Thus, several somatostatin receptor inhibitors have been studied in recurrent meningiomas with questionable therapeutic effects. doi: 10.1038/sj.onc.1200853. Acta Neuropathol. Schrell UM, Rittig MG, Anders M, Kiesewetter F, Marschalek R, Koch UH, et al. Radiat Oncol. Introduced in the 1970s, the modern operating microscope and refinement of microsurgical technique significantly enhanced the neurosurgeons ability to carefully dissect meningiomas (71, 72). doi: 10.1038/sj.onc.1202531, 47. The extent of resection is the most important modifiable predictor of local control and progression free survival, independent of tumor grade and other prognostic factors (30, 60, 64). Systemic and local immunosuppression in patients with high-grade meningiomas. Barnett GH, Steiner CP, Weisenberger J. Intracranial meningioma resection using frameless stereotaxy. 34. Int J Radiat Oncol Biol Phys. One common theme among all the reports of secondary meningiomas is that the tumor typically occurred several decades after the radiation exposure. Atypical and anaplastic meningiomas remain challenging to treat. (1993) 33:95563. Br J Neurosurg. Neurol Res. J Neurooncol. Hasan S, Young M, Albert T, Shah AH, Okoye C, Bregy A, et al. This gene encodes a tumor suppressor protein, merlin, involved in regulating activation of the mTOR pathway. In atomic bomb survivors a significant dose related increase in intracranial tumors, including meningiomas (25). Attia A, Chan MD, Mott RT, Russell GB, Seif D, Daniel Bourland J, et al. doi: 10.1136/jnnp.20.1.22, 61. Furthermore, advancements in understanding the pathophysiology and molecular genetics of meningiomas is critical for improving risk stratification, predicting prognosis and recurrence, and designing novel treatments for these patients (1416). doi: 10.1007/s00401-018-1844-9. doi: 10.1016/0090-3019(85)90180-6, 18. doi: 10.1016/j.wneu.2011.08.021, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. doi: 10.3171/2016.11.JNS161170, 100. Advocates argue adjuvant radiation reduces recurrence and lengthens progression free survival in those who recur; conversely, opponents contend adjuvant radiation does not reduce recurrence and introduces further costs and potential harm from possibly unnecessary radiation. Several growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF), and their associated receptors are overexpressed in meningiomas, which stimulates tumor growth and progression in such tumors. Prayson R. Neuropathology. (2016) 131:80320. (2017) 18:68294. Ideally, the approach is wide enough to expose enough of the meningioma, its dural attachment, and surrounding structures to allow disruption of blood supply while simultaneously minimizing brain retraction and manipulation of critical structures to reduce procedure-related morbidity (68). (2014) 7:5696700. Atypical meningioma (WHO grade II). (2010) 66:6618; discussion 668669. Philadelphia, PA: Elsevier Saunders (2012). Meningioma grading: an analysis of histologic parameters. doi: 10.3171/2014.7.JNS131644, 30. Progesterone and estrogen receptors in meningiomas: prognostic considerations. Hopefully, the results of this study will clarify the controversy regarding adjuvant radiotherapy in these patients and guide clinical decision making (97). Figure 1. doi: 10.1007/s11060-016-2172-3, 149. *Correspondence: Warren Boling, wboling@llu.edu, Meningioma: From Basic Research to Clinical Translational Study, View all
Jenkinson MD, Javadpour M, Haylock BJ, Young B, Gillard H, Vinten J, et al. Under physiologic conditions, immune checkpoints modulate the immune response and prevent autoimmunity; however, meningiomas and other tumors also utilize these checkpoints to evade immune system detection and create an immunosuppressed microenvironment (57). Surg Neurol Int. Cushing H. The meningiomas (dural endotheliomas): their source and favored seats of origin (Cavendish Lecture). Menon AG, Rutter JL, von Sattel JP, Synder H, Murdoch C, Blumenfeld A, et al. (2008) 62:538; discussion 5860. Several retrospective studies of FSRS have described delivery of radiation doses of 1535 Gy over 36 fractions in meningiomas with similar local tumor control and slightly lower rates of perilesional edema ranging from 2.7 to 26% compared with SRS (103, 105, 109112). Goldbrunner R, Minniti G, Preusser M, Jenkinson MD, Sallabanda K, Houdart E, et al. (2012). (2010) 12:8794. Riemenschneider MJ, Perry A, Reifenberger G. Histological classification and molecular genetics of meningiomas. doi: 10.1056/NEJMoa1414905, 66. Overexpression is hypothesized to promote tumor growth. Pravdenkova S, Al-Mefty O, Sawyer J, Husain M. Progesterone and estrogen receptors: opposing prognostic indicators in meningiomas. (2019) 9:1472. doi: 10.3389/fonc.2019.01472, 58. Chamberlain MC, Glantz MJ. Neurol Res. doi: 10.18632/oncotarget.3082, 57. (2020) 87:9009. A retrospective analysis]. (1999) 81:21725. Hormonal dysregulation occurs frequently in meningiomas. (2014) 156:147581. Recurrent high-grade meningioma: a phase II trial with somatostatin analogue therapy. (1996) 29:197205. (2006) 105:16373. (2006) 24:72733. A multicenter, retrospective study of the Rare Cancer Network. Acta Neurochir (Wien). Ho DM-T, Hsu C-Y, Ting L-T, Chiang H. Histopathology and MIB-1 labeling index predicted recurrence of meningiomas: a proposal of diagnostic criteria for patients with atypical meningioma. Clinic for Neurosurgery with Pediatric Neurosurgery, Charit University Medicine Berlin, Germany. Thus, the WHO classification is inadequate for entirely predicting tumor aggressiveness, recurrence, and prognosis, and alternative methods are required for more adequate risk stratification (37). Jskelinen J, Haltia M, Laasonen E, Wahlstrm T, Valtonen S. The growth rate of intracranial meningiomas and its relation to histology. Alterations in protein expressions are seen in meningiomas. Neurosurg Focus. An overview of meningiomas. Int J Clin Exp Med. 104. (1993) 72:63948. (B) H&E staining, 400 magnification, demonstrating mitoses >20 per high powerfield. Goodwin JW, Crowley J, Eyre HJ, Stafford B, Jaeckle KA, Townsend JJ. doi: 10.1002/cncr.10351, 43. Recurrent meningiomas may even be treated with higher doses at ranges of 6570 Gy (13). Chemotherapy and other systemic therapies have demonstrated limited clinical efficacy in treating meningiomas (122). Similar to other neoplasms, meningiomas often overexpress VEGF, PDGF, EGF, and other growth factor receptors. Atypical and malignant meningiomas: a clinicopathological review. doi: 10.1016/j.ijrobp.2004.07.691, 96. Case Series and Analysis of a Grade Zero Resection. Meningiomas are very rare in children, but those with a history of cranial ionizing radiation are reported to have a 610 times increased relative risk of developing a meningioma with an elevated risk of atypical or anaplastic features (23). (2015) 84:2806. Recent studies have begun to investigate epigenetic modification on the level of histones with particular focus on H3K27 trimethylation (H3K27me3). With the exception of one grade 5 radiation-induced toxicity of necrosis, the other acute and late toxicities were limited to grade 13. Furthermore, progression is also applied for meningiomas that transform from a lower to a higher-grade tumor. Diagnosis and treatment of atypical and anaplastic meningiomas: a review. doi: 10.1007/s11060-014-1358-9, 147. Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM. doi: 10.1093/jjco/hyr022, 111. 69. da Silva EB Jr, Milano JB, da Silva LFM Jr, Aurich LA, Ramina R. Neuronavigation for Intracranial Meningiomas. (2000) 48:15160. Chemotherapy and other medical therapies are available as salvage treatment once standard options are exhausted; however, efficacy of these agents remains limited. Simon M, von Deimling A, Larson JJ, Wellenreuther R, Kaskel P, Waha A, et al. Based on evidence in the literature, adjuvant radiation is usually recommended for atypical meningiomas following incomplete resection, for anaplastic meningiomas regardless of the extent of resection, and for recurrent meningiomas (8186). (2018) 129:3547. Norden AD, Raizer JJ, Abrey LE, Lamborn KR, Lassman AB, Chang SM, et al. Programmed-death 1 (PD-1) and its ligand, (PD-L1), function as part of the immune checkpoint pathway that regulates T cell lymphocytes, and its expression in meningiomas is correlated with higher tumor grade and aggressiveness (56, 58, 59). (2004) 60:124156. Dose-painting intensity-modulated proton therapy for intermediate- and high-risk meningioma. Despite these challenges, however, advances in oncologic research and technology provide hope by uncovering new and informative genetic mutations, aberrant signaling pathways, and protein biomarkers associated with tumor behavior and recurrence risk. doi: 10.1007/s11060-010-0386-3, 24. Madani I, Lomax AJ, Albertini F, Trnkov P, Weber DC. doi: 10.1080/01616412.1999.11740896. In the 2000 WHO classification, brain invasion was not a criterion for grade II or grade III meningiomas; however, later studies have shown brain invasion to be associated with aggressive behavior and increased risk of recurrence. Moreover, many neurosurgeons report an enhanced appreciation of anatomy and increased perception of safety (74, 80). doi: 10.1093/jnci/94.20.1555, 26. 40 Articles, This article is part of the Research Topic, Creative Commons Attribution License (CC BY), Loma Linda University, Loma Linda, CA, United States. Cobb MA, Husain M, Andersen BJ, al-Mefty O. Advancements in understanding the pathophysiology and molecular biology of meningiomas is critical for improving risk stratification, predicting prognosis and recurrence, and designing novel treatments for these patients. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. doi: 10.3171/jns.1989.71.5.0665, 10. doi: 10.1016/0360-3016(95)02166-3, 102. Chin J Cancer Res. In addition to conventional fractionated photon radiotherapy, these modalities include stereotactic radiosurgery (SRS), fractionated stereotactic conformal radiotherapy (FSRS), intensity modulated photon radiation therapy (IMRT), and particle therapies with protons or carbon ions. Mozes P, Dittmar JO, Habermehl D, Tonndorf-Martini E, Hideghety K, Dittmar A, et al. 75. However, as mentioned above, ROAM-EORTC 1308 is a phase III randomized clinical trial investigating adjuvant RT vs. active monitoring in patients with atypical meningioma following gross total resection. doi: 10.3171/jns.2005.102.s_supplement.0283, 92. Patients randomized to the radiosurgery arm will receive 60 Gy in 30 fractions over 6 weeks. Clinical utility and cost-effectiveness of interactive image-guided craniotomy: clinical comparison between conventional and image-guided meningioma surgery. (2000) 47:407; discussion 4748. A meta-analysis of 14 retrospective studies by Hasan et al. In the most recently published 2016 WHO classification, there were no further modifications to grading criteria (11). J Neurosurg. Combs SE, Hartmann C, Nikoghosyan A, Jkel O, Karger CP, Haberer T, et al. doi: 10.1007/s11060-009-9948-7, 145. 54. A higher MIB-1 index is associated with worse prognosis with one study reporting MIB-1 indices of 1.9, 4.5, and 11.7% in benign, atypical, and anaplastic meningiomas, respectively (3941). Benign meningiomas: primary treatment selection affects survival. J Neurol Neurosurg Psychiatry. Interferon-alpha is an immunomodulating agent demonstrating slight therapeutic benefit in recurrent meningiomas not amenable to resection. A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas. Bailo M, Gagliardi F, Boari N, Castellano A, Spina A, Mortini P. The role of surgery in meningiomas. Neurochirurgie. 72. 73. (2011) 41:60916. Another study comparing PBT with IMRT for atypical, anaplastic, and recurrent meningiomas reported similar dose conformity to the tumor volume but observed significantly less extraneous radiation exposure to surrounding structures with PBT. doi: 10.1007/s00701-014-2188-4, 143. A study comparing proton beam therapy (PBT) alone (56 GyE in 1.82 GyE daily fractions), IMRT (50 in 2 Gy daily fractions) with carbon ion radiotherapy (CIRT) boost (18 with 3 Gy daily fractions), IMRT (median 56 in 1.82 Gy daily fractions), and fractionated SRT (56 in 1.82 Gy daily fractions) found tumor shrinkage and local control at 1 and 2 years follow up was independent of radiation modality. Surg Neurol. doi: 10.1007/s00262-019-02342-8, 60. Meningiomas: knowledge base, treatment outcomes, and uncertainties. (2017) 103:65563. (2012) 109:6370. doi: 10.1007/s11060-010-0343-1, 14. (2004) 18:4959. Medical management of meningiomas: current status, failed treatments, and promising horizons. Radiother Oncol. Additionally, when these high grade meningiomas occur at the skull base, they have lower recurrence rates and better overall prognosis than similar tumors found over the convexities (27, 28). These grades are referenced to describe outcomes in some of the below studies. Cancer. Neurooncology. A systematic review of ion radiotherapy in maintaining local control regarding atypical and anaplastic meningiomas. doi: 10.1016/j.neuchi.2017.03.004, 88. 105. Olar A, Wani KM, Sulman EP, Mansouri A, Zadeh G, Wilson CD, et al. Cancer Res. Neurosurgery. PLoS ONE. Figure 2. Epidemiology of intracranial meningioma. A systematic review of preoperative embolization for meningiomas by Shah et al. J Neurooncol. doi: 10.1007/BF03038510, 93. Carbon ion radiation therapy for high-risk meningiomas. (64) with seven studies plus data from the author's institution comparing GTR alone vs. GTR plus RT in patients with atypical meningioma found a trend toward lower 5 year recurrence rates in patients treated with radiation; however, this did not reach statistical significance (12 vs. 19%; p = 0.2). The role of adjuvant treatment in patients with high-grade meningioma. Extent of resection and overall survival for patients with atypical and malignant meningioma. Whereas these abnormalities are rare in benign meningiomas, they are observed frequently in atypical and anaplastic meningiomas (48, 49). Neurology. As mentioned above, overexpression of somatostatin receptors is associated with more aggressive tumors and higher recurrence rates. Advocates argue that adjuvant radiation reduces the risk of recurrence, increases time to recurrence and tumor burden in those who develop recurrence, and improves disease-specific survival (34, 61, 64, 84, 85, 8892). London: IntechOpen. doi: 10.1007/s11060-012-0828-1, 82. Thus, the goal of surgery, when feasible, is GTR; however, tumor location, involvement of nearby neurovascular structures, or brain invasion may limit the extent of resection, in which case maximum safe resection is appropriate. Comparison of intensity modulated radiotherapy (IMRT) with intensity modulated particle therapy (IMPT) using fixed beams or an ion gantry for the treatment of patients with skull base meningiomas. doi: 10.1097/00006123-199702000-00007. However, several retrospective studies have described SRS to be associated with high rates of symptomatic perilesional edema ranging from 2.5 to 50%. Oncogene. Furthermore, recurrent meningiomas often become refractory to standard surgical and radiation therapies, which makes management challenging. Science. Simpson grading remains the standard method for describing surgical resection, and it is determined by the neurosurgeon's assessment and, more recently, postoperative imaging. doi: 10.3171/FOC/2008/24/5/E3. doi: 10.1093/neuonc/now207, 8. Strahlenther Onkol. doi: 10.1128/MCB.01581-08, 19. Erlotinib and gefitinib are both small molecule kinase inhibitors of EGF receptor that have been studied in phase II trials for recurrent meningioma. Pathology and genetics of meningiomas. Risk factors associated with developing perilesional edema include prior radiation treatment, larger tumor volume, higher tumor grade, and parasagittal location (103105). The microscope in neurosurgerytechnical improvements. NF2 gene mutations and allelic status of 1p, 14q and 22q in sporadic meningiomas. J Neurooncol. doi: 10.1007/s00701-014-2156-z, 6. (2016) 18:v175. doi: 10.1023/A:1005981731739, 101. Barthlemy EJ, Sarkiss CA, Lee J, Shrivastava RK.
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