Journal of Neuropathology and Experimental Neurology Vol. 63, No.

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Copyright q 2004 by the American Association of Neuropathologists April, 2004
pp. 275 286

Meningioma Pathology, Genetics, and Biology

KATRIN LAMSZUS, MD

Abstract. Over the past 5 to 10 years, important advances were made in the understanding of meningioma biology. Progress
in molecular genetics probably represents the most important accomplishment in the comprehensive knowledge of meningioma
pathogenesis. Several genes could be identified as targets for mutation or inactivation. Additional chromosomal regions were
found to be commonly deleted or amplified, suggesting the presence of further tumor suppressor genes or proto-oncogenes,
respectively, in these regions. Histopathologically, the most important innovation is represented by the revised WHO classi-
fication in the year 2000. Meningioma grading criteria in the new classification scheme are more precise and objective, and
should thus improve consistency in predicting tumor recurrence and aggressive behavior. This review focuses mainly on the
advances in molecular biology that were achieved in recent years. It summarizes the most important aspects of meningioma
classification as the basis to place biological observations into a correlative context, and, further, includes mechanisms of
angiogenesis and edema formation as well as the role of hormone receptors in meningiomas.

Key Words: Angiogenesis; Classification; Edema; Meningioma; Neurofibromatosis; Progesterone.

INTRODUCTION attention, although, more recently, progress has some-

Meningiomas have long been a subject of intense ge-
netic and biological interest. They were among the first
solid neoplasms studied using cytogenetic techniques.
Frequent monosomy of chromosome 22 in meningiomas
was reported as early as 1972 (1). Cytogenetically, me-
ningioma has meanwhile become one of the best-studied
neoplasms in humans. Over the past decade, advanced
techniques such as automated sequencing, microsatellite
analysis, fluorescence in situ hybridization (FISH), or
comparative genomic hybridization (CGH) have further
facilitated rapid identification of alterations at the molec-
ular genetic level.
For the first time, the revised WHO classification of
2000 includes genetic findings in addition to pathological
and immunohistochemical features. For glial tumors, ge-
netic alterations meanwhile have even become clinically
relevant, insofar as deletions on chromosome arms 1p
and 19q have been found associated with responsiveness
to chemotherapy and therapeutic outcome of oligoden-
droglial tumors. For meningiomas, none of the typical
genetic aberrations have yet attained clinical relevance.
However, the comprehensive analysis of these aberrations
in relation to histological grade has led to a model in
which early alterations that are presumably involved in
meningioma formation could be distinguished from later
alterations that are associated with tumor progression (2).
In addition to genetic alterations, other biological fea-
tures of meningiomas have also been investigated. Since
the late 1970s, hormone receptors have received great
From Department of Neurosurgery, University Hospital Hamburg-
Eppendorf, Hamburg, Germany.
Correspondence to: Katrin Lamszus, MD, Laboratory for Brain Tu-
mor Biology, Department of Neurosurgery, University Hospital Ham-
burg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. E-mail:
lamszus@uke.uni-hamburg.de
what stagnated as receptor expression profiles are now
relatively well characterized and therapeutic efforts tar-
geting these receptors have so far been largely disap-
pointing. Another field that has attracted interest, espe-
cially since the advancement of imaging techniques in
the 1990s, are mechanisms of edema formation. These
appear to be closely related to tumor angioarchitecture,
and a variety of growth factors have since been analyzed
for their contribution to edema formation and meningi-
oma angiogenesis.
The purpose of this review is to outline (i) important
aspects of meningioma classification and grading, (ii)
common gene and chromosome alterations that form the
basis for a tumor progression model, (iii) the current sta-
tus in hormone receptor research, and (iv) mechanisms
of edema formation and angiogenesis.
CLINICOPATHOLOGICAL ASPECTS
Incidence and Etiology
Meningiomas are composed of neoplastic meningothe-
lial (arachnoidal cap) cells. They constitute approximate-
ly 20% of all primary intracranial tumors, with an ap-
proximate annual incidence of 6 per 100,000 (2). The
peak incidence is between the sixth and seventh decades
of life. Particularly among middle-aged patients, menin-
giomas are significantly more frequent in woman than in
men with a greater than 2:1 ratio. The majority of me-
ningiomas are attached to the dura mater and arise within
the intracranial cavity, the spinal canal, or, rarely, the or-
bit. Some meningiomas, especially those of the sphenoid
wing, may arise primarily as intraosseous tumors. Ap-
proximately 40% of meningioma patients suffer from sei-
zures; other clinical symptoms depend upon the location
of the tumor.
Several endogenous and exogenous factors predispose
to meningioma development (2). The majority of patients

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who suffer from neurofibromatosis type 2 (NF2) develop
meningiomas. In addition, families with an increased sus-
ceptibility to meningiomas but without NF2 have been
reported. The clearest exogenous association exists for
ionizing radiation, after which meningiomas develop with
an average latency period of several decades. In addition,
sex hormones have been implicated, mainly due to the
overrepresentation of females among meningioma pa-
tients.
Classification and Prognosis
The most important factors that determine the likeli-
hood of meningioma recurrence are extent of tumor re-
section and histological grade. Extent of resection is still
classified according to a scheme proposed by Simpson in
1957, ranging from grade 1 (complete resection) to grade
5 (decompression only) (3). The histopathological me-
ningioma classification received special attention by the
working group that devised the 2000 WHO classification,
and several substantial changes were introduced (4).
These changes are mainly based on a series of studies
from the Mayo Clinic in which histopathological param-
eters were correlated with clinical prognostic parameters
(5, 6). Whereas the previous WHO classification that
dates back to 1993 had ill-defined borders between be-
nign, atypical, and anaplastic meningiomas, grading cri-
teria are now much more stringent and objective.
The majority of meningiomas (80%–90%) are benign
and classified as WHO grade I (MI) (2, 5). A variety of
histopathological subtypes fall into this category, includ-
ing meningothelial, fibrous, and transitional meningiomas
as the most common variants. Less common subtypes are
psammomatous, angiomatous, microcystic, secretory,
lymphoplasmacyte-rich, and metaplastic meningioma. MI
carry a relatively low risk of recurrence (7%–20%) and
of aggressive behavior. Occasional mitoses and pleomor-
phic nuclei are tolerable features within MI. However, the
location in which these tumors arise has a critical impact
on prognosis. Whereas tumors of the convexity are usu-
ally cured by surgical resection, skull base tumors often
have an unfavorable outcome. In particular, meningiomas
that arise in the petroclival region or involve the cavern-
ous sinus or orbit often display slow but relentless
growth, leading to widespread invasion and destruction
of bony structures. These tumors may either remain his-
tologically benign over many years or they may eventu-
ally progress towards a higher grade.
Between 5% and 15% of meningiomas are classified
as atypical, corresponding to WHO grade II (MII) (2, 5).
Diagnostic criteria for atypical meningiomas are either
increased mitotic activity (defined as $4 mitoses/10 high-
power fields of 0.16 mm2) or 3 or more of the following
features: increased cellularity, small cells with high nu-
cleus to cytoplasm ratio, prominent nucleoli, uninterrupt-
ed patternless or sheet-like growth, and necroses. These
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LAMSZUS
criteria correlate with higher recurrence rates (30%–
40%). In addition to tumors that fulfill the criteria for
atypia, chordoid and clear cell meningiomas are also as-
sociated with a high rate of recurrence and aggressive
behavior and are therefore also classified as WHO grade
II.
Anaplastic (malignant) meningiomas, WHO grade III
(MIII) are rare (1%–3% of meningiomas) (2). They dis-
play histological features of frank malignancy far in ex-
cess of the abnormalities present in atypical meningio-
mas. Such features comprise either obviously malignant
cytology (e.g. resemblance to sarcoma, carcinoma, or
melanoma) or high mitotic indices ($20 mitoses/10 high-
power fields). The rare variants of papillary or rhabdoid
meningioma are also classified as WHO grade III due to
their highly aggressive behavior. Malignant meningiomas
have recurrence rates of 50% to 80%, and are usually
fatal within less than 2 years following diagnosis.
Notably, neither brain invasion nor proliferation indi-
ces (e.g. MIB-1 labeling) have been incorporated into the
current WHO grading criteria. Brain invasive meningio-
mas have a higher chance of recurrence and behave like
atypical meningiomas; therefore, some authors prefer to
assign them to WHO grade II (5, 7). However, brain in-
vasion is considered a feature more pertinent to staging
than to malignancy grade, and molecular genetic inves-
tigations have failed to reveal alterations characteristic of
high-grade meningiomas in MI with brain invasion (4).
In addition, proliferation indices were not included into
the grading criteria; due to high interinstitutional and in-
terindividual variations, reliable cut-off levels for differ-
ent grades cannot be defined. Nevertheless, brain inva-
sion as well as proliferation indices provide valuable
additional prognostic information. Therefore, the WHO
working group recommended adding phrases such as
‘‘with brain invasion’’ or ‘‘with high proliferative activ-
ity’’ to the diagnosis if appropriate (4).
Despite the incorporation of genetic and immunohis-
tochemical findings, meningioma classification is still
based entirely on conventional histological criteria. Im-
munohistochemistry mainly has a role in differential di-
agnosis, for example, when distinguishing meningioma
from hemangiopericytoma or other mesenchymal tumors.
Genetic analyses have also made important contributions
to differential diagnostics, for example, when recognizing
hemangiopericytoma as an entity distinct from meningi-
oma (8); however, they currently have no role in routine
meningioma diagnosis. The present WHO classification,
with its more stringent criteria, should provide an im-
proved framework for genetic studies and foster their
comparability, which, hopefully, will lead to even more
refined combined histologic-genetic models.
Many of the genetic studies that are reviewed in the
next sections were performed on the basis of the 1993
WHO classification. It should be kept in mind that the
 MENINGIOMAS
reported findings may require some adjustment according
to the current classification.
GENETICS
NF2 Gene
Mutations in the NF2 tumor suppressor gene, located
in the chromosomal region 22q12.2, represent the most
frequent gene alteration in meningiomas. Early cytoge-
netic studies had already found monosomy of chromo-
some 22 in up to 70% of meningiomas (for review see
Collins et al [9]). This observation correlated well with
subsequent molecular genetic studies that identified loss
of heterozygosity (LOH) at polymorphic markers on 22q
as the most common molecular genetic alteration, present
in 40% to 70% of all meningiomas (10, 11). Mutations
in the NF2 gene were detected in up to 60% of sporadic
meningiomas and are typically associated with LOH 22q
(12–14).
Most NF2 mutations have a truncating effect, indicat-
ing that inactivation of the NF2 gene product merlin
(schwannomin) is functionally important for meningioma
pathogenesis. Absent or strongly reduced immunoreactiv-
ity for merlin was found in the majority of meningiomas
(15–17), and was strongly associated with LOH 22q (14).
Merlin belongs to the 4.1 family of structural proteins
that link the cytoskeleton to proteins of the cytoplasmic
membrane (18). The mechanism by which merlin exerts
a tumor suppressive activity is still poorly understood.
The disruption of the signaling cascade that leads to cy-
toskeletal reorganization is considered to be critical to
tumor formation. Overexpression of merlin in both NF2-
negative and NF2-positive human meningioma cells sig-
nificantly inhibited their proliferation in vitro, which pro-
vides further evidence for a role of merlin as a negative
regulator of tumor growth (19).
Molecular genetic as well as protein studies showed
that the frequency of NF2/merlin alterations differs
among the 3 most common benign meningioma variants.
Whereas fibroblastic and transitional meningiomas harbor
NF2 mutations in approximately 70% to 80% of cases,
meningothelial meningiomas carry mutations in only
25% (13). A close correlation between the fibroblastic
variant and LOH 22q was also found (20). Correspond-
ingly, reduced merlin expression was observed in the ma-
jority of fibroblastic and transitional meningiomas, but
rarely in meningothelial tumors (15, 17). The low fre-
quency of NF2 alterations in the meningothelial variant
suggests that the genetic origin of these tumors is largely
independent of NF2 gene alterations. Moreover, the sim-
ilar frequency of NF2 mutations in atypical and anaplas-
tic as well as in benign fibroblastic and transitional me-
ningiomas suggests that NF2 mutations are not involved
in progression to higher-grade meningiomas. Rather, NF2
mutations appear to represent an early alteration that is
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Fig. 1. Hypothetic model of genomic alterations associated
with the formation of benign meningiomas and progression to-
wards atypia and anaplasia. Only those alterations that were
found in more than 30% of tumors of a specific grade in the
majority of studies (see text) are listed as contributing to the
development of a particular grade (arrow). Alterations that in-
crease in frequency by at least another 20% (averaged over
several studies) in tumors of the next higher histological grade,
despite already contributing to the previous grade, are listed
again.
involved in the formation of most benign meningiomas
(Fig. 1).
In some meningiomas no NF2 mutation or LOH 22q
could be detected despite a lack of merlin. An alternative
mechanism that involves merlin degradation by the pro-
tease m-calpain was proposed to account for this phenom-
enon (21). Different studies demonstrated activation of
m-calpain in more than 50% of meningiomas, although
no association between activation of m-calpain and merlin
status could be established (14, 17). Instead, concordance
of LOH 22q and merlin loss suggested that other mech-
anisms, such as homozygous deletions or methylation as
well as undetected NF2 mutations, may account for the
loss of merlin (14).
Meningiomas in NF2 Patients
Most patients who suffer from NF2 develop meningi-
omas. NF2-associated meningiomas differ from sporadic
ones in several respects: (i) they usually arise several de-
cades earlier in life, (ii) they are frequently multiple, and
(iii) they belong more often to the fibroblastic variant
(22). NF2-associated meningiomas exhibit deletions on
chromosome arm 22q in almost 100% of cases, a fre-
quency that is significantly higher than in sporadic me-
ningiomas (7, 23). Additional genetic alterations such as
deletions on 1p, 6q, 9p, 10q, 14q, and 18q occur at sim-
ilar frequency as in sporadic cases (23).
Most investigations found that the frequency of atyp-
ical or malignant meningiomas was not increased among
NF2-associated tumors (23–25). The MIB-1 labeling in-
dex in NF-2-associated meningiomas appeared to be
J Neuropathol Exp Neurol, Vol 63, April, 2004
 278
slightly higher in 1 study (25), but a more detailed anal-
ysis of a larger number of samples revealed no difference
compared with sporadic meningiomas (23). In a recent
study, NF2-associated meningiomas together with pedi-
atric meningiomas were found to contain a higher per-
centage of WHO grade II and grade III tumors than spo-
radic cases (7). However, the feature of brain
invasiveness in an otherwise benign tumor was consid-
ered equivalent to WHO grade II. The experience in our
institution is that NF2 patients rarely develop malignant
meningiomas and that mortality in these patients is usu-
ally due to other causes.
Multiple and Recurrent Meningiomas
Multiple meningiomas are independently arising and
spatially separate tumors. They are observed in 1% to
8% of meningioma patients. Multiple meningiomas are
particularly common in NF2 patients and also in rare
non-NF2 families with a hereditary meningioma predis-
position. Several studies investigated whether multiple
meningiomas represent metastatic meningeal seeding of
1 tumor or de novo formation of separate tumors. Iden-
tical NF2 mutations and patterns of X-chromosome in-
activation revealed that the majority of multiple as well
as recurrent meningiomas are of clonal origin, so that
multiplicity most likely represents subarachnoid spread
(26–29). Alternatively, NF2 mosaicism could underlie
some cases. NF2 mutations and clonal origin were more
frequently found in patients with a larger number of tu-
mors than in patients with only 2 tumors, which is com-
patible with either mosaicism or with an increased ability
of liquorigenic seeding caused by a mutant NF2 gene.
A recent study focused specifically on differences be-
tween multiple meningiomas in sporadic versus familial
non-NF2 cases (30). All NF2 mutations that were de-
tected occurred in tumors from patients with no affected
relatives, suggesting that the NF2 inactivation is frequent-
ly involved in multiple sporadic meningiomas but is rare
in multiple meningioma kindreds. In agreement with this
observation, linkage analysis of a family with multiple
meningiomas showed no segregation with the NF2 locus
(31). In another multiple meningioma kindred, immuno-
reactivity for merlin was detected, implying that the NF2
gene was not inactivated (32). Interestingly, most non-
NF2 meningioma family members develop meningothe-
lial meningiomas, which is in line with the observation
that this variant seems to arise independently of NF2 in-
activation.
Other Genes on Chromosome 22
Several studies suggested that other tumor suppressor
genes may lie outside the NF2 region on the long arm of
chromosome 22. The frequency of LOH 22 exceeds that
of NF2 mutations in meningiomas, and deletion mapping
revealed interstitial deletions on 22q that did not include
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LAMSZUS
the NF2 locus in some tumors (20). Furthermore, a recent
case report described monosomy for chromosome 22 but
lack of NF2 mutation in multiple meningiomas from a
single patient (33).
Several candidate tumor suppressor genes on 22q were
cloned in recent years, and some were screened for mu-
tations and/or altered expression levels in meningiomas.
Three of these genes map to the 22q12.2 region in rela-
tively close proximity to the NF2 gene, namely ADTB1
(b-adaptin, BAM22), RRP22, and GAR22. The ADTB1
gene was cloned based on a 140-kb homozygous deletion
in a sporadic meningioma. Expression analysis showed
that 12% of sporadic meningiomas lacked ADTB1 tran-
scripts. However, no mutations could be identified in 110
sporadic meningiomas, suggesting epigenetic mecha-
nisms of gene inactivation (34). Similarly, no RRP22 or
GAR22 mutations were detected in 12 meningiomas, of
which half displayed LOH in the 22q12-q22 region, al-
though none exhibited NF2 mutations (35).
Several other candidate genes map outside the 22q12.2
region. The MN1 gene is located at the 22q12.1 segment.
MN1 was found to be disrupted by a translocation in a
meningioma (36), however, subsequent studies demon-
strated that it acts as an oncogenic transcription coacti-
vator rather than a tumor suppressor.
The hSNF5/INI1 (SMARCB1) gene, which maps to
22q11.23, is frequently mutated in atypical teratoid/rhab-
doid tumors. In 1 study, an identical missense mutation
in the hSNF5/INI1 gene was identified in 4 of 126 me-
ningiomas analyzed (37). Three of these 4 tumors also
contained NF2 mutations, suggesting that loss of hSNF5/
INI1 function does not represent an alternative mecha-
nism to NF2 inactivation in the pathogenesis of menin-
giomas, but that silencing of hSNF5/INI1 may co-operate
with impairment of NF2 function.
Expression of the CLTCL1/CLH-22 gene, which maps
to 22q11.21, was found to be absent in 80% (37 of 46)
meningiomas analyzed, suggesting that this gene may
also be relevant to tumor development (38). Among tu-
mors with absent gene expression were cases with and
without chromosome 22 deletions. However, mutations
of CLTCL1/CLH-22 have not been reported and the
mechanism of its loss of expression is unclear.
The LARGE gene maps distally to the NF2 region
(22q12.3), and represents another interesting candidate
gene (39). However, it is one of the largest human genes,
and mutation or expression analyses have not been pub-
lished.
DAL-1 Gene and Other Alterations on Chromosome 18
The DAL-1 protein shares significant homology with
merlin and also belongs to the 4.1 family of membrane-
associated proteins. It has tumor suppressor properties
and maps to chromosomal region 18p11.3. Recent im-
munohistochemical studies showed that DAL-1 expres-
sion is lost in 76% of sporadic meningiomas, a frequency
 MENINGIOMAS
similar to that detected for loss of merlin (40, 41). Lack
of DAL-1 protein was only slightly, and not significantly,
more frequent in anaplastic meningiomas (87%) than in
benign and atypical meningiomas (70%–76%), suggest-
ing that it represents an early event in meningioma tu-
morigenesis (41). These immunohistochemical findings
were largely reflected at the mRNA expression level. Al-
though LOH at 18p11.3 was detected in 71% of inves-
tigated cases (40), the mechanism of DAL-1 inactivation
is still unresolved. Mutations were not detected, but
screening had not included the full gene (40). Given the
frequent LOH at the DAL-1 gene location, homozygous
deletions are unlikely, so that epigenetic alterations re-
main a more likely possibility.
Combined loss of DAL-1 and merlin was detected in
58% of investigated cases (41), suggesting that both are
not part of a single growth regulatory pathway in which
inactivation of either member causes the same effect. A
tendency for more frequent combined DAL-1 and merlin
loss was observed in anaplastic meningiomas (70%)
compared to atypical (60%) and benign (50%) ones, sug-
gesting that although both alterations are considered early
changes, simultaneous loss of both proteins may provide
a selective growth advantage (41).
Cytogenetic and CGH analyses have failed to recog-
nize 18p11.3 as a region of frequent chromosomal losses.
Microsatellite analysis revealed that deletions in this re-
gion are centered around the DAL-1 gene locus and are
too small to be detected by karyotyping or CGH (41). In
contrast, CGH analysis frequently identified losses of ge-
netic material from the long arm of chromosome 18.
These losses were associated with increasing histological
grade and therefore appear to be associated with menin-
gioma progression (Fig. 1). Losses on 18q were detected
in 67% of MIII and 40% of MII, but only 13% of MI
(42, 43). Büschges et al investigated 37 meningiomas for
mutation and expression of 4 tumor suppressor genes lo-
cated at 18q21, namely MADH2, MADH4, APM-1, and
DCC (43). However, only 1 missense mutation in the
APM-1 gene was found in an atypical meningioma. No
other mutations were identified and transcripts for all 4
genes were detectable in all tumors. These findings do
not support a significant role for MADH2, MADH4,
APM-1, and DCC alterations in meningioma pathogene-
sis. Based on CGH analysis, which identified a single
meningioma in which loss was restricted to 18q22-qter
(42), and on studies of non-CNS tumors with losses on
18q, it was suggested that a putative meningioma pro-
gression-associated gene may be located distally to the
18q21 region (43).
Chromosome 1
Deletions on 1p are the second most frequent chro-
mosomal abnormality in meningiomas. The frequency of
1p deletions increases with tumor grade and occurs in
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13% to 26% of MI, in 40% to 76% of MII, and 70% to
100% of MIII. Moreover, 1p deletions were found to be
associated with tumor progression in several individual
cases of recurrent meningiomas (42, 44–50). These find-
ings suggest that loss of genomic information from 1p is
relevant to meningioma progression rather than tumor
formation (Fig. 1).
Several genes on 1p were screened for alterations in
meningiomas, including CDKN2C (p18 INK4c ), p73,
RAD45L, and ALPL. In 3 different studies of more than
100 meningiomas only 1 mutation in the CDKN2C gene,
which is located at 1p32, and 1 homozygous deletion
were found (49, 51, 52). No loss of CDKN2C transcripts
and no aberrant methylation were detected, suggesting
that the CDKN2C gene is rarely altered in meningiomas
(49, 51). The RAD54L gene also maps to 1p32. No
RAD54L mutations were detected in a series of 29 me-
ningiomas (53), however, a silent polymorphism at nu-
cleotide 2,290 turned out to be associated with a higher
frequency of meningioma development (54).
The ALPL gene at 1p36.1-p34 encodes for alkaline
phosphatase. Loss of alkaline phosphatase activity was
reported to be strongly associated with loss of 1p in me-
ningiomas, leading to the assumption that ALPL might
have tumor suppressor function (55, 56). However, struc-
tural ALPL alterations have not been documented, and
functional evidence for tumor suppressor properties of
alkaline phosphatase is lacking.
Another candidate meningioma suppressor gene is
TP73, which maps to 1p36.32. However, only 1 mutation
was found in more than 50 meningiomas analyzed (57,
58), which argues against a significant role of TP73 in-
activation in meningioma progression. Expression of
TP73 was found to increase with tumor grade, suggesting
that TP73 might have a dominant oncogenic function
rather than a classic tumor suppressor function (58).
Taken together, the analyses of individual genes on 1p
do not support a significant meningioma suppressor func-
tion of any of the genes investigated. Deletion mapping
studies defined at least 2 different commonly deleted re-
gions on 1p, suggesting that more than 1 tumor suppres-
sor gene on 1p might be involved in meningioma pro-
gression. One of these regions was mapped to 1p32 (52,
54, 59, 60). However, sequence information that became
available through the human genome project indicates
that mapping data that were previously interpreted mainly
on the basis of recombination events require revision in
several instances. For example, Sulman et al had mapped
the minimally deleted region at 1p32 between microsat-
ellite markers D1S2713 distally and D1S2134 proximally
(59). According to current databases, however, D1S2713
maps to 1p34.1, and D1S2134 maps to 1p33 (http://
genome.cse.ucsc.edu/cgi-bin/, and http://www.ncbi.nlm.
nih.gov/mapview/maps.cgi). Similarly, Leraud et al had
identified a commonly deleted region between D1S234
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 280
distally and D1S2797 proximally, supposedly at 1p32,
whereas current databases map D1S234 to 1p36.11 and
D1S2797 to 1p33 (52). Even the order of microsatellite
markers that were chosen in different studies is not al-
ways in agreement with current databases. Correct inter-
pretation of previous mapping results would require an
extensive re-analysis of the data on the basis of the avail-
able sequence information. Such an analysis is beyond
the capacity and scope of this review.
A second common region of deletion was mapped to
1pter-p34 distally to the D1S496 locus (46, 49). Accord-
ing to current databases, this microsatellite still maps to
1p34.3 and consequently there is less confusion for this
region than for the more proximal region. A terminally
located region of deletion at 1p36 was also reported by
Bello et al (60). This group further identified up to 3 other
commonly deleted regions, including a frequently affect-
ed region at 1p34-p32 and 2 less frequently deleted re-
gions at 1p22 and 1p21.1-p13.
Taken together, it appears that at least 2 common re-
gions of deletion are present on chromosome arm 1p,
namely one at 1p34-p32 and another at 1pter-p34. It re-
mains to be shown whether re-analysis of previous stud-
ies based on genomic sequence information can clarify
some of the confusing mapping data and can narrow
down regions containing putative tumor suppressor
genes. Naturally, the current confusion is not unique to
meningiomas, since deletions on 1p are also common in
oligodendrogliomas, neuroblastomas, and many epithelial
cancers.
Chromosome 14
Cytogenetically, loss of chromosome 14 represents the
third most frequently detected abnormality in meningio-
mas after aberrations of chromosomes 22 and 1 (61).
LOH and FISH analyses identified deletions on chro-
mosome arm 14q in up to 31% of MI, 40% to 57% of
MII, and 55% to 100% of MIII (42, 45, 47, 50, 62, 63).
The strongly increased frequency of 14q deletions in tu-
mors of higher grade suggests an involvement in menin-
gioma progression (Fig. 1). A recent study demonstrated
that deletions on this chromosome arm were an indepen-
dent adverse prognostic parameter, which when combined
with histological grade and patient age could identify pa-
tients at increased risk of relapse (64). A similar obser-
vation was made in another study in which losses of 14q
in MI were predictive of tumor recurrence (50).
No specific meningioma suppressor gene has yet been
identified on chromosome 14. Deletion mapping studies
have defined several commonly deleted regions on 14q;
however, as already described for 1p, their interpretation
requires caution since most studies were performed be-
fore completion of the Human Genome Project. Simon
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LAMSZUS
et al had mapped a critical region to 14q24.3-q32.33 be-
tween microsatellites D14S48 and D14S23 (45). Similar-
ly, Menon et al had identified 14q24.3-q32.3 as the small-
est commonly deleted region. Also Tse et al described a
cluster region of deletion at 14q24.3-q31, but found an-
other region at 14q32.1-q32.2 (63), whereas Leone et al
suggested 2 different regions, one at 14q22-q24 and an-
other at 14q32 (47). In contrast, a CGH study by Weber
et al, 1 tumor defined a region of common deletion at
14q21 (42). It has to be concluded from these studies that
no consistent commonly deleted region has yet been iden-
tified on 14q, and no particular tumor suppressor gene
has evolved as prime candidate for a meningioma pro-
gression gene.
Chromosome 10
Deletions on chromosome 10 have received almost as
much attention in meningiomas as alterations on 14q.
Rempel at al initially discovered an association between
allelic losses on chromosome 10 with meningioma pro-
gression (65). Most subsequent LOH or CGH analyses
detected deletions preferably on the long arm of chro-
mosome 10. In several large studies, frequencies of 10q
deletions were in the order of 5% to 12% for MI, 29%
to 40% for MII, and 40% to 58% for MIII (42, 45, 66,
67). These percentages were even higher in 2 recent stud-
ies by Mihaila et al in which 11 different microsatellite
loci on chromosome 10 in 208 meningiomas were ana-
lyzed (68, 69). Correlative analyses revealed an unfavor-
able prognostic significance for LOH at D10S179 (1p14)
or D10S169 (1q26.3), which predicted higher tumor
grade, and of D10S209 (10q26.12) and D10S169
(10q26.3), which may predict shorter survival and/or
shorter time to recurrence, respectively (68).
No specific tumor suppressor gene on chromosome 10
has yet been shown to be inactivated in a major fraction
of meningiomas. The PTEN gene at 10q23.3 was ana-
lyzed in a large number of samples, however, mutations
were only detected in 2 different MIII and no homozy-
gous deletions were found (66, 70, 71). The DMBT1
gene, which maps to 10q26.11-q26.12, has also been in-
vestigated, but no homozygous deletions were found in
atypical or malignant meningiomas (67).
Mapping studies defined several different commonly
deleted regions on chromosome 10. Simon et al had ini-
tially mapped such a region to 10q24-qter (45). However,
according to current databases, the order and placement
of microsatellite loci are slightly different, so that a par-
tial deletion in one of the analyzed tumors would now
place the minimally deleted region distally to a marker
at 10q25.3. Peters et al observed LOH most often at mi-
crosatellite loci D10S676 (10q22.1) and D10S677
(10q23.33) (66). By CGH analysis, Weber et al obtained
evidence for commonly deleted regions on both chro-
mosome arms, namely one at 10p15 and one at 10q25-
qter (42). The latest study by Mihaila et al defined 1
 MENINGIOMAS
region on 10p between 10pter and D10S89 (p12.1), and
3 regions on 10q, namely between D10S109 (10q22.3)
and D10S215 (10q23.31), between D10S187 (10q25.3)
and D10S209 (10q26.12), and between D10S169
(10q26.3) and 10qter. Taken together, these studies indi-
cate that the pattern of allelic losses on chromosome 10
is so complex that no single consistent minimal region
of deletion could yet be identified.
Chromosome 9
Losses of genetic material on chromosome 9 were fre-
quently found in malignant meningiomas, but only rarely
in benign or atypical ones (42). The short arm of chro-
mosome 9 has attracted particular attention, as it contains
the tumor suppressor genes CDKN2A (p16INK4a/MTS1),
p14ARF, and CDKN2B (p15INK4b/MTS2) at 9p21, which are
inactivated at a high frequency in a variety of human
tumors. The p16 and p15 proteins regulate cell cycle pro-
gression at the G1/S-phase checkpoint by inhibiting cy-
clin-cdk complexes, which are involved in the transcrip-
tional control and phosphorylation of pRB. The p14ARF
protein blocks Mdm2-mediated degradation of p53.
Losses on 9p, as determined by combined CGH and
microsatellite analysis, were found in 38% of MIII, 18%
of MII, and 5% of MI (49). By FISH analysis the fre-
quencies of deletion at 9p21 or monosomy 9 were ;2-
fold to 3-fold higher, most likely because FISH analysis
on tumor sections also detects alterations that are only
focal (72). Boström et al found homozygous deletions of
CDKN2A, p14ARF, and CDKN2B in 46% of MIII, and 3%
of MII but never in MI (49). Two of 13 MIII carried
somatic point mutations in CDKN2A and p14ARF. In ad-
dition, 5 tumors without homozygous loss or mutation
lacked detectable transcripts for at least 1 of the 3 genes
(5% of MI, 9% of MII, and 8% of MIII). Thus, the ma-
jority of malignant meningiomas displayed alterations of
CDKN2A, p14ARF, and CDKN2B, whereas these were in-
frequent in benign meningiomas. Similarly, in an expres-
sion analysis by Simon et al, only ;26% of MI and MII,
but 57% of MIII lacked both p16 and p15 protein ex-
pression. In addition, 36% of non-malignant but 71% of
the anaplastic meningiomas lacked p14 protein (73).
These studies show that both the pRB and p53 pathways
are disrupted in the majority of MIII, and that inactivation
of cell cycle regulation at the G1/S-phase checkpoint may
be critical to the malignant progression of meningiomas.
Interestingly, a recent study demonstrated a prognostic
relevance for CDKN2A alterations, showing that among
patients with anaplastic meningiomas, those with
CDKN2A deletions had a significantly shorter survival
(72).
Chromosome 17
The tumor suppressor gene TP53, which is located on
the short arm of chromosome 17, is one of the most fre-
quently mutated genes in human cancer in general and in
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astrocytomas in particular. However, TP53 mutations are
rare in meningiomas. Several relatively large studies re-
ported either no or only single meningiomas with spo-
radic TP53 mutations (49, 71, 74, 75). Mutation of TP53
frequently results in increased stability of the p53 protein,
which, in contrast to wild-type p53, then becomes de-
tectable by immunohistochemistry. Other stabilization
mechanisms may also lead to p53 accumulation and thus
detectability. Immunohistochemical analyses of p53 in
meningiomas have yielded contradictory results, and
there seems to be a substantial degree of overlap between
different malignancy grades (76). In essence, most (but
not all) studies demonstrated an association between p53
accumulation and malignancy grade (75–78). The biolog-
ical significance of this p53 accumulation in meningio-
mas is not clear.
More recently, the long arm of chromosome 17 has
also attracted interest since CGH analysis demonstrated
high-level amplification on 17q in 42% of anaplastic me-
ningiomas but in almost none of the non-malignant me-
ningiomas (42). A subsequent study identified copy num-
ber increases at 17q microsatellite markers in 61% of
MIII in contrast to only 21% in MII and 14% MI (79).
However, only 2 MIII in this series displayed high-level
amplification defined as a .5-fold increase in the copy
number of 1 allele. The amplification patterns defined
several common regions of increased allele copy number,
one of which encompassed the putative proto-oncogene
PS6K at 17q23. However, in contrast to another recent
study by Cai et al, which identified PS6K amplification
in 3/22 anaplastic meningiomas (80), only low level copy
number increases were detected in 13/44 tumors (i.e. 4/
19 MII and 9/18 MIII), despite high-level amplification
of adjacent loci in 2 MIII. This discrepancy could have
technical reasons, because Cai et al used FISH analysis,
which recognizes also only focal areas with high-level
PS6K amplification, whereas focal high-level amplifica-
tions may have appeared as low-level amplification in the
real-time PCR analysis performed by Büschges et al (79).
Taken together, these studies suggest that PS6K may
not be the major target gene for high-level amplification
detected by microsatellite analyses in malignant menin-
giomas, but that its amplification in tumor cell subpop-
ulations may still be important for progression. Mapping
results define at least a bipartite common region of am-
plification at 17q22-q23, between markers D17S790 and
D17S1607 as well as between D17S1160 and PS6K, sug-
gesting the possibility of more than one relevant proto-
oncogene (79).
Alterations on Other Chromosomes
Numerous other chromosomal alterations have also
been identified in meningiomas, albeit less consistently
than those described in the previous paragraphs. Rela-
tively frequent among them are losses on 3p, 6q, X, and
J Neuropathol Exp Neurol, Vol 63, April, 2004
 282
Y, as well as gains on 1q, 9q, 12q, 15q, and 20q (42, 81–
83). Very few studies have searched for specific alter-
ations on these chromosome arms. For example, some
studies showed that the CDK4 and MDM2 genes, which
are located on chromosome arm 12q, are rarely amplified
in meningiomas (42, 49, 84, 85). Similarly, no other spe-
cific gene alterations on these less commonly altered
chromosomes could be identified in a significant number
of cases.
Radiation-Induced Meningiomas
Ionizing radiation to the skull is a well-established risk
factor for meningioma development. Most of the knowl-
edge about this association was obtained from immi-
grants to Israel who had been treated with low-dose cra-
nial irradiation for tinea capitis between 1948 and 1960.
Usually, patients who were treated during childhood de-
veloped meningiomas after a latency period of 20 to 40
years. Radiation-induced meningiomas (RIM) are often
clinically and histologically more aggressive (corre-
sponding to MII or MIII), are often multiple, and have a
higher proliferative activity than their sporadic counter-
parts (2).
A few studies addressed the genetic mechanisms in-
volved in RIM development. Mutation analyses of alto-
gether more than 30 RIM showed that NF2 mutations are
relatively rare and occur in less than 25% of RIM com-
pared to more than 50% in sporadic control cases (71,
86). Likewise, allelic losses on 22q were only detected
in 2/7 RIM (86), and a recent CGH study found mono-
somy for chromosome 22 in only 1/5 cases (87). Thus,
NF2 alterations appear to play a less important role in
the pathogenesis of RIM than in sporadic meningiomas.
Several other genes, including some that are prone to
developing radiation-associated mutations, were also an-
alyzed in RIM. Mutations in the TP53 and PTEN genes
were confined to single cases, and no mutations were
observed in the HRAS, KRAS and NRAS genes (71). Al-
lelic losses on 1p were detected at a slightly higher fre-
quency in RIM than in sporadic meningiomas and CGH
analysis identified losses on 7p, which are uncommon in
sporadic meningiomas, in 67% of RIM (87). Therefore,
putative tumor suppressor genes on 1p and 7p could be
relevant to the development of RIM, although the avail-
able series are too small to draw reliable conclusions.
Telomerase
Telomeres consist of stretches of repetitive DNA se-
quences that maintain chromosomal stability. Telomeric
DNA is progressively shortened with each mitosis. When
telomeres reach a critical length, cells ultimately become
senescent. Moreover, shortened telomeres can initiate ab-
errant fusion or recombination of chromosome ends and
thus contribute to cancer development. Telomerase is a
reverse transcriptase that stabilizes telomere length and is
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LAMSZUS
necessary for unlimited cell proliferation. In contrast to
germ-line cells and most embryonic cells, telomerase is
not active in most normal adult tissues. However, it is
frequently reactivated in cancer.
Telomerase activity has been detected in only 3% to
21% of benign meningiomas, but in 58% to 92% of MII
and 100% of MIII (88–90). Langford et al described that
telomerase activity was strongly associated with poor
outcome in benign meningiomas, suggesting that it may
provide a prognostic marker (88). Two essential compo-
nents were identified in human telomerase: an RNA sub-
unit termed hTR (telomerase RNA) that contains a tem-
plate sequence for telomeric repeat synthesis, and a
reverse transcriptase subunit hTERT (telomerase reverse
transcriptase). Generally, expression of hTERT correlates
best with telomerase activity, whereas hTR can be present
even when enzyme activity is repressed. Simon et al
showed that the detection rate for hTERT expression in
meningiomas was even higher than that for telomerase
activity and that all telomerase-positive tumors also ex-
pressed hTERT, but not vice versa (89). In addition, some
tumors that subsequently recurred expressed hTERT but
lacked detectable telomerase activity. These findings sug-
gest that hTERT might even be a more sensitive marker
for an aggressive clinical course than telomerase activity.
BIOLOGY
Angiogenesis, Edema, and Growth Factors
Meningiomas derive their blood supply predominantly
from meningeal vessels originating in the external carotid
circulation. Additional supply from cerebral-pial vessels
is present in approximately 60% of patients (91). Menin-
giomas are of variable vascularity, ranging from sparsely
vascularized to highly vascular angiomatous meningio-
mas. They further display variable degrees of peritumoral
brain edema, ranging from absent to life-threatening con-
ditions. In contrast to gliomas, there is no obvious asso-
ciation between edema and histological grade in menin-
giomas.
Vascular endothelial growth factor-A (VEGF-A),
which has also been termed vascular permeability factor,
is considered a key regulator of angiogenesis and edema
formation. The VEGF-A mRNA is expressed by menin-
gioma cells (92, 93). Several studies demonstrated that
VEGF-A levels in meningiomas are associated with the
extent of peritumoral edema (92–94). Moreover, menin-
giomas with striking VEGF-A expression usually ap-
peared to receive some blood supply through cerebral-
pial arteries, and both VEGF-A expression as well as
cerebral-pial blood supply were associated with the extent
of brain edema (94).
Two small studies suggested that VEGF-A mRNA ex-
pression may correlate with meningioma vascularity (93,
95). However, when determining VEGF-A protein levels
 MENINGIOMAS
in a relatively large number of 69 meningiomas, no as-
sociation with microvessel density could be confirmed
(96). Moreover, and in contrast to gliomas, there was no
association between microvessel density and histological
grade. Nevertheless, VEGF-A levels were increased 10-
fold in anaplastic meningiomas and 2-fold in atypical me-
ningiomas compared to benign ones. VEGF-A contained
in protein extracts of human meningiomas induced cap-
illary-like tube formation and migration of endothelial
cells in vitro, indicating biological activity in this context
(96). Another recent study reported a correlation between
VEGF-A protein expression and recurrence of benign
meningiomas (97). Taken together, these findings suggest
that VEGF-A is probably involved in vascular remodel-
ing and angiogenesis in meningiomas which does, how-
ever, not result in a net increase in vessel number with
increasing histological grade. Supposing that the more
malignant meningiomas have a higher oxygen and met-
abolic demand, VEGF-A might facilitate adaptation by
modulating vascular permeability.
Several other growth factors, including VEGF-B, pla-
centa growth factor, scatter factor/hepatocyte growth fac-
tor, and fibroblast growth factor-2 have also been ana-
lyzed in meningiomas. However, no clear correlation
between either of these factors and meningioma angio-
genesis or malignancy grade has yet been established.
Moreover, expression of several other growth factors and
their receptors, including epidermal growth factor, plate-
let-derived growth factor, and insulin-like growth factor
and others has been analyzed in meningiomas. Their de-
tailed discussion is beyond the scope of this article; for
reviews see Black et al (98) and Sanson and Cornu (99).
Hormones
Meningiomas are more than 2-fold more frequent in
woman than in men (2, 99). Accelerated meningioma
growth has been observed during pregnancy and during
the luteal phase of the menstrual cycle. Moreover, me-
ningiomas seem to arise at a slightly increased rate in
breast cancer patients. Taken together, these observations
suggest an etiological role for sex hormones in the
growth of these tumors.
Most hormone receptor studies in meningiomas were
performed in the 1990s using immunohistochemistry.
These studies showed that estrogen receptors are only
expressed in approximately 10% of meningiomas and
only at very low levels (reviewed in Black et al [98],
McCutcheon [100], and Sanson and Cornu [99]). In con-
trast, progesterone and androgen receptors are present in
approximately two thirds of meningiomas. Both are more
frequently expressed in women than in men (101–103).
Progesterone receptors have attracted the greatest interest.
Their expression is inversely associated with histological
grade, and a study on 70 meningioma patients showed
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that the presence of progesterone receptors was a favor-
able prognostic factor (103). Meningioma cell prolifera-
tion was found to be inhibited by the progesterone re-
ceptor antagonist mifepristone (RU486) in vitro,
suggesting a treatment modality. However, several small
clinical trials that were performed reported only marginal
responses (reviewed in Sanson and Cornu [99] and Ragel
and Jensen [104]), and some prospective trials are still
awaiting completion. Anti-androgens also have antipro-
liferative effects on meningioma cells in vitro, but their
clinical usefulness has not yet been investigated.
Meningiomas also express non-steroid hormone recep-
tors, including growth hormone, somatostatin and dopa-
mine receptors. Several in vitro or experimental in vivo
studies demonstrated antiproliferative effects of the
growth hormone receptor antagonist pegvisomant, the so-
matostatin agonist octreotide, and the dopamine D2 re-
ceptor agonist bromocriptine on meningiomas (99, 104).
However, full-scale clinical trials with these substances
have not been performed.
OUTLOOK
The completion of the Human Genome Project togeth-
er with the development of increasingly more sophisti-
cated molecular research techniques have set the stage
for future high resolution genome-wide studies. The ex-
ample of the DAL-1 tumor suppressor gene, where allelic
deletions were too small to be picked up by conventional
screening methods, underscores the need for more sen-
sitive techniques. A great improvement in sensitivity is
achieved by matrix-CGH (array-CGH), which has an ap-
proximately 100-fold higher resolution than conventional
CGH analysis and is able to narrow chromosomal gains
or losses to 75,000 bp segments. Another expanding field
is that of high-density cDNA arrays, which have so far
been applied to meningiomas in only a few studies (105,
106). Gene expression profiling by microarrays revealed
characteristic profiles for different meningioma grades
and can thus provide prognostic information. Patterns of
gene over- or underexpression may also lead to discovery
of unknown tumor suppressor genes or oncogenes. How-
ever, for several genes that lack expression in a major
fraction of meningiomas no structural gene alterations
can be identified. Inactivation of these genes apparently
does not follow the classic scheme described for tumor
suppressor genes. Instead, epigenetic inactivation by ab-
errant methylation or suppression of transcription by oth-
er mechanisms most likely accounts for the absence of
gene expression. Recently, array technology was expand-
ed also to methylation analysis, so that high-throughput
screening may soon generate comprehensive profiles of
methylated genes. The investigation to what extent ab-
errant methylation can explain inactivation of genes rel-
evant to meningioma formation or progression remains
J Neuropathol Exp Neurol, Vol 63, April, 2004
 284 LAMSZUS
one of the major challenges in the field besides further
genomic and expression analyses.
ACKNOWLEDGMENTS
I thank Prof. Guido Reifenberger and Prof. Manfred Westphal for
critically reading the manuscript and for helpful suggestions. I wish to
apologize for not being able to cite several articles pertinent to the
subject due to limitations in space and number of references allowed.
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