Meningiomas
Meningiomas are the most common primary intracranial tumor, accounting for approximately 38–40% of all primary CNS neoplasms. They arise from arachnoid cap cells (meningothelial cells) of the meninges and are typically slow-growing, extra-axial, dural-based masses. While the majority are benign (WHO grade 1), a significant minority exhibit atypical or anaplastic features with higher recurrence rates and worse prognoses. Understanding the diverse clinical presentations based on tumor location, the nuances of WHO grading, emerging molecular classifications, and the indications for observation, surgery, and radiation is essential for neurologists managing these common tumors.
Bottom Line
- Most common primary intracranial tumor: Female predominance (2:1); incidence increases with age; prior radiation is the strongest known risk factor
- WHO grading predicts behavior: Grade 1 (80%, benign, low recurrence), Grade 2 (atypical, 15–20%, higher recurrence), Grade 3 (anaplastic, 1–3%, aggressive)
- Molecular subtypes emerging: NF2/merlin loss is most common; non-NF2 mutations (AKT1, SMO, TRAF7, KLF4, PIK3CA) correlate with specific locations and may guide future therapies
- Observation is appropriate for small, asymptomatic, incidental meningiomas — many never require treatment
- Surgery remains the primary treatment: Simpson grading for extent of resection; gross total resection is curative for most grade 1 tumors
- Radiation (SRS or fractionated): Excellent tumor control for small tumors, residual/recurrent disease, or when surgery is contraindicated
- Systemic therapy has limited role: No consistently effective medical therapy; somatostatin receptor expression offers a potential target
Epidemiology and Risk Factors
Meningiomas have an overall incidence of approximately 8–9 per 100,000 persons per year, making them the most frequently diagnosed primary CNS tumor. Their prevalence is even higher when accounting for incidental tumors discovered on imaging performed for unrelated reasons — autopsy studies suggest meningiomas are present in 2–3% of the general population.
Key Epidemiologic Features
- Sex distribution: Female-to-male ratio approximately 2:1 for intracranial meningiomas; ratio approaches 1:1 for higher-grade (atypical/anaplastic) tumors; spinal meningiomas have an even higher female predominance (~4:1)
- Age: Incidence increases with age; median age at diagnosis is 65 years; uncommon in children (when present, consider NF2)
- Radiation exposure: The best-established environmental risk factor; prior cranial irradiation (even low-dose, as for tinea capitis) increases meningioma risk 6–10-fold; radiation-induced meningiomas tend to be higher grade and multifocal
- Hormonal factors: Female predominance, growth during pregnancy, and progesterone receptor expression suggest hormonal influence; the association with exogenous hormones (oral contraceptives, HRT) is complex — high-dose progestins (cyproterone acetate) are definitively linked to increased risk
- NF2 (neurofibromatosis type 2): 50–75% of NF2 patients develop meningiomas, often multiple; NF2-associated meningiomas may be more aggressive
- Obesity: Consistently associated with increased meningioma risk, possibly via adipokine-mediated growth factor signaling
WHO Grading and Histopathology
WHO Grade 1 (Benign) — ~80% of Meningiomas
Grade 1 meningiomas encompass multiple histologic subtypes (meningothelial, fibrous, transitional, psammomatous, angiomatous, microcystic, secretory, lymphoplasmacyte-rich, metaplastic). These tumors have low mitotic activity (<4 mitoses per 10 HPF) and lack brain invasion. The 10-year recurrence rate after gross total resection is approximately 7–25%.
WHO Grade 2 (Atypical) — 15–20%
Atypical meningiomas are defined by one or more of the following criteria:
- ≥4 mitoses per 10 HPF
- Brain invasion
- ≥3 of 5 histologic features: increased cellularity, small cells with high nuclear-to-cytoplasmic ratio, prominent nucleoli, sheeting (loss of architecture), spontaneous necrosis (not iatrogenic)
- Clear cell or chordoid histologic subtypes are automatically grade 2
The 10-year recurrence rate is 29–52%, significantly higher than grade 1.
WHO Grade 3 (Anaplastic/Malignant) — 1–3%
Anaplastic meningiomas exhibit frankly malignant histology with ≥20 mitoses per 10 HPF or carcinoma/sarcoma-like features. Papillary and rhabdoid subtypes are automatically grade 3. These tumors have high recurrence rates (>50%) and may metastasize (lung is the most common extracranial site). Median survival is 2–5 years.
| Feature | Grade 1 (Benign) | Grade 2 (Atypical) | Grade 3 (Anaplastic) |
|---|---|---|---|
| Frequency | ~80% | ~15–20% | ~1–3% |
| Mitotic rate | <4 per 10 HPF | ≥4 per 10 HPF | ≥20 per 10 HPF |
| Brain invasion | Absent | May be present (sufficient for grade 2) | Common |
| 10-year recurrence (GTR) | 7–25% | 29–52% | >50% |
| 5-year overall survival | >90% | ~75–85% | ~40–60% |
| Adjuvant RT | Not routine (consider if STR) | Recommended after STR; consider after GTR | Recommended regardless of resection extent |
Molecular Classification
Advances in genomics have revealed that meningiomas harbor distinct molecular subtypes that correlate with tumor location, histology, and clinical behavior. This molecular understanding is beginning to inform clinical decision-making and is opening avenues for targeted therapies.
| Molecular Alteration | Frequency | Typical Location | Key Features |
|---|---|---|---|
| NF2/Merlin loss | ~40–60% | Convexity, posterior fossa, spinal | Most common alteration; associated with fibrous/transitional subtypes; higher-grade tumors |
| TRAF7 mutations | ~25% | Anterior skull base, medial sphenoid wing | Often co-occurs with KLF4 K409Q or AKT1 E17K; associated with secretory subtype |
| AKT1 E17K | ~7–12% | Anterior skull base, medial sphenoid wing | Activates PI3K/AKT/mTOR pathway; potential target for AKT inhibitors |
| KLF4 K409Q | ~5–8% | Anterior skull base | Almost always co-occurs with TRAF7; associated with secretory meningioma |
| SMO mutations | ~3–5% | Olfactory groove, anterior midline | Activates Hedgehog pathway; potential target for SMO inhibitors (vismodegib) |
| PIK3CA mutations | ~3–5% | Anterior skull base | Activates PI3K pathway; often co-occurs with TRAF7 |
| TERT promoter mutation | ~5–10% (mostly higher grade) | Variable | Associated with aggressive behavior; independent predictor of recurrence and progression |
Clinical Relevance of Molecular Subtypes
- NF2-mutant meningiomas are more likely to be convexity or posterior fossa tumors and have a higher rate of atypical features; they are also the predominant type in NF2 syndrome
- Non-NF2 meningiomas (AKT1, SMO, TRAF7/KLF4) are typically skull base tumors and are almost always grade 1; they tend to have a more indolent course
- TERT promoter mutations and CDKN2A/B homozygous deletion are associated with aggressive behavior and poorer prognosis, regardless of WHO grade; these molecular markers may warrant closer surveillance or earlier adjuvant therapy
- DNA methylation profiling can classify meningiomas into prognostically distinct groups (e.g., the Sahm/Heidelberg classifier), sometimes reclassifying grade 1 tumors as higher-risk or grade 2 tumors as lower-risk
Clinical Presentation by Location
Meningiomas produce symptoms primarily through mass effect on adjacent brain structures, cranial nerves, and vascular structures. The clinical presentation is therefore highly dependent on tumor location.
| Location | Frequency | Key Clinical Features |
|---|---|---|
| Parasagittal / Falcine | ~25% | Seizures (most common presenting symptom); contralateral leg weakness (parasagittal cortex compression); bilateral leg weakness if involving superior sagittal sinus |
| Convexity | ~20% | Seizures, focal neurologic deficits depending on location (motor, sensory, language); headache |
| Sphenoid wing (lateral) | ~15–20% | Temporal lobe seizures; proptosis and orbital symptoms (if extending to orbit); may encase the MCA |
| Sphenoid wing (medial/clinoidal) | ~5% | Visual loss (optic nerve compression); ophthalmoplegia (cavernous sinus invasion); may encase the ICA |
| Olfactory groove | ~8–10% | Anosmia (often bilateral, may go unnoticed); personality/behavioral changes (frontal compression); visual loss (late); Foster Kennedy syndrome (ipsilateral optic atrophy + contralateral papilledema) — rare |
| Tuberculum sellae / Planum sphenoidale | ~5–10% | Progressive visual loss (chiasmal compression); bitemporal hemianopia; may mimic pituitary adenoma |
| Posterior fossa (tentorial, petroclival, CPA) | ~10% | Cranial neuropathies (V, VII, VIII for CPA tumors); hearing loss, facial pain/numbness; cerebellar ataxia; hydrocephalus |
| Foramen magnum | ~2–3% | Suboccipital pain; slowly progressive spastic quadriparesis (often initially unilateral); lower cranial neuropathies (XI, XII); may mimic cervical spondylotic myelopathy |
| Intraventricular | ~1–3% | Obstructive hydrocephalus; headache; may present with positional symptoms |
| Spinal | ~10% of all meningiomas | Thoracic spine most common; progressive myelopathy; radiculopathy; 80% female; typically lateral or anterolateral |
Diagnostic Mimics and Pitfalls
- Dural metastasis: Breast, prostate, lung carcinomas can produce dural-based enhancing lesions that mimic meningioma; clinical context and multiplicity are clues
- Hemangiopericytoma (solitary fibrous tumor): Can appear similar on imaging; tends to be more heterogeneous, may lack calcification, and has higher recurrence rate
- Dural lymphoma: Low-grade B-cell lymphoma can present as a dural mass; enhancing but may have more diffuse dural thickening
- Granulomatous disease: Sarcoidosis, IgG4-related disease, and tuberculous pachymeningitis can mimic meningioma
- En plaque meningioma: Sheet-like growth along the dura rather than a discrete mass; may present with hyperostosis and proptosis (sphenoid wing location)
Imaging Characteristics
MRI with gadolinium is the gold standard for meningioma diagnosis and surgical planning.
Characteristic MRI Features
- T1-weighted: Isointense to slightly hypointense relative to gray matter
- T2-weighted: Variable signal; isointense to slightly hyperintense; calcified regions may be hypointense
- Post-contrast: Intense, homogeneous enhancement is the hallmark; heterogeneous enhancement raises concern for higher grade
- Dural tail sign: Linear enhancing thickening of the dura adjacent to the tumor; present in ~60–70% of meningiomas; not pathognomonic (can be seen with other dural pathologies)
- CSF cleft sign: Rim of CSF between the tumor and brain parenchyma, confirming extra-axial location
- Calcification: Common (seen on CT as hyperdensity); suggests slower growth
- Hyperostosis: Thickening of adjacent bone, particularly with en plaque meningiomas; best visualized on CT with bone windows
- Flow voids: Represent tumor vascularity; prominent in angiomatous or highly vascular meningiomas
- MR spectroscopy: High alanine peak is relatively specific for meningiomas; may help distinguish from other dural lesions
CT Features
CT remains useful for demonstrating calcification (present in 20–25% of meningiomas) and hyperostosis. Meningiomas appear as well-circumscribed, hyperdense or isodense extra-axial masses with homogeneous enhancement. CT angiography can delineate vascular encasement for surgical planning.
Management
Observation
Many meningiomas are discovered incidentally and may never require treatment. Observation with serial MRI is appropriate for:
- Small (<2–3 cm), asymptomatic meningiomas
- Elderly patients or those with significant comorbidities
- Meningiomas in surgically challenging locations (e.g., petroclival, cavernous sinus) when asymptomatic
Surveillance Protocol for Observed Meningiomas
- Initial interval: Repeat MRI at 3–6 months after discovery to establish growth trajectory
- Stable tumors: Annual MRI for 5 years, then every 1–2 years
- Growth rate: Average volumetric growth of observed meningiomas is ~1–4 mm/year in linear dimension; ~25–50% remain stable over 5 years
- Triggers for intervention: Symptomatic progression, significant growth on serial imaging (≥2–3 mm/year), new peritumoral edema, or proximity to critical structures with potential for irreversible damage (e.g., optic nerve compression)
Surgical Treatment
Surgery is the primary treatment for symptomatic meningiomas and for asymptomatic tumors with documented growth or risk of neurologic compromise. The goal is gross total resection including the dural attachment and any involved bone.
| Simpson Grade | Description | 10-Year Recurrence Rate |
|---|---|---|
| Grade I | Complete resection including dural attachment and abnormal bone | ~9% |
| Grade II | Complete resection with coagulation (not excision) of dural attachment | ~19% |
| Grade III | Complete resection without dural resection or coagulation (e.g., leaving involved dura intact) | ~29% |
| Grade IV | Subtotal resection (residual tumor left intentionally) | ~40% |
| Grade V | Biopsy only or simple decompression | High |
Surgical Considerations by Location
- Convexity: Most amenable to Simpson grade I resection; lowest surgical morbidity
- Parasagittal: Resection may be limited by superior sagittal sinus (SSS) involvement; posterior-third SSS involvement is particularly challenging due to drainage of Rolandic veins
- Skull base: Higher surgical morbidity due to proximity to cranial nerves, major arteries, and critical neural structures; subtotal resection with planned adjuvant radiation may be safer than aggressive total resection
- Petroclival: Among the most surgically challenging; high rates of cranial nerve deficits (III, V, VI, VII, VIII); subtotal resection + SRS is often preferred
- Cavernous sinus invasion: True cavernous sinus invasion is almost never curable surgically; residual tumor is managed with SRS
- Spinal: Typically amenable to complete resection through laminectomy; excellent outcomes; recurrence rate <10%
Preoperative Embolization
- Considered for highly vascular meningiomas to reduce intraoperative blood loss
- Typically performed 24–72 hours before surgery
- Most effective when the tumor is supplied by external carotid artery (ECA) branches (middle meningeal artery is the most common feeder)
- Risk of cranial nerve injury (particularly with embolization of petrous or cavernous branches) and stroke (if particles reflux into the ICA or vertebral artery)
- Not all meningiomas require embolization; decision depends on vascularity, size, and surgeon preference
Radiation Therapy
Radiation plays an increasingly important role in meningioma management, both as primary treatment and as adjuvant therapy.
| Modality | Indication | Typical Dose | Tumor Control Rate |
|---|---|---|---|
| Stereotactic radiosurgery (SRS) | Small tumors (<3 cm); residual/recurrent after surgery; primary for surgically inaccessible | 12–16 Gy single fraction (Gamma Knife, CyberKnife, LINAC-based) | ~90–95% at 10 years (grade 1) |
| Fractionated stereotactic RT (FSRT) | Tumors >3 cm or near critical structures (optic apparatus, brainstem) | 50–54 Gy in 28–30 fractions (grade 1); 59.4–60 Gy (grade 2–3) | ~85–95% at 10 years (grade 1) |
| Proton beam therapy | Skull base tumors near critical structures; dose advantage over photon RT | Variable; dose conformality advantage | Comparable to photon FSRT |
Radiation: Key Decision Points
- Grade 1, GTR (Simpson I–III): Observation; adjuvant RT not routinely needed
- Grade 1, STR (Simpson IV–V): Consider adjuvant SRS/FSRT for residual tumor, especially if in a location where regrowth would cause significant morbidity
- Grade 2, GTR: Controversial — adjuvant RT may reduce recurrence but OS benefit is unclear; many centers recommend observation with close MRI surveillance
- Grade 2, STR: Adjuvant RT is generally recommended
- Grade 3: Adjuvant RT recommended regardless of extent of resection
- SRS dose to optic apparatus: Must be limited to ≤8–10 Gy to minimize risk of radiation-induced optic neuropathy; tumors within 2–3 mm of the optic apparatus should receive fractionated RT instead of single-fraction SRS
Recurrence and Surveillance
Meningioma recurrence depends on WHO grade, extent of resection, and molecular features. Surveillance MRI is essential for all patients, whether treated or observed.
| Scenario | Recommended Surveillance |
|---|---|
| Grade 1, GTR | Annual MRI for 5 years, then every 2 years; some guidelines suggest extending to 10+ years given late recurrences |
| Grade 1, STR or post-SRS | MRI every 6–12 months for 5 years, then annually |
| Grade 2 | MRI every 3–6 months for 2–3 years, then every 6–12 months |
| Grade 3 | MRI every 3–4 months for 2 years, then every 6 months |
Special Situations
NF2-Associated Meningiomas
Neurofibromatosis type 2 (NF2) is an autosomal dominant tumor predisposition syndrome caused by mutations in the NF2 gene (encoding merlin). Patients develop bilateral vestibular schwannomas (the hallmark), multiple meningiomas (50–75% of patients), and spinal ependymomas. NF2-associated meningiomas tend to be multiple, may be higher grade, and can be challenging to manage given the multiplicity of concurrent tumors. Treatment must balance intervention for symptomatic lesions against the cumulative morbidity of multiple surgeries and radiation treatments.
Meningiomas in Pregnancy
Approximately 60–70% of meningiomas express progesterone receptors. During pregnancy, some meningiomas exhibit accelerated growth due to hormonal influences and increased blood volume. Symptomatic growth typically occurs in the second and third trimesters. Management is conservative when possible (dexamethasone for edema, delivery planning), with surgery reserved for life-threatening situations. Most pregnancy-associated meningioma growth stabilizes or regresses postpartum.
Spinal Meningiomas
Spinal meningiomas account for approximately 25–30% of all spinal tumors and ~10% of all meningiomas. They have a striking female predominance (~80%) and most commonly occur in the thoracic spine (60–80%). These tumors are overwhelmingly WHO grade 1 and are typically cured with surgical resection. Presentation is with progressive myelopathy, often insidious over months to years, sometimes with radiculopathy. The lateral or anterolateral intradural extramedullary location is characteristic.
Systemic Therapy
Systemic therapy for meningiomas remains an area of significant unmet need. No medical therapy has demonstrated consistent efficacy in large, well-controlled trials.
Systemic Therapy Options (Limited Evidence)
- Somatostatin receptor agonists (octreotide LAR): Meningiomas express somatostatin receptors (SSTR2a); octreotide has shown modest stabilization in small studies but no significant tumor regression; DOTATATE PET can confirm receptor expression and may guide therapy
- Bevacizumab: Some case reports and small series suggest benefit in recurrent meningiomas; limited data
- Hydroxyurea: Once commonly used for recurrent meningiomas; multiple studies show minimal to no benefit; no longer recommended
- Targeted therapies in development: AKT inhibitors for AKT1-mutant tumors; SMO inhibitors for SMO-mutant tumors; mTOR inhibitors; CDK4/6 inhibitors; these are being explored in clinical trials
- Checkpoint immunotherapy: Pembrolizumab and nivolumab are being investigated; early results have been modest, though some benefit may be seen in tumors with higher mutational burden
- Peptide receptor radionuclide therapy (PRRT): 177Lu-DOTATATE (used in neuroendocrine tumors) is being explored for SSTR-positive meningiomas; early results are encouraging
Peritumoral Edema and Medical Management
Peritumoral Edema in Meningiomas
- Prevalence: Present in approximately 40–60% of meningiomas; more common with larger tumors, those with cortical contact, and vascular subtypes
- Mechanism: Likely multifactorial — disruption of cortical venous drainage, secretion of VEGF, tumor-brain interface disruption
- Significance: Edema, rather than the tumor itself, often accounts for the presenting symptoms (seizures, focal deficits, headache)
- Management: Dexamethasone (4–16 mg/day) effectively reduces edema; taper over weeks once definitive treatment is planned or completed
- Predictors of edema: Absence of calcification, larger tumor size, brain invasion, T2 hyperintense signal within the tumor, and absence of CSF cleft sign
Seizure Management
Seizures occur in approximately 20–50% of patients with supratentorial meningiomas. Convexity and parasagittal meningiomas have the highest seizure risk. Levetiracetam is the preferred anticonvulsant. Prophylactic anticonvulsants are not routinely recommended in seizure-free patients; perioperative prophylaxis for 7 days is commonly used. Post-surgical seizure freedom rates are high (~70–80%) after complete resection of the meningioma and epileptogenic cortex.
Prognosis and Long-Term Outcomes
| Prognostic Factor | Favorable | Unfavorable |
|---|---|---|
| WHO grade | Grade 1 | Grade 2, especially grade 3 |
| Extent of resection | Simpson grade I–II | Simpson grade IV–V |
| Molecular markers | Non-NF2 skull base subtypes (AKT1, SMO) | TERT promoter mutation, CDKN2A/B deletion, high-risk methylation profile |
| Location | Convexity (amenable to GTR) | Skull base (limits resection), parasagittal with sinus invasion |
| Ki-67 index | <4% | ≥4% (especially ≥10%) |
| Age | Younger patients (better treatment tolerance) | Pediatric meningiomas (more often higher grade, NF2-related) |
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