks of Selected Second Cancers of Other Sites Following Biliary Tract Cancers 1st Primary All Biliary Tract 2nd Primary Men UAT Colorectum Prostate Women UAT Colorectum Breast Ovary & Uteri Ovary Corpus Uteri Cervix
Gallbladder
Ob
Ex
RR (95% CI)
Ob
Ex
16 13 21
16.4 10.5 17.0
0.98 (0.56–1.59) 1.24 (0.66–2.12) 1.23 (0.76–1.89)
5 4 4
5.2 3.5 5.9
7 22 17 15 12 3 2
8.1 13.1 18.9 7.9 2.7 5.1 1.3
0.87 (0.35–1.78) 1.68 (1.05–2.54)* 0.90 (0.52–1.44) 1.90 (1.06–3.14)* 4.43 (2.29–7.74)* 0.59 (0.12–1.71) 1.58 (0.18–5.70)
4 10 9 10 8 2 1
4.5 7.8 10.9 4.5 1.6 2.9 0.7
Bile Duct
RR (95% CI)
Ob
Ex
RR (95% CI)
0.96 (0.31–2.24) 1.16 (0.31–2.96) 0.68 (0.18–1.73)
11 9 17
11.2 7.1 11.1
0.98 (0.49–1.76) 1.28 (0.58–2.42) 1.53 (0.89–2.45)
0.88 (0.24–2.25) 1.28 (0.61–2.36) 0.82 (0.38–1.56) 2.21 (1.06–4.07)* 5.13 (2.21–10.11)* 0.68 (0.08–2.47) 1.35 (0.02–7.52)
3 12 8 5 4 1 1
3.5 5.3 7.9 3.4 1.1 2.2 0.5
0.85 (0.17–2.47) 2.25 (1.16–3.94)* 1.01 (0.43–1.99) 1.48 (0.48–3.46) 3.48 (0.94–8.91) 0.46 (0.01–2.53) 1.90 (0.02–10.56)
Prim ⫽ primary; Ob ⫽ Observed number of cases; Ex ⫽ expected number of cases; RR ⫽ relative risk; CI ⫽ confidence interval; UAT ⫽ upper aerodigestive tract. * Significant result.
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bladders are often resected routinely. Additionally, the statistical power for detecting a RR of ⱕ1.5 at some cancer sites was low due to the rarity of biliary tract cancers. Finally, an implicit assumption of SIR calculation is that as long as a patient with a first primary cancer lives, is followed up, or remains free of second primary cancer, his/her expected risk of a second primary cancer would be the same (5) as for his/her race at the time period and age of his/her first diagnosis. However, it is conceivable that as a person ages and the time period changes, his/her normally expected risk should change too. On the other hand, the relatively short survival of most cancer patients, and the fact that most of our calculated expected numbers of second primary cancers agree with the observed numbers, i.e., RRs around 1, indicate that this assumption is reasonable and serves our purpose well. Of general note, this study identified distinct association patterns for gallbladder cancer and bile duct cancer. This supports the notion that biliary tract cancers of different subsites are distinct disease entities (1) and may have different etiologies (2). The discussion here will therefore only consider gallbladder cancer and bile duct cancer separately. Etiology of Gallbladder Cancer In the past, gallbladder cancer has mostly been associated with gallstones, which, in turn, have been associated with obesity, multiple pregnancies, the use of exogenous estrogens, dietary factors, and genetic susceptibility (1, 3). Multiparity, in particular, has been consistently observed to increase the risk of gallbladder cancer (1, 23). Our finding of a strong, more than twofold elevated risk of gallbladder cancer after cervical cancer is consistent with multiple pregnancies as a common risk factor for gallbladder cancer and cervical cancer (1, 24). Further strengthening this hypothesis is the fact that the incidence rates for both gallbladder cancer and cervical cancer are the highest among Hispanic and Native American women, as well as in Latin America, where multiparity is commonly observed (1, 24). Likewise, consistent with our finding that gallbladder cancer is negatively associated with prostate cancer, the racial distribution pattern for gallbladder cancer is almost completely inverted for prostate cancer, with Native Americans at the low end, blacks and whites at the high end (25). A similarly reduced risk of liver and biliary tract cancer after the occurrence of prostate cancer was also reported by a Connecticut Tumor Registry study (7) and the reverse by a Danish Cancer Registry study (8), although it was significant only in the former, as in our case, due to low statistical power. Possible factors involved in the protective effect of prostate cancer include testosterone, estrogen, and fat consumption. Testosterone level is high among prostate cancer patients (25), and may confer protection against gallbladder cancer by antagonizing estrogen (1). Alternatively, estrogen was a major component of prostate cancer therapy in the past (25), and has been found to reduce the risk of gallbladder cancer (26, 27), despite some findings to the contrary.
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Finally, high fat intake may increase the risk of prostate cancer (25), but reduce the risk of gallbladder cancer (2, 28 –30). That the risk of second primary gallbladder cancer is reduced after colorectal cancer, but not vice versa, could be due to the fact that gallbladders containing gallstones were often removed at the time of right-sided colon cancer surgery. Our study shows no significantly altered risk of gallbladder cancer after cancers of the breast and uterine corpus, for both of which estrogen has been implicated as a major risk factor (31, 32). The slightly decreased risk of gallbladder cancer after breast cancer, which was found to be significant by a smaller Danish Cancer Registry study for liver and biliary tract cancer combined (9), but not by our study, was probably due to the protective effect of nulliparity associated with breast cancer (31). Therefore, estrogen exposure does not appear to be a significant risk factor for gallbladder cancer, as previously hypothesized (1, 22, 26, 27). Although significant associations were found with cervical cancer and ovarian cancer, neither seems to be directly related to estrogen (24, 33). Some other evidence also contradicts a role for estrogen in the pathogenesis of gallbladder cancer. First, previous epidemiological studies on biliary tract tumors have shown no clear association with exogenous estrogens (1 ). Second, unlike cardiovascular diseases where estrogen plays a clear role and the incidence rates of women after menopause match those of men, gallbladder cancer rates are higher among women at all ages (1), showing little relative change with endogenous estrogen levels (34). The significantly increased risk of ovarian cancer after gallbladder cancer, as found in our study, was also observed by the Danish Cancer Registry (8), which reported a RR of 3.2 for liver and biliary tract cancer combined, which is within the confidence interval that we found. The unidirectional association would suggest a treatment effect or detection bias. The fact that there is a more than threefold elevated risk of ovarian cancer after bile duct cancer, as well as after gallbladder cancer, seems to support a detection bias after all biliary tract cancers. Etiology of Bile Duct Cancer Risk factors suggested by previous studies for bile duct cancer include gallstones and obesity (albeit to a lesser degree than for gallbladder cancer), prior gallbladder diseases, ulcerative colitis, tobacco and alcohol use, and certain inherited conditions (1). The association of bile duct cancer with colorectal cancer has been extensively documented by previous case series (1, 11, 15–18, 35–37), and is also clearly implicated in our study by the mutually increased risks between the two cancers following each other. Ulcerative colitis is a risk factor for both (1, 38, 39). Additionally, patients with familial adenomatous polyposis and Gardner’s syndrome are at increased risk for both colorectal cancer and neoplasms of the ampulla of Vater. Hereditary nonpolyposis colon cancer also carries an excess risk of neoplasms of the ampulla of
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Vater. With its male excess, the positive correlation between bile duct cancer and cancers of the ovary and corpus uteri in women was unexpected. The fact that the latter two cancers and colorectal cancer were associated with bile duct cancer in the same direction, however, is in accordance with the known relationship between cancers of the colorectum, ovary, and uterine corpus (5). We found no association between biliary tract cancers and smoking-related upper aerodigestive tract cancers. Although the statistical power for the analyses was insufficient for us to confidently rule out the existence of an association, other inconsistencies also cast doubt on the role of smoking. Although smoking has been suggested to contribute to the male predominance of extrahepatic bile duct cancer, its effect at the same time has been linked mainly to an increased risk of symptomatic gallstones (1), a risk factor of more importance for the female-predominant gallbladder cancer than for the male-predominant bile duct cancer. Additionally, smoking does not appear to be particularly common among populations traditionally at high risk of bile duct cancer, such as Japanese and American Indians (1). A recent cohort study (40) also reported a much weaker effect of smoking than previous case-control studies. In fact, smoking was found to have no effect at all after other risk factors were controlled for in one of the most recent case-control studies (23).
CONCLUSIONS Several important conclusions emerged from this study. As previously identified (1), the positive associations between gallbladder cancer and cervical cancer suggest that multiparity is a risk factor for gallbladder cancer. The lack of an association between either gallbladder cancer and estrogenrelated cancers of the breast and uterine corpus, or between bile duct cancer and smoking-related upper aerodigestive tract cancers suggests that estrogen exposure and smoking, despite their possible roles in gallstone formation (1), may nonetheless have little impact on the pathogenesis of biliary tract cancers. Reprint requests and correspondence: Alfred I. Neugut, M.D., Ph.D., Division of Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. Received Sep. 29, 1998; accepted Apr. 15, 1999.
REFERENCES 1. Fraumeni JF Jr, Devesa SS, McLaughlin JK, et al. Biliary tract cancer. In: Schottenfeld D, Fraumeni JF Jr, eds. Cancer epidemiology and prevention, 2nd ed. New York: Oxford University Press, 1996:794 – 805. 2. Kato K, Akai S, Tominaga S, et al. A case-control study of biliary tract cancer in Niigata Prefecture, Japan. Jpn J Cancer Res 1989;80:932– 8.
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3. Tominaga S, Kuroishi T. Biliary tract cancer. Trends in cancer incidence and mortality. Cancer Surveys 1994;19/20:125–137. 4. Neugut AI, Robinson E. Multiple primary neoplasms. Cancer J 1992;5:245– 8. 5. Schottenfeld D. Multiple primary cancers. In: Schottenfeld D, Fraumeni JF Jr, eds. Cancer epidemiology and prevention, 2nd ed. New York: Oxford University Press, 1996:1370 – 87. 6. Schottenfeld D, Berg JW, Vitsky B. Incidence of multiple primary cancers, II. Index cancers arising in the stomach and lower digestive system. J Natl Cancer Inst 1969;43:77– 86. 7. Kleinerman RA, Liebermann JV, Li FP. Second cancer following cancer of the male genital system in Connecticut, 1935– 82. Natl Cancer Inst Monogr 1985;68:139 – 47. 8. Lynge E, Jensen OM, Carstensen B. Second cancer following cancer of the digestive system in Denmark, 1943– 80. Natl Cancer Inst Monogr 1985;68:277–308. 9. Ewertz M, Mouridsen HT. Second cancer following cancer of the female breast in Denmark, 1943– 80. Natl Cancer Inst Monogr 1985;68:325–9. 10. Hoar SK, Wilson J, Blot WJ, et al. Second cancer following cancer of the digestive system in Connecticut, 1935– 82. Natl Cancer Inst Monogr 1985;68:49 – 82. 11. Spigelman AD, Farmer KCR, James M, et al. Tumors of the liver, bile ducts, pancreas and duodenum in a single patient with familial adenomatous polyposis. Br J Surg 1991;78:979 – 80. 12. Takayasu K, Kasugai H, Ikeya S, et al. A clinical and radiologic study of primary liver cancer associated with extrahepatic primary cancer. Cancer 1992;69:45–51. 13. Kitano S, Morotomi I, Oiwa T, et al. Simultaneous early carcinoma of the ampulla of Vater and the stomach, report of a case involving chronic inactive hepatitis. S Afr Med J 1984;66:656 – 8. 14. Renault PF, Hillemand B, Anagnostides JC, et al. Congenital cyst of the common hepatic duct, adenocarcinoma of the gallbladder and of the stomach. J Chir (Paris) 1978;115: 623– 6. 15. Mecklin JP, Jarvinen HJ, Virolainen M. The association between cholangiocarcinoma and hereditary nonpolyposis colorectal carcinoma. Cancer 1992;69:1112– 4. 16. Mir-Madjlessi SH, Farmer RG, Easley KA, et al. Colorectal and extracolonic malignancy in ulcerative colitis. Cancer 1986;58:1569 –1574. 17. Broome U, Lofberg R, Veress B, et al. Primary sclerosing cholangitis and ulcerative colitis: Evidence for increased neoplastic potential. Hepatology 1995;22:1404 – 8. 18. Tiesenga MF, Neal RH, Rottschafer HW. Carcinoma multiplex. Illinois Med J 1969;136:141–142, 204. 19. Surveillance, Epidemiology, and End Results (SEER): Program special public use tape (1973–1993). Natl Cancer Inst, DCPC, Surveillance Program, Cancer Statistics Branch, November 1996. 20. Ries LAG, Miller BA, Hankey BF, ed. SEER cancer statistics review, 1973–1991: Tables and graphs. Bethesda, MD: National Cancer Institute, NIH Pub, No. 94-2789, 1994. 21. Neugut AI, Ahsan H, Robinson E. Pancreas cancer as a second primary malignancy, a population-based study. Cancer 1995; 76:589 –92. 22. Breslow NE, Day NE. Statistical methods of cancer research, vol. 2. The design and analysis of cohort studies. Lyon, France: International Agency for Research on Cancer, IARC Scientific publication no. 82, 1987. 23. Tavani A, Negri E, La Vecchia C. Menstrual and reproductive factors and biliary tract cancers. Eur J Cancer Prev 1996;5: 241–7. 24. Schiffman MH, Brinton LA, Devesa SS, et al. Cervical cancer. In: Schottenfeld D, Fraumeni JF Jr, eds. Cancer epidemiology
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Vol. 94, No. 8, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00358-5
The Association Between Biliary Tract Cancers and Cancers of Other Sites Yun Su, M.D., M.P.H., Habibul Ahsan, M.D., MMed.Sc., and Alfred I. Neugut, M.D., Ph.D. Division of Epidemiology, Joseph L. Mailman School of Public Health; Division of Oncology, Department of Medicine; and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York
OBJECTIVE: Cancers of the biliary tract, including cancers of the gallbladder and bile duct, generally carry a very poor prognosis. Little is known about their etiology. The pattern of co-occurrence of two cancers may give clues to shared etiological risk factors. We therefore investigated the association of biliary tract cancer with other cancers, especially with estrogen- and tobacco-related cancers. METHODS: We used data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Associations between biliary tract cancer and other cancers were evaluated using the standardized incidence ratio as an estimate of the relative risk of a second primary malignancy. RESULTS: Estrogen-related cancers of the breast and uterine corpus and smoking-related upper aerodigestive tract cancers were not associated with biliary tract cancer. The risk of gallbladder cancer was inversely related to the risk of prostate cancer in men, but positively related to the risk of cervical cancer in women. CONCLUSIONS: This study suggests that smoking and estrogen exposure have minimal roles in the pathogenesis of biliary tract cancer. Our finding of an inverse relationship between prostate cancer and gallbladder cancer requires confirmation by further studies. (Am J Gastroenterol 1999; 94:2256 –2262. © 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION Cancers of the biliary tract, including cancers of the gallbladder, extrahepatic bile duct, and ampulla of Vater, are uncommon but fatal, with about 4300 deaths per year in the United States (1). Each of them has a distinct demographic distribution (1). Although gallbladder cancer occurs more frequently among women than among men, bile duct and ampullary cancers occur more frequently among men. Their racial and geographical variations also follow different patterns. These epidemiological variations and the different physiological functions of the different subsites of the biliary tract suggest that biliary tract cancers of different subsites could have different etiologies (2). Little is known about the etiology of biliary tract cancers (1, 3), except for a close relationship with gallstones. Other
factors suspected to be associated with biliary tract cancers, either directly or indirectly through cholelithiasis, include reproductive and hormonal factors, obesity, dietary factors, tobacco and alcohol use, ulcerative colitis, and genetic predisposition. Few analytical epidemiological studies have been done to clarify the roles these factors may play in the pathogenesis of biliary tract cancers (1). Multiple primary neoplasms are a fairly common clinical occurrence (4). Although some cancers may co-occur by chance, a greater-than-chance association between two cancers can provide clues to a shared etiology (4, 5). A unidirectional, significantly altered risk of one primary cancer following another, but not vice versa, usually suggests surveillance bias, cancer effects, or treatment effects. A bidirectional, mutually altered risk of two cancers following each other suggests shared environmental, genetic, or immunological predisposing risk factors. In the past, biliary tract cancers have been found to co-occur with cancers of the prostate (6, 7), ovary (8), breast (9), esophagus (10), rectum (10), pancreas (10, 11), liver (11, 12), stomach (12–14), and colorectum (15–18). These findings, however, are mostly from individual case reports, with only a few systematic studies of very limited sample size, making it impossible to draw meaningful inferences (6 –10). Additionally, liver cancer and biliary tract cancer were sometimes considered as one disease entity (7–10), which makes interpretation of these studies difficult. Finally, none of the previous epidemiological studies adjusted for race in their risk estimates. Given the widely varying incidence rates of biliary tract cancer among different ethnic groups (1), race is a likely confounding variable, which should be taken into account in assessing epidemiological associations. In the present study, we investigated the associations of biliary tract cancers with cancers of other sites using a large population-based cancer registry. Separate analyses were conducted for biliary tract cancers of different subsites. Race was controlled for in the risk estimates. Hypotheses regarding the effects of smoking and estrogen were tested in particular by assessing the associations of biliary tract cancers with tobacco/alcohol-related upper aerodigestive tract cancers, and with female sex hormone-related cancers of the
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Table 1. Person-Years of Follow-up for Second Biliary Tract Cancers Following Cancers of Other Sites 2nd Primary All Biliary Tract 1st Primary Men UAT Lung Colorectum Prostate Bladder Kidney Women UAT Lung Colorectum Breast Ovary Corpus Uteri Cervix Bladder Kidney
Persons at Risk
Person-Years of Follow-up
Gallbladder Persons at Risk
Bile Duct
Person-Years of Follow-up
Persons at Risk
Person-Years of Follow-up
99,509 79,677 82,966 163,121 45,556 12,976
245,290 159,708 381,749 668,679 255,836 60,474
99,509 79,677 79,677 79,677 79,677 79,677
245,315 159,718 159,718 159,718 159,718 159,718
99,510 79,678 82,978 163,125 45,556 12,977
245,299 159,715 381,732 688,704 255,841 60,496
48,636 43,352 81,243 204,266 24,796 51,289 21,181 15,064 7573
120,731 100,534 404,440 1,227,786 106,170 410,906 137,483 86,214 36,905
48,637 43,353 81,246 204,273 24,796 51,290 21,181 15,064 7573
120,739 100,542 404,485 1,227,868 106,173 410,950 137,483 86,215 36,915
48,637 43,542 81,260 204,269 24,799 51,292 21,181 15,065 7573
120,736 100,540 404,533 1,227,834 106,176 410,943 137,486 86,216 36,905
UAT ⫽ upper aerodigestive tract; follow-up ⫽ begins at the sixth month after the diagnosis of the first primary cancer.
breast, ovary, and uterine corpus. In addition to being implicated by previous studies in the etiology of biliary tract cancers (1), tobacco/alcohol and female reproductive hormones are two of the major shared risk factors underlying multiple primary malignancies (5).
MATERIALS AND METHODS SEER Database Data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, for the period 1973 through 1993 (19), were used in this study. The SEER data are drawn from population-based cancer registries in nine major U.S. areas, covering approximately 10% of the U.S. population. The populations included are rea-
sonably representative of the entire U.S. population (20). Cancer registration is generally considered rather complete and of high quality, with 95% of the diagnoses confirmed microscopically (21). Among other variables, information contained in the SEER cancer data for each incidence case includes identification numbers for each patient; demography; the type of reporting source; the date of diagnosis; the length of survival; primary site; morphology; stage; and sequence number indicating the presence or absence of multiple primary cancers and the order of occurrence of each. Cases In this study, as shown in Tables 1 and 2, a primary cancer of each site was defined by either its International Classifi-
Table 2. Person-Years of Follow-up for Second Cancers of Other Sites Following Biliary Tract Cancers 1st Primary All Biliary Tract ICD-O 239–249 2nd Primary Men UAT Colorectum Prostate Women UAT Colorectum Breast Ovary Corpus Uteri Cervix
Gallbladder ICD-O 239, 249
Bile Duct ICD-O 240–248
Persons at Risk
Person-Years of Follow-up
Persons at Risk
Person-Years of Follow-up
Persons at Risk
Person-Years of Follow-up
2035 2033 2033
4602 4598 4554
618 617 618
1288 1280 1281
1417 1416 1415
3314 3318 3273
2935 2930 2928 2934 2934 2935
6271 6229 6199 6266 6254 6273
1703 1699 1700 1702 1702 1703
3650 3620 3616 3646 3629 3651
1232 1231 1228 1232 1232 1232
2621 2610 2583 2620 2624 2623
UAT ⫽ upper aerodigestive tract; ICD-O 1976 ⫽ International Classification of Disease for Oncology, 1976. Follow-up ⫽ begins at the sixth month after the diagnosis of the first primary cancer.
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cation of Disease for Oncology (ICD-O), 1976 topography codes, or its ICD-O, 1976 morphology codes, or both, as they are used in the SEER database. Biliary tract cancers that were not otherwise specified (NOS, ICD-O topography code 249) were grouped with gallbladder cancer, as it is the most common type (1), constituting about 30% of biliary tract cancers. Because of their many similarities, extrahepatic bile duct cancer and ampulla of Vater cancer were combined for analytic purposes (referred to as bile duct cancer). Included in the upper aerodigestive tract cancer category according to Schottenfeld (5) were cancers of the lip, oral cavity, pharynx, esophagus, larynx, lung, and bronchus; primary cancers occurring after a second primary cancer were excluded. Also excluded were those second primary cancers diagnosed within 6 months after the diagnosis of a first primary cancer. First and second primary cancers occurring in the same person were linked by the same SEER participant number and case number, which together identifies each patient. To fulfill the criteria of multiple primary cancers described by Schottenfeld (5), only malignant tumors were included, i.e., noninvasive in situ neoplasms were excluded. Also excluded were those cancers that were reported by autopsy or death certificate only. The first primary cancers chosen for analysis were the more common cancers, to allow sufficient statistical power for analysis. Cases with unknown race and cases with unknown dates of diagnosis, for whom person-years of follow-up could not be calculated, were excluded also. The excluded cases were a small fraction of all cases available for each cancer site, at most fewer than 2% (data not shown). Analyses We used a retrospective cohort design. The standardized incidence ratio (SIR) uses the general population incidence rates rather than the incidence rates in an unexposed group. The comparison group was used in calculating the relative risk (RR). If the general population differs systematically from the unexposed population with respect to the risk factors, then bias may arise. The SIR was used as an estimate of the RR for developing a second primary cancer after a first primary cancer of another site. SIR is the ratio of the gender-specific observed to expected number of cases of a second primary cancer. The gender-specific observed number of cases was determined directly from the database. The gender-specific expected number of cases was adjusted for age, time period, and race, and was calculated by multiplying the gender-, race-, age-, and period-specific standard population incidence rates by the corresponding stratumspecific person-years of follow-up for the first primary cancer, and then summing by gender. Race was specific for white, black, and others; age and period were specific for each 5-yr age group (0 – 85⫹), and each 3-calendar year (1973–1993), respectively. The gender-, race-, age-, and period-specific person-years of follow-up began at the sixth month after the diagnosis of the first primary cancer; and
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was censored at the diagnosis of the second primary cancer, or at the end of the survival time as defined in the SEER database, whichever was first. The 95% confidence interval (CI) around the RR was calculated using Byar’s limits, assuming a Poisson distribution (22). The RRs of biliary tract cancers occurring as second malignancies after first primary cancers of other sites were determined. For those first primary cancers with significant findings or that were important for our hypothesis testing, their RRs as second primary cancers after first primary biliary tract cancers were also estimated. Gallbladder cancer and bile duct cancer were first combined and analyzed as one entity, biliary tract cancer, and then analyzed separately, as the available numbers of cases allowed.
RESULTS Tables 1 and 2 show the persons at risk, and person-years of follow-up starting at the sixth month after the diagnosis of the first primary cancer. The RRs of second primary biliary tract cancer after other cancers are shown in Table 3 and the RRs of selected second primary cancers of other sites after biliary tract cancers are shown in Table 4. Associations of Gallbladder Cancer With Other Cancers As seen in Table 3, there is a significantly reduced risk of gallbladder cancer after colorectal cancer in both men and women. The risk of gallbladder cancer is also significantly or almost significantly altered after two gender-related tumors: reduced after prostate cancer in men, but elevated after cervical cancer in women. Although with very high statistical power, the reduction in risk for gallbladder cancer after breast cancer was only close to significance. The risk of gallbladder cancer was not significantly altered after either uterine corpus cancer or ovarian cancer. In light of these findings, important associations were tested in the reverse direction, with biliary tract cancers as the first primary cancer, followed by other cancers (Table 4). The statistical power for such analyses was generally low, due to small numbers of cases and poor survival of biliary tract cancer patients. Not surprisingly, although the risks of prostate cancer and cervical cancer seemed to be altered similarly after gallbladder cancer as they were in the reverse direction, neither was significant. Moreover, unlike what was found in the reverse direction, the risk of second primary colorectal cancer was elevated, not reduced, in both men and women. On the other hand, a significant, greatly elevated risk of ovarian cancer was found after gallbladder cancer in the absence of a reciprocal finding. Association Between Bile Duct Cancer and Other Cancers As shown in Table 3, the most important finding is a significantly elevated risk of bile duct cancer after colorectal cancer in both men and women. Among the trio of female gender-related cancers, almost significantly elevated risk of
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Table 3. Relative Risks of Second Biliary Tract Cancers Following Cancers of Other Sites 2nd Primary All Biliary Tract 1st Primary Men UAT Lung Colorectum Prostate Bladder Kidney Women UAT Lung Colorectum Breast Ovary Corpus Uteri Cervix Bladder Kidney
Gallbladder
Bile Duct
Ob
Ex
RR (95% CI)
Ob
Ex
RR (95% CI)
Ob
Ex
RR (95% CI)
25 13 51 68 25 5
18.7 12.6 39.1 86.6 24.1 3.9
1.34 (0.86–1.97) 1.03 (0.55–1.76) 1.30 (0.97–1.71) 0.79 (0.61–1.00)* 1.04 (0.67–1.53) 1.29 (0.42–3.02)
12 6 7 22 14 2
7.7 5.2 16.7 37.3 10.2 1.6
1.56 (0.81–2.73) 1.15 (0.42–2.51) 0.42 (0.17–0.86)* 0.59 (0.37–0.89)* 1.38 (0.75–2.31) 1.27 (0.14–4.57)
13 7 44 46 11 3
11.0 7.4 22.5 49.2 14.0 2.3
1.18 (0.63–2.02) 0.94 (0.38–1.94) 1.96 (1.42–2.63)* 0.93 (0.68–1.25) 0.79 (0.39–1.41) 1.31 (0.26–3.83)
10 9 47 97 7 41 11 11 4
10.0 8.5 53.0 99.1 6.0 32.1 5.4 10.5 2.8
1.00 (0.48–1.83) 1.06 (0.49–2.02) 0.89 (0.65–1.18) 0.98 (0.79–1.19) 1.16 (0.46–2.39) 1.28 (0.92–1.73) 2.04 (1.02–3.64)* 1.05 (0.52–1.88) 1.41 (0.38–3.60)
7 7 19 54 4 23 8 8 3
6.6 5.6 35.4 65.7 4.0 21.3 3.5 7.0 1.9
1.06 (0.43–2.19) 1.26 (0.50–2.59) 0.54 (0.32–0.84)* 0.82 (0.62–1.07) 1.00 (0.27–2.57) 1.08 (0.69–1.62) 2.26 (0.97–4.46) 1.14 (0.49–2.26) 1.60 (0.32–4.67)
3 2 28 43 3 18 3 3 1
3.4 2.9 17.6 33.4 2.1 10.9 1.9 3.5 1.0
0.87 (0.18–2.55) 0.69 (0.08–2.48) 1.59 (1.06–2.30)* 1.29 (0.93–1.74) 1.46 (0.29–4.26) 1.66 (0.98–2.62) 1.61 (0.32–4.71) 0.86 (0.17–2.52) 1.03 (0.01–5.75)
Prim ⫽ primary; Ob ⫽ Observed number of cases; Ex ⫽ expected number of cases; RR ⫽ relative risk; CI ⫽ confidence interval; UAT ⫽ upper aerodigestive tract. * Significant result.
bile duct cancer was seen after uterine corpus cancer, but not after breast or ovarian cancer. No significant association was found with upper aerodigestive tract cancers, with low statistical power again clouding the picture. On analyses in the reverse direction (Table 4), corresponding to the earlier-stated finding, a significantly elevated risk of colorectal cancer was found in women after bile duct cancer. However, the elevated risk was not significant in men. Probably due to inadequate statistical power, the risk for uterine corpus cancer was not elevated after bile duct cancer. Comparable to the finding with gallbladder cancer and far exceeding what was found in the reverse direction, there is an increased risk of ovarian cancer, nearly significant in this case, after bile duct cancer.
DISCUSSION This retrospective cohort study was large and populationbased. It gave us the opportunity to comprehensively and systematically examine the associations between biliary tract cancers and other cancers, and shed some new light on the etiology of biliary tract cancers. This study had some limitations. It was unable to adjust for many potential confounding variables for which information was lacking in the database (22), e.g., patients’ history of cholelithiasis, other noncancerous comorbid conditions, smoking, and their basic physiological characteristics, such as weight. This might be of particular importance, for example, in the context of colorectal cancer, where gall
Table 4. Relative Risks of Selected Second Cancers of Other Sites Following Biliary Tract Cancers 1st Primary All Biliary Tract 2nd Primary Men UAT Colorectum Prostate Women UAT Colorectum Breast Ovary & Uteri Ovary Corpus Uteri Cervix
Gallbladder
Ob
Ex
RR (95% CI)
Ob
Ex
16 13 21
16.4 10.5 17.0
0.98 (0.56–1.59) 1.24 (0.66–2.12) 1.23 (0.76–1.89)
5 4 4
5.2 3.5 5.9
7 22 17 15 12 3 2
8.1 13.1 18.9 7.9 2.7 5.1 1.3
0.87 (0.35–1.78) 1.68 (1.05–2.54)* 0.90 (0.52–1.44) 1.90 (1.06–3.14)* 4.43 (2.29–7.74)* 0.59 (0.12–1.71) 1.58 (0.18–5.70)
4 10 9 10 8 2 1
4.5 7.8 10.9 4.5 1.6 2.9 0.7
Bile Duct
RR (95% CI)
Ob
Ex
RR (95% CI)
0.96 (0.31–2.24) 1.16 (0.31–2.96) 0.68 (0.18–1.73)
11 9 17
11.2 7.1 11.1
0.98 (0.49–1.76) 1.28 (0.58–2.42) 1.53 (0.89–2.45)
0.88 (0.24–2.25) 1.28 (0.61–2.36) 0.82 (0.38–1.56) 2.21 (1.06–4.07)* 5.13 (2.21–10.11)* 0.68 (0.08–2.47) 1.35 (0.02–7.52)
3 12 8 5 4 1 1
3.5 5.3 7.9 3.4 1.1 2.2 0.5
0.85 (0.17–2.47) 2.25 (1.16–3.94)* 1.01 (0.43–1.99) 1.48 (0.48–3.46) 3.48 (0.94–8.91) 0.46 (0.01–2.53) 1.90 (0.02–10.56)
Prim ⫽ primary; Ob ⫽ Observed number of cases; Ex ⫽ expected number of cases; RR ⫽ relative risk; CI ⫽ confidence interval; UAT ⫽ upper aerodigestive tract. * Significant result.
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bladders are often resected routinely. Additionally, the statistical power for detecting a RR of ⱕ1.5 at some cancer sites was low due to the rarity of biliary tract cancers. Finally, an implicit assumption of SIR calculation is that as long as a patient with a first primary cancer lives, is followed up, or remains free of second primary cancer, his/her expected risk of a second primary cancer would be the same (5) as for his/her race at the time period and age of his/her first diagnosis. However, it is conceivable that as a person ages and the time period changes, his/her normally expected risk should change too. On the other hand, the relatively short survival of most cancer patients, and the fact that most of our calculated expected numbers of second primary cancers agree with the observed numbers, i.e., RRs around 1, indicate that this assumption is reasonable and serves our purpose well. Of general note, this study identified distinct association patterns for gallbladder cancer and bile duct cancer. This supports the notion that biliary tract cancers of different subsites are distinct disease entities (1) and may have different etiologies (2). The discussion here will therefore only consider gallbladder cancer and bile duct cancer separately. Etiology of Gallbladder Cancer In the past, gallbladder cancer has mostly been associated with gallstones, which, in turn, have been associated with obesity, multiple pregnancies, the use of exogenous estrogens, dietary factors, and genetic susceptibility (1, 3). Multiparity, in particular, has been consistently observed to increase the risk of gallbladder cancer (1, 23). Our finding of a strong, more than twofold elevated risk of gallbladder cancer after cervical cancer is consistent with multiple pregnancies as a common risk factor for gallbladder cancer and cervical cancer (1, 24). Further strengthening this hypothesis is the fact that the incidence rates for both gallbladder cancer and cervical cancer are the highest among Hispanic and Native American women, as well as in Latin America, where multiparity is commonly observed (1, 24). Likewise, consistent with our finding that gallbladder cancer is negatively associated with prostate cancer, the racial distribution pattern for gallbladder cancer is almost completely inverted for prostate cancer, with Native Americans at the low end, blacks and whites at the high end (25). A similarly reduced risk of liver and biliary tract cancer after the occurrence of prostate cancer was also reported by a Connecticut Tumor Registry study (7) and the reverse by a Danish Cancer Registry study (8), although it was significant only in the former, as in our case, due to low statistical power. Possible factors involved in the protective effect of prostate cancer include testosterone, estrogen, and fat consumption. Testosterone level is high among prostate cancer patients (25), and may confer protection against gallbladder cancer by antagonizing estrogen (1). Alternatively, estrogen was a major component of prostate cancer therapy in the past (25), and has been found to reduce the risk of gallbladder cancer (26, 27), despite some findings to the contrary.
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Finally, high fat intake may increase the risk of prostate cancer (25), but reduce the risk of gallbladder cancer (2, 28 –30). That the risk of second primary gallbladder cancer is reduced after colorectal cancer, but not vice versa, could be due to the fact that gallbladders containing gallstones were often removed at the time of right-sided colon cancer surgery. Our study shows no significantly altered risk of gallbladder cancer after cancers of the breast and uterine corpus, for both of which estrogen has been implicated as a major risk factor (31, 32). The slightly decreased risk of gallbladder cancer after breast cancer, which was found to be significant by a smaller Danish Cancer Registry study for liver and biliary tract cancer combined (9), but not by our study, was probably due to the protective effect of nulliparity associated with breast cancer (31). Therefore, estrogen exposure does not appear to be a significant risk factor for gallbladder cancer, as previously hypothesized (1, 22, 26, 27). Although significant associations were found with cervical cancer and ovarian cancer, neither seems to be directly related to estrogen (24, 33). Some other evidence also contradicts a role for estrogen in the pathogenesis of gallbladder cancer. First, previous epidemiological studies on biliary tract tumors have shown no clear association with exogenous estrogens (1 ). Second, unlike cardiovascular diseases where estrogen plays a clear role and the incidence rates of women after menopause match those of men, gallbladder cancer rates are higher among women at all ages (1), showing little relative change with endogenous estrogen levels (34). The significantly increased risk of ovarian cancer after gallbladder cancer, as found in our study, was also observed by the Danish Cancer Registry (8), which reported a RR of 3.2 for liver and biliary tract cancer combined, which is within the confidence interval that we found. The unidirectional association would suggest a treatment effect or detection bias. The fact that there is a more than threefold elevated risk of ovarian cancer after bile duct cancer, as well as after gallbladder cancer, seems to support a detection bias after all biliary tract cancers. Etiology of Bile Duct Cancer Risk factors suggested by previous studies for bile duct cancer include gallstones and obesity (albeit to a lesser degree than for gallbladder cancer), prior gallbladder diseases, ulcerative colitis, tobacco and alcohol use, and certain inherited conditions (1). The association of bile duct cancer with colorectal cancer has been extensively documented by previous case series (1, 11, 15–18, 35–37), and is also clearly implicated in our study by the mutually increased risks between the two cancers following each other. Ulcerative colitis is a risk factor for both (1, 38, 39). Additionally, patients with familial adenomatous polyposis and Gardner’s syndrome are at increased risk for both colorectal cancer and neoplasms of the ampulla of Vater. Hereditary nonpolyposis colon cancer also carries an excess risk of neoplasms of the ampulla of
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Vater. With its male excess, the positive correlation between bile duct cancer and cancers of the ovary and corpus uteri in women was unexpected. The fact that the latter two cancers and colorectal cancer were associated with bile duct cancer in the same direction, however, is in accordance with the known relationship between cancers of the colorectum, ovary, and uterine corpus (5). We found no association between biliary tract cancers and smoking-related upper aerodigestive tract cancers. Although the statistical power for the analyses was insufficient for us to confidently rule out the existence of an association, other inconsistencies also cast doubt on the role of smoking. Although smoking has been suggested to contribute to the male predominance of extrahepatic bile duct cancer, its effect at the same time has been linked mainly to an increased risk of symptomatic gallstones (1), a risk factor of more importance for the female-predominant gallbladder cancer than for the male-predominant bile duct cancer. Additionally, smoking does not appear to be particularly common among populations traditionally at high risk of bile duct cancer, such as Japanese and American Indians (1). A recent cohort study (40) also reported a much weaker effect of smoking than previous case-control studies. In fact, smoking was found to have no effect at all after other risk factors were controlled for in one of the most recent case-control studies (23).
CONCLUSIONS Several important conclusions emerged from this study. As previously identified (1), the positive associations between gallbladder cancer and cervical cancer suggest that multiparity is a risk factor for gallbladder cancer. The lack of an association between either gallbladder cancer and estrogenrelated cancers of the breast and uterine corpus, or between bile duct cancer and smoking-related upper aerodigestive tract cancers suggests that estrogen exposure and smoking, despite their possible roles in gallstone formation (1), may nonetheless have little impact on the pathogenesis of biliary tract cancers. Reprint requests and correspondence: Alfred I. Neugut, M.D., Ph.D., Division of Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. Received Sep. 29, 1998; accepted Apr. 15, 1999.
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