Ionizing Radiation

At present, the primary environmental risk factor identified for meningioma is exposure to ionizing radiation (IR), with risks from 6- to 10-fold reported.6–10 At high dose levels, data exist for atomic bomb survivors9 and show a greatly increased risk for meningioma, with increasing risk correlating with the proximity to the epicenter of the explosion.^29,30 Evidence also exists for lower dose levels. In one of the most well-known studies to date of IR and meningioma risk, children who were given radiation therapy for scalp ringworm in Israel between 1948 and 1960 (the Tinea Capitis Cohort) were observed to have a relative risk of almost 10 for meningioma.7 Several studies have linked the number of full-mouth dental radio-graphs to risk of meningioma, although the sample sizes are limited, and most later studies (also small in size) did not confirm these findings. The most recent case-control study of 200 meningioma patients reported that the full-mouth series was associated with a significantly increased risk of meningioma [odds ratio (OR): 2.06, 95% confidence interval (CI): 1.03 to 4.17], although evidence for a dose response relation was lacking (p for trend = 0.33).10 Radiation therapy for intracranial tumors has also been linked to meningioma risk,7 and animal studies support the contention that IR can induce intracranial tumors, including meningiomas, by damaging DNA, with resultant single-strand or double-strand breaks. No recent large-scale studies of meningioma risk relative to IR exist, when x-ray doses for dental and other procedures have decreased but during which time new radiographic procedures have been introduced, including computed tomography (CT).

Hormones

An association between hormones and meningioma risk has been suggested by several findings, including the increased incidence of the disease in women versus men (2:1); the presence of estrogen, progesterone, and androgen receptors on some meningiomas; an association between breast cancer and meningiomas; 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 has been observed.3,4 A pilot study of 31 meningioma samples reported that gene expression appeared more strongly associated with progesterone receptor (PR) status than with estrogen receptor (ER) status.11 Genes on the long arm of chromosome 22 and near the NF2 gene (22q12) were most frequently noted to have expression variation, with significant upregulation in PR+ versus PR− lesions suggesting a higher rate of 22q loss in PR− lesions.

Researchers have only begun to address the question of whether the use of exogenous hormones such as oral contraceptives and/or hormone replacement therapy is associated with an increased risk of meningioma.4,12–16 Data from two cohort studies and several case-control studies exist. In a case-control study nested within the Nurse’s Health Study (including 125 cases of meningioma), the relative risk of meningioma associated with hormone use for premenopausal women was 2.48 (95% CI: 1.29 to 4.77) when compared with postmenopausal women who had never used hormones.14 For postmenopausal women who were hormone users the relative risk was 1.86 (95% CI: 1.07 to 3.24). No excess risk was associated with past hormone use. No association was found for past or current use of oral contraceptives. Recently published data from a cohort study of 1.3 million women with a mean age of 55.9 and recruited from 1996 to 2001 (The Million Women Study) did not find an association between oral contraceptive use within the past 5 years and meningioma risk (OR:1.06, 95% CI:0.8 to 1.38), but did not report results for hormone replacement therapy use.12 In the largest and most recent case-control study to date, the Interphone Group reported an increased relative risk of meningioma among postmenopausal women for every use of hormone replacement therapy (OR:1.7, 95% CI: 1.0 to 2.8).16 Women who had used long-acting hormonal contraceptives also had an increased risk of meningioma; the odds ratio for at least 10 years of use was 2.7 (95% CI: 0.9 to 7.5). A retrospective cohort study using the Mayo Clinic Jacksonville patient database between 1993 and 2003 confirms the positive Nurse’s Health Study findings (OR: 2.2, 95% CI: 1.9 to 2.6) of an association between hormone replacement therapy use and meningioma risk,13 whereas a case-control study including 219 meningioma cases identified from three Chicago area hospitals between 1987 and 1992 reports a protective effect for oral contraceptive use (OR: 0.2, 95% CI: 0.0 to 0.8) and a nonstatistically significant protective effect associated with hormone replacement therapy use.15 Hence, at present, there is limited statistical evidence of an increased risk of meningioma among users of oral contraceptives. Although not definitive, available data suggest an association between the use of hormone replacement therapy and increased meningioma risk. Further evaluation of exogenous hormone use in women with meningioma in a large sample is needed, with particular attention to stratification by hormone (i.e., estrogen and/or progesterone) composition, duration of and age at use, and tumor receptor subtype.

Researchers have also reported conflicting results when examining meningioma risk across categories of pregnancy, menstrual, and anthropometric variables.4,12–17 In the Nurse’s Health Study,14 when examining age at first menstrual period, investigators observed a relative risk of 1.29 (95% CI: 0.86 to 1.92) for meningioma in women with age at menarche between 12 to 14 years, and 1.97 (95% CI: 1.06 to 3.66) in women with age at menarche after 14 years when compared with those women with menarche before the age of 12 years. The group also observed a tendency for increased risk of meningioma for parous compared with nonparous women [relative risk (RR): 2.39, 95% CI: 0.76 to 7.53), although this value is not statistically significant. In a second nested case-control study, Lambe et al17 examined 1088 patients with meningioma within the Swedish Cancer Registry and matched to data from the Swedish Fertility Registry. This group found no association between either parity or age at first birth and meningioma risk; however, they were not able to adjust their analyses for other possible meningioma risk factors such as use of exogenous hormones or radiation history. Data from the Interphone Study suggest that meningioma risk among women aged < 50 years is increased with increasing number of live births (OR: 1.8; 95% CI: 1.1 to 2.8 for three vs no live births) but found no association with menopausal status.16 The Million Women Cohort reported an increasing risk of meningioma with increasing body mass index (OR: 1.46, 95% CI: 1.11 to 1.91) but no association with number of pregnancies or age at first birth.12 An additional case-control study,15 which included 219 women, found a protective effect for pregnancy, which increased with the number of pregnancies and age at first pregnancy. Neither age at menarche or menopause was reported to show any effect in unadjusted analyses, although menopause showed an increased risk (OR: 2.0, 95% CI: 1.0 to 4.0) in adjusted analyses. As this review makes evident, the associations between pregnancy and menstrual risk factors and meningioma risk are not consistent and deserve a more formal examination.