Neuro-Oncology
Paraneoplastic syndromes
Oct. 15, 2024
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Meningiomas are the most common primary intracranial tumors. Although most are benign, morbidity can be high, and in some cases the tumor is fatal. The author reviews the pathophysiology, presentation, and treatment of this tumor, including new prognostic indicators in atypical and malignant meningiomas.
• Many meningiomas can be followed clinically and radiographically and may not require therapeutic intervention. | |
• Surgery and radiation form the cornerstones of therapeutic management of meningiomas. There are ongoing studies to assess the safety and efficacy of targeted systemic agents. | |
• Molecular targets, such as NF2, AKT1, SMO, and CDK4/6 pathways, are involved in the pathogenesis of meningiomas, which may serve as potential therapeutic targets in the medical management of these challenging tumors. | |
• TERT alterations and CDKN2A/B deletions are associated with aggressive biological behavior and poor outcome despite management with surgery and radiation. |
The word "meningioma" was first used by Cushing in 1922 to describe a tumor originating from the meninges (20). In 1938 Cushing and Eisenhardt, in a classic monograph, described a classification system for these tumors (21). Meningiomas originate from the arachnoidal cap cell, a meningothelial cell in the arachnoidal membrane. They generally arise where arachnoidal villi are numerous (44). Meningiomas were classified by their site of origin, and this system is still used and is augmented by the neuroanatomically specific incidence of specific mutations within subtypes of meningiomas. The common sites of origin and incidence rates are shown in Table 1 (21; 55; 77).
Meningiomas are classified according to the World Health Organization (WHO) grading scale as grade 1, grade 2, or grade 3, which corresponds to a previously used more descriptive classification of benign (1), atypical (2), or malignant (3). The WHO classification has moved away from these descriptive names to the more straightforward numerical system. WHO grade 1 meningiomas are not encapsulated; they grow invaginating, but demarcated, from the brain. They grow with finger-like projections and penetrate surrounding mesenchymal tissue, including bone. They may produce both an osteoblastic and a lytic reaction (44). Meningiomas immunostain with vimentin, desmoplakin, and epithelial membrane antigen. Meningiomas grow in three primary histologic patterns: (1) meningothelial, (2) fibroblastic, or (3) transitional, a combination of meningothelial and fibrous. Meningothelial meningiomas consist of lobules of cells with oval pale nuclei, with chromatin marginated around the nucleus. Fibroblastic meningiomas have parallel interlacing bundles of spindle-shaped cells with abundant collagen and reticulin between cells. Whorl formation and psammoma bodies are infrequent in these two histologic pattern types. Transitional meningiomas have a mixed pattern of both meningothelial and fibroblastic features. They more often contain whorls or psammoma bodies. The other nine meningioma subtypes are psammomatous, papillary, angiomatous, microcystic, secretory, clear cell, chordoid, lymphoplasmacyte-rich, and metaplastic. Although these subtypes have distinct histologic features, they have only limited impact on the natural history (some subtypes delineate tumors as WHO grade 2 or 3) and, at this time, do not impact treatment response.
WHO grade 2 meningiomas, previously known as atypical meningiomas, include chordoid and clear cell subtypes (10). These tumors make up 5% to 7% of all meningiomas (61). Grade 2 meningiomas are diagnosed based on increased mitotic index of equal to or greater than four mitoses per 10 high-power fields or three or more of the following features: increased cellularity, small cells with high nuclear:cytoplasmic ratio, prominent nucleoli, uninterrupted patternless or sheet-like growth, and foci of "spontaneous" or "geographic necrosis" (15). The updated WHO classification system from 2016 includes “brain invasion” as criteria for WHO grade 2 meningiomas (53). This assessment is deemed to have some subjectivity and can be influenced by the location of tumor evaluated.
WHO grade 3 meningiomas make up 1.0% to 2.8% of all meningiomas. Grade 3 meningiomas are were previously known as anaplastic meningiomas or malignant meningiomas. Previously (WHO 2016), rhabdoid and papillary histologies were classified as WHO grade 3. This is no longer the case for the current (WHO 2021) classification system (10). Grade 3 meningiomas have further increase in mitoses and cellularity with conspicuous necrosis (59). Twenty or more mitoses per 10 high-power fields is a defining characteristic of grade 3 meningiomas (15). Grade 2 and 3 meningiomas have a much higher recurrence rate after resection than benign meningiomas. Recurrence rates were 6.9% for grade 1 meningiomas, 34.6% for grade 2 meningiomas, and 72.7% for grade 3 meningiomas (59). Either of two molecular features, TERT promoter mutations and/or CDKN2A/B deletions, now confer a WHO grade 3 classification.
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 (15). Eighty-five percent to 90% of meningiomas are located supratentorially. The most common locations include convexity, sphenoid ridge, and planum sphenoidale (15). Meningiomas are rare in children and, when they occur, are more often aggressive and located either in the posterior fossa or intraventricularly. The most common presenting symptoms of meningiomas are headache (36%), change in mental status (21%), and paresis (22%). The most common signs are paresis (33%), normal examination (27%), and memory impairment (16.5%). The site-specific symptoms are of much greater significance and are shown in Table 1. Often, however, meningiomas may be asymptomatic and may be diagnosed as incidental radiographic findings.
Meningioma mutational profile may also be related to anatomic tumor location and clinical outcome. NF2 mutated meningiomas often are located along the cerebral convexities and posterior skull base, whereas non-NF2 mutated meningiomas cluster towards the anterior skull base (99).
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 (77).
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 1 meningiomas, 65.4% of grade 2 meningiomas, and 27.3% of grade 3 meningiomas were cured by surgery (59). A study from Finland found the recurrence rate for grade 1 meningiomas to be higher, with 19% recurring at 20 years (40). Another study of 9000 cases found the 5-year rate of recurrence to be 20.2% (60). The larger series above shows a 5-year survival rate of only 70%, 75%, and 55% for grade 1, 2, and 3 meningiomas, respectively (60). Another study noted a 25% 10-year recurrence rate in gross totally resected meningiomas and a 61% 10-year recurrence rate in subtotally resected meningiomas (87). Median time to recurrence was 11.9 years for grade 2 meningiomas and 2 years for grade 3 meningiomas. Five-year and 10-year survival was 81% to 95% and 58% to 79% for grade 2 meningiomas, and 60% to 64% and 35% to 60% for grade 3 meningiomas, respectively (69; 19). Following subtotal resection of meningioma, radiation therapy decreases recurrence rate from 60% with surgery alone to 32% with radiation therapy, with a longer time to recurrence in the radiated group (05). 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 1 meningiomas (33). 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: https://www.meningioma.app (64).
The prognostic significance of brain invasion as a sole criteria for higher-grade behavior has been questioned (65).
A clinical concern for patients with meningiomas is seizures. A retrospective study demonstrated that meningiomas with sporadic NF2 mutations, WHO grade 2 or 3, atypical histology, vasogenic edema, and brain invasion were associated with increased risk of preoperative seizures (32). Seizure freedom was associated with extent of resection, with patients undergoing gross total resection having the best outcome. Factors associated with postoperative seizures included tumor recurrence, having preoperative seizures, and tumors requiring radiation (32).
Metastasis from meningioma is uncommon and is estimated to occur in far less than 1% of patients. Meningiomas rarely metastasize; however, if they do, the lungs are the most common site, followed by the abdominal viscera, bones, and lymph nodes (62; 75). In a retrospective single center study of almost 1200 patients, the incidence of extracranial metastases was 0.67% (8 in 1193 patients) (22). There was an increased incidence in WHO grade 2 (2%) and WHO grade 3 (8.6%) meningiomas. A proposed screening paradigm is to obtain systemic imaging (preferably with DOTATATE PET/CT or FDG PET/CT) in patients with multiple recurrent WHO grade 2 and grade 3 meningiomas.
Molecular. There have been significant efforts to develop integrated prognostic and risk stratification scores based on the epigenetic, genetic, and transcriptional landscape. High-grade meningiomas have also been noted to have increased chromosomal instability characterized by copy number variations (08). A 36-gene signature risk panel has been developed to help stratify risk of recurrence and survival outcome and compares well to the standard WHO grade criteria (16).
The 2021 WHO Classification of Tumors of the CNS (WHO5) has incorporated molecular biomarkers into the classification and grading. Mutations in TERT or homozygous deletion of CDKN2A/2B are now classified as WHO grade 3 meningiomas (54). TERT mutation has been demonstrated to specifically be associated with shorter time to progression and is estimated at 10 months compared to 180 months in meningiomas without TERT mutation (78).
More contemporary molecularly defined classification systems have been proposed by multiple groups. The group from Princess Margaret Cancer Center have proposed four molecular groups (immunogenic, benign NF2 wild-type, hyper metabolic, and proliferative) based on a combination of DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation, and mRNA abundance (66). Another group used an optimized gene expression biomarker of 34 genes to predict clinical outcome for radiation therapy (74).
Meningiomas with mutations in TRAF7, AKT1, SUFU, PRKAR1A, and POLR2A may have better clinical outcomes than those with NF2 mutations (95). Conversely, as previously mentioned, mutations in TERT are associated with poor outcome. Other mutations associated with higher grade behavior include ARID1A, PTEN, and PBRM1 (97). Certain mutations are often associated with specific meningioma histologic subtypes such as SMARCE1 loss being found in nearly all cases of clear cell meningioma and BAP1 inactivation being associated with rhabdoid subtype, which is known to have a poor outcome (26; 81).
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.
The etiology of the majority of meningiomas is unknown. Radiation is the only definite causative factor, with an increased incidence of meningiomas in children radiated with as little as 10 gray for tinea capitis (63; 56). 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 (37; 56).
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 (89). 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 (02).
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 (03).
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 (88). 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 studies have suggested that obesity is a risk factor for meningiomas in both men and women (82; 67; 79). Potential biological mechanisms may include increased levels of insulin and insulin-like growth factor 1 as well as estrogen from adipose tissue (67).
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 one locus on chromosome 22 (36; 91).
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 (18). Brastianos and colleagues also analyzed the genomes of non-NF2 associated meningiomas, also finding mutations in AKT1 and SMO, associated with skull base location (12). 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 2 and 3 meningiomas (73; 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 (52). 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 (42; 58). A significant correlation was found between telomerase activity and the Ki-67 proliferation index (14). Alterations in TERT have been further validated as associated with very significantly poor outcome (78; 23).
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 1, 2, and 3 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).
Multiple meningiomas are uncommon, representing 1.1% of all meningiomas (83). Multiple meningiomas from each of four patients were studied with polymerase chain reaction for X chromosome inactivation to determine if the multiple tumors of each patient came from the same clonal population. In each patient, the same X chromosome was inactivated, suggesting the tumors originated from a single progenitor cell (50). Additionally, although the presence of multiple meningiomas usually alerts the physician to suspect a possible mutation in the NF2 gene, an entity called “familial multiple meningiomas” is described when no association with NF2 is found. Research has found SMARCB1 to be a causative germline mutation that predisposes to multiple meningiomas (17). Not only was this germline mutation identified, its pathogenesis was also found to follow the 2-hit hypothesis in which the mutant allele is retained and the wild-type allele is lost in these multiple meningiomas. Finally, in some cases of multiple meningioma, both mutations, that of NF2 and SMARCB1, have been found, suggesting even a four-hit hypothesis in these subsets of patients.
Meningiomas account for over one third 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. Most studies report a steady increase in incidence rate of meningiomas after 20 years of age (21; 55; 77). Grade 2 and 3 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% (84). However, about half demonstrate novel NF2 fusions.
There are no known preventive measures to stop the occurrence of meningiomas.
The differential diagnosis of meningioma depends entirely on the suspected anatomic location of the tumor. No single symptom is diagnostic of a meningioma. Grade 1 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; lymphoproliferative disorders, such as Rosai-Dorfman; 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 2 or 3 biological behavior and need to be distinguished from benign meningiomas because of their high rate of recurrence and metastases (59; 44).
Meningiomas are the second most common tumor type in neurofibromatosis type 2 (NF2), with an incidence of 45% to 58% (04). Patients with NF2 are more likely to have multiple meningiomas, with almost 30% of patients having seven or more. Meningiomas in NF2 patients can behave more aggressively, though the vast majority are WHO grade 1 (31). In addition, NF2 patients with meningiomas have a 2.5-fold higher relative risk of mortality compared to patients without them (06).
Meningiomatosis, or multiple meningiomas, can be a sporadic or familial condition. Familial meningiomatosis is associated with germline mutations in NF2 and SMARCB1 (17). Sporadic meningiomatosis, however, may have a more diverse mutational profile, with the following possible driver mutations: TRAF7, PIK3CA, AKT1, NF2, SMO, and NF1 (41).
The diagnostic procedure of choice for meningioma is a gadolinium-enhanced MRI.
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 (93). 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.
Management of meningiomas can range from clinical and radiographic follow-up to multimodality therapy, with a number of factors influencing the clinical decision making (80).
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 (72). 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 (68; 72; 13; 29; 98; 38). Asymptomatic meningiomas have a much higher operative morbidity in patients older than 70 years of age (49). Some authors felt a more aggressive surgical approach was appropriate in patients younger than 60 years of age (38).
Embolization. Transarterial embolization is a standard treatment in the preoperative management of meningiomas (24).
Surgery. Surgery is the treatment of choice for symptomatic meningiomas. Preoperative management includes the administration of anticonvulsants, dexamethasone, and occasionally preoperative embolization in highly vascular tumors. The goal of embolization is to achieve distal loading of the vascular bed to produce confluent tumor necrosis prior to surgery in order to expand the spectrum of tumors that can be operated on safely (71). 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 (85).
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 two patients developing cerebral radiation necrosis, and three patients developing visual loss (30; 45). The 10-year survival rate of patients with 38 inoperable meningiomas following radiation therapy was 46%, with 38% of patients having an improvement in neurologic performance (28). Grade 1 meningioma, partially resected (eight patients), or recurrent grade 1 meningioma (29 patients) treated with a combination of photon and proton radiation have a 100% and 88% 5-year and 10-year recurrence-free survival (96).
Proton beam radiation has been used alone for skull base meningiomas with radiologic control in the majority of patients (92).
Following gross total resection, patients with grade 3 meningiomas should receive radiation as well as patients with recurrent grade 1 meningiomas on recurrence or after resection of recurrence (86; 90). Patients with grade 1 meningiomas who received radiation therapy following resection had a local control rate of 89%, versus 30% with surgery alone (90).
A retrospective review also points out a potential role of radiotherapy in grade 2 meningiomas following gross total resection. In their experience, they had improved local control in patients who received postoperative radiotherapy, though a prospective trial is required to better delineate the role in gross totally resected grade 2 meningiomas (47).
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 (94).
Initial results for RTOG 0539, a phase II trial for patients with intermediate grade meningiomas (defined as WHO grade 2 with gross total resection or recurrent WHO grade 1 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).
Stereotactic radiosurgery. Currently, stereotactic radiosurgery is used most frequently in smaller grade 1 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% (70). 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 (39).
The role of stereotactic radiosurgery and the dose used in the treatment of meningiomas are evolving. Gamma knife radiosurgery and LINAC radiosurgery are both reported on favorably. In patients with grade 1 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 2 tumors had 100% control at 1 year, 92% at 2 years, and 77% at 5 years with grade 3 meningiomas being 100% at 1 and 2 years and 19% at 5 years (27; 46; 51).
In recurrent cavernous sinus meningiomas, tumor control was obtained in all 34 patients, with 56% of patients having tumor shrinkage using stereotactic radiosurgery (25). 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 (43).
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 (34). Therefore, the appropriate technique should be chosen based on location and size of tumor and tailored to the individual patient.
Interstitial brachytherapy. Thirteen skull-base meningiomas were initially treated with high-activity iodine-125 seeds, with 9 of 11 patients without calcification having a complete response and the two with calcification having a partial response (48). How these results compare with stereotactic radiosurgery or with new skull-base surgery techniques has not been determined. A more contemporary retrospective analysis of patients receiving iodine-125 brachytherapy at resection demonstrated that median time to progression after brachytherapy was 11.4 months in WHO grade 2 and 3 meningiomas. Treatment was relatively well tolerated, though 16% of patients suffered from radiation necrosis, 12% had sound breakdown, and 8% had hydrocephalus (57).
GammaTile, a bioresorbable tile using titanium-encapsulated cesium-131 seeds, is a more recently developed brachytherapy. It has been studied in recurrent meningioma with data suggesting improved local progression-free survival (PFS) compared to standard external beam radiotherapy (89% vs. 50% 18 month PFS), with rates of symptomatic radiation necrosis at 10% (11).
Chemotherapy. Conventional cytotoxic chemotherapy has no role in the upfront treatment of grade 1 meningiomas and has significant morbidity without significant efficacy in the more aggressive grades and in recurrent disease. It is utilized when patients have failed surgical and radiotherapeutic approaches.
Ongoing studies are investigating various medical agents in the treatment of recurrent, inoperable, or radiation-refractory meningiomas as this continues to be a great unmet need in the field of neuro-oncology. At this point in time, most studies are focused on the use of targeted or molecular agents, as these appear to be well-tolerated and efficacious in theory, though the clinical efficacy has yet to be determined.
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 (35). This discovery has led to clinical trials of PD-1 inhibitors in recurrent high-grade meningiomas (NCT03279692 and NCT02648997).
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.
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.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Karan S Dixit MD
Dr. Dixit of Northwestern University Feinberg School of Medicine has no relevant financial relationships to disclose.
See ProfileRimas V Lukas MD
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novartis and Novocure for speaking engagements, honorariums from Cardinal Health, Novocure, and Merck for advisory board membership, and research support from BMS as principal investigator.
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