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Year : 2022  |  Volume : 65  |  Issue : 5  |  Page : 83-93
Meningiomas transition from traditional histological grading to molecular profiling in WHO CNS5: A Review

1 Department of Neurosurgery, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India

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Date of Submission08-Nov-2021
Date of Acceptance22-Dec-2021
Date of Web Publication11-May-2022


Despite being the most common primary intracranial tumor, meningiomas are classified largely based on histological features. The current system of grading has been shown to be unsatisfactory due to its poor reproducibility as well as the considerable variability within grades. With the increasing availability of genomic and epigenomic profiling, several markers have been suggested to correlate with the location, histological subtype, and clinical behavior of meningiomas. These developments have enabled the development of targeted therapy, as well as individualized use of currently available adjuvant methods. These include copy number alterations (CNAs), specific genetic abnormalities (germline and sporadic), and genome-wide methylation profiles. In this review, we recapitulate the changes in the classification of meningiomas thus far, discuss the various histological subtypes recognized, and present the available literature on the genetic and epigenetic profiles of meningiomas. The recognition and further study of these markers have the potential to usher in an era of personalized therapy in the management of meningiomas, vastly improving outcomes as has been observed in the case of several other tumors.

Keywords: Classification, histological, meningioma, molecular, review

How to cite this article:
Goyal-Honavar A, Jayachandran R, Chacko G. Meningiomas transition from traditional histological grading to molecular profiling in WHO CNS5: A Review. Indian J Pathol Microbiol 2022;65, Suppl S1:83-93

How to cite this URL:
Goyal-Honavar A, Jayachandran R, Chacko G. Meningiomas transition from traditional histological grading to molecular profiling in WHO CNS5: A Review. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 28];65, Suppl S1:83-93. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/83/345041

   Introduction Top

Meningiomas are the most common primary intracranial tumors, accounting for approximately 38% of primary central nervous system (CNS) neoplasms.[1] They arise from leptomeningeal arachnoid cap cells and are known to occur along the entire neuroaxis.[2] The present World Health Organization (WHO) grading of these tumors is based almost entirely on histopathological features.[3] In the face of emerging evidence that genetic and epigenetic profiles of meningiomas may predict clinical behavior, it is important to consider the various molecular alterations that may serve as therapeutic targets. We may therefore be able to improve the outcomes achieved with the current standard of care namely, surgical resection followed by adjuvant radiation if concerning histopathological features are present.

Though the extent of tumor resection and histological grade are the two strongest predictors of tumor recurrence,[4] there is substantial variability in the biologic behavior of these tumors that cannot be accounted for by these two parameters alone. In this review, we discuss the various morphological patterns, the evolution of the WHO grading scheme, and the newer developments in understanding the genetic and epigenetic alterations in meningiomas and how they contribute to diagnosis and prognosis.

   Epidemiology Top

Large-scale population-based data reveal that meningiomas are the most frequently reported primary tumor of the CNS, accounting for 25%–38% of all reported primary CNS tumors.[1] More than 80% of meningiomas originate from the cerebral meninges, whereas less than 5% are noted in the spinal meninges. Current WHO grading segregates 15 morphologic subtypes of meningioma into 3 grades – the majority of meningiomas are classified into WHO Grade 1 and 2 (70%–75% and 9%–20%, respectively), and 5%–9% are WHO Grade 3 with the rates of recurrence increasing with grade.[1],[5] Although Grade 1 meningiomas have a low 5-year recurrence rate after surgery, even the most histologically benign meningiomas recur despite seemingly complete surgical resection with approximately 30% invariably recurring over the patient's lifetime. Grade 1 meningiomas also show varying degrees of progression to higher Grades; nearly 17%–38% of Grade 2 tumors are derived from Grade 1 and 54%–70% of Grade 3 from their less aggressive counterparts.[6]

The incidence of meningiomas peaks above 65 years of age, whereas it is very rare under 14 years of age. There is a documented predilection for females although less pronounced or even reversed in atypical or anaplastic meningiomas.[7],[8]

Ionizing radiation is a well-established risk factor for the development of a meningioma, especially in the context of therapeutic radiation for malignancies.[4] Meningiomas that arise following radiation exposure frequently show multifocality, high proliferative indices, and a predilection for a younger age, with a latency of development of radiation-induced meningioma reported between 10.8 years and 35 years.[8],[9] Additional risk factors include the use of oral contraceptives, estrogen hormonal therapy, high BMI, smoking, diabetes, hypertension, and history of head trauma.[10],[11]

Up to 70%–90% of meningiomas express progesterone receptors (PR), and 2%–30% express estrogen receptors (ER).[12],[13] It has been hypothesized that the expression of hormone receptors explains their propensity for females, increased risk of meningioma with the use of hormone replacement therapy (HRT), and rapid growth during pregnancy.[14] Meningiomas that express PR are lower grade, less likely to possess chromosomal abnormalities, and demonstrate a lower rate of recurrence.[15],[16],[17] However, attempts at targeted therapy-selective estrogen receptor modulators like tamoxifen and the progesterone receptor antagonist mifepristone have failed to significantly improve outcomes.[18],[19]

The most common genetic disease associated with meningioma is neurofibromatosis, type 2 (NF2) which is an autosomal dominant condition with a chromosomal mutation on 22q12.[20] This subset of meningiomas occurs in a younger age group, are usually multiple, and more commonly fibroblastic meningiomas. Other predisposing genetic syndromes include Cowden [phosphatase tensin homologue (PTEN) syndrome], Gorlin (nevoid basal cell carcinoma) syndrome, multiple endocrine neoplasia 1 (MEN 1), schwannomatosis, and familial meningioangiomatosis.[2]

   Historical Overview of Meningioma Classification Top

The earliest known attempt to classify dural tumors was that of Virchow in 1863, followed by Engert in 1900 who described four types: fibromatous, cellular, sarcomatous, and angiomatous.[21] Cushing and Bailey in 1920 approached the classification of meningiomas in terms of their anatomic location (frontal, paracentral, parietal, occipital, and temporal) as well as histopathologic features (meningothelial, fibroblastic, angioblastic, and osteoblastic). The latter four histological categories were expanded by Bailey and Bucy in 1931 to include nine histological subtypes.[21] In 1938, Cushing and Eisenhardt distinguished 9 main types and 20 subtypes of meningioma based on anatomical sites and histological characteristics, later simplified by a working classification in 1941 to five major types: syncytial, fibroblastic, transitional, angioblastic, and mixed patterns.[21]

The first World Health Organization (WHO) classification of CNS tumors, published under the “Histologic Typing of tumors of the Central Nervous System” or the “Blue book” in 1979 described six subtypes of Grade I meningiomas, including hemangioblastic and hemangiopericytic subtypes. This classification also included papillary and anaplastic meningioma, which corresponded to either Grade II or III.[22] Its revision in 1993 went on to include 11 subtypes of benign meningiomas in addition to papillary, atypical, and anaplastic meningiomas while also recognizing hemangiopericytoma as a class of mesenchymal/non-meningothelial tumors.[23] However, it continued to be plagued by the use of imprecise terminology, such as “increased” cellularity and “frequent” mitoses in defining various grades of meningioma. The 2000 and 2007 revisions to the WHO classification did not greatly enhance our understanding of the genetic basis of these tumors, and merely served to add a category of rhabdoid meningiomas, based on histology, while refining the histological criteria used in the diagnosis of atypical and anaplastic meningiomas.[22],[24]

The 2016 classification was heralded as the first to break with the principle of diagnosis based entirely on microscopy, integrating molecular parameters into the classification of CNS tumor entities.[25] Due to the lack of broad availability of genotype testing at the time, the classification relied on “integrated diagnoses” combining genotypic and phenotypic features and set the stage for a paradigm shift to solely genotype-based classification with minimal reliance on histologic features.[25] While previously ambiguous histological categories, such as the oligoastrocytoma benefitted from the increased objectivity afforded by the use of molecular markers, and ependymomas, gliomas and medulloblastomas were effectively prognosticated based on genotype,[26],[27],[28] meningiomas continued to be classified purely on the basis of histology. The major change in their grading was the introduction of brain invasion as a histological criterion for the diagnosis of atypical WHO Grade II meningioma, before which it was included as a “staging” factor that predicted recurrence and higher mortality rates regardless of grade.[25] The WHO Grade of II was assigned to atypical meningiomas and meningiomas with chordoid or clear cell morphology, whereas the WHO Grade of III was assigned to anaplastic, papillary, and rhabdoid meningiomas.

While the current WHO grades appear to have a significant bearing on the prognosis of meningiomas, they suffer from suboptimal reproducibility as demonstrated by the NRG Oncology Radiation Therapy Oncology Group (RTOG) Trial 0539, which reported a concordance rate for tumor Grade of 87.2% in a series of 172 patients.[29] They concluded that the development of biomarkers was a more promising strategy than the clarification of subjective histologic criteria. The WHO CNS5 classification apart from the introduction of Arabic numerals for the different grades, incorporated a change in terminology, classifying all meningiomas as a single “type” and all 15 histologic entities as “subtypes.” This amendment maintained the grading of meningiomas as before, with clear cell, choroid, and atypical morphology assigned to WHO Grade 2 and papillary, rhabdoid, and anaplastic assigned to WHO Grade 3.[3] The WHO CNS5 however advises that the WHO Grade of 2 and 3 should be assigned not solely on the basis of the histological subtype but with applying the histological criteria for WHO grade 2 and 3.[3] Several molecular biomarkers have also been introduced, that serve an adjunctive role in classification and grading, such as SMARCE1 for clear cell subtype, BAP1 for rhabdoid subtype, KLF4/TRAF7 for secretory subtype, TERT promoter mutations, and/or homozygous deletion of CDKN2A/B for WHO Grade 3, and loss of nuclear expression of H3K27me3 signaling worse prognosis and methylome profiling for prognostic subtyping.

   Histological Features Top

The most common histological subtypes are meningothelial (57.5% of all meningiomas), originating most commonly from the parasagittal area, followed by transitional (19%) and fibrous subtypes (13%).[30] It has been suggested that the anatomic location of meningiomas correlates with the histological subtype and grade of tumor, such as the posterior fossa, skull base, and intraventricular regions more frequently giving rise to malignant meningiomas with higher mortality.[30] This may be related to the relationship of subtypes to cerebral vasculature (angiomatous meningiomas related to the venous sinuses at the posterior petrous apex),[31] or differential embryogenesis of leptomeningeal cells in different anatomic locations leading to varying proportions of arachnoid cap cells and trabecular cells.[32]

Meningothelial meningiomas present lobules of different sizes formed by epithelioid cells, separated by collagenous septa. The monomorphic cells resemble arachnoid cap cells, resembling meningothelial hyperplasia that can occur alongside other neoplasms [Figure 1]a. One common although nonspecific feature is the presence of eosinophilic pseudoinclusions in the nucleus which are formed by intranuclear invaginations of the cytoplasm. In the absence of typical meningothelial whorls, this may aid in making a histological diagnosis of meningioma.
Figure 1: (a) Meningothelial meningioma: Lobules of tumour cells arranged in a syncytial pattern (H and E ×100). (b) Fibrous meningioma: Storiform arrangement of tumour cells. (H and E × 100). (c) Transitional meningioma: Whorls and interlacing fascicles of tumour cells. (Hand E ×100). (d) Psammomatous meningioma: Tumor replaced almost entirely by numerous psammoma bodies. (H and E ×200). (e) Microcystic and angiomatous meningioma: Hyalinized vascular channels admixed with tumor cells (H and E × 200). (f): Secretory meningioma: Intracytoplasmic eosinophilic secretions, pseudopsammoma bodies (H and E ×200). (g): Lymphoplasmacyte rich meningioma: Inflammatory infiltrate adjoining tumor cells (H&E × 200). (h): Metaplastic meningioma: Osseous metaplasia within a meningioma. (H and E × 100)

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Fibrous or fibroblastic meningiomas have elongated cells arranged in fascicles, with varying amounts of interlacing collagen [Figure 1]b. When associated with extensive collagen deposition, they may resemble solitary fibrous tumor, however, the latter may be differentiated by its positive nuclear staining for STAT6.

The transitional meningioma consists of meningothelial and fibrous patterns, as well as areas transitioning between the two patterns. Whorl formation and psammoma bodies are frequent [Figure 1]c. Psammomatous meningiomas are characterized by lamellar calcifications, often confluent, with scant meningioma cells identified by immunostaining for antiepithelial membrane antigen (EMA) or somatostatin receptor 2A (SSTR2A) [Figure 1]d.

The angiomatous subtype is rich in small vessels, typically hyalinized, and occupying more than half of the tumor volume.[33] The abundance of thin- or thick-walled vascular channels may make the identification of meningioma cells challenging. In addition to microcystic and secretory subtypes, it is frequently associated with disproportionately severe peritumoral brain edema. While the exact mechanism of this association remains unclear, several factors appear to be relevant, including increased expression of hypoxia-inducible factor α (HIF-α), vascular endothelial growth factor A (VEGF-A), and disruption of the lymphatic system.[34],[35],[36]

Microcystic meningiomas are characterized by tumor cells with thin elongated processes and variable mucinous matrix. Despite degenerate nuclear atypia seen in cases of angiomatous and microcystic subtypes, they are largely benign subtypes. The microcystic subtype is often intermixed with the angiomatous pattern [Figure 1]e.[37].

Secretory meningioma is a subtype characterized by eosinophilic intracellular inclusions within gland-like spaces. These inclusions known as pseudopsammoma bodies are positive for periodic acid Schiff (PAS) and carcinoembryonic antigen (CEA) in addition to other epithelial markers like cytokeratin [Figure 1]f.[38]

The rare lymphoplasmacyte-rich subtype is defined by its prominent inflammatory infiltrate, outnumbering the tumor cells [Figure 1]g.[39] Predominance of macrophages over plasma cells in many cases has led some authors to describe this subtype as “inflammation-rich meningioma.”[39] Another rare subtype, the metaplastic meningioma, is characterized by focal or widespread mesenchymal differentiation with the formation of bone, cartilage, fat, and xanthomatous tissue elements singly or in combination [Figure 1]h.[40]

Chordoid meningiomas resemble chordomas with cords and trabeculae of round to polygonal cells with eosinophilic, vacuolated cytoplasm surrounded by abundant myxoid stroma, and patchy chronic inflammatory cell infiltrates [Figure 2]a.[41] This pattern is often seen mixed with meningothelial or transitional histology. Pure chordoid morphology though uncommon is difficult to distinguish from other chondroid/myxoid CNS tumors such as chordoma, chordoid glioma, myxoid chondrosarcoma, and myxopapillary ependymomas. Clear cell meningiomas are exceedingly rare, accounting for 0.2% of all meningiomas, characterized by sheets of round to polygonal cells with glycogen-rich, clear cytoplasm that is periodic acid–Schiff (PAS)-positive and diastase-sensitive.[42] The most prominent feature of this subtype is abundant interstitial and perivascular collagen [Figure 2]b.
Figure 2: (a) Chordoid meningioma: Chord of tumor cells set in a myxoid stroma (H and E ×100). (b) Clear cell meningioma: Prominent intercellular collagen and tumor cells with clear cytoplasm (H and E ×100). (c) Papillary meningioma: Discohesive cell clusters with a papillary and pseudopapillary pattern (H and E ×100). (d) Rhabdoid meningioma: Loosely cohesive cells with eccentrically placed nuclei & abundant cytoplasm (H&E ×100)

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The papillary subtype is defined by foci of perivascular papillary or pseudopapillary growth pattern with discohesive cell clusters among classical meningothelial morphology [Figure 2]c. Brain invasion is frequent as is peritumoral edema and bony destruction.[43],[44] This variant is associated with frequent reports of leptomeningeal dissemination and metastasis.[43] Rhabdoid meningiomas are composed of sheets of loosely cohesive cells with eccentrically placed nuclei, prominent nucleoli, and abundant amounts of cytoplasm containing whorled paranuclear eosinophilic inclusions [Figure 2]d.[45] They are associated with increased rates of recurrence and extracranial metastasis.[46],[47]

Atypical meningiomas are tumors with increased mitotic activity- mitotic count ≥4/10 high power fields (HPF), brain invasion (not including extension along with Virchow-Robin spaces), and/or at least three of the following features: increased cellularity, small cells with high N: C ratio, prominent nucleoli, sheeting, and foci of spontaneous, noniatrogenically-induced necrosis [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d, [Figure 3]e, [Figure 3]f. This subtype is associated with increased rates of recurrence and metastases.[48],[49],[50] Anaplastic/malignant meningioma shows distinct features of malignancy including either the presence of ≥20 mitoses/10 high power field (HPF) or the presence of frank anaplasia defined as carcinoma, melanoma, or sarcoma-like histology [Figure 4]a. They are frequently associated with a high Ki-67 index that when present, signals poor prognosis and recurrence.[51] This histology may arise de novo or as a progression from a WHO Grade 1 or 2 meningioma, the latter being associated with worse outcomes.[6],[52]
Figure 3: Meningioma CNS WHO Grade 2: (a) Mitotic activity ≥4/10HPF; (b) Hypercellularity & sheeting; (c) Macronucleoli; (d) Small cell formation; (e) Micronecrosis; (f) Brain invasion (H and E)

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Figure 4: (a) Meningioma CNS WHO Grade 3: Tumor exhibiting brisk mitotic activity (H and E ×200). (b) Immunopositivity for epithelial membrane antigen in a meningioma (×200)

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On immunohistochemistry, all meningiomas show membrane positivity for epithelial membrane antigen (EMA), Vimentin, and SSTR2A [Figure 4]b.

The various histological subtypes of meningioma, and their specific immunohistochemical markers are summarized in [Table 1].
Table 1: Overview of histological subtypes of meningiomas belonging to various WHO grades

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   Molecular Alterations in Meningiomas Top

The spectrum of clinical outcomes is varied despite histological grading, fueling the need to understand the genetic basis of the initiation and progression of meningiomas to further enhance the prognostic power and management at an individual patient level, and potentially identify molecular targets for therapy.

NF2- the tip of the molecular iceberg

The earliest genetic change to be identified and the most frequent is the allelic loss of chromosome 22q, harboring the NF2 gene leading to loss of heterozygosity (LOH).[53] First noted during the analysis of neurofibromatosis 2 (NF2) patients, NF2-mutated meningiomas represent the largest group of molecular alterations – 40%–60% of all meningiomas, including 50% of WHO Grade 1 meningiomas and 75%–85% of WHO Grade 3 meningiomas.[20],[54],[55] Biallelic loss of NF2 is usually the result of a two-hit mechanism, loss of heterozygosity (LOH) followed by a second mutation on the remaining allele.[54] There is a vast spectrum of mutations affecting NF2 – nonsense and frameshift mutations comprise the most common types and are associated with an increased frequency of recurrence than the less common splice site and nontruncating mutations.[56],[57],[58],[59] The protein product of the NF2 gene is the 69 kDa protein neurofibromin 2/schwannomin/merlin (moesin-ezrin-radixin-like protein), a cytoskeletal protein of the Band 4.1 family that regulates many essential pathways linked to cell proliferation and survival, including the hippo pathway, mammalian target of rapamycin (mTOR)/PI3K/AKT pathway, and receptor tyrosine kinases (RTKs).[60],[61] In its absence, the formation of mesenchymal-like cell phenotypes predominates over epithelioid ones. Consequently, NF2 loss is observed in less than 30% of meningothelial subtypes and 80% of fibroblastic and transitional meningiomas, usually located in the posterior skull base and the cerebellar convexities.[62],[63],[64] Despite extensive characterization of the spectrum of alterations observed in the NF2 gene, no promising therapeutic target has been identified.

Copy number alterations in meningiomas

While chromosome 22q is the most frequently involved in copy number alterations (CNAs), other CNAs that are identified are loss of chromosomes 1p (the second-most frequently encountered), 6q, 9p, 10, 14q, 18q, and gain of 1q, 9q, 12q, 15q, 17q, and 20q.[65],[66],[67] The frequency of chromosome 22q loss appears to be equal among different grades, and tumors with NF2 mutations behave vastly different, even within the same patient, implying that it is an important initiating alteration rather than a progression-associated alteration.[68] It is observed, however, that NF2-mutated meningiomas display higher chromosome instability during progression.[69] Higher grade meningiomas accumulate greater numbers of CNAs, leading to more complex cytogenetic profiles among atypical and anaplastic meningiomas, up to a median of 3.0 in Grade 2 and 9.5 in Grade 3 meningiomas [Figure 5].[65],[67] It has been suggested that the number of CNAs accumulated by a meningioma may be used to guide adjuvant therapy.[70] While the total number of CNAs appears to be significantly associated with recurrence following gross total resection,[70] specific CNAs also tend to confer aggressive clinical courses, such as losses of chromosome 1p, 9p, and 14q that are more frequently associated with recurrence in higher grade meningiomas, and in some cases among WHO Grade 1 meningiomas.[65],[66],[67],[71],[72] Co-deletions of chromosomes 1p and 14q are noted to be poor prognostic factors independent of WHO Grade.[73]
Figure 5: Copy number alterations associated with the various stages of meningioma development

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The discovery of these CNAs spurred research into regions that may harbor potential meningioma driver genes. Among genes on chromosome 1, methylation of the p73 promoter (locus 1p36.33) appears to occur in 81.8% of Grade 2 and 71.4% of Grade 3 meningiomas, compared to none of the Grade 1 meningiomas.[74] Other candidate genes include CDKN2C, RAD54, EPB41, GADD45A, ALPL on chromosome 1[75],[76],[77] as well as N-myc downstream-regulated gene (NDRG) family member 2 (NDRG2 located at 14q11.2) and maternally expressed gene 3 (MEG3) identified on chromosome 14.[78],[79] Chromosome 9p hosts several important genes – cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B), as well as P14, a tumor suppressor and regulator of cell apoptosis through modulation of the p53 pathway.[80] This is reflected in its association with malignant progression to anaplastic meningioma, shorter survival, and overall worse prognosis.[69],[81] The majority of these genetic alterations appear to be exclusive to the meningothelial lineage and are not observed in other meningeal tumors.[72]

Molecular profile of non-NF2 mutated meningiomas

Non-NF2 mutated meningiomas represent up to 40% of all meningiomas, constituting the majority of anterior and medial skull base meningiomas and are in turn driven by various distinct alterations.[82] The most common among these is TNF receptor-associated factor 7 (TRAF7) on chromosome 16p which produces a proapoptotic E3 ubiquitin ligase, found in 15%–25% of sporadic meningiomas.[82] The TRAF family of proteins is critically involved in downstream activation of the nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and interferon-regulatory factor pathways.[83] It is exclusive of NF2 mutations, and often in conjunction with Kruppel-like factor 4 (KLF4), AKT1, and PIK3CA mutations. While largely a feature of low-grade, meningothelial subtypes, combined TRAF7/KLF4 mutations invariably predict– the secretory subtype.[84]

The KLF4 gene on chromosome 9q accounts for a quarter of all non-NF2 mutated meningiomas (9%-12% of all meningiomas). It belongs to a family of DNA-binding transcriptional regulators that control cellular proliferation and apoptosis, the deletion of which induces self-renewal and maturation block in hematopoietic cells.[85] A recurrent mutation at codon 409, substituting lysine for glutamine (p.Lys409Gln) has been characterized that impairs the interaction of the transcriptional regulator with DNA. The absence of its regulation of cytokeratins explains the presence of cytokeratin-positive globules in secretory meningiomas.[86]

Cell signaling pathways are networks of the signal cascade that control various intracellular processes such as embryogenesis, cell differentiation, and cell proliferation. The mutation of any one gene product within the cascade can affect signal transduction of the entire pathway. V-akt murine thymoma viral oncogene homolog 1 (AKT1) on chromosome 14q, and smoothened, frizzled family receptor (SMO) on chromosome 7q mutations constitutively activate cellular proliferation pathways, and occur exclusive of NF2 mutations and of each other.[64] The AKT1 mutation (p.Glu17Lys) upregulates the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway, whereas SMO mutations (p.Leu412Phe and p.Trp535Leu) activate the sonic hedgehog (SHH) pathway.[64],[82],[87] AKT1 mutations occur in 7%–12% of Grade 1 meningiomas, frequently co-existing with TRAF7 mutations in the anterior skull base, meningothelial meningiomas, and predicting decreased time to recurrence.[88] SMO mutations occur in 1%–5% of non-NF2-mutated meningiomas and are associated with Grade 1, meningothelial meningiomas in the medial and anterior skull base.[89] Among olfactory groove meningiomas, they represent a distinct entity, recurring in over a third of cases.[90] The use of targeted therapy in the form of Vismodegib, an SMO inhibitor is under investigation.[91]

Another member of the PI3K/AKT/mTOR signaling pathway, PI3K is affected in mutations involving PI3KCA on chromosome 3q, constitutively activating the pathway.[92] It is as common among meningiomas as AKT1 and SMO mutations (4%–7% of meningiomas) but remains mutually exclusive of both. It is commonly present in Grade 1 meningothelial or transitional meningiomas of the skull base.[92]

The breast cancer (BRCA) 1-associated protein 1 (BAP1), encoded by the BAP1 gene is a ubiquitin carboxy-terminal hydrolase inactivated in high-grade rhabdoid meningiomas. A subset of these patients represents germline BAP1 mutations (BAP1 cancer predisposition syndrome), and are prone to develop other malignancies including uveal and cutaneous melanoma, lung adenocarcinoma, mesothelioma, renal cell carcinoma, and papillary thyroid cancer.[93] In meningiomas, it is associated with aggressive clinical behavior, significantly greater rates of recurrence, and lower time to progression.[93] Another pair of genes implicated in germline and rarely sporadic mutations are SMARCB1 and SMARCE1, coding for subunits of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex.[94] Germline mutations may produce several hereditary syndromes including the atypical teratoid/rhabdoid tumor (AT/RT),[95] schwannomatosis,[96] and Coffin-Siris syndromes,[97] however only schwannomatosis is associated with meningiomas. Both germline and sporadic variants are associated with spinal and cranial clear cell meningiomas with aggressive features and high rates of recurrence.[98]

Chromosome 9p harbors 2 genes, cyclin-dependent kinase inhibitor 2A and 2B (CDKN2A and CDKN2B) that code for tumor suppressor proteins p16 (INK4A), p14, and p15 (INK4B).[75] p16 and p15 bind cyclin-dependent kinases (CDK) 4 and 6, preventing cell cycle progression, whereas p14 controls the G1 phase via regulation of p53 degradation. Homozygous CDKN2A and/or CDKN2B deletion are associated with high-grade anaplastic histology, predicting brain invasion, lower survival[80] and is evidence for diagnosing CNS WHO grade 3 meningioma.[3]

The TERT gene located on chromosome 5p encodes the telomerase complex, a reverse transcriptase that serves to add TTAGGG repeats to the ends of DNA (telomeres) that, in somatic cells, are progressively shortened until such time as the cell is signaled to exit the cell cycle, leading to senescence.[99] Mutations in the hotspot regions C228T and C250T in 6.5%–11% of meningiomas upregulate the activity of telomerase, immortalizing cancer cells. Similar to its implication among gliomas, it portends a poor prognosis in meningiomas, with greater prevalence among grade 3 meningiomas (20% vs. 1.7% in grade 1) and secondary atypical meningiomas that progressed from benign tumors.[100],[101] Specifically, these tumors have dramatically lower time to progression irrespective of histological grade.[3] When present in benign tumors, it signals a high risk of recurrence and malignant transformation. The current landscape of molecular alterations among non-NF2 mutated meningiomas is summarized in [Table 2].
Table 2: Overview of genetic alterations noted among non-NF2 mutated meningiomas

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Above and beyond genes- Epigenetic profiling among meningiomas

While genetic mutations certainly have a role in risk stratification, as described above, their rarity and unproven accuracy in estimation are a hurdle to their routine implementation. Hypermethylation of genes such as tissue inhibitor of metalloproteinase (TIMP3), CDKN2A, and tumor protein 73 (TP73) are noted in up to 10% of meningiomas.[107] TIMP3, found on chromosome 22q12 is a tumor suppressor, the downregulation of which occurs frequently in 40%–60% of high-grade meningiomas via hypermethylation, predicting a shorter time to recurrence.[108] TP73 promoter methylation occurs in 70%–80% of high-grade tumors and may serve as a biomarker of high-grade meningiomas.[74]

More recently, genome-wide DNA methylation profiling has proven of greater value than single-gene methylation analysis, distinguishing six distinct methylation classes that are clinically relevant and associated with typical mutational, cytogenetic, and gene expression patterns [Table 3].[109],[110],[111] The use of methylome predictors in combination with traditional prognostic factors (WHO Grade and Simpson extent of resection) has been shown to be of benefit in personalizing the decision to administer adjuvant radiation following excision of meningiomas.[110]
Table 3: Epigenetic subclassification of meningiomas based on DNA methylation profiling

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Beyond DNA methylation, assessment of histone methylation (H3K27 trimethylation/H3K27me3) appears to be significant in stratifying WHO Grade 1 and 2 tumors. Lack of immunostaining for H3K27me3 was significantly associated with rapid progression in one study. However, it was not useful as an adjunct in Grade 3 tumors.[112]

   Conclusion Top

Meningiomas are common CNS tumors. The most important factors predicting recurrence on a population-scale are the extent of resection and WHO Grade although significant heterogeneity exists within grades. It appears evident, then, that genetic assessment tools are needed to complement the current system of grading. Further understanding of genetic and epigenetic mechanisms may provide effective molecular therapeutic targets. Larger collaborative gene expression studies are required to effectively translate molecular advances into clinically meaningful therapies.

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Correspondence Address:
Geeta Chacko
Professor and Head, Department of Pathology, Christian Medical College, Vellore - 632 004, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_1085_21

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