Epithelial ovarian tumors are divided into several histologic subtypes, including serous, mucinous, endometrioid, clear cell, and other less common forms. Because these different subtypes differentiate into histologically distinct cells, they may have different etiologies. In particular, Risch et al. 1 have proposed that mucinous epithelial ovarian tumors are etiologically distinct from nonmucinous tumors. However, the data to evaluate this hypothesis are mixed; although some studies 1–6 have found differences in risk factors among the various subtypes, others 7–13 have failed to note any differences. Most of these studies have explored reproductive risk factors, such as oral contraceptive use and parity.
Nonreproductive risk factors, such as saturated fat intake 1 and current cigarette smoking, 12,14 may also vary according to histologic type. In particular, there is biological evidence to support the association of mucinous tumors with cigarette smoking. Mucinous tumors are histologically similar to cervical adenocarcinomas and colon tumors, 15 which have been associated with cigarette smoking. 16–19 Moreover, both cotinine, a major metabolite of nicotine, and B[a]P-DNA adducts, formed from the potent B[a]-P mutagen and carcinogen found in cigarette smoke, have been found in ovarian follicular cells. 20,21 Together, these data suggest a possible link between cigarette smoking and mucinous epithelial ovarian cancer. To explore this potential link, we examined the association between cigarette smoking and the development of mucinous and nonmucinous tumors, using data from a large, population-based case-control study of epithelial ovarian cancer.
This analysis is based on the SHARE (Study of Health and Reproduction) Project, a case-control study of contraceptive and reproductive risk factors for epithelial ovarian cancer. This study has been described elsewhere. 22,23 Briefly, cases were women, 20–69 years of age, who were diagnosed with incident epithelial ovarian cancer within the 6 months before interview. Between May 1994 and July 1998, 873 eligible women were identified at 39 hospitals around the Delaware Valley. Fourteen physicians did not consent to their patients’ participation and 92 women refused to participate. Thus, our analyses are based on 767 completed case interviews (88% of potentially eligible, incident cases). The diagnosis of epithelial ovarian cancer was confirmed by pathology in all cases.
Controls age 65 or younger were ascertained by random digit dialing and frequency-matched to cases by 5-year age groups and 3-digit telephone exchanges. Of the 14,551 telephone numbers screened for this purpose, we identified 1,637 households with a potentially eligible control; of these, 1,215 (74%) completed interviews. Controls 65–69 years of age were ascertained through Health Care Financing Administration (HCFA) lists. Of the 263 potentially eligible participants identified, 152 (58%) were interviewed. Therefore, of the 1,900 screened and potentially eligible controls, 1,367 (72%) are included in our analyses.
Institutional Review Board approval was obtained at all hospital from which subjects were recruited, and study subjects gave informed consent for participation.
A standardized 1.5-hour in-person interview of cases and controls provided detailed information on a subject’s medical history, general demographic and anthropometric data, gynecologic and obstetric history, and lifestyle factors such as cigarette smoking. Questions relating to cigarette smoking included age at first daily use, average number of cigarettes smoked per day, and age at last use.
Because matching was based on frequencies for only two broad criteria (age within 5-year intervals and 3-digit telephone exchange), we did not preserve the “match” in the analyses. Never smoking was defined as not having smoked cigarettes daily for 6 months or more. For women who reported smoking daily for at least 6 months, current smoking was defined as smoking within 6 months of diagnosis (cases) or interview (controls). Former smoking was defined as quitting smoking more than 6 months before diagnosis or interview. For former smokers, recency of smoking was defined as the number of years from the last smoke until the date of diagnosis or interview. For all smokers, latency was defined as the number of years since first smoke until the date of diagnosis or interview. Pack-years of smoking were computed as: (average number of cigarettes smoked per day × number of years smoked)/20 cigarettes per pack. 14
Cases were divided into mucinous and nonmucinous ovarian cancer according to the histologic subtype of their tumors as determined from pathology reports. We used multivariate unconditional logistic regression methods to calculate the odds ratio (OR) and 95% confidence interval (CI) for mucinous and nonmucinous ovarian cancer associated with cigarette smoking. Adjustments were made for age at diagnosis (cases) or interview (controls), number of live births, ever-use of oral contraceptives, history of tubal ligation, and family history of ovarian cancer. These variables either were shown to differ between cases and controls in univariate analyses or are known to be associated with ovarian cancer risk. To control for the potential influence of socioeconomic status on cigarette smoking, we performed all analyses in models both with and without education level (less than high school, high school graduate, more than high school). Because inclusion of education level did not alter the odds ratios for any model, we did not include it in the final models reported here.
Among the 767 cases, 112 (15%) were classified as mucinous tumors and 655 were classified as nonmucinous tumors, a distribution that is consistent with other studies. 1,2,11Table 1 shows the demographic and risk factor data for controls, and for cases according to mucinous or nonmucinous subtype. The two case groups were similar except for age. Compared with controls, both mucinous and nonmucinous cases were less likely to have borne children, used oral contraception (OCs), or had a tubal ligation. In addition, nonmucinous cases were somewhat older than controls and were more likely to report a family history of the disease. Notably, there were no differences in education level between the two case groups or between either case group and the controls, suggesting similar socioeconomic levels.
Compared with controls, women who developed mucinous epithelial ovarian tumors were more likely to have smoked (adjusted OR = 1.9; 95% CI = 1.3–1.9) and to be current smokers (adjusted OR = 2.7; CI = 1.7–4.3) (Table 2). In contrast, the odds ratios for ever-smokers or current smokers were not elevated in women who developed nonmucinous tumors. Moreover, the results were unchanged when stratified by age (Table 3).
Regardless of when women started smoking, the odds ratios for mucinous ovarian tumors among ever-smokers compared with never-smokers were elevated (OR = 6.2, 3.6, and 1.8 for <5, 5–14, and >14 years since first use, respectively; adjusted P for trend = 0.01). No such elevated risk was observed among nonmucinous tumors. Similar results were obtained when comparing never-smokers and current smokers, and when analyzing only invasive tumors (data not shown).
Similarly, regardless of the age at which the woman started to smoke, the odds ratios were elevated for mucinous ovarian cancer but not for nonmucinous ovarian cancers (Table 2).
Finally, compared with never-smokers, the odds ratios for smokers increased with increasing cumulative pack-years of smoking among mucinous tumors (adjusted P for trend = 0.01) but not among nonmucinous tumors. Similar results were obtained when comparing never-smokers and current smokers and when analyzing only invasive tumors (data not shown). Moreover, the results were unchanged when stratified by age (Table 3).
In this study, we investigated the association of cigarette smoking with mucinous and nonmucinous epithelial ovarian cancer. Our data suggest that cigarette smoking is associated with mucinous ovarian tumors but not nonmucinous tumors. The association is stronger for current smokers and increases with increasing number of pack-years of use.
Most 24–28 but not all 29 previous studies have failed to find an association between epithelial ovarian cancer and smoking, although the earlier analyses did not examine the association according to histologic subtype. Marchbanks et al. 14 recently performed a subset analysis on data from the Cancer and Steroid Hormone Study. They found an elevated risk associated only with current cigarette smoking for mucinous ovarian cancer, but not for the other histologic types (OR = 2.3; 95% CI = 1.4–3.9, for mucinous tumors; OR = 0.9, 1.0, and 0.7 for serous, endometrioid, and other tumors). They further found elevated risk for increasing time since first use (OR = 2, 3.6, and 2.5 for < 5, 5–14, and 15+ years since first use) and for increasing number of pack-years (OR = 2.6, 2.7, and 3.1 for <5, 5–24, and 25+ pack-years) for mucinous tumors only. No such increased risk was observed among the other histologic types. A limitation of their study was that it was restricted to women ages 20–54; half of ovarian cancer cases are diagnosed after age 63. 30 Nonetheless, their results are very similar to those presented here. Moreover, when we restricted our analyses to women age 50 or less, our results were consistent.
Kuper et al.31 also found an increased association with cigarette smoking among women with mucinous tumors. However, the association was evident only in women who smoked an average of 40 or more cigarettes per day, and no significant differences were found in pack-years of smoking among the different histologic types. A small sample size and incomplete interview data on 45% of cases may explain the differences in findings between their results and those presented here.
The association between mucinous tumors and cigarette smoking is biologically plausible. Mucinous tumors consist of mucin-producing epithelial cells similar to cervical and intestinal epithelial cells. 15 Smoking has been associated with both cervical and colon cancers. 16–19 Moreover, cotinine, a major metabolite of nicotine, has been found in the granulosa-lutein cells of women exposed to active and passive smoke cigarette smoke. 20 In addition, benzo[a]pyrene-DNA (B[a]P-DNA) adducts have also been found in the granulosa-lutein cells of women exposed to cigarette smoke. 21 These adduct levels appear to be related to smoke exposure and dose, both recent and long term. B[a]P is a potent mutagen and carcinogen present in cigarettes. Its metabolites can covalently bind to DNA, forming adducts. 32–33 Such adducts are believed to be the first step in the carcinogenic process, as evidenced by their association with lung cancer mutational spots. 34
The major strengths of this study are that it is one of the largest population-based studies of epithelial ovarian cancer ever conducted, and that it included women up to age 70. Study data were collected through a standardized, structured interview administered by trained personnel.
The major limitation of this study is the possibility of error in the histologic classification because pathology data on cases came from pathologists at 39 hospitals. However, the overall distribution of histologic types in our study was consistent with other studies. 1,2,11 Thus, our classifications are likely to be reasonably accurate. Moreover, the possibility of misclassifying a mucinous tumor as a nonmucinous tumor, or vice versa, is small. 35 Even if the histologic classification of some tumors were incorrect, the misclassification would be nondifferential with respect to cigarette smoking. This would bias our results towards the null, thereby weakening any true associations. Another limitation is that we did not differentiate between filtered and unfiltered cigarettes and thus we have only gross measures of exposure.
Another limitation is the possibility for selection bias among controls. Because women with a higher socioeconomic status tend to have higher study participation rates, and because these women tend to smoke less frequently, it is possible that smokers are underrepresented in our control group. However, the similarities in age and education level between cases and controls suggest that differences in socioeconomic status between the two groups are unlikely. Finally, we did not include in our analyses potential confounders, such as alcohol use or dietary fat intake.
In conclusion, the data presented here support the hypothesis that mucinous tumors may be etiologically distinct from nonmucinous tumors. Additional studies of risk factors for epithelial ovarian cancer by histologic type are warranted.
We thank the anonymous reviewers for their comments, which greatly improved this manuscript. We further thank the participants and other researchers involved in the SHARE Study.
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Keywords:© 2002 Lippincott Williams & Wilkins, Inc.
ovarian neoplasms; risk factors; smoking; case-control studies