Meningioma

Overview

• Harrison's Principles of Internal Medicine 22E, p. 765
• Bradley and Daroff's Neurology in Clinical Practice, p. 1560

Anatomy & Location

• 90% are supratentorial, arising in decreasing frequency from:
  1. Parasagittal region / superior sagittal sinus
  2. Cerebral convexities
  3. Sphenoid ridge
  4. Olfactory groove
• Infratentorial meningiomas favor the posterior surface of the petrous bones and clivus, and can mimic vestibular schwannomas
• Meningioma is the second most common CPA tumor (after vestibular schwannoma)
• Rare variants: meningioma en plaque (flat, infiltrating), intraventricular meningiomas

WHO Classification (Histologic Grading)

Imaging

CT

• 60% are spontaneously hyperdense on non-contrast CT
• Up to 20% contain calcification
• Intense, uniform contrast enhancement
• Hyperostosis of adjacent bone is characteristic (vs. bone thinning with schwannomas)
• Bone destruction suggests atypical/malignant grade

MRI

• Frequently isointense to gray matter on both T1 and T2 - may be invisible without contrast
• Vivid, homogeneous enhancement after gadolinium
• Classic "dural tail" sign: thickened enhanced dura extending from the mass - frequent but NOT pathognomonic
• May have "capping cysts" with CSF-like signal
• Vasogenic edema is not uncommon; its extent does not correlate with tumor size, but presence may predict higher recurrence risk

Advanced MRI

• MR spectroscopy: alanine peak is characteristic, but seen in <50% of cases
• Perfusion-weighted imaging (PWI): markedly elevated rCBV, helping differentiate from dural metastases (which have lower rCBV)
• DWI/ADC: conflicting results for grading; may help suggest higher-grade transformation

Clinical Presentation

• Headache
• Seizures (convexity tumors compressing cortex)
• Focal neurologic deficits (motor, sensory, visual, cranial nerve palsies)
• Cognitive/behavioral change (frontal lobe tumors)
• CPA tumors: sensorineural hearing loss, tinnitus, imbalance, facial paresthesia, diplopia, ataxia
• Hearing preservation is more common with meningiomas than with vestibular schwannomas

Molecular Pathogenesis

Histology

• Psammoma bodies (concentric calcified lamellae) are a hallmark
• Characteristic whorled pattern of meningothelial cells
• EMA (epithelial membrane antigen) positive

Management

Observation

• Small, asymptomatic meningiomas without mass effect or venous sinus compression can be followed with serial MRI
• Many meningiomas do not grow over years, especially in older adults

Surgery

• First-line for symptomatic, growing, or large tumors
• Complete surgical resection (Simpson grade I/II) is potentially curative for Grade I
• More challenging locations: dural venous sinus invasion, medial sphenoid, skull base, en plaque, posterior fossa, intraventricular
• Complications: infection, CSF leak, cerebral venous thrombosis, cranial neuropathies

Radiation

• External beam radiotherapy (EBRT) or stereotactic radiosurgery (SRS) for:
  • Residual/unresectable tumor
  • Recurrence or progression
  • Adjuvant to surgery in higher-grade tumors
• Less aggressive surgery + SRS reduces morbidity and may improve progression-free survival (PFS)

Medical/Systemic Therapy

• Hormonal therapy (tamoxifen, mifepristone): disappointing in clinical trials despite receptor expression
• Somatostatin analogs: failed to show clear benefit in recurrent meningioma despite receptor expression
• VEGF inhibitors (bevacizumab, sunitinib, vatalanib): retrospective data suggest disease stability; still investigational
• Hydroxyurea, alpha interferon, chemotherapy regimens: some partial responses in recurrent/malignant cases
• Targeted therapies against NF2, TRAF7/KLF4, AKT1, SMO pathways are under investigation

Differential Diagnosis

• Hemangiopericytoma / solitary fibrous tumor (SFT) - shares NAB2-STAT6 fusion; higher propensity for local recurrence and systemic metastasis
• Vestibular schwannoma (in CPA)
• Epidermoid cyst

Prognosis

• Grade I: low recurrence after complete resection; excellent prognosis
• Grade II: recurs despite surgery + radiation
• Grade III: aggressive, poor prognosis
• Molecular profile (especially DNA methylation class and del 1p/monosomy 14) predicts outcomes more reliably than WHO grading alone

Recent evidence note: A 2024 systematic review and meta-analysis (PMID 38902484) evaluated diagnostic imaging for meningioma grading, confirming the evolving role of advanced MRI in non-invasively predicting histologic grade - relevant for surgical planning.

Meningioma - Pathogenesis

Cell of Origin

Risk Factors

Two Major Molecular Subtypes

1. NF2-Mutant Meningiomas (~60%)

• Loss of chromosome 22q12.2 (monosomy 22 or focal deletion) is present in ~60% of sporadic meningiomas
• This is an early event in tumorigenesis
• NF2 is a classical tumor suppressor gene - both alleles must be lost (two-hit model)

• The NF2 gene encodes merlin (also called schwannomin), a membrane-cytoskeleton scaffolding protein
• Merlin mediates cell-cell contact inhibition and acts upstream of multiple oncogenic pathways
• Loss of merlin disrupts:
  • Hippo pathway - normally activates LATS1/2 kinases → phosphorylates YAP/TAZ → inhibits nuclear entry. Without merlin, YAP/TAZ translocate to the nucleus and drive proliferation genes
  • mTOR/PI3K signaling - merlin suppresses mTORC1; loss activates mTOR-driven cell growth
  • FAK/Src signaling - merlin normally suppresses focal adhesion kinase; loss promotes invasion
  • EGFR/ErbB2 recycling - merlin limits receptor tyrosine kinase signaling; loss causes sustained growth factor receptor activation

• NF2 mutations found in 80% of transitional and fibroblastic meningiomas
• Only 25% of meningothelial meningiomas
• Virtually none of secretory or microcystic meningiomas
• Predominantly hemispheric convexity and lateral skull base location

2. NF2-Wildtype Meningiomas (~40%)

• Cerebral convexity / spinal meningiomas → 22q deletion / NF2 mutations
• Skull base meningiomas → AKT1, TRAF7, SMO, PIK3CA mutations

Progression to Higher Grade

The 2021 WHO CNS5 classification was the first to integrate molecular markers into meningioma grading: TERT promoter mutations and homozygous CDKN2A/B deletions now independently define Grade III, regardless of histology. The cIMPACT-NOW update 8 (2025) further proposes upgrading Grade I-morphology tumors to Grade II when 1p deletion co-occurs with 22q/NF2 alterations. - PMID 39212325

Hormonal Influence

• Meningiomas express estrogen receptors (ER) and progesterone receptors (PR)
• Female predominance, association with pregnancy, and increased growth with exogenous progestin use support a hormonal role in growth modulation
• However, clinical trials with tamoxifen (anti-estrogen) and mifepristone (PR antagonist/RU-486) have been disappointing - hormones modulate growth but are not primary drivers
• Somatostatin receptors are also expressed but somatostatin analogs have failed to show benefit

Vascular Pathogenesis

• Meningiomas are highly vascular tumors supplied primarily by dural (meningeal) arteries
• Overexpression of VEGF contributes to tumor vascularity and peritumoral edema
• This has rationale for VEGF-targeted therapies (bevacizumab, sunitinib) in recurrent cases
• Vasogenic edema extent does not always correlate with tumor size but is more common around higher-grade and secretory variants

Summary Diagram (Conceptual)

Arachnoid cap cell
        |
  Initiating event
  /              \
NF2 loss (~60%)    NF2-wildtype (~40%)
(Chr 22q12)        TRAF7, AKT1, SMO, KLF4, PIK3CA
      |
Loss of MERLIN
      |
↑Hippo → YAP/TAZ nuclear entry → proliferation
↑mTOR → growth
↑FAK → invasion
↑EGFR → sustained signaling
      |
  Grade I (benign)
      |
+ del 1p, monosomy 14, del 9p21
+ TERT promoter mutation
+ CDKN2A/B homozygous deletion
      |
  Grade II / Grade III

• Quick Compendium of Clinical Pathology 5th ed.
• Bradley and Daroff's Neurology in Clinical Practice
• Goldman-Cecil Medicine, Chapter 175
• 2025 AJNR molecular review (PMID 38844366)
• cIMPACT-NOW Update 8, 2025 (PMID 39212325)
• EANO guideline on molecular testing for meningioma (PMID 39577862)