Epidemiology and = etiology of meningioma

Received:=20 1 July 2010 Accepted:=20 24 August 2010 Published online:=20 7 September 2010

Keywords Meningioma - = Epidemiology - Etiology - Risk=20 factor - Ionizing radiation - Hormones

Epidemiologic research on meningioma

Compared to the malignant glial tumors, meningiomas = are=20 relatively understudied with regards to etiologic risk factors. The = challenges=20 to meningioma research are several: (i) as a relatively rare disease, = large or=20 multicenter studies are necessary for sufficient numbers; (ii) the long = latency=20 of meningioma of 20=9630 years or more, exhibited most evidentially = in=20 studies with known doses of ionizing radiation [1],=20 makes exposure ascertainment difficult due to recall bias; (iii) the = prevalence=20 of subclinical disease in up to 2.8% of the population, as suggested by = autopsy=20 studies [2,=20 3],=20 indicates that the pool of susceptible persons are much larger than = those with=20 clinically confirmed diagnoses; and (iv) the problem of detection = bias=97many=20 meningiomas are discovered incidentally via MRIs for conditions such as = head=20 trauma or sinus problems. These incidentally discovered meningiomas, and = a=20 significant portion of primarily discovered meningiomas are managed=20 =93conservatively,=94 meaning by observation and not surgical removal. = One way=20 epidemiologists can minimize detection bias is to only ascertain cases = who have=20 undergone surgical removal and pathological confirmation, ensuring that = cases=20 have clinically-significant meningioma. Only a few epidemiologic studies = of=20 intracranial tumors to date have been adequately powered to study = separately=20 risk factors for meningioma. These include the large European cohorts = such as=20 the Interphone [4],=20 and the Million Women Study in the United Kingdom [5].=20 Several large European country- or region-specific case=96control = studies were=20 spawned from the Interphone study [6=968].=20 In 2002, The Benign Brain Tumor Cancer Registries Amendment Act (H.R. = 5204) was=20 passed, mandating registration of benign brain tumors such as meningioma = in the=20 United States. This legislation has and will continue to enhance = reporting of=20 both incidence rates and survival times for patients with meningioma. = Before=20 this act, meningioma mortality rate estimates were hampered by = incomplete=20 reporting and potential selection biases with respect to the individuals = who=20 were included in the databases, as well as limited follow-up = information. The=20 better quality of new information affords exceptional opportunities to = the=20 research and clinical communities in the coming years.

Population statistics

The prevalence of pathologically-confirmed = meningioma is=20 estimated to be approximately 97.5/100,000 in the United States with = over=20 170,000 individuals currently diagnosed with this tumor [9].=20 Since a proportion of meningiomas are not surgically managed, these = estimates=20 are low. In addition, autopsy and imaging studies have estimated = subclinical=20 meningioma rates of up to 2.8% in women [2,=20 3].=20 Data from the Central Brain Tumor Registry of the United States (CBTRUS) = demonstrates a more than twofold higher incidence among females = [age-adjusted=20 incidence rate (per 100,000 person years) of 8.36 and 3.61 for females = and=20 males, respectively] [9].=20 The female:male ratio of approximately 2:1 may be inverted for rare = pre-pubertal=20 meningiomas [10,=20 11].=20 Atypical and malignant meningiomas comprise a small fraction of the = total (~5%)=20 and have a slight male predominance. Reported rates for Black = Non-Hispanics are=20 slightly higher (6.67) than for White Non-Hispanic and Hispanics (5.90 = and 5.94,=20 respectively) [9].=20 Age-specific incidence rates (Fig. 1)=20 reveal increasing risk with age in both men and women. Increasing risk = of=20 meningioma over the past several decades noted in CBTRUS [9]=20 may be an artifact of increasingly accurate reporting of this disease.=20

Fig. 1 Age and=20 gender-specific incidence rates (per 100,000 population) for meningioma = in the=20 United States (2002=962006) (from reference 4). The left Y-axis = scale=20 refers to the bar graphs. The ratio of female to male incidence = is=20 indicated by a diamond at each age group, and the axis for the = ratio is=20 along the right hand side of the figure. The peak ratio of 3.15,=20 female:male, is among the 35=9644 year age group

Molecular etiology

Meningioma cells exhibit a striking similarity to = arachnoid cap=20 cells, which are the likely tumor cell of origin. Despite the fact that=20 meningioma has a benign pathophysiology in 95% of cases, like carcinoma = it=20 always results from a clonal outgrowth derived from a single cell as = exemplified=20 by cytogenetic and array-comparative genomic hybridization (array-CGH) = studies=20 [12,=20 13].=20 Sporadic meningiomas are typically associated with one or more focal = chromosomal=20 deletion(s), and atypical and malignant grades tend to have multiple = chromosomal=20 copy number alterations consistent with the acquisition of =93mutator=94 = mutations=20 which foster genomic instability [14].=20 Deletion and inactivation of NF2 on chromosome 22 is a = predominant=20 feature in sporadic meningiomas, and biallelic deletions are common = [13].=20 Additional genes are likely involved as well, since loss of NF2 = occurs in=20 only 1/3 of patients who exhibit loss of heterozygosity of chromosome 22 = [15].=20 Additional genomic regions which are recurrently lost in meningiomas = include=20 14q, 1p, 6q, and 18q [16].=20 Although in one study, familial meningiomas did not demonstrate = inherited copy=20 number alterations, such families typically have a germline defect in = NF2=20 or other predispositing mutations [14].=20 Indeed, meningiomas are reported in families of several cancer = predisposition=20 syndromes including those involving the genes NF1, PTCH,=20 CREBBP, VHL, PTEN, and CDKN2A (reviewed in = [17]).=20 Epigenetic aberrations in meningioma have not been thoroughly assessed, = but one=20 study suggests that DNA methylation events may impact meningioma biology = more=20 significantly than DNA copy number mutations [18].=20 Clearly, complexity of genetic aberrations in meningioma increases with = tumor=20 grade [19].=20 A relatively small number of mutations may be necessary for most = meningiomas;=20 however their slow growth makes long latency an issue, lending = difficulty in=20 identifying the source and timing of the initiating mutations, = presenting a=20 further complication for epidemiology studies.

Risk factors

Ionizing radiation

At present, the primary environmental risk factor = identified for=20 meningioma is exposure to ionizing radiation (IR) with risks from six = fold to=20 ten fold reported [20=9623].=20 At high dose levels, data exist for atomic bomb survivors showing a = greatly=20 increased risk for meningioma [21].=20 Evidence also exists for lower dose levels. In one of the most = well-known=20 studies of ionizing radiation and meningioma risk, children who were = given=20 radiation therapy for scalp ringworm in Israel between 1948 and 1960 = (the Tinea=20 Capitis Cohort), were observed to have a relative risk of almost 10 for=20 meningioma [24].=20 A number of studies have linked the number of full-mouth dental = radiographs to=20 risk of meningioma (reviewed in [25])=20 although the sample sizes are limited and some subsequent studies (also = small in=20 size) did not replicate earlier studies [26,=20 27].=20 However, the most recent case/control study of 200 meningioma patients = reported=20 that patients reporting full-mouth X-rays had a significantly increased = risk of=20 meningioma (OR 2.06, 95% CI 1.03, 4.17) although evidence for a dose = response=20 relation was lacking (P for trend =3D 0.33) [28].=20 Radiation therapy for intra-cranial tumors has also been linked to = meningioma=20 risk [22].=20 No recent large-scale studies of meningioma risk relative to ionizing = radiation=20 exist. Such studies are still highly relevant in the current era in = which X-ray=20 doses for dental and other procedures have decreased, since new = radiographic=20 procedures with significant exposure risks have been introduced, = including=20 computed tomography (CT).

Hormones

An association between hormones and meningioma risk = has been=20 suggested by a number of findings including the increased incidence of=20 post-pubertal disease in women versus men (2:1) with the highest ratio = of 3.15:1=20 during the peak reproductive years (Fig. 1),=20 the presence of estrogen, progesterone, and androgen receptors on some=20 meningiomas, an association between breast cancer and meningiomas (see = below),=20 indications that meningiomas change in size during the luteal phase of = the=20 menstrual cycle and pregnancy, and the regression of multiple = meningiomas in a=20 patient following cessation of estrogen agonist therapy [29,=20 30].=20 Despite these sentinel clues, meningioma is far from exhibiting a = =93hormone-fed=94=20 character in the clinic and epidemiologic measures of endogenous and = exogenous=20 hormones are not consistently associated with meningioma incidence.

Researchers have only begun to address the question of = whether=20 the use of exogenous hormones such as oral contraceptives (OC) and/or = hormone=20 replacement therapy (HRT) is associated with an increased risk of = meningioma=20 [5,=20 29,=20 31=9635].=20 Data from two cohort studies and several case/control studies exist. In = a=20 case/control study nested within the Nurse=92s Health Study (NHS) = (including 125=20 cases of meningioma), the relative risk of meningioma associated with = hormone=20 use for pre-menopausal women was 2.48 (95% CI 1.29, 4.77) when compared = with=20 postmenopausal women who had never used hormones [34].=20 For postmenopausal women who were hormone users the relative risk was = 1.86 (95%=20 CI 1.07, 3.24). No excess risk was associated with past hormone use. No=20 association was found for past or current use of oral contraceptives. = Recently=20 published data from a cohort study of 1.3 million women with a mean age = of 55.9=20 and recruited from 1996 to 2001 (The Million Women Study) did not find = an=20 association between OC use (OR 1.06, 95% CI 0.81=961.38 for use within = the past=20 five years) and meningioma risk (n =3D 390) but did not = report=20 results for HRT use [5].=20 In a large and recent case/control study, the Interphone Group reported = an=20 increased relative risk of meningioma (n =3D 178) among = postmenopausal women for ever-use of HRT (OR 1.7, 95% CI 1.0=962.8) = [35].=20 Women who had used long-acting hormonal contraceptives also had an = increased=20 risk of meningioma; the odds ratio for at least 10 years of use was = 2.7=20 (95% CI 0.9=967.5). A retrospective records-based cohort study using the = Mayo=20 Clinic Jacksonville patient database between 1993 and 2003 confirms the = positive=20 NHS findings (OR 2.2, 95% CI 1.9=962.6) of an association between HRT = use and=20 meningioma risk, comparing the frequency of HRT use among a case = population of=20 1,390 with over 350,000 other women in the health system [31],=20 while a case/control study including 219 meningioma cases identified = from three=20 Chicago area hospitals between 1987 and 1992 reports a protective effect = for=20 oral contraceptive use (OR 0.2, 95% CI 0.0=960.8) and a = non-statistically=20 significant protective effect associated with HRT use [32].=20 This latter study used the spouses of men with back pain as controls. = Hence at=20 present, there is limited statistical evidence of an increased risk of=20 meningioma among users of oral contraceptives. Although not definitive,=20 available data suggest an association between the use of hormone = replacement=20 therapy and increased meningioma risk. Further evaluation of exogenous = hormone=20 use in women with meningioma in a larger study is needed with particular = attention to stratification by hormone composition (i.e. estrogen and/or = progesterone), duration of and age at use as well as meningioma = subgroups=20 defined by tumor receptor expression (see below).

Researchers have also reported conflicting results = when=20 examining meningioma risk across categories of pregnancy, menstrual and=20 anthropometric variables [5,=20 29,=20 31=9636].=20 When examining age at first menstrual period, investigators in the = Nurse=92s=20 Health Study observed a relative risk for meningioma for women with age = at=20 menarche 12=9614 years of 1.29 (95% CI 0.86=961.92) and for women = with age at=20 menarche after 14 years a relative risk of 1.97 (95% CI = 1.06=963.66) compared=20 to those with menarche before age 12 [34].=20 A tendency for increased risk of meningioma for parous compared to = non-parous=20 women (RR =3D 2.39, 95% CI 0.76=967.53) was also observed, = although this=20 value was not statistically significant [34].=20 In a second nested case/control study, Lambe et al. examined 1088 = patients with meningioma within the Swedish Cancer Registry and matched = to data=20 from the Swedish Fertility Registry [36].=20 This group found no association between either parity or age at first = birth and=20 meningioma risk, however their analyses were not adjusted for other = possible=20 meningioma risk factors such as use of exogenous hormones or radiation = exposure=20 history. Data from the Interphone Study suggest that meningioma risk = among women=20 aged <50 years is increased with increasing number of = livebirths=20 (OR 1.8, 95% CI 1.1=962.8 for three versus no livebirths) but found no = association=20 with menopausal status [35].=20 The Million Women Cohort reported an increasing risk of meningioma with=20 increasing body mass index (OR 1.46, 95% CI 1.11=961.91) but no = association with=20 number of pregnancies or age at first birth [5].=20 Body mass index, or more specifically body fat, is positively associated = with=20 aromatase activity resulting in higher endogenous estrogen exposure. An=20 additional case/control study which included 219 cases found a = protective effect=20 for pregnancy which increased with number of pregnancies and age at = first=20 pregnancy [32].=20 Neither age at menarche or menopause were reported to show any effect in = unadjusted analyses although menopause showed an increased risk (OR 2.0, = 95% CI=20 1.0=964.0) in adjusted analyses. In summary, the association between = traditional=20 hormone-based pregnancy and menstrual risk factors and meningioma risk = is not=20 consistent and deserve a more formal examination. Such an examination = requires=20 precise exposure assessments as well as an incorporation of a more = thorough=20 examination of biological features of individual patients data, = including the=20 expression of hormone receptors as described below, which may reveal = subtypes=20 with more clear evidence of hormone associations.

The functional significance of hormone receptors = expressed on=20 meningiomas is still controversial. Hormone receptors (estrogen, = progesterone,=20 and androgen) are expressed in an equivalent proportion of meningiomas = derived=20 from men and women [37],=20 but their assessment has only been performed once in an epidemiologic = study=20 [38],=20 and different laboratory methods for receptor expression capture widely = varying=20 proportions of positive patients [39=9641].=20 A pilot study of 31 meningioma samples reported that a specific gene = expression=20 pattern appeared more strongly associated with PR status than with ER = status=20 [42].=20 Genes on the long arm of chromosome 22 and near the NF2 gene = (22q12) were=20 most frequently noted to have expression variation, with significant=20 up-regulation in PR positive versus PR negative lesions = suggesting a=20 higher rate of 22q loss in PR negative lesions. Pathway analyses = indicated that=20 genes in collagen and extracellular matrix pathways were most likely to = be=20 differentially expressed by PR status [42].=20 The future incorporation of receptor expression into epidemiology = studies may=20 revolutionize the field as various molecular markers have done for = cancers, for=20 example hormone receptors in breast cancer. The field first needs to = harmonize=20 methodology to classify hormone receptors so that different studies can = be=20 compared and contrasted.

Head trauma

Head trauma has been suggested as a risk factor for = meningioma=20 since the time of Harvey Cushing, although the results across studies = are not=20 consistent. While some small case/control studies report an increased = risk of=20 meningioma associated with head trauma for both males and females = [43,=20 44],=20 other studies report no such association [45,=20 46].=20 In a cohort study of 228,055 Danish residents hospitalized for = concussion, skull=20 fracture or other head injury between 1977 and 1992 and followed for an = average=20 of eight years, the standardized incidence ratio (SIR) for meningioma = after the=20 first year was 1.2 (95%CI 0.8, 1.7) [47].=20 As mentioned above, associations of head trauma and meningioma may be an = example=20 of detection bias.

Cell phone use

The question of whether cell phone use is related to = meningioma=20 risk remains a question of great interest to the general public. At = least ten=20 studies have examined the association between cell phone use and tumors = of the=20 brain. At present, little evidence exists for an association between the = two=20 although sample sizes specific to meningiomas are relatively small, the=20 follow-up time since commencement of cell-phone use is relatively short, = and, in=20 some instances, the measurement of cell-phone use is somewhat crude = [48=9650].=20 Newly reported data from the large Interphone study may also suffer some = reporting bias; this study replicated earlier negative findings even for = the=20 highest exposed groups (>10 years of heavy exposure) [4].=20 If the latency times of 17=9636 years observed in ionizing = radiation studies=20 on the epidemiology of meningioma [24,=20 51]=20 are taken as a guideline, the true extent of any possible relationship = between=20 cell phone use and meningioma risk may not be uncovered for decades and=20 therefore this topic deserves continued attention.

Association with breast cancer

An association between breast cancer and meningioma = has been=20 examined in several studies [29,=20 52,=20 53].=20 A number of explanations have been proposed for this association = including the=20 presence of common risk factors such as endogenous and exogenous = hormones as=20 well as shared genetic predisposition, including variants in DNA repair=20 polymorphisms [52].=20 A review of the literature as well as an analysis of the association = between=20 breast cancer and meningioma using the western Washington State cancer = registry=20 data was provided by Custer et al. [53].=20 The relative risks observed across existing studies range between 1.5 = and 2.0=20 with the majority statistically significant. Most of these studies have = been=20 conducted with tumor registry data and have relatively small sample = sizes and=20 none have been able to examine the association while controlling for = risk=20 factors which are likely to be shared by the two tumors, such as = pregnancy and=20 menstrual variables and exogenous hormone use. The fact that studies = which=20 identify risk of breast cancer in women who had meningioma, and vice = versa, both=20 have similar magnitude increased risk suggests that there is not a = causal=20 relationship between these tumors, rather that they share the same risk = factors=20 such as gender, age, hormone induction, and possibly other demographic = variables=20 [53].=20

Occupation/diet/allergy

Attempts to link specific chemicals with meningiomas = in=20 occupationally or industrially exposed groups have proved inconclusive = (reviewed=20 in [54]).=20 An international case/control study found no association between diet = and=20 meningioma (n =3D 332) [55].=20 Although a number of studies which examine the relationship between = glial brain=20 tumors and allergic disease such as asthma and eczema have found = evidence for an=20 association, little evidence has been found for such an association for=20 meningioma [6,=20 8,=20 56].=20 A meta-analysis however demonstrated a significant inverse relationship = of=20 meningioma with allergy when excluding the single study that was most=20 heterogeneous from the others (pooled RR =3D 0.84, 95% = CI=20 0.72=960.98, P =3D 0.029) [57],=20 and a large recent study showed consistent inverse risk with asthma, = hayfever,=20 and eczema [7].=20 A study of innate immune genes did not find strong evidence of risk = imparted by=20 variants in such genes, but more investigation is warranted [58].=20

Family history of meningioma

Few studies have examined the relationship between = meningioma=20 risk and family history of meningioma. Malmer et al. examined cancer = risk in=20 spouses and first degree relatives of brain tumor patients in Sweden and = reported that a meningioma diagnosis conferred a two fold increase in = meningioma=20 risk to first degree relatives (standardized incidence ratio [SIR] 2.2, = 95% CI=20 1.4, 3.1) but not to spouses of affected individuals [59].=20 An inverse association between risk and age at onset was observed with = an SIR of=20 2.5 (95% CI 1.5=964.0) for probands less than 50 years of age = versus 1.3 (95%=20 CI 0.6=962.6) for probands older than 50 years of age. Similar = analyses by=20 Hemminki et al. using data from the Swedish and Norweigian = Registry=20 Databases, reveal an increased risk with increasing numbers of affected = first=20 degree relatives with persons having one or two first degree family = members with=20 meningioma (SIR 1.6, 95% CI 1.3=9642.0, and SIR 5.0, 95% CI 0.9=9614.8), = respectively [60].=20 Despite the fact that up to one to three percent of the adult population = may=20 harbor a meningioma [2,=20 3],=20 the total number of families with multiple members diagnosed with = meningioma are=20 relatively rare (indicating, in part, a wide spectrum of phenotypic = expression=20 with respect to clinical import and hence screening undertaken), and = most such=20 families are currently attributed to inherited NF2 mutations. At = present=20 no family based linkage or segregation analyses studies of meningioma = have been=20 reported.

Molecular epidemiology

In the most recent and largest study to date of = genetic=20 polymorphisms and meningioma risk, Interphone study investigators = reported a=20 statistically significant association with meningioma for 12 SNPs drawn = from DNA=20 repair genes [52].=20 These investigators examined 1,127 tagging SNPs selected to capture most = of the=20 common variation in 136 DNA repair genes as well as an additional 388 = putative=20 functional SNPs. These included 69 nonsynonymous coding SNPs that may = identify=20 functional changes in expressed proteins. A total of 631 cases and 637 = controls=20 drawn from five case/control series from the Interphone Study were = genotyped.=20 The Interphone study is a case/control project initially designed to = examine the=20 relationship between cell phone use and the risk of brain tumors, = including=20 meningioma. Study subjects are primarily Western European background. = The group=20 reported a novel and biologically intriguing association between = meningioma risk=20 and three variants in the gene that encodes breast cancer susceptibility = gene=20 1-interacting protein 1 (BRIP1) (17q22). The most significant was = SNP=20 rs4968451 that maps to intron 4 of the gene (OR 1.61, 95% CI 1.26=962.06 = heterozygotes, OR 2.33, 95% CI 1.25=964.34 homozygotes). The = BRIP1 gene is=20 involved in the repair of DNA double-strand breaks by homologous = recombination=20 in a manner that depends on its association with BRCA1. Defects = in=20 BRIP1 are linked to breast cancer susceptibility (as well as = Fanconi=20 anemia), leading researchers to speculate that the reported association = between=20 breast cancer and meningioma risk may be due to similar defects in DNA = repair=20 genes rather than/in addition to the previously assumed shared hormonal = risk=20 factors (such as hormone replacement therapy). This group also reported = a=20 statistically significant association between four variants in the = ATM=20 gene, a member of the phosphatidylinositol-3 kinase family known to be = involved=20 in homologous and non-homologous DNA break repair, and meningioma risk. = Previous=20 groups have also noted significant associations between ATM = variants for=20 meningioma as well as breast cancer [23,=20 61].=20 These findings are again of interest in light of the associations = between=20 ionizing radiation and meningioma risk as well as between breast cancer = and=20 meningioma risk.

Additional candidate genes studies have suggested a = role for=20 genes in apoptotic pathways [62],=20 and as discussed above, immune regulatory pathways [58]=20 and meningioma risk. Earlier studies examined variants in phase II = metabolic=20 genes, which would impact response to environmental or occupational = chemical=20 exposures; a meta-analysis of these studies implicates a potential role = for the=20 detoxifying enzyme GSTT1 in modulating meningioma risk=20 (OR =3D 1.95, 95% CI 1.02=963.79) [63].=20 The lack of replication/confirmation and low number of variants assessed = in=20 candidate genes studies distracts from knowledge on the true genetic=20 susceptibility of meningioma, which awaits results from agnostic = genome-wide=20 association studies.

Directions for future studies

Because of its =93benign=94 nature, research in = meningioma=20 epidemiology and etiology has lagged behind that for more malignant = intracranial=20 neoplasms. The study of risk factors for meningioma remains challenging, = and=20 there are currently few large-scale studies. The two main known risk=20 factors=97genetic predisposition and high dose radiation = exposures=97account for a=20 small proportion of cases. Although a role for hormones is possible = given the=20 gender distribution of meningiomas, little specific or consistent data = exist on=20 hormonal risk factors. Epidemiologic tools may be used to collect and = define=20 appropriate subject data from well-characterized source populations, = being=20 mindful of detection or diagnostic bias in patient ascertainment, in an = effort=20 to delineate risk factors both for the overall group of meningioma = patients as=20 well as for specific subgroups. High quality follow-up data for = sufficient time=20 periods must be collected on meningioma patients to obtain = representative=20 estimates of sex- and age-specific rates for recurrence, quality of life = and=20 overall survival. In addition to the collection of data on environmental = risk=20 factors such as hormone use, new projects will need to consider the = inclusion of=20 information on relevant genetic variants derived from ongoing whole = genome and=20 gene pathway scans. In addition to exploring environmental and genetic = factors=20 for meningioma risk separately, the interaction between the two must be=20 examined. For example, the integration of environmental risk factors = such as=20 oral contraceptive use or radiation exposure with information on genetic = polymorphisms in steroid hormone or DNA repair genes may help = researchers to=20 understand the complex relationship between genetic susceptibility and=20 environmental exposures in the development of meningioma. Given the = large=20 numbers of subjects needed to study such gene-environment interactions,=20 especially within defined subsets of meningioma such as the rare = atypical and=20 malignant subtypes, collaborative, multi-center efforts between a = variety of=20 researchers will be needed, including experts from such fields as = neurosurgery,=20 epidemiology, genetics, statistics, and neuropathology.

Meningioma epidemiology and etiology will benefit from = the=20 increased size and quality of disease reporting to cancer registries,=20 facilitated in the USA by the Benign Brain Tumors Act of 2002. This act = has=20 resulted in the formation of a multicenter meningioma consortium, which = is=20 matched by several large studies in Europe. These studies will = facilitate a=20 rapid and thorough investigation into the genetic susceptibility factors = for=20 meningioma via genome-wide association and whole genome sequencing in = the near=20 future. The collection of blood and tumor material must accompany such = studies=20 to facilitate the rational classification of the disease into etiologic = subtypes=20 to further specify genetic, immunologic, and environmental risk factors. = Exposure assessments will continue to hinder progress in meningioma = case=96control=20 studies, which are hampered by information bias because of poor or = differential=20 recall by study subjects, and the lack of verifiable biomarkers of = exposure=20 since information is obtained in retrospect. Future large cohort studies = may=20 help to ameliorate this problem, and large linked health databases may = help=20 study iatrogenic risk factors such as diagnostic and therapeutic = ionizing=20 radiation, and therapeutic hormone use.

Acknowledgments This work was supported by NIH R01 grants CA109745, = CA109468,=20 CA109461, CA108473, CA109475, CA52689, CA097257, the Brain Science = Foundation,=20 and the Meningioma Mommas.

Open=20 Access =20

This article is distributed under the terms of the = Creative=20 Commons Attribution Noncommercial License which permits any = noncommercial use,=20 distribution, and reproduction in any medium, provided the original = author(s)=20 and source are credited.

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Invited Review

References