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ORIGINAL RESEARCH |
From the Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia; Duke University Medical Center, Program of Cancer Prevention, Detection and Control Research, Durham, North Carolina; and Ob-Gyn Epidemiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
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Abstract |
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Methods: We used data from the Cancer and Steroid Hormone Study, a multicenter, population-based, case control investigation. Cases were 447 women aged 20–54 years with diagnoses of epithelial ovarian cancer. Controls were 3868 women selected by random-digit dialing. Conditional logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) as estimators of the relative risk of ovarian cancer. With age and study site as conditioning variables, OR point estimates were additionally adjusted for parity and use of oral contraceptives.
Results: The OR of mucinous epithelial ovarian cancer for women who had ever smoked was 2.3 (95% CI 1.4, 3.9) and for current smokers was 2.9 (95% CI 1.7, 4.9). The OR of mucinous tumors for current smokers was significantly elevated regardless of years since first cigarette or age at which women first smoked. The OR of mucinous tumors for current smokers increased slightly as cumulative pack-years of smoking increased, although the trend was not significant. Similar patterns of elevated risk were not observed among serous, endometrioid, or other histologic types. Odds ratio point estimates for former smokers were not significantly elevated for any histologic type.
Conclusion: Current cigarette smoking was a risk factor for mucinous epithelial ovarian cancer, but not other histologic types.
In rodents, polycyclic hydrocarbons such as dimethyl–benzanthracene induce ovarian neoplasms, probably by toxic effects on oocytes, premature elevation of gonadotropins, and ovarian stimulation.1 Mattison and Thorgeirsson2 proposed that tobacco smoke components might have similar effects in women, accounting for earlier menopause and higher rates of ovarian cancer in western societies. Some support for that hypothesis was provided by a British cohort study that identified greater risk of ovarian cancer associated with cigarette smoking.3 However, an association between cigarette smoking and ovarian cancer was not found in a subsequent cohort study,4 nor in several case control studies,5–7 including a previous analysis from the Cancer and Steroid Hormone Study.8
None of those previous studies examined the association between cigarette smoking and ovarian cancer within histologic types. There is some evidence that risk factors for ovarian cancer might vary by histologic type,9–11 and cigarette smoking is a modifiable exposure, so we explored the association between cigarette smoking and specific histologic types of epithelial ovarian cancer with data from the Cancer and Steroid Hormone Study.
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Materials and Methods |
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Women who were 20–54 years of age, lived in one of the eight study locations, and had ovarian cancer initially diagnosed between December 1, 1980, and December 31, 1982, were eligible. Of 816 eligible women, 579 (71%) were interviewed.13 Reasons for noninterview included death (3%), illness (5%), patient or physician refusal (8%), and inability to conduct the interview within 6 months of diagnosis (13%). After interviews were completed, 31 women were excluded owing to possible histories of ovarian cancer, diagnoses of a benign or metastatic tumor, or inadequate information to classify tumors.13 Of 548 remaining women, 494 (90%) had ovarian cancer of epithelial origin.
Collection of histology reports and slides of ovarian cancer specimens was initiated at six of eight study locations (Atlanta, Detroit, Seattle, San Francisco, Iowa, and Connecticut); collection was successful for 516 of 535 (97%) epithelial and nonepithelial ovarian cancer cases from those six sites.13 Slides were reviewed by a panel of three pathologists that classified each case of ovarian cancer as epithelial or nonepithelial. The panel also characterized each case according to histologic type and tumor behavior (carcinoma in situ, borderline, or malignant).
For cases in which slides were not available, epithelial or nonepithelial ovarian cancer diagnoses from local pathologists were obtained from separate data tapes when possible. Concordance between panel diagnoses and local diagnoses was examined with those data.13,14 Although concordance was high for dichotomous classifications of ovarian cancer as epithelial or nonepithelial, agreement on specific epithelial histologic type was less certain. Histologic type was the focus of this analysis, so we excluded 45 women with epithelial ovarian cancer whose histology slides could not be reviewed (12 of 45 were from retrieval sites and 33 were from New Mexico and Utah, where slides were not retrieved). From the remaining 449 cases, we excluded two women with diagnoses of carcinoma in situ, which left 447 cases for analysis.
Controls consisted of women aged 20–54 years at enrollment, selected by random-digit dialing procedures15,16 from the same geographic areas as cases, during the same period of case enrollment. Controls in the Cancer and Steroid Hormone Study were frequency matched to breast cancer cases by study site and 5-year age distribution.12 Incidence of breast cancer is higher than ovarian cancer, so the number of controls is larger than the number of cases. Of 5698 women selected as controls, 4754 (83%) were interviewed.13 Reasons for no interviews included refusal (12%) and inability to conduct the interview within 6 months of selection (5%). After interviews were completed, 516 women without ovaries or with unknown numbers of ovaries were excluded,13 leaving 4238 controls. No cases of ovarian cancer from New Mexico or Utah were included in this analysis, so we excluded controls from those locations. A total of 3868 controls from the same six geographic locations as the cases remained for analysis.
A trained interviewer went to each study participant’s home to administer a detailed questionnaire. Each interview lasted about an hour and focused on reproductive and medical history, use of contraception and medical services, and personal habits. A life calendar from menarche to menopause was constructed for each woman to help her recall contraceptive and reproductive experiences in relation to major events such as marriages, divorces, births, and deaths.
Never smoking was defined as not having smoked a lifetime total of 100 cigarettes or more. For women who had smoked 100 cigarettes or more, current smoking was defined as last smoking in the same year as diagnosis (cases) or interview (controls). Former smoking was defined as last smoking 1 or more years before diagnosis or interview. Recency of smoking was defined as the number of years from last smoking to the date of diagnosis or interview. Latency was defined as the number of years from when smoking was started to the date of diagnosis or interview. Pack-years of smoking were calculated as:
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Age was defined as age at diagnosis for cases and age at interview for controls. Although all controls were aged 20–54 years at enrollment, some were 55 years of age at interview. Whenever age was categorized, those women were included in the 50–54-year stratum.
With study site and age as conditioning variables, we used conditional logistic regression to calculate odds ratios (ORs) as estimators of relative risk (RR) of epithelial ovarian cancer according to histologic type; 95% confidence intervals (CIs) accompany all OR point estimates. We constructed separate models for each histologic type of epithelial ovarian cancer. In conditional logistic regression, independent characteristics for the conditioning variables are not required in the models; therefore, a conditional approach is useful when the number of characteristics in the corresponding unconditional logistic regression model would be large relative to the number of subjects. We selected a conditional approach because we were concerned that the small samples for certain analyses would not support the number of independent characteristics required in unconditional models that controlled for age and study site, in addition to other important covariates.
In previous work from the Cancer and Steroid Hormone Study on the association between cigarette smoking and ovarian cancer,8 multivariable analyses were adjusted for age, parity, and OC use. Additional adjustments for many factors such as race, education, infertility, menopausal status, noncontraceptive estrogen use, alcohol use, adiposity, and family history of ovarian cancer did not alter OR point estimates. Based on that work, our adjusted analyses controlled for parity (0, 1–2, and 3+), defined as the number of pregnancies of over 6 months’ duration, and ever use of OC (for at least 3 consecutive months) in conditional logistic regression models that contained study site and age (in 5–year categories) as conditioning variables.
Adjusted tests for linear trend were calculated by entering the categoric variable of interest as a single term into our conditional logistic model, as described. For that purpose, categoric variables were coded 0 for no exposure, 1 for the first level of exposure, 2 for the second level of exposure, and so forth. We then tested for significance of the regression coefficient associated with that variable. Because trend tests can be significant if risk increases for any amount of exposure relative to no exposure (even when risks among different exposure levels remain constant),17 a binary variable to control for ever smoking was included in all trend test models.
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Results |
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). Mucinous and endometrioid tumors each accounted for approximately 20%. Eighty-eight (38.1%) of the 231 serous tumors were classified as borderline tumor behavior, and 143 (61.9%) as malignant; 35 (43.2%) of the 81 mucinous tumors were classified as borderline tumor behavior, and 46 (56.8%) as malignant. Tumors of all remaining histologic types were classified as malignant.
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). Variations in age, parity, and use of OCs were across histologic types. Compared with the other three histologic types, a greater percentage of women with mucinous tumors were younger, nulliparous, and ever users of OCs.
Compared with women who had never smoked, the OR of mucinous epithelial ovarian cancer for women who had ever smoked was 2.3 (95% CI 1.4, 3.9) (Table 2). Odds ratios for serous, endometrioid, and other types of epithelial ovarian cancer were no more than 1.0, and not statistically significant. Current smokers had a similar elevated risk. Among the small subgroup of former smokers, several slightly increased and decreased associations were observed across histologic types but none were statistically significant. We concentrated further analyses on current smokers because of the small number of former smokers, as well as the lack of a significant effect among the former smoking group.
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). A distinct pattern was not observed in the other three histologic types.
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Compared with women who had never smoked, the OR of mucinous epithelial ovarian cancer for current smokers increased slightly as cumulative pack-years of smoking increased (adjusted P for trend = .7) and point estimates were significantly elevated in all pack-year intervals (Table 4). A similar pattern was not observed in the other three histologic types.
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Discussion |
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Mucinous tumors of the ovary are characterized by the presence of epithelial cells that contain abundant mucin and resemble cells that line the inner portion of the cervix and intestines.18 Those histologic similarities support the biologic credibility of an association between cigarette smoking and mucinous tumors because smoking has been linked to cervical and colon cancers. Smoking increases risk of cervical cancer, especially squamous types,19 and increases risk of cervical adenocarcinomas that more closely resemble ovarian mucinous tumors.20 Even stronger evidence shows cigarette smoking might be linked to increased risk of colon cancer and colon adenomas.21–23
Tobacco smoke might affect quantity and quality of mucus production in various cells. Smokers appear to have increased production of mucus in their airways24 and possibly in the large bowel.25 Tobacco smoke components, including potent nitrosamine carcinogens, have been found in the cervical mucus of smokers.26 In a study of a proposed screening test for tumor-associated mucins, smokers had elevated levels of the MUC1 marker.27
We believe the literature supports the biologic plausibility of an association between mucinous ovarian tumors and cigarette smoking. Additional strengths of our study include its population-based design, the review of ovarian cancer diagnoses by a pathology panel, and a detailed, standardized data collection procedure conducted in each participant’s home. However, our analysis had limitations that should be recognized. The Cancer and Steroid Hormone Study was not designed to investigate the relationship between cigarette smoking and ovarian cancer. The small number of ovarian cancer cases, lack of information on possible confounding factors such as talc exposure and diet, and relatively young age of the study population were also limitations. Although the Cancer and Steroid Hormone Study was restricted to women aged 20–54 years at enrollment, more than one third of ovarian cancer cases occur in women 65 years of age or older.28
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Footnotes |
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The authors acknowledge the many contributors to the Cancer and Steroid Hormone Study, including: George L. Rubin, Phyllis A. Wingo, Nancy C. Lee, Michele G. Mandel, Raymond Greenberg, J. Wister Meigs, W. Douglas Thompson, G. Marie Swanson, Elaine Smith, Charles Key, Dorothy Pathak, Donald Austin, David Thomas, Joseph Lyon, Dee West, Fred Gorstein, Robert McDivitt, Stanley J. Robboy, Lonnie Burnett, Robert Hoover, Peter M. Layde, Howard W. Ory, James J. Schlesselman, David Schottenfeld, Bruce Stadel, Linda A. Webster, Colin White, Walter Bauer, William Christopherson, Deborah Gersell, Robert Kurman, Allen Paris, and Frank Vellios.
Received April 13, 1999. Received in revised form July 30, 1999. Accepted August 12, 1999.
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References |
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]anthracene. I. Effect of steroid hormones and carcinogenic concentration in vivo. J Natl Cancer Inst 1966;37:409–20.2. Mattison DR, Thorgeirsson SS. Smoking and industrial pollution, and their effects on menopause and ovarian cancer. Lancet 1978;i: 187–8.
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6. Whittemore AS, Wu ML, Paffenbarger RS, Sarles DL, Kampert JB, Grosser S, et al. Personal and environmental characteristics related to epithelial ovarian cancer. II. Exposures to talcum powder, tobacco, alcohol, and coffee. Am J Epidemiol 1988;128:1228–40.
7. Polychronopoulou A, Tzonou A, Hsieh CC, Kaprinis G, Rabelakos A, Toupadaki N, et al. Reproductive variables, tobacco, ethanol, coffee and somatometry as risk factors for ovarian cancer. Int J Cancer 1993;55:402–7.[Medline]
8. Franks AL, Lee NC, Kendrick JS, Rubin GL, Layde PM, and the Cancer and Steroid Hormone Study Group. Cigarette smoking and the risk of epithelial ovarian cancer. Am J Epidemiol 1987;126: 112–7.
9. Risch HA, Marrett LD, Jain M, Howe GR. Differences in risk factors for epithelial ovarian cancer by histologic type: Results of a case-control study. Am J Epidemiol 1996;144:363–72.
10. Kvale G, Heuch I, Nilssen S, Beral V. Reproductive factors and risk of ovarian cancer: A prospective study. Int J Cancer 1988;42:246–51.[Medline]
11. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Epithelial ovarian cancer and combined oral contraceptives. Int J Epidemiol 1989;18:538–45.
12. 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;128:206–17.
13. Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. The reduction in risk of ovarian cancer associated with oral contraceptive use. N Engl J Med 1987;316:650–5.[Abstract]
14. Tyler CW Jr, Lee NC, Robboy SJ, Kurman RJ, Paris AL, Wingo PA, et al. The diagnosis of ovarian cancer by pathologists: How often do diagnoses by contributing pathologists agree with a panel of gynecologic pathologists? Am J Obstet Gynecol 1991;164:65–70.[Medline]
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16. Hartge P, Brinton LA, Rosenthal JF, Cahill JI, Hoover RN, Waksberg J. Random digit dialing in selecting a population-based control group. Am J Epidemiol 1984;120:825–33.
17. Breslow NE, Day NE. Statistical methods in cancer research. Vol. II. The design and analysis of cohort studies. Lyon, France: International Agency for Research on Cancer, 1987.
18. Scully RE. Tumors of the ovary and maldeveloped gonads. Atlas of tumor pathology. Fascicle 16. Washington, DC: Armed Forces Institute of Pathology, 1979.
19. Brinton LA, Schairer C, Haenszel W, Stolley P, Lehman HF, Levine R, et al. Cigarette smoking and invasive cervical cancer. JAMA 1986;255:3265–9.[Abstract]
20. Ngelangel C, Munoz N, Bosch FX, Limson GM, Festin MR, Deacon J, et al. Causes of cervical cancer in the Philippines: A case-control study. J Natl Cancer Inst 1998;90:43–9.
21. Kikendall JW, Bowen PE, Burgess MB, Magnetti C, Woodward J, Langenberg P. Cigarettes and alcohol as independent risk factors for colonic adenomas. Gastroenterology 1989;97:660–4.[Medline]
22. Newcomb PA, Storer BE, Marcus PM. Cigarette smoking in relation to risk of large bowel cancer in women. Cancer Res 1995;55:4906–9.
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24. Steiger D, Fahy J, Boushey H, Finkbeiner WE, Basbaum C. Use of mucin antibodies and cDNA probes to quantify hypersecretion in vivo in human airways. Am J Respir Cell Mol Biol 1994;10:538–45.[Abstract]
25. Pullan RD. Colonic mucus, smoking, and ulcerative colitis. Ann R Coll Surg Engl 1996;78:85–91.[Medline]
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27. McGuckin MA, Ramm LE, Joy GJ, Devine PL, Ward BG. Circulating tumor-associated mucin concentrations determined by the CASA assay in healthy women. Clin Chim Acta 1993;214:139–51.[Medline]
28. iSaia PJ, Creasman WT. Clinical gynecologic oncology. 4th ed. St. Louis, Missouri: Mosby Year Book, 1993.
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