Meningioma

MENINGIOMADr. Ayush Garg

IntroductionEpidemiologyRisk FactorsClinical FeaturesInvestigationsTreatmentFollow Up

INTRODUCTIONMeningioma 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)

EPIDEMIOLOGY2-10 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 FACTORSLikely First degree relative.NF2 gene Chromosome 22q12.2Merlin 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 radiationCranial 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 ContraceptiveCurrent 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 SyndromesHereditary 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.

A useful mnemonic to remember the associated neoplasias is below:MEN I (3 Ps) - Pituitary, Parathyroid, PancreasMEN IIa (1M,2Ps) - Medullary Thyroid Ca, Pheochromocytoma, ParathyroidMEN IIb (2Ms,1P) - Medullary Thyroid Ca, Marfanoid habitus/mucosal neuroma, Pheochromocytoma

7

CauseUnknownNF2 gene familial cases.

CLINICAL FEATURES

Foster Kennedy refers to a constellation of findings associated with tumors of the frontal lobe.[1]The syndrome is defined as the following changes:

1) optic atrophy in the ipsilateral eye2) Papilledema in the contralateral eye3) Central scotoma (loss of vision in the middle of the visual fields) in the ipsilateral eye4) anosmia (loss of smell) ipsilaterally

This syndrome is due to optic nerve compression, olfactory nerve compression, and increased intracranial pressure (ICP) secondary to a mass (such as meningioma or plasmacytoma, usually an olfactory groove meningioma).[4][5] There are other symptoms present in some cases such as nausea and vomiting, memory loss and emotional lability (i.e. frontal lobe signs).[5]

9

Presentation depends on size and location of tumor frequent manifestations include: Partial seizures (most common symptom)HeadachePersonality changesNeuropsychological deficitsSensory-motor symptomsVisual symptoms eg Foster-KennedyAphasia

MechanismIrritation: 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

Location85-90% supratentorial 45% parasagittal, convexities15-20% sphenoid ridge10% olfactory groove / planum sphenoidale 5-10% juxtasellar

5-10% infratentorial

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

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 IIObservation

meningioma treatment approach treatment of asymptomatic meningiomafor 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 tumorradiotherapy for tumor with potential for neurologic consequencesfor 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 IIobservationtreatment of symptomatic meningiomafor lesions < 3 cm, options includesurgery if tumor is accessible, followed by radiotherapy for WHO Grade III tumorsradiotherapyfor 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 tumorsradiotherapytreatment 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

32

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 tumorsRadiotherapy

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

MedicalIndications of Medical TherapyMalignant tumors, Inoperable tumors, Patients not candidates for surgery, or When other treatment options have been exhausted

Types:ChemotherapyHormonal therapy for unresectable or recurrent meningiomaOtherSomatostatin receptor agentsTargeted molecular agents for recurrent or progressive meningioma

ChemotherapyHydroxyureaPatients 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

hydroxyureapatients with progression of World Health Organization (WHO) Grade II or III meningioma treated with hydroxyurea reported to have median 2 months progression-free survival (level 3 [lacking direct] evidence)based on case series of 35 patients previously treated with surgery plus radiotherapypatients given hydroxyurea 1,000 mg/m2 orally in 2 divided doses per dayReference - J Neurooncol 2012 Apr;107(2):315hydroxyurea reported to stabilize disease in most patients with unresectable or residual meningioma following surgery (level 3 [lacking direct] evidence)based on case series of 20 patients treated with hydroxyurea 20 mg/kg/day orallymedian time to progression was 176 weeks70% had no progression within 1 yearReference - Br J Neurosurg 2004 Oct;18(5):495 EBSCOhost Full Textcyclophosphamide, adriamycin, and vincristine (CAV) chemotherapy regimenpatients with malignant meningioma treated with CAV chemotherapy following surgery and radiation therapy reported to have median survival 5.3 years (level 3 [lacking direct] evidence)based on case series of 14 patients (median age 51 years)median time to tumor progression 4.6 yearsdose reduction or early termination of CAV regimen in 7 patients due to myelosuppression Reference - J Neurosurg 1996 May;84(5):733full-text

36

Hormonal TherapyTamoxifen 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

tamoxifen reported to improve or stabilize refractory unresectable meningioma in some patients (level 3 [lacking direct] evidence)based on case series of 21 patients, 19 evaluablepatients given tamoxifen 40 mg/m2 twice daily for 4 days followed by 10 mg/m2 twice daily thereafter3 patients had minor or partial response by neuroimaging6 patients remained stable for median 31 months10 patients had tumor progressionReference - J Neurooncol 1993 Jan;15(1):75mifepristone reported to improve tumor size or visual field in some patients with unresectable meningioma (level 3 [lacking direct] evidence)based on case series of 28 patients treated with mifepristone 200 mg/day orally for median 35 months5 patients had small decrease in tumor size3 patients had improved visual field exam 3 patients developed endometrial hyperplasia or polyps and 1 developed peritoneal adenocarcinoma after 9 years treatmentReference - Cancer Invest 2006 Dec;24(8):727 EBSCOhost Full Textfull-textpatients with refractory recurrent meningioma treated with temozolomide reported to have median survival 7.5 months (level 3 [lacking direct] evidence)based on case series of 16 patients with previous surgery and radiation therapypatients treated with temozolomide orally for 42 consecutive days every 10 weeksmedian survival 7.5 months (range 4-9 months)median time to tumor progression 5 months (range 2.5-5 months)no patient had neuroradiographic complete or partial responseReference - Neurology 2004 Apr 13;62(7):1210

37

Other AgentsSomatostatin 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

patients with recurrent WHO Grade II or III meningioma treated with octreotide reported to have median 4.2 months to progression (level 3 [lacking direct] evidence)based on case series of 9 patients (median age 65 years) with prior surgery and radiation therapypatients treated with octreotide (somatostatin analog) 30-40 mg intramuscularly once every 28 days until progressionall patients had progressive disease at 10 monthsno partial radiographic responsesReference - Cancer Chemother Pharmacol 2014 May;73(5):919patients with recurrent or progressive unresectable meningioma treated with octreotide reported to have median 17 weeks to progression (level 3 [lacking direct] evidence)based on case series of 12 patients with previous surgery and radiation therapy (1 patient had hemangiopericytoma)patients treated with octreotide 500 mcg subcutaneously 3 times dailymedian survival 2.7 years2 patients had long progression-free periods (30 months and 18 years)no radiographic response reportedReference - Neuro Oncol 2011 May;13(5):530full-textpatients 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 (level 3 [lacking direct] evidence)based on case series of 29 patients (median age 54 years) with previous meningioma treatment (surgery, radiation therapy) and scintigraphically proven somatostatin subtype 2 receptor-positive meningiomapatients given peptide receptor radionuclide therapy using 90Y-edotreotide (DOTATOC)median time to progression 61 months for WHO Grade I tumors and 13 months for WHO Grade II-III tumors no patient had radiographic complete or partial responseReference - Eur J Nucl Med Mol Imaging 2009 Sep;36(9):1407 EBSCOhost Full Text

38

Interferon

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

based on case series of 35 patients (median age 61 years) with tumor progression following surgery, radiation therapy, and chemotherapyall patients treated with interferon alpha 10 million units/m2 subcutaneously every other daymedian survival 8 months (range 3-28 months)progression-free survival 54% at 6 months and 31% at 12 monthsmedian time to tumor progression 7 months (range 2-24 months)no patient had neuroradiographic complete or partial responsetreatment terminated in 3 patients due to toxicity and 7 patients had dose reductionReference - Cancer 2008 Oct 15;113(8):2146full-text

39

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.

imatinibpatients with recurrent meningioma following surgery and radiation therapy treated with imatinib 600-800 mg/day reported to have median progression-free survival of 2 months in case series of 23 patients (Neuro Oncol 2009 Dec;11(6):853full-text)patients with recurrent or progressive meningioma treated with imatinib plus hydroxyurea reported to have 24-month survival of 100% for WHO Grade I tumors and 46.2% for WHO Grade II-III tumors despite significant tumor progression (level 3 [lacking direct] evidence)based on case series of 21 patients treated with imatinib 400-1,000 mg/day plus hydroxyurea 500 mg twice dailymost patients had previous surgery or radiation therapy8 patients had WHO Grade I tumors and 13 patients had WHO Grade II-III tumors24-month survival 100% for WHO Grade I tumors and 46.2% for WHO Grade II-III tumors24-month progression-free survival 12.5% for WHO Grade I tumors and 7.7% for WHO Grade II-III tumorsReference - J Neurooncol 2012 Jan;106(2):409full-textpatients with recurrent meningioma treated with an epidural growth factor inhibitor, gefitinib or erlotinib, reported to have median overall survival of 23 months (level 3 [lacking direct] evidence)based on case series of 25 patients (median age 57 years) treated with gefitinib 500 mg/day (16 patients) or erlotinib 150 mg/day (9 patients)8 patients had benign tumors and 17 had atypical or malignant tumorsmedian overall survival of 23 months12-month survival was 60%12-month progression free survival was 16% no significant differences in overall survival or progression-free survival comparing patients with benign vs. atypical or malignant meningiomaReference - J Neurooncol 2010 Jan;96(2):211full-textpatients with progressive or recurrent meningioma treated with bevacizumab therapy, alone or in combination with chemotherapy, reported to have 6-month progression-free survival of 86% in case series of 14 adults (J Neurooncol 2012 Aug;109(1):63full-text)

40

Seizure ProphylaxisProphylactic 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 craniotomyComparing phenytoin to placebo or no treatmentPhenytoin significantly reduced early seizures (< 1 week postoperatively) in 1 of 4 trialsNo 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 1957Grade Icomplete removal including resection of underlying bone and associated dura9%symptomaticrecurrence at 10 years

Grade IIcomplete removal and coagulation of dural attachment19%symptomaticrecurrence at 10 years

Grade IIIcomplete removal w/o resection of dura or coagulation29%symptomaticrecurrence at 10 years

Grade IVsubtotal resection44% symptomaticrecurrence at 10 years

Grade Vdecompression withor without biopsy100%symptomaticrecurrence at 10 years (small sample in original paper)

EmbolizationPreoperative 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.

preoperative embolization of meningioma to minimize intraoperative bleeding(1, 3)dense vascularization common and may be assessed preoperatively by magnetic resonance angiography preoperative embolization in selected patients may reduce intraoperative bleeding and need for transfusion, operation time, and postoperative complicationsrisks include hemorrhage, extensive edema, and vascular infarctionembolization of meningioma in 1,012 patients reported to result in complications in 1.5% of patients but no significant disability in 91.3% of patients in Japanese neuroendovascular registry (Neuroradiology 2014 Feb;56(2):139)embolization may be an alternative primary treatment of meningioma for patients not candidates for craniotomy and surgical resection(3)embolization of meningioma by microcatheter delivery of gelatin microspheres reported associated with marked tumor shrinkage over 20 months in 6 of 7 patients not candidates for surgery in case series (Neuroradiology 2003 Jul;45(7):451)conservative management (active surveillance)asymptomatic meningiomas may be treated conservatively with close monitoring of clinical and radiological disease status(1, 2, 3)conservative management of asymptomatic meningioma associated with tumor growth in 37% of patients and development of symptoms in 16% within 5 yearsbased on retrospective cohort study1,434 patients with meningioma were evaluated603 patients (42%) were asymptomaticof 67 patients with conservative treatment and > 5 years follow-up25 (37%) had tumor regrowth11 (16%) developed symptomsof 213 patients with surgical treatment, morbidity rate was 4.4% in patients < 70 years old and 9.4% in patients 70 years oldReference - J Neurosurg 2006 Oct;105(4):538full-text, commentary can be found in J Neurosurg 2006 Oct;105(4):536

44

Radiotherapy

OverviewConventional radiation therapy

Stereotactic radiosurgeryGamma KnifeCyber Knife

Fractionated stereotactic radiosurgery

Intensity-modulated radiation therapy (IMRT)

Indications/Side effectsPrimary treatment for inoperable meningioma or for patients for whom surgery would be inappropriatefollow-up treatment for patients with incomplete resection of meningiomaComplete tumor eradication not possible but tumor shrinkage reportedTreatment to dose of 54 Gy for Grade I and 60 Gy for Grade II-III.Complications of radiation therapy may includeAlopeciaTooth lossNew onset seizuresNeurological deficitsCranial nerve palsyHeadacheEdemaRadio-necrosisDelayed hydrocephalus

Conventional Whole Brain RadiotherapyConventional 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

based on cohort study92 patients with benign World Health Organization (WHO) Grade I cerebral meningioma had total tumor resection (48 patients), partial tumor resection (32 patients), or partial tumor resection plus adjuvant radiation therapy (12 patients), and were followed for median 7.7 yearsoverall survival rate was 93% (no significant differences between groups)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

48

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 2.5 to 3 cm0% 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

survivalmedian patient survival reported as(1)10 years for WHO Grade I meningioma11.5 years for WHO Grade II meningioma2.7 years for WHO Grade III meningiomapatients with meningioma have reduced survival compared to general populationbased on retrospective cohort study1,986 patients in Finland with histologically verified intracranial meningioma (1953-1984) were followed through 1987compared to population without meningioma, meningioma associated with83% 1-year relative survival rate71% 15-year relative survival rateReference - Cancer 1992 Sep 15;70(6):15685-year survival rate 81% for patients aged 21-64 years and 56% for patients 65 years oldbased on retrospective cohort study9,827 patients with meningioma from National Cancer Data Base were evaluated5-year survival81% for patients aged 21-64 years56% for patients 65 years old70% for benign tumors75% for atypical tumors55% for malignant meningiomafor 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 hospitalsfor 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 hospitalReference - J Neurosurg 1998 May;88(5):831full-text

69

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

THANK YOU