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Table of Contents    
Year : 2018  |  Volume : 66  |  Issue : 1  |  Page : 161-162

Meningiomas: A continuum of progress in risk-stratification

Department of Neuropathology, Christian Medical College, Vellore, Tamil Nadu, India

Date of Web Publication11-Jan-2018

Correspondence Address:
Dr. Geeta Chacko
Department of Neuropathology, Christian Medical College, Vellore, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.222841

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How to cite this article:
Chacko G. Meningiomas: A continuum of progress in risk-stratification. Neurol India 2018;66:161-2

How to cite this URL:
Chacko G. Meningiomas: A continuum of progress in risk-stratification. Neurol India [serial online] 2018 [cited 2020 May 25];66:161-2. Available from:

Meningiomas account for over 30% of primary central nervous system neoplasms.[1] Nearly 20-25% of meningiomas are atypical and 1-6% anaplastic, both associated with high rates of recurrence (40% and 80% respectively).[2]

The most recently updated World Health Organization (WHO) classification recognizes, as before, 13 histological variants and 3 grades.[1] Clear cell and chordoid meningiomas are WHO grade II, while papillary and rhabdoid are WHO grade III tumors. The 9 WHO grade I meningiomas include the meningothelial, fibrous, transitional, angiomatous, microcystic, secretory, lymphoplasmacyte-rich and metaplastic variants. In the 2016 update of the WHO classification, invasion of brain parenchyma by a meningioma was included as a stand-alone criterion for the diagnosis of an atypical WHO grade II meningioma.[1] The other criteria for atypia remain the same, namely, either greater than or equal to 4 mitoses/10 high power fields, or at least 3 of 5 histological features (hypercellularity, presence of small cells, sheeting architecture, prominent nucleoli and foci of spontaneous necrosis). Anaplastic or malignant meningiomas, WHO grade III, are those tumors that show marked anaplasia with carcinoma, sarcoma or melanoma like histology.[1]

Grade however does not always correlate with outcome. Some histologically benign meningiomas have been found to recur in studies with a long-term follow-up.[3] Whilst the extent of surgical resection is the single best predictor of outcome, there are other parameters that also correlate with biological behavior.[1] Assessment of proliferation by markers such as MIB-1, the Ki-67 antibody, has been found to be a useful prognostic variable. However, given the inter laboratory variation in staining and interpretation, no cut-off value has been defined to correlate with the grade of tumor.[1]

The lack of accurate correlation of histological grade with clinical outcome, prompted research into the genetic basis of meningioma initiation and progression, with the hope of discovering molecular signatures that would help to stratify these tumors better. It has been observed that there is a sequential accumulation of genetic abnormalities associated with malignant progression of meningiomas. Monosomy 22 is seen in 40-70% of meningiomas across all grades and particularly in patients with NF2. Chromosomal copy number alterations, either losses or gains, are seen with increasing frequency in higher grade meningiomas. Gains of chromosomes 1q, 9q, 12q, 15q, 17q, and 20q and loss of chromosomes 1p, 6q, 9p, 10, 14q and 18q are seen in grade II and III meningiomas.[4],[5]

NF2 mutations have been reported in approximately 40-60% of meningiomas, including both familial and sporadic meningiomas, and are thought to be an early tumorigenic event.[4] Several recurrent somatic mutations have been observed in sporadic meningiomas using next generation sequencing.[4],[5],[6] The more frequently seen mutations include: the pro-apoptotic E3 ubiquitin ligase, TNF receptor associated factor 7 (TRAF7) mutation, the pluripotency transcription factor, Kruppel-like factor 4 (KLF4) mutation, mutation of the proto-oncogene v-Akt murine thymoma viral oncogene homolog 1 (AKT-1), the frizzled family receptor smoothened (SMO) mutation, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, alpha (PI3K3CA) mutation and polymerase (RNA) II (DNA directed) polypeptide A (POLR2A) mutation. The TRAF7 mutation is a frequent mutation which can overlap with mutations of KLF4, AKT1 or PI3K3CA. They are, however, mutually exclusive with NF2 and SMO mutations. SMO mutations are seen in about 10% of non-NF2 mutated meningiomas. Mutations in SMARCB1 and SMARCE1 are found in familial meningiomas. More recently, TERT promoter mutations have been reported in higher grade meningiomas and are associated with a shorter progression-free survival.[5],[7]

Amongst the histological subtypes, inactivation of NF2 is seen in fibrous and transitional meningiomas. TRAF7/KLF4 mutations are seen with secretory, and TRAF7/AKT-1 and SMO mutations with meningothelial and transitional meningiomas. SMARCE1 mutations are noted in some clear cell meningiomas. BRAF V600E mutations are seen in rhabdoid meningiomas. Angiomatous meningiomas show multiple polysomies, especially of chromosome 5, 13 and 20.[4],[5]

By location, SMO or TRAF7/AKT-1 mutations are seen in anterior skull base meningiomas, and SMO, TRAF7/AKT-1 or TRAF7/KLF4 mutations in median middle cranial fossa tumors. Convexity meningiomas harbor NF2 mutations, exhibit loss of heterozygosity of chromosome 22, or show TRAF7/AKT1 mutations.[4],[5]

Mutation based profiling, however, has limitations, particularly in the context of those with NF 2 mutations, as these tumors can have varied clinical outcomes making risk stratification difficult. Moreover, almost 20% of menigiomas lack any identifiable oncogenic driver mutations.[4],[7] Besides, analysis of copy-number alterations, can only detect aberrations that accumulate during progression, but have no prognostic or predictive power.[7]

A recent study using deoxyribonucleic acid (DNA) methylation profiling has shown clinically meaningful stratification of meningiomas that is superior to the WHO classification and grading of meningiomas.[7] Two major epigenetic groups A and B were defined with six distinct methylation classes, 4 in group A, and 2 in group B. The group A methylation classes were designated, Methylation classes benign 1-3 (MC ben-1, MC ben -2 and MC ben-3) and Methylation class intermediate A (MC int-A). The 2 methylation classes of Group B included Methylation class intermediate B (MC int-B) and Methylation class malignant (MC mal). Compared with the WHO grade, this subtyping was found to identify more accurately, patients at high risk of recurrence. WHO grade I meningiomas with intermediate methylation class, MC int, were found to have a less favorable prognosis than histologically defined WHO grade I meningiomas; and, WHO grade II meningiomas with benign methylation class (MC ben) were found to have a better outcome than histologically defined WHO grade II meningiomas.[7]

The current issue of Neurology India features a study which evaluated the chromosomal status of 22q, 18p, 14q, and 1p in 15 chordoid meningiomas using locus-specific single-color probes by fluorescent insitu hybridization (FISH). Of the 5 cases that showed recurrence, 4 had complete deletions of all the 4 aforementioned chromosomal loci in comparison to only 1 of 10 cases in the non-recurrent group. The 5 cases with recurrence underwent either a Simpson's Grade 2, 3 or 4 excision of the tumor. The extent of excision in the single case in the non-recurrent group with complete deletion is not mentioned.[8] Chordoid meningiomas are known to have a very high rate of recurrence after subtotal excision.[9] Whilst this could have been a contributing factor to the recurrences seen in these 5 cases, the finding of known progression associated chromosomal losses of 1p and 14q within these Grade II meningiomas corroborates the observation by others that high grade meningiomas have a higher burden of chromosomal copy number alterations.[4] Loss of 22 q and 18p is in keeping with loss of NF2 gene or its various homologues in the early stages of meningioma tumorigenesis.

The WHO 2016 classification supports the concept of integrating genotypic characteristics with phenotypic characteristics of tumors. It is likely that future updates to the classification of meningiomas might include a molecularly defined layer which looks at mutational data and/or DNA methylation class for better risk stratification of individual patients.

  References Top

Perry A, Louis DN, Budka H, von Deimling A, Sahm F, Rushing EJ, Mawrin C, Claus EB, Loeffler J, Sadetzki S. Meningioma In: WHO Classification of Tumours of the Central Nervous System. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Ellison DW, Figarella-Branger D, Perry A, Reifenberger G, von Deimling A. (eds) 4th ed. 2016. International Agency for Cancer Research, Lyon pp 232-45.  Back to cited text no. 1
Commins DL, Atkinson RD, Burnett ME. Review of meningioma histopathology. Neurosurg Focus 2007;23(4):E3.  Back to cited text no. 2
Jääskeläinen J. Seemingly complete removal of histologically benign intracranial meningioma: Late recurrence rate and factors predicting recurrence in 657 patients. A multivariate analysis. Surg Neurol 1986;26:461-9.  Back to cited text no. 3
Bi WL, Zhang M, Wu WW, Mei Y, Dunn IF. Meningioma genomics: Diagnostic, prognostic and therapeutic applications. Front. Surg 2016;3:40. Available from:  Back to cited text no. 4
Yuzawa S, Nishihara H, Tanaka S. Genetic landscape of meningioma. Brain Tumor Pathol 2016;33:237-47.  Back to cited text no. 5
Clark VE, Erson- Omay EZ, Serin A, Yin J, Cotney J, Ozduman K, et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1 and SMO. Science 2013; 339:1077-80.  Back to cited text no. 6
Sahm F, Schrimpf D, Stichel D, Jones DTW, Hielscher T, Schefzyk S, et al., DNA methylation- based classification and grading system for meningioma: A multicentre, retrospective analysis. Lancet Oncol 2017.18:682-94.  Back to cited text no. 7
Harsha SS, Shastry AH, Nishant S, Dwarakanath S, Santosh V, Sampath S. Chromosomal aberrations in chordoid meningioma – An analysis. Neurol India 2018;66:156-60.  Back to cited text no. 8
Couce ME, Aker FV, Scheithauer BW. Chordoid meningioma: A clinicopathologic study of 42 cases. Am J Surg Pathol 2000;24:899-905.  Back to cited text no. 9


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