There are nine Grade I subtypes, three Grade II subtypes, and three Grade III subtypes in the WHO grading scale, most recently revised in 2007 (Table 1)16. Although genetic and immunohistochemical (IHC) markers have been increasingly employed in the evaluation of meningiomas, grading of meningiomas is based entirely on conventional histologic criteria as defined by the WHO122021.

Since the WHO revised the diagnostic criteria of Grade II meningiomas in 2000 and 2007, there has been a significant increase in atypical meningioma diagnosis26. Tumors classified as Grade II now comprise 10-30% of all meningiomas11. Grade II meningiomas behave more aggressively than Grade I tumors, and have a high rate of recurrence (41% at 5 years)327. For instance, in chordoid meningiomas, subtotal resection has been shown to be an invariable predictor of recurrence, even up to 16 years postoperatively28.

Meningiomas classified as WHO Grade III are considered anaplastic/malignant and are further differentiated into three subtypes (Table 1). Papillary meningiomas are more common in younger patients and frequently recur; they can metastasize within the subarachnoid space or even outside of the CNS293031.

Although molecular and genetic studies of meningiomas are being increasingly used to characterize these tumors, the standard classification scheme remains the WHO grading scale. As tumor grade increases, the recurrence rate increases and prognosis of the patient markedly decreases; the ten-year survival rate for Grade III tumors is 14.2%3233. However, even benign meningiomas may still recur following Simpson Grade I resection424253334. Therefore, timely definitive diagnosis of the tumor and determination of its specific characteristics is paramount to the patient’s well-being. Some have suggested the use of MIB-1 labeling indices as a key to predict recurrence35. Although the WHO grading scale has recently been revised (in 2000 and 2007) to standardize the diagnostic criteria for each grade, like any subjective scale it is susceptible to sampling error and inter-user variability3637. Additionally, some tumors vary in aggressiveness from the norm, within the spectrum of each grade3538. Multiple studies have also shown that tumor location (i.e., non-skull base vs. skull base) is a significant factor in tumor grade and malignant potential at both diagnosis and recurrence17193539. Adjuvant radiation modalities, including stereotactic radiosurgery, have been shown to be effective in arresting the growth of intracranial meningiomas, including those tumors arising from difficult-to-access skull base locations, with minimal morbidity404142434445464748. At any rate, the WHO classification scheme does not always accurately predict the behavior of these lesions, and some authors have called for new schemes based in part on molecular markers and/or cytogenetic evaluation of the tumor384950. Indeed, a great deal of recent investigation in the genetic and epigenetic changes of these tumors has begun to clarify the complex heterogeneity of meningioma pathogenesis and progression62051.

Although many genes have been implicated in the pathogenesis of meningiomas, a clear understanding of the specific, stepwise genetic changes required for meningiomas to develop and progress has not been elucidated. In benign tumors, loss of heterozygosity of chromosome 22 is a common finding, but other mutations are rarely found5253. Meningiomas with higher grade have more complex karyotypes, but there is a great deal of heterogeneity among tumors of the same grade. Chromosomal losses on 1p, 6q, 9p, 10q, 14q, and 18q, as well as gains on 1q, 9q, 12q, 15q, 17q, and 20q, have been identified in this subset of meningiomas53545556. Here we review the major known genetic aberrations in meningiomas, in light of the associations with the WHO grading scale.

Loss of heterozygosity (LOH) of chromosome 22 is the most frequent abnormality in all meningioma types; it is always found in meningiomas occurring in patients with neurofibromatosis 2 (NF2) gene mutations162057585960. Loss of NF2 expression is variable within the most common WHO Grade I subtypes, with mutations occurring in fibroblastic (70%) and transitional (83%) types far more frequently than in meningothelial (25%) types61. Inactivation of NF2 in grade II and III meningiomas is present in about 70% of cases, suggesting that the loss of the gene is a common event of tumorigenesis rather than malignant progression626364.

The NF2 gene is located on 22q12.2, encoding a tumor suppressor protein called schwannomin or merlin (moesin, ezrin, radixin-like protein)6566. This 70-kDa protein is part of the 4.1 superfamily of cystoskeletal proteins, linking actin cytoskeleton to plasma membrane proteins. Merlin contains three domains, including the N-terminal FERM domain, which interacts with other cytoskeletal regulators, including other ERM proteins6768.

Proposed functions of the merlin product includes contact-mediated growth inhibition and secondary signaling pathways64666769707172. Various NF2 gene mutations have been found in up to 60% of meningiomas, including small insertions, nonsense mutations, deletions affecting splicing sites, or terminal deletions of the NF2 sequence7374; these mutations result in an inactive form of merlin which has been shown to aid tumorigenesis through decreased cell adhesion and dysregulation of several pathways, including the Ras and Hippo pathways757677.

Merlin has also been demonstrated to regulate contact inhibition of growth through a complex with other 4.1 superfamily proteins and CD4472. It has been suggested that the merlin-ERM-CD44 interaction forms a molecular “switch”: in a phosphorylated state the merlin protein interacts with ezrin, moesin, radixin, and CD44 to promote growth in the absence of cell/matrix contact. Once contact is achieved, the complex reconfigures without the ERM proteins and results in cellular arrest71.

Recently, merlin has been proposed to interact with as-yet unspecified membrane proteins, resulting in signal transduction that phosphorylates LATS1/2. LATS1/2 inhibits a downstream effector of the Hippo pathway called Yes-associated peptide (YAP). When the expression of merlin is reduced, YAP is upregulated which results in cellular hyperplasia, delayed cell-cycle exit, apoptosis inhibition, and enhanced cell survival77.

DAL-1 (4.1B) and 4.1R

The DAL-1 gene on the 18p11.3 locus encodes another member of the 4.1 superfamily (namely, protein 4.1B); the loss of expression of this gene has been demonstrated in up to 76% of Grade II and 87% of Grade III lesions and has also been associated with familial meningiomas. Although originally thought to be part of early tumorigenesis, the loss of the DAL-1 gene product has more recently been implicated in meningioma progression787980. The gene for a third 4.1 superfamily protein, 4.1R, is located at 1p36; it is also lost in up to 40% of meningiomas Overexpression of this protein in vitro has been shown to reduce cellular proliferation818283.

Collectively, this data suggests a critical role of the protein 4.1 superfamily of cytoskeletal in the formation and progression of meningiomas, although the exact mechanisms have yet to be defined.

1p and 14q aberrations and elusive tumor suppressor candidates

Losses on 1p and 14q are the next most common mutations after LOH of 22q, and these aberrations have been independently correlated with increased tumor grade and increased recurrence rate54558485868788899091. Several candidates genes on 1p (including CDKN2C, p18, ALPL, RAD54 L, p73, and EPB41) have been identified, but further analysis has failed to find mutations or polymorphisms of these genes9293949596.

Potential tumor suppressor genes on 14q include NDRG3 at 14q11.2 and MEG3 at 14q3288. Inactivation of the NDRG2 gene has been shown to be a frequent feature in Grade III meningiomas as well as in a subset of Grade II tumors with clinically aggressive behavior88. However, the precise role of NDRG2 in the progression of meningiomas remains unknown. Recently, a study evaluating the role of the MEG3 gene has suggested an important role in the progression of these tumors97. The MEG3 transcript is a non-coding RNA with anti-proliferative functionality; it is readily expressed in normal arachnoidal cells, but loss of expression was common in both human meningioma specimens and two established human meningioma cell lines. The degree of expressional loss/prevalence of allelic loss in human specimens was also correlated with increasing tumor grade.

Losses of 9p have been proportionately associated with increasing tumor grade; tumor suppressor genes implicated include CDK2NA/P16^INKa, p14^ARF, and CDK2NB/p15^ARF, all found at the 9p21 locus620569298. The products of these genes are associated with regulation of the G₁/S-phase cell cycle checkpoint.

Sex hormone receptors have long been suspected to play a role in the pathogenesis of meningiomas due to the higher overall predominance in females111. It has been well studied that a majority of benign meningiomas express progesterone receptors111112113114115116117118119. Despite the female predominance, meningiomas tend to be more aggressive in males, which further clouds the involvement of sex hormones in pathogenesis.

Early studies have shown that a high percentage of meningiomas express PR112120121122. Others have demonstrated that meningiomas with PR-positive cells, even if few in number, have a better prognosis than tumors with complete absence of the receptor116. However, reports of higher incidences of PR-positive cells in recurrent disease suggests that PR may play a role in recurrent meningiomas123.

The role of estrogen and androgen signaling has also been controversial. Estrogen receptor (ER) positivity ranges from 7.1%-40.3% in Grade I tumors, and ER-positive cells have been shown to have a higher MIB-1 proliferation index than ER-negative tumors116123. Androgen receptor and artomatase have also been implicated in tumorigenesis and recurrence115119120123. Although there is a strong case for the role of estrogen and androgens signaling in tumorigenesis, studies reporting no difference in receptor levels between men and women invalidate the conclusion that PR and ER is responsible for the predominance of meningiomas in females123.

As meningioma treatment moves towards therapies targeted at the specific genetics and biology of the patient’s tumor, a formidable challenge remains due to the limited understanding of the complex heterogeneity of this disease. Studies have identified karyotypically frequent areas of aberrations and some specific gene candidates for tumorigenesis and progression, but the associations of these mutations with specific oncogenic events remains unknown. Epigenetic analytical data has also produced promising correlations of gene expression regulation and tumor properties, but the data is difficult to synergize with an incomplete picture of the cytogenetic progression of disease. Also frustrating is the lack of effective chemotherapeutics for these tumors as well as the difficulty in creating stable cell lines and animal models for experimentation. As such, the mainstay treatments for meningiomas remain: surgical resection, stereotactic radiosurgery, and radiotherapy. Although these modalities may never disappear, in the future a combination of these coupled with molecular therapies tailored to the individual genetics and molecular biology of the patient’s tumor holds great promise in the treatment of this disease.