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Risk Factors for Synchronous Primary Endometrial and Ovarian Cancers
Risk Factors for Synchronous Primary Endometrial and Ovarian Cancers LISA J. HERRINTON, PhD, LYNDA F. VOIGT, PhD, NOEL S. WEISS, MD, DrPH, SHIRLEY A. A. BERESFORD, PhD, AND PHYLLIS A. WINGO, PhD
PURPOSE: The incidence of synchronous primary endometrial and ovarian cancer is 2- to 10-fold higher than that expected based on the incidence of each cancer alone. We sought to evaluate reasons for this in a case-control study. METHODS: We combined data on a maternal history of cancer and reproductive and menstrual factors from 56 women with synchronous multiple primary disease who had participated in three populationbased studies of gynecologic cancer. For comparison, we analyzed the same information from 280 women with endometrial cancer alone, 280 with ovarian cancer alone, and 280 without a history of either cancer. RESULTS: The reduced risk of multiple primary disease associated with high parity (2 or more births vs 0: OR 0.37, 95% Cl, 0.19–76) and long-term use of oral contraceptives (12 or more months vs none: OR 0.60, 95% Cl, 0.24–1.5) tended to be more pronounced than that associated with endometrial cancer alone or with ovarian cancer alone. CONCLUSIONS: Though limited by relatively small numbers, our results suggest that the presence of some common etiologies is a basis for the unusually high co-occurrence of endometrial and ovarian cancers. Ann Epidemiol 2001;11:529-533. © 2001 Elsevier Science Inc. All rights reserved. KEY WORDS:
Endometrial Neoplasms, Ovarian Neoplasms, Multiple Primary Neoplasms, Synchronous Neoplasms, Risk Factors, Epidemiology.
INTRODUCTION The incidence of synchronous primary endometrial and ovarian cancers has been reported to be two- to 10-fold higher than that expected based on the incidence of each cancer alone (1–3). Endometrial and ovarian cancer have several risk factors in common, and on this basis alone could occur together in the same women with relatively high frequency. It is also possible, however, that the joint presence of these two tumors is an indicator of an etiologically distinct condition. This study sought clues to the etiology of multiple primary disease by analyzing the combined information obtained from three populationbased case-control studies of reproductive cancers in women. Reproductive and menstrual characteristics of women with synchronous primary endometrial and ovarian cancers, with endometrial cancer alone, and with ovarian cancer alone, were compared to those of population-based
From the Division of Research, Kaiser Permanente, Oakland, CA (L.J.H.); the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (L.F.V., N.S.W., S.A.A.B.); the Department of Epidemiology, University of Washington, Seattle, WA (N.S.W., S.A.A.B.); and the American Cancer Society, Atlanta, GA (P.A.W.). Address correspondences to: Lisa Herrinton, Division of Research, Kaiser Permanente, 3505 Broadway Ave, Oakland, CA 94611. Received September 25, 2000; revised March 14, 2001; accepted March 30, 2001. © 2001 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
controls with no prior endometrial or ovarian cancer. Differences in the associations with multiple primary disease relative to single primary disease were evaluated.
MATERIALS AND METHODS Identification of Cases and Controls Data from the population-based Cancer and Steroid Hormone (CASH) study and two other population-based casecontrol studies of gynecologic cancer that were conducted in western Washington (WA1, WA2) were combined in this analysis (Table 1). The CASH study was a multi-center, population-based, case-control study of oral contraceptive use in relation to breast, endometrial, and ovarian cancer diagnosed among women aged 20–54 years during the period 1980 through 1982. The study centers included eight locations in the United States served by cancer registries participating in the Surveillance, Epidemiology, and End-Results (SEER) program. Pathology material from all diagnoses of ovarian and endometrial cancer identified by the cancer registries were submitted to review by a panel of expert pathologists convened for this purpose. Population controls were identified through random-digit dialing. The WA1 study included residents aged 35–74 years of King and Pierce counties, Washington, diagnosed with ovarian and endometrial cancer during the period July 1976 1047-2797/01/$–see front matter PII S1047-2797(01)00237-X
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Selected Abbreviations and Acronyms OR odds ratio CI confidence interval CASH Cancer and Steroid Hormone Study WA1 1976-79 western Washington Study WA2 1985-90 western Washington Study
through June 1979. The WA2 study was undertaken in several parts. Originally, only residents of King county, Washington, aged 40–64 years with endometrial cancer diagnosed during the period 1985 through 1986, and their controls, were included. Additional funding was obtained later to include women ages 45–74 years who resided in King, Pierce, and Snohomish counties, Washington, who were diagnosed with endometrial cancer during the years 1987 through 1990. The ovarian cancer cases that were included in the study were residents of the same three Washington counties, aged 20–79 years, who had been diagnosed during the period 1986 through 1988. Case ascertainment in the western Washington studies was through the western Washington Cancer Surveillance System, a participant in the SEER program, and was based on the original hospital pathologist’s diagnoses. Population-based controls were selected for the western Washington studies using area sampling methods (WA1) or random-digit dialing (WA2). The 56 women in the three studies who had both primary epithelial endometrial and epithelial ovarian cancer diagnosed within a 12-month period were available as cases in the present study. To compare the characteristics of multiple primary diseases with those of endometrial or ovarian cancer alone, we also, for each multiple primary case, randomly selected five subjects with endometrial cancer only and five subjects with ovarian cancer only. We also randomly selected five subjects who had served as controls in the original studies and had no prior endometrial or ovarian cancer. The single primary cases and the controls were matched to the multiple primary cases on the original study (CASH, WA1, WA2) and 5-year age category, leading to TABLE 1. Characteristics of studies from which study subjects were selected
Study CASH (5) WA1 (6, 7)
Location
Eight SEER sites King and Pierce Counties, WA WA2 King County, WA Endometrial King, Pierce, and cancer (8) Snohomish counties, WA Ovarian cancer King, Pierce, and (9) Snohomish counties, WA
Diagnosis Dates
Age Range (years)
Jan. 1980–Dec. 1982 20–54 July 1976–June 1979 35–74 Jan. 1985–Dec. 1986 40–64 Jan. 1987–Dec. 1990 45–74
Jan. 1986–Dec. 1988 20–79
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the creation of 18 groups (defined on original study and age group) containing as few as one, or as many as 10, cases. We used the common case-control ratio of five across the 18 categories defined by original study and age group to maximize the power of the study while simplifying the interpretation of the analyses. Had we used all of the available subjects who participated in the original studies, it would have been difficult to interpret the results of univariate analyses for endometrial cancer alone with those for multiple primary diseases because the distributions of age and study period would have differed appreciably. We sought to exclude women with a prior hysterectomy or bilateral oophorectomy from the present study; however, in subjects who had participated in the WA1 study, oophorectomy history was obtained only for women who reported a prior hysterectomy, and it is possible that a small number of women who underwent oophorectomy without hysterectomy were included in the present study. Information. In each of the original three studies, trained professional interviewers had administered a standard questionnaire to the subjects in a face-to-face interview. In each of the studies, information was obtained before the date of diagnosis for the cases. In the two western Washington studies, information was obtained before an index date in the controls that was comparable to the diagnosis date in the cases. In the CASH study, the index date of the controls was the date of interview. The three studies used comparable questions to obtain information on educational attainment, a history of use of oral contraceptives, the number and outcome of pregnancies, menopausal status, and age at menopause. Among women who described their periods as having stopped, the age at menopause was taken to be the age at last menstrual period. In two studies, comparable questions were used to obtain information on family income, breastfeeding history, age at menarche, and use of post-menopausal estrogens. These variables, except for family income and educational attainment, were evaluated as independent risk factors for multiple primary diseases. Data Analysis. The odds ratios and 95% confidence intervals were estimated using conditional logistic regression (4) for a matched analysis. Age, index year, family income, and educational attainment were evaluated as potential confounding factors. Separate analyses were performed for each case group. In addition, to evaluate whether the association for an exposure with multiple primary disease differed from that with endometrial cancer alone or with ovarian cancer alone, we conducted analyses in which women with multiple primary cancer were coded as cases and women with single primary endometrial cancer, or single primary ovarian cancer, were coded as controls. The p values were for the test of the hypothesis that the magni-
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tude of the association with multiple primary disease was the same as with single primary disease.
multiple primary disease was markedly reduced in women who had one or two prior full-term pregnancies (two pregnancies: OR 0.37; 95% CI, 0.19–0.76). The risk of single primary endometrial and ovarian cancer was reduced as well but to a lesser extent (p for difference relative to the association with single primary cancer: endometrium, 0.120; ovary, 0.150). Women with synchronous endometrial and ovarian tumors tended to have a later age at menarche than did controls. Relative to the risk in women who started menstruating at age 11 years or earlier, the risk in those who started at age 12 years was 3.0 (95% CI, 0.84–11); the risk in those who started at 13 years or older was 1.7 (95% CI, 0.49–5.7). This association differed significantly from those for endometrial (p 0.033) or ovarian (p 0.009) cancer alone. For multiple primary diseases, the relative odds associated with using postmenopausal estrogen for one year or more was 1.6 (0.60–3.9). This association was smaller than that for single primary endometrial cancer (OR 5.5, p for difference between the associations, 0.045). (Only two of the study subjects had a history of use of progestin, and neither had used estrogen.) A history of breastfeeding and menopausal status was not strongly associated with any of the three cancer types.
RESULTS The number of subjects for whom there was information on each characteristic varied because not all of the original studies ascertained information on the characteristics discussed in this report, and also because information was missing for some respondents (Table 2). A smaller proportion of the women with ovarian cancer alone than the subjects in the three other groups had attended college. There was also a slight difference in the distribution of family income among the four groups, with the multiple primary cases and the ovarian cancer cases having a somewhat lower family income. A history of using oral contraceptives (OCs) for 12 months or longer was more strongly associated with a decreased risk of multiple primary disease (OR 0.60, 95% CI, 0.24–1.5) than with either endometrial cancer or ovarian cancer alone (p for difference relative to the association with single primary cancer: endometrium, 0.175; ovary, 0.003) (Table 3). The risk of
TABLE 2. Demographic and sampling characteristics of cases and controls
Characteristic Original study CASH WA1 WA2 Age at reference, yr 49 50–59 60 Reference year 1975–76 1977–79 1980–82 1985–87 1988–90 Race Caucasian Asian Educational attainmenta High school graduate or less At least some college Annual family incomeb $30,000 $30,000 a b
Controls (N 280) (%)
Endometrial Cancer Cases (N 280) (%)
Ovarian Cancer Cases (N 280) (%)
Synchronous Endometrial and Ovarian Cancer Cases (N 56) (%)
36 34 30
36 34 30
36 34 30
36 34 30
37 40 24
37 40 24
38 39 23
38 39 23
19 15 36 16 14
28 6 36 16 14
14 20 36 19 11
14 20 36 16 14
98 2
99 1
99 1
98 2
42 58
49 51
57 43
47 53
51 49
52 48
57 43
57 43
Information not obtained for 1 multiple primary case, 1 endometrial cancer control, 2 ovarian cancer controls, and 2 nondiseased controls. Information not obtained in the WA1 study, nor for an additional two multiple primary cases, 7 endometrial cancer controls, 11 ovarian cancer controls, and 10 nondiseased controls.
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TABLE 3. Reproductive history and use of prior oral contraceptives and post-menopausal estrogen in relation to the risk of synchronous, multiple primary endometrial and ovarian cancer Controls Characteristic Maternal history of breast cancer No Yes Maternal history of endometrial cancer No Yes History of OC use Never 11 mo 12 mo Gravidity 0 1 2 Parity 0 1 2 History of breastfeedingd Never Ever Age at menarche, yearse 11 12 13 Menopausal status Pre Peri or post History of use of post-menopausal estrogenf,g Never 11 mo 12 mo
Endometrial Cancer
(%)
(%)
(n 271) 96 4 (n 271) 98 2 (n 280) 62 19 20 (n 280) 14 9 79 (n 276) 15 8 77 (n 212) 57 43 (n 185) 17 29 54 (n 278) 34 66 (n 133) 66 14 20
(n 276) 95 5 (n 276) 94 6 (n 280) 68 14 18 (n 280) 18 12 71 (n 279) 21 15 64 (n 179) 56 64 (n 185) 24 24 52 (n 268) 34 66 33 20 47
OR
Synchronous Endometrial and Ovarian Cancer
Ovarian Cancer CI
(%)
OR
(n 179) 95 0.51–2.5 5 (n 179)g 1.0 97 2.5 0.96–6.5 3 (n 280) 1.0 63 0.59 0.33–1.1 20 0.82 0.50–1.3 17 (n 279) 1.0 18 1.5 0.74–3.1 8 0.73 0.46–1.2 75 (n 278) 1.0 20 1.4 0.71–2.6 10 0.61 0.39–0.97 69 (n 139) 1.0 65 0.95 0.65–1.4 35 (n 185) 1.0 22 0.61 0.33–1.1 20 0.69 0.40–1.2 58 (n 280) 1.0 37 0.92 0.58–1.5 63 (n 122) (n 126) 1.0 59 2.2 1.0–4.6 13 5.5 2.8–10.6 29
CI
g
1.0 1.1
1.0 1.2
0.48-3.1
1.0 1.5
0.42–5.8
1.0 1.1 0.81
0.64–2.0 0.50–1.3
1.0b 0.79 0.67
0.36–1.7 0.42–1.1
1.0b 0.80 0.63
0.39–1.6 0.40–1.0
1.0 0.97
0.56–1.7
1.0 0.54 0.81
0.29–1.0 0.47–1.4
1.0 0.77
0.47–1.2
1.0 1.0 1.6
0.46–2.2 0.87–3.0
(%) (n 54) 96 4 (n 54) 93 7 (n 55) 78 7 15 (n 55) 29 9 62 (n 55) 32 11 57 (n 32) 63 37 (n 37) 10 43 46 (n 56) 33 67 (n 29) 52 24 24
OR
CI
1.0 0.79
0.17–3.6
1.0 3.4
0.95–12
1.0a 0.23 0.60
0.07–0.77 0.24–1.5
1.0c 0.72 0.40
0.21–2.4 0.19–0.82
1.0c 0.47 0.37
0.15–1.5 0.19–0.76
1.0 0.83
0.36–1.9
1.0 3.0 1.7
0.84–11 0.49–5.7
1.0 0.94
0.40–2.2
1.0 2.2 1.6
0.70–6.6 0.59–4.5
a
OR adjusted for parity and educational attainment. OR adjusted for educational attainment. c OR adjusted for history of oral contraceptive use and educational attainment. d Parous women only. e Information not obtained in the WA1 study. f Postmenopausal women only. g Information not obtained for the ovarian cancer cases who participated in the WA2 study. Excludes WA2 subjects. No. of women remaining: 195 controls, 179 cases with ovarian cancer alone, 40 women with multiple primary disease. b
We also examined the histologic types of cancer among the women selected for the three Washington State studies for whom histologic type could be obtained (35 with multiple primary disease). The distribution of histologic types of the endometrial cancer among women with multiple cancers was similar to the distribution among women with endometrial cancer alone, with 80% having adenocarcinoma, not further specified; however, there were more endometrioid (43% observed vs. 10% expected) and less mucinous/serous (31% observed and 54% expected) ovarian cancers among the women with multiple primary disease than among those with single primary ovarian cancer.
DISCUSSION Our analysis was limited primarily by the relatively small number of subjects with synchronous primary endometrial and ovarian cancers. As a consequence, our ability to examine dose-response relationships and to evaluate the presence of confounding was limited, and our estimates have somewhat wide confidence intervals. We undertook this study on the basis of reports that the incidence of synchronous endometrial and ovarian cancer is higher than would be expected on the basis of the incidence of each tumor separately. Relative to the general
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population, Connecticut women diagnosed with ovarian cancer or endometrial cancer during the period 1935 through 1982 were at 2.9-fold (number of cancers, 6) and 9.1-fold (number of cancers, 19) increased risk of having the other malignancy diagnosed within 12 months (1). A similar study of Danish women diagnosed with ovarian and endometrial malignancies during the period 1943 to 1980 revealed relative risk estimates of 2.8 (number of cancers, 11) for endometrial cancers occurring after ovarian cancer and 2.1 (number of cancers, 13) for ovarian cancer occurring after endometrial cancer (2). Women identified through the U.S. National Cancer Surveys and tumor registries with ovarian cancer diagnosed during the period 1935 to 1972 (37% of whom also were included in the Connecticut study) were at 10-fold (n 46) increased risk of having endometrial cancer diagnosed within two years (3). These studies were not able to take into account the higher prevalence of hysterectomy and oophorectomy among gynecologic cancer patients, and thus greatly underestimated the risk of being diagnosed with synchronous multiple endometrial and ovarian cancers. Several explanations could account for all or part of this increase, two of which are related to artifacts in the data. First, there could be detection bias favoring identification of a second gynecologic cancer following diagnosis of the first, and second some secondary endometrial and ovarian tumors may be misclassified as primary malignancies. We believe that the first of these is likely to be present, but not to a degree to produce an incidence of synchronous tumors that is 2- to 10-fold higher than expected. With respect to the misclassification of secondary tumors, we believe this to have occurred to only a minimal extent as well, in those instances in which an endometrial tumor has spread beyond the myometrium. With respect to the misclassification of secondary tumors, we observed a larger-than-expected proportion of endometrioid ovarian cancers among the women with multiple primary diseases. As described in the Methods section, the pathologic diagnoses of multiple primary diseases were confirmed by an expert panel for the CASH study, although not for the western Washington studies. To the extent that detection bias or misclassification of multiple primary diseases is present in our data, they obscure our ability to find differences with single primary disease. Because endometrial and ovarian cancer have several
risk factors in common, they could occur together in the same women with relatively high frequency. Our findings that women with multiple primary diseases have lowerthan-expected parity and less past use of oral contraceptives are consistent with this explanation; however, it is also possible that the two tumors occur together in an etiologically distinct condition. We observed that women with multiple primary tumors had an unusually late age at menarche—an association that was not also present for women with only one tumor. The differences that we observed were not great given the size of our case group; other studies, or a pooling of studies, of women with synchronous endometrial and ovarian tumors would be needed for our tentative findings to be corroborated and for other possible risk factors for synchronous disease to be explored. This research was supported in part by grants no. R35 CA 39779, R35 CA 49761, and K01 70969 from the National Cancer Institute.
REFERENCES 1. Curtis RE, Hoover RN, Kleinerman RA, Harvey EB. Second cancer following cancer of the female gential system in Connecticut, 1935– 82. NCI Monogr. 1985;68:113–137. 2. Storm HH, Ewertz M. Second cancer following cancer of the female genital system in Denmark, 1943–80. NCI Monogr. 1985;68:331–340. 3. Reimer RR, Hoover R, Fraumeni JF, Young RC. Second primary neoplasms following ovarian cancer. J Natl Cancer Inst. 1978;61:1195– 1197. 4. Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic Research: Principles and Quantitative Methods. Belmont, CA: Lifetime Learning Publications; 1982:461–468. 5. Wingo PA, Ory HW, Layde PM, Lee NC, and the Cancer and Steroid Hormone Study Group. The evaluation of the data collection process for a multicenter, population-based case-control design. Am J Epidemiol. 1988;128:206–217. 6. Weiss NS, Szekely DR, English DR, Schweid AI. Endometrial cancer in relation to patterns of menopausal estrogen use. J Am Med Ass. 1979;242:261–264. 7. Weiss NS, Lyon JL, Liff JM, Vollmer WM, Daling JR. Incidence of ovarian cancer in relation to the use of oral contraceptives. Int J Cancer. 1981;28:669–671. 8. Voigt LF, Weiss NS, Chu J, Daling JR, McKnight B, van Belle G. Progestagen supplementation of exogenous oestrogens and risk of endometrial cancer. Lancet. 1991;338:274–277. 9. Kamb ML. The risk of genital powder application for epithelial ovarian cancer. Unpublished thesis, University of Washington; 1990.
PURPOSE: The incidence of synchronous primary endometrial and ovarian cancer is 2- to 10-fold higher than that expected based on the incidence of each cancer alone. We sought to evaluate reasons for this in a case-control study. METHODS: We combined data on a maternal history of cancer and reproductive and menstrual factors from 56 women with synchronous multiple primary disease who had participated in three populationbased studies of gynecologic cancer. For comparison, we analyzed the same information from 280 women with endometrial cancer alone, 280 with ovarian cancer alone, and 280 without a history of either cancer. RESULTS: The reduced risk of multiple primary disease associated with high parity (2 or more births vs 0: OR 0.37, 95% Cl, 0.19–76) and long-term use of oral contraceptives (12 or more months vs none: OR 0.60, 95% Cl, 0.24–1.5) tended to be more pronounced than that associated with endometrial cancer alone or with ovarian cancer alone. CONCLUSIONS: Though limited by relatively small numbers, our results suggest that the presence of some common etiologies is a basis for the unusually high co-occurrence of endometrial and ovarian cancers. Ann Epidemiol 2001;11:529-533. © 2001 Elsevier Science Inc. All rights reserved. KEY WORDS:
Endometrial Neoplasms, Ovarian Neoplasms, Multiple Primary Neoplasms, Synchronous Neoplasms, Risk Factors, Epidemiology.
INTRODUCTION The incidence of synchronous primary endometrial and ovarian cancers has been reported to be two- to 10-fold higher than that expected based on the incidence of each cancer alone (1–3). Endometrial and ovarian cancer have several risk factors in common, and on this basis alone could occur together in the same women with relatively high frequency. It is also possible, however, that the joint presence of these two tumors is an indicator of an etiologically distinct condition. This study sought clues to the etiology of multiple primary disease by analyzing the combined information obtained from three populationbased case-control studies of reproductive cancers in women. Reproductive and menstrual characteristics of women with synchronous primary endometrial and ovarian cancers, with endometrial cancer alone, and with ovarian cancer alone, were compared to those of population-based
From the Division of Research, Kaiser Permanente, Oakland, CA (L.J.H.); the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (L.F.V., N.S.W., S.A.A.B.); the Department of Epidemiology, University of Washington, Seattle, WA (N.S.W., S.A.A.B.); and the American Cancer Society, Atlanta, GA (P.A.W.). Address correspondences to: Lisa Herrinton, Division of Research, Kaiser Permanente, 3505 Broadway Ave, Oakland, CA 94611. Received September 25, 2000; revised March 14, 2001; accepted March 30, 2001. © 2001 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
controls with no prior endometrial or ovarian cancer. Differences in the associations with multiple primary disease relative to single primary disease were evaluated.
MATERIALS AND METHODS Identification of Cases and Controls Data from the population-based Cancer and Steroid Hormone (CASH) study and two other population-based casecontrol studies of gynecologic cancer that were conducted in western Washington (WA1, WA2) were combined in this analysis (Table 1). The CASH study was a multi-center, population-based, case-control study of oral contraceptive use in relation to breast, endometrial, and ovarian cancer diagnosed among women aged 20–54 years during the period 1980 through 1982. The study centers included eight locations in the United States served by cancer registries participating in the Surveillance, Epidemiology, and End-Results (SEER) program. Pathology material from all diagnoses of ovarian and endometrial cancer identified by the cancer registries were submitted to review by a panel of expert pathologists convened for this purpose. Population controls were identified through random-digit dialing. The WA1 study included residents aged 35–74 years of King and Pierce counties, Washington, diagnosed with ovarian and endometrial cancer during the period July 1976 1047-2797/01/$–see front matter PII S1047-2797(01)00237-X
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Selected Abbreviations and Acronyms OR odds ratio CI confidence interval CASH Cancer and Steroid Hormone Study WA1 1976-79 western Washington Study WA2 1985-90 western Washington Study
through June 1979. The WA2 study was undertaken in several parts. Originally, only residents of King county, Washington, aged 40–64 years with endometrial cancer diagnosed during the period 1985 through 1986, and their controls, were included. Additional funding was obtained later to include women ages 45–74 years who resided in King, Pierce, and Snohomish counties, Washington, who were diagnosed with endometrial cancer during the years 1987 through 1990. The ovarian cancer cases that were included in the study were residents of the same three Washington counties, aged 20–79 years, who had been diagnosed during the period 1986 through 1988. Case ascertainment in the western Washington studies was through the western Washington Cancer Surveillance System, a participant in the SEER program, and was based on the original hospital pathologist’s diagnoses. Population-based controls were selected for the western Washington studies using area sampling methods (WA1) or random-digit dialing (WA2). The 56 women in the three studies who had both primary epithelial endometrial and epithelial ovarian cancer diagnosed within a 12-month period were available as cases in the present study. To compare the characteristics of multiple primary diseases with those of endometrial or ovarian cancer alone, we also, for each multiple primary case, randomly selected five subjects with endometrial cancer only and five subjects with ovarian cancer only. We also randomly selected five subjects who had served as controls in the original studies and had no prior endometrial or ovarian cancer. The single primary cases and the controls were matched to the multiple primary cases on the original study (CASH, WA1, WA2) and 5-year age category, leading to TABLE 1. Characteristics of studies from which study subjects were selected
Study CASH (5) WA1 (6, 7)
Location
Eight SEER sites King and Pierce Counties, WA WA2 King County, WA Endometrial King, Pierce, and cancer (8) Snohomish counties, WA Ovarian cancer King, Pierce, and (9) Snohomish counties, WA
Diagnosis Dates
Age Range (years)
Jan. 1980–Dec. 1982 20–54 July 1976–June 1979 35–74 Jan. 1985–Dec. 1986 40–64 Jan. 1987–Dec. 1990 45–74
Jan. 1986–Dec. 1988 20–79
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the creation of 18 groups (defined on original study and age group) containing as few as one, or as many as 10, cases. We used the common case-control ratio of five across the 18 categories defined by original study and age group to maximize the power of the study while simplifying the interpretation of the analyses. Had we used all of the available subjects who participated in the original studies, it would have been difficult to interpret the results of univariate analyses for endometrial cancer alone with those for multiple primary diseases because the distributions of age and study period would have differed appreciably. We sought to exclude women with a prior hysterectomy or bilateral oophorectomy from the present study; however, in subjects who had participated in the WA1 study, oophorectomy history was obtained only for women who reported a prior hysterectomy, and it is possible that a small number of women who underwent oophorectomy without hysterectomy were included in the present study. Information. In each of the original three studies, trained professional interviewers had administered a standard questionnaire to the subjects in a face-to-face interview. In each of the studies, information was obtained before the date of diagnosis for the cases. In the two western Washington studies, information was obtained before an index date in the controls that was comparable to the diagnosis date in the cases. In the CASH study, the index date of the controls was the date of interview. The three studies used comparable questions to obtain information on educational attainment, a history of use of oral contraceptives, the number and outcome of pregnancies, menopausal status, and age at menopause. Among women who described their periods as having stopped, the age at menopause was taken to be the age at last menstrual period. In two studies, comparable questions were used to obtain information on family income, breastfeeding history, age at menarche, and use of post-menopausal estrogens. These variables, except for family income and educational attainment, were evaluated as independent risk factors for multiple primary diseases. Data Analysis. The odds ratios and 95% confidence intervals were estimated using conditional logistic regression (4) for a matched analysis. Age, index year, family income, and educational attainment were evaluated as potential confounding factors. Separate analyses were performed for each case group. In addition, to evaluate whether the association for an exposure with multiple primary disease differed from that with endometrial cancer alone or with ovarian cancer alone, we conducted analyses in which women with multiple primary cancer were coded as cases and women with single primary endometrial cancer, or single primary ovarian cancer, were coded as controls. The p values were for the test of the hypothesis that the magni-
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tude of the association with multiple primary disease was the same as with single primary disease.
multiple primary disease was markedly reduced in women who had one or two prior full-term pregnancies (two pregnancies: OR 0.37; 95% CI, 0.19–0.76). The risk of single primary endometrial and ovarian cancer was reduced as well but to a lesser extent (p for difference relative to the association with single primary cancer: endometrium, 0.120; ovary, 0.150). Women with synchronous endometrial and ovarian tumors tended to have a later age at menarche than did controls. Relative to the risk in women who started menstruating at age 11 years or earlier, the risk in those who started at age 12 years was 3.0 (95% CI, 0.84–11); the risk in those who started at 13 years or older was 1.7 (95% CI, 0.49–5.7). This association differed significantly from those for endometrial (p 0.033) or ovarian (p 0.009) cancer alone. For multiple primary diseases, the relative odds associated with using postmenopausal estrogen for one year or more was 1.6 (0.60–3.9). This association was smaller than that for single primary endometrial cancer (OR 5.5, p for difference between the associations, 0.045). (Only two of the study subjects had a history of use of progestin, and neither had used estrogen.) A history of breastfeeding and menopausal status was not strongly associated with any of the three cancer types.
RESULTS The number of subjects for whom there was information on each characteristic varied because not all of the original studies ascertained information on the characteristics discussed in this report, and also because information was missing for some respondents (Table 2). A smaller proportion of the women with ovarian cancer alone than the subjects in the three other groups had attended college. There was also a slight difference in the distribution of family income among the four groups, with the multiple primary cases and the ovarian cancer cases having a somewhat lower family income. A history of using oral contraceptives (OCs) for 12 months or longer was more strongly associated with a decreased risk of multiple primary disease (OR 0.60, 95% CI, 0.24–1.5) than with either endometrial cancer or ovarian cancer alone (p for difference relative to the association with single primary cancer: endometrium, 0.175; ovary, 0.003) (Table 3). The risk of
TABLE 2. Demographic and sampling characteristics of cases and controls
Characteristic Original study CASH WA1 WA2 Age at reference, yr 49 50–59 60 Reference year 1975–76 1977–79 1980–82 1985–87 1988–90 Race Caucasian Asian Educational attainmenta High school graduate or less At least some college Annual family incomeb $30,000 $30,000 a b
Controls (N 280) (%)
Endometrial Cancer Cases (N 280) (%)
Ovarian Cancer Cases (N 280) (%)
Synchronous Endometrial and Ovarian Cancer Cases (N 56) (%)
36 34 30
36 34 30
36 34 30
36 34 30
37 40 24
37 40 24
38 39 23
38 39 23
19 15 36 16 14
28 6 36 16 14
14 20 36 19 11
14 20 36 16 14
98 2
99 1
99 1
98 2
42 58
49 51
57 43
47 53
51 49
52 48
57 43
57 43
Information not obtained for 1 multiple primary case, 1 endometrial cancer control, 2 ovarian cancer controls, and 2 nondiseased controls. Information not obtained in the WA1 study, nor for an additional two multiple primary cases, 7 endometrial cancer controls, 11 ovarian cancer controls, and 10 nondiseased controls.
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TABLE 3. Reproductive history and use of prior oral contraceptives and post-menopausal estrogen in relation to the risk of synchronous, multiple primary endometrial and ovarian cancer Controls Characteristic Maternal history of breast cancer No Yes Maternal history of endometrial cancer No Yes History of OC use Never 11 mo 12 mo Gravidity 0 1 2 Parity 0 1 2 History of breastfeedingd Never Ever Age at menarche, yearse 11 12 13 Menopausal status Pre Peri or post History of use of post-menopausal estrogenf,g Never 11 mo 12 mo
Endometrial Cancer
(%)
(%)
(n 271) 96 4 (n 271) 98 2 (n 280) 62 19 20 (n 280) 14 9 79 (n 276) 15 8 77 (n 212) 57 43 (n 185) 17 29 54 (n 278) 34 66 (n 133) 66 14 20
(n 276) 95 5 (n 276) 94 6 (n 280) 68 14 18 (n 280) 18 12 71 (n 279) 21 15 64 (n 179) 56 64 (n 185) 24 24 52 (n 268) 34 66 33 20 47
OR
Synchronous Endometrial and Ovarian Cancer
Ovarian Cancer CI
(%)
OR
(n 179) 95 0.51–2.5 5 (n 179)g 1.0 97 2.5 0.96–6.5 3 (n 280) 1.0 63 0.59 0.33–1.1 20 0.82 0.50–1.3 17 (n 279) 1.0 18 1.5 0.74–3.1 8 0.73 0.46–1.2 75 (n 278) 1.0 20 1.4 0.71–2.6 10 0.61 0.39–0.97 69 (n 139) 1.0 65 0.95 0.65–1.4 35 (n 185) 1.0 22 0.61 0.33–1.1 20 0.69 0.40–1.2 58 (n 280) 1.0 37 0.92 0.58–1.5 63 (n 122) (n 126) 1.0 59 2.2 1.0–4.6 13 5.5 2.8–10.6 29
CI
g
1.0 1.1
1.0 1.2
0.48-3.1
1.0 1.5
0.42–5.8
1.0 1.1 0.81
0.64–2.0 0.50–1.3
1.0b 0.79 0.67
0.36–1.7 0.42–1.1
1.0b 0.80 0.63
0.39–1.6 0.40–1.0
1.0 0.97
0.56–1.7
1.0 0.54 0.81
0.29–1.0 0.47–1.4
1.0 0.77
0.47–1.2
1.0 1.0 1.6
0.46–2.2 0.87–3.0
(%) (n 54) 96 4 (n 54) 93 7 (n 55) 78 7 15 (n 55) 29 9 62 (n 55) 32 11 57 (n 32) 63 37 (n 37) 10 43 46 (n 56) 33 67 (n 29) 52 24 24
OR
CI
1.0 0.79
0.17–3.6
1.0 3.4
0.95–12
1.0a 0.23 0.60
0.07–0.77 0.24–1.5
1.0c 0.72 0.40
0.21–2.4 0.19–0.82
1.0c 0.47 0.37
0.15–1.5 0.19–0.76
1.0 0.83
0.36–1.9
1.0 3.0 1.7
0.84–11 0.49–5.7
1.0 0.94
0.40–2.2
1.0 2.2 1.6
0.70–6.6 0.59–4.5
a
OR adjusted for parity and educational attainment. OR adjusted for educational attainment. c OR adjusted for history of oral contraceptive use and educational attainment. d Parous women only. e Information not obtained in the WA1 study. f Postmenopausal women only. g Information not obtained for the ovarian cancer cases who participated in the WA2 study. Excludes WA2 subjects. No. of women remaining: 195 controls, 179 cases with ovarian cancer alone, 40 women with multiple primary disease. b
We also examined the histologic types of cancer among the women selected for the three Washington State studies for whom histologic type could be obtained (35 with multiple primary disease). The distribution of histologic types of the endometrial cancer among women with multiple cancers was similar to the distribution among women with endometrial cancer alone, with 80% having adenocarcinoma, not further specified; however, there were more endometrioid (43% observed vs. 10% expected) and less mucinous/serous (31% observed and 54% expected) ovarian cancers among the women with multiple primary disease than among those with single primary ovarian cancer.
DISCUSSION Our analysis was limited primarily by the relatively small number of subjects with synchronous primary endometrial and ovarian cancers. As a consequence, our ability to examine dose-response relationships and to evaluate the presence of confounding was limited, and our estimates have somewhat wide confidence intervals. We undertook this study on the basis of reports that the incidence of synchronous endometrial and ovarian cancer is higher than would be expected on the basis of the incidence of each tumor separately. Relative to the general
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population, Connecticut women diagnosed with ovarian cancer or endometrial cancer during the period 1935 through 1982 were at 2.9-fold (number of cancers, 6) and 9.1-fold (number of cancers, 19) increased risk of having the other malignancy diagnosed within 12 months (1). A similar study of Danish women diagnosed with ovarian and endometrial malignancies during the period 1943 to 1980 revealed relative risk estimates of 2.8 (number of cancers, 11) for endometrial cancers occurring after ovarian cancer and 2.1 (number of cancers, 13) for ovarian cancer occurring after endometrial cancer (2). Women identified through the U.S. National Cancer Surveys and tumor registries with ovarian cancer diagnosed during the period 1935 to 1972 (37% of whom also were included in the Connecticut study) were at 10-fold (n 46) increased risk of having endometrial cancer diagnosed within two years (3). These studies were not able to take into account the higher prevalence of hysterectomy and oophorectomy among gynecologic cancer patients, and thus greatly underestimated the risk of being diagnosed with synchronous multiple endometrial and ovarian cancers. Several explanations could account for all or part of this increase, two of which are related to artifacts in the data. First, there could be detection bias favoring identification of a second gynecologic cancer following diagnosis of the first, and second some secondary endometrial and ovarian tumors may be misclassified as primary malignancies. We believe that the first of these is likely to be present, but not to a degree to produce an incidence of synchronous tumors that is 2- to 10-fold higher than expected. With respect to the misclassification of secondary tumors, we believe this to have occurred to only a minimal extent as well, in those instances in which an endometrial tumor has spread beyond the myometrium. With respect to the misclassification of secondary tumors, we observed a larger-than-expected proportion of endometrioid ovarian cancers among the women with multiple primary diseases. As described in the Methods section, the pathologic diagnoses of multiple primary diseases were confirmed by an expert panel for the CASH study, although not for the western Washington studies. To the extent that detection bias or misclassification of multiple primary diseases is present in our data, they obscure our ability to find differences with single primary disease. Because endometrial and ovarian cancer have several
risk factors in common, they could occur together in the same women with relatively high frequency. Our findings that women with multiple primary diseases have lowerthan-expected parity and less past use of oral contraceptives are consistent with this explanation; however, it is also possible that the two tumors occur together in an etiologically distinct condition. We observed that women with multiple primary tumors had an unusually late age at menarche—an association that was not also present for women with only one tumor. The differences that we observed were not great given the size of our case group; other studies, or a pooling of studies, of women with synchronous endometrial and ovarian tumors would be needed for our tentative findings to be corroborated and for other possible risk factors for synchronous disease to be explored. This research was supported in part by grants no. R35 CA 39779, R35 CA 49761, and K01 70969 from the National Cancer Institute.
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