Hasan S, Young M, Albert T, Shah AH, Okoye C, Bregy A, et al. Cancer Invest. J Neurooncol. EANO guidelines for the diagnosis and treatment of meningiomas. FSRT delivers several fractions of higher radiation doses while maintaining stereotactic precision. (2019) 132:28291. Table 4. A study on recurrence and disease-specific survival. (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. Modha A, Gutin PH. Jo K, Park H-J, Nam D-H, Lee J-I, Kong D-S, Park K, et al. Kondziolka D, Mathieu D, Lunsford LD, Martin JJ, Madhok R, Niranjan A, et al. Pasquier D, Bijmolt S, Veninga T, Rezvoy N, Villa S, Krengli M, et al. Loss of genetic loci at chromosome 1p is the second most common aberration, and this is oftentimes seen in association with chromosome 22q mutations. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Prasad RN, Breneman JC, Struve T, Warnick RE, Pater LE. doi: 10.3171/foc.1997.2.4.6, 63. doi: 10.2217/imt-2016-0017, 59. doi: 10.1097/00006123-200103000-00054, 76. A challenge to traditional radiation oncology. J Natl Cancer Inst. Neurosurg Clin N Am. Meningiomas: knowledge base, treatment outcomes, and uncertainties. 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). Moreover, many neurosurgeons report an enhanced appreciation of anatomy and increased perception of safety (74, 80). A multicenter, retrospective study of the Rare Cancer Network. (2014) 82:125663. (2016) 27:24960. 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). doi: 10.1007/s11060-005-9093-x, 130. (2017) 12:193. doi: 10.1186/s13014-017-0924-7, 119. J Neurosurg. Genomic alterations in human meningiomas detected by restriction landmark genomic scanning and immunohistochemical studies. J Kans Med Soc. (2017) 18:68294. 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. Chemotherapy and other systemic therapies have demonstrated limited clinical efficacy in treating meningiomas (122). (2002) 94:155563. Furthermore, using multiplanar imaging, neuronavigation provides real-time intraoperative guidance and data regarding the location and orientation of surgical instruments in relation to nearby structures (69, 70, 74). Grunberg SM, Weiss MH, Spitz IM, Ahmadi J, Sadun A, Russell CA, et al. J Neurol. Neurosurg Focus. 54. Neurosurgery. (1996) 29:197205. Sim M, Argyriou AA, Maci M, Plans G, Majs C, Vidal N, et al. Unlike conventional photon radiation, particle therapy uses protons or carbon ions to deliver radiation. Alahmadi H, Croul SE. 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. Presence of this mutation is predictive of higher risk of recurrence. doi: 10.1093/neuonc/nos013, 37. J Korean Neurosurg Soc. DNA topoisomerase II and mitosin expression predict meningioma recurrence better than histopathological grade and MIB-1 after initial surgery. doi: 10.1007/s11060-012-0861-0, 152. Despite maximum treatment, atypical, and anaplastic meningiomas have a strong proclivity for recurrence. Surg Neurol. (2009) 11:85360. Primarily resected meningiomas: outcome and prognostic factors in 581 Mayo Clinic patients, 1978 through (1988). A RANO review. (2020) 87:9009. Zattara-Cannoni H, Gambarelli D, Dufour H, Figarella D, Vollot F, Grisoli F, et al. doi: 10.1002/alr.21143, 80. Mifepristone treatment in patients with surgically incurable sphenoid-ridge meningioma: a long-term follow-up. 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. Oncogene. Compared with photons, protons and carbon ions are more homogeneous and have better dose conformity, allowing more precise delivery of higher radiation doses to tumor cells while limiting radiation to surrounding healthy brain structures. 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). Towards molecular classification of meningioma: evolving treatment and diagnostic paradigms. Barnett GH, Steiner CP, Weisenberger J. Intracranial meningioma resection using frameless stereotaxy. Menon AG, Rutter JL, von Sattel JP, Synder H, Murdoch C, Blumenfeld A, et al. doi: 10.3171/jns.1996.84.1.0085, 39. Frequent loss of chromosome 14 in atypical and malignant meningioma: identification of a putative tumor progression locus. Results support that the benefits of adjuvant radiation may outweigh the risks; however, the authors caution that due to the small number of retrospective studies available for their meta-analysis, no clear recommendations can be made (84). A meta-analysis of 14 retrospective studies by Hasan et al. Cancer. doi: 10.1016/j.ijrobp.2019.11.028, 114. 134. Following complete resection, the 5-year recurrence rate is 2958% for atypical and 7294% for anaplastic meningiomas (12, 30, 64) The 5-year risk of progression for incompletely resected meningiomas is as high as 83100% (30, 65) Specifically, the 5-year survival rates are 7891% and 4165% for atypical and anaplastic meningiomas, respectively, and the 10-years survival rates decrease to 53% in atypical and 0% in anaplastic (34, 61, 6567). (C) H&E staining, 200 magnification, demonstrating frank necrosis. Hydroxyurea for recurrent surgery and radiation refractory meningioma: a retrospective case series. (1999) 15:45966. Int J Radiat Oncol Biol Phys. Winther TL, Torp SH. 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. However, most authors agree that larger, prospective trials should be conducted to better evaluate this modality. doi: 10.1007/BF00165649, 5. Is there a tumor volume threshold for postradiosurgical symptoms? Int J Radiat Oncol Biol Phys. 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. Oncol. Philadelphia, PA: Elsevier Saunders (2012). (2015) 16:519. doi: 10.1186/s13063-015-1040-3, 98. Overexpression is hypothesized to promote tumor growth. doi: 10.3171/jns.2006.105.2.163, 23. Clinically, this translates into difficulty predicting prognosis and determining the optimal management approach. doi: 10.2217/fon-2018-0006, 31. 55. A recent phase II trial (RTOG 0539), investigated outcomes of recurrent grade I and completely resected grade II meningiomas treated with adjuvant RT using a standard dose of 54 Gy. doi: 10.3340/jkns.2016.1111.009, 83. (C) H&E staining, 200 magnification, demonstrating necrosis. Acta Neuropathol. The role of adjuvant radiotherapy after gross total resection of atypical meningiomas. 105. Oncogene. 27. (1997) 40:2715. They reported a 90% PFS at 3 years and a 96.4% survival rate over the same time period (98). 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. Coggins WS, Pham NK, Nguyen AV, Branch DW, Guillet JY, Korst G, et al. doi: 10.1016/j.wneu.2019.08.149, 122. doi: 10.1097/00000478-199712000-00008, 36. van Alkemade H, de Leau M, Dieleman EMT, Kardaun JWPF, van Os R, Vandertop WP, et al. The rhabdoid and papillary subtypes are also classified as anaplastic (10, 11, 33). Radiat Oncol. Cho M, Joo J-D, Kim IA, Han JH, Oh CW, Kim C-Y. Patterns of failure after treatment of atypical meningioma with gamma knife radiosurgery. J Neurosurg. Histopathology of Atypical Meningiomas. Emerging indications for fractionated gamma knife radiosurgery. J Neurooncol. Neurosurgery. (D) Ki67 staining, 400 magnification, demonstrating proliferation indices. (2013) 3:58891. Acta Neuropathol. Int J Clin Exp Med. PLoS ONE. Aizer AA, Bi WL, Kandola MS, Lee EQ, Nayak L, Rinne ML, et al. Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01-08). 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. J Neurooncol. (1998) 82:22629. Comparing use of the Sonopet() ultrasonic bone aspirator to traditional instrumentation during the endoscopic transsphenoidal approach in pituitary tumor resection. 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). 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). Harris AE, Lee JYK, Omalu B, Flickinger JC, Kondziolka D, Lunsford LD. Palma L, Celli P, Franco C, Cervoni L, Cantore G. Long-term prognosis for atypical and malignant meningiomas: a study of 71 surgical cases. (2014) 156:18315. Sahm F, Schrimpf D, Stichel D, Jones DTW, Hielscher T, Schefzyk S, et al. (1995) 1:4652. Int J Radiat Oncol Biol Phys. Furthermore, evidence in ongoing research suggests that genetic profiles may vary by meningioma location (52). (1993) 15:757. (2017) 19:144756. IMRT is an advanced form of radiotherapy that delivers a conformal isodose of photons to the target. Significance of tumor volume related to peritumoral edema in intracranial meningioma treated with extreme hypofractionated stereotactic radiation therapy in three to five fractions. Similar to Hasan et al., the results support that benefits of adjuvant radiation may outweigh risk, but due to the small number of retrospective studies available for analysis, these authors also reported that no definitive recommendations can be made. (1997) 86:11320. doi: 10.1227/01.NEU.0000311061.72626.0D, 103. Atypical meningioma (WHO grade II). Atypical and malignant meningiomas: a clinicopathological review. Approximately 7080% of meningiomas express progesterone receptors, and to a lesser extent, estrogen receptors, which corroborates the theory of a hormonal component to growth and provides an explanation for the higher incidence in females. Pia HW. Loss of histone H3K27me3 identifies a subset of meningiomas with increased risk of recurrence. Chin J Cancer Res. Furthermore, recurrent meningiomas often become refractory to standard surgical and radiation therapies, which makes management challenging. 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). 69. da Silva EB Jr, Milano JB, da Silva LFM Jr, Aurich LA, Ramina R. Neuronavigation for Intracranial Meningiomas. Fowler JF, Tom WA, Fenwick JD, Mehta MP. Meningioma grading: an analysis of histologic parameters. Goodwin JW, Crowley J, Eyre HJ, Stafford B, Jaeckle KA, Townsend JJ. James MF, Han S, Polizzano C, Plotkin SR, Manning BD, Stemmer-Rachamimov AO, et al. Through whole genome analysis, global DNA methylation profiling has demonstrated higher levels of methylation are associated with increased tumor aggressiveness and risk of recurrence. Risk factors associated with developing perilesional edema include prior radiation treatment, larger tumor volume, higher tumor grade, and parasagittal location (103105). Age, male sex, and prior cranial ionizing radiation are risk factors for high grade meningiomas. Oermann EK, Bhandari R, Chen VJ, Lebec G, Gurka M, Lei S, et al. Huffmann BC, Reinacher PC, Gilsbach JM. Front Oncol. doi: 10.1016/j.wneu.2018.08.019, 48. (2015) 17:11621. 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). 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. Ultrasound microneurosurgery. doi: 10.1093/neuonc/nop017, 146. Adeberg S, Harrabi SB, Verma V, Bernhardt D, Grau N, Debus J, et al. Pravdenkova S, Al-Mefty O, Sawyer J, Husain M. Progesterone and estrogen receptors: opposing prognostic indicators in meningiomas. Neurology. Chamberlain MC, Johnston SK. J Neurosurg. 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. Other hormone receptor inhibitors, including antiestrogen and antiprogesterone agents, have not demonstrated clinical benefits (137142). (2010) 95:549. Neurosurg Focus. 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). doi: 10.1080/0284186X.2016.1259659, 116. Revisiting adjuvant radiotherapy after gross total resection of World Health Organization grade II meningioma. doi: 10.1093/jnci/djv377, 16. Ron E, Modan B, Boice JD, Alfandary E, Stovall M, Chetrit A, et al. (E) EMA staining, 200 magnification. Neurooncology. Thus, the authors reported that higher radiation doses allowable with PBT may improve local tumor control and reduce radiation-induced toxicities (120). doi: 10.1001/jama.297.11.1207, 25. Morales-Valero SF, Van Gompel JJ, Loumiotis I, Lanzino G. Craniotomy for anterior cranial fossa meningiomas: historical overview. (2012) 70:63945. Table 2. Dose-painting intensity-modulated proton therapy for intermediate- and high-risk meningioma. (2014) 7:5696700. (2016) 17:e383391. doi: 10.1093/neuonc/nou148, 144. Hydroxyurea for treatment of unresectable and recurrent meningiomas. (2014) 26:6537. Preston DL, Ron E, Yonehara S, Kobuke T, Fujii H, Kishikawa M, et al. The potential risk factors for atypical and anaplastic meningiomas: clinical series of 1,239 cases. Semin Oncol. London: IntechOpen. 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). II. Neurochirurgie. Bi WL, Wu WW, Santagata S, Reardon DA, Dunn IF. One common theme among all the reports of secondary meningiomas is that the tumor typically occurred several decades after the radiation exposure. doi: 10.1023/A:1005981731739, 101. Willems PWA, van der Sprenkel JWB, Tulleken CAF, Viergever MA, Taphoorn MJB. (2006) 5:104554. doi: 10.1227/00006123-200007000-00010, 81. The effect of radiosurgery during management of aggressive meningiomas. Acta Neuropathol. Although most meningiomas are benign (80%) and slow-growing, atypical (1520%) and anaplastic (13%) meningiomas are more aggressive with a proclivity for recurrence, worse clinical outcomes, and higher disease-specific mortality (7, 1013). Loss of expression is associated with shorter time to recurrence and worse prognosis. The WHO classification is an important prognostic tool, but it has several limitations. Clin Cancer Res. High-risk meningioma: initial outcomes from NRG Oncology/RTOG 0539. Figure 1. 78. doi: 10.1056/NEJMoa1414905, 66. doi: 10.1016/j.ijrobp.2007.12.020, 94. (2014) 117:93101. Currently, several trials of PD-1 and PD-L1 antibody-mediated inhibition in meningiomas are underway (57). Immunotherapy. Due to advancements in radiation technique, several new options have emerged for delivery of radiation to meningioma. 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. In 1957, Donald Simpson described this strong association between extent of recurrence (60). Atypical and anaplastic meningiomas remain challenging to treat. Jallo GI. 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). Since the 2000 edition, the WHO classification system has remained largely unchanged with the exception of brain invasion, as these newer editions have more objective criteria with less variation in classifying tumors among physicians. Most studies describe predominantly skin irritation and alopecia with minimal to no acute or late severe toxicity (114118). Contribution of cytogenetics and FISH in the diagnosis of meningiomas. Cancer. doi: 10.3892/ijo.15.3.459. Tumors of the nervous system and pituitary gland associated with atomic bomb radiation exposure. doi: 10.1126/science.1233009, 45. With contemporary neuronavigation systems, neurosurgeons are able to preoperatively plan surgeries and explore alternate approaches. The primary treatment for atypical and anaplastic meningiomas is surgical resection. Long-term survival analysis of atypical meningiomas: survival rates, prognostic factors, operative and radiotherapy treatment. (2018) 9:133. doi: 10.4103/sni.sni_264_17, 151. (1995) 55:4696701. doi: 10.1227/00006123-199312000-00001, 22. doi: 10.1136/jnnp.20.1.22, 61. Ann Genet. However, controversy surrounds the role of adjuvant radiation for completely resected grade II meningiomas (Figure 3). doi: 10.1007/s00415-006-0158-3, 71. Regarding the literature, there is a paucity of high-quality evidence regarding adjuvant radiation for patients with completely resected atypical meningiomas. [Hydroxyurea treatment for unresectable meningioma]. Runnels JB. Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM. doi: 10.1002/(SICI)1097-0142(19980601)82:11<2262::AID-CNCR23>3.0.CO;2-R, 42. doi: 10.1093/jjco/hyr022, 111. Future Oncol. J Neurooncol. J Neurooncol. Progesterone and estrogen receptors in meningiomas: prognostic considerations. (D) Ki67 staining, 400 magnification, demonstrating proliferation indices. Using immunohistochemistry, one study found that meningiomas absent of H3K27me3 staining were associated with significantly higher risk of progression. J Neurosurg. Kosaki K, Ecker S, Habermehl D, Rieken S, Jkel O, Herfarth K, et al. doi: 10.1007/s11060-013-1219-y, 86. 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.