Version May 2024
INTRODUCTION — Meningiomas account for approximately one-third of primary central nervous system tumors (table 1 and figure 1). Most meningiomas are benign (World Health Organization [WHO] grade 1), although up to one-fourth of such tumors are classified as atypical (WHO grade 2) or malignant (WHO grade 3). (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Pathology'.)
The management of patients with meningioma requires a balance between definitive treatment of the tumor and avoidance of neurologic damage from the treatment. Patient-specific factors (eg, presence or absence of symptoms, age, comorbidity), the location of the meningioma in relation to critical brain structures and regions, and the histopathologic characteristics (WHO grade) of the meningioma are all important factors in determining the optimal treatment.
The management of WHO grade 2 and grade 3 meningiomas will be reviewed here. Other topics on meningioma include:
●Epidemiology, pathology, clinical features, and diagnosis of meningioma (see "Epidemiology, pathology, clinical features, and diagnosis of meningioma")
●Treatment of benign meningiomas (see "Management of known or presumed benign (WHO grade 1) meningioma")
●Systemic treatment for recurrent meningioma (see "Systemic treatment of recurrent meningioma")
PREOPERATIVE EVALUATION — The diagnosis of meningioma is generally suspected on the basis of characteristic imaging findings and is then confirmed by histopathology, obtained at the time of surgical resection. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Diagnostic evaluation'.)
Differentiating an atypical or malignant meningioma from a benign meningioma purely on the basis of neuroimaging is difficult. While the presence of one or more atypical imaging features may suggest high-grade histology, none of these neuroimaging findings are sufficiently specific to be clinically useful. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Neuroimaging'.)
SURGICAL RESECTION — Complete surgical resection is preferred when a meningioma is in an accessible location, since complete resection of the tumor and its dural attachment can be curative, and extent of resection is consistently identified as an independent prognostic factor for both progression-free and overall survival [1,2].
Multiple advances in neurosurgery, including microsurgery, neuroendoscopy, improved preoperative imaging, and intraoperative image-guided approaches, have extended the neurosurgeon's ability to resect lesions that were previously considered only partially resectable or unresectable, while minimizing damage to normal brain. The goals of surgery, the classification of the extent of surgical resection, surgical morbidity, and the perioperative medical management for all patients with meningioma are discussed separately. (See "Management of known or presumed benign (WHO grade 1) meningioma", section on 'Extent of resection'.)
ADJUVANT RADIATION THERAPY — Complete surgical resection is sometimes difficult to achieve for malignant and atypical meningiomas, and partially resected tumors have a high rate of local recurrence as well as increased disease-specific mortality [3,4]. Adjuvant radiation therapy (RT) is a standard component of initial therapy in patients with malignant meningiomas and subtotally resected atypical meningiomas in an effort to improve local control [2]. For patients with atypical meningioma who undergo apparent gross total resection, the role of adjuvant radiation is less clear, as discussed below. (See 'Atypical meningioma' below.)
Newer RT techniques that have been used in small series include stereotactic radiosurgery (SRS) [5-7], hypofractionated stereotactic RT [8,9], and particle irradiation (proton beam, carbon ion) [10,11]. No single approach has been shown to be superior to others, but they all reflect advances in conformal techniques. Selection of a specific modality is often limited by technical considerations; as an example, a tumor must be adequately small to be safely eligible for SRS. The delivery of RT for meningiomas using various techniques is discussed separately. (See "Management of known or presumed benign (WHO grade 1) meningioma", section on 'Radiation therapy'.)
Malignant meningioma — Malignant meningiomas are locally aggressive neoplasms with a very high rate of recurrence or progression, even after apparent complete resection. Adjuvant RT is a standard component of initial management for all malignant meningiomas, regardless of the extent of resection, in an attempt to improve local control and overall survival.
The natural history of malignant meningiomas and support for the use of adjuvant RT are derived from observational studies, most of which are small, single-center retrospective analyses with heterogeneous pathologic inclusion criteria and treatment approaches [12-17]. Within these limitations, the data suggest that malignant meningiomas are associated with a recurrence rate of approximately 60 to 90 percent by five years after surgery and a five-year overall survival of 20 to 50 percent. Adjuvant RT appears to decrease the recurrence rate by approximately half and may improve five-year survival to greater than 50 percent [15,18].
The optimal dose of RT for malignant meningioma is not well established, and several studies have suggested that a dose of greater than 60 Gy is necessary to achieve durable local control [10,12,13,19]. We generally suggest a dose of 60 Gy when treating malignant meningiomas, based on the maximal safe dose deliverable to the surrounding normal brain. Even at this dose, local failures are common, however, suggesting that further investigation into safe dose escalation techniques and other novel strategies is needed to optimize outcomes [10,19,20].
Atypical meningioma — Atypical meningiomas are associated with an intermediate recurrence rate compared with benign and malignant meningiomas, and in some cases, particularly with progressive or multiply recurrent tumors, overall survival is shortened.
Incompletely resected tumors — For patients who undergo incomplete resection or biopsy of an atypical meningioma, the rate of recurrence or progression ranges from 60 to 100 percent [21,22]. Adjuvant RT improves local control, aims to prevent further neurologic morbidity related to growth of the residual tumor, and may improve survival [23,24].
Accurate delineation of the residual tumor following surgery using contemporary imaging studies is critical for optimal results with postoperative RT [25]. Absent prospective randomized trials, doses of 54 to 60 Gy are typically used when treating atypical meningiomas [21,26,27]. Even with a target dose of 60 Gy, however, disease progression commonly occurs [18].
For small tumors amenable to stereotactic radiotherapy, this technique can be used to maximize radiation conformality. SRS is sometimes used to treat small tumors; however, there may be a higher risk of local failure at the margins, and further studies with long-term follow-up are needed [28].
Completely resected tumors — For patients who undergo apparent complete resection of an atypical meningioma, the role of adjuvant RT is debated. Although multicenter trials are ongoing, there are no randomized data yet available to guide decision-making in these patients, and practice varies across centers. The potential benefits of adjuvant RT in terms of preventing or delaying tumor recurrence are more closely balanced with the risks and side effects of RT, and it is particularly important to assess individual patient preferences and tolerance for risk, which may vary when presented with similar information.
●Our approach – Based on the available data and clinical experience, for most patients who undergo gross total resection of an atypical meningioma and are at low risk for complications of RT, we suggest adjuvant RT. The goal of RT is to maximize local tumor control and prevent neurologic morbidity associated with tumor recurrence. For patients with an increased risk for complications of RT, we suggest observation with close follow-up and imaging surveillance.
●Risk of recurrence – The estimated recurrence rate after imaging-confirmed gross total resection in patients not treated with adjuvant RT is approximately 30 to 50 percent at a median of five years or less, with rates of failure trending higher with longer follow-up [26,29-31].
Certain defining histopathologic features may be associated with a higher risk of recurrence than others, although this has not been well defined. Individual pathologic features that have been reported to independently increase risk for recurrence after gross total resection of an atypical meningioma include the presence of brain invasion [32], a high number of mitoses per 10 high-powered fields (eg, closer to 20 than 4) [16,33-35], and prominent nucleoli [26]. Molecular genetic risk stratification is also being studied. Clinical risk factors reported in one or more studies include older age, nonconvexity tumor location, and less than Simpson grade I resection [17,26]. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Molecular risk stratification' and "Management of known or presumed benign (WHO grade 1) meningioma", section on 'Extent of resection'.)
●Efficacy of adjuvant RT – Most but not all observational studies suggest that adjuvant RT improves local control and progression-free survival after complete resection of an atypical meningioma [22,23,26,31,36-39]. The impact of RT on overall survival is less clear, however, and most studies have included insufficient numbers of patients or length of follow-up to adequately assess this outcome.
Examples of observational studies that support the use of adjuvant RT in the management of completely resected atypical meningiomas including the following [21,26,31,39-42]:
•In the intermediate-risk group of the prospective Radiation Therapy Oncology Group (RTOG) 0539 trial, 52 patients with completely resected, newly diagnosed atypical meningioma (n = 36) or recurrent grade 1 meningioma (n = 16) were enrolled prospectively; all received RT (54 Gy in 30 fractions) [40]. Three-year progression-free survival was 94 percent, which was improved compared with an expected rate of 70 percent based on historical controls. There were no serious (grade 3 or 4) treatment-related adverse events. Further follow-up is ongoing, which may help better define whether the dose of RT used in the trial (54 Gy) was sufficient to maintain long-term local control. Very similar three-year progression-free survival (89 percent) was reported in the prospective arm of the European Organisation for Research and Treatment of Cancer (EORTC) 22042-26042 study that included 56 patients with completely resected atypical meningiomas who received a higher dose of postoperative RT (60 Gy in 30 fractions) [41].
•In a retrospective, single-institution cohort study of 230 patients with atypical meningioma who underwent complete or partial resection, 51 patients (22 percent) received immediate postoperative adjuvant RT (most commonly 59.4 Gy in 33 fractions) [39]. Compared with surveillance, RT was associated with substantially lower risk of progression/recurrence (hazard ratio [HR] 0.21, 95% CI 0.11-0.41). Among patients who underwent gross total resection (n = 151; 18 patients received early RT), early RT was associated with improved progression-free survival compared with surveillance at both 5 years (94 versus 70 percent) and 10 years (94 versus 63 percent). Disease-specific survival for the entire cohort was very high (96 percent), and RT was not associated with differences in overall survival with a median follow-up of nearly seven years.
In addition to these series, several population-based studies using cancer data registries have examined survival outcomes after gross total resection of atypical meningiomas [1,43-45]. In the largest of these, which included over 7800 atypical meningioma cases, five-year overall survival rates for grade 1, 2, and 3 meningioma were 86, 76, and 55 percent, respectively. In a multivariable analysis that included 3529 atypical meningiomas for which complete details on extent of resection and postoperative RT were available, both gross total resection (HR 0.70, 95% CI 0.55-0.89) and adjuvant RT (HR 0.70, 95% CI 0.53-0.92) were associated with improved overall survival. Among patients who underwent gross total resection, five-year overall survival rates with and without adjuvant RT were 88 and 79 percent, respectively.
●Risks of adjuvant RT – The potential benefits of RT are weighed against the short- and long-term side effects and risks of RT. Factors that increase the risk of side effects or delayed toxicities of RT include advanced age, low functional status, large treatment volume, and proximity of the radiation field to critical structures such as the optic pathways or pituitary gland. (See "Management of known or presumed benign (WHO grade 1) meningioma", section on 'Quality of life'.)
Ongoing protocols — Several ongoing or completed prospective cooperative group protocols are studying the role of RT in the management of patients with WHO grade 2 or 3 meningioma:
●EORTC 22042-26042 (NCT00626730) – In a phase II study run by the EORTC, patients with atypical or malignant meningioma were treated with adjuvant RT following surgical resection [46]. A dose of 60 Gy was used for newly diagnosed patients with atypical or anaplastic meningioma following a gross total resection, and a dose of 70 Gy was used for subtotally resected tumors (Simpson grades 3 and 4). Initial results of the completely resected atypical meningioma cohort has been published. (See 'Completely resected tumors' above.)
●NRG BN-003 (NCT03180268) and the ROAM (Radiation versus Observation following resection of Atypical Meningioma) trial – NRG BN-003 and ROAM are multicenter cooperative trials in which patients are randomly assigned to RT or observation after gross total resection of an atypical meningioma.
SURVEILLANCE AFTER INITIAL TREATMENT — Cranial imaging (preferably magnetic resonance imaging [MRI]) is used following initial treatment to monitor for evidence of recurrence or progression of residual disease. There are no prospective studies that define the optimal schedule for such imaging. In general, patients with malignant meningioma require closer radiology surveillance than patients with atypical meningioma.
An approach that is consistent with the National Comprehensive Cancer Network (NCCN) includes the following [47]:
●For patients with atypical meningioma, we typically obtain an MRI at 3, 6, and 12 months postoperatively, then every 6 to 12 months for five years, then every one to three years.
●For patients with malignant meningioma, we typically obtain MRIs every three to six months for three to five years after initial therapy, then every 6 to 12 months.
RECURRENT DISEASE — Most recurrences of meningioma are local or adjacent to a radiation treatment field. Although the majority occur within the first two to three years after resection, late recurrences are not uncommon.
Metastases of cranial meningiomas to the spinal cord due to spreading through the cerebrospinal fluid are rare and are more frequently associated with atypical or malignant meningiomas [48,49]. Extracranial metastases to sites such as bone, lungs, and liver are rare but do occur, more commonly in association with malignant tumors; the rate of distant spread has been reported to be as high as 10 percent in retrospective series [12,16,33,50,51].
Risk factors for recurrent disease after surgery and RT include grade 3 histology, brain and/or bone involvement, and elevated proliferation index [52]. Certain molecular genetic alterations may also predict worse biologic behavior. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Molecular risk stratification'.)
For patients who recur locally after their initial treatment, additional surgery and/or radiation therapy (RT) can sometimes provide effective therapy, and occasionally permit long-term overall and recurrence-free survival. However, several series indicate that recurrent atypical meningiomas have a high rate of treatment failure and survival outcomes that are similar to or worse than those of malignant meningioma [18,53,54]. In the high-risk arm of the Radiation Therapy Oncology Group (RTOG) 0539 phase II study, five-year progression-free and overall survival with radiation for recurrent atypical meningioma were 30 and 48 percent, respectively [18].
The principles underlying the use of surgery or radiation are similar to those for patients presenting de novo, but appropriate management requires a consideration of the effects of prior surgery and/or RT. (See "Management of known or presumed benign (WHO grade 1) meningioma".)
Systemic therapy for recurrent disease is discussed separately. (See "Systemic treatment of recurrent meningioma".)
PROGNOSIS — Atypical and malignant meningiomas are associated with an increased risk of local recurrence and decreased overall survival compared with grade 1 meningiomas.
Population-based survival estimates from the Surveillance, Epidemiology, and End Results (SEER) registry in the United States are available for atypical meningiomas diagnosed between 2004 and 2018, spanning several modifications to the WHO classification schema for meningioma grading. Among 4476 atypical meningiomas, 1-, 5-, and 10-year survival rates were 92, 69, and 34 percent, respectively [55]. Patients with malignant meningioma have worse outcomes, with five-year overall survival rates of less than 50 percent and median survival ranging from 42 to 50 months [56-58].
Aside from histopathologic grade, the most commonly reported risks factors for worse outcome are subtotal resection, large tumor size, and nonconvexity tumor location (including infratentorial tumors) [44,55,57,59]. Age has been inconsistently associated with outcome and may have a bimodal effect, with worse outcomes at both extremes of the age distribution. As with benign meningiomas, the quality of life of patients with atypical and malignant meningiomas can be impacted by short- and long-term consequences of the tumor itself, surgery, and radiation therapy (RT). (See "Management of known or presumed benign (WHO grade 1) meningioma", section on 'Quality of life'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)
SUMMARY AND RECOMMENDATIONS
●Surgical resection – Complete surgical resection is the preferred initial approach when a meningioma is in an accessible location, since complete resection of the tumor and its dural attachment can be curative. Atypical (grade 2) and malignant (grade 3) meningiomas are associated with a significantly increased risk for recurrence even after apparent complete resection. (See 'Adjuvant radiation therapy' above.)
●Adjuvant radiation therapy – The role of adjuvant radiation therapy (RT) varies according to the grade of the tumor and the extent of resection.
•Malignant (grade 3) meningioma – For patients with malignant meningioma, we recommend adjuvant RT, regardless of the extent of surgery (Grade 1B). (See 'Malignant meningioma' above.)
•Atypical (grade 2) meningioma, incomplete resection – For patients with atypical meningioma who have undergone incomplete resection or biopsy, we recommend RT rather than observation after surgery (Grade 1B). (See 'Incompletely resected tumors' above.)
•Atypical (grade 2) meningioma, gross total resection – For patients with atypical meningioma who have undergone gross total resection, the potential benefits of RT are more closely balanced with the risks of side effects and delayed toxicities. Factors that increase the risk of complications from radiation include advanced age, low functional status, large radiation field, and proximity of critical structures. (See 'Completely resected tumors' above.)
-For patients who are at low risk for complications of radiation, we suggest adjuvant RT rather than observation after surgery (Grade 2C). Patients who are particularly concerned about radiation toxicity could reasonably choose not to undergo adjuvant radiation, in favor of surveillance by imaging.
-For patients who are at increased risk for complications of radiation, we suggest observation rather than adjuvant RT (Grade 2C). Patients who want to maximize the chance of avoiding a recurrence and are willing to accept the risk of treatment-related toxicity could reasonably choose adjuvant radiation.
●Surveillance after initial treatment – All patients with atypical and malignant meningioma require active surveillance after initial therapy to monitor for recurrence. For patients with atypical meningioma, we obtain MRI at 3, 6, and 12 months postoperatively, then every 6 to 12 months for five years, then every one to three years. Patients with malignant meningioma typically require even more intense follow-up. (See 'Surveillance after initial treatment' above.)
●Recurrent disease – Most recurrences of meningioma are local or adjacent to a radiation treatment field and can occur within the first two to three years after resection. Additional surgery and/or RT are commonly used to treat recurrent disease. Systemic therapy is as yet ineffective. (See 'Recurrent disease' above.)
●Prognosis – Atypical and malignant meningiomas are associated with an increased risk of local recurrence and decreased overall survival compared with grade 1 meningiomas, and quality of life can be impacted by short- and long-term consequences of the tumor itself, surgery, and RT. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Black, MD, PhD, who contributed to an earlier version of this topic review.
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