Written with Louise Eisenhardt and published in 1938, Meningiomas is a monograph of incredible description and detail. The meticulous categorization of meningiomas, their presentation, clinical outcome, and surgical therapies are even further supplemented by Cushing's personal commentary, questions, and recollections. Cushing's genius was evident in his ability not only to make insightful clinical observations, but also to synthesize these ideas within the neurosurgical context of his era. As he says in Meningiomas, “Thus the pathological curiosity of one day becomes in its proper time a commonplace… most of which are one and the same disorder–had, for their interpretation, to await the advent of the Neurosurgeon 1).
Meningiomas are the most common primary tumors and account for up to 30% of all central nervous system CNS tumors. Although they represent about a third of all the tumors of the central nervous system, knowledge concerning meningioma epidemiology (including incidence data and exploration of the risk factors) remains scarce compared to that of gliomas. A limited number of cancer registry worldwide only record malignant brain tumors, however their completeness and accuracy have been questioned. Even if comparisons are made difficult due to differences in methodologies, available annual incidence rates (sex- and age-standardized, generally on US or World standard population), provided by population-based registries range from 1.3/100,000 to 7.8/100,000 for cerebral meningiomas. An increase in the incidence of primary brain tumors in general and of meningiomas in particular has been observed during the past decades in several countries. It has been suggested that this trend could be artefactual and could be the resultant of an ageing population, improvement in health access and in diagnostic procedures, changes in coding classification for tumors recorded in registries, and/or an increase in the rate of histological confirmation, even in the elderly. All these factors are likely to play a role but they might not fully explain the increase in incidence, observed in most age groups. 2).
Brain invasion was the basis of the last modification of the meningioma grading published in the in the 2007 edition of the WHO classification of the tumours of the central nervous system.
According to the WHO 2007 classification system, the meningiomas are classified into 3 histological grades and 15 subtypes. This histopathological classification is generally used to predict the clinical course of meningioma. Most meningiomas are benign, well-circumscribed, slow growing tumors corresponding to WHO grade I 3).
High-grade (World Health Organization [WHO] Grade II and III) meningiomas constitute a minority of all meningioma cases but are associated with significant morbidity and mortality, due to more aggressive tumor behavior and a tendency to recur despite standard therapy with resection and radiotherapy. They display a higher degree of vascularity than WHO Grade I meningiomas and produce angiogenic and growth factors, including vascular endothelial growth factor (VEGF).
Meningothelial meningioma 9531/0
Fibrous meningioma (fibroblastic) 9532/0
Transitional meningioma(mixed) 9537/0
Psammomatous meningioma 9533/0
Angiomatous meningioma 9534/0
Microcystic meningioma 9530/0
Secretory meningioma 9530/0
Lymphoplasmacyte-rich meningioma 9530/0
Metaplastic meningioma 9530/0
Chordoid meningioma 9538/1
Clear cell meningioma 9538/1
Atypical meningioma 9539/1
Papillary meningioma 9538/3
Rhabdoid meningioma 9538/3
Anaplastic meningioma (malignant) 9530/3
Meningiomas originate from the arachnoid cap cells, which are found in the meninges that surround the brain and spinal cord.
An increased risk of meningiomas has been associated with certain tumor-susceptibility syndromes, especially neurofibromatosis type II, but no gene defects predisposing to isolated familial meningiomas have thus far been identified.
Other intrinsic risk factors (gender, ethnic groups, allergic conditions, familial and personal history, genetic polymorphisms)
They have been suspected to play a role in the etiology of meningiomas and their changes with time is likely to impact incidence trends. A causal link has been established only for ionising radiation but the role of many other factors have been hypothesised: electromagnetic fields, nutrition, pesticides, hormonal as well as reproductive factors. Considering the serious or even lethal potentiality of some meningiomas and the apparent rise in their incidence, all practitioners involved in neuro-oncology should feel concerned today of the necessity to better assess their public health burden and to study their epidemiological features 4).
Obesity but not overweight is associated with an increased risk of meningioma. Due to the limited number of studies, further research is needed to confirm the association 5).
Evidence suggests that female sex hormones play a role in the meningioma tumorigenesis. In particular, progesterone, has a receptor (PR) that is highly expressed in the majority of grade I meningiomas. Multiple meningiomas (diffuse meningiomatosis) are less frequent, but have a higher female predominance and a higher PR expression. They are, therefore, attractive candidates for anti-PR therapy.
Touat et al., treated three consecutive women with multiple meningiomas with mifepristone (RU 486). It is a synthetic steroid with high affinity for both progesterone and glucocorticoid receptors.
The treatment was well tolerated, and they observed an important and long-lasting clinical (3/3) and radiological response (2/3) or stabilisation. All the three patients are now stable after five to nine years of treatment.
These encouraging results strongly support a prospective clinical trial in this preselected population 6).
A myriad of aberrant signaling pathways involved with meningioma tumorigenesis, have been discovered. Understanding these disrupted pathways will aid in deciphering the relationship between various genetic changes and their downstream effects on meningioma pathogenesis. Torres-Martin et al. identified a subset of genes that were upregulated in meningiomas and schwannomas when compared to their respectively healthy tissues, including PDGFD, CDH1 and SLIT2. Thus, these genes should be thoroughly studied as targets in a possible combined treatment 7).
Classic cytogenetic studies have disclosed a progressive course of chromosomal aberrations, especially in high-grade meningiomas. The application of unbiased next-generation sequencing approaches has implicated several novel genes whose mutations underlie a substantial percentage of meningiomas. These insights may serve to craft a molecular taxonomy for meningiomas and highlight putative therapeutic targets in a new era of rational biology-informed precision medicine 8).
The major known genetic contributor to meningioma formation was NF2, which is disrupted by mutation or loss in about 50% of tumors. Besides NF2, several recurrent driver mutations were recently uncovered through next-generation sequencing.
Tang et al., performed whole-genome sequencing across 7 tumor-normal pairs to identify somatic genetic alterations in meningioma. As a result, Chromatin regulators, including multiple histone members, histone-modifying enzymes and several epigenetic regulators, are the major category among all of the identified copy number variants and single nucleotide variants. Notably, all samples contained copy number variants in histone members. Recurrent chromosomal rearrangements were detected on chromosome 22q, 6p21-p22 and 1q21, and most of the histone copy number variants occurred in these regions. These results will help to define the genetic landscape of meningioma and facilitate more effective genomics-guided personalized therapy 9).
Non-NF2 meningiomas concern AKT1, SMO, KLF4 and TRAF7. The molecular mechanisms underlying tumorigenesis of high histological grades have been progressively deciphered with the recent discovery of TERT promoter mutations in progressing tumors. A better understanding of the genetics and clinical behavior of high-grade meningiomas is mandatory in order to better design future clinical trials. New genetically engineered mouse models of benign and histologically aggressive meningioma represent a substantial resource for the establishment of relevant pre-clinical trials. By studying the mechanisms underlying these new tumorigenesis pathways and the corresponding mouse models, we should be able to offer personalized chemotherapy to patients with surgery- and radiation-refractory meningiomas in the near future 10).
An understanding of the genetic and molecular profile of meningioma would provide a valuable first step towards developing more effective treatments for this intracranial tumor. Chromosomes 1, 10, 14, 22, their associated genes, and other potential targets have been linked to meningioma proliferation and progression. It is presumed that through an understanding of these genetic factors, more educated meningioma treatment techniques can be implemented. Future therapies will include combinations of targeted molecular agents including gene therapy, si-RNA mediation, proton therapy, and other approaches as a result of continued progress in the understanding of genetic and biological changes associated with meningiomas 11).
Some authors believe that even with a long-term follow up, the more aggressively removed meningiomas will regrow, possibly because of remaining cells or the molecular biology of the tumors.
Cytogenetics aspects involved in the recurrence and progression of World Health Organization (WHO) grade I meningiomas are well known, including losses in 1 p and other chromosomal abnormalities and play an important role in the recurrence of the meningioma 12) 13).
Classic cytogenetic studies have disclosed a progressive course of chromosomal aberrations, especially in high-grade meningiomas. The application of unbiased next-generation sequencing approaches has implicated several novel genes whose mutations underlie a substantial percentage of meningiomas. These insights may serve to craft a molecular taxonomy for meningiomas and highlight putative therapeutic targets in a new era of rational biology-informed precision medicine 14).
There are three main grades (classifications) of meningiomas:
Grade I – Benign meningioma: This non-cancerous type of brain tumor grows slowly and has distinct borders. Approximately 78-81% of meningiomas are benign (non-cancerous).
Grade II – Atypical meningioma: Approximately 15-20% of meningiomas are atypical, meaning that the tumor cells do not appear typical or normal. Atypical meningiomas are neither malignant (cancerous) nor benign, but may become malignant. Grade II atypical meningiomas also tend to recur and grow faster.
Grade III – Malignant or anaplastic meningioma.
Conventional morphologic criteria as studied in routine Haematoxylin and Eosin stained sections (H & E) may not be accurate in grading and assessing prognosis in small stereotactic biopsy specimens. Thus, arises the need for objective methods for assessing tumour biology. Angiogenesis is a key event in the spread of tumours and denotes a poor prognosis. Intratumoural Microvessel Density (MVD) helps in quantification of angiogenesis.
MIB-1 index LI is an important complementary tool to accurately grade meningothelial tumours and assess tumour biology. Specific cycling endothelial markers along with CD 34 & MVD could be used to assess the prognosis of these tumours 15).
The most common clinical features of meningiomas are neurological deficits.
The cross-sectional imaging modalities, MRI and CT, have improved in resolution and fidelity. These modalites now provide not only improved structural information but also insights into functional behavior. MRI has, in particular, proven to have powerful capabilities in evaluating meningiomas because of the ability to assess soft tissue characteristics such as diffusion and vascular supply information, such as perfusion. Recent investigational advances have also been made using a combination of X-ray fluoroscopy for selective catheterization followed by MR perfusion measurement performed with intra-arterial injection of contrast. Together all these modalities provide the radiographer with powerful capabilities for evaluating meningiomas 16).
ASL-PWI may provide a reliable and noninvasive means of predicting angiographic vascularity of meningiomas. It may thus assist in selecting potential candidates for preoperative digital subtraction angiography and embolization in clinical practice 17).
Grade II/III tumors had lower ADC mean values than grade I meningiomas. ADCmean correlated negatively with tumor proliferation index and ADCmin with tumor cell count. These associations were different in several meningiomas. ADCmean can be used for distinguishing between benign and atypical/malignant tumors 18).
The estimated threshold ADC value of 0.85 can differentiate grade I meningioma from grade II and III tumors. The same ADC value is helpful for detecting tumors with high proliferation potential 19).
Meningiomas are treated with radiation therapy, stereotactic radio-surgery or surgical resection. At the moment surgical resection is the only definite treatment, and the removal of the tumour also removes the peritumoral edema. Based on the localization of the meningioma, surgery can be complicated.
Due to the strong dependencies between the results from surgical therapy and the localisation of the tumor, it is only possible to derive recommendations on whether or not to perform the surgical therapy with respect to the localisation of the tumor. Only for patients with tumors with a spinal localisation or WHO Grade I meningiomas with a cortical localisation, primary treatment with by means of microsurgery can be suggested. For all other localisations of the tumor, alternative treatment by radiosurgery should be discussed. From the literature identified, a clear recommendation of one or the other therapy however can not be deduced. Thus, there is a strong need for randomised clinical trials or prospective or contrasting cohort studies, which compare rigorously microsurgery with radiosurgery concerning different localisations of tumors 20).
At present, there are no completed prospective, randomized trials assessing the role of either surgery or radiation therapy. Successful completion of future studies will require a multidisciplinary effort, dissemination of the current knowledge base, improved implementation of WHO grading criteria, standardization of response criteria and other outcome end points, and concerted efforts to address weaknesses in present treatment paradigms, particularly for patients with progressive or recurrent low-grade meningioma or with high-grade meningioma. In parallel efforts, Response Assessment in Neuro-Oncology (RANO) subcommittees are developing a paper on systemic therapies for meningioma and a separate article proposing standardized end point and response criteria for meningioma 21).
Shah et al. analyze new therapeutic options for the embolization of meningiomas, as well as the future of meningioma treatment through recent relevant cohorts and articles. They investigate various embolic materials, types of meningiomas amenable to embolization, imaging techniques, and potential imaging biomarkers that could aid in the delivery of embolic materials. They also analyze perfusion status, complications, and new technical aspects of endovascular preoperative embolization of meningiomas. A literature search was performed in PubMed using the terms “meningioma” and “embolization” to investigate recent therapeutic options involving embolization in the treatment of meningioma. They looked at various cohorts, complications, materials, and timings of meningioma treatment. Liquid embolic materials are preferable to particle agents because particle embolization carries a higher risk of hemorrhage. Liquid agents maximize the effect of devascularization because of deeper penetration into the trunk and distal tumor vessels. The 3 main imaging techniques, MRI, CT, and angiography, can all be used in a complementary fashion to aid in analyzing and treating meningiomas. Intraarterial perfusion MRI and a new imaging modality for identifying biomarkers, susceptibility-weighted principles of echo shifting with a train of observations (SW-PRESTO), can relay information about perfusion status and degrees of ischemia in embolized meningiomas, and they could be very useful in the realm of therapeutics with embolic material delivery. Direct puncture is yet another therapeutic technique that would allow for more accurate embolization and less blood loss during resection 22).
The vast majority of meningiomas are benign, well differentiated, and with low proliferative potential.
Histological type is the major predictor of meningioma behavior.
The outcomes of patients with surgery and radiation refractory meningiomas treated with medical therapies are poorly defined. Published reports are limited by small patient numbers, selection bias, inclusion of mixed histologic grades and stages of illness, and World Health Organization (WHO) criteria changes.
A PubMed literature search was performed for all English language publications on medical therapy for meningioma. Reports were tabulated and analyzed for number of patients, histologic grade, prior therapy, overall survival, progression-free survival (PFS), and radiographic response.
Forty-seven publications were identified and divided by histology and prior therapies, including only those that treated patients who were surgery and radiation refractory for further analysis. This included a variety of agents (hydroxyurea, temozolomide, irinotecan, interferon-α, mifepristone, octreotide analogues, megestrol acetate, bevacizumab, imatinib, erlotinib, and gefitinib) from retrospective, pilot, and phase II studies, exploratory arms of other studies, and a single phase III study. The only outcome extractable from all studies was the PFS 6-month rate, and a weighted average was calculated separately for WHO grade I meningioma and combined WHO grade II/III meningioma. For WHO I meningioma, the weighted average PFS-6 was 29% (95% confidence interval [CI]: 20.3%-37.7%). For WHO II/III meningioma, the weighted average PFS-6 was 26% (95% CI: 19.3%-32.7%). This comprehensive review confirms the poor outcomes of medical therapy for surgery- and radiation-refractory meningioma. We recommend the above PFS-6 benchmarks for future trial design 23).
The serum levels of miR-106a-5p, miR-219-5p, miR-375, and miR-409-3p were significantly increased, whereas the serum levels of miR-197 and miR-224 were markedly decreased. The area under the ROC curve (AUC) for the six combined miRNAs was 0.778. The 4 increased miRNAs were significantly decreased, while the 2 decreased miRNAs were significantly increased after tumor removal. Furthermore, the expression levels of miR-224 were associated with sex, and the expression levels of miR-219-5p were positively associated with the clinical stages of meningioma. Finally, the high expression of miR-409-3p and low expression of miR-224 were significantly correlated with higher recurrence rates. The study revealed that the panel of 6 serum miRNA may have the potential to be used clinically as an auxiliary tool for meningioma patients 24).
Tumor recurrence remains the major clinical complication of meningiomas, the majority of recurrences occurring among WHO grade I/benign tumors.
Domingues et al, found an adverse impact on patient relapse-free survival (RFS) for males, presence of brain edema, younger patients (<55 years), tumor size >50 mm, tumor localization at intraventricular and anterior cranial base areas, WHO grade II/III meningiomas, and complex karyotypes; the latter 5 variables showed an independent predictive value in multivariate analysis. Based on these parameters, a prognostic score was established for each individual case, and patients were stratified into 4 risk categories with significantly different (P < .001) outcomes. These included a good prognosis group, consisting of approximately 20% of cases, that showed a RFS of 100% ± 0% at 10 years and a very poor-prognosis group with a RFS rate of 0% ± 0% at 10 years. The prognostic impact of the scoring system proposed here was also retained when WHO grade I cases were considered separately (P < .001) 26).
Gousias et al., reviewed their institutional experience with a policy based on maximal safe resections for meningiomas, and they analyzed the impact of the degree of resection on functional outcome and progression free survival (PFS).
They retrospectively analyzed 901 consecutive patients with primary meningiomas (716 WHO Grade I, 174 Grade II, and 11 Grade III) who underwent resections at the University Hospital of Bonn between 1996 and 2008. Clinical and treatment parameters as well as tumor characteristics were analyzed using standard statistical methods.
The median follow-up was 62 months. PFS rates at 5 and 10 years were 92.6% and 86.0%, respectively. Younger age, higher preoperative Karnofsky Performance Scale (KPS) score, and convexity tumor location, but not the degree of resection, were identified as independent predictors of a good functional outcome (defined as KPS Score 90-100). Independent predictors of PFS were degree of resection (Simpson Grade I vs II vs III vs IV), MIB-1 index (< 5% vs 5%-10% vs >10%), histological grade (WHO I vs II vs III), tumor size (≤ 6 vs > 6 cm), tumor multiplicity, and location. A Simpson Grade II rather than Grade I resection more than doubled the risk of recurrence at 10 years in the overall series (18.8% vs 8.5%). The impact of aggressive resections was much stronger in higher grade meningiomas.
A policy of maximal safe resections for meningiomas prolongs PFS and is not associated with increased morbidity 27).