This is the largest and most recent case-control study to examine the relationship between cigarette smoking and meningioma risk. Unlike previous studies we were able to both stratify by gender and control for a number of confounding factors such as education, alcohol use and body mass index. In these data, active cigarette smoking was associated with an increased risk in men but a decreased risk in females. A number of previous authors have examined the relationship between cigarette smoking and meningioma risk with inconsistent results when males and females are grouped together (10
) but as formally examined by our meta-analysis, remarkably consistent results (with the exception of the early study by Preston-Martin (18
) which included 185 females cases from the Los Angeles area) when stratified by gender.
The finding of a protective effect of smoking among women in our study is intriguing in light of the suggestive but poorly defined role for hormonal factors for meningioma (26
). An association between hormones and meningioma risk has been suggested by the increased incidence of the disease in women versus men, the presence of hormone (particularly progesterone) receptors on some meningiomas, an association between breast cancer, uterine fibroids, endometriosis and meningiomas (27
), indications that meningiomas change in size during the luteal phase of the menstrual cycle and pregnancy, and in vitro proliferation of meningioma-cell lines in culture after exposure to estrogens. In the one previous case/control study to examine risk by menopausal status a stronger effect was noted in pre-menopausal women (19
) although we were not able to detect such an effect, potentially due to the smaller number of premenopausal women in our data. Cigarette smoking is hypothesized to be anti-estrogenic by enhancing the metabolism of estradiol to inactive cathechol estrogens, increasing the binding of estrogen by serum sex-hormone-binding globulin, as well as decreasing adipose-derived estrogen (28
). The effect of smoking has been examined in a number of hormone associated cancers including breast for which results have been inconsistent and endometrial (9
) for which smoking has been consistently associated with decreased risk. In addition to a hormonal difference, the observed variation in risk associated with cigarette smoking for women versus men may be due to other factors including differences in patterns of cigarette use by gender (28
). Smoking may also serve as a marker for other variables associated with risk in men but not women including alcohol use, weight (and hence amount of adipose tissue) and socio-economic variables, although these variables were controlled for in our analyses.
Strengths to the study include the population-based study design, large sample size, and relatively consistent magnitude and direction of risk estimates. Histologic confirmation was obtained for all case subjects suggesting that these results may only be applicable to lesions that are deemed in need of surgery rather than conservative management.
Limitations for this study include the possibility of mis-reporting of cigarette smoking by study participants. Self-reporting of cigarette smoking may also vary by gender although data that correlate thiocyanate and cotinine levels in male and female study subjects with self-reported cigarette use suggest that self-report is a reliable and cost efficient means to measure smoking behavior in both men and women (31
). Differential recall by case-control status is possible although a widespread knowledge of any association between meningioma and smoking among the general public is unlikely given the limited research on this topic. We noted lower than expected (although in line with other recent studies of brain tumors) response rates among control subjects. Cases and controls did not differ by race, age, sex, or geographical site but did differ with respect to education and income with controls reporting higher income and education than controls, suggesting a greater willingness among persons of higher socio-economic status to participate in epidemiology research. Although these variables were adjusted for in all analyses, such differences in socio-economic status, a factor likely related to cigarette smoking use, may lead to bias in risk estimation, although the opposite direction of risks identified here seems to argue against such a bias.
The extent to which risk for meningiomas associated with exposure to cigarette smoke is modified by genotype is unknown and this is an important area for future study. Genetic variants in genes involved in the control of aromatic hydrocarbons have been implicated in meningioma risk, but not confirmed (32
Given the important role of IR in meningioma risk, several previous groups have attempted to control for IR exposure when assessing risk associated with smoking. In their population-based case-control study including 200 cases of meningioma, Phillips et al (2005) (15
) assessed risk with cigarette smoking that occurred 10 or more years prior to the meningioma surgery and reported gender-specific findings quite similar to ours. Although the actual estimates were not presented, when the authors controlled for subjects who reported ever having a full-mouth dental x-ray series, findings for active smoking were strengthened. Flint-Richter et al (2011) (16
) assessed the role of smoking in presumed radiation- and non-radiation-related meningiomas utilizing data from the Tineas Capitas Cohort (3
). They reported an increased risk associated with smoking for men. For women, they observed a significant inverse association of meningioma with smoking (OR: 0.32, 95%CI: 0.14,0.77) with a dose-response association (p < 0.01) in non-irradiated (mean dose 1.5 Gy) women and a non-significant increase risk of meningioma in irradiated women. These findings lead the authors to speculate on the existence of an interaction between ionizing radiation and smoking in meningioma risk for women. No effect modification by exposure to IR (either diagnostic or therapeutic) was appreciated in our analyses. Further study of the possible role of IR in the examination of smoking and meningioma risk is of interest. Studies such as this one allow for the collection of large numbers of persons with varying gene*environment combinations and hence comparison of the effect of exposures such as ionizing radiation across genetic variant; our group plans to examine these interactions in future work.
Our results suggest a gender specific relationship between smoking and intra-cranial meningioma risk. The large size of our dataset (which includes information on important confounding variables) allows us to confirm a reduced risk for women who are active smokers and offers additional insight into what is likely a complex relationship between hormonal factors and meningioma risk.