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Although there are reports of long-term progression-free survival, radiation treatment of meningiomas fails in some cases.

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Previous Article Next Article. Petroclival Tumors and Cavernous Extension Meningiomas of the petroclival region usually involve the petrous apex and the upper two-thirds of the clivus. Related Articles Neurological Oncology. Multiple Sclerosis. The evolution of WHO grading scales associates with an improved correlation between grade and survival However, inter-observer differences and representative sampling of select sections from large tumors may bias the final grading and, therefore, prediction of natural history.

As with other CNS tumors, unbiased criteria for diagnostic arbitration, such as molecular signatures, can abet definitive stratification of tumor class. Furthermore, an association between such molecular signatures, tumor phenotype, and, ultimately, prognosis would improve initial planning for treatment interventions.

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Independent of tumor classification, the clinical course of meningiomas following surgical resection highlights its biologic proclivity for invasiveness. Furthermore, meningiomas with benign histopathologic features that invade the brain exhibit a similar likelihood of recurrence as higher grade, atypical, meningiomas. Thus, despite being the quintessential icon of CNS extra-axial tumors, the invasive potential of meningioma cells highlights an inherent limitation to debulking strategies and should be accounted for in therapeutic strategies.

Surgical resection aside, radiation serves as a common adjuvant treatment for meningioma, especially in high-grade and recurrent tumors. A few biological agents, such as hydroxyurea and somatostatin inhibitors, have been trialed with limited success in meningiomas refractory to standard treatment modalities These treatments rely upon the biologic response of non-senescent tumor cells. Additionally, the development of targeted pharmacologic inhibitors, as widely studied for systemic cancers and discussed below for meningioma, presumes a global distribution of the oncogenic driver or modulator target.

The presence of intratumoral heterogeneity poses a fundamental impediment to the efficacy of these therapeutic strategies. The observation of meningioma heterogeneity stems from a number of potential etiologies, including intratumoral necrosis, cystic degeneration, heterogeneous tumor cell expansion, imbalances in cell density, and hemorrhage. In particular, subclonal expansion within an admixture of functionally distinct cancer cells has been posited to account for incomplete treatment response, acquired and innate treatment resistance, and disease relapse for malignancies, such as glioblastoma and systemic cancers.

Similarly, molecular and cellular heterogeneity is increasingly appreciated in meningioma 16 , and may present a similar challenge to the development of therapeutic strategies. These characteristics of meningiomas echo challenges posed by other tumors, some of which serve as exemplars in decrypting the molecular code toward a more unified front in diagnosis and treatment, as discussed below.

The development of meningiomas in NF2 -knockout mice corroborates its role as an early oncogenic driver in meningioma tumorigenesis 21 , Notably, mutations of these genes in meningiomas occur to large degree without concurrent alteration of NF2 or loss of chromosome Figure 2. B Recurrent chromosomal copy number alterations in meningioma. Chromosomal arm-level gains red and losses blue are observed with increasing frequency in higher-grade meningiomas, compared to grade I meningiomas.

This may recapitulate embryologic mechanisms to spur tumor formation, given the role of KLF4 as a transcription factor that promotes reprograming of differentiated somatic cells back to a pluripotent state in normal development Another recurrent mutation in AKT1 , located on chromosome 14q32, is observed in 6. These SMO alterations result in activation of Hedgehog signaling, another well-characterized pathway in cancer that is notably dysregulated in basal-cell carcinoma and medulloblastoma 28 , Collectively, these somatic mutations hold significant promise for advancing the molecular taxonomy of meningioma.

Beyond mutations, insertions, and deletions at the single nucleotide level, meningiomas harbor a classic constellation of chromosomal copy number alterations Figure 2 B. Aside from loss of chromosome 22, the copy number landscape of benign meningiomas is typically neutral. One exception is the angiomatous subtype of grade I meningiomas, which notably express multiple polysomies across the genome, most commonly of chromosome 5 In comparison, higher-grade meningiomas express a markedly higher burden of chromosomal losses and gain.

Surgical and Radiation Treatment of Skull Base Meningiomas

These include frequent loss of chromosomes 1p, 6q, 10, 14q, and 18q, as well as gain of chromosomes 1q, 9q, 12q, 15q, 17q, and 20q 7 , 33 , Among these, loss of chromosomes 1p and 14q is the most frequent cytogenetic abnormality observed in meningiomas after chromosome 22, affecting half of grade II and nearly all grade III meningiomas Investigations into candidate oncogenes on these chromosomal arms have yet to elucidate clear drivers for meningioma tumorigenesis.

In addition to mutations and copy number alterations, epigenomic changes may provide another complementary biologic mechanism in meningioma development and progression Overall, all existing evidence suggests a progression in genomic complexity in high-grade meningiomas.

These significant advances in our understanding of meningiomas provide an expanding toolbox to formulate a molecular taxonomy and explore novel therapeutic options for this surprisingly diverse tumor entity. This paradigm shift toward molecular taxonomy is inspired by examples from several tumor types, including glioblastoma, medulloblastoma, and ependymoma, where molecular stratification has transformed their diagnosis and management 36 — Similarly, associations between molecular signatures with characteristic phenotypes, intracranial locations, tumor subclass, and clinical prognosis have begun to emerge as an increasing number of meningiomas are systematically characterized.

The histologic subtype and location of meningioma associates with its molecular profile Table S1 in Supplementary Material. Grade II and III meningiomas harbor an incremental complement of chromosomal alterations, as discussed above. Copy number gains, especially polysomy 5, are also characteristic of angiomatous meningiomas, a grade I subtype Additionally, clear cell meningiomas are associated with loss-of-function mutations of SMARCE1 in the hereditary multiple spinal meningioma syndrome and some cranial locations 39 , Interestingly, genetic alterations also correlate with anatomic location in some meningiomas.

In comparison, convexity meningiomas are more likely to express NF2 mutations and loss of heterozygosity of chromosome The association between tumor location and genotype may aid candidate selection in future clinical trials that target specific oncogenic mutations. Aside from the role of molecular biomarkers in abetting the diagnosis of meningioma, one fundamental question in the clinical management of meningioma patients is the risk of recurrence following surgical resection.

Diagnosing Meningioma

There is particular ambiguity among grade II meningiomas, for which no consensus exists regards appropriate adjuvant treatment modality and timing. Recently, analysis of a cohort of atypical meningiomas following gross total resection revealed an association between increased chromosomal copy number alterations and risk of recurrence By summing the incidence of broad copy number events across an aggregate pool of common chromosomal aberrations in meningiomas, this strategy bypasses the limitations of assessing isolated molecular candidates in meningioma oncogenesis and offers a rapid molecular appraisal of potential outcome through routine clinical cytogenetic testing.

In other words, patients harboring grade II meningiomas with high chromosomal disruption, which may have a higher risk of recurrence, may benefit from closer surveillance or adjuvant therapies. The validity of such molecular prognostication strategies remains to be proven in future studies. If corroborated, they may serve a powerful tool in counseling patients, guiding management decisions, and stratifying clinical trials. Elucidation of critical oncogenic drivers in a number of cancers e.

While this genomically stratified trial augurs an exciting direction for refractory meningiomas that progress after standard therapy, other meningiomas that do not express these mutations, including most high-grade tumors, remain devoid of effective pharmacologic options. Furthermore, recognition of intratumoral cellular and molecular heterogeneity, which may foster resistant subclonal growth following targeted therapies, encourages investigation of alternative treatment strategies — such as immunotherapy Deployment of the innate and adaptive immune response offers an attractive option for genomically complex tumors, where presumably a higher neoantigen load is available for immune targeting 45 , Suppression of inhibitors of T-cell activation, known as immune checkpoints, has achieved durable clinical responses in several advanced systemic cancers In grade II and III meningiomas that progress after surgery and standard radiation, a phase 2 clinical trial evaluating checkpoint blockade with nivolumab is anticipated to initiate NCT Contemporary advances in molecular, genomic, epigenetic, and immune profiling has ushered a renaissance in the study of meningiomas.

These systematic approaches suggest a molecular taxonomy that promises to influence diagnosis, disease classification, and, ultimately, clinical management. Furthermore, appreciation of shared biological characteristics between meningiomas and other CNS cancers — including invasiveness and intratumoral heterogeneity — may lead to an expansion of the therapeutic arsenal in the treatment of this increasingly disparate tumor.

All authors critically revised the manuscript and approved the final submission. All authors contributed to this article and attest to no conflicts of interest. All authors have no financial disclosures. The majority of copy number variants and single-nucleotide variants were chromatin regulators, including multiple histone members, histone-modifying enzymes, and several epigenetic regulators. Recurrent chromosomal arrangements on chromosome 22q, 6p, and 1q were detected Imaging characteristics, advanced imaging technology, and radiomics are playing an increasingly important role in tumor diagnosis, prognosis, and treatment response.

Diffusion-weighted magnetic resonance imaging MRI , diffusor tensor imaging, and positron emission tomography PET imaging have been studied for preoperative prediction of biological behavior of meningiomas; however, their clinical utility is not yet established. Peritumoral edema around meningiomas has been associated with higher proliferation index and irregular tumor margins which may be a marker for more aggressive phenotype Increased vascular endothelial growth factor VEGF secretion and associated angiogenesis may also be associated with peritumoral edema Recently, a retrospective analysis of a small cohort of patients showed that preoperative fractal analysis of MRIs, a software method which better describes complexity of an image, may play a role in identifying non-BMs 1 , 24 — Since the s, octreotide scintigraphy has been demonstrated as an effective method to image meningiomas More contemporary imaging techniques such as PET imaging have added a new dimension in the diagnosis and grading of meningiomas.

Moreover, tumors with fast growth rate and transosseous expansion have the highest binding of the radionuclide, which indicates the potential for DOTATATE-based therapy Surgery and radiation therapy RT have been the cornerstone of treatment for meningiomas of all grades.

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Chemotherapy thus far has shown limited benefit on the basis of several retrospective studies; however, with increasing understanding of molecular pathways, there may be a greater role for targeted drugs. An important aspect in the management of meningioma is predicting the risk of recurrence. With the publishing of the Simpson grading scale in , the extent of resection has been a central component of meningioma management and predictive of recurrence Tumor location has also been considered a predictor of recurrence Male gender, lack of calcification, reduced expression of chromosome 1p, VEGF expression, and MIB-L1 monoclonal antibody tumor proliferation marker are other factors associated with meningioma recurrence 29 , Small, asymptomatic presumed meningiomas can be followed conservatively by observation and periodic imaging, and surgical intervention can be pursued if patients become symptomatic or there is significant growth Surgery with the goal of gross total resection GTR is the treatment of choice for symptomatic meningiomas.

Gross totally resected BMs can be followed with serial imaging. Stereotactic radiosurgery SRS has also been used as first-line therapy, usually in patients whose meningioma presents significant surgical challenges 36 — These challenges are related to tumor location, patient age, comorbidities, recurrence after incomplete resection, and risks of neurologic morbidity if resection is pursued Local control rates are best for tumors less than 10 cm 3 in volume.

Though non-invasive when compared with surgery, SRS is associated with potential toxicities, including cranial neuropathies from RT-induced injury. To avoid these complications in vital structures such as the optic nerve, the standard minimum distance between the meningioma and anterior optic apparatus is 5 mm; however, with modern radiosurgical technology and hypofractionated SRS regimens, the distance has been decreased to nearly zero Adaptive hybrid approaches of near total resection followed by SRS for meningiomas located in critical areas near important vascular and neural structures are increasingly being used The benefit of adjuvant external beam radiation after GTR for AM is debated; prior retrospective studies show mixed results of early adjuvant RT following GTR and thus the current recommendation is active surveillance 43 , 47 , SRS after STR may have a tumor control similar to that of external beam radiation; however, SRS is more beneficial for smaller meningiomas 39 , 49 , A prospective phase II trial ClinicalTrials.

Based on a few retrospective analyses, adjuvant radiation demonstrated improved PFS and OS compared with surgery alone 52 , Post-operative external beam radiation should be performed after any extent of resection for WHO grade III meningiomas There are limited chemotherapy options for meningiomas. According to National Comprehensive Cancer Network guidelines, alpha interferon, somatostatin receptor agonists, and VEGF inhibitor are the only classes of recommended drugs and have previously shown only modest benefit 54 — Numerous agents such as tyrosine kinase inhibitors, especially epidermal growth factor receptor EGFR inhibitors, hydroxyurea, traditional cytotoxic chemotherapy, and hormone receptor—targeted agents, have been studied and have not shown any appreciable impact on survival.

However, much of this data is based on retrospective analysis or small phase II trials rather than controlled prospective trials Kaley et al. Future trials would greatly benefit from standardization of reporting prior therapies, pre-treatment growth rate, and PFS and OS Bevacizumab, an anti-angiogenic VEGF inhibitor, is a commonly used agent and its use as monotherapy for recurrent meningiomas is being studied ClinicalTrials.

There are two ongoing trials for recurrent AM and MM using Optune, a device worn on the scalp which uses alternating electrical fields, with and without bevacizumab ClinicalTrials. An improved understanding of meningioma biology has led to the study of several novel targets.

There have been promising responses in preclinical studies such as with pegvisomant, a growth hormone receptor antagonist; valproic acid as a radiosensitizer and apoptic marker upregulator; a combination of tumor necrosis factor—related apoptosis-inducing ligand TRAIL, a cytokine that binds to death receptors and bortezomib a proteasome inhibitor ; and amino levulinic acid 5-ALA as a photosensitizing agent 45 , 60 — An Alliance consortium group trial ClinicalTrials. There have been numerous advances in our understanding of meningiomas and minor refinements in their diagnosis and management; however, we are still limited in our ability to predict recurrence and there are only a few medical treatment options.

There are significant ongoing efforts to further understand the molecular, genetic, epigenetic basis of meningiomas which will undoubtedly revolutionize the classification system with important implications for diagnosis, prognosis, and therapeutics and trial design in the future. F Faculty Reviews are commissioned from members of the prestigious F Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published.