MENINGIOMA

Dr. Ayush Garg

• Introduction•Epidemiology•Risk Factors•Clinical Features• Investigations•Treatment•Follow Up

INTRODUCTION

• Meningioma was first coined by Harvey Cushing (1922).

• Refers to a set of tumors that arise contiguously to the meninges.

• Meningiomas may occur intracranially or within the spinal canal. They are thought to arise from arachnoidal cap cells, which reside in the arachnoid layer covering the surface of the brain.

Meningiomas can also occur in an intraventricular or intraosseous location. (Rare)

EPIDEMIOLOGY• 2-10 cases per 100,000 individuals.

• Account for approximately 20% of all primary intracranial neoplasms.majority are benign, with about 1%-3% classified as malignant98% are intracranial but may arise anywhere in central nervous system

• 2.3% of individuals have undiagnosed asymptomatic meningioma on autopsy.

• Synchronous Meningiomas in 5-40% of cases.

• Women affected twice as often as men. (1:1.4 to 1:2.8)8.4-9.6 for women vs 2.2-3.8 for men per 100,000.

• Incidence increases with age.

RISK FACTORS• Likely First degree relative.NF2 gene – Chromosome 22q12.2• Merlin Protein (thought to be involved in cell-to-cell contact and motility)• Lower expression in meningioma and loss of Merlin protein lead to development of

benign meningioma.

Exposure to ionizing radiation• Cranial radiation associated with increased risk of meningioma and other central nervous

system tumors in survivors of childhood cancer.

• Computed tomography scans during childhood or adolescence associated with increased risk of brain cancer.

any cancerbrain cancer

• PossibleHRTObesityIntrathecal MethotrexateOral Contraceptive• Current or past hormone replacement therapy associated with

increased risk of meningioma.

• Increased with any estradiol-only therapy.

• Increased with use of estradiol-only for ≥ 3 years.

• Not significantly affected by use of estradiol plus progestin.

• Obesity associated with increased risk of meningioma compared to normal weight.

Associated Syndromes•Hereditary syndromes associated with meningioma includeLi-Fraumeni syndrome – AD, TP53, Sarcoma, breast,

leukaemia and adrenal gland (SBLA) syndrome.

Turcot – DNA repair, HNPCC + Brain tumour.

Gardener – Cr5q21, APC, AD

Von Hippel-Lindau – Cr3p25, AD, VHL suppresor gene

Cowden – PTEN tumour suppresor.

Gorlin – Cr9q22 PTCH1 tumour suppressor

Multiple endocrine neoplasia type I – pituitary, parathyroid, and pancreas.

Cause

• Unknown• NF2 gene – familial cases.

CLINICAL FEATURES

• Presentation depends on size and location of tumor frequent manifestations include:

– Partial seizures (most common symptom)– Headache– Personality changes– Neuropsychological deficits– Sensory-motor symptoms– Visual symptoms eg Foster-Kennedy– Aphasia

Mechanism• Irritation: By irritating the underlying cortex, meningiomas can cause

seizures. New-onset seizures in adults justify neuroimaging (eg, MRI) to exclude the possibility of an intracranial neoplasm.

• Compression: Localized or nonspecific headaches are common. Compression of the underlying brain can give rise to focal or more generalized cerebral dysfunction, as evinced by focal weakness, dysphasia, apathy, and/or somnolence.

• Causing reactive swelling in brain tissue surrounding the tumor

• Blocking the flow of the cerebrospinal fluid (CSF) (hydrocephalus) in the brain and spinal cord resulting in its accumulation

• Blocking the flow of blood in various veins and arteries in the head by compressing these structures or invading them.

• Others: Meningiomas in the vicinity of the sella turcica may produce

panhypopituitarism.

Meningiomas that compress the visual pathways produce various visual field defects, depending on their location. – e.g. Foster Kennedy syndrome

Location• 85-90% supratentorial

45% parasagittal, convexities15-20% sphenoid ridge10% olfactory groove / planum sphenoidale 5-10% juxtasellar

• 5-10% infratentorial

• < 5% miscellaneous intracranial intraventricular meningioma (choroid plexus)optic nerve meningiomapineal glandspinal : especially thoracic

• <1% "extra dural"sinonasal cavity : most common intraosseous and may involve scalpparotid glandskin

IMAGING

• Meningiomas are located at any site where meninges are found.

• ModalitiesX RayCTMRI

X Ray

• X Ray no longer have a role in the diagnosis or management of meningiomas. Historically a number of features were observed, including:

enlarged meningeal A. grooveshyperostosis or lytic regionscalcification

Computerized TomographyCT is often the first modality employed to investigate neurological signs or symptoms, and often is the modality which detects an incidental lesion.

• 60% slightly hyper-dense to normal brain

• 20-30% have some calcification 8

• 72% brightly and homogenously contrast enhance 8, less frequent in malignant or cystic variants

• Hyperostosiso typical for meningiomas that abut the base of skulloneed to distinguish reactive hyperostosis from skull vault invasion (eventually involves the outer table

too)

Lytic regions

MRI

• MRI is the investigation of choice for the diagnosis and characterization of meningiomas. • When appearance and location is typical, the diagnosis can be made

with a very high degree of certainty.• Typically appear as extra-axial masses with a broad dural base. They

are usually homogeneous and well circumscribed.

Frontal view at MRI of a typical convexity meningioma

Parafalx meningioma Buckling of white matter(Thick arrow) and Dural tail enhancement(thin arrow)

Dural tail

CECTMRI:POST CONTRAST AXIA & SAGITTAL:Sphenoid wing meningiomaCisterns are widened(thick arrow) & Dural tail enhancement(Thin arrow)

EXTRAAXIAL SOLS: MENINGIOMAs, Dural tail enhancement& widened cisterns

PET-CT Scan

• There is no established role of PET-CT Scan

Pathology

MacroscopicMicroscopicIn general there are two main macroscopic forms: globose and en plaque. 

• Globose are rounded, well defined dural masses, likened to the appearance of a fried egg seen in profile. • En plaque meningiomas on the

other hand are extensive regions of dural thickening. 

• Arise from meningothelial arachnoid cells

• Histological sub types includeTransitionalFibroblasticSyncytialPsammomatous SecretoryMicrocyticPapillary and rhabdoid : have a

propensity to recur

HISTOLOGICAL GRADING• WHO grading 1993, 2000, 2007:• WHO 1 meningioma : 80-90%• Varying rates of progression to higher grade• 7%-20% recurrence rate• Pathologic features include • Pleomorphic, • Occasional mitotic figures, • Absence of pathologic features found in atypical or anaplastic meningiomas

• Histologic types include • Meningothelial, • Psammomatous, • Secretory, • Fibroblastic, • Angiomatous, • Lymphoplasmacyte rich, • Transitional, • Microcytic, • Metaplastic

•WHO 2 atypical meningioma (atypical, clear cell, chordoid) : 5-15 % • 30%-40% recurrence rate• Pathologic features include any of • 4 mitotic figures per 10 high-power fields of 0.16

mm2

• 3 of (a) increased cellularity, (b) small cells with high N:C ratio, (c) prominent nucleoli, (d) sheet-like growth, (e) necrosis• Brain invasion

• WHO 3  malignant meningioma (rhabdoid, anaplastic, papillary) : 1-3 %• 50%-80% recurrence rate• pathologic features require 20 mitotic figures per 10 high-power

fields of 0.16 mm2 or frank anaplastic features

TREATMENT

Overview

• Treatment depends on meningioma size and location, and on patient age, symptoms, comorbidities, health status, and treatment preference

• Conservative management, consisting of observation with close monitoring of clinical and disease status, may be option for patients with asymptomatic meningioma

• For patients with symptomatic meningioma, or with asymptomatic progressively enlarging tumors, complete surgical resection recommended, where possible• Alternative options include

Partial surgical resection plus radiation therapyRadiation therapy

• For patients with inoperable or recurrent meningioma after surgery or radiation therapy, medical therapies may be tried but have limited and inconsistent evidence of efficacy

Treatment Modalities

The available treatment modalities are-

Observation Surgery Radiotherapy Chemotherapy

Selecting treatment modality

• Meningioma treatment approach treatment of asymptomatic meningioma

For lesions < 3 cm (long axis), options includeObservationSurgery for tumor with potential neurologic consequences if

accessible, followed by radiation therapy for world health organization (WHO) grade III tumor or for subtotal resection of WHO grade II tumor

Radiotherapy for tumor with potential for neurologic consequences

For lesions > 3 cm, options includeSurgery if tumor is accessible followed by radiotherapy if tumor is

WHO grade III, and consider radiotherapy if resection is incomplete and tumor is WHO grade I or II

Observation

• Treatment of symptomatic meningioma

For lesions < 3 cm, options includeSurgery if tumor is accessible, followed by radiotherapy for

WHO grade III tumorsRadiotherapy

For lesions > 3 cm, options includeSurgery if tumor is accessible, followed by radiotherapy for

WHO grade III tumors, and consider radiotherapy for incomplete resection of WHO grade I or II tumors

Radiotherapy

• Treatment options for recurrent meningioma includeSurgery if accessible, or radiotherapyAdditional radiotherapy if tumor not surgically accessibleChemotherapy if tumor not surgically accessible and additional

radiotherapy not possible

Medical• Indications of Medical Therapy

Malignant tumors, Inoperable tumors, Patients not candidates for surgery, or When other treatment options have been exhausted

• Types:ChemotherapyHormonal therapy for unresectable or recurrent meningiomaOther

Somatostatin receptor agentsTargeted molecular agents for recurrent or progressive

meningioma

Chemotherapy

• Hydroxyurea• Patients with progression of World Health Organization (WHO)

Grade II or III meningioma treated with hydroxyurea reported to have median 2 months progression-free survival.

• Cyclophosphamide, Adriamycin, and Vincristine (CAV)• Patients with malignant meningioma treated with CAV

chemotherapy following surgery and radiation therapy reported to have median survival 5.3 years

Hormonal Therapy

• Tamoxifen reported to improve or stabilize refractory unresectable meningioma in some patients

• Mifepristone reported to improve tumor size or visual field in some patients with unresectable meningioma

• Patients with refractory recurrent meningioma treated with temozolomide reported to have median survival 7.5 months

Other Agents

Somatostatin Analogues

• Patients with recurrent WHO grade II or III meningioma treated with octreotide reported to have median 4.2 months to progression

• Patients with recurrent or progressive unresectable meningioma treated with octreotide reported to have median 17 weeks to progression

• Patients with progressive recurrent meningioma treated with 90y-edotreotide radionuclide therapy reported to have median survival 69 months for WHO grade I tumors and 30.5 months for WHO grade II-III tumors

Interferon α

• Patients with progression of WHO grade I unresectable meningioma treated with interferon alpha reported to have median survival 8 months

• Targeted molecular agents for recurrent or progressive meningioma

• Patients with recurrent meningioma following surgery and radiation therapy treated with Imatinib (tyrosine kinase inhibitor) 600-800 mg/day reported to have median progression-free survival of 2 months in case series of 23 patients.

• Patients with recurrent meningioma treated with an epidural growth factor inhibitor, Gefitinib or Erlotinib, reported to have median overall survival of 23 months.

Seizure Prophylaxis

Prophylactic antiepileptic drugs may not be effective for prevention of seizures in patients having craniotomy

• Systematic review of 6 randomized trials evaluating prophylactic treatment with antiepileptic drugs in 1,398 patients without epilepsy having craniotomy• Comparing phenytoin to placebo or no treatment

• Phenytoin significantly reduced early seizures (< 1 week postoperatively) in 1 of 4 trials• No significant differences in late seizures in 3 of 3 trials

• No significant differences in any outcomes comparing other antiepileptics vs. No treatment or comparing different antiepileptics

Surgery

Simpson Grading 1957• Grade I

complete removal including resection of underlying bone and associated dura9% symptomatic recurrence at 10 years

• Grade IIcomplete removal and coagulation of dural attachment19% symptomatic recurrence at 10 years

• Grade IIIcomplete removal w/o resection of dura or coagulation29% symptomatic recurrence at 10 years

• Grade IVsubtotal resection44% symptomatic recurrence at 10 years

• Grade V decompression with or without biopsy100% symptomatic recurrence at 10 years (small sample in original paper)

Embolization

• Preoperative embolization of meningioma to minimize intraoperative bleeding

• Embolization may be an alternative primary treatment of meningioma for patients not candidates for craniotomy and surgical resection. - Reported associated with marked tumor shrinkage over 20 months.

Radiotherapy

Overview

• Conventional radiation therapy

• Stereotactic radiosurgeryGamma KnifeCyber Knife

• Fractionated stereotactic radiosurgery

• Intensity-modulated radiation therapy (IMRT)

Indications/Side effects• Primary treatment for inoperable meningioma or for patients for whom

surgery would be inappropriatefollow-up treatment for patients with incomplete resection of meningioma

• Complete tumor eradication not possible but tumor shrinkage reported• Treatment to dose of 54 Gy for Grade I and 60 Gy for Grade II-III.• Complications of radiation therapy may include

AlopeciaTooth lossNew onset seizuresNeurological deficitsCranial nerve palsyHeadacheEdemaRadio-necrosisDelayed hydrocephalus

Conventional – Whole Brain Radiotherapy• Conventional radiation therapy used to treat incompletely resected

meningioma, or treat patients for whom surgery is inappropriate

• Addition of radiation therapy to partial resection may not improve overall survival but may reduce tumor progression in patients with WHO Grade I cerebral meningioma.

5-year progression-free survival91% for partial tumor resection plus radiation therapy vs. 38% for partial tumor resection alone (p = 0.0005)

77% for total tumor resection vs. 52% for partial tumor resection with or without radiation therapy (p = 0.02)

65% overall

• Whole-brain irradiation is administered through parallel-opposed lateral portals. The inferior field border should be inferior to the cribriform plate, the middle cranial fossa, and the foramen magnum, all of which should be distinguishable on simulation or portal localization radiographs. • The safety margin depends on penumbra width, head fixation, and

anatomic factors but should be at least 1 cm, even under optimal conditions. • A special problem arises anteriorly because sparing of the ocular

lenses and lacrimal glands may require blocking with margins <5 mm at the cribriform plate.

• The anterior border of the field should be approximately 3 cm posterior to the ipsilateral eyelid for the diverging beam to exclude the contralateral lens. However, this results in only approximately 40% of the prescribed dose to the posterior eye. • A better alternative is to angle the beam approximately 3 degrees or

more (100- or 80-cm source-to-axis distance midline, but also field size dependent) against the frontal plane so that the anterior beam border traverses posterior to the lenses (approximately 2 cm posterior to eyelid markers). • Placing a radiopaque marker on both lateral canthi and aligning the

markers permits individualization in terms of the couch angle. • This arrangement provides full dose to the posterior eyes. However,

the eyelid-to-lens and eyelid-to-retina topography is individually more constant than the canthus, and lateral beam eye shielding is better individualized with the aid of CT or MRI scans.• When in doubt about tumor coverage or lens sparing for tumors in a

subfrontal or middle cranial fossa location, one should consider CT-based contouring and planning.

SRS

• Stereotactic radiosurgery (SRS) may be alternative to external beam radiation in patients with recurrent or partially resected meningiomas < 35 mm in diameter

• Contraindications to surgery due to comorbidities or tumor location

• Skull base tumors of small or moderate size, for which surgical resection carries greater risk

• Allows larger radiation doses to be delivered more accurately and limits radiation exposure to surrounding tissue.

Fractionated SRS

• Fractionated stereotactic radiation therapy spares normal tissue sensitive to hypofractionation.

• Preferred treatment of optic nerve sheath meningioma.

Examples of radiation therapy planning of (A) stereotactic radiosurgery as a salvage therapy for a patient with recurrent meningioma,

(B) fractionated stereotactic radiotherapy as a definitive therapy for a patient with unresectable tumor due to a high risk of cranial nerve damage after a surgery and

(C) 3-dimensional conformal radiotherapy as a postoperative radiotherapy for a patient with residual tumor after surgical resection.

Gamma KnifeBased on case series of 4,565 patients with 5,300 benign meningiomas

• 10-year progression-free survival 88.6% and 5-year progression-free survival 95.2%• Permanent morbidity rate at last follow-up 6.6% • Tumor volume after treatment

Decreased in 58%Unchanged in 34.5% Increased in 7.5%

Gamma knife stereotactic radiosurgery as primary treatment for cavernous sinus meningiomas may be associated with better neurologic recovery than surgical resection with adjuvant radiosurgery.

The scans below show a patient with meningioma

The scans below show the same patient with meningioma SIX MONTHS after gamma knife treatment.

Cyber Knife

Multisession Cyber Knife radiosurgery for a petrosal meningioma in a patient affected by multiple sclerosis.

IMRT

• IMRT is computer optimized 3D conformal tumor localization with computer-controlled radiation intensity modulation

• Appropriate for tumors that are irregularly shaped and too large for stereotactic radiosurgery.

Emerging Role of Proton Therapy

Radiation oncologists at the Roberts Proton Therapy Center are conducting a Phase II clinical trial to ascertain the feasibility of proton therapy as an adjunct to surgery for WHO Grade I-III meningiomas and hemangiopericytomas.This study seeks to assess the effect of proton therapy on rates of acute toxicity, fatigue and quality of life in the same population. The frequency of recurrence and long term toxicity will also be evaluated.

The Most Significant Benefits of Proton Therapy• Causes fewer short- and long-term

side effects• Proven to be effective in adults and

children• Targets tumors and cancer cells with

precision, reducing the risk of damage to surrounding healthy tissue and organs• Reduces the likelihood of secondary

tumors caused by treatment• Treats recurrent tumors, even in

patients who have already received radiation• Improves quality of life during and

after treatment

Study Compares Effects of X-ray Radiation with Proton Therapy• A study analyzed patients

treated with X-ray radiation and compared them with patients treated with proton therapy. • Of the patients treated with X-

ray radiation, 12.8% developed secondary cancers caused by treatment, while only 6.4% of the proton therapy patients developed secondary cancers.

Follow up and Prognosis

Follow up• No standard guidelines for follow-up.

• For symptomatic patients, individualize follow-up based on tumor grade, previous treatment, and remaining treatment options

Consider first magnetic resonance imaging 3-6 months after surgery or radiotherapy

Perform subsequent magnetic resonance imaging (MRI) every 6 months for 2 years in clinically stable patients, and then every year as indicated, and thereafter, every 2 years

For patients with atypical or malignant meningioma, MRI every 3 months during first year and subsequently as for malignant brain tumors

• For asymptomatic meningiomaObservation with close clinical and radiological follow-upSerial volumetric measurements of tumor are useful, especially in younger

patients with greater potential for tumor growth

Prognosis• Median patient survival reported as:

10 years for WHO grade I meningioma 11.5 years for WHO grade II meningioma 2.7 years for WHO grade III meningioma

• Patients with meningioma have reduced survival compared to general population.

Compared to population without meningioma, meningioma associated with83% 1-year relative survival rate

71% 15-year relative survival rate

• 5-year survival rate: 81% for patients aged 21-64 years and 56% for patients ≥ 65 years old

• Larger tumor size at presentation and faster tumor growth rate might be associated with new or worsening symptoms in patients with untreated meningiomas

4% with tumor diameter < 2 cm, 17% with tumor diameter > 2.5 to 3 cm 0% with tumor diameter 2-2.5 cm growing at ≤ 10% per year AND42% with tumor

diameter 2-2.5 cm growing at ≥ 10% per year

• For benign meningiomas, factors independently associated with longer survival included:

female sex, Caucasian race, surgery, small tumor size, no radiation treatment, skull base tumor, and treatment at community hospitals

• For malignant meningiomas, factors independently associated with longer survival included:

Younger age at diagnosis, female sex, surgery, no radiation treatment, and ≥ 800 new cancer cases seen per year by the treating hospital

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