MENINGIOMAS account for 30% of all primary brain tumor diagnoses in adults in the United States. The overall age-adjusted incidence rate is 4.52 per 100,000.9 Although age-adjusted incidence rates are reportedly similar across racial groups, the incidence in women is approximately twice that in men. The incidence increases with increasing age, peaking in the seventh and eighth decades of life; these tumors are very rare in children. The incidence of both diagnostically and nondiagnostically confirmed meningiomas increased between 1985 and 1999 potentially reflecting both the increased use of improved imaging techniques such as MR imaging and increased numbers of meningiomas treated with observation or primary radiotherapy rather than through surgical intervention. The vast majority of meningiomas are considered histologically benign (92.8%); only 2.2% are defined as uncertain or atypical, and 5% as malignant. Five-year survival rates are high for this tumor type (reported to be anywhere from 70 to 95%) and therefore the estimated population prevalence (number of individuals living with this tumor) is relatively high, 50.4 per 100,000.15 Long survival times coupled with potentially significant neurocognitive and physical deficits could lead to significant medical costs over time. The estimated average years of potential life lost in persons with meningiomas is 13 years, providing further evidence of the long-term burden of this disease.
Causes and Risk Factors
In addition to increasing age, the most consistent factor associated with risk of meningioma is exposure to ionizing radiation; many other environmental, lifestyle and genetic risk factors have been studied with inconclusive results. Some of the factors that have been studied are endogenous and exogenous hormone use, cell phone use, and genetic variants or polymorphisms. Other risk factors have included preexisting conditions (such as diabetes, hypertension, and epilepsy), occupational lead exposure, personal hair dye use,5 radio frequency/microwave electromagnetic field exposure, cigarette smoking, head trauma and allergies. For most of these factors, either no significant association or inconsistent associations with meningioma risk have been reported. Many of these studies have had small sample sizes, short follow-up times, and differences in eligibility criteria and exposure measurement, making reproducibility across studies difficult.
The strongest evidence to date for an increased risk of meningioma is exposure to ionizing radiation. Studies of ionizing radiation have focused on the tinea capitis cohort in Israel, atomic bomb survivors, and patients with exposures in medical and occupational settings (diagnostic or therapeutic radiation).The strongest evidence for high-dose radiation exposure in the development of meningiomas comes from individuals who underwent therapeutic radiation treatment to the head or neck for neoplastic conditions. The strongest evidence for low-dose radiation exposure comes from the tinea capitis cohort studies.Studies of meningioma risk in atomic bomb survivors who received moderate to high doses of radiation—depending on their distance from the hypocenter of the bomb explosion— are less consistent,as is evidence from diagnostic radiation exposure from dental x-ray studies. The latency periods for meningiomas arising after radiation show a trend towards diminishing latency period with increasing radiation dose; 35.2 years for low-dose (, 10 Gy), 26.1 for moderate dose (10–20 Gy), and 19.5 years for high-dose (. 20 Gy).
Given the predominance of meningiomas in women compared with men, the presence of hormone expression in some tumors, the possibility of an association with breast cancer, as well as reported changes in tumor size during pregnancy, the menstrual cycle, and menopause, the authors of a number of studies have focused on the relationship between hormones and meningioma risk. In studies of exogenous hormone exposure, researchers have looked at the risk of meningioma associated with the use of oral contraceptives and HRT in both pre- and postmenopausal women. Overall, the data currently reveal no evidence for an association between oral contraceptive use and meningioma risk but do suggest a possible association with the use of HRT.Wigertz and colleagues found a significantly increased risk of meningiomas in postmenopausal women in Sweden who had ever used HRT, confirming earlier findings
by Jhawar and colleagues within the Nurses Health Study. It should be noted that despite these reports, not all studies have supported an association between HRT use and meningiomas. Larger studies that examine the relationship between exogenous hormone use and meningioma risk by hormone receptor subtype and by hormone composition (opposed compared with unopposed estrogen, for example) using a larger patient cohort are needed. In the studies of endogenous hormone exposure, researchers have looked at the risk of meningioma associated with menopausal status, parity, ever having been pregnant, and age at menarche. Multiple studies have also investigated the presence of various hormone receptors (estrogen, progesterone, and or androgen) in meningiomas to try to explain the female predominance of this tumor.The majority of benign meningiomas express the progesterone receptor (~ 60– 90%),37,45,59,86 whereas most meningiomas do not express estrogen and androgen receptors. Multiple studies have shown the prognostic significance of the presence of progesterone receptors for recurrence status and recurrencefree and progression-free survival. How the expression of these hormone receptors in these tumors would translate into better therapeutic treatments for meningiomas remains unclear; the results from studies of antiestrogen and antiprogesterone agents have been equivocal. One study of tamoxifen (an antiestrogen therapy) as a chemotherapy for meningiomas, was too inconclusive to enable a definite recommendation about its use in this patient population.
Cell Phone Use
Although public interest in the topic remains high, to date little evidence exists to suggest an association between cell phone use and the risk of meningioma. Multiple studies have been performed in United States, European, and Israeli populations including the Interphone case–control study of cell phones and brain tumor risk. None of these studies found a significant association between cell phone use and meningioma risk. However, inconsistent findings have been reported for an increased risk of acoustic neuroma, some types of high-grade gliomasand long-term cell phone usage (.10 years). Follow-up time in the majority of these studies is relatively short and measurements of cell phone exposure vary between studies, therefore further long-term study of cell phone exposure may be warranted.
The majority of meningiomas are sporadic tumors; patients with sporadic lesions have no family history of any kind of brain tumor. Known inherited genetic syndromes that predispose to meningioma development are few and rare. Meningioma is observed in patients with NF2, a rare autosomal dominant disorder caused by germline mutations in the NF2 gene on 22q12 (US incidence: 1 per 30,000–40,000 persons).However, there are probably many genes other than NF2 involved in familial meningioma. Excess familial risk of meningioma has been reported in Swedish families without any evidence of NF2 in whom there was a significant association between meningioma diagnosis and parental history of a meningioma (standardized incidence ratio. In addition, in the tinea capitis cohort from Israel, the patients with meningiomas who had received radiation were more likely than those who did not to have family members affected with radiation-induced cancers, highlighting a potential inherited genetic susceptibility. Interestingly, approximately 50% of all sporadic meningiomas are also believed to harbor mutations in the NF2 gene or genetic losses that include the 22q12 chromosomal band. Additionally, sporadic meningiomas reveal a host of other
chromosomal losses (1p, 6q, 10, 14q, and 18q) and gains (1q, 9q, 12q, 15q, 17q, and 20q), many associated with tumor grade. A number of researchers have examined the relationship between specific genetic variants and meningioma risk, focusing on genes involved in DNA repair, cell cycle regulation, detoxification, and hormone metabolic pathways. The majority of these studies have focused on variants in the GST and CYP450 genes, which are genes involved in metabolism and detoxification of exogenous and endogenous carcinogens. Results from these six studies were generally consistent, finding few significant associations with variants in these genes and an increased risk of meningioma. Authors of three of these studies found a significantly increased risk of meningioma associated with having the GSTT1 null genotype compared to those with the GSTT1 positive genotype (~ 1.5 to 3.5- fold increased risk). In one of these studies a significant increased risk for meningioma was found to be associated with having the GSTM3 *B/*B genotype. The remaining two studies found no significant associations between meningioma risk and variants at various GST or CYP450 genes. The remaining three studies focused on the most wellknown tumor suppressor gene, TP53, and on DNA repair and cell cycle control genes.Malmer et al. studied three variants in TP53 and found that overall there was no associated increased risk of meningioma for any of the individual variants or for combinations of these variants.