NcXHF

MENINGIOMA MANAGEMENT
TABLE 1. Meningioma Subtypes, Grading, and
Associated Molecular Alterations
Histologic Subtype WHO Grade Molecular Alteration*
Meningothelial meningioma 1 NF2
Fibroblastic meningioma 1 NF2
Transitional (mixed) meningioma I NF2
Psammomatous meningioma 1
Angiomatous meningioma 1
Microcystic meningioma 1
Secretory meningioma 1 KLF4/TRAF7
Lymphoplasmacyte-rich meningioma 1
Metaplastic meningioma 1
Chordoid meningioma 2
Clear cell meningioma 2 SMARCB1
Atypical meningioma 2 NF2
Brain invasive meningioma 2
Papillary meningioma 3
Rhabdoid meningioma 3
Anaplastic meningioma 3 NF2
*Includes only molecular changes with high frequency and/or association with a specific
tumor location.
KEY POINTS
Meningiomas are the most frequent types of intracranial
tumors.
Surgery and radiotherapy are established treatments.
No standard treatments exist for recurrent/progressive
meningiomas.
Vascular endothelial growth factor pathway inhibitors
sunitinib, vatalinib, and bevacizumab showed potential
activity in small, uncontrolled studies that require
confirmation.
broblastic meningiomas are more likely to develop at the
convexity of the brain. 11,12 If the location is related to the
grade of malignancy, the proportion of grade 2 or grade 3
meningiomas at the convexity or with a parasagittal location
is much higher than at the skull base. 13 In addition to the
three main grade 1 tumor types, other rare variants might be
seen, and some of them are associated with specifıc genetic
alterations.
Approximately 20% of meningiomas fall into the group of
atypical WHO grade 2 tumors. Interestingly, these tumors
have been increasingly recognized in the last few years,
mainly as a result of a diagnostic shift from grade 1 to grade 2
meningiomas that is based on a better defınition of histopathologic
criteria. 14 Atypical meningiomas are characterized
by aggressive histologic features, such as increased
mitotic activity, nuclear atypia, and necroses. The aggressive
biology is reflected by the roughly eight-fold increased risk of
recurrence experienced by patients with grade 2 meningiomas
compared with benign WHO grade 1 tumors, and by the
considerably increased risk of mortality associated with
grade 2 versus grade 1 in with age- and sex-matched controls.
Meningiomas with proven brain invasion also are considered
grade 2 tumors, and patients with these tumors are prone to
an increased risk of tumor recurrence. However, the molecular
mechanisms driving brain invasion are not well understood
so far. Malignant meningiomas (WHO grade 3) are
rare, accounting for only 1% to 2% of all meningiomas, but
are associated with a considerable risk of death from disease
and an average survival of less than 2 years. 15-17 Although the
characteristic histopathologic features of meningiomas are at
least focally found in atypical meningiomas, malignant
WHO grade 3 meningiomas may completely lack any morphologic
hint that points toward a meningeal origin, thus requiring
extensive pathologic investigations to confırm the
true nature of the tumor.
For differential diagnoses, meningiomas can present with a
wide spectrum of histopathologic patterns, and coexistence
of various morphologic features within one tumor may occur.
Using immunohistochemistry, meningiomas usually express
epithelial membrane antigen (EMA) and vimentin.
Cytokeratins are usually not expressed, which helps to rule
out metastatic carcinoma. Exceptions include secretory
meningiomas and some anaplastic meningiomas. Highly vascularized
meningiomas must be separated from hemangiopericytoma
and solitary fıbrous tumor (SFT). There typically is diffuse
CD34 positivity in SFT. Extensive staining for CD99 and B-cell
lymphoma 2 is common to both SFT and hemangiopericytoma,
but it is missing in meningiomas. In contrast, EMA expression is
much more typical of meningioma. 10
MOLECULAR GENETIC ALTERATIONS IN
MENINGIOMAS
The fırst genetic alteration described was the loss of chromosome
22, and chromosome 22 alterations are still the most
frequent fındings in meningiomas. Subsequently, a gene on
chromosome 22 responsible for the hereditary tumor syndrome
NF2 was identifıed. 18,19 Although bilateral vestibular
schwannomas are the hallmark of the disorder, the majority
of patients with NF2 develop multiple meningiomas, which
suggests a role for the NF2 gene in meningioma development.
20 Indeed, allelic losses of chromosome 22, including
the NF2 region, occur in more than 50% of sporadic
meningiomas. 21-24 In meningiomas with allelic losses (loss of
heterozygosity [LOH]) at the NF2 locus, point mutations in
the remaining allele can be found in sporadic meningiomas,
which suggests complete gene inactivation. 25,26 Merlin, the
gene product of NF2, has signifıcant sequence homology to
members of the ezrin/radixin/moesin (ERM) family of proteins,
which link various cell-adhesion receptors to the cortical
actin cytoskeleton. 27 The frequency of NF2 inactivation is
roughly equal among different WHO grades, which suggests
that NF2 loss is an initiating rather than progressionassociated
alteration. 16,28-30 With variant histology, differences
in the frequency of NF2 alterations have been reported.
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