Meningiomas are leptomeningeal neoplasms thought to originate from arachnoid membranes that form the cranial and spinal meninges 1).
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 2).
They account for the most World Health Organization (WHO) classified Central Nervous System (CNS) tumors in the USA 3).
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. 4).
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
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
see Meningioma etiology.
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 5).
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 6).
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 7).
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 8).
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 9).
Several options for drug treatment of unresectable, recurrent and/or biologically aggressive high grade meningiomas are currently under evaluation, such as tyrosine kinase inhibition, AKT inhibition and mTOR inhibition. Direct DNA targeting by trabectedin has shown promising in vitro results and is currently being investigated in a large clinical trial (EORTC‑1320) 10).
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 11).
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 12).
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 13).
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 14).
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 15).
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) 17).
In November 2016, Almutairi et al. performed a title-specific search of the Scopus database using “Meningioma” as the search query term without publication date restrictions. The top 100 most cited articles were obtained and reviewed.
The top 100 most cited articles received a mean 198 citations per paper. Publication dates ranged from 1953 to 2013; most articles were published between 1994 and 2003, with 50 articles published during that period. NEUROSURGERY published the greatest number of top cited articles (22 of 100). The most frequent study categories were laboratorial studies (31 of 100) and natural history studies (28 of 100). Non-operative management studies were twice as common as operative management studies in the top cited articles. Neurosurgery as a specialty contributed to 50% of the top 100 list. The most contributing institute was the Mayo Clinic (11%); the majority of the top cited articles originated in the United States (53%).
They identified the top 100 most-cited articles on meningioma that may be considered significant and impactful works, as well as the most noteworthy. Additionally, they recognized the historical development and advances in meningioma research, and the important contributions of various authors, specialty fields, and countries. A large proportion of the most cited articles were written by authors other than neurosurgeons, and many of these articles were published in non-neurosurgery journals 18).
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 19).