Although several of these studies reported lower recurrence rates with adjuvant radiation, many were unable to demonstrate statistical significance (31, 34, 64, 85, 89). World Neurosurg. Schrell UM, Rittig MG, Anders M, Kiesewetter F, Marschalek R, Koch UH, et al. (1996) 84:8590. The 2007 WHO classification of tumours of the central nervous system. (2013) 3:213. doi: 10.3389/fonc.2013.00213, 113. Currently, the standard of care is maximum safe resection followed by adjuvant radiation for grade III and incompletely resected grade II meningiomas. 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. Recently, a sixth category, Grade 0, has been proposed in which there is complete tumor removal plus an additional 23cm from tumor insertion site with good results (63). (2019) 68:9991009. doi: 10.3340/jkns.2016.1111.009, 83. Semin Diagn Pathol. (2012) 7:44. doi: 10.1186/1748-717X-7-44, 118. (2012) 106:40915. (2014) 7:5696700. doi: 10.1056/NEJMoa1414905, 66. The rhabdoid and papillary subtypes are also classified as anaplastic (10, 11, 33). J Clin Neurosci. A systematic review of preoperative embolization for meningiomas by Shah et al. SRS delivers a single high dose of precisely targeted radiation. Ramazanov R, Dreval ON, Akatov OV, Zaretsky AA. Thus, several somatostatin receptor inhibitors have been studied in recurrent meningiomas with questionable therapeutic effects. doi: 10.3171/2012.7.JNS111439, 95. Furthermore, H3K27me3-negative meningiomas were associated with DNA methylation patterns observed in more aggressive meningiomas, and there was a proportionally higher percentage of NF2 mutations among H3K27me3-negative meningiomas. doi: 10.3171/2014.7.JNS131644, 30. Neurooncology. DNA topoisomerase II and mitosin expression predict meningioma recurrence better than histopathological grade and MIB-1 after initial surgery. 105. 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. (78), reported that liquid embolic agents were preferable to particle agents as liquid agents demonstrated deeper penetration into the tumor vessels and had a smaller risk of hemorrhage. In 1957, Donald Simpson described this strong association between extent of recurrence (60). Loss of histone H3K27me3 identifies a subset of meningiomas with increased risk of recurrence. The clear cell and chordoid subtypes are also considered atypical (10, 11, 33). Hormonal dysregulation occurs frequently in meningiomas. Currently, several trials of PD-1 and PD-L1 antibody-mediated inhibition in meningiomas are underway (57). J Neurooncol. doi: 10.3892/ijo.15.3.459. Most importantly, however, technology does not replace the neurosurgeon's knowledge and skills, and it is critical for neurosurgeons to be aware of limitations and potential for error, especially regarding neuronavigation systems. 69. da Silva EB Jr, Milano JB, da Silva LFM Jr, Aurich LA, Ramina R. Neuronavigation for Intracranial Meningiomas. (2015) 84:2806. doi: 10.1016/S0360-3016(97)00317-9, 62. Chamberlain MC, Johnston SK. (1998) 41:16475. Thus, a variety of therapies using monoclonal antibodies or small molecule kinase inhibitors targeting one or more of these receptors have been studied in recurrent meningiomas. doi: 10.1016/j.ijrobp.2019.11.028, 114. 78. Curr Treat Options Neurol. Neurosurg Clin N Am. doi: 10.1002/alr.21143, 80. doi: 10.3171/jns.1997.86.1.0113, 20. doi: 10.1038/sj.eye.6701370, 138. Maruno M, Yoshimine T, Muhammad AK, Ninomiya H, Hayakawa T. Chromosomal losses and gains in meningiomas: comparative genomic hybridization (CGH) study of the whole genome. Overexpression is hypothesized to promote tumor growth. Neurology. As molecular analyses of meningiomas continue to evolve, several cytogenetic, genomic, epigenetic, and expression alterations associated with tumor aggressiveness and proclivity for recurrence have been identified as potential biomarkers to enhance diagnosis and risk stratification as well as serve as sites to target new therapies. In the five studies reporting survival rates, there were similar 5-year overall survival rates in those with GTR vs. GTR plus RT (89.7 vs. 89.4%; p = 0.95). (2017) 103:65563. Furthermore, progression is also applied for meningiomas that transform from a lower to a higher-grade tumor. (B) H&E staining, 200 magnification, demonstrating whorls, and early focus of degeneration. Int Forum Allergy Rhinol. Another meta-analysis by Graffeo et al. Pendleton C, Olivi A, Brem H, Quiones-Hinojosa A. Harvey Cushing's early treatment of meningiomas: the untold story. Unger KR, Lominska CE, Chanyasulkit J, Randolph-Jackson P, White RL, Aulisi E, et al. Int J Radiat Oncol Biol Phys. J Neurol Neurosurg Psychiatry. doi: 10.3171/jns.1991.74.6.0861, 140. Moreover, many neurosurgeons report an enhanced appreciation of anatomy and increased perception of safety (74, 80). Cho M, Joo J-D, Kim IA, Han JH, Oh CW, Kim C-Y. Clinical applications of proton and carbon ion therapy. doi: 10.1007/s00262-019-02342-8, 60. doi: 10.3171/2015.10.JNS15877, 4. doi: 10.1016/j.wneu.2017.04.095, 65. Generally, Simpson Grades IIII are considered gross total resection (GTR), and Simpson Grades IVV constitute subtotal resection (13, 34, 61, 62). 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). The main findings regarding efficacy of post-surgery adjuvant radiation were summarized in Table 3. (1997) 86:84552. doi: 10.1002/cncr.25591, 21. Linac-based fractionated stereotactic radiosurgery for high-risk meningioma. Recurrent high-grade meningioma: a phase II trial with somatostatin analogue therapy. Perry A. Unmasking the secrets of meningioma: a slow but rewarding journey. 104. Int J Radiat Oncol Biol Phys. Treatment doses typically range from 12 to 20 Gy (67, 81, 90, 91, 106108). Fuentes S, Chinot O, Dufour H, Paz-Paredes A, Mtellus P, Barrie-Attarian M, et al. In this review, we will discuss the risk factors, classification, molecular biology, and current management strategies as well as novel therapeutic approaches and future directions for managing patients with atypical and anaplastic meningiomas. Magill ST, Young JS, Chae R, Aghi MK, Theodosopoulos PV, McDermott MW. Currently, these options are used for salvage therapy for meningiomas recurrence or progression following surgery and radiation that have become refractory or no longer amenable to these standard treatment options. In a recent systematic review of ion therapies in atypical and anaplastic meningiomas, PBT and CIRT demonstrated higher rates of PFS compared with conventional photon radiation. Stafford SL, Perry A, Suman VJ, Meyer FB, Scheithauer BW, Lohse CM, et al. Longstreth WT, Dennis LK, McGuire VM, Drangsholt MT, Koepsell TD. Histopathology of Atypical Meningiomas. doi: 10.1097/00006123-200103000-00054, 76. Since this change, the proportion of atypical meningiomas has increased from ~7 to 1520% (13, 31, 32). Katz LM, Hielscher T, Liechty B, Silverman J, Zagzag D, Sen R, et al. The ROAM/EORTC-1308 trial: Radiation versus Observation following surgical resection of Atypical Meningioma: study protocol for a randomised controlled trial. P. 51360. Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma. Liang R-F, Xiu Y-J, Wang X, Li M, Yang Y, Mao Q, et al. doi: 10.1053/j.seminoncol.2019.07.005, 120. doi: 10.1016/j.ijrobp.2004.07.691, 96. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. Although marginal, interferon-alpha, somatostatin receptor antagonists, and VEGF receptor inhibitors are the only FDA-approved agents providing any benefit to these patients. Unlike conventional photon radiation, particle therapy uses protons or carbon ions to deliver radiation. doi: 10.1007/s11060-009-9948-7, 145. doi: 10.1016/j.neuchi.2017.03.004, 88. Studies have shown that the MIB-1 proliferation index is a more sensitive proliferation marker than mitotic rate. Meningioma grading: an analysis of histologic parameters. A retrospective analysis]. Multiple factors, including neurosurgeon preference, tumor size and location, extent of dural attachment, and relationship to surrounding neurovascular structures influence surgical approach. 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). Acta Neurochir (Wien). In addition to the aforementioned WHO criteria, the mouse intestinal bacteria 1 (MIB-1) proliferation index is a histopathological biomarker that is associated with higher recurrence rates in meningiomas (38). Following encouraging results in other tumors, immune checkpoint inhibitors are being explored for treatment of meningiomas (57). (2015) 25:26675. One common theme among all the reports of secondary meningiomas is that the tumor typically occurred several decades after the radiation exposure. Several cytogenetic abnormalities have been identified in meningiomas. (1993) 15:757. Despite maximum treatment, atypical, and anaplastic meningiomas have a strong proclivity for recurrence. Figure 1. Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma. Treatment of atypical meningioma. Radiat Oncol. doi: 10.1002/(SICI)1097-0142(19980601)82:11<2262::AID-CNCR23>3.0.CO;2-R, 42. Alterations in protein expressions are seen in meningiomas. Adeberg S, Harrabi SB, Verma V, Bernhardt D, Grau N, Debus J, et al. Clin Cancer Res. *Correspondence: Warren Boling, wboling@llu.edu, Meningioma: From Basic Research to Clinical Translational Study, View all Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma. doi: 10.3171/2011.5.JNS11112, 32. Goodwin JW, Crowley J, Eyre HJ, Stafford B, Jaeckle KA, Townsend JJ. The editor and reviewer's affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. In a phase I/II trial of CIRT (18 Gy) boost with either FSRT or IMRT (54 Gy) for atypical and anaplastic meningiomas, addition of CIRT appeared to be well tolerated and potentially beneficial to these patients. (2007) 69:96973. doi: 10.1007/s11060-011-0687-1, 148. Radiosurgery as definitive management of intracranial meningiomas. (E) EMA staining, 200 magnification. Despite maximum treatment, atypical and anaplastic meningiomas have a strong proclivity for recurrence. 50. (2012) 109:18793. Thus, higher radiation doses were prescribed for PBT (66 in 2.2 Gy fractions) than for IMRT (54 in 1.8 Gy fractions) with fewer radiation induced tumors. (1997) 14:6116. doi: 10.1002/1097-0142(19930801)72:3<639::AID-CNCR2820720304>3.0.CO;2-P, 7. Meningiomas and their associated microenvironment are associated with a local immune response, and analysis of immune cell infiltrate has revealed potential biomarkers and targets for immunotherapy (56). Neurosurgery. doi: 10.1007/BF01050266, 139. (2004) 62:12102. EANO guidelines for the diagnosis and treatment of meningiomas. doi: 10.1016/S1470-2045(16)30321-7, 84. J Natl Cancer Inst. Milosevic MF, Frost PJ, Laperriere NJ, Wong CS, Simpson WJ. A RANO review. Shankar GM, Santagata S. BAP1 mutations in high-grade meningioma: implications for patient care. Benign meningiomas: primary treatment selection affects survival. Komotar RJ, Iorgulescu JB, Raper DMS, Holland EC, Beal K, Bilsky MH, et al. (1998) 39:6570. (2008) 24:E3. Immunohistochemical determination of five somatostatin receptors in meningioma reveals frequent overexpression of somatostatin receptor subtype sst2A. Pasquier D, Bijmolt S, Veninga T, Rezvoy N, Villa S, Krengli M, et al. Stereotactic radiosurgery for atypical and anaplastic meningiomas. (1995) 55:4696701. Rogers L, Gilbert M, Vogelbaum MA. *GTR, Gross total resection; STR, Subtotal resection; Dotted line represents lack of consensus regarding serial monitoring vs. adjuvant radiation following complete resection of WHO grade II meningioma. Table 1. WHO classifications for Grade II and Grade III meningiomas by year. This alteration occurs in 4060% of meningiomas. Am J Surg Pathol. doi: 10.18632/oncotarget.3082, 57. A phase II trial of IMRT administered radiation doses ranging from 54 to 60 Gy in 30 fractions for treatment of incompletely resected atypical meningiomas, anaplastic meningiomas regardless of extent of resection, and recurrent meningiomas. Summary of radiation treatments types. Int J Oncol. Front. Chamberlain MC, Tsao-Wei DD, Groshen S. Salvage chemotherapy with CPT-11 for recurrent meningioma. (2015) 6:470416. doi: 10.1016/j.wneu.2014.07.042, 112. One study reported that rates of perilesional edema rose as radiation dose per fraction increased with rates of 2.7, 8.8, and 11.9% with fractions of 6 Gy or less, 714 Gy, and 15 Gy or higher, respectively (105). Ann Genet. Lancet Oncol. J Neurooncol. Hammouche S, Clark S, Wong AHL, Eldridge P, Farah JO. J Neurosurg. With the exception of one grade 5 radiation-induced toxicity of necrosis, the other acute and late toxicities were limited to grade 13. Neurooncology. Graffeo CS, Leeper HE, Perry A, Uhm JH, Lachance DJ, Brown PD, et al. He classified extent of resection into five categories (Table 2). Anatomic location is a risk factor for atypical and malignant meningiomas. Risk factors for posttreatment edema in patients treated with stereotactic radiosurgery for meningiomas. Front Oncol. (D) Ki67 staining, 400 magnification, demonstrating proliferation indices. Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM. Mahmood A, Caccamo DV, Tomecek FJ, Malik GM. (2010) 17:13626. (2007) 114:97109. Through whole genome analysis, global DNA methylation profiling has demonstrated higher levels of methylation are associated with increased tumor aggressiveness and risk of recurrence. Rackwitz T, Debus J. doi: 10.1227/01.NEU.0000366112.04015.E2, 109. Criteria for grade II and grade III meningiomas across the different WHO editions are shown (Table 1). The 1993 WHO classification was the first effort of the WHO to organize meningiomas by tumor grade, but there was criticism over this edition due to vague criteria, which led to high interobserver variability in reporting tumor grade. A phase II evaluation of tamoxifen in unresectable or refractory meningiomas: a Southwest Oncology Group study. 133. (2016) 108:djv377. Cranial radiation on the order of 12 Gy significantly increased the risk of meningioma and glioma with the highest relative risk of development of nerve sheath tumors. Primarily resected meningiomas: outcome and prognostic factors in 581 Mayo Clinic patients, 1978 through (1988). doi: 10.1093/jjco/hyr022, 111. Neurooncology. Sahm F, Schrimpf D, Stichel D, Jones DTW, Hielscher T, Schefzyk S, et al. Other, less common, cytogenetic abnormalities associated with tumor aggressiveness and recurrence include loss at 6q, 9p, 10p, 10q, 14q, and 18q and gain at 17q and 20q (4547). Similarly, in a phase II trial of imatinib, a small molecule kinase inhibitor of PDGF receptor, in recurrent meningioma, the therapy was well tolerated, but did not prolong PFS in these patients (149). Several studies using bevacizumab, a monoclonal antibody against the VEGF receptor, have reported mild improvement in PFS in patients with recurrent meningiomas (150152). Application of CUSA Excel ultrasonic aspiration system in resection of skull base meningiomas. 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. J Neurooncol. 75. J Neurosurg. Simon M, von Deimling A, Larson JJ, Wellenreuther R, Kaskel P, Waha A, et al. Several studies have reported less radiation-induced toxicity with particle therapy than with photon radiation. doi: 10.1007/s00701-014-2156-z, 6. (1998) 73:93642. (2008) 71:138893. (2018) 5:26976. Baddour HM, Lupa MD, Patel ZM. (2015) 10:72. doi: 10.1186/s13014-015-0384-x, 121. Eye (Lond). 1. doi: 10.1007/BF03038510, 93. (1995) 1:4652. doi: 10.1080/01616412.1998.11740572, 40. Mayo Clin Proc. Grade III (anaplastic) meningiomas exhibit histologic features of overt malignancy, including high mitotic activity (20 or more mitotic figures per 10 high power microscope fields), frank anaplasia with focal, or diffuse loss of meningothelial differentiation, and their cytology often resembles carcinoma, sarcoma, or melanoma (Figures 2AE). (2004) 50:4617. (1997) 21:145565. Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01-08). Adjuvant postoperative high-dose radiotherapy for atypical and malignant meningioma: a phase-II parallel non-randomized and observation study (EORTC 22042-26042). doi: 10.1007/BF00165649, 5. Muhr C, Gudjonsson O, Lilja A, Hartman M, Zhang ZJ, Lngstrm B. Meningioma treated with interferon-alpha, evaluated with [(11)C]-L-methionine positron emission tomography. J Neurosurg. Morales-Valero SF, Van Gompel JJ, Loumiotis I, Lanzino G. Craniotomy for anterior cranial fossa meningiomas: historical overview. doi: 10.1016/j.nec.2015.11.002, 123. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. 51. Most studies describe predominantly skin irritation and alopecia with minimal to no acute or late severe toxicity (114118). doi: 10.4065/73.10.936, 68. El Shafie RA, Czech M, Kessel KA, Habermehl D, Weber D, Rieken S, et al. doi: 10.1007/s11060-012-0828-1, 82. J Neurosurg. (2001) 48:6957. (1992) 55:48690. IMRT is an advanced form of radiotherapy that delivers a conformal isodose of photons to the target. (1998) 82:22629. Comparing ion therapies, PBT had superior PFS compared with CIRT (121). The WHO classification is an important prognostic tool, but it has several limitations. Intracranial meningiomas of atypical (WHO grade II) histology. (1997) 86:11320. doi: 10.1007/s11060-007-9338-y, 107. doi: 10.1053/j.semdp.2011.01.002, 46. No life-threatening radiation-induced toxicities were reported. Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone. 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). Radiother Oncol. Int J Radiat Oncol Biol Phys. doi: 10.1007/s00401-007-0243-4, 11. doi: 10.1002/(SICI)1522-712X1:1<46::AID-IGS7>3.0.CO;2-M. 74. 73. With contemporary neuronavigation systems, neurosurgeons are able to preoperatively plan surgeries and explore alternate approaches. doi: 10.1097/00006123-199702000-00007. (1997) 2:e3. Int J Radiat Oncol Biol Phys. (2018) 13:86. doi: 10.1186/s13014-018-1026-x, 115. Neurosurg Focus. (2008) 113:214651. doi: 10.1097/00000478-199712000-00008, 36. van Alkemade H, de Leau M, Dieleman EMT, Kardaun JWPF, van Os R, Vandertop WP, et al. Neurochirurgie. Atypical and anaplastic meningiomas remain challenging to treat. 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). Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. 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. (2015) 16:519. doi: 10.1186/s13063-015-1040-3, 98. Evidence suggests methylation status may predict tumor behavior more accurately than the current WHO classification, and DNA methylation status has been proposed as an alternate classification system for meningiomas (16). (2010) 66:6618; discussion 668669. Summary of the main studies regarding efficacy of adjunctive radiotherapy in atypical (Grade II) meningiomas. Comparing use of the Sonopet() ultrasonic bone aspirator to traditional instrumentation during the endoscopic transsphenoidal approach in pituitary tumor resection. A meta-analysis of 14 retrospective studies by Hasan et al. Prayson R. Neuropathology. Figure 3. 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. (2019) 9:1472. doi: 10.3389/fonc.2019.01472, 58. (2016) 131:80320. Introduced in the 1970s, the modern operating microscope and refinement of microsurgical technique significantly enhanced the neurosurgeons ability to carefully dissect meningiomas (71, 72). J Neurooncol. Neurosurgery. Newton HB, Scott SR, Volpi C. Hydroxyurea chemotherapy for meningiomas: enlarged cohort with extended follow-up. However, in patients with completely resected atypical meningiomas, the role of adjuvant radiosurgery remains undefined, and there remains considerable debate regarding optimal management of these patients with treatment decisions varying based upon physician preference (5, 31, 34, 64, 85, 8789). 28. Emerging indications for fractionated gamma knife radiosurgery. Impaired survival and long-term neurological problems in benign meningioma. J Korean Neurosurg Soc. Bi WL, Wu WW, Santagata S, Reardon DA, Dunn IF. The authors recommend that sunitinib warrants further investigation with a larger, randomized trial to better characterize the efficacy of sunitinib in this population of patients (143). (2018) 119:36673. These devices are used to internally debulk meningiomas, which helps avoid damage to adjacent brain and other neurovascular structures during tumor dissection. Int J Clin Exp Med. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. Long-term administration of mifepristone (RU486): clinical tolerance during extended treatment of meningioma. (2015) 38:E7. Hydroxyurea has been studied in many other cancers, and it is one of the most studied chemotherapeutic agents in meningioma. Recurrence is utilized to describe patients whose meningioma returns despite complete surgical resection. Neurosurg Focus. (2012) 117:67986. Moreover, the literature offers inconsistent and ultimately inconclusive data. (2017) 80:2106. The incidence of meningiomas increases with age, peaking around the 6th and 7th decades, but high grade meningiomas have a lower median age of diagnosis than benign meningiomas. It has been increasingly utilized over time due to its high rates of local tumor control, improved dose conformity with better dose conformity and sparing surrounding normal tissue from extraneous radiation, and convenience of being delivered in a single fraction (102105). Neurosurgery. doi: 10.3171/2012.7.JNS112113, 90. (2014) 36:E14. The 2007 WHO classification was therefore revised to include brain invasion as an independent criterion for grade II (atypical) meningiomas (10). doi: 10.3171/jns.1996.84.1.0085, 39. J Natl Cancer Inst. 2nd ed. Simpson grading remains the standard method for describing surgical resection, and it is determined by the neurosurgeon's assessment and, more recently, postoperative imaging. Riemenschneider MJ, Perry A, Reifenberger G. Histological classification and molecular genetics of meningiomas. Schrell UM, Rittig MG, Anders M, Koch UH, Marschalek R, Kiesewetter F, et al. A phase II trial of bevacizumab plus everolimus (an mTOR inhibitor) reported PFS similar to prior studies of bevacizumab alone (148). Sci Rep. (2016) 6:35743. doi: 10.1038/srep35743, 87. The role of adjuvant treatment in patients with high-grade meningioma. Chamberlain MC, Glantz MJ. doi: 10.1212/01.wnl.0000271382.62776.b7, 135. Cancer. Moreover, as endovascular techniques advance, preoperative embolization has been increasingly used to facilitate meningioma resection and decrease intraoperative blood loss, especially in select patients with giant convexity meningiomas or petroclival meningiomas in which the feeding arteries may be less accessible during surgery. doi: 10.1093/neuonc/now207, 8. Significance of tumor volume related to peritumoral edema in intracranial meningioma treated with extreme hypofractionated stereotactic radiation therapy in three to five fractions. N Engl J Med. Neurosurgery. Chemotherapy and other medical therapies are available as salvage treatment once standard options are exhausted; however, efficacy of these agents remains limited. Prognosis is strongly related to the histopathological grade and extent of resection. Whereas benign meningiomas have a much higher incidence in females, atypical and anaplastic meningiomas occur almost twice as often in males (17, 18). Condra KS, Buatti JM, Mendenhall WM, Friedman WA, Marcus RB, Rhoton AL. FSRT delivers several fractions of higher radiation doses while maintaining stereotactic precision. doi: 10.1080/07357900601062339, 141. Typically, unless contraindicated, contrast-enhanced CT or MRI imaging is used, but these images can be fused with additional studies, such as PET or functional MRI, to improve visualization of structures of interest (73). (2015) 17:11621. The neurofibromin 2 gene, also known as merlin, is located on chromosome 22q, and deletion or any other mutation at this site is associated with meningioma development (29). N Engl J Med. However, several retrospective studies have described SRS to be associated with high rates of symptomatic perilesional edema ranging from 2.5 to 50%. doi: 10.3171/jns.1997.86.5.0840, 125. (1999) 21:736. Acta Neuropathol. doi: 10.1007/BF01406557. However, controversy surrounds the role of adjuvant radiation for completely resected grade II meningiomas (Figure 3). Rohringer M, Sutherland GR, Louw DF, Sima AA. p. 6584. [Hydroxyurea treatment for unresectable meningioma]. Disadvantages to both proton and carbon ion therapies are limited availability and higher cost than photon radiation therapies. Neurosurg Focus. Table 3. Standard of care includes surgical resection followed by adjuvant radiation in anaplastic and partially resected atypical meningiomas; however, the role of adjuvant radiation for incompletely resected atypical meningiomas remains debated. Matsuno A, Fujimaki T, Sasaki T, Nagashima T, Ide T, Asai A, et al. Kuhn EN, Taksler GB, Dayton O, Loganathan A, Bourland D, Tatter SB, et al. Philadelphia, PA: Elsevier Saunders (2012). (2011) 115:8119. Neurochirurgie. McTyre E, Helis CA, Farris M, Wilkins L, Sloan D, Hinson WH, et al. Lamberts SW, Tanghe HL, Avezaat CJ, Braakman R, Wijngaarde R, Koper JW, et al. London: IntechOpen. doi: 10.3171/jns.2005.102.s_supplement.0283, 92. Tumors of the brain and nervous system after radiotherapy in childhood. (2009) 64:5660; discussion 60. doi: 10.1227/01.NEU.0000330399.55586.63, 35. (1999) 81:21725. doi: 10.3171/jns.2006.105.2.163, 23. Paleologos TS, Wadley JP, Kitchen ND, Thomas DG. Alahmadi H, Croul SE. (E) H&E staining, 400 magnification, demonstrating brain invasion. J Neurosurg. (2014) 75:53645; discussion 544545; quiz 545. doi: 10.1227/NEU.0000000000000519. Presence of this mutation is predictive of higher risk of recurrence. High levels of progesterone receptors are associated with favorable prognosis, whereas meningiomas with loss or absence of progesterone receptors tend to be more aggressive with increased rates of recurrence (9, 1922). Instead, tumor grade and extent of resection appeared to be the determining factors of tumor shrinkage and local control (115). (2010) 95:549. Ultrasonic aspiration devices are another valuable tool for resecting meningiomas, especially larger ones. Aizer AA, Bi WL, Kandola MS, Lee EQ, Nayak L, Rinne ML, et al. doi: 10.3171/2014.12.FOCUS14728, 79. Other hormone receptor inhibitors, including antiestrogen and antiprogesterone agents, have not demonstrated clinical benefits (137142). It is generally used in atypical and anaplastic meningiomas with residual or recurrent disease. Acta Neurochir (Wien). The use of the operating binocular microscope. J Neurooncol. doi: 10.1016/j.wneu.2014.12.037, 85. This study found that H3K27me3 may play a role in risk stratification, especially in meningiomas at the border of WHO I and II; however, it is less useful in grade III meningiomas (53). doi: 10.3171/foc.1997.2.4.6, 63. World Neurosurg. Radiat Oncol. Lou E, Sumrall AL, Turner S, Peters KB, Desjardins A, Vredenburgh JJ, et al. Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. J Neurooncol. Chemotherapy and other systemic medical therapies are reserved as salvage therapies in these patients; however, they have shown limited success with a few medical treatments demonstrating marginal clinical benefit. Medical management of meningiomas: current status, failed treatments, and promising horizons. Additionally, in the five studies with survival data, there was a trend toward improved overall survival in patients treated with radiation; however, this also did not reach statistical significance (96 vs. 87%; p = 0.4). J Neurooncol. A systematic review of ion radiotherapy in maintaining local control regarding atypical and anaplastic meningiomas.