NcXHF

MENINGIOMA MANAGEMENT
and 1p and 14q loss especially are associated with meningioma
progression. 60-62 Interestingly, 1p loss commonly is
found in tumors located at the convexity but is rare in skull
base or spinal meningiomas. 13 Moreover, 1p loss is associated
with faster meningioma recurrence. 63 Losses of 6q, 9p, 13,
and 14 are found exclusively in highly proliferating meningiomas.
64 Radiation-induced aggressive meningiomas show
cytogenetic aberrations on chromosome 1p, 6q, and 22. 65
Few specifıc genes associated with chromosomal alterations
have been identifıed. Besides NF2, the tissue inhibitor of
metalloproteinase 3 gene (TIMP3), location on 22q12, is another
gene associated with meningioma progression . Hypermethylation
of the TIMP3 promoter occurs in 17% of benign,
22% of atypical, and 67% of anaplastic meningiomas and is
associated with allelic loss on 22q12. 66 The TIMP3 protein
inhibits matrix metalloproteinases, which suggests that epigenetic
inactivation of TIMP3 by promoter hypermethylation
might favor aggressive invasive tumor growth. TIMP3
has additional tumor suppressor activity, and in vitro overexpression
of TIMP3 reduces tumor growth and induces apoptosis.
67 However, TIMP3 hypermethylation does not seem
associated with tumor recurrence or overall survival. 63
Alterations on 9p21 have been found to represent losses of
the tumor suppressor genes CDKN2A (p16 INK4a ), p14 ARF ,
and CDKN2B (p15 INK4b ). 30,68 In anaplastic grade 3 meningiomas,
deletions ofCDKN2A/CDKN2B are associated with poorer
survival. 69 In mouse models, deletion of CDKN2A, together
with NF2 inactivation, results in increased meningioma frequency
and the development of grade 2 or 3 meningiomas,
which proves that loss of CDKN2A and CDKN2B is a feature for
aggressive meningioma development. 70
Amplifıcation of the S6 kinase gene region on chromosome
17q23 is present in malignant meningiomas, 71,72 which suggests
that mammalian target of rapamycin (mTOR) signaling
pathway inhibition might be a therapeutic target. 73 The
14q32 region has been implicated in meningioma progression
because of the maternally expressed gene 3 (MEG3),
which has antiproliferative activity in meningiomas. Aggressive
meningiomas show allelic losses, promoter hypermethylation,
and reduced expression of MEG3 compared with
normal arachnoidal cells. 74,75 The important role of chromosome
14q loss was supported by fındings that showed
NDRG2 as a gene commonly inactivated in meningioma progression.
NDRG2 is downregulated in anaplastic meningiomas
and in a small subset of lower-grade meningiomas and
atypical meningiomas with aggressive clinical behavior. The
reduced expression of NDRG2 is associated with promoter
hypermethylation. 76,77
MOLECULAR FACTORS AFFECTING MENINGIOMA
PROGNOSIS
The histologic tumor grading is one of the strongest factors
influencing tumor recurrence and overall prognosis. 17
A high MIB-1 labeling index is associated with poor prognosis.
78 Losses of 1p and 14q have a poor prognostic implication.
60-63,79-81 Patients who have tumors greater than 50
mm and a combined loss of 1p and 14q represent a subgroup
at high risk for early relapse. 82 Relapse-free survival is negatively
associated with male sex, presence of brain edema, intraventricular
and anterior cranial base tumor location, age
younger than 55, and tumor size larger than 50 mm. 83
MOLECULAR SIGNALING PATHWAYS
Molecular signaling pathways, including those involved in
mitogenic signal transduction, have been studied intensively
in meningiomas. Nearly all of the growth factor receptors/
kinases known to be involved in tumor growth (epidermal
growth factor receptor [EGFR], platelet-derived growth factor
receptor [PDGFR] beta, vascular endothelial growth factor
receptor [VEGFR], insulin-like growth factor receptor
[IGFR]) have been expressed in meningiomas. 84-87 Mitogenic
signals of EGFR and PDGFR are mediated by the Ras-
Raf-Mek-MAPK pathway. Indeed, these pathways are
activated in meningiomas. 88,89 The phosphoinositide 3-kinase–AKT/protein
kinase B p70 signaling pathway is another
important mediator of growth-favoring signals in meningiomas.
73,89,90 The mTOR signaling pathway is of relevance for
both NF2 mutant meningiomas and for meningiomas with
other mechanisms of mTOR pathway activation, such as S6K
gene amplifıcation. 71,72 Merlin (NF2) is a negative regulator
of the mTOR complex 1 (mTORC1) kinase complex, and
constitutive activation of mTORC1 signaling is present in
meningioma cells from patients with NF2. 91,92 Other signaling
pathways activated in meningiomas include the phospholipase
A2-arachadonic acid-cyclooxygenase pathway 93,94
and the PLC-gamma1-PKC pathway. 89,95 The transforming
growth factor-beta (TGF-beta)-SMAD signaling pathway
represents an inhibitory mechanism, and TGF-beta, and the
TGF-beta receptor, are expressed in meningiomas. 96-98 All of
these activated signaling pathways represent potential therapeutic
targets.
MANAGEMENT OF MENINGIOMAS
The overall management approach for newly diagnosed
meningiomas is usually dependent on a number of factors
including the patient’s age, comorbidities, and clinical symptoms
as well as the tumor location (proximity to critical
structures or regions of brain), size, and mass effect. For patients
who are symptomatic as a result of the mass effect from
the tumor, surgery is typically recommended. For other patients,
discussion with the patient and interdisciplinary discussion
of all management options, including observation,
surgical resection, and radiotherapy (including radiosurgery
and fractionated radiotherapy) are considered.
OBSERVATION
For patients who have asymptomatic meningiomas that are
not in close proximity to critical structures, an observational
approach may be considered. Most meningiomas are low
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