Meningiomas

Terminology

When describing meningiomas, a variety of terms can be used to describe these common tumors more accurately.

Most commonly, they are either classified according to the histological subtype (e.g. rhabdoid or papillary, etc.), location (e.g. skull base, spinal, intraosseous, intraventricular, etc.), or by etiology (e.g. radiation-induced, etc.).

A broad division of meningiomas into primary intradural (which may or may not have a secondary extradural extension) and primary extradural is also used, although the latter is rare, accounting for only 1-2% of cases 25. Ectopic primary meningiomas include tumors residing in the head and neck, orbit, nose, paranasal sinuses, oropharynx, and even more remote sites (e.g. lung).

Epidemiology

Meningiomas are more common in women, with a ratio of 2:1 intracranially and 4:1 in the spine. Atypical and malignant meningiomas are slightly more common in males. They are uncommon in patients before the age of 40 and should raise suspicion of neurofibromatosis type 2 when found in young patients.

Clinical presentation

Many small meningiomas are found incidentally and are entirely asymptomatic. Often, they cause concern as they are mistakenly deemed to be the cause of vague symptoms, most frequently headaches. Larger tumors or those with adjacent edema or abutting particularly sensitive structures can present with a variety of symptoms. Most common presentations include 8:

• headache: 36%
• paresis: 22%
• change in mental status: 21%
• Meningiomas may also become clinically apparent due to mass effect, depending on their location:
• supratentorial: 85-90% 8
• parasagittal, convexities: 45%
• seizures and hemiparesis
• sphenoid ridge: 15-20%
• olfactory groove/planum sphenoidale: 10%
• anosmia (usually not recognized)
• Foster Kennedy syndrome
• juxtasellar: 5-10%
• visual field defects
• cranial nerve deficits
• infratentorial: 5-10%
• obstructive hydrocephalus
• cranial nerve deficits
• miscellaneous intradural: <5%
• intraventricular meningioma
• optic nerve meningioma
• pineal gland
• Parinaud syndrome
• obstructive hydrocephalus

Occasionally, transosseous, or intraosseous involvement with prominent hyperostosis may result in local mass effect (e.g. proptosis).

Although dural venous sinus invasion and occlusion do occur, it usually occurs very gradually. Therefore, most cases of venous invasion are asymptomatic as collateral veins have had time to enlarge.

Pathology

Meningiomas are thought to arise from meningocytes or arachnoid cap cells, which themselves arise from pluripotent mesenchymal progenitor cells, thereby accounting for the unusual location of primary extradural tumors 17,18.

Although the majority of tumors are sporadic, they are also seen in the setting of previous cranial irradiation and of course in patients with neurofibromatosis type 2 (Merlin gene on Chromosome 22). Additionally, meningiomas demonstrate estrogen and progesterone sensitivity and may grow during pregnancy.

Subtypes

In the 5th Edition (2021) WHO classification of CNS tumors a total of 15 subtypes of meningioma are recognized.

• angiomatous meningioma
• atypical meningioma: grade 2
• anaplastic (malignant) meningioma: grade 3
• chordoid meningioma: grade 2
• clear cell meningioma: grade 2
• fibrous meningioma (7%)
• lymphoplasmacytic-rich meningioma
• meningothelial meningioma (17%)
• metaplastic meningioma
• microcystic meningioma
• papillary meningioma: usually more aggressive behavior
• psammomatous meningioma
• rhabdoid meningioma: usually more aggressive behavior
• secretory meningioma
• transitional meningioma (40%): mixed histology, typically containing meningothelial and fibrous components

Grading

Unlike other tumors, the term "atypical" and "anaplastic"/"malignant" have been retained as histological subtypes with grade 2 and grade 3 tumors, respectively 31.

Otherwise, meningiomas are graded from grade 1 to 3 based on histological features (e.g. mitotic index), some histological subtypes (e.g. chordoid and clear cell meningiomas), and molecular features (see below) 7,11,21,31.

An important change in the 5th Edition (2021) WHO classification of CNS tumors is that the identification of some histological subtypes (e.g. papillary meningiomas and rhabdoid meningiomas) is no longer sufficient to denote a higher grade. However, they often have other histological features that will confer a higher grade 31.

Grade 2 criteria

• increased mitotic figures: 4 to 19 in 10 consecutive high-power fields (HPF)
• brain invasion (see below)
• chordoid or clear cell histological subtype
• three or more of the following:
• increased cellularity
• prominent nucleoli
• necrosis
• sheet-like growth
• small cells with a high nuclear to cytoplasmic ratio

Grade 3 criteria

• increased mitotic figures: ≥20 in 10 consecutive high power fields (HPF)
• homozygous deletion of CDKN2A/B
• sarcoma, carcinoma, or melanoma-like appearance
• TERT promoter mutation

Brain invasion

Brain invasion as a stand-alone feature remains controversial. In prior editions of the WHO classification (e.g. 2016), if a meningioma (regardless of histology) demonstrated any brain invasion, it was designated as grade 2, as it was believed to indicate a poorer prognosis and a higher likelihood of recurrence 7. In many instances, growth is actually along perivascular spaces rather than truly into the brain parenchyma. The 5th Edition has backed away from this dogmatic recommendation recognizing the difficulty in assessing this in some instances 31,32. Nonetheless, overt brain invasion remains sufficient to denote a grade 2 tumor.

Macroscopic features

• In general, there are two main macroscopic forms easily recognized in imaging studies:
• globose: rounded, well-defined dural masses, likened to the appearance of a fried egg seen in profile (the most common presentation)
• en plaque: extensive regions of dural thickening

The cut surface reflects the various histologies encountered, ranging from very soft to extremely firm in fibrous or calcified tumors. They are usually light tan in color, although again this will depend on histological subtypes.

Molecular markers

Increasingly, molecular markers are being incorporated into the diagnosis and grading of meningioma subtypes 31.

• SMARCE1 mutations: clear cell subtype
• BAP1 mutations: papillary and rhabdoid subtypes
• KLF4/TRAF7 mutations: secretory subtype
• TERT promoter mutation: grade 3
• homozygous deletion of CDKN2A/B: grade 3
• H3K27me3 loss of nuclear expression: worse prognosis
• methylome profiling: prognostic subtyping

Radiographic features

Meningiomas are best imaged with contrast-enhanced MRI, as this most accurately delineates the tumor, the presence of intra- and trans-osseous extension, and its relationship to the underlying brain. CT, however, is useful if bony anatomy is required (e.g. at the base of the skull), when patients cannot have an MRI, and especially when the meningioma is entirely ossified/calcified (see burnt-out meningioma).

Note that, in addition to histological variants, many of which have less typical imaging appearances, a number of 'special examples' of meningiomas are best discussed separately. These include:

• burnt-out meningioma
• cystic meningiomas
• intraosseous meningioma
• intraventricular meningioma
• optic nerve sheath meningioma
• radiation-induced meningioma

The remainder of this section focuses on more typical imaging appearances of run-of-the-mill meningiomas.

Plain radiograph

• Plain films no longer have a role in the diagnosis or management of meningiomas. Historically, several features were observed, including:
• enlarged meningeal artery grooves
• hyperostosis or lytic regions
• calcification
• displacement of calcified pineal gland/choroid plexus due to mass effect

CT

• CT is often the first modality employed to investigate neurological signs or symptoms, and often is the modality that detects an incidental lesion:

non-contrast CT

• 60% slightly hyperdense to normal brain, the rest are more isodense
• 20-30% have some calcification 8
• >50% demonstrate variable adjacent edema (see below) 22

post-contrast CT

• 72% brightly and homogeneously contrast-enhanced 8
• malignant or cystic variants demonstrate more heterogeneity/less intense enhancement
• hyperostosis (5%) 21
• typical for meningiomas that abut the base of the skull
• need to distinguish reactive hyperostosis from:
• direct skull vault invasion by adjacent meningioma
• primary intraosseous meningioma
• enlargement of the paranasal sinuses (pneumosinus dilatans) has also been suggested to be associated with anterior cranial fossa meningiomas 19
• lytic/destructive regions are seen particularly in higher grade tumors but should make one suspect alternative pathology (e.g. hemangiopericytoma or metastasis) 20

MRI

As is the case with most other intracranial pathologies, MRI is the investigation of choice for the diagnosis and characterization of meningiomas. When appearance and location are typical, the diagnosis can be made with a very high degree of certainty. In some instances, however, the appearances are atypical and careful interpretation is needed to make a correct preoperative diagnosis.

Meningiomas typically appear as extra-axial masses with a broad dural base. They are usually homogeneous and well-circumscribed, although many variants are encountered. It seems that the signal intensity of meningiomas on T2-weighted images correlates with the histological subtypes 27.

Signal characteristics

• Signal characteristics of typical meningiomas include:

T1

• usually isointense to grey matter (60-90%) 3,8,13
• hypointense to grey matter (10-40%): particularly fibrous, psammomatous variants
• T1 C+ (Gd): usually intense and homogeneous enhancement

T2

• usually isointense to grey matter (~50%) 3,8,13
• hyperintense to grey matter (35-40%)
• usually correlates with a soft texture and hypervascular tumors 13
• seen in microcystic, secretory, cartilaginous (metaplastic), chordoid, and angiomatous variants 12
• hypointense to grey matter (10-15%): compared to grey matter, and usually correlates with a harder texture and more fibrous and calcified contents

DWI/ADC: grade 2 and 3 tumors may show greater than expected restricted diffusion, although this is not universally useful in prospectively predicting histological grade 14,15

• MR spectroscopy: usually does not play a significant role in diagnosis, but can help distinguish meningiomas from mimics. Features include:
• increase in alanine (1.3-1.5 ppm)
• increased glutamine/glutamate
• increased choline (Cho): cellular tumor
• absent or significantly reduced N-acetylaspartate (NAA): non-neuronal origin
• absent or significantly reduced creatine (Cr)
• MR perfusion: good correlation between volume transfer constant (k-trans) and histological grade 26
• MR tractography: allows the identification of white matter tracts adjacent to the meningioma

this may aid in preoperative planning for meningioma resection by allowing planning of a safer access route that would result in less residual functional iatrogenic deficits 28

Helpful imaging signs

• Several helpful imaging signs have been described, including:

CSF cleft sign, which is not specific for meningioma, but helps establish the mass to be extra-axial; loss of this can be seen in grade II and grade III, which may suggest brain parenchyma invasion

• dural tail is seen in 60-72% 2 (note that a dural tail is also seen in other processes)
• sunburst or spoke-wheel appearance of the vessels
• white matter buckling sign
• arterial narrowing
• typically seen in meningiomas, which encase arteries
• useful sign in parasellar tumors, in distinguishing a meningioma from a pituitary macroadenoma; the latter typically does not narrow vessels
• peripheral rim of enhancement between meningioma and brain parenchyma in post-contrast 3D-FLAIR can help in distinguishing meningioma from other dural-based tumor 35

Edema

More than half of the meningiomas demonstrate a variable amount of vasogenic edema in adjacent brain parenchyma 22. Correlations between age, gender, tumor size, rapid growth, location (convexity and parasagittal > elsewhere), histologic type, and invasion in malignant meningiomas have been suggested in the literature but not yet confirmed. Although in general, the presence of severe adjacent edema is considered more compatible with aggressive meningiomas, in some histologically benign types such as secretory type, edema can be disproportionately larger than the small tumor size.

The underlying mechanism is most likely multifactorial however it has been shown that there is a strong association between the presence and severity of the peritumoral vasogenic edema (i.e. edema index) and expression of the vascular endothelial growth factor (VEGF) or expression of CEA and CK 16,23.

• List of some of the proposed underlying mechanisms is:
• venous stasis/occlusion/thrombosis
• compressive ischemia
• aggressive growth/invasion
• parasitization of pial vessels
• histologic subtype: secretory meningioma 23
• vascular endothelial growth factor (VEGF): produced within the meningioma that enters the adjacent parenchyma
• expression of CEA and CK

Angiography (DSA)

Catheter angiography is rarely of diagnostic use but rather is performed for preoperative embolization to reduce intraoperative blood loss and alleviate resection of a tumor. This is especially useful for skull base tumors, or those thought to be particularly vascular (e.g. microcystic variants or those with very large vessels). Particles are favored typically 7-9 days prior to surgery although they are not free of complications, particularly one study showed a high prevalence of complications associated with particles smaller than 150 μm, so risks and benefits should be thoroughly assessed 24.

Meningiomas can have a dual blood supply. The majority of tumors are predominantly supplied by meningeal vessels; these are responsible for the sunburst or spoke-wheel pattern observed on MRI/DSA. Some tumors also have a significant pial supply to the periphery of a tumor.

A well-known angiographic sign of meningiomas is the mother-in-law sign, in which the tumor contrast blush "comes early, stays late, and is very dense".

Treatment and prognosis

Treatment is usually with surgical excision. If only incomplete resection is possible (especially at the base of the skull) or if surgery is deemed high-risk, then other treatments may be used as well or instead:

• radiation therapy: external-beam radiation therapy (or even brachytherapy) can be used 8,29, and has been shown to improve local control and prolong overall survival 33
• embolization: particularly in highly vascular tumors (see angiography section, above), e.g. with particles (polyvinyl alcohol or tris-acryl gelatin microspheres) 37,38

No systemic chemotherapeutic or other therapy has been proven efficacious, although some mTOR inhibitors and antiangiogenic treatments show promise 34.

The Simpson grade correlates the degree of surgical resection completeness with symptomatic recurrence rate, which also varies with grade and length of follow-up 8,20. Metastatic disease is rare but has been reported 8.

The 2023 NCCN guidelines for surgically treated Grade 1 and 2 meningiomas recommend a follow-up brain MRI at 3, 6, and 12 months, then every 6-12 months for 5 years, and subsequently every 1-3 years. For WHO Grade 3 meningiomas, recommendations include a brain MRI every 2-4 months for the first 3 years, followed by every 3-6 months thereafter 36.

History and etymology

The term "meningioma" was first introduced by Harvey Cushing (1869-1939), a renowned American neurosurgeon, in 1922 9,22.

Differential diagnosis

The differential diagnosis generally includes other dural masses as well as some location-specific entities.

• The main dural masses to consider include:
• solitary fibrous tumors of the dura
• more aggressive, often destroying bone
• extensive peripheral vascularity
• more microlobulation
• dural metastases (e.g. breast cancer)
• for other less common differentials, see dural masses
• Specific location differentials include:
• cerebellopontine angle
• acoustic schwannoma
• pituitary region
• pituitary macroadenoma
• craniopharyngioma
• base of the skull
• hypertrophic pachymeningitis
• extramedullary hematopoiesis
• chondrosarcoma
• chordoma
• In the setting of hyperostosis, consider:
• Paget disease
• fibrous dysplasia
• sclerotic metastases (e.g. prostate and breast carcinoma)