Intracranial Meningiomas:

 
Dr. A. Vincent Thamburaj,   
Neurosurgeon, Apollo Hospitals,  Chennai , India.

They are the most common benign tumors of the brain. Dural endothelioma, fibroma, sarcoma, epithelioma, and fungoid tumors of the dura are some of the older names that existed until Cushing established the term meningioma in his Cavendish lecture of 1922. About 90 per cent of all CNS meningiomas are intracranial.

Incidence: 

 

The incidence ranges around 20 per cent of all brain tumors. In India, the incidence  ranges from 9-15 per cent of all intracranial neoplasms in various series. The incidence seems to be higher in Africa, at 24-38 per cent. Meningiomas most commonly occur in the middle decades of life.  In India, these tumors have been reported to occur predominantly between the third and the fifth decades, with a peak in the fourth decade.  Western literature suggests maximum prevalence of meningiomas between the fourth and the sixth decades. Meningiomas are more commonly encountered in women than in men. There is no sex preference in older patients.

Familial incidence of meningiomas, usually multiple, is largely found in association with central neurofibromatosis (NF-2).   

Meningiomas are rare in children, they form 0.4-0.6 per cent of all intracranial neoplasms in childhood.  About two per cent of all meningiomas occur in childhood and adolescence. Meningiomas in children are more commonly malignant and often of the haemangiopericytic and papillary type.  A higher prevalence of cystic meningiomas has also been reported in children. The other distinctive features of meningiomas in children are i) no sex preference, ii) a particularly high incidence of intraventricular tumors, and iii) significant association with neurofibromatosis.   

Etiology: 

Though the origin of a meningioma, like of any other neoplasm, is uncertain, some antecedent factors have been implicated in the initiation and growth of meningiomas.   

Trauma to the head has been blamed for a long time as an important contributory cause. Though in the majority there are no morphological signs of trauma at the site of the tumor, in some cases the tumor had arisen under a fracture, from an area of dural scarring or even from a retained foreign body intracranially. Despite these conflicting reports, there is enough evidence to suggest that at least some cases of intracranial meningiomas are initiated by head injury.  

Chronic irritation, from an ossified subdural hematoma or tubercular pachymeningitis, was incriminated in the past as a causative factor.  However, it is not considered relevant. Papova virus large T-antigens have been demonstrated in a high percentrage of meningiomas. Herpes virus large T- antigens seem to induce meningioma growth.  Recent technical developments have allowed the identification of small pieces of viral proteins in human tumors, including meningiomas.  Although it is not possible to say whether these viral genes or vital proteins are the etiological gents in meningiomas, their presence is an important step in establishing a relationship between the virus and meningioma. 

Irradiation induced meningiomas have appeared following high dose irradiation for intracranial growths and low dose radiation to the scalp for fungal disease and occasionally, for a vascular nevus. The onset of tumor formation can be 12-27 years later. While the majority of the radiation induced tumors following high doses were thought to be sarcomas, a recent review of the world literature suggested, radiation induced meningiomas are at least five times more numerous than gliomas or sarcomas. Some of the unique features of radiation induced meningiomas are 1)The neoplasm lies below and often invades the atrophic scalp with alopecia, 2)The tumor occurs in a much younger age group; the greater the radiation dose, the shorter the latency and the younger the patient’s age at presentation, 3) No female predominance, 4) A calvarial location abutting against the sagittal sinus, 5) Multiple tumors are more common (25-29 per cent), 6) Recurrence following excision is common.  

The carcinogenic effect of thorium dioxide has been blamed in the genesis of some meningiomas.   

Chromosomal abnormalities in meningiomas are now well established and probably more consistently seen than in any other tumor except chronic granulocytic leukemia.  In approximately 80 per cent of the tumors analyzed there is a loss of heterozygosity on at least one chromosome 22 DNA marker. The frequency and consistency with which monosomy 22 appear has led to the postulation of a uniform pathogenetic mechanism and it has been hypothesized that with the loss of genetic material on chromosome 22, a previously suppressed oncogene is probably unmasked. The role of SV-40 virus in meningiomas is disputed by some.

Increased incidence of meningiomas, usually multiple, are associated with neurofibromatosis 1 & 2.  Patients with von Recklinghausen’s disease develop meningiomas at an early age; 19-24 per cent of adolescents with meningiomas have neurofibromatosis. The other evidence of heredofamilial occurrence is the association of meningioma with Von Hippel-Lindau disease. 

Hormonal association is indicated by the greater incidence of meningiomas in females, its increase in size related to pregnancy and the luteal phase of the menstrual cycle, and the documented association between meningioma and breast carcinoma in the same patient.  However, the existence of sex-specific hormone receptors in meningiomas has long been a controversial issue. 

Despite the frequent inconsistencies, binding assay techniques in meningiomas suggest: (1) high levels of progesterone receptors, (2) moderate concentration of androgen receptors, and (3) an equivocal report about the status of estrogen receptors.  The recent cloning of complementary deoxyribonucleic acid (cDNA), encoding human estrogen, progesterone and androgen receptors has facilitated the direct investigation of hormone receptor gene expression without the limitation of variations in binding assay interpretation. The coexpression of androgen and progesterone receptor messenger ribonucleic acid (mRNA) and protein product have been reported in few meningioma.  Estrogen receptors in mRNA expression were not detected.  

Pathology: 

Almost all meningiomas are intradural. However, extradural meningiomas, both cranial and spinal, have been reported.  Meningiomas may be globular in form or flat. 

The globular tumors may be rounded, ovoid or lobulated and usually have a relatively small dural attachment. Globular tumors are usually smoothly lobulated and well encapsulated with the result that

characteristically, the adjacent brain is not invaded and an intact pial covering is usually present. 

 

On the contrary, the flat tumors commonly referred to as meningioma en-plaque, are less well encapsulated with a tendency to involve the pia as well as the overlying bony structures.  They are attached over a relatively broad area of the dura. 

 

Meningiomas have a tendency to invade the dura and its venous sinuses and may grow through the skull into extracranial tissue. 

Meningothelial meningioma (H&E): meningothelial cells and fibrous areas with attempts at whorl formation (doublearrow) and psammoma bodies(arrow).

A majority of the tumors are solid, but areas of cystic degeneration or a predominantly cystic tumor may occur.  Granular or patchy calcification may occur, especially in the psammomatous variety and occasionally, the tumor may be totally calcified.  Peritumoral brain edema is a common feature and suggests an aggressive nature.

 

Multiple meningiomas are more commonly encountered in the pediatric population (11 per cent), in the elderly (up to 20 per cent) and in patients with neurofibromatosis (20 per cent). These tumors can occur at any location within the cranium, and the association of cranial and spinal meningioma is rare.  Multiplicity may result from a multicentric origin of the tumor or from dissemination of tumor cells by CSF during surgery. 

 

Occassional association with aneurysms and AVMs and gliomas has been reported and considered coincidental.

Association with other intracranial neoplasms, such as acoustic neurinoma, in the absence of neurofibromatosis, is extremely rare. 

Cystic changes may, occasionally occur at the periphery of a meningioma (peritumoral) or inside the tumor (intra-tumoral).  Intratumoral cysts arise from degeneration, hemorrhage or necrosis.  Peritumoral cysts arise from adhesions and accumulation of protein containing CSF, reactive gliosis, fibroblastic proliferation in the final stage of peritumoral oedema or rarely as an exudate from the tumor surface.  From a surgical point of view, peritumoral cystic meningiomas present greater difficulties and unless every effort is made to excise not only the mural nodule, but also the cyst wall with the help of an operating microscope, recurrence is likely to occur. The cystic variety is more commonly encountered in males, in children and in the supratentorial compartment. Cystic changes in a meningioma may have a serious connotation as eight per cent of cystic meningiomas are reported to be malignant and 12 per cent are reported to be angioblastic, probably hemangiopericytic. 

Meningiomas arise from the arachnoid cells. The arachnoid cell has a polyblastic character and is functionally multipotential.  This results in different histological and cytological variations of meningiomas.

 

Classification of the meningiomas has been changed several times.

The WHO classification of meningioma (2000): 

 

                   Classification                                                 Features

Meningothelial (grade I)

  Fairly uniform polygonal cells with indistinct cytoplasmic borders arranged in sheaths or medium size globules.
Fibroblastic (grade I)   Spindle shaped cells in a dense collagen matrix.
Transitional (grade I)   Mixed of above types.
Psammomatous (grade I)   Cells are more elongated and separated .  Form whorls which by degeneration forms Pssmmonian bodies (concentric laminas of degenerated cells have a concentration of calcium salts).
Angiomatous (grade I)   Abundant sclerosing blood vessels.

Microcystic (grade I)

  Cells have stellate and vacuolated cytoplasm with long cytoplasmic processes.
Secretory (grade I)   Epithelial differentiation of meningothelial cells resulting in the production of hyaline inclusions.
Lymphoplasmacyte-rich (grade I)   Lymphoplasmacytic infiltration in the meningothelial component of the tumor.
Metaplastic (grade I)   Meningothelial cells with differentian into spindle cells.
Clear cell (grade II)   Mixture of clear cells and meningothelial cells.
Chordoid (grade II)   Spindle or epitheloid cells disposed in chordoma-like clusters and cords in a myxoid matrix.
Atypical (grade II)   More cellularity and cytologic atypia than grade I tumors.
Papillary (grade III)   Papillary pattern with few anaplastic features.
Rhabdoid (grade III)   Abundant eosinophilic cytoplasm resembling rhabdoid tumor.
Anaplastic (grade III)   Has a high cellularity, brain invasion, frequent mitosis, invasion of the blood vessels and necrosis.   
 

The meningotheliomatous meningioma is the commonest histological type, though some report them to be less common. Recent advances in pathology include the recognition of cystic types, evaluation of proliterative activity and the use of markers in the evaluation of the aggressiveness of meningiomas in the delineation of malignant phenotypes. 

 

Sites of Origin:

Approximately 90 per cent of the intracranial meningiomas are supratentorial.  In the cranial cavity as a whole, the anterior half is involved far more frequently than the posterior half.     

The most common sites are the convexity, parasagittal, falx, and sphenoid ridge, together making up 60 per cent of intracranial meningiomas. 

Parasagittal Meningiomas arise from the arachnoid villi of the superior sagittal sinus and often involve the adjacent convexity dura and falx.  Nearly 50 per cent invade the sinus, 50 per cent get secondary attachment to the falx and 25 per cent are bilateral.  Hyperostosis is associated with 25 per cent of these tumors and is a valuable pointer to their diagnosis. 

 

Falcine meningioma arises from the falx cerebri or inferior sagittal sinus and may rarely invade the superior sagittal sinus.  It is usually completely concealed by the overlying cerebral cortex and does not cause bony changes.  About 50 per cent of the tumors grow through the falx to become bilateral.  Falx meningiomas are about five to seven times less common than parasagittal meningiomas. 

 
         Site     Distribution
Convexity      34%
Parasagittal      22%
Sphenoid ridge      17%
Lateral ventricle      5%
Cerebellar convexity      5%
Tentorium      4%
Tuberculum sella      3%
Orbital      2%
Cerebello pontine angle      2%
Olfactory groove      3%
Foramen magnum      1%
Clivus      1%

The distribution of parasagittal and falx meningiomas along the longitudinal axis is about 20, 50 and 30 per cent in the anterior, middle and posterior third, respectively. 

Convexity Meningiomas may occur anywhere over the convexity of the cerebrum. Convexity tumors may cause erosion of the overlying skull and may come to lie under the scalp.   

Olfactory meningiomas may arise from the anterior part near the crista galli, from near the cribriform plate or the planum sphenoidale. These tumors can be silent for a long time.  Growing posteriorly, these tumors compress the optic nerve and chiasma leading to unilateral blindness or bitemporal hemianopia with optic atrophy.  With the rise in intracranial pressure, there may be papilledema in the opposite eye and Foster Kennedy syndrome may be seen. Further extension posteriorly puts pressure on the hypothalamus and pituitary gland. By this time, the ICP rises to cause obvious features of raised ICP.  It is not unusual, even today, to see large olfactory groove meningiomas presenting with blindness and raised ICP.  Rarely, by eroding through the orbital roof or the cribriform plate, the tumor may cause proptosis. 

Suprasellar Meningiomas include meningiomas arising from the tuberculum sellae, planum sphenoidale, diaphragma sellae and/or anterior clinoid process in close proximity to the optic chiasma, displacing it posteriorly and superiorly and stretching it. They may extend into the orbit, paranasal sinuses, cavernous sinus, sella, infratemporal fossa, and posterior fossa. 

Medial Sphenoid Wing (clinoidal) Meningioma can be divided into two general categories.  These are: 1) globular and 2) diffuse or enplaque.  The globular meningioma grows en mass from the anterior clinoid and medial sphenoid, involves the ICA and MCA to variable degrees and displaces or engulfs the optic nerves, chiasma, and optic tracts and compresses the adjacent frontal and temporal lobes.  The second variety grows diffusely from a similar area with involvement of the cavernous sinus and often without symptoms of an intracranial mass. As they grow bigger, the branches of the fifth, fourth and sixth cranial nerves may be affected. 

Middle-third Sphenoidal Wing (Alar) Meningiomas arise from the middle third of the sphenoid wing in relation to the superior orbital fissure (SOF) and the anterior portion of the middle cranial fossa (MCF).  Growing posteriorly, it indents the temporal lobe.  

Lateral Sphenoidal Wing (Pterional) Meningiomas with a minimal reaction in the sphenoid ridge is more common than the en plaque variety.  The tumor occupies the middle cranial fossa, may extend into the anterior fossa and attain a large size before symptoms become obvious. Meningioma en plaque, is uncommon and behaves in a peculial fashion, in that the tumor spreads along the meninges as a plaque causing an intense bony reaction.  There is hyperostosis of the pterion as well as the lateral half of the lesser wing of the sphenoid.  Tumor may also be present in the lateral and posterior orbit and may involve the optic canal. 

Cavernous Sinus Meningiomas may be classified into (a) the confined and (b) the extensive group.  The confined tumors are small tumors that involve the cavernous sinus and Meckel’s cave, the middle fossa or the sella turcica.  The extensive tumors include petroclival, medial sphenoid wing and infratemporal tumors that involve the cavernous sinus. These are generally known to be slow growing tumors, though the natural history is not clear.   

Middle Cranial Fossa Meningiomas may arise anywhere in the middle cranial fossa or may extend into it from the anterior surface of the petrous temporal bone or lateral surface of the cavernous sinus. Paresthesia or numbness of the face may be present and lacrymation may be impaired.  The tumor indents the undersurface of the temporal lobe and may remain asymptomatic for a long time. The foramen spinosum and the middle meningeal artery are considerably enlarged.   

Posterior Fossa Meningiomas constitute 8-12 per cent of all intracranial meningiomas and 7-12 percent of all posterior fossa tumors. They are, conventionally, classified according to the site of dural attachment as follows: 1) cerebellar convexity, 2) tentorium, 3) posterior surface of the petrous bone, 4) clivus, 5) foramen magnum, and 6) fourth ventricular (tela choroidea. The posterior surface of the petrous bone is the commonest site of attachment (42 per cent) in posterior fossa meningiomas and these meningiomas constitute 6-8 per cent of all cerebellopontine angle tumors. The other characteristic features of these tumors are a broad base towards the petrous bone and associated hyperostosis or erosion of the petrous.

Meningiomas arising from the clivus are attached at any of the several sites along the petroclival borderline where the sphenoid, petrous, and clival bones meet. The zone of adherence to the dura is commonly wide and overlaps two or more of these sites.  Moreover, almost all these tumors have wide tentorial occupation. Foramen magnum meningiomas are the commonest tumors of the foramen magnum.  

Tentorial Meningiomas may arise from any location on the tentorium and account for two to three per cent of all intracranial meningiomas.  Tentotial meningiomas may grow upwards into the posterior fossa or in both directions.  Nearly 20 per cent have significant supra and infratentorial extensions. 

Torcular meningiomas have, as part of their dural base, the dura forming the torcular, i.e., they arise from, invade, or are attached to a wall of the torcular itself.  These tumors represent about one per cent of intracranial meningiomas.  True torcular meningiomas are usually bilateral, based on the torcular.  When there is only unilateral extension from the torcular it is usually a lateral tentorial meningioma which has got secondary attachment to the torcular.  Often, these tumors have both infra and supratentorial extension bilaterally. 

Intraventricular Meningiomas constitute 1-1.7 percent of intracranial meningioma and usually arise from the choroids plexus of the lateral ventricle, but may occur rarely in the third or fourth ventricle. The lesion is more frequent in the left lateral ventricle in middle aged women, but has been well documented in children. 60-94 per cent of the lateral ventricular meningiomas arise from the choroid plexus at the trigone. Intraventricular meningiomas are thought to arise from arachnoid tissue, which is carried with the choroid plexus as the ventricular system invaginates.   

Intra-temporal meningiomas are rare. The usual sites are near the jugular foramen, the internal auditory meatus, the region of the geniculate ganglion and the sulci of the superficial petrosal nerves. Jugular foramen meningiomas are often clinically indistinguishable from glomus jugulare tumors. Occurring inside the temporal bone, these tumors often infiltrate the surrounding bone.  Some of these cases have en plaque tumors over the petrous. 

Orbital Meningiomas are discussed elsewhere. 

Extracranial Meningiomas: ExtracraniaL (excluding spinal) meningiomas constitute one per cent of all meningiomas and can be classified into four groups. These are as follows: 

Group 1: Arising from intracranial dura and extending extracranially. This is the most common type of extracranial meningioma.  Extracranial extension of intracranial meningiomas is described in four principal sites: 1) the orbit (7.5 per cent), 2) the outer dipole and scalp (six per cent), 3) the upper respiratory tract (2.5 per cent) and 4) the parotid region and infratemporal fossa (1.25 per cent).  Most parapharyngeal meningiomas are related to the cranial nerves, particularly 7th, 9th, 10th, 11th and 12th.   

Group 2: Head and neck extracalvarial meningiomas: Extracranial meningioma, in the absence of an intracranial mass, but associated with hyperostosis of the underlying skull, osteolytic changes and intra-osseous tumor infiltration have been described in the outer surface of the frontal, temporal and parietal bones.  A primary intra-osseous location without underlying dural involvement is very rare. Arachnoidal cell clusters normally found at the level of the internal auditory meatus(IAM), jugular foramen, geniculate ganglion, roof of the eustachian tube or in association with the greater or lesser petrosal nerves, may represent the cells of origin of temporal bone meningiomas. 

Group 3: Ectopic meningiomas not associated with the craniospinal meninges: An ectopic meningioma was first reported by Winkler, who, in 1904, described a case of paravertebral subcutaneous meningioma in a 10 year old girl.  Other ectopic sites reported are the glabella, pterygopalatine fossa, intraoral, nasal cavity, paranasal sinuses, parotid gland, neck, cutaneous areas of the scalp, the face, mediastinum, lung, little finger, brachial plexus, lung, and adrenal gland 

Group 4: Metastatic meningiomas: Metastases from a meningioma could be extraneural or through the CSF pathways.  A total of 16 cases with CSF spread have been reported.  Eleven cases had features of malignancy in the original neoplasm and seven cases had associated extraneural metastases.  In five cases both the original tumor and the deposits preserved their benign character.  Though tumor seeding at operation might have been the explanation in two, no surgery was performed in three and these are examples of spontaneous leptomeningeal metastases. 

Extraneural metastasis is more frequent than CSF dissemination. The hemangiopericytic and papillary variant had a greater propensity to metastasize. Seventy per cent of patients recorded to have had a metastasizing meningioma have been subjected to previous craniotomy.  However, spontaneous hematogenous metastases have been reported and have been attributed to invasion of the superior sagittal sinus, cavernous sinus and its perineural lymphatics.  Nearly one-third of all the metastases were observed in the lung and the other common metastatic sites were liver (19 per cent), lymph node (12 per cent) and bone (nine per cent).  The rare sites reported are the mediastinum, kidney, thyroid and parotid. 

Clinical features:

The clinical presentation of a meningioma is classically with seizures, hemiparesis, visual field loss, aphasia or other focal symptoms. The clinical presentation depends on the location of the meningioma. Most meningiomas are slowly growing lesions and symptoms and signs will frequently develop very slowly. Finally an increasing number of meningiomas are asymptomatic and are incidental findings. 

Convexity meningiomas: They may exist for a long time without symptoms or they may lead to early irritation of the cerebral cortex, resulting in partial or generalized epilepsy, especially if located adjacent to the central sulcus.  The tumor makes a bed for itself on the surface of the brain. 

Parasagittal and falx meningiomas: Anterior-third meningiomas, located between the crista galli and the coronal suture, have a more insidious onset and often attain a large size before diagnosis.  Headache is the predominant symptom and may be present for years followed by gradually progressive impairment of memory, intelligence and personality changes. Generalized epilepsy is a presinting symptom in 25-50 per cent of patients.  Ataxia, tremor and ipsilateral facial pain may, occasionally, accompany a large meningioma in this location and thus may be misdiagnosed a posterior fossa tumor. Tumors in the middle-third, from the coronal suture to the lamboid suture, classically present with contralateral focal motor sensory epilepsy followed by progressive weakness of the lower limb.  These tumors are detected at an early stage because of focal epilepsy.  Bilateral tumors may, occasionally, give rise to bilateral disturbances and rarely paraplegia which may be wrongly attributed to spinal pathology.  Tumors in the posterior-third, between the lamboid suture and the torcular Herophili, may present with features of raised ICP alone.  The only characteristic sign, a homonymous field defect, either quadrantanopic or hemianopic, may not be noticed by the patient.  Epilepsy is uncommon. 

Olfactory meningiomas: Headache is the most common presenting symptom. Though anosmia occurs in 85-90 per cent of cases, it is rarely the initial or presenting symptom.  As these tumors grow in size, symptoms of pressure on the frontal lobe may be apparent.  Mental symptoms often lead the patient to seek treatment from a psychiatrist.  While inferior tumors may cause excitement or restlessness, pressure over the convexity of the frontal lobe may lead to indifference and apathy.  The more anterior tumors cause a central scotoma and papilledema.  Growing posteriorly, these tumors press on the optic nerve and chiasma leading to unilateral blindness or bitemporal hemianopia with optic atrophy.  With the rise in intracranial pressure, there may be papilledema in the opposite eye and Foster Kennedy syndrome may be seen. Further extension posteriorly puts pressure on the hypothalamus and pituitary gland.  By this time, the ICP rises to cause obvious features of raised ICP.  It is not unusual, even today, to see large olfactory groove meningiomas presenting with blindness and raised ICP.  Rarely, by eroding through the orbital roof or the cribriform plate, the tumor may cause proptosis. 

Suprasellar meningiomas: Meningiomas arising from the tuberculum sellae, planum sphenoidale, diaphragma sellae and/or anterior clinoid process are conventionally grouped under suprasellar meningiomas.  As these tumors arise in close proximity to the optic chiasma, displacing it posteriorly and superiorly and stretching it, visual symptoms are early and common, leading to earlier detection than olfactory groove meningiomas.  Ninety to ninety nine percent of the patients complain of either monocular (55 per cent) or binocular (45 per cent) visual loss.  The other common symptoms are headache, epilepsy and mental changes.  The presence of bitemporal hemianopic field defects in the presence of a normal sized sella should suggest the possibility of a suprasellar meningioma.  However, in the early stages vision may be affected in only one eye. Pituitary hypofunction is uncommon and is found in only 4-13 per cent of these patients.   

Medial sphenoid wing meningiomas: They present with slowly progressive ipsilateral visual impairment with or without diplopia.  Diplopia secondary to oculomotor paresis is more common in the diffuse variety.  As they grow bigger, the branches of the fifth, fourth and sixth cranial nerves may be affected.  There may be proptosis because of either obstruction of the anterior end of the cavernous sinus or draining orbital veins. The other presenting symptoms may be headache, epilepsy or psychiatric disturbances.  Pressure on the hypothalamus may become apparent as the tumor grows upwards and medially. 

Middle-third Sphenoidal Wing (Alar) Meningiomas:  Proptosis is a frequent early symptom. The tumor usually attains a large size before it is diagnosed. Growing posteriorly, it indents the temporal lobe and thus uncinate fits or other symptoms of complex partial epilepsy may become manifest. 

Lateral Sphenoidal Wing (Pterional) Meningiomas: They present with a very slowly progressive unilateral, painless, non-pulsatile proptosis and fullness under the temporalis muscle.  Some patients complain of a dull pain over the temple and mild local tenderness.   

Cavernous Sinus Meningiomas: These are generally known to be slow growing tumors, though the natural history is not clear.  The symptoms are of long duration and include retro-ocular pain, mild exophthalmos and double vision due toe VI nerve involvement.  Anesthesia in the distribution of the first division of the V nerve may be seen.  The confined tumors generally cause more symptoms than the extensive tumors. 

Middle Cranial Fossa Meningiomas: Paresthesia or numbness of the face may be present and lacrymation may be impaired.  The tumor indents the undersurface of the temporal lobe and may remain asymptomatic for a long time.   

Posterior Fossa Meningiomas: Depending on the site of origin, the tumor causes cerebellar, cerebellopontine angle or brainstem syndromes with multiple cranial nerve palsies.  Features of raised ICP appear earlier than in supratentorial meningiomas. 

Intratemporal meningiomas: They present with otological problems; symptoms of ear discharge, mastoiditis, polyps or granulation tissue.  Hearing impairment and facial nerve paresis often develop. These patients invariable have some degree of lower cranial nerve paresis.  It is not uncommon for these patients to present with a submandibular swelling or a swelling in the posterior pharyngeal wall.  When the lesion extends into the posterior fossa, cerebellar signs may become prominent.   

Intraventricular meningiomas usually present with symptoms of increased ICP; frontal lobe signs may be present.   

Hemorrhage in meningiomas has been more frequently reported in tumors with a parasagittal or convexity location, and more often in the malignant or angioblastic varieties. However, an apoplectic presentation is much less common. Other reported intracranial vascular events related to meningiomas are rare and are secondary to either dural venous sinus occlusion manifesting as pesudotumor cerebri or arterial occlusion. 

Imaging:

Plain X-ray: Abnormalities in the skull films of patients with intracranial meningiomas have been variously reported as 36-77.5 per cent in the literature. Relatively less vascular meningiomas may cause a deposit of minerals in the bone, leading to an increased.

density and thickening or hyperostosis, the commonest primary change. Sclerosis of the bone does not necessarily represent bone invasion, however, sclerosis of the outer table of the skull as well as spiculation of the bone suggest penetration of the bone by the tumor.  Hyperostosis may be focal near the attachment of the tumor to the meninges, the bony projection resembling a osteoma. In other cases there is a diffuse thickening of the bone. This process is particularly well marked in the region of the sphenoid wing. Hyperostosis is reported in 15-44 per cent of adults and 10 per cent of children with meningiomas. 

A highly vascular tumor nears the skull causes rarefaction and bone absorption. Lytic skull defects suggest penetration of the bone by the tumor and occasionally, the tumor may protrude through a defect in the skull and lie under the scalp.  Meningiomas associated with a lytic destructive reaction are reported to be biologically more aggressive and are more likely to recur. Osteolytic changes are seen in 12 per cent of adults and nine per cent of children with meningiomas. 

Increased vascular markings are reported in 4-20 per cent of adults and four per cent of children: these could be either focal areas of increased vascularity at the tumor attachment producing a sinusoidal appearance in the bone, or an enlargement and tortuosity of meningeal vascular channels. Asymmetric unilateral enlargement of meningeal vascular channels and an ipsilateral dilated foramen spinosum are highly suggestive of a meningioma.

Tumor calcification has been reported in 9-20 per cent of adults and 13 per cent of children.  Psammoma bodies, stromal calcification and rarely, tumor ossification result in calcific changes. 

Magnetic Resonance Imaging: It is the imaging of choice. On the unenhanced MR meningiomas are often isointense with brain on T1 and T2 weighted images.  Extra-axial mass effect suggested by white matter buckling, a rim of CSF around the mass, a pial vascular rim and a shorter T2 of the mass are described as characteristics of meningioma.  Gadolinium enhanced MR suggest that MR is better suited for identifying the extra-axial location of the tumor, the broad contact with the meninges, the tumor capsule and meningeal contrast enhancement adjacent to the tumor, i.e., the meningeal sign.  CT is, however, superior in demonstrating calcification and atypical tumor density.  Both methods provided nearly equal results in demonstrating mass effect, hyperostosis and contrast enhancement.  Contrast enhanced MR (CEMRI) is particularly superior in the diagnosis of meningiomas of the skull base, posterior fossa and high convexity.

A thickened and enhanced dura, variously called ‘dural tails’ and ‘the meningeal sign’ can be identified adjacent to some meningiomas. Dural tails are considered as signs of tumor infiltration along the dura, as proven by histopathological examination.  Incomplete excision of this extensive dural tail may lead to recurrence. 

MR spectroscopy may also be used for metabolic or functional studies of meningiomas. 

Computed Tomography (CT): Plain and contrast enhanced (CE) CT scans are positive in 96 per cent and diagnostic of a meningioma in 90 per cent of cases. Meningiomas are dura based extra-axial mass lesions with broad contact with the meninges. On the plain CT 75 per cent of tumors are hyperdense and 14.4 per cent are isodense. They are often multi-lobulated and smooth in contour, adjacent to dural structures and may be calcified in some areas.  Intravenous X-ray contrast enhances meningiomas uniformly and brightly.  In about 15% of cases atypical patterns such as, necrosis, cyst formation or hemorrhage is found.  Indistinct margins, marked edema, mushroom like projection from the tumor, invasion deeply into the brain, and heterogeneous enhancement all suggest aggressive types. Peritumoral brain edema is seen in 60-75 per cent of meningiomas. The edema around the tumor is associated with aggressive tumors, and is either a result of a break down of the blood-brain barrier or a secretion of the tumor itself. The association of bone changes like hyperostosis or a lytic area at the tumor base helps in the diagnosis of meningiomas. Peritumoral low attenuation may also be caused by demyelination, entrapped ventricular CSF, a subarachnoid cyst or peritumoural cyst, or the co-existence of a glioma.  

3D CT angiography and MR angiography delineates the encasement and displacement of the intracranial vessels and is as good as angiography.  

Angiography: The availability of CT and MR has considerably decreased the indications for angiography in the diagnosis of brain tumors.  Still, angiography is often preferred by the surgeons in the management of parasagittal, falx and basal meningiomas and also to study the encasement of major intracranial arteries, the patency of the dural sinuses and the venous anatomy (e.g. cortical venous drainage to the sagittal sinus in parasagittal or falx meningiomas and the anatomy of the vein of Labbe in petroclival meningiomas), for planning the operative approach.  Occasionally, angiography may be helpful in the diagnosis of a meningioma in an atypical case, by demonstrating external carotid supply to the tumor, although other primary tumors of the meninges and metastatic tumors of the calvarium may also have an external carotid supply. Currently angiography is more often used in the evaluation of the feasibility of embolisation. 

Positron emission tomography (PET) with F-2-fluorode-oxyglucose has been used to evaluate small changes in CT or MR imaging to determine whether these were recurrent tumours.  Research in meningioma receptor ligands for PET scans may reveal additional information of the tumor biology useful for the preoperative assessment.

MANAGEMENT: 

Surgery:  

The objective of surgery is total removal of the meningioma, including the dural attachment and bone that is involved by the tumor.  The completeness of surgical removal is the single most important prognostic factor. However, when total removal entails unacceptable risks of morbidity or mortality, it is prudent to be satisfied with subtotal excision.  Sound judgment in choosing the best treatment depends on a high level of clinical acumen, for the best treatment is that which is best for the patient, not necessarily what is best for the tumor.  The factors having a direct bearing on the surgery of meningiomas are its location, vascularity, size and consistency.   

Preoperative embolization in the external carotid system, though helpful in reducing bleeding and shortening the operation time; is not without the hazard of inadvertent reflux of emboli into the internal carotid system causing cerebral infarction.  Surgery should follow within 24 hours of embolization. As an alternative, I prefer to expose the carotids at the neck for temporary occlusion in highly vascular lesions. 

Preoperatively, all patients are prophylactically put on anticonvulsants. I prefer to give intravenous dexamethosone (0.5 mg/kg body weight stat followed by 4mg 6 hourly) the day before the surgery along with H2 antagonist. 

  
   Bifalcine meningioma-MRI Falx meningioma-MRI
   
Convexity meningioma with hyperostosis- MRI Convexity meningioma with hyperostosis- X-ray
   
Orbital meningioma-CT  Parasagittal meningioma-MRI
Meningioma with Associated pituitary adenoma-MRI

Olfactory groove

meningioma-MRI

 
  Petrous meningioma-MRI Suprasellar meningioma-MRI
   

Tuberculum sella

meningioma-CT

Diaphragm sella

meningioma-MRI

   
Meningioma with skull infiltration-MRI

Intradiploic

meningioma-MRI

 
Sp. Wing en plaque meningioma-MRI Meningioma extending through foramen ovale -MRI
    

Intraventricular

meningioma-MRI

Cystic meningioma

with dural tail-MRI

 
Tentorial meningioma-MRI Torcular meningioma-MRI
    
Hemangiopericytoma-MRI

Jugular foramen

meningioma-MRI

 
F.M meningioma-pre op-MRI Multiple Meningiomas -MRI

At surgery, the head is secured higher than the level of the heart and without compression of the neck veins.

As a general rule, the site of incision is positioned as the highest area in the scalp to maximize the accessibility of the tumor. Free bone flaps are generally preferred over the osteoplastic flap. Hyperostosis and infiltration of bone by the tumor increases the difficulty during elevation of the flap. Bleeding from the bone can be most troublesome as the saw cut is being made and also when the bone flap is being elevated. Vigorous and frequent application of bone wax and rapid turning of the flap help to minimize bleeding.  

Fortunately, a layer of arachnoid usually separates the meningiomas from the brain, cranial nerves, and blood vessels. By accessing and staying within this surgical plane, the chances of neural and vascular injury are minimized. Early extensive debulking, helps in definition of the archnoidal plane. Operative microscope is mandatory to stay within the archnoidal plane. The best way to free the adherent arteries is to begin the dissection at uninvolved segments of the vessels. 

Once the tumor is excised, the involved dura and the bone are excised as well and duraplasty with pericranium or temporalis fascia is carried out. Unresectable dura should be aggressively cauterised.  Calvarial cranioplasty is better deferred as a later procedure to accommodate post operative edema. 

Considerations by tumor location: 

Convexity meningiomas offer the greatest potential for total tumor removal with a wide dural margin. A circumferential dural incision around the tumor insertion allows for early devascularization in the tumor. Central debulking helps in accessing the arachnoidal plane.  

In Parasagittal and Falcine meningiomas, their proximity to, and the extent of involvement to the sagittal sinus and the draining cerebral veins must be considered. Tumor invasion anterior to coronal suture may be managed with sinus ligation and excision. Excision of patent sagittal sinus, posterior to coronal suture carries significant risk of morbidity and mortality. Tumors attached to the lateral wall, without significant infiltration into the sinus lumen, can be managed by dissecting the tumor off the sinus and achieving hemostasis by a combination of coagulation and pressure over surgicel and gelfoam.  If the tumor has infiltrated the sinus lumen in the lateral aspect only, it may be excised and the sinus progressively closed with a continuous running suture.  Excision of the sinus followed by repair with autogenous venous grafts is being increasingly practiced. It is prudent to perform a near total tumor resection, leaving the involved sinus undisturbed.  Utmost care is taken when dissecting at depth to avoid injury to anterior cerebral arteries. Every effort should be made to preserve large cortical veins. Extensive tumor debulking avoids excessive brain retraction. Inferior sagital sinus is usually involved in falcine meningiomas and may be excised. 

The anterior and middle skull base tumors may extend to several intra and extracranial compartments. Orbital and/or zygomatic osteotomies and other more extensive skull base approaches may be needed to allow a more basal approach to minimize brain retraction, and also help clear the involved bone and the dura of the skull base. Continuous CSF drainage though a lumbar catheter may obviate the need for brain retraction. 

Tuberculum sella meningiomas displace the optic chiasm back and the optic nerves laterally and superiorly; carotid artery may be found medial to the displaced optic nerve. The pituitary stalk is posterior to the tumor along the membrane of Lilliequist, which separates the tumor from the neurovascular structures of the posterior fossa. Optic deroofing may be required to remove tumor extension. Olfactory Groove Meningiomas arise more anteriorly, and push the optic chiasm and optic nerves dowm. Large tumors may require a midline a bilateral bone flap.  The anterior end of the sagittal sinus may be ligated and the falx cerebri detached from its inferior attachment when indicated. Any extension of the tumor into the air sinuses can be removed by a frontobasal approach or a combined craniofacial approach.  Meticulous repair of the anterior cranial fossa is necessary to prevent CSF rhinorrhoea. The approach may be modified for other suprasellar meningiomas.  They may derive blood supply from the branches of the anterior cerebral artery and anterior communicating complex. They must be traced to the tumor prior to sacrifice. 

Total excision of medial sphenoid wing meningiomas, especially those with significant involvement of the cavernous sinus, though not impossible, is usually associated with significant morbidity.  Moreover, whether the patient really experiences long term benefits from more extensive surgery and the increased risk of surgery, or, whether partial removal of the tumor followed by radiotherapy is better, is still debated. The ICA and its branches, as well as the optic, oculomotor, and olfactory nerves are at risk.  The ophthalmic artery crosses the anterior corner of the opticocarotid triangle, and its location must be anticipated. The anterior clinoid meningiomas usually extend into cavernous sinus. Attempts at radical excision of the tumor in the SOF usually results in ophthalmoplegia.  Hence, a more conservative alternative is excision of the intracranial mass followed by radiosurgery or periodic observation. 

Pterional Meningiomas are usually easily achieved with careful microdissection of the branches of the MCA. The uncommon, meningioma en plaque, is approached through a frontotemporal extradural route. The hyperostotic posterolateral wall of the orbit needs to be drilled out exposing the periorbita and frontotemporal dura.  Bone above and below the superior orbital fissure, over the optic canal, anterior clinoid process, roof of the orbit and floor of the middle cranial fossa may also need to be removed depending on the extent of the lesion.  Dural excision and intradural tumor removal completes the surgical exercise.  Careful reconstruction of the dural and bone defect is essential.  This extensive surgery should be contemplated with utmost caution, as it is rarely possible to completely eradicate the tumor and moreover, some patients may develop visual deterioration following surgery. 

The decision regarding surgery in Cavernous Sinus Meningiomas depends on the age and general condition of the patient and whether relief from symptoms can be provided by operative treatment. Recent advances in microsurgical skull base techniques have made total excision of these tumors invading the cavernous sinus feasible with reconstruction of the internal carotid artery by a bypass graft.

Medial tentorial meningiomas can be approached by various routes depending on their disposition in the longitudinal axis.  An anteriorly located tumor can be managed by either a frontotemporal approach, extended anterior temporal approach with an anterior temporal lobectomy or by a subtemporal approach.  In large tumours, it may be better to sacrifice a part of the inferior temporal gyrus, to avoid excessive retraction and contusion of the temporal lobe while employing the subtemporal approach. The vein of Labbe should be protected at all costs to prevent temporal lobe infarction.  For more posterior medial tentorial tumors, subtemporal approach is preferred.  

Tentorial apex meningiomas are best approached by the occipital transtentorial route. An alternative approach is the supracerebellar route popularised. Torcular meningiomas are approached by either a supra or infratentorial approach or a combined approach depending on the extent of the tumor.  Almost always a bilateral approach is necessary.  Unless the torcular Herophili is occluded completely and adequate collaterals have developed, only subtotal excision is advisable.  Focal external cobalt beam irradiation of the residual tumor is recommended in such an event.  

The lateral tentorial meningiomas are approached either by a subtemporal, occipital, or temporoparietal route depending on the dominant extension of the tumor.  The main limiting factor for excision of the posterolateral tumor is involvement of the transverse and sigmoid sinuses. The main limiting factor for excision of the posterolateral tumor is involvement of the transverse and sigmoid sinuses. Total excision with ligation of the sinus is indicated only in the presence of good torcular anastomosis and a patent contralateral transverse sinus.  In tumors with both supra and infratentorial extensions either a subtemporal or a combined supra and infratentorial approach is recommended. Though microsurgical techniques have improved the results of surgery in these difficult tumors, still there is significant morbidity associated with their management, especially in medial tentorial tumors.  

Cerebellar convexity in the posterior fossa can be excised totally without significant problem, except when the venous sinuses are involved.  In the latter instance, total excision of the tumor along with the involved sinus can be achieved only if either the sinus is completely occluded or the collaterals are well developed.  Cerebellar convexity meningiomas have a propensity to develop near the transverse-sigmoid sinus junction and hence, sinus anatomy should be studied before planning surgery. 

CPAngle meningiomas are best excised by the retrosigmoid approach in the lateral decubitus position. It is beneficial to expose the presigmoid dura even during a retrosigmoid approach so that the dura and the sigmoid sinus can be retracted laterally, thus decreasing their obstruction of the surgeon’s view. It is important to skeletonize the entire sinus from the tranverse sinus junction to the jugular bulb in order to allow the full freedom of movement of the sinus once the tentorium is sectioned. When the tumor is huge with extensions into the tentorial hiatus, and the parasellar region, or has a wide tentorial attachment, a combined subtemporal and retromastoid approach or a petrosal approach may be necessary. 

Foramen magnum meningiomas, especially, the ventral ones, pose a challenge to the surgeon, with a high risk of morbidity. Various posterolateral approaches have been recommended. Essentially it involves mobilizing the vertebral artery medially and shaving off the outer third of the occipital condyle, so that the surgeon will have unobstructed view.  Good microsurgical technique is mandatory, whichever approach is chosen.  

Intratemporal meningiomas are better approached by infratemporal approach of Fisch or one of its many modifications.  These tumors are inseparable from the lower cranial nerves and hence it may be prudent to be satisfied with subtotal excision rather than total excision with severe postoperative morbidity.  Some of these cases have en plaque tumors over the petrous.  In such cases, excision is hazardous and unless the tumor is producing significant mass effect, it may be periodically followed. 

Intraventricular Meningiomas are approached similar to that of other tumors in the same location. The tumors in the trigone are best managed either by a parieto-occipital approach or mid-temporal gyrus approach. Various other approaches to the lateral ventricle have been described. 

Post-operatively, as a rule, basal meningiomas need much greater vigil than convexity meningiomas.

Postoperative course is usually uneventful unless major veins have been sacrificed.  Patients with tumors located over the central sulcus, even with no apparent venous disturbance at surgery, frequently have transient post-operative focal deficit on the appropriate side of the body. Post-operative epilepsy is frequent. Careful attention is warranted to facilitate cotical venous drainage; mannitol is avoided unless it becomes life saving and hypervolemic treatment helps.

Patients with a meningioma in the skull base may have a stormy post-operative course, in spite of microsurgical techniques.  The commonest problem is that of a CSF leak with its associated complications.  A few days of prophylactic ventricular or lumbar drainage may be useful.  Cranial nerve paresis is not uncommon and when the lower cranial nerves are involved, adequate care of the airway with ventilatory support may be essential.  A short period of nasogastric tube feeding may be necessary.   

Recurrent meningiomas: 

Among extra-axial brain tumors, meningiomas represent the largest group capable of recurrence.  These tumors may recur, either because of incomplete removal or a true recurrence.  The overall recurrence rates range from 13-40 per cent.

The most important factor in the recurrence of meningiomas was the extent of removal.

Simpson classified the types of excision into five grades and found that while the recurrence rate was nine per cent in grade I excision (complete macroscopic tumor removal with excision of involved dura and bone), it was 44 per cent in grade IV excision (intracranial tumor was left in situ).  This relationship has been confirmed by other authors.  As a meningioma is a slow growing tumor, the risk is also directly related to the length of follow up. Complete removal of a meningioma is not always feasible and remnants of the tumor may be left behind in the dura, involved bone, venous sinus wall or parts of the tumor adherent to vital structures thus leading to recurrence.   

 Simpson’s Grading

 
 GRADES                         FEATURES
  I Complete removal, including resection of dura and bone
  II Complete tumor removal with coagulation of dural attachment.
  III

Complete tumor removal without resection or coagulation of dural attachment.

  IV Subtotal removal
   V Decompression

Gadolinium MR can help to identify these dural extensions preoperatively to help excision. These dural extensions could explain recurrence after apparent complete tumor removal in a surface meningioma.  It is recommended that by removing an additional margin of two cm of dura around the tumors and enbloc resection of hyperostotic bone with ahealthy margin and the pericranium to prevent redrowth in convexity meningiomas.   

Studies evaluating proliferative activity and tumor kinetics by the argyrophilic method for the demonstration of nucleolar organizer regions (Ag-NOR), flowcytometry, and bromodeoxyuridine labelling index (BUdRLI) allow the detection of aggressive behavior in meningiomas indicating regrowth potential. The recurrence rate is significantly higher in atypical meningiomas than in other histopathological types and it has been suggested that a higher Ag-NOR count is suggestive of aggressive behaviour in meningiomas and is associated with an increased risk of recurrence. 

Other factors like bone invasion and brain infiltration have been considered important for the higher incidence of recurrence by some, but not by others.  It has been suggested that the recurrence is more frequent in the younger age group; Some surgeons feel the age is no predictor of recurrence. 

Hence, the decision for further therapy needs careful judgment.  It is not difficult to decide on reoperation in a patient with recurrence in a resectable location and progressive symptomatology.  However, a small recurrence, especially in a difficult location like the skull base or posterior half of the parasagittal region, may be better followed periodically or, radiosurgery may be considered.  In case the patient becomes symptomatic with an increase in the size of the tumor, a second operation is justified.  In cases following reoperation, those with an en plaque tumor, and patients with anticipated problems at excision, adjuvant radiotherapy may be considered.  Hormone therapy with anti-progesterone drugs may play a role in the future. 

Radiation Therapy: 

The role of radiotherapy in meningiomas is controversial.  Wara et al, reported that after incomplete tumor removal the incidence of recurrence at five years was 29 per cent in an irradiated group as opposed to 74 per cent in non-irradiated patients.  Radiation has also been shown to improve survival in malignant meningiomas and in incompletely resected and inoperable meningiomas of all three histological types (benign, ‘aggressive benign’, malignant).   

Stereotactic radiosurgery also may have a role in patients with residual/recurrent tumors, in tumors in high risk locations, and in patients who are unfit for surgery because of age or an associated medical condition.  Kondziolka et al, in a recent review of the results of radiosurgery in meningiomas, found that among 24 patients with 12-36 months follow up, 54 per cent had a reduction in tumor volume and 38 per cent showed no change.  The actuarial two year tumor growth control was 96 per cent.  Between 3-12 months, three patients developed neurological deficits because of delayed radiation injury.  However, an extended follow up is warranted, before any definite conclusion can be drawn as to the effectiveness of radiosurgery. 

In the treatment of skull base meningiomas which have been incompletely resected or have recurred, interstitial irradiation with I 125 seeds has been found to be safe and effective. Preoperative radiotherapy in vascular meningiomas administering 30 Gy or radiation makes surgical excision feasible six weeks after radiation. 

Chemotherapy: 

Antagonism of possible mitogenic hormones (estrogen and progesterone) has been the main focus of chemotherapy of meningioma. There is little benefit with Tamoxifen (40mg/m2 twice daily for 4 days and 10mg twice daily thereafter) in unresectable or refractory meningiomas. Some benefit with 200mg daily of Mifepristone (RU-486) has been reported. Post operative radiotherapy and 3-6 weeks of chemotherapy with cyclophosphamide, adriamycin and vincristine, reportedly, improves survival. A high affinity dopamine D1 binding sites in meningioma tissue using kinetic studies have been reported. Bromocriptine is found to have some inhibitory effect on meningiomas. dFurther studies are required. 

The future: 

It is well established that the patient with a meningioma has a high frequency of chromosome 22 monosomy (72%) and frequently has deletion of the long arm of chromosome 22.  Recent studies have demonstrated specific loss of chromosome 22 markers. It is therefore believed that meningioma growth is due to loss of the tumor suppressor gene or the anti-oncogene at the LIF locus.  The exact gene has still to be identified, clones and the apparatus that controls the gene deciphered, which would then lead to another major insight into the etiology of meningiomas and it would be possible to develop diagnostic and therapeutic strategies likely to revolutionize the management of these neoplasms. 

Oncogenes have also been found in meningiomas and DNA coding for both EGF receptors and PGF have been found. The DNA studies are developing very fast and application of these techniques in molecular meningioma studies increases the insight in meningioma pathogenesis. 

The relationship of sex hormones and meningioma has been known since Cushing, who noted that meningiomas had increased

growth during pregnancy, and the relationship between the breast carcinoma and meningioma is also well-known.  Recent studies

have demonstrated progesterone receptors and oestrogen receptors.  Receptor activity for progesterone has been demonstrated,

but receptor activity for oestrogen has not been demonstrated. In studies of growth characteristics of meningiomas

bromodeoxyuridase have been used and shown to be more sensitive than mitotic index in distinguishing a group of histologically

benign tumors form malignant tumors and thereby are a better guide for the best treatment and follow-up of a meningioma patient.

 
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 

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