Meningiomas Jeffrey Raizer and Wendy J. Sherman Sojka

Department of Neurology, Northwestern University, Chicago, IL, USA

Introduction

Meningiomas represent the most common primary intracranial tumor, accounting for approximately one - third of all primary central nervous system (CNS) tumors. They can present both symptomatically and as an incidental fi nding on cranial imaging or at autopsy. While most meningiomas are benign, the clini-cian needs to know the appropriate diagnostic steps to follow in order to allow for appropriate management.

Epidemiology

The Central Brain Tumor Registry of the United States reported that meningiomas account for more than 30% of all primary brain tumors, fol-lowed by glioblastomas (20%) and astrocytomas (9.8%). The estimate for meningiomas may be low given that many remain undiagnosed and are therefore not included in the registry.

The incidence of meningiomas increases with age. While benign meningiomas are much more common in women, atypical (grade II) and anaplastic meningiomas (grade III), the more aggressive subtypes, are slightly more common in men. As meningiomas are contiguous with the meninges, they can also occur within the

spinal canal, but intracranial lesions are far more common.

Pathophysiology

Histologically, meningiomas are thought to arise from arachnoidal cap cells, most commonly within the arachnoid villi, but may be found throughout the arachnoid space. Most reports involve convexity or skull base tumors, though there have been rare case reports of intraven-tricular or intraosseous lesions. Because of their origin from arachnoidal cap cells, they have both epithelial and mesenchymal components, making their histologic differentiation from other tumor types diffi cult at times.

Why arachnoidal cap cells differentiate to become meningiomas has been studied and investigators are continuing to unmask aberrant signaling pathways responsible for this transfor-mation, hoping to further guide targeted therapies. At this point in time, the pathway most implicated in meningioma tumorigenesis involves the NF2 gene. Loss of heterozygosity for chromosome 22q results in NF2 gene inactiva-tion, a gene that codes for the Merlin protein, thought to be a tumor suppressor protein. Multi-ple other genes, proteins, and pathways have

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Table 11.1. WHO II classifi cation of meningiomas.

WHO Grade I WHO Grade II WHO Grade III

• Meningothelial • Fibrous (fi broblastic) • Transitional (mixed) • Psammomatous • Angiomatous • Microcystic • Secretory • Lymphoplasmacyterich • Metaplastic

• Atypical • Clear cell • Chordoid

• Rhabdoid • Papillary • Anaplastic

(malignant) • Meningiomas

of any subtype or grade with highproliferation index and/or brain invasion

been potentially implicated in meningioma tum-origenesis, but not so convincingly as NF2 . This area requires further research.

science revisited

Other pathways implicated include:

• VEGF (angiogenesis) • Hedgehog (embryogenesis) • Notch (activation results in chromosomal

instability • mTORC1 (tumor suppression)

(EMA), and higher grade tumors have increased mitotic activity.

The Simpson classifi cation of surgical resec-tion (Table 11.2 ), fi rst described in 1957, is still used in combination with histologic grading to stratify risk of recurrence. The Simpson system describes fi ve grades of resection, taking into account the extent of tumor removal, as well involvement of dura, bone, and venous sinuses.

Aside from histologic grade and Simpson clas-sifi cation of surgical resection, the third impor-tant component in determining likelihood of

Classifi cation

Meningiomas are classifi ed according to the World Health Organization (WHO) II system. Their classifi cation is based upon histologic fea-tures categorizing meningiomas into three groups. Grade I meningiomas are classifi ed as having a low risk of recurrence and nonaggres-sive behavior, commonly referred to as benign. Grade II and III meningiomas have a higher like-lihood of recurrence and behave more aggres-sively. Grade II meningiomas are referred to as atypical and grade III meningiomas as malig-nant. Within each grade, there are further sub-types (Table 11.1 ). Many of these features are seen on hematoxylin and eosin staining. Menin-giomas stain for epithelial membrane antigen

Table 11.2. Simpson classifi cation of surgical resection.

Simpson grade Extent of resection

Grade I Complete tumor removal with excision of dural attachment,+ / – excision of bone/sinus

Grade II Complete tumor removal with coagulation of dural attachment

Grade III Complete tumor removal only

Grade IV Partial tumor removal

Grade V Biopsy only

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recurrence is proliferation index. Proliferation index can be determined using multiple immu-nohistochemical stains, including Ki - 67 and pro-liferating cell nuclear antigen (PCNA) indices.

tips and tricks

Recurrence risk factors include:

• High proliferation index • Partial resection • Histologic grading

Etiology

Ionizing radiation is the environmental risk factor most strongly linked with the incidence of meningiomas. It has been found that the risk of meningioma is related both to the number of radiation treatments, as well as to the dosage used in radiation treatments. In a recent population - based study in Britain, in a cohort of 17,980 patients surviving at least 5 years after the diagnosis of childhood cancer, incidence of subsequent development of CNS tumors was compared with doses of both radiation and chemotherapy. It was found that the risk of devel-oping meningiomas had a strong, linear, and independent relationship with dose of radiation received to the meninges, as well as to the dose of intrathecal methotrexate received. Spe-cifi cally, compared with control subjects, radia-tion doses of 0.01 – 9.99, 10.00 – 19.99, 20.00 – 29.99, 30.00 – 39.99, and ≥ 40 Gy administered to the meninges was associated with a twofold, eight-fold, 52 - fold, 568 - fold, and 479 - fold increased risk, respectively.

Hormones have a strong association with meningiomas, a relationship supported by several fi ndings including the presence of estro-gen, progesterone, and androgen receptors seen on many meningiomas. Clearly, there is a well - established increased incidence in postpubertal women, with the highest incidence ratio of 3.15 : 1 during the peak reproductive years. Additionally, some studies have indicated that meningiomas change in size during the luteal phase of the menstrual cycle, as well as during pregnancy. Oral contraceptive use has not been found to be

associated with an increased incidence of men-ingiomas; however, the potential association with hormone replacement therapy appears to be more controversial. In a large prospective study of over 1 million postmenopausal women, there was a relative risk of 1.34 (95% confi dence interval [CI] 1.03 – 1.75) of meningioma in women being treated with hormonal replacement therapy when compared with non - users, sug-gesting a slightly increased risk. Finally, there is a report of a patient with multiple meningiomas, all of which regressed after cessation of estrogen agonist therapy.

Head trauma is a controversial risk factor for the development of meningiomas. While there are some small studies supporting an associa-tion, a large cohort study of 228,055 patients hos-pitalized with head trauma found no association, with an incidence ratio of 1.2 (95% CI 0.8 – 1.7). It is thought that the suspected association between head trauma and meningioma is secondary to a detection bias given the imaging that ensues fol-lowing head injury.

Debates are currently ongoing regarding expo-sure to electromagnetic waves from cell phone use and their potential correlation with meningi-oma formation. Multiple studies have looked at the association between cell phone use and brain tumors. Currently there is no consensus. It is thought that the follow - up time has not been long enough at this point in the history of cell phone use to assess the association accurately, given previous studies have shown that time from radiation exposure to meningioma detec-tion averages 20 – 40 years.

Clinical p resentation

The clinical presentation of meningiomas varies widely and depends greatly on the specifi c loca-tion (Table 11.3 ). The most common presenting symptoms include headache and altered mental status. Additionally, when meningiomas overlie the cerebrum, they can lead to focal seizures, as well as transient neurologic symptoms which may resemble transient ischemic attacks. As imaging in medicine has exponentially increased, so has the number of incidental meningiomas found in asymptomatic patients with a normal neurologic examination.

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omas are found during work - up for headaches, they are fi rst found on CT imaging. Characteristi-cally, on CT imaging meningiomas are isointense with brain parenchyma, many demonstrating microcalcifi cations. Following administration of intravenous contrast, meningiomas show homo-geneous enhancement. In particular, psam-momatous meningiomas may have predominant calcifi cations that are best appreciated on CT imaging, as opposed to MRI. Additionally, CT imaging is also useful to determine bony involve-ment of meningiomas, specifi cally hyperostosis.

Table 11.3. Location of meningioma and site - specifi c symptoms. From Raizer J, Sherman W. (2011) Meningiomas. In: Gilman S. (editor - in - chief) Medlink Neurology . MedLink Corporation, San Diego. Available at www.medlink.com . Accessed February 5, 2011. Reprinted with permission.

Tumor location Relative incidence (%) Site - specifi c symptoms

Convexity 34.7 Headaches, seizures, motor and sensory defi cits

Parasagittal 22.3 Anterior : chronic headaches, memory and behavior changes

Middle: motor and sensory defi cits Posterior: homonymous hemianopsia All: venous occlusion

Sphenoid ridge 17.1 Medial: visual loss, CN III, IV, V1, VI palsies

Lateral: headaches, seizures, motor and sensory defi cits

Lateral ventricle 5.2 Headaches, seizures, hydrocephalus

Tentorium 3.6 Ataxia, headaches, visual loss, diplopia

Cerebellar convexity 4.7 Headaches, ataxia, dizziness, facial pain, dysarthria

Tuberculum sellae 3.6 Visual loss, headaches, optic atrophy, noncongruent homonymous hemianopsia

Optic nerve sheath 2.1 Visual loss

Cerebello - pontine angle 2.1 Hearing loss, headaches, ataxia, dizziness, tinnitus, facial palsy

Olfactory groove 3.1 Anosmia, Foster Kennedy syndrome, headaches

Foramen magnum 0.52 Nuchal and occipital pain, emesis, ataxia, dysphagia, motor and sensory defi cits

Clivus 0.5 Headaches, emesis, ataxia, motor and sensory defi cits

Other 0.5

tips and tricks

Frontoparietal parasagittal meningiomas may present with slowly progressive spastic weakness or numbness contralaterally, then bilaterally, followed by incontinence.

Imaging

Meningiomas have characteristic fi ndings on both computed tomography (CT) and magnetic resonance imaging (MRI). As many meningi-

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Figure 11.1. T1 post contrast magnetic resonance image (MRI) of a patient with a large grade I interhemispheric meningioma.

Figure 11.2. T1 post contrast MRI of a patient with a grade III right sphenoid ridge meningioma.

Gadolinium - enhanced MRI is the modality of choice in the diagnostic work - up. On T1 sequencing, meningiomas are typically isoin-tense compared with brain parenchyma, similar to noncontrast CT imaging. The appearance of meningiomas on T2 sequencing is more variable. However, upon administration of gadolinium, meningiomas characteristically show intense homogeneous enhancement, usually with a signifi cant “ dural tail. ” Findings on MRI that are suggestive of a more aggressive tumor sub-type include prominent edema, heterogeneous enhancement, and irregular borders. Shown in Figure 11.1 is an example of a benign meningi-oma, and in Figure 11.2 a malignant meningioma on contrast - enhanced MRI.

science revisited

The classic “ dural tail ” sign is thought to represent hypervascularity at the tumor base.

Perfusion MRI is being investigated for poten-tial utility in differentiating extra - axial tumors. A small case series indicated that a dural - based tumor with low perfusion should suggest an alternative diagnosis, such as a dural metastasis, as most meningiomas demonstrate increased perfusion. Additionally, intraventricular tumors with low perfusion parameters should argue against the diagnosis of meningioma. As its utility is still being determined, it is not standard of care at present, but represents an additional imaging modality that may help with diagnosis and management.

Finally, cerebral angiography may help in pre-surgical planning, as well as in preparation for embolization prior to surgery.

Management

In determining the appropriate course of man-agement for a patient presenting with a menin-gioma, the clinician must fi rst make the determination as to whether the patient is symp-tomatic or asymptomatic. In asymptomatic patients with small meningiomas, many studies have demonstrated a slow growth rate, prompt-ing many clinicians to monitor these with serial imaging every 1 – 2 years, initiating treatment

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when there is evidence of growth or when patients become symptomatic.

Figure 11.3. Management fl owchart for asymptomatic meningiomas.

Asymptomaticmeningioma

<2cm in diameter≥2cm in diameter

Risk factors foraggressive tumor

behavior

Considerneurosurgical and

oncologic evaluationregarding further

management

Monitor with serialMRI

Can likely monitorwith serial MRI, mayconsider specialty

consultation on a caseby case basis

No risk factors foraggressive tumor

behavior

caution!

While the meningioma may have been an incidental fi nding, it is important to conduct a thorough neurologic review of systems to evaluate whether the lesion is truly asymptomatic.

Some institutions support being more aggres-sive in their management, even when lesions are small and asymptomatic. In a review of 22 studies, encompassing 675 patients, with median follow - up length of 4.6 years, tumors < 2 cm in diameter only became symptomatic in 2% of patients. Additionally, 51% of untreated meningiomas ≤ 2.5 cm in diameter demonstrated no growth

over the mean follow - up period of 4.6 years, with an additional 26% growing less than 10% per year. They found that the greatest risk for pro-gression included tumors of 2 – 2.5 cm in initial diameter, tumor growth rate greater than 10% per year, or those tumors that were hyperintense on T2 sequencing. Tumors > 2.5 cm were shown to subsequently develop new symptoms or have worsening of their pre - existing symptoms in 17% of patients. Based on this observed natural history of untreated meningiomas, though addi-tional studies are warranted, meningiomas < 2 cm in diameter without other characteristics or locations associated with increased aggressive-ness may be imaged serially, monitoring for growth, development of symptoms, and encroachment upon adjacent structures. The optimal management for those tumors > 2 cm in asymptomatic patients remains to be defi ned, but observation in most cases is likely reasonable (Figure 11.3 ).

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Post - radiation edema has been reported in as many as 25% of patients after SRS, with risk factors for edema development including pre - existing edema as well as larger tumor to brain surface area. Other risk factors identifi ed include age > 60 years, perilesional edema preceding SRS, no previous surgical resection, larger treatment volume, anterior cranial fossa location, and a higher margin dose.

In regards to management of symptomatic WHO grade I meningiomas, surgical resection has historically been the treatment of choice, allowing confi rmatory histology, relief of mass effect, and the chance of a cure in cases of total resection. This continues to be the treatment of choice for large meningiomas or those immedi-ately adjacent to radiosensitive structures, such as structures of the optic pathway.

Stereotactic radiosurgery (SRS) has emerged as a reliable treatment modality in the management of meningiomas, with many groups demonstrat-ing excellent control rates with good side - effect profi les. While SRS was initially used as adjuvant therapy or for recurrent disease, newer studies have indicated its use as a more defi nitive primary management strategy. In a large cohort of 972 patients treated with SRS, the overall control rate for benign meningiomas was 93%. After 10 years, WHO grade I tumors were controlled in 91%, demonstrating its utility in symptomatic, low risk benign meningiomas. SRS is an appealing option in that it minimizes the volume of irradiated normal brain tissue. One review advocated that SRS should be considered in patients with men-ingiomas involving critical neuronal or vascular structures, residual skull base tumor after surgery, and tumors where complete resection was not achieved.

Complications following SRS are uncommon, and most are transient. Most studies report a complication rate around 8%, with 3% being transient and 5% permanent. Complications seen include radiation effects seen on imaging, such as edema and necrosis, as well as cranial nerve dysfunction, depending on the location of the meningioma being irradiated, highest for parasellar or skull base tumors. Seizures have been reported following SRS, but appear to be relatively rare, with a higher incidence in those with seizures prior to treatment.

caution!

Higher risk for cranial nerve dysfunction following stereotactic radiosurgery in parasellar or skull base tumors.

caution!

Patients with seizure as part of their initial presentation should be continued on their anticonvulsant during surgery/radiation, as well as in the postoperative period, but not if a seizure was never documented.

tips and tricks

Post - radiation edema is usually easily controlled with a short course of steroids.

Fractionated external beam radiotherapy (EBRT) is used as postoperative adjunctive therapy in the treatment of intracranial meningi-omas. While prospective randomized data regarding the utility of EBRT in the management of intracranial meningiomas is lacking, retro-spective studies have demonstrated improved progression - free survival when EBRT is used fol-lowing subtotal resection. Additionally, EBRT is used as defi nitive treatment of unresectable tumors (i.e. optic nerve sheath meningiomas), as well as a method of obtaining local control in cases of anaplastic or atypical meningioma. The advantage over SRS of stereotactic fraction-ated EBRT is its feasibility in patients with adja-cent radiosensitive normal structures who may benefi t from dose - limitation.

Preoperative endovascular embolization is used is selected cases, namely tumors with angioblastic features, as well as those involving the skull base or critical vascular structures. Some studies also support its use in tumors that lie in surgically inaccessible areas, with the goal of reducing blood supply.

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in approximately 10% of meningiomas; proges-terone and androgen receptors are present in approximately two - thirds of meningiomas. Addi-tionally, progesterone receptors are most com-monly found in benign meningiomas.

Estrogen receptor inhibitors, specifi cally tamoxifen, have not been shown to be effective in inhibition of meningioma growth. This has been explained by the presence of estrogen receptors in only 10% of meningiomas. Thus, as may have been expected, one study of 19 patients only saw a partial or minor response in three of the study participants.

On the other hand, the predominance of pro-gesterone receptors in the meningioma popula-tion has created great interest in the potential effi cacy of progesterone receptor inhibitors, namely mifepristone (RU486). Initially, some small studies demonstrated a small potential benefi t, but this was refuted by a large prospec-tive randomized multicenter study enrolling 180 patients to either daily mifepristone or placebo, which failed to show a benefi t of mifepristone over placebo. It has been postulated that mife-pristone may still be potentially effi cacious as the majority of studies enrolled patients with meningiomas exhibiting increased proliferation index and of a higher histologic grade, as it has been shown that the incidence of proges-terone receptors is markedly decreased in these meningioma subtypes. Many novel agents that target VEGF, PDGF, and other components of the MAPK pathway are being investigated with variable activity. Aside from medical therapies aimed at the tumor itself, medical therapy is also used commonly for symptoms associated with meningiomas. Anticonvulsant therapy is indicated preoperatively only if patients have had a seizure and should not be given prophy-lactically outside of the perioperative period. Furthermore, if patients are on anticonvulsant therapy preoperatively, the medication should be continued postoperatively if the patient initially presented with a seizure. Many physi-cians will monitor the patient on therapy for 6 – 12 months; at that point, if patients continue to be free of seizures, pending other social considerations at the physician ’ s discretion, they can be tapered off their anticonvulsant. However, if they fail this taper, they will likely

While most symptomatic meningiomas can be effectively treated with surgery and radiation, there is an evolving role for medical therapy, par-ticularly when meningiomas are inoperable or in cases of recurrence when further surgery or radi-otherapy is not an option. Medical modalities considered as potential therapies include chem-otherapy, interferon, hormonal therapy, as well as newer targeted immunotherapies.

Chemotherapy has very limited use in menin-gioma management, with its primary use in cases of recurrent disease following surgery and radio-therapy. Many chemotherapies tested have had disappointing results, including temozolo-mide, dacarbazine, adriamycin, and ifosfamide with mesna. A small series of patients with malignant meningiomas achieved a modest benefi t in survival with 3 – 6 cycles of cyclophos-phamide, Adriamycin ® , and vincristine, though patients suffered substantial toxicity following treatment.

Hydroxyurea, an oral ribonucleotide reductase inhibitor, has become standard therapy in men-ingiomas refractory to surgery and radiation. The mechanism by which hydroxyurea arrests men-ingioma cell growth is through arrest of the S phase of the cell cycle, thus inducing apoptosis. There have been debates as to whether some earlier studies truly showed slowed progression or rather refl ected the natural course. A recent retrospective case series showed very limited benefi t to therapy with hydroxyurea, with no radiographic response in any of 60 patients, with 35% having stable disease and 65% with progressive disease during follow - up. Combina-tion therapy with hydroxyurea is currently under investigation.

Initial studies indicated a potential role for interferon alpha, which has been shown to inhibit meningioma cells in vitro . Repeated studies showed a mixed response, but given the lack of control data there is no consensus on the utility of interferon alpha in the management of meningiomas.

Hormonal receptors, fi rst elucidated by the predominance of meningiomas in women during reproductive years, led to the use of hormonal therapy being investigated as a potential medical management option. Regarding the specifi c hor-monal receptors, estrogen receptors are expressed

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Primary brain and central nervous system tumors diagnosed in the United States in 2004 – 2006 . CBTRUS , Hinsdale, IL .

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require anticonvulsant therapy throughout their lifetime.

Regarding corticosteroid therapy, corticoster-oids may be required in short bursts to reduce edema following surgery or radiation. These are often not required long - term and should be tapered rapidly.

Summary

• Meningiomas are the most common intracra-nial tumor.

• While the overall prognosis is good, this greatly depends on the histologic subtype and location.

• Asymptomatic tumors < 2 cm in diameter can often be monitored with serial imaging.

• Symptomatic tumors, tumors near critical structures, or ≥ 2 cm in diameter should be evaluated by a neurosurgeon for possible resection.

• Radiation may have a role depending on the extent of resection and tumor location.

• Medical therapy may be indicated in recur-rent tumors, although evidence to confi rm effi cacy of a variety of different options is minimal.

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