Neurochirurgie 64 (2018) 5–14

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Meningiomas/Les méningiomes

Epidemiology of meningiomas
Épidémiologie des méningiomes
I. Baldi a , J. Engelhardt b , C. Bonnet b , L. Bauchet c , E. Berteaud a , A. Grüber a , H. Loiseau b,∗
a
Laboratoire santé travail et environnement, université de Bordeaux 2, hôpital Pellegrin„ place Amélie Raba-Léon, 33076 Bordeaux cedex, France
b
Service de neurochirurgie, université de Bordeaux 2, hôpital Pellegrin„ place Amélie-Raba-Léon, 33076 Bordeaux cedex, France
c
Service de neurochirurgie et French Brain Tumor DataBase, hôpital Gui-de-Chauliac, CHU de Montpellier, 80, avenue Augustin-Fliche, 34295 Montpellier
cedex 5, France

a r t i c l e i n f o a b s t r a c t

Article history: Although they represent about a third of all the tumors of the central nervous system, knowledge con-
Received 19 February 2014 cerning meningioma epidemiology (including incidence data and exploration of the risk factors) remains
Received in revised form 15 May 2014 scarce compared to that of gliomas. A limited number of cancer registries worldwide only record malig-
Accepted 24 July 2014
nant brain tumors, however their completeness and accuracy have been questioned. Even if comparisons
Available online 22 September 2014
are made difficult due to differences in methodologies, available annual incidence rates (sex- and age-
standardized, generally on US or World standard population), provided by population-based registries
Keywords:
range from 1.3/100,000 to 7.8/100,000 for cerebral meningiomas. An increase in the incidence of primary
Brain tumors
Meningioma
brain tumors in general and of meningiomas in particular has been observed during the past decades in
Epidemiology several countries. It has been suggested that this trend could be artefactual and could be the resultant
Risk factor of an ageing population, improvement in health access and in diagnostic procedures, changes in coding
Incidence classification for tumors recorded in registries, and/or an increase in the rate of histological confirmation,
Registry even in the elderly. All these factors are likely to play a role but they might not fully explain the increase
in incidence, observed in most age groups. In addition to intrinsic risk factors (gender, ethnic groups,
allergic conditions, familial and personal history, genetic polymorphisms), some exogenous risk factors
have been suspected to play a role in the etiology of meningiomas and their changes with time is likely to
impact incidence trends. A causal link has been established only for ionising radiation but the role of many
other factors have been hypothesised: electromagnetic fields, nutrition, pesticides, hormonal as well as
reproductive factors. Considering the serious or even lethal potentiality of some meningiomas and the
apparent rise in their incidence, all practitioners involved in neuro-oncology should feel concerned today
of the necessity to better assess their public health burden and to study their epidemiological features.
© 2014 Elsevier Masson SAS. All rights reserved.

r é s u m é

Mots clés : Bien que représentant plus d’un tiers des tumeurs primitives du système nerveux central (SNC), les
Tumeur cérébrale données épidémiologiques concernant les méningiomes (chiffres d’incidence et facteurs de causalité)
Méningiomes demeurent réduites comparativement à celles disponibles dans les gliomes. Un nombre limité de reg-
Épidémiologie istres de cancers, à travers le monde, enregistrent non seulement les tumeurs malignes mais aussi les
Facteurs de risque
méningiomes. Leur pertinence et la qualité du recueil ont été l’objet de discussions importantes. Même
Incidence
si les comparaisons sont difficiles à cause des différences méthodologiques, les données disponibles,
Registre
d’incidence annuelles des méningiomes (standardisée selon le sexe et l’âge en utilisant soit la popula-
tion Nord-Américaine, soit la population mondiale) sont compris entre 1,3/100 000 et 7,8/100 000. Une
augmentation de l’incidence des tumeurs primitives du SNC, en général, et des méningiomes, en par-
ticulier, a été observée au cours des dernières décennies dans plusieurs pays. Il a été suggéré que ces
tendances pouvaient être artéfactuelles et seraient la ou les résultantes de tout ou partie du vieillisse-
ment de la population, de l’amélioration non seulement de son accès mais aussi de la qualité de l’imagerie
diagnostique, et des modifications des prises en charge chirurgicale y compris chez les sujets les plus âgés

∗ Corresponding author.
E-mail address: hugues.loiseau@chu-bordeaux.fr (H. Loiseau).

https://doi.org/10.1016/j.neuchi.2014.05.006
0028-3770/© 2014 Elsevier Masson SAS. All rights reserved.
6 I. Baldi et al. / Neurochirurgie 64 (2018) 5–14

induisant une augmentation des confirmations histologiques et, enfin, des modifications des classifi-
cations histologiques. Tous ces facteurs ont un rôle indéniable, mais ne permettent pas d’expliquer
l’augmentation de l’incidence qui a été observée, pour les méningiomes, dans toutes les tranches d’âge.
Au-delà des facteurs intrinsèques (groupes ethniques, sexe, terrain allergique, antécédents personnels et
familiaux, polymorphismes et syndromes de prédisposition génétiques), un certain nombre de facteurs
extrinsèques sont suspectés de jouer un rôle dans la survenue des méningiomes, et leurs changements au
cours du temps est à même d’impacter les tendances en termes d’incidence. Une relation de causalité a été
définie seulement pour les radiations ionisantes mais l’impact de nombreux autres est suspecté: champs
électromagnétiques, facteurs nutritionnels, pesticides, traitements facteurs hormonaux. Dans la mesure
où, d’une part, les méningiomes représentent une menace fonctionnelle et/ou vitale, et que, d’autre part,
ils voient leur incidence augmenter, les différents acteurs de la communauté neuro-oncologique doivent
se sentir concernés par ces affections, non seulement au niveau de leurs prises en charge mais aussi par
les données épidémiologiques afférentes.
© 2014 Elsevier Masson SAS. Tous droits réservés.

1. Introduction care planning. Prevalence rate (e.g. the proportion of a popula-

Meningiomas arise from the arachnoid cap cells embedded in
the arachnoid villi, at any site, most commonly the skull vault and
the skull base, but they can also be located in the spinal cord.
Although they are very common tumors in the central nervous sys-
tem, data on their epidemiology, clinical characteristics, as well as
their therapeutic management remain poor compared to gliomas.
This can be explained to some extent by the benign and frequently
silent course of a large proportion of meningiomas. In fact, more
than 80% of them are graded I according to the World Health Orga-
nization (WHO) Classification. However, the serious or even lethal
potentiality of some meningiomas and the apparent rise in their
incidence should encourage further consideration.
The overall 5-years survival of meningiomas is less than 70%
[1,2] and it declines with patient age. For completely removed
benign meningiomas the 5-year rate of tumor recurrence is about
20% [2].
Currently surgery is essential to establish the diagnosis and
achieve the complete resection of the tumor in less than 50% of
the patients. Radiological presentation of meningiomas is often
very evocative. Under these conditions, a large number of patients
are treated with radiotherapy without histological confirmation.
However, it is very difficult to know the exact number.
The epidemiology of brain tumors include knowledge of their
incidence, explored through data from population registries, and
examination of their risk factors, obtained from observational stud-
ies. However, to date, findings remain globally inconclusive, partly
due to the low consideration given to the specific types of tumors.
Despite international recommandations for registering all types of
brain tumors in cancer registries, including benign tumors, the col-
lection of meningiomas remains incomplete in many surveillance
systems, so that data on meningioma incidence and their evolu-
tion is scarce at the international level. Moreover, studies have
reported an increase in the incidence over the past decades, which
remain unexplained. Furthermore, historically, case-control stud-
ies on brain tumors have frequently focused on gliomas, so that
even less is known about the etiology of meningiomas.
Completing previous studies [3–10], this article aims to review
data available on the epidemiology of meningiomas, which will
provide an insight into the incidence and risk factors of these
tumors.
tion affected by a disease at a given point in time, including new
patients and former patients who are survivors) is not routinely
available and has to be estimated by combining incidence, sur-
vival and population ageing. Depending on the uncertainties of
these parameters, prevalence rates for meningiomas are variable
and range from 50.4/100,000 [11] to 70.7/100,000 [12]. Including
nonmalignant tumors and especially meningiomas in prevalence
estimates is crucial because of their better prognosis, which impact
on the burden of the disease in the population and the health care
needs.
The main statistics allowing spatial and time-related compari-
son is the incidence (e.g., number of new brain tumors in a given
population, usually per 100,000 inhabitants and per year). Annual
incidence rates of meningiomas reported by some of the main
registries worldwide are summarized in Table 1. Available inci-
dence rates (sex- and age-standardized, generally on US or World
standard population) range from 1.28/100,000 to 7.80/100,000 for
cerebral meningiomas. They are the most common brain tumors
reported to the US Central Brain Tumor Registry in the United
States (CTBRUS) before gliomas (6,0/100,000). Data on spinal
meningiomas are scarce but the incidence rate is estimated to be
0.32/100,000 from the US registry [13].
Incidence rates evidence important variations with sex and
age, consistent between various studies [1,14]. The age and sex
pattern of meningioma incidence is illustrated in Fig. 1 from
the Central Nervous System Registry in Gironde, France for the
period 2000–2011. Female incidence is about three-fold the male
incidence, with the largest difference observed between 30 and
59 years (up to 3.6 fold). The rate increases progressively until
89 years of age and peaks at 22.2/100,000 between 75 and 89 years.
Shapes of the incidence curves are quite similar within the reg-
istries although some differences have been observed. Between
1973 and 1974 in the US, the overall incidence peaked earlier,
at 20/100 000 between 55 and 75 years [15]. Some registries have
recorded a continuous increase until 80 years of age with similar
peak incidence, but with a decrease beyond that age [16]. In England
[17] and Denmark [18] peak incidence is the half of that observed
in CNS registry in Gironde, while it is two-fold higher in the US
according to recent data [1].
2.2. Changes in incidence with time: magnitude and explanations

2. Descriptive epidemiology An increase in the incidence of primary brain tumors in gen-

2.1. Burden of meningiomas in populations
Prevalence and incidence are basic parameters used to describe
the burden of tumors in patient populations and to help in medical
eral has been observed over the past decades in several countries.
For gliomas, this increase was generally more pronounced in
the elderly population [19,20]. A limited number of cancer reg-
istries worldwide record not only malignant brain tumors but also
benign tumors such as meningiomas, and their completeness and
 I. Baldi et al. / Neurochirurgie 64 (2018) 5–14 7

Table 1
Worldwide annual incidence rates of meningioma according to population-based-registries (per 100 000 inhabitants).
Incidence annuelle des méningiomes–données des principaux registres mondiaux (pour 100 000 habitants).

Country Rochester Lothian Kumamoto Cbtrus United states Austria California Estonie England Gironde
Authors [15] [49] [16] [26] [1] [127] [29] [41] [36]

Age-ajusted population Local Local Japanese population US US US US World World Crude

Period of recruitement 1950–1989 1989–1990 1989–2008 1990–1994 2006–2010 2005 2001–2005 1986–1996 1995–2003 2000–2011
Number of cases 339 228 5448 20 765 326 711 1 688 24 293 1 665 54 336 1160
Population 70000 748,703 1,860,000 33,000,000 289,719,439 8,200,000 36,500,000 1,500,000 1,200,000
Ages All All All All All All All All <85 All
Histological confirmation 63% 78% 58.1% 86.9% 62.9% 80.9% 79% 80.8% 100% 61%
Histological classification WHO 1993 WHO 1993 WHO 1993 WHO 1993 WHO ICDO-3 WHO 1993 WHO 1993 WHO 2000 WHO 2000
Asymptomatic Included Included 60%
Autopsic studies Yes No Included No No
Spinal location Excluded Included Included Included
Annual incidence
Tumors of Meninges 3.00 2.76 7.71 5.31 4.5 1.38 6.99
Meningioma 7.80 2.70 4.97 2.63 7.44 5.23 1.63 1.28 6.52
Other mesenchymal 0.04 0.27 0.08 0.47
Benign and malignant

accuracy have been questioned [21–23]. Even fewer of them have
recorded data for an extensive time-period enabling researchers to
analyze temporal patterns. Therefore, trends for meningioma inci-
dence have been available since the 1940s to 1970s in the US, in
Scandinavian countries and in Japan and since the 1980s in some
other European countries and Australia. These data mainly concern
intracranial tumors. Only two studies have provided trends in inci-
dence data for spinal meningiomas, and showed a stability during
the period 1999–2007 in US [13] and during the period 1973–1982
in Sweden [24].
2.2.1. United States
In the United States, the first longitudinal data on meningiomas
came from Rochester, Minnesota, where benign tumors have
been registered together with brain malignant tumors since 1950.
Trends were described but no overall changes were observed in
meningioma incidence between 1950–1969 and 1970–1989 [15].
However, this apparent stable incidence might have resulted from
the combination of a decrease in patients diagnosed incidentally
at autopsy and an increase in asymptomatic patients diagnosed
using neuroimaging studies. Later, a pilot study compiled all benign
tumors diagnosed between 1984 and 1989 in four US registries
(Connecticut, Massachusetts, Missouri and Utah) with the aim of
assessing the feasibility of a central registry for all primary CNS
tumors [25]. This study demonstrated an increase in the incidence
rate of meningiomas between the period 1985–1989 and earlier
Connecticut data (1935–1964). It also initiated the formation of
the CBTRUS in 1992. CBTRUS was consequently first expanded to
11 state cancer registries [26]. Six of them (Connecticut, Delaware,
Idaho, Massachusetts, Montana, Utah) combined their data and,
from a 5282 meningioma collection, determined a 1.5% (95%CI:
0.9–2.1) average annual percent change (APC) on the 1985–1999
period [27,28]. This increase was observed for symptomatic as well
as for asymptomatic tumors and in all age groups.
Even if several US registries, including California from 2001
[29], voluntarily collected data on benign and uncertain behaviour
tumors, it is only since 2004, with the enactment of a federal
public law, that all state and metropolitan cancer registries were
required to collect non-malignant tumors. CBTRUS now obtains
incidence data from 50 population based cancer registries (includ-
ing five that participate in the Surveillance Epidemiology, and End
Results (SEER) program which has collected data on malignant
brain tumors across the US since 1973, for the earliest of them
[30]. The most recent data of CBTRUS estimated an increase in

Fig. 1. Gironde Registry. Incidence curves according to age and sex.

Registre de la Gironde. Répartition de l’incidence selon l’âge et le sexe.
8 I. Baldi et al. / Neurochirurgie 64 (2018) 5–14
meningioma incidence from 3.86/100,000 during the period
1995–1999 to 7.44/100,000 in 2006–2010 [1].
2.2.2. Scandinavian countries
The Danish Cancer registry provided data on meningiomas
as early as 1943 [18]. For the period 1943–1997 the incidence
of meningiomas in Denmark increased 3.9-fold (from 0.61 in
1943–1947 to 2.42/100,000 in 1993–1997) [18] and this increase
was observed for all age groups and both sexes for each calen-
dar period. The Norwegian Cancer registry also has information on
meningiomas dating back to 1951which showed a levelling off in
trends in the incidence of tumors of the meninges during the period
1970–1999 [31].
Combining data from the Danish, Finnish, Norwegian and Swed-
dish cancer registries, an increase in the incidence of meningiomas
was observed for the 1968–1997 period, more so for women
(2.6 to 4.5/100,000) than for men (1.4 to 1.9/100,000), in all age
groups [14]. This investigation was updated and extended for the
1974–2003 period and confirmed a positive APC in meningiomas in
20-79-year-old individuals, and more pronounced in women ([3.8%
after 1990, 95%CI: 3.2–4.4%] than in men [0.8% between 1974 and
2003, 95%CI: 0.4–1.3%]) [32].
2.2.3. Japan
Patients with brain tumors have been recorded since 1969 in the
Japan Brain Tumor Registry, based on the participation of a large
number of health institutions. Estimates at the national level have
been provided for the years 1973–1993 [33]. Time trend for menin-
giomas showed a gradual linear increase before the 1980s followed
by a plateau level. This increase in incidence for the 20-year period
was more pronounced in women (from 1 to 4.4/100,000) than in
men (from 0.9 to 1.3/100,000).
Additionally, repeated incidence surveys of primary CNS tumors
have been performed in the Kumamoto Prefecture in Southern
Japan since 1989 and demonstrated an increase in incidence.
Age-adjusted annual incidence increased from 2.76/100,000 (dur-
ing the period 1989–1994) and 4.97/100,000 (during the period
1989–2008) [16,34].
Curiously, in Osaka and during the recent 10-year period
1995–2004, the age-standardized incidence rates of meningioma
appeared to decrease significantly [35].
2.2.4. Other countries
In the United Kingdom, a network of eight population-based
regional registries that recorded malignant, benign and uncertain
behavior tumors during the 1979–2003 period enabled to estimate
time-trends for meningiomas at the national level in patients aged
0–84 years. The APC was 1.2 (95%CI: 1–1.5) between 25 and 64 years
of age and 2.9 (95%CI: 2.6–3.3) between 65 and 84 years of age
[36]. Curiously, during the period 1996–2008 The Health Improve-
ment Network UK primary care database recently recorded a stable
incidence of meningioma (5.3/100,000) [17].
In France, a population-based registry in Gironde (Bordeaux
area) recording all types of primary CNS tumors (malignant, benign,
uncertain behavior) showed an increase in meningioma incidence
during the 2000–2007 period, with a 5.4% APC, more pronounced
than for other brain tumors (95%CI: 1.1–9.8) [37].
In Italy, the Tuscan Cancer Registry (Florence and Prato region)
provided incidence data for primary CNS tumors during the period
1985–2005. An increased incidence was observed for benign brain
tumors (APC: +6.2, 95%CI 4.5–7.9), essentially represented by
meningiomas [38].
In Australia a significant increasing incidence was also observed
for meningioma between 2000 and 2008 (APC 1.9%, 95%CI 1.6–5.5),
more pronounced in men (APC 5.3%; 95%CI, 2.6–8.1) especially in
those aged 20–64 years (APC, 6.3; 95% CI, 3.8–8.8) than in women
(0.6, 95%CI 3.6–5,0 [39].
Most of incidence studies, generally based on hospital data,
developed in miscellaneous places such as the Varazdin County
in Croatia [40], Estonia [41], Taiwan [42], Eastern Germany [43]
observed a significant increase in incidence rate of meningiomas.
However, some countries did not observe this trend, like in Greece
[43] or in the Labin region in Croatia [44].
Some authors have suggested that the increase in the incidence
of CNS tumors in general and of meningioma in particular was
artefactual, and had to be interpreted as the result:
• ageing of the populations [45,46];
• improvement in health access and in diagnostic procedures, cor-
responding to the introduction of CT-scan during the 1970s and
MRI during the 1980s;
• changes in coding classification for tumors recorded in registries;
• increase in the rate of histological confirmation, even in the
elderly, because of the expansion of neurosurgical procedures in
the elderly.
The aging of the population seems to be an explanation for the
increase in incidence of glioma, which was observed to triple over
70 yrs [19,47], which is more plausible than for meningiomas where
the increase in incidence also concerns young patients [18].
Improvement in the access to imaging new technologies could
also partly explain the increase in meningiomas [48], in so far as
the period of increase is consistent with the dates of introduction of
CT-scan and MRI in the populations. This occurred in Japan [33] but
was questionable for the trends observed in Rochester, Minnesota
as they were observed as early as the 1960s and remained when
excluding patients diagnosed by chance in neuroimaging studies.
[15]. In the same way, an increase in the incidence should reach a
plateau level after the dramatic increase in the number of imaging
installations. However, in some studies such a plateau level was not
observed [3,18,28].
Changes in histological classifications (with the successive ver-
sions of the WHO classifications) that gradually led to adjustments
in some categories such as gliomas concern meningiomas only
marginally. However, it has been argued that registration proce-
dures have evolved with time, with an increase in the inclusion
of asymptomatic meningiomas (from 60% [16] to 380% [15]). How-
ever, excluding asymptomatic tumors did not change the increasing
trends in some registries [37].
The indication of surgical procedures has changed over time. As
more patients undergo surgery, the number of histological confir-
mations increases, which could also partly explain the increase in
incidence. However, this should have a minimal impact on menin-
giomas as their diagnosis based on radiological images is generally
highly reliable (e.g. cavernous sinus meningiomas).
2.3. Geographical variations in incidence
Large geographical variations have been observed in the inci-
dence of meningiomas provided by population-based registries:
from 1.28 to 7.8/100,000 (Table 1). Compiling data originating from
Western Europe, Israel and North America, Christensen et al. have
reported an incidence ranging from 0.6 to 7.8/100,000 [18]. Even
within comparable populations using similar recording procedures
like the Scandinavian countries, for the years 1968–1997, the inci-
dence of meningioma in Sweden appeared to be 50% higher than
that observed in the three other Scandinavian countries [14].
These geographical variations can be explained by several
factors:
 I. Baldi et al. / Neurochirurgie 64 (2018) 5–14
• differences in socio-economic characteristics within countries
influence the access to medical care, the availability of innova-
tive treatment procedures, the care of the elderly, the possibilities
of detecting asymptomatic tumors, and the autopsy rate. Public
health resources also impact the age structure of the population,
and the relative burden of the diseases;
• methodological issues concerning incidence calculation is a sec-
ond source of variations. Comparison within studies are made
difficult by variations in age-adjustments procedures: some
publications present crude incidence rates while others are stan-
dardized on national, US or world population. Variations in the
use of histological classifications, in the types of tumors recorded
(e.g. including or not spinal meningiomas), in the definition of
time periods, in the age groups considered (whether or not
excluding children or subjects over a given age threshold), in data
sources also impact the incidence calculation. Including asymp-
tomatic tumors, tumors discovered at autopsy are two additional
factors that make comparisons difficult. Indeed, histological con-
firmation is not always required for an appropriate health care
of patients with meningioma, especially when the radiographic
appearance is sufficiently evocative, or the patient too old for neu-
rosurgery and susceptible to be treated with radiotherapy. Thus,
the proportion of patients without histological confirmation is
ranging from 14% to 32% [27,28,33,34,41,49–51];
• incomplete recording of meningiomas is also a major factor of
geographical variation. Many publications have pointed to the
frequent underestimation of meningioma incidence in national
and regional cancer registries that routinely collect many types
of primary tumors [21,50]. In fact, many cancer registries do not
record benign tumors and this poses a particular problem for
CNS tumors as a significant proportion of them are pathologically
benign, such as many meningiomas [21,52]. In the Scandinavian
Cancer Registries, the proportion of benign tumors–including
meningioma- recorded is reported to be 98% [53] but this pro-
portion could be as low as 11% in the Estonian Cancer Registry
[41] and 50% in the Regional Cancer Intelligence Unit [51]. A pilot
study in the US demonstrated that incorporating benign tumors
in the SEER program would increase the incidence rate of brain
tumors from 6.5 to 9.6/100,000, e.g. an overall 49% increase (36%
for males and 68% for females) [25]. This situation has been under-
lined as early as the 1990s in the United States [22] and led to the
implementation of the CBTRUS system in the US and to interna-
tional recommendations for brain tumor registration [54,55].
It must additionally be mentioned that the procedures in cancer
registries tend to count patients and not tumors. So that recurrences
and second location of a meningioma in a same patient are not taken
into account.
3. Intrinsic risk factors
3.1. Sex
Across countries and populations, incidence of brain tumors
is consistently related to sex, with opposite patterns for menin-
giomas and gliomas. The female predominance of meningiomas
was identified by Harvey Cushing nearly a century ago and demon-
strated to appear after age 10 to 14 years (i.e. onset of menses)
and to decrease after menarch [45,56]. Incidence rates for menin-
giomas globally appear more than twice as greater in women as
compared to men. Thus, meningiomas are among the tumors with
the largest difference in incidence between men and women. This
difference suggests that sex hormones and/or genetic differences
between males and females may play a role in the occurrence of
these tumors.
9
3.2. Ethnic groups
Based on data from general cancer registries, between-country
or between-continent comparisons have been essentially per-
formed for malignant tumors. However, CBTRUS makes possible
comparisons for the various types of tumors between the vari-
ous ethnic groups living in the United States. Incidence rates for
most histological subtypes appear higher for whites than other
ethnic groups. In contrast, for meningiomas and tumors of the pitu-
itary, incidence rates for blacks significantly exceed those observed
for whites. The incidence of meningiomas ranges from 5.10 in
American Indian and Alaska Natives to 8.81/100,000 in Blacks [1].
Additionally, some studies observed a higher incidence of brain
meningioma in the Jewish population, with OR as high as 4.3 (95%CI
2.0 to 9.0) [57].
These differences between ethnic groups might result from
genetic, nutritional or environmental factors, but also possibly from
greater access to diagnostic facilities and medical care in some eth-
nic groups [58].
3.3. Rare inherited genetic syndromes and familial predisposition
Increased risk of meningioma is observed in some rare hered-
itary cancer syndromes, mainly neurofibromatosis type 1 and 2
[59]. Recently, Turner’s syndrome and Werner’s syndrome were
identified as a predisposing condition for meningioma (respec-
tively standardized incidence ratio -SIR = 12; 95%CI: 4.8–24.8 and
SIR = 36.2 95%CI: 17.3–55.7) [60,61]. It is not known how large a
fraction of adult brain cancers these syndromes account for [62],
but it has been estimated that 3% of patients with nervous-system
tumours have a first-degree relative with a CNS tumor, suggesting
the role of familial history [62–64]. Outside the context of the rare
cancer-prone families, an increased risk for primary brain tumors
among relatives of brain tumor patients, especially gliomas, was
suggested by Wrensch et al. more than 10 years ago [65] and has
since been proven statistically significant. The familial forms could
account for 5% of the cases [66]. Thus, international efforts are cur-
rently in progress to investigate brain tumors and try to identify
susceptibility alleles and explain familial aggregation and early-
onset pediatric cases.
Miscellaneous studies have associated the occurrence of menin-
giomas with the familial history of some cancers such as bladder
cancers [67], thyroid cancer, leukemia, breast cancer [68,69], and
melanoma. During the period 1958–1994 a significant increased
risk for developing meningioma was also observed in Sweden after
a personal history of colorectal cancer, (SIR 1.60, 95%CI; 1.32–1.94)
and after breast cancer (SIR 1.57, 95%CI 1.36–1.81) [70].
3.4. Allergy, auto-immune diseases, personal predisposition
The role of allergy in tumors in general remains controversial: on
one hand, those with a history of allergy may possess an enhanced
capacity for immune surveillance and limit abnormal cell prolifera-
tion, and on the other hand, the immune response may be related to
tumor development. Studies on gliomas have consistently reported
an inverse association with a history of allergy (atopic diseases
such as asthma, eczema, hay fever, food allergies etc.) but the
association with meningioma is less consistent. A meta-analysis
including six studies on meningiomas found no clear association
between allergy and meningioma [71]. A recent meta-analysis was
in line with this conclusion considering overall allergy but found
a decreased risk for eczema [72]. However, the most recent stud-
ies, exploring allergy [68,73,74], immunoglobolulin E [73], varicella
infection status, auto-immune diseases [75,76] points to potential
association between meningioma and immune function. The exist-
ence of a serologic antimeningioma response has been proposed
10 I. Baldi et al. / Neurochirurgie 64 (2018) 5–14
as an underlying mechanism, and would differ between men and
women. If confirmed, this phenomenon may affect gender-specific
incidence rates [77].
3.5. Genetic polymorphisms
Identification of individual genetic features liable to interact
with extrinsic factors constitutes an important research perspec-
tive. Genetic polymorphisms could play a role in several pathways
such as DNA repair, cell cycle, inflammation, angiogenesis and
subsequently leading to cell transformation. Several genes impli-
cated in DNA repair provide interesting hypotheses (mainly X-ray
repair cross-complementing group and excision repair cross-
complementing group). A three-fold increased risk of meningioma
was found for homozygous variant genotypes [78]. In a subgroup
of a tinea capitis cohort, a 1.7 increase was found [79].
Folate metabolism plays an important role in carcinogenesis
due to its involvement in DNA methylation and nucleotide syn-
thesis. To test that hypothesis polymorphic variation in the folate
metabolism genes were studied. Few diplotypes and reduced enzy-
matic activity were significantly associated with an increasing risk
ranging from 1.4 to 2.11 [80]. Similar results were found in northern
China [81].
Genes involved in DNA repair were studied. A 3.5 fold increase
in meningioma risk was found with the T variant of GLTSCR1 [82].
A 1.57 increased risk was observed in patients harbouring
polymorphism in breast cancer susceptibility gene1–interacting
protein 1, was consistently associated with an increased risk of
developing meningioma [83]. Approximately 28% of the European
population are carriers of such genotype [83].
Some genetic polymorphisms in innate immunity genes were
also thought to be associated with risk of meningioma. [84].
Involvement of the immune system was studied throughout the
human leukocyte antigen system. Few significant increased menin-
gioma risks, ranging from 1.8- to 2.5-fold, were found in patients
harbouring some haplotypes. Conversely other authors reported a
decreased risk of meningioma [85].
A very interesting development in the polymorphisms studied
was conducted by Inskip’s group. They demonstrated that a specific
polymorphism in the ␦-aminolevulinic acid dehydratase was asso-
ciated with a 1.6- to 3.5-fold increase in meningioma risk according
to gender [86]. Then, they matched the impact of lead exposure and
that polymorphism. Increased risk of meningioma was 12.8-fold
increased with occupational lead exposure [87]. The same group
found few results with some genes involved in oxidative stress
response [88]. Combining these results with lead exposure they
found a significant association [89].
Studies investigating the association between genetic polymor-
phisms of glutathione S-transferases and risk of meningioma have
reported conflicting results. Significant results were found in dif-
ferent variants with an increasing risk ranging from 1.95 to 3.6-fold
according to the variant [90,91].
The associations of variants genes involved in aromatic hydro-
carbon metabolism with the risk of brain tumor have been studied.
Few variants were associated with decreased risk of meningioma
[91].
Polymorphisms and haplotypes in p53 and ATM could also be
associated with meningioma risk. [66].
The over-representation of radiation-associated meningioma
(RAM) and other cancers in specific families provide support for
inherited genetic susceptibility to radiation-induced cancer [92].
Studying various haplotype associations, some authors concluded
that any underlying genetic susceptibility to RAM is likely to be
mediated through the co-inheritance of multiple risk alleles rather
than a single major gene locus determining radiosensitivity [93].
Additionally, it was demonstrated that neither NF2 mutations
nor mutations in the PTEN, TP53, HRAS, KRAS and NRAS genes play
a prominent role in the pathogenesis of radiation-induced com-
pared to sporadic meningiomas [94]. This raises the question of
a certain genetic susceptibility that led to the first cancer. How-
ever, an increased risk of occurrence has also been observed after
irradiation for other reasons.
Some negative results have been found with IGF polymorphic
variants [95], caspase-8 polymorphism D302H [96].
A new susceptibility locus for meningioma was recently iden-
tified at 10p12.31 (MLLT10, rs11012732, OR: 1.46, Pcombined = 1.88
× 10−14 ) [97].
Data regarding genetic polymorphisms have become abundant.
One can simply regret that these considerable studies do not try
to confirm what was previously published and identify a grow-
ing number of abnormalities to explain meningioma occurrence,
as other primary brain tumors. The general idea which consists
of taking into account the individual susceptibility together with
the environment is more than attractive, despite the complexity of
underlying statistical analyses.
4. Extrinsic risk factors
The role of some environmental factors have been suggested
from toxicological studies performed in animals which were
exposed to genotoxic or carcinogenic substances (oncoviruses,
nitrates) and from observational studies in human populations.
Although the literature appears abundant, the studies have
frequently focused on the etiology of malignant tumors and menin-
giomas remain relatively unexplored.
4.1. Electromagnetic radiation
4.1.1. Ionizing radiation
Ionizing radiation is to date the only established risk factor
for CNS tumors. The invention of X-ray machines to image body
structures and treat health conditions was rapidly followed by the
finding that they could harm tissue by breaking and rearranging the
genes, a process potentially inducing cancer. Thus, the concept of
radiation-induced tumors was proposed in 1948 by W. Cahan and
defined by the occurrence of new tumors in the irradiated area after
a period of five years and in the absence of other predisposing fac-
tor [98]. The literature relating long-term effects of irradiation on
neural tissue, including radiation-induced meningioma, has been
reviewed and has evidenced four main exposure situations from
high levels of radiation to lower doses exposures [99]:
• survivors from atomic bomb. More than 80,000 Hiroshima and
Nagasaki survivors and 27,000 non exposed people were included
in the Life Span cohort. The analysis demonstrated that a signifi-
cant dose-related excess (evidenced from 1 sievert dose) of brain
tumors occurred, especially schwannoma, but also meningioma,
glioma and other types of brain tumors, with higher risks for those
exposed during childhood [11,68,81,100,101];
• radiotherapy for tinea capitis of the scalp. Prior to the introduc-
tion of griseofulvin in 1960, the world standard for treatment
of tinea capitis was scalp irradiation. Several epidemiological
studies, including a cohort of 11,000 Israeli adults treated for
tinea capitis as children demonstrated the causal role of radia-
tion in the development of meningiomas in some patients. It was
assessed that 1–2 Gy administered during childhood led to a 9.5-
fold increase in meningioma incidence, with a mean latency of
about 36 years [92,102–104];
• cranial irradiations in children for oncologic purposes. Several
epidemiological studies have demonstrated that survivors of
 I. Baldi et al. / Neurochirurgie 64 (2018) 5–14
childhood cancer were at risk of subsequent CNS tumors after cra-
nial radiation. A systematic review of 14 cohort studies including
more than 150,000 childhood cancer survivors recently reported
that survivors of childhood cancer who received cranial radiation
therapy have an increased risk for subsequent CNS tumors [105].
Higher risks were reported for meningiomas than for gliomas.
For subsequent meningioma, the standardized incidence ratio
was calculated to range from 41.2 to 714.7. In the British Child-
hood Cancer Survivor Study, a higher relative risk of meningioma
appeared at exposure dose of 20 Gy [106] and in the North Ameri-
can Childhood Cancer Survivor Study, the risk peaked at exposure
doses of 30-44 Gy [107];
• dental X-ray exposure. A higher incidence of meningioma has also
been observed in individuals with a history of full-mouth den-
tal x-rays [108]. Therefore, it is suggested that exposure to some
dental X-rays performed in the past, when radiation exposure
was greater, is associated with an increased risk of intracranial
meningioma.
Other circumstances of irradiation have been less explored, like
the risk of developing treatment- induced meningiomas in adult
cancers treated by radiotherapy or chemotherapy [109], or the role
of other sources of radiation like cosmic radiation. This radiation
increases with higher elevations and has been suggested to be of
concern in the occurrence of brain tumors in aircrew members. To
date, studies on these populations remain inconclusive, as demon-
strated in a recent review of 65 studies [110].
4.1.2. Electromagnetic fields
The universal use of electricity and the rapid development of
associated technologies over the past decades have raised ques-
tions about the potential contribution of electromagnetic fields
in the development of brain tumors. Extremely low frequency
fields resulting from power lines have been differentiated from
radiofrequencies, including those generated by mobile phones, as
effects on cells, if any, could be subtended by different mecha-
nisms. Extremely low frequency fields and the electromagnetic
fields produced by mobile phones have been classified as possibly
carcinogenic to humans by the International Agency for Research
on Cancer (Class 2B). The recent and rapid increase in the use of
cell phones in the 1990s has stimulated epidemiological research
on the contribution of radiofrequencies to the development of brain
tumors. Two main streams of data have been identified: the “Hard-
ell group” studies performed in Sweden [111] and the international
“INTERPHONE group” studies [112]. While the first study concluded
for the possibility of elevated risks of developing ipsilateral astro-
cytoma and acoustic schwannoma, the data from the second group
did not support the same conclusion. The controversy is less active
with meningiomas than in other types of brain tumors and there is
a consensus that the evidence of an association between exposure
to electromagnetic field and meningioma remains limited to date,
both for EBF and RF. However, it is also admitted that the absence
of association might result from an observation period too short for
assessing the effects of long-term and highly frequent uses. Further
investigation is needed, also for meningiomas, which have been less
studied, to better assess risks associated with specific exposure cir-
cumstances such as highly frequent use, occupational exposures,
children exposure.
4.2. Nutrition and nitroso-compounds (NOC)
Some nitroso compounds (mainly represented in food by N-
nitrosamines and N-nitrosamides) have been classified as probable
human carcinogens by the International Agency for Research
on Cancer because of experimental results showing that N-
nitrosoureas can lead to the formation of ethylnitrosoureas in the
11
presence of nitrite and subsequently induce brain tumors in ani-
mals [113]. The question is whether the ingestion of these nitroso
compounds from dietary sources (smoked meats, types of water
treatment, etc.) or their endogenous formation in the stomach, and
other sources of exposures (smoking, occupational exposure, etc.)
could play a role in the development of meningiomas.
Concerning nutrition, positive associations have been repeat-
edly found between maternal intake of cured meat and pediatric
brain tumors [114]. However, results in adults are less conclu-
sive [115]. The inconsistency in the findings suggests the need for
studies with an accurate methodology for N-nitroso compounds
exposure assessment and accurate analysis by histological types.
Thus, to date, there is no evidence for an association between diet
and meningioma.
Well-designed studies that have explored the role of smoking on
brain neoplasm in humans are very few compared to other cancer
sites, and most of them have only considered gliomas. A systematic
review identified 7 case-control and 2 cohort studies and concluded
(despite one of the reports studied showing a strong positive asso-
ciation in China [116]) to an overall non-significant risk estimate
for developing a meningioma among ever smokers. However, inter-
estingly, an elevation in risk could be observed in men [117]. This
result was confirmed in a recent large case-control study in the US,
including 1433 intracranial meningioma [118]. Thus, the associa-
tion of smoking and meningioma appears to vary significantly by
gender, with men at greater risk. The potential antiestrogenic effect
of smoking could play a role in this complex relationship..
4.3. Pesticides
The role of pesticides in the risk of CNS tumors was first sug-
gested by studies on the mortality of farmers in the United States
and in Scandinavian countries. Indeed, farmers globally present a
lower risk of cancer than the general population, but a higher risk
for some specific cancer sites, including the CNS. This result was
consistent between studies and was confirmed in a meta-analysis
[119]. Based on 33 studies, a meta-analysis [120] calculated a 30%
statistically significant increase in the risk of brain tumors in farm-
ers (OR = 1.3, 95%CI: 1.09–1.56).
Some pesticides have been proven as carcinogens in animals,
and the use of insecticides in agriculture has been classified by the
International Agency for Cancer Research as probably carcinogenic
(2A) in humans. However, the multiplicity of substances (about
1000 molecules marketed since Second World War) and the small
number of studies precisely assessing exposures make the task
arduous. As for other risk factors, most studies have focused on
malignant brain tumors. Regarding meningiomas, a French study
did not find an increase in risk with occupational exposure to pes-
ticides, not even in analysis restricted to the most exposed subjects
[121]. Conversely, a significant increased risk of meningioma was
associated in women use herbicides in their occupation (OR = 2.4,
95%CI: 1.4–4.3) with a dose-effect relationship [122].
4.4. Hormonal factors
The possible role of hormones was first suggested by the inci-
dence of meningioma being twice as high in women as in men,
especially during the reproductive life period. Epidemiological
studies have also shown an association between meningioma and
breast cancer, uterine fibroids and endometrioses, diseases for
which the role of hormones is clearly demonstrated [68]. More-
over, case reports have shown exacerbation of symptoms due to the
progression of meningioma after the placement of a contraceptive
implant, during the luteal phase of the menstrual cycle and dur-
ing pregnancy. More recently, the decreased risk for never-smoker
women suggested that the antioestrogenic role of smoking could
12 I. Baldi et al. / Neurochirurgie 64 (2018) 5–14
play a role. In vitro studies have shown a proliferation of menin-
gioma cells when exposed to progesterone or estrogens together.
The hypothesis of the role of hormones has been reinforced by
the identification of hormonal receptors in tumor tissues: ∼ 80%
of meningiomas have progesterone receptors, 40% estrogen recep-
tors and 40% androgen receptors, and many other tumor types
also present hormonal receptors (chordoma, craniopharyngioma,
insulinoma, etc.) [123]. Yet, the role of these receptors remains
controversial as their functionality is not proven, and hormonal
therapies have proven ineffective.
Thus, some epidemiological studies have been conducted in
recent years to search for an association between sex hormones
and the occurrence of brain tumor. For meningioma, the most
consistent results concerned an increase in risk with hormonal
replacement treatment and menopause. The evidence for an asso-
ciation with oral contraceptives, number of children, breastfeeding
or age at menarche is limited [124]. In a recent case-control
study current use of oral contraceptives in premenopausal women
was significantly associated with meningioma risk but there was
limited evidence of an association between reproductive vari-
ables [125]. In another one, hormonal cancers and therapies were
not associated with meningioma in females but some risks were
observed in males who used androgen analogues or high-dose
cyproterone acetate [126].
5. Conclusion
An increase in the incidence of primary brain tumors in gen-
eral and of meningioma in particular has been observed in the past
decades in several countries. It has been suggested that this trend
could be artefactual and would be the resultant of ageing of the
populations, improvement in health access and in diagnostic pro-
cedures, changes in coding classification for tumors recorded in
registries, and/or increase in the rate of histological confirmation,
even in the elderly. All these factors are likely to play a role but
they might not fully explain the increase in incidence, observed
in most age groups. Beside intrinsic risk factors (gender, ethnic
groups, allergic conditions, familial and personal history, genetic
polymorphisms), some exogenous risk factors are suspected to play
a role in the etiology of meningioma and their changes with time
is likely to impact incidence trends. A causal link has been estab-
lished only for ionising radiations but the role of many other factors
have been hypothesised: electromagnetic fields, nutrition, pesti-
cides, hormonal and reproductive factors. Considering the serious
or even lethal potentiality of some meningiomas and the apparent
rise in their incidence, all practitioners involved in neuro-oncology
should feel today concerned by the necessity to better assess their
public health burden and to study their epidemiological features.
Disclosure of interest
The authors declare that they have no conflicts of interest con-
cerning this article.
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