Clinical manifestations

Presentation and course

The clinical symptoms of a meningioma are determined by its anatomic site (see Table 1). Meningiomas originate extra-axially and occur where arachnoid cells are most numerous, especially within the arachnoid villi along the dural venous sinuses (14). Eighty-five percent to 90% of meningiomas are located supratentorially. The most common locations include convexity, sphenoid ridge, and planum sphenoidale (14). Meningiomas are rare in children and, when they occur, are more often aggressive and located either in the posterior fossa or intraventricularly. The site-specific symptoms are shown in Table 1.

Table 1. Location of Meningioma and Site-Specific Symptoms

Parasagittal meningiomas occur anywhere along the anterior or posterior course of the falx, with symptoms dependent on the location. Anterior parasagittal tumors produce headaches, memory loss, and personality changes. Tumors located in the middle of the falx can produce motor and sensory deficit, and those located posteriorly can produce homonymous hemianopsia. Anterior tumors may obstruct cerebrospinal fluid outflow at the foramen of Monro, and obstruction of the sagittal sinus by posterior tumors can produce a sagittal sinus syndrome. The symptoms of sphenoid ridge meningiomas depend on the medial to lateral location along the sphenoid ridge. The medial tumors originate from near the anterior clinoid process, with early unilateral visual loss. They invade the cavernous sinus, with attendant cranial nerve deficits. The lateral tumors displace the frontal and temporal lobes while growing in the Sylvian fissure, and produce headache, seizures, and motor and speech deficits.

In a large study series, malignant meningiomas were located exclusively in the convexity, parasagittal, or tuberculum sellae locations (69).

Prognosis and complications

The prognosis for meningiomas following gross total resection depends on the histology. In a single series of 1799 meningioma specimens from 1582 patients followed for an estimated average of 13 years, 93.1% of grade I meningiomas, 65.4% of grade II meningiomas, and 27.3% of grade III meningiomas were cured by surgery (52). A study from Finland found the recurrence rate for grade I meningiomas to be higher, with 19% recurring at 20 years (37). Another study of 9000 cases found the 5-year rate of recurrence to be 20.2% (53). The larger series above shows a 5-year survival rate of only 70%, 75%, and 55% for grade I, II, and III meningiomas, respectively (53). There can be significant variability in patient outcome; thus, high-risk features for meningioma recurrence are being identified. Subtotal resection, posterior fossa location, nuclear atypic, and elevated MIB-1 index (greater than 4.5%) were prognostic factors for increased risk of recurrence in WHO grade I meningiomas (30). Using the Surveillance, Epidemiology, and End Results database (SEER), an individual-patient prediction for malignancy and survival was devised and made available online as an application for clinicians and can be accessed at the following site: https (56). More recent work has revealed prognostic benefit from the methylation profile classification of the tumors.

Metastasis from meningioma is uncommon and is estimated to occur in less than 1% of patients. The lungs are the most common site followed by the abdominal viscera, bones, and lymph nodes (67). In a retrospective single center study at UCSF of almost 1200 patients, the incidence of extracranial metastases was 0.67% (8 in 1193 patients). There was an increased incidence in WHO grade II (2%) and WHO grade III (8.6%) meningiomas (67).

Clinical vignette

A 52-year-old female had a long history of increasingly severe headaches that were recently more constant in the right face and retro-orbital region. Neurologic exam was normal. T1-weighted MRI showed a mass medial to the temporal lobe extending medially to the cavernous sinus. It extended inferiorly and medially to the right internal carotid artery and encased it. It extended laterally en plaque inferior to the temporal lobe. It was felt to be a meningioma on the basis of its imaging characteristics, and not surgically resectable. Stereotactic biopsy showed a transitional cell meningioma. Radiation therapy was recommended.

Biological basis

Etiology and pathogenesis

The etiology of the majority of meningiomas is unknown. Radiation is the only definite modifiable causative factor, with an increased incidence of meningiomas in children radiated with as little as 10 gray for tinea capitis (55; 50). Moderate radiation doses between 10 and 20 gray, as well as large doses greater than 20 gray and most often greater than 40 gray, also produce an increased rate of meningiomas (34; 50).

In a large population-based study in Britain, the incidence of subsequent development of CNS tumors was compared with doses of both radiation and chemotherapy in a cohort of 17,980 patients surviving at least 5 years after the diagnosis of childhood cancer (78). In this large study, it was found that the risk of developing meningiomas had a strong, linear, and independent relationship with the dose of radiation to meningeal tissues, as well as to the dose of intrathecal methotrexate received. Specifically, compared to controls, radiation doses of 0.01 to 9.99, 10.00 to 19.99, 20.00 to 29.99, 30.00 to 39.99, and greater than or equal to 40 Gy administered to the meninges was associated with a 2-fold, 8-fold, 52-fold, 568-fold, and 479-fold increased risk, respectively. Approximately half of radiation-induced meningiomas harbor a unique NF fusion that appears to be pathognomonic for radiation-induced meningiomas (03).

There is little prospective evidence that head trauma plays an etiologic role in the development of meningiomas. In a prospective study of nearly 3000 patients with head injury, no increased incidence was found (04).

There has been ongoing investigation in regards to a hypothesis that cell phone use increases one’s risk of meningioma formation. However, at this point in time, a review of the current data seems to argue against this hypothesis, at least in regards of up to 15 years of cell phone use (77). Longitudinal studies beyond 15 years are still needed to further define whether cell phone use is correlated with the incidence of meningiomas.

Although the presence of androgen receptors in meningiomas has long been established, the relationship between exogenous hormonal therapy and development of meningiomas has been under investigation. In a large prospective study of over 1 million postmenopausal women, there was a relative risk of 1.34 (95% CI 1.03 to 1.75) of meningioma in women being treated with hormonal replacement therapy as compared to non-users (07), suggesting a slightly increased risk.

Several meta-analyses have suggested that obesity is a risk factor for meningiomas in both men and women (73; 59; 71). Potential biological mechanisms may include increased levels of insulin and insulin-like growth factor 1 as well as estrogen from adipose tissue (59).

Chromosomal abnormalities may be important in the pathogenesis of sporadic meningiomas and have been described on several chromosomes and on multiple sites on chromosome 22. Sporadic meningiomas were examined for loss of heterozygosity on chromosome 22 in the region of the neurofibromatosis type 2 gene, because of the almost 50% incidence of meningiomas in neurofibromatosis type 2. Sixty percent to 65% of patients had a loss of heterozygosity in at least 1 locus on chromosome 22 (33; 80).

In a genomic analysis of 300 meningiomas not associated with NF2, new mutations were detected, suggesting there may be distinct molecular subtypes of meningiomas. Clark and colleagues found mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, to be present in almost a quarter of all meningiomas analyzed. In meningiomas found to have a TRAF7 mutation, a mutation in KLF4, a transcription factor known to induce pluripotency, was often associated. SMO mutations involved in Sonic Hedgehog signaling were found in a separate subset of meningiomas analyzed, which tended to have a more benign clinical course and more often located at the skull base (16). Brastianos and colleagues also analyzed the genomes of non-NF2 associated meningiomas, also finding mutations in AKT1 and SMO, associated with skull base location (11). The SMO mutation is found particularly in meningiomas arising in the region of the olfactory groove. This finding suggests that perhaps medical therapy targeting these pathways could be useful in skull base tumors, which often pose therapeutic challenges.

Genomic instability is an important differentiator between the different grades of tumor. Chromosome 1p and 14q loss are the most frequent abnormalities observed in meningiomas after loss of chromosome 22 and are seen in almost half of grade II and III meningiomas (66; 08).

Telomerase activity has been shown to be important in the control of cell proliferation and regulation of cell senescence. The expression of telomerase activity may produce unlimited cell proliferation and immortality. Two groups have examined telomerase activity in meningiomas, and have found a much higher incidence of telomerase activity in malignant or atypical meningiomas than in benign meningiomas (47). The protein product (hTERT) of telomerase messenger expression was analyzed and its presence in meningioma tissue was correlated with MRI recurrence, and its level with recurrence in a second study (38; 51). A significant correlation was found between telomerase activity and the Ki-67 proliferation index (13).

In a study, full exome analysis was performed on different samples within a single morphologically heterogenous intraventricular meningioma that fulfilled histopathological criteria for WHO grade I, II, and III meningioma. This genetic analysis demonstrated mutations in the TERT promotor and ARID1A within the higher grade regions, as well as increased aneuploidy, which may highlight potential mechanisms for meningioma dedifferentiation (01).

Vascular endothelial growth factor is expressed in human meningioma tumor, and the extent of peritumoral edema on T2-weighted MRI has been directly related with the vascular endothelial growth factor staining intensity (27; 64). This suggests that VEGF-A expression is related to histologic grade. The expression of mRNA stability factor HuR was found to be involved in upregulation of VEGF-A expression in primary meningioma cell cultures (70).

Interleukin-6 was studied by Park and colleagues to be involved with peritumoral brain edema in meningiomas. Interleukin-6 is expressed in various tumors and is involved in induction of endothelial barrier dysfunction and increasing endothelial cell permeability. Il-6 mRNA expression was present in moderate-to-severe edema-producing tumors, suggesting a direct relationship between this inflammatory cytokine and peritumoral brain edema. Interleukin-6 can also increase peritumoral edema by stimulating VEGF and other factors known to be directly correlated (63).

Epidemiology

Meningiomas account for approximately 37% of all primary central nervous system tumors in the United States. Their incidence increased with age with a more notable increase after the age of 65 years. They are almost twice as common in females than in males (61). Most studies report a steady increase in incidence rate of meningiomas after 20 years of age (19; 49; 69). Atypical and anaplastic forms are more common in men (10).

Radiation-induced meningiomas arise after low dose radiation, and are often multiple, aggressive, and malignant. They do not have mutations in the 17 exons of the NF2 gene on chromosome 22, in contrast to sporadic meningiomas, where the incidence is 50% (74).

Grade I meningiomas have a recurrence rate of 7% to 25%. Satoshi and colleagues investigated histopathologic features that would predict recurrence in grade I meningiomas. This study investigated 135 grade I meningiomas, of which 120 were totally resected. Recurrence rate in patients with total removal was 7.5% at 10 years and 9.3% at 20 years. Histopathologic features that were found to be statistically significant and correlated with recurrence include an MIB-1 index of greater than 2%, existence of mitosis, absence of calcification, and a paucity of fibrosis (57).

Grade II meningioma after gross total resection had higher recurrence rates than grade I meningiomas. In a large retrospective case series (n=108) performed at the University of California, San Francisco, recurrence rates following gross total resection without postoperative radiation was analyzed. Tumor recurrence was 7% at 1 year, 41% at 5 years, and 48% at 10 years. Of these 108 patients, 8 received postoperative radiation without recurrence of tumor. Risk factors for recurrence include older age and histologic changes such as prominent nucleoli and increased mitoses (02).

Given that higher grade meningiomas have a high recurrence rate following surgery, researchers have looked into noninvasive methods to predict aggressiveness so as to best tailor individual therapy. In a retrospective multivariate analysis of 378 patients with meningioma at a single institution, it was found that nonskull base location and male sex both have a 2-fold increased risk for grade II/III pathology (39).

In a retrospective study done by Gabeau-Lacet and colleagues, bone involvement in atypical meningioma and outcome was investigated. This study involved 47 patients with atypical meningioma. Bone involvement was associated with an increased rate of disease progression and decreased survival. It is important to note that 78% of patients with bone involvement at initial diagnosis had tumor recurrent within the bone. This evidence suggests that bone assessment should be undertaken at initial diagnosis of atypical meningioma (24).

Prevention

There are no known preventive measures to stop the occurrence of meningiomas.

Differential diagnosis

Meningiomas are the second most common tumor type in neurofibromatosis type 2 with an incidence of 45% to 58% (05). Patients with neurofibromatosis type 2 are more likely to have multiple meningiomas with almost 30% of patients having 7 or more. Meningiomas in neurofibromatosis type 2 patients can behave more aggressively, though the vast majority are WHO grade I (29). In addition, neurofibromatosis type 2 patients with meningiomas have a 2.5-fold higher relative risk of mortality compared to patients without them (06).

Confusing conditions

The differential diagnosis of meningioma depends entirely on the suspected anatomic location of the tumor. No single symptom is diagnostic of a meningioma. Benign meningiomas grow slowly over years and produce symptoms when they encroach on critical structures. Radiographically, the differential diagnosis includes solitary fibrous tumors of the CNS and dural metastases.

Hemangiopericytoma, now termed solitary fibrous tumor of the nervous system, is an aggressive mesenchymally derived tumor with oval nuclei with scant cytoplasm. There is dense intercellular reticulin staining. Tumor cells can be fibroblastic, myxoid, or pericytic. These tumors, in contrast to meningiomas, do not stain with epithelial membrane antigen. They have a grade II or III biological behavior and need to be distinguished from benign meningiomas because of their high rate of recurrence (68.2%) and metastases (52; 41).

Diagnostic workup

The diagnostic procedure of choice for meningioma is a gadolinium-enhanced MRI. On T1-weighted images prior to gadolinium, 65% of tumors were isointense, and 35% hypointense when compared to gray matter of the brain (22). On T2-weighted images, 47% were isointense with gray matter, 35% hyperintense, and 18% hypointense. In 1 series, fibroblastic and transitional meningiomas were found more often to be hypointense, whereas meningothelial and angioblastic meningiomas were hyperintense relative to brain gray matter (22). On T1-weighted images with gadolinium, these tumors typically enhance diffusely and homogeneously. The dural tail of a meningioma can be visualized to guide the surgeon in extent of resection. MRI can image vascular and neural distortion and invasion of blood vessels, particularly in the optic nerve, tuberculum sellae, and medial sphenoid ridge, and guide the neurosurgeon. Postoperatively, MRI is useful in looking for residual tumor, as such a finding would require either further monitoring or additional treatment (58).

By studying radiomics, several radiographic features including necrosis/hemorrhage, intratumoral heterogeneity, nonspherical shape, and larger tumor volume were associated with more aggressive tumors and higher histologic grade (17).

Positron emission tomography (PET) usage is also being investigated for meningiomas. Given overexpression of somatostatin receptors, radio-labeled somatostatin ligands such as 68Ga-DOTATOC, 68Ga-DOTATATE, and 68Ga-DOTANOC, which are currently used for neuroendocrine tumors, have shown to be effective (81). 18F-FDG (F-fluorodeoxyglucose)-PET can be used in the detection of high-grade meningiomas, and some studies indicate that FDG-PET can be used as a predictor of tumor recurrence. Lee and colleagues showed that the tumor-to-gray matter ratio of FDG uptake was significantly increased in high-grade meningiomas versus grade I meningiomas. In this study, it was also illustrated that there is a positive correlation between FDG uptake and high MIB-1 index and mitotic count (45).

Management

Management of meningiomas can range from clinical and radiographic follow-up to multimodality therapy, with a number of factors influencing the clinical decision making (72).

Asymptomatic tumors. In an epidemiologic study, only 25% of meningiomas were symptomatic. Three quarters of the meningiomas were found incidentally on imaging study or postmortem (65). Several epidemiological studies have concluded that patients with asymptomatic meningiomas can be followed with noninvasive imaging studies at intervals, and the meningiomas only require operation if there is significant growth or if the patient becomes symptomatic or is likely to become symptomatic (60; 65; 12; 26; 83; 35). Asymptomatic meningiomas have a much higher operative morbidity in patients older than 70 years of age (44). Some authors felt a more aggressive surgical approach was appropriate in patients younger than 60 years of age (35).

Embolization. Transarterial embolization is a standard treatment in the preoperative management of meningiomas (20).

Surgery. Surgery is the treatment of choice for symptomatic meningiomas. Preoperative management includes the administration of anticonvulsants, dexamethasone, and rarely preoperative embolization in highly vascular tumors. The primary aim is gross total resection, with improvement or preservation of neurologic function. In addition to removal of the mass, surgery provides tissue for diagnosis and grading as well as molecular analysis. Since the publication of the Simpson grading scale for extent of meningioma resection, it has been a central component to management and is a predictor of recurrence. The Simpson scale is graded on extent of resection of tumor and associated dural and osseous involvement, if present (75).

External beam radiation therapy. External beam radiation therapy has traditionally been used for the treatment of meningiomas when only a subtotal resection could be performed. The median treatment dose was 54 gray for both benign and malignant meningiomas, with the upper end of the dose range to 59 gray for benign meningiomas, and 69 gray for malignant meningiomas. The 5-year progression-free survival for patients with benign meningiomas was 98% when CT or MRI was used for treatment planning. The 5-year progression-free survival for malignant meningiomas was slightly less than 50%. Morbidity was 3.6%, with 2 patients developing cerebral radiation necrosis, and 3 patients developing visual loss (28; 42). The 10-year survival rate of patients with 38 inoperable meningiomas following radiation therapy was 46% (25).

Following gross total resection, patients with grade III meningiomas should receive radiation as well as patients with recurrent benign meningiomas on recurrence or after resection of recurrence (76; 79). Patients with grade I meningiomas who received radiation therapy following resection had a local control rate of 89%, versus 30% with surgery alone (79).

Another retrospective study of 170 patients receiving hypofractionated proton beam irradiation demonstrated safety and efficacy, with 5- and 10-year progression free survival of 93% and 85%, respectively, and hypofractionated proton beam irradiation may be a viable option for patients with large or completely unresectable meningiomas (82).

Initial results for RTOG 0539, a phase II trial for patients with intermediate grade meningiomas (defined as WHO grade II with gross total resection or recurrent WHO grade I with any extent of resection) treated with postoperative radiation, demonstrated an excellent 3 year progression-free survival of 93.8% compared to historical control of 70% following gross total resection (Rogers at al 2018).

A large retrospective study performed at Memorial Sloan-Kettering of atypical and anaplastic meningiomas suggested better tumor control and reduction of risk of subsequent recurrence with adjuvant radiation at first recurrence with no significant effect of extent of resection (15).

Stereotactic radiosurgery. Currently, stereotactic radiosurgery is used most frequently in smaller grade I meningiomas as it provides excellent long-term control in this tumor type. Meningiomas located at the skull base can prove difficult to resect entirely secondary to their anatomical location, and stereotactic radiosurgery may be used adjunctively to treat residual tumor postsurgically. Overall, in a meta-analysis of stereotactic radiosurgery in the management of meningiomas, stereotactic radiosurgery has a stabilization rate of 89%, with a low complication rate of 7% (62). One retrospective study of 320 patients with asymptomatic meningiomas who underwent stereotactic radiosurgery demonstrated an increased risk of peritumoral edema if the tumors were greater than 4.2 cm, were located near the cerebral hemispheres, or had pretreatment edema (36).

The role of stereotactic radiosurgery and the dose used in the treatment of meningiomas are evolving. In patients with grade I meningiomas, LINAC radiosurgery was used to treat 210 with local control 100% at 1 and 2 years and 93% to 97.9% control at 5 years. Grade II meningiomas had 100% control at 1 year, 92% at 2 years, and 77% at 5 years ,with grade III meningiomas being 100% at 1 and 2 years and 19% at 5 years (23; 43; 46).

In recurrent cavernous sinus meningiomas, tumor control was obtained in all 34 patients, with 56% of patients having tumor shrinkage using stereotactic radiosurgery (21). In 12 patients with recurrent atypical or malignant meningiomas, radiosurgery was used to treat 30 tumors with 13 lesions showing progression in the treated field after a mean follow-up of 43.5 months. Recurrence rate was dose dependent with 64% of lesions receiving less than 20 Gy recurring and only 25% when the tumor received greater than 20 Gy (40).

A retrospective review compared outcomes of skull base meningiomas treated with either stereotactic radiosurgery, hypofractionated stereotactic radiotherapy, or fractionated stereotactic radiotherapy. The reviewers did not find a significant difference in clinical or radiographic response to the different treatment techniques (31). Therefore, the appropriate technique should be chosen based on location and size of tumor and tailored to the individual patient.

Systemic therapy. Thus far, systemic therapies have not proven definitively efficacious for the treatment of meningiomas. However, ongoing studies taking advantage of specific molecular targets hold substantial promise.

Immunotherapy. There have been significant strides in the use of immunotherapy in systemic malignancies and are actively being studied in many nervous system malignancies. Aggressive and higher grade meningiomas have demonstrated increased expression of PD-L1 expression (32). This discovery has led to clinical trials of PD-1 inhibitors in recurrent high-grade meningiomas (NCT03279692 and NCT02648997). It is not known whether these types of approaches will prove successful.

Special considerations

Pregnancy

Meningiomas have been reported to present and show rapid symptom progression during pregnancy, followed by decrease or disappearance of symptoms following delivery (09). The increase in meningioma size is thought to be caused by gonadal hormone receptor stimulation or by vascular engorgement secondary to the increase in blood volume during pregnancy. Treatment of the tumor is best deferred until after pregnancy unless disease progression jeopardizes the patient's health.

Anesthesia

No specific anesthesia is recommended, but techniques should be used to increase brain relaxation and minimize brain retraction. Hyperventilation of a pCO2 of 25 to 30 will decrease the vascular compartment. Mannitol infusion will decrease the extracellular space. Spinal drainage is used occasionally in the absence of large tumors or increased intracranial pressure and hydrocephalus.