1 Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, MA.
2 Slone Epidemiology Center, Boston University, Boston, MA.
3 Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, and Division of General Internal Medicine, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA.
Received for publication May 7, 2003; accepted for publication July 21, 2003.
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ABSTRACT |
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case-control studies; neoplasms by histologic type; ovarian neoplasms; smoking
Abbreviations: Abbreviation: CI, confidence interval.
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INTRODUCTION |
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Ten to twenty percent of epithelial ovarian cancers are of the mucinous type, a histologic type that often indicates a poor prognosis if the disease is advanced. In the late 1980s, Koch (3) reported that the percentage of smokers was significantly higher among women with mucinous ovarian cancer than among those with ovarian cancer of other histologic types. Recently, three other studies provided additional evidence that cigarette smoking is associated with increased risk of mucinous ovarian cancer (46), but a population-based case-control study found no association (7). Therefore, we examined cigarette smoking in relation to different histologic types of epithelial ovarian cancer using data from the Case-Control Surveillance Study.
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MATERIALS AND METHODS |
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Over the course of the study, different diagnoses were given priority for interview. Each nurse interviewer generally covered several hospitals and would spend specific days at each one. The nurse interviewers identified potentially eligible patients through examination of admission lists and ward logs. The proportion of hospitalized patients with a particular diagnosis who were enrolled in the Case-Control Surveillance Study varied, depending on whether the diagnosis was being given priority, the level of staffing, and whether the patients physician permitted his/her patients to be included in the study. The major reason for failure to enroll eligible patients was that they were unavailable because they were undergoing tests or treatments or had visitors.
To guard against potential selection bias from referrals to the hospital, study investigators enrolled only patients who lived in areas that were within an hours drive of the hospital; to ensure that this criterion was met, the nurse interviewers were supplied with lists of acceptable zip codes. The participation rate among patients targeted for interview was 95 percent. Seven previous papers on risk factors for ovarian cancer have been based on Case-Control Surveillance Study data (814). A detailed description of the studys methods is available elsewhere (15).
For cigarette smoking, subjects were first asked about their current smoking statusthat is, whether they were a never, past, or current smoker (had smoked within the previous year). Current and past smokers were then asked about number of years of cigarette smoking, number of cigarettes smoked per day, and age at which they had started smoking. Past smokers were asked about the number of years since stopping smoking. The question on age at starting smoking was not asked until 1988.
After discharge, each patients diagnosis, including the primary diagnosis that led to hospital admission, was abstracted from the hospital record. The present study included women interviewed through the end of 2001.
Selection of cases
Eligible cases were 731 women aged 2074 years who met the following criteria: 1) a diagnosis of epithelial ovarian cancer recorded in the discharge summary or pathology report that had been made within the year before the current admission and 2) no other primary cancer or history of cancer. Women whose tumors were classified as borderline malignancies were not eligible. Case women with epithelial ovarian cancer were classified into four groups based on pathology reports (9): serous cell type, mucinous cell type, endometrioid cell type, and other cell types. The latter group included cases with undifferentiated carcinoma, cases with mixed epithelial adenocarcinoma, and cases with an unknown histologic type. Of the 731 case women, information on smoking was available for 709 (97 percent), and they comprised the final case series. Of the latter cases, 577 (81 percent) had been diagnosed within the preceding 6 months; the median age at cancer diagnosis was 51 years, and 136 case women (19 percent) were under 40 years of age.
Selection of controls
Controls were selected from a pool of 2,223 women aged 2074 years with no history of cancer or bilateral oophorectomy who had been admitted to the hospital for diseases that we considered unassociated with cigarette smoking. Eligible diagnoses included appendicitis, hernia of the abdominal cavity, and traumatic injury, other than osteoporotic fractures. Subjects with missing information on smoking status were not eligible as potential controls. The median age was 41 years, and 48 percent of subjects were under age 40.
From this pool of controls, we randomly selected for each case up to three controls matched by age (within the same 5-year age category), year of interview (within the same 5-year category), and geographic region (New York City, Boston, Philadelphia, or Baltimore). The final control series comprised 951 women, who were eligible to serve as controls for more than one cell type: 684 for cases of serous ovarian cancer, 195 for cases of mucinous ovarian cancer, 259 for cases of endometrioid ovarian cancer, and 297 for cases of other types of epithelial ovarian cancer.
Statistical analysis
A woman was considered a nonsmoker if she had never smoked in her life, a current smoker if she had smoked within the year before interview, and an ex-smoker if she had stopped smoking at least 1 year prior to interview. We divided the number of cigarettes smoked per day into three categories: less than one pack per day, one pack per day, and more than one pack per day. We calculated cumulative exposure to cigarettes in pack-years by multiplying the average number of cigarettes smoked per day by the number of years of smoking and dividing by 20. We then divided the pack-years into three categories: 0.15 pack-years, 5.115 pack-years, and more than 15 pack-years. For the smokers, the age at starting smoking was divided into two categories: less than 20 years of age and age 20 years or more.
We examined the relation of cigarette smoking to the estimated relative risk (odds ratio) of each histologic type of ovarian cancer using a conditional logistic regression model. In the multivariable regression model, we adjusted for race, education, body mass index (weight (kg)/height (m)2), age at menarche, menopausal status, parity, oral contraceptive use, and postmenopausal hormone use.
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RESULTS |
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Most characteristics, including age at interview, educational level, age at menarche, and estrogen use, were similarly distributed between cases and controls (table 1). The proportion of White women was significantly higher among ovarian cancer cases than among controls. While case women were more likely to be postmenopausal, had a lower prevalence of high parity (4), and were less likely to have used oral contraceptives than their matched controls, these differences were not statistically significant.
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DISCUSSION |
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To our knowledge, at least four studies (47) have examined the relation between cigarette smoking and different types of epithelial ovarian cancer. Using data from the Cancer and Steroid Hormone Study, Marchbanks et al. (5) reported an odds ratio of 2.9 for mucinous ovarian cancer among current smokers and an odds ratio of 2.3 among ever smokers, relative to never smokers. The risk of mucinous ovarian cancer among current smokers significantly increased as the number of cigarettes smoked increased, regardless of years since first smoking or age at first smoking. No association was found between cigarette smoking and risk of other types of epithelial ovarian cancer. Two subsequent population-based case-control studies showed similar findings (4, 6). However, such an association was not observed in another population-based case-control study (7). In that study, more than 40 percent of case women with ovarian cancer could not be interviewed because of death, an unknown address, or refusal by the patient or her physician, and approximately 30 percent of control women approached also declined to participate. It is possible that nonparticipants, especially those who died, were more likely to have been heavy smokers. If that were the case, the effect of smoking on risk of ovarian cancer may have been diluted.
A biologic mechanism for a link between cigarette smoking and risk of mucinous ovarian cancer has not been well established. Scully (16, 17) suggested that mucinous ovarian tumors are histologically similar to cervical and colon epithelial cancer cells, both of which have been associated with cigarette smoking (1820). In addition, Zenzes et al. (21, 22) found cotinine, a major metabolite of nicotine, and benzo(a)pyrene-DNA adducts in the granulosa lutein cells of women exposed to cigarette smoking.
Our study had some limitations. First, there will have been some degree of histologic misclassification, since the pathology reports were provided by different pathologists and there was no standardized review procedure. However, in one of our early studies of ovarian cancer (10), 79 percent of the original pathologic diagnoses of histologic type were confirmed by an independent pathologist with extensive experience in gynecologic pathology. This suggests that there was reasonable agreement with the original classification. Furthermore, of the cases for which histologic type was classified in the present study, 12.3 percent of the cancers were mucinous. This proportion is similar to those (14.014.6 percent) found in population-based case-control studies that have assessed the relation of smoking to risk of epithelial ovarian cancer (4, 6, 7).
Second, of 709 epithelial ovarian cancer cases, the cell type for 105 cases could not be classified because of a lack of such information in the pathology report. However, unless most case women with missing information on cell type had mucinous cancers and were also nonsmokers or light smokers, this should not have materially changed the present findings.
Third, information on age at starting smoking was not collected from approximately 20 percent of the women. This limited the studys power to assess the relation between age at starting smoking and risk of ovarian cancer of different cell types. Among subjects whose data were available, we did not find any association between age at starting to smoke and risk of mucinous ovarian cancer. Results from the two previous studies did not provide evidence for an association between age at starting smoking and risk of mucinous ovarian cancer (4, 6).
Selection of appropriate controls in a case-control study is a challenge, especially when the researchers interest is in assessing the effect of cigarette smoking using hospital controls. Many diseases for which patients are hospitalized are likely to be associated with cigarette smoking. It has been well documented that the prevalence of cigarette smoking is higher in hospitalized patients than in the general population (2325). Such selection bias would have resulted in underestimation of an adverse effect of cigarette smoking on risk of mucinous ovarian cancer in the present study. We selected our controls from patients with diseases we regarded as unrelated to tobacco use (26). Indirect evidence for the validity of our control selection is the fact that the percentages of women who smoked were similar across subgroups of controls. In addition, there was a greater proportion of White women and a smaller proportion of oral contraceptive users among cases than among controls, which is consistent with the results of previous studies (2731).
It is unlikely that biased reporting of cigarette smoking accounts for the present results, because there is no reason to suspect that patients with mucinous epithelial ovarian cancer would have reported their smoking differently from patients with other types of ovarian cancer.
In conclusion, despite some inconsistencies in our data, these results strengthen the evidence that cigarette smoking may play a role in the development of mucinous ovarian cancer.
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ACKNOWLEDGMENTS |
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The authors thank the many physicians who allowed their patients to be interviewed; the nurse interviewers who collected the data; Marguerite Angeloni, who coordinated data collection; and Leonard Gaetano, who was responsible for data management.
The following hospitals participated in this study: New York, New YorkBrookhaven Memorial Hospital, Lenox Hill Hospital, Memorial Sloan-Kettering Cancer Center, and New York Hospital; Philadelphia, PennsylvaniaAmerican Oncologic Hospital, Crozier Chester Medical Center, Hahnemann University Hospital, Hospital of the Medical College of Pennsylvania, Hospital of the University of Pennsylvania, Lankenau Hospital, Montgomery Hospital, Pennsylvania Hospital, Presbyterian Hospital, and Thomas Jefferson University Hospital; Boston, MassachusettsSancta Maria Hospital, Beth Israel Hospital, Newton Wellesley Hospital, Mount Auburn Hospital, Massachusetts General Hospital, Brigham and Womens Hospital, University Hospital, and New England Medical Center; Baltimore, MarylandJohns Hopkins Hospital, University of Maryland Medical Center, Sinai Hospital, Greater Baltimore Medical Center, and Mercy Medical Center.
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NOTES |
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REFERENCES |
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