1. GENERAL INFORMATION

1.1 Incidence

1.1.1 General data
Meningiomas are mostly benign tumours originating from non-neuroepithelial progenitor cells, the arachnoid cap cells. Arachnoidal cap cells form a morphologically distinct and highly metabolic active subgroup of arachnoidal cells, are involved in the resorption of cerebrospinal fluid. They are situated at the apex of Pacchionian bodies and exposed to venous blood flow, often within a dural sinus. Incidence: meningiomas are estimated to constitute between 13 and 26 % of all intracranial tumours. Most meningiomas are benign, corresponding to grade I of the WHO histopathologic classification (Louis 2000). Atypical meningiomas (WHO grade II) are reported in 5 - 7 % of all cases, whereas the incidence of malignant meningiomas (WHO grade III) has been described as low as 0.17/100.000/ year (Rohringer 1989). In large autopsy series, the incidence of meningiomas is as high as 1.4 % (Rausing 1970), due to the inclusion of asymptomatic meningiomas during life time ("incidentalomas"). Multiple meningiomas occur in less than 10% of cases.

1.1.2 Age and gender
Meningiomas show rising incidence with age and are most common in the sixth and seventh decade of life. In adults, there is a marked female bias with a female: male ratio of 3:2 to 2:1 (Louis 2000) and for spinal lesions 9:1. The annual occurrence of meningiomas is estimated to 2-7/100.000/year for women and 1-5/100.000/year for men (Lantos 1996; Longstreth 1993). The incidence of meningiomas is increasing over time, particularly in the elderly. This increase is related to wider indications for cranial imaging, better imaging facilities and ageing populations (Lantos 1996; Pobereskin 2000). A Danish survey found a 3.9 fold increase of meningioma diagnoses since 1943 (Christensen 2003). Atypical and anaplastic meningiomas might be more common in males, possibly related to the higher proliferation indices discovered in meningiomas of male patients (Jääskelainen 1985). In children and adolescents, meningiomas are equally rare in both sexes and show a tendency for more aggressive subtypes. They occur associated with hereditary syndromes, most frequently Neurofibromatosis type 2 (NF-2) (Lantos 1996; Zwerdling 2002; Rushing 2005), but also Gorlin syndrome and Cowden syndrome.

1.2 Aetiological and risk factors

There are established risk factors for the development of meningiomas.

1.2.1 Deletion in NF2 gene
One risk factor is the deletion affecting the neurofibromatosis type 2 gene, an autosomal dominant disorder, often associated with a cytogenetically visible deletion of the long arm of chromosome 22 at q12. Neurofibromatosis type 2 is characterized by the occurrence of sometimes multiple schwannomas, meningiomas and gliomas in the affected patients (Louis 2000). The NF2 is a tumour suppressor gene acting via its product, the protein merlin (schwannomin). Merlin shows a strong similarity to a family of cytoskeleton proteins such as protein 4.1, talin, moesin, ezrin, radixin and tyrosine phosphatases. A putative function of the protein is to build a link between the cell membrane and the actin cytoskeleton.

1.2.2 Ionizing radiation
Another well established risk factor ionizing radiation has been proved by large epidemiological surveys. Low dose irradiation with 8 Gy, used to treat tinea capitis of the scalp, was found responsible for single or multiple meningiomas with a life time risk of 2.3 % after a latency period of 35 years (Sadetzki 2002). Patients who received cranial radiotherapy for gliomas, leukemias and lymphomas or cerebral metastases were found to develop menigiomas within the previous radiation field after a shorter median latency period of 24 years. Half of the examined meningiomas induced by high dose cranial irradiation were found to be atypical with a high proliferative index. In a recent survey, the cumulative risk of meningioma in a cohort of 445 children 16 years or younger treated with high-dose cranial irradiation between 1968 and 1990 in Slovenia was 0.53%, 1.2%, and 8.18% at 10,20 and 25 years, respectively (Strojan 2000). In the Hiroshima and Nagasaki tumour registries, 88 meningiomas were observed within 80,160 atomic bomb survivors, which corresponds to an excess of 6.8 cases, (fitted linear excess relative risk (ERR) 0.64 (0.01 to 1.8) (Preston 2002). There is some evidence, that even very small doses of radiation to the head, such as the dose used for dental radiography could possibly increase the risk for meningioma development (Bondy 1996; Rodvall 1998). The widespread use of cellular phones has lead to some concern about a potential induction of brain tumors by phone use. Several case control studies have been conducted in Germany and in scandinavian countries. One of these studies reported a moderate increase of risk for the development of vestibular schwannomas (Hardell 2005; Hardell 2006), but none an statistical significant increased risk of meningiomas, whatever phone was used (Christensen 2005; Lonn 2005; Schuz 2006; Klaeboe 2005).

1.2.3 Head injury
A role of head injury for the induction of meningiomas has been suspected but as yet this question cannot be answered definitely. A potential mechanism is the local alteration of the blood brain barrier due to a head injury with a consequent massive influx of cytokines, histamine and bradykinin into the extravasal space. In a prospective study of nearly 3,000 people with head trauma and 30,000 observation years the occurrence of subsequent brain tumours was not associated with the severity or location of the head injury (Annegers 1979). The authors conclude that head trauma does not seem to be a significant aetiological factor in meningiomas, as meningiomas have a higher incidence in females, whereas males suffer 2- to 3-fold more frequently from a head trauma. Even in studies that suggest a potential influence, the odds ratio of 1.5 was lower for serious injuries, e.g. those leading to medical attention with loss of consciousness and hospitalization than for less severe injuries, which were undocumented but remembered after a median delay of more than ten years (Preston-Martin 1990; Phillips 2002). Recently, it could be shown that a subset of 104 genes of 1200 analysed is upregulated after traumatic brain injury. Genes controlling transcription regulation, signal transduction and intercellular adhesion were mostly affected (Michael 2005).

1.2.4 Hormonal receptors
It has been demonstrated that approximately two thirds of all meningiomas express progesterone receptors on their cell membranes, occurring more frequently in female patients, although to a variable extent. In a recent series about 500 meningiomas from Finland, 88% of the primary meningiomas were progesterone receptor positive, 40% positive for estrogen, and 39% for androgen receptors (Korhonen 2006). The role of sex hormones in the genesis of meningiomas is yet not clarified, but there is growing evidence that progesterone might at least contribute to the growth of PR positive meningiomas. Reversible aggravation of symptoms due to meningiomas during periods of relative progesterone excess, such as during the luteal phase of the menstrual cycle and during pregnancy strongly support progesterone dependency (Inoue 2002; Strik 2002; Nagashima 2001).
However, little evidence was found so far that exogenous hormone exposure like the use of hormonal contraception or of hormonal replacement therapy might increase the risk of meningioma development (Custer 2006)Maiuri 2002; Markopoulos 1998). There are some case reports dealing with breast cancer metastases within meningiomas intracranially and in the spine (Aghi 2005; Caroli 2006a). Patients with breast cancer who show an enhancing intracranial mass still have a chance that this mass is a meningioma. Furthermore, female patients with meningioma should be counselled to undergo regular breast cancer screening, on a type R basis.

1.2.5 Associations with other diseases
In a case-control survey including 7466 subjects from Germany, Schneider et al postulated that diabetes mellitus was associated with meningiomas, as well as arterial hypertension in females, whereas rheumatois arthritis showed a negative association (Schneider 2005).

1.3 Survival and prognostic factors

Most meningiomas have good long-term prognosis. In population-based cancer registry series of patients, overall 5-year relative survival exceeds 80%, the 10-year figures were 74%-79%, and those at 15 years since diagnosis were about 70% (Talback 2004). The spontaneous growth rate of meningiomas has been studied in 33 patients with subtotal resection: grade 1 meningiomas grew 1,513 cm/year, leading to a tumor doubling time of 5,2 years. In young patients, the growth rates were higher, whereas they were significantly lower in meningiomas with calcifications (Nakamura 2005). Asymptomatic meningioma show a lower growth rates, and approximately 60% of them did not exhibit tumor growth. Consevative treatment with close follow-up review may be the best treatment strategy for these cases (Yano 2006). Old age, male gender and significant comorbidities are unfavourable prognostic factors (Sankila 1992). The safety of meningioma surgery in the elderly varies with institution, radiosurgery may be a reliable alternative to surgery (Bateman 2005).In a large US study, mortality and adverse outcome were lower when meningioma surgery was performed by high-volume providers (Curry 2005). Malignant and atypical meningiomas carry a considerable poorer prognosis than classic meningioma: in EUROCARE patients diagnosed in 1990-94 had a 5-year relative survival of 57% (Berrino 2003), compared with 90% for classic meningioma (EUROCARE-4 personal communication) High histological grading and papillary and haemangiopericytic morphology, large tumour size and high mitotic index are associated with high recurrence rate (Maier 1992; Takahashi 2004). Absence of PR receptors is associated with high mitotic index, increased apoptosis, and early recurrences (Konstantinidou 2003a). Chromosomal abnormalities such as deletions in various chromosomes and loss of heterozygosity seem to be associated with shorter survival and high recurrence rates (Leuraud 2004; Mihaila 2003; Maillo 2003).

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2. PATHOLOGY AND BIOLOGY

2.1 Histologic subtypes of meningiomas

Most meningiomas are slowly growing, benign neoplasms, deriving from arachnoid cap cells, which were grouped as WHO grade I meningiomas in the WHO grading scale. Certain histological subtypes are associated with a higher proliferation potential and correspond to WHO grades II and III (Louis 2000; Kleihues 1993). Definition of atypical meningioma includes increased mitotic activity or three or more of the following features: increased cellularity, small cells with high nucleus: cytoplasm ratio, prominent nucleoli, uninterrupted pattern less or sheet-like growth, and foci of spontaneous or geographic necrosis. Anaplastic meningiomas are defined by histological features of frank malignancy far in excess of the abnormalities present in atypical meningioma (Kleihues 2000). Such features include either obviously malignant cytology (e.g., having an appearance similar to sarcoma, carcinoma or melanoma) or a high mitotic index (20 or more mitoses per 10 HPF). Invasion of brain is not sufficient for a diagnosis of anaplastic meningioma (Perry 1999).

Tab. 1 Histologic subtypes of meningiomas grouped by likelihood of recurrence and grade according to the WHO Classification (Kleihues 2000 )

Corresponding to the WHO grading scales, a pattern of genetic changes associated with meningioma development has been established, starting with loss of material from the long arm of chromosome 22q, where the NF2 gene is located, and another gene involved in the initiation of meningioma growth is suspected. A considerable numeric instability has been observed in meningiomas with inactivation of NF2,manifested by bi- and multinucleated cells, multiple spindle poles and unseparated chromatids (van Tilborg 2005). Candidate genes for initiation of meningiomas are BAM 22, a member of the b-adaptin gene family and MN1, a gene that was found disrupted in meningioma (Louis 2000; Kros 2001). Using DNAmicroarray, Wada et al found amplifications of MSH2 in 51% and deletions of GSCL in 41% and of HIRA in 22% of 31 meningiomas analyzed (Wada 2005). In atypical meningiomas non random chromosomal changes of increasing complexity were demonstrated, leading to loss of 1p, 6q, 10q, 14q,17p and 18q and gains of 20q, 12q, 15q, 1q, 9q and 17q (Weber 1997; Espinosa 2006). Maillo et al et al detected that loss of the long arm of chromosome 14 was associated with male gender and with a higher relapse rate among histologically benign patients (Maillo 2003) and with adverse prognostic impact (Tabernero 2005).

2.2 Cytological proliferative potential:

The proliferative potential of meningiomas has been studied using several different proliferation markers, mainly employing monoclonal antibodies against proliferation-associated antigens, such as the monoclonal anti Ki-67 antigen clone Mib-1 (Perry 1998), PCNA (proliferating cell nuclear antigen) (Cerda-Nicolas 2000), topoisomerase II-alpha (Roessler 2002; Korshunov 2002), and mitosin (Konstantinidou 2003b). Meningiomas are highly vascularized, as demonstrated by cerebral angiography and by strong contrast enhancement in CT/MRI imaging. Increased expression of vascular endothelial growth factor (VEGF) correlates significantly with vascularity, peritumoral oedema and with proliferation (Yoshioka 1999). Increased VEGF expression and increased expression of vascular permeability factor correlated with increased microvessel density and microcystic morphology of meningiomas (Christov 1999). Another peptide found to stimulate neoangiogenesis in meningiomas was endothelin 1 and high affinity for a selective endothelin receptor antagonist was demonstrated, offering another potential therapeutic approach (Harland 1998). A novel finding is that all components of the notch signaling pathway are expressed in meningiomas and that an Inhibitor of the notch pathway suppresses meningioma cell survival. The transducin-like enhancers TLE 2 and TLE3 are induced only in high grade meningiomas. These findings suggest that the notch pathway is involved in meningioma pathogenesis and progression (Cuevas 2005). Like other benign tumors of the central nervous system, meningiomas were shown to express survivin, an inhibitor of apoptosis which is overexpressed in foetal tissues and human cancers, but almost undetectable in normal tissues (Hassounah 2005). Binding sites for cytokine TGF beta (transforming growth factor beta) have been described in meningiomas, and in vitro experiments with meningioma cells demonstrated a growth inhibitory effect of TGF beta 1 (Johnson 1992). The expression of the anti-apoptotic protein bcl-2 was found to decrease with increasing tumour grades (Roessler 1999). Additionally, telomerase activation might be a critical step in the pathogenesis of atypical and malignant meningiomas (Nakatani 1997). It has been demonstrated that meningioma cells express the platelet-derived growth factor ß and that PDGF-BB stimulates meningioma cell proliferation, partly via activation of RAF-1-MEK-1-MAPK/ERK pathway (Wang 1990; Johnson 2001; Johnson 2005). Another pathway found activated in WHO grade I meningiomas is the P13K-Akt/protein kinase B-P7056 pathway (Johnson 2002). Loss of alkaline phosphatase activity, correlated with loss of a distal part of 1p was demonstrated to be an independent predictor of early recurrence in meningiomas (Niedermayer 1997). Hunt et al described that expression of minichromosome maintenance-2 protein correlated with early recurrence in benign meningiomas (Hunt 2002). Additionally, it could be shown that atypical and anaplastic meningiomas showed increased immunohistochemical expression of the transcription factor Ets-1 and matrix-metalloproteinases 2 and 9, potentially involved in the invasive process in meningiomas (Okuducu 2006). It is still unknown why some WHO grade I meningiomas relapse after resection whereas others do not. Several groups have been searching to identify biological markers associated with recurrence in benign meningiomas. It could be shown that in relapsed meningiomas the labeling indices for the proliferation index Ki-67, for proliferating cell nuclear antigen (PCNA) and for the human telomerase reverse transcriptase (hTERT) are significantly increased (Maes 2005; Maes 2006). In a series of 35 meningiomas, 10 (5 of WHO grade I and 5 atypical) expressed HER2 protein. The rate of recurrence was significantly higher in HER2 overexpressing meningiomas than in HER2 negative meningiomas (Loussouarn 2006). A receptor to cholocystokinin (CKK) is expressed in 66% of meningiomas and cultured meningioma cells showed dose dependent growth stimulation when exposed to CKK (Oikonomou 2005). Moreover, in atypical meningiomas, the protein levels of cathepsin B and L were found to be significantly higher than in benign meningiomas, whereas protein and mRNA levels of their inhibitors stefin and cystatin C were significantly lowered. This could be used as diagnostic and prognostic marker for potential invasive and progressive behaviour of meningiomas (Trinkaus 2005). Sadetzki et al could demonstrate that intragenic SNPs in the Ki-ras and ERCC2 were associated with the risk to developing meningiomas, whereas SNPs in cyclin D1 and p16 might be protective (Sadetzki 2005).

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3. DIAGNOSIS

3.1. Symptoms

Interpreting the symptomatology of meningiomas according to their location was one of the most fascinating topics that has exploited the full potential of the clinical neurologic examination. However, the availability of modern imaging techniques has facilitated the diagnosis of meningiomas at an earlier stage, so that the full burden of symptoms associated with the different locations is rarely seen (Bindal 2003).
As the anatomical distribution of meningiomas is parallelled by the location of arachnoid villi, meningiomas are found in all parts of the skull, most frequently in the parasagittal area, followed by the falx, the sinus cavernosus, tuberculum sellae (5-10%), lamina cribrosa, foramen magnum and torcular zones. Spinal meningiomas are most often situated in the thoracic spine. Focal hyperostosis of the bone close to the tumour is a not uncommon and characteristic finding in meningiomas and is almost invariably the sign of bone invasion by meningioma cells. This may result in focal bulging of involved bones and in localized pain. Parasagittal meningiomas make up the largest subgroup of meningiomas (17-20%) and occur most often in the frontal lobe. They can grow to considerable size before symptoms, mostly Jacksonian seizures of the lower limbs or headache, become apparent. Papilloedema and homonymous hemianopia were characteristic features of advanced anterior parasagittal meningiomas. In falcine meningiomas the clinical signs vary according to the area from which they arise. Meningiomas of the anterior falx often cause a long history of headache and optic atrophy as well as gradual personality changes with apathy and dementia. Patients with meningiomas of the frontal skull base most often complain about impaired vision (54%), headache (48%), anosmia (40%), mental changes (34%) and seizures (20%) (Solero 1983). The most prominent finding in tuberculum sellae meningiomas is an insiduous visual loss in one eye, followed by scotomaous defects in the other eye. Transient visual loss during pregnancy with recovery after delivery has been repeatedly documented (Symon 1979; Finn 1974). Lateral sphenoid wing meningiomas often cause a painless unilateral exophthalmos, followed by unilateral loss of vision and hearing loss. Tumours distorting the temporal lobe frequently cause seizures. In most patients with suprasellar meningiomas, only minor hormonal abnormalities are found. Clinoidal meningiomas cause a wide variety of visual impairment, cranial nerve palsies and exophthalmos. Peritorcular meningiomas present with neurologic symptoms due to compression of the occipital lobe or the cerebellum, such as headache with occipitally localized pain, papilledema and homonymous field deficits as well as ataxia, dysmetria, hypotonia and nystagmus. Epileptic seizures as the first symptom are reported to occur in 20% to 50% of meningioma patients (Rohringer 1989). In a recent survey on 222 consecutive, surgically treated meningioma patients, 26.6% of patients presented with epilepsy as their initial symptom (Lieu 2000). The incidence of preoperative epilepsy in the temporal lobe was eightfold higher than in the occipital lobe and twofold higher than in the frontal and parietal lobes. A strong correlation was also found with peritumoral oedema (p < 0.001), but no correlation with histological subtype). Surgical removal of the meningioma resulted in cessation of the epilepsy in 62.7 % of patients with preoperative epileptic seizures. Approximately 20% of the patients without history of preoperative seizures developed postoperative epilepsy, which could be controlled successfully in 70 % of this cohort. Rarely, spontaneous bleeding occurs in meningiomas. There are 143 cases reported in the literature. Increased bleeding tendency was found in two age groups, patients aged less than 30 years and patients older than 70 years. The mortality associated with bleeding of meningiomas was high, 21% for all patients and as high as 75% in patients that did not reach consciousness before surgery (Bosnjak 2005; Sakowitz 2005).

3.2 Imaging techniques

There is to date no established screening procedure for meningiomas. Current clinical practice is that every person with recent onset of seizures or with focal neurological signs possibly associated with an intracranial mass should undergo magnetic resonance imaging of the brain. EV, on a type C basis. In every imaging modality meningiomas show highly characteristic features that allow their accurate diagnosis and nowadays even give clues to the histological differentiation. Most focal, extra-axial masses are meningiomas. In plain radiographs, their characteristic markers are hyperostosis (ca 25%), increased vascular markings and psammomatous calcifications (Hodges 1989). In CT and MRI scans, meningiomas appear as sessile or pedunculated, rarely carpet like (on the skull base) and mostly isodense masses associated to dural surfaces with a characteristic "mottling" structure due to the high vascularization. Often dural base or a "dural tail" indicates the anchoring point to the dura. In a prospective study, it could be shown, that the "dural tail sign" had a sensitivity of 58% and a specificity of 94% in 98 histologically examined intracranial tumors (Rokni-Yazdi 2006). Peritumoral edema is variable and can be important in secretory meningiomas or in malignant meningiomas. Atypical density/intensity is seen in 10-15% of cases, reflecting unusual histological features (Elster 1989). Time resolved, two dimensional substraction digital MR angiography allows visualization of the feeding arteries without catherter angiography (Yoshikawa 2000).
Magnetic resonance perfusion and diffusion studies has allowed quantifcation of the relative regional cerebral blood flow and has shown that patients with significant perilesional oedema had highly significantly diminished regional blood flow in brain areas adjacent to the tumour compared with patients without oedema (Bitzer 2002). Thorough examination of the shapes of the tumor-brain interface as observed by T(1)(W1) weighted imaging, t(2)W1 and FLAIR (fluid attenuated inversion recovery) as well of the vascular supply observed by digital substraction angiography (DSA) were closely correlated to the degree of tumour_brain adhesion encountered during surgery, as examined in 36 patients by Takeguchi et al ( Takeguchi 2003). Meningiomas show a characteristic profile in MR spectroscopy with alanine, high choline and glutamine peaks and low concentrations of creatine, N-acetyl- aspartate and lipids; this allows correct classification even in radiologically unclear cases (Galanaud 2002; Majos 2003; Rutten 2006). Moreover, when it is intended to characterize intracranial masses without histological verification, preliminary results were reported by Dorenbeck et al who reported, that intracranial contrast-enhancing lesions as meningiomas, metastases, lymphomas and schwannomas could be differentiated from each other by diffusion weighted MR (Dorenbeck 2005). Preoperative evaluation of the microcirculation in meningiomas using perfusion imaging, continuous arterial spinlabeling or even kinetic positron emission tomography studies can be used in selected cases to evaluate areas of aggressive proliferation or as was shown in a case report, a metastasis from breast cancer within a meningioma (Jun 2006; Kimura 2006; Murakami 2005).

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Surgery is the standard therapeutic option on a type C basis. Surgical excision alone cures the vast majority of meningioma patients. The progress in meningioma treatment is a reflection of the advances in neurosurgery which are put to maximum use to improve treatment (Al Mefty 1991). The more complete the removal of tumour, the less opportunity for recurrence and the greater the chance for cure. After initial diagnosis, most patients opt for surgical removal of the tumour, expecting the disappearance of their symptoms - or at least relief of symptoms - and cure. All the techniques of modern neurosurgery, microneurosurgery and image guided surgery methods have contributed to the ability to successfully remove tumours previously considered as unresectable. This has long been the case for meningiomas involving the cavernous sinus, clival and petroclival meningiomas and others with difficult access and with intimate relations to vital structures, infiltration of sinus walls or extensive invasion of the skull base. The primary goal of surgery is the complete removal of the meningioma, including the dural attachment and infiltrated bone. However, the decision to operate is guided by the clinical history of the patient, the severity of symptoms, the natural history of the meningioma, the accessibility of the tumour and estimation of the clinical benefit achievable by surgery (Wolbers 2001; Braunstein 1997; Bindal 2003; Ausman 2003). Microsurgical techniques and the use of anti-edematous, anticonvulsive medications have allowed considerable progress in meningioma surgery. Of primary importance is thorough access planning and the careful positioning of the patient to guarantee optimal exposure. Meningiomas have to be isolated very carefully from the brain, by finding the arachnoid plane of cleavage and avoiding any pressure or traction to the cortex and any bleeding. In 1957, Simpson proposed evaluating the quality of surgical resection in terms of the surgeon's estimate of the grade of resection. He proposed a classification scheme that has been used since and adapted accordingly as further imaging techniques became available (Simpson 1957).

Radical:
Grade/Stage 1: complete excision, including dura and bone; hence, a (partial) resection of the sinus has been executed in the case of sinus invasion
Grade/Stage 2: complete excision plus apparently reliable coagulation of dural attachments

Non-radical:
Grade/Stage 3: complete excision (of the solid tumour), but insufficient dural coagulation or bone excision, e.g. in the case of invasion into a sinus or skull base.
Grade/Stage 4: incomplete resection, macroscopic tumour residue visible
Grade/Stage 5: biopsy only

A Simpson grade 0 resection has been proposed. This would consist of excision of a dural margin of 2 - 4 cm around the tumour to reduce the probability of recurrence, presuming that the single meningioma represents the only visible predominant growth in the midst of a wide neoplastic field in the dura mater (Borovich 1986). This concept is only applicable in exceptional cases.
As somatostatin receptor receptors have been found in vitro in all meningiomas, intraoperative radiodetection using a hand-held gamma probe for somatostatin receptor could be helpful to guide resection of somatostatin receptor expressing meningiomas. The validity of this concept could be proven in pilot study on 18 patients with en plaque sphenoid wing and convexity meningiomas ( Gay 2005). Another approach to enhance the possibilities to delineate meningioma from surrounding normal tissue is to evaluate tissue autofluorescence with a laser-induced fluorescence spectroscopy (Butte 2005). Intraoperative delineation of the tumor can also be supported by the use of sononavigation (Shinoura 2006) and, if available by a compact intraoperative magnetic resonance imager (Schulder 2006). Twelve percent of all meningiomas recur within 5 years after gross total resection, 19% recur by 20 years (Jaaskelainen 1985; Stafford 1998). One fourth of meningiomas arising at the skull base cannot be completely resected. Tumors invading the dural sinuses, bone, vital vascular structures such as the cavernous sinus or cranial nerves may also be operable with a significant risk of morbidity. WHO grade II meningiomas show a recurrence rate of 29-40% 5 years following gross total resection (Perry 1997; Johnson 2005).

Figure 1 and Table 2 show the recurrence rates of WHO grade I meningiomas after surgery and, following incomplete resections, after radiotherapy (adapted from Wolbers EORTC Protocol 26021 Phase II study.)

After an incomplete resection the progression is, as a rule of thumb, 30, 60 and 90% at 5, 10 and 15 years, respectively. A second operation for tumour progression is an unfavourable prognostic sign for survival (Condra 1997). As shown in the table, progression free survival after subtotal resection plus irradiation is similar to the results obtained after gross total excision. Two recent papers report about meningioma resection in elderly patients; in the survey from USA 26% of patients undergoing meningioma resection were aged 70 years and older. The in-hospital mortality was increased fourfold compared to younger patients (Bateman 2005). In a series of 37 patients who underwent meningioma resection in the ninth decade of life fro Rome, D'Andrea et al noted, that the higher mortality in the elderly patients was associated to those with ASA Class higher than II and to a Karnovsky score of 70 and lower, arguing for a better selection of elderly patients for invasive procedures (D'Andrea 2005). The recent achievements of neurosurgical techniques allows removal or reduction of meningiomas in previously difficultly accessible sites and has been reflected in published case series summarized in table 3.

Table 3: Outcome and complications of resection of meningiomas "in difficult locations"

Taking into account the significant morbidity and recurrence rates after meningioma resection "in difficult locations", some groups proposed predictive scoring systems, allowing assessing the chance of respectability in a given patient. A convincing an easily reproducible system was proposed by a group in Salamanca that tested the applicability of their algorithm in 85 patients.
Grade 1: skull base meningioma which encases none or only one cranial nerve or artery
Grade 2: skull base meningioma which encases one cranial nerve and up to two main arteries
Grade 3: skull base meningioma which encases more arteries and or nerves.
In grade 1 patients, the rate of complete resection was 98.5% and 96% of patients reached postoperatively a Karnofsky performance score (KPS) of at least 70. In Grade 2 meningiomas, the rate of complete resection diminished to 83% and the probability to reach a KPS of 70 was 70%. In grade 3 meningiomas, the rate of complete resection fell to 43% and the probability to reach KPS 70 to 60% (Morales 2005). This scheme involves less variables than the Levine-Sekhar grading system (Morales 2005; Saberi 2006; Levine 1999). However, both classification systems offer a base for pretherapeutic discussion of patients with skull base meningioma, allowing considering all potential treatment alternatives in order to optimize patient's outcome.

6.1.2 Preoperative meningioma embolization
Preoperative meningioma embolization is suitable for individual clinical use on a type 3 level of evidence
. The surgical removal of meningiomas requires their separation from highly vascularized tissues, eg. bone, dura and brain tissue. Additionally, most meningiomas are also abundantly vascularized. Therefore, preoperative embolization to facilitate removal by allowing centrotumoral necrosis, reducing vascularity and operative blood loss can greatly help to improve the outcome of surgery. Feeder arteries to meningiomas principally originate from the external carotid artery, mainly in convexity meningiomas, but may also be of pial origin, especially in skull base meningiomas. The possibility of "dangerous anastomoses" leading to neurological deficits or extracranial necroses must be studied carefully before any attempt is started to devascularize the tumour. The goals of the endovascular approach are to reach the tumour capillary bed, to de-arterialize this region, while preserving arteries leading to normal structures and ensuring uncompromised healing during the postoperative period ( Ragel 2003; Rosen 2002). Embolization may also be used as a palliative treatment option (Bendszus 2003). However, the procedure carries the risk of ischemic and of hemorrhagic complications. Bendszus et al reported a complication rate of 3.2 % each for ischemic and for hemorrhagic complications in a series of 185 patients undergoing preoperative particle embolization in meningioma (Bendszus 2005).

6.2 Radiotherapy

The role of radiotherapy (RT) in the treatment of meningiomas has been controversial for a long time. It is generally considered standard in in atypical, malignant or recurrent meningioma, on a type 3 level of evidence.
The role of radiotherapy (RT) in the treatment of meningiomas has been controversial for a long time. Conventional opinion was that most meningiomas are radioresistant. However, the low doses, between 30 and 40 Gy, typically used in older studies may have contributed to the poor results seen ( Simpson 1957; Bouchard 1966). More recently, the application of modern techniques using single daily doses of 1.8 to 2.0 Gy up to a total dose of 45 to more 60 Gy (mostly more then 54 Gy) has proved effective in patients with incomplete resection of meningiomas by improving 5 year recurrence free survival to the same extent as complete surgical resection (Table 2) (Mirimanoff 1985; Taylor 1988; Goldsmith 1994; Kondziolka 1999; Debus 2001).
Individualized 3-D planning techniques and stereotactically guided conformal radiotherapy (SCRT) allow reductions in the volume of normal tissue irradiated compared with conventional irradiated two field techniques and may lead to a reduction in long-term toxicity. Recently, intensity-modulated radiation therapy and 3D conformal radiation using a combination of photons and protons have proven their efficacy in the management of meningiomas with very low toxicity rates ( Noel 2005; Sajja 2005). Modern imaging techniques such as CT, MRI and PET are used to define the target area for irradiation. The planning target volume (PTV) is defined as the clinical target volume (CTV, e.g. macroscopic tumour plus subclinical spread) plus a safety margin (Alheit 1999). The safety margin depends on grade of malignancy and tumour resection. In practice, a margin of 0.5 - 1 cm is usually added to the CTV (Knöös 1998). Although Borovich detected meningothelial tumour cells in the meninges as far as 3 cm from the resected dural attachment, and therefore suggested setting up radiation treatment margins of up to 4 cm from the resection borders, his approach is not ordinarily followed (Borovich 1986)
. Furthermore, the survey of Mc Carthy et al, shows a 5-year survival rate for patients treated with surgery and radiation therapy of 58% after complete removal and 65% after partial resection. The authors suggested that poorer prognostic features in patients whose meningiomas could be totally resected accounted for these paradoxical results ( McCarthy 1998). These findings are in contrast to those obtained in the series of Debus, where excellent results were obtained after radiation therapy of incompletely resected meningiomas with 97% survival at five years and 96% at ten years (Debus 2001).
The use of radiation therapy after the first resection of benign meningiomas, is still controversial, but it is currently used in cases of incomplete resection or in cases of tumour progression. Similarly, although radiation is widely used, actual guidelines for the use of radiation therapy in cases of WHO grade II and III tumors, or the presence of NF2 mutation are still lacking. Considering the presumed advantage of modern forms of radiotherapy, it is unclear how much possible neurotoxicity can adversely affect quality of life, for example by effects on pituitary, cranial nerves and cognitive functions (Dufour 2001). These unresolved issues should be examined prospectively in a highly qualitative randomised study that compares a policy of watchful waiting versus adjuvant (conformal) irradiation (Wolbers EORTC 26021 and 26022).
Meningiomas that have recurred once, tend to recur again at shorter intervals (Mirimanoff 1985). Technically, second resections are often more difficult than first surgery. At recurrence or in cases of primary anaplastic meningiomas, external beam radiation with a total dose of usually 54 Gy (45- 70 Gy) has been effective and slows further recurrence (Mirimanoff 1985; Maire 1995). New sophisticated radiation techniques help to control tumour progression in about 80-90% of cases. Prospective, comparative studies are not available and published data are scarce; a few series of recurrent tumours have small patient numbers containing only 16 to 46 patients. The probability of 2-5 year progression free survival after first recurrence might be about 50% after second surgery and about 80% if followed by radiotherapy. The beneficial effect of irradiation in preventing recurrences might also be extrapolated from reports on adjuvant radiotherapy after an incomplete resection at first surgery where adjuvant irradiation improved the 5 year progression-free survival from 63% to 78-98% and from series of patients with unresectable meningiomas.

Table 4: Rate of progression free survival (2-8 years) in patients with meningiomas after the first recurrence

Recently published series of meningiomas treated with fractionated radiotherapy show local control rates beyond 90% even in series with longer than 5 years of follow up (Milker-Zabel 2005; Brell 2006) underlining the efficiency of this treatment. Long-term toxicity occurs in less than 10%. A series of 27 patients with atypical and 9 patients with malignant meningiomas treated using 1.5 Gy single dose given twice daily up to 60 Gy which yielded a high toxicity rate ( 55% grade 3-5 toxicity) and did not improve the local control rate of near 50% at 5 years of atypical and malignant meningiomas (Katz 2005). In the difficult situation of optic nerve sheath meningiomas, there is accumulating evidence that fractionated stereotactic radiotherapy can provide stabilization and sometimes even improvement of the visual function ( Kerty 2005; Richards 2005; Berman 2006). Table 5 summarizes efficacy and outcomes of fractionated radiotherapy in patients with meningiomas.

Table 5: Outcome and complications after fractionated stereotactic radiotherapy for meningiomas

MMS mini mental Score

IMRT: intensitiy modulated radiotherapy

6.2.1 Stereotactic radiotherapy
Stereotactic radiotherapy is to be considered standard in in atypical, malignant or recurrent meningioma, on a type 3 level of evidence.
The precise definition of the position of the planning target volume and the steep dose falloff characterize stereotactic radiotherapy. The therapy can be delivered in a few sessions using a linear accelerator or in a single session as radiosurgery by using a Gamma-knife or a linear accelerator. Due to the location of the tumour, the median marginal tumour dose given is 14 Gy. In radiosurgery there is a steep dose falloff near the target boundary (with dose gradients of up to 30% per mm). This allows treatment of tumours situated close to organs at risk, such as the optic pathway, which typically have a tolerance dose lower than the therapeutic dose of the tumour. It also minimizes the volume of the tumour which has, of necessity, to be undertreated because of its location adjacent to critical tissues ( Lomax 2003). Therefore, radiosurgery has recently become the preferred treatment modality for the management of well-circumscribed, small, benign, intracranial meningiomas, smaller then 3 cm and/or inaccessible to surgery (Kondziolka 1999; Lee 2002; Subach 1998). Because the blood supply of meningiomas usually arises from the dura, it can be included in the planning target volume, and this can further cause tumour infarction and necrosis. In a retrospective comparison of 198 adult meningioma patients, who had undergone either surgery or radiosurgery as first treatment, Pollock et al found that radiosurgery provided tumour control equivalent to a Simpson Grade 1 resection and had higher rate of tumour control when compared with patients that had undergone Grade 2 or more resections (Pollock 2003).
Gamma-knife-radiosurgery is very attractive for patients, as it can be performed in one day and the rates of side effects and complications are low. Postradiosurgery neurological sequelae after treatment of meningiomas at the skull base consist of oedema with headaches, transient worsening of pre-existing symptoms - mostly responsive to corticosteroids - trigeminal nerve problems, and temporary or permanent visual field deficits ( Flickinger 2003). The actual rate of developing any postradiosurgical injury reaction was 9% at 5 and 10 years. Radiosurgery has been proven safe and effective, especially in locations difficult to operate, such as cavernous sinus meningiomas and petroclival meningiomas either as primary therapy or after incomplete resection (Flickinger 2003; Lee 2002).
Moreover, the complication rates, e.g. edema, are higher for meningiomas at the convexity, parasagittal region and falx cerebri, embedding significant regions of cortex, than skull base meningiomas (Kim 2005; Mindermann 2004; Chang 2003). An overview about recent series of patients with meningiomas treated with radiosurgery is given in table 6. Tumor control rates are higher than 90% in almost all series and complication rates stay less than 5% when the radiation dose at the margin does not surpass 15 Gy. Flickinger reviewed a large series of 219 meningiomas treated with radiosurgery without prior tissue diagnosis. Tumour progression occurred in 8 patients, three of them suffered from tumours other than meningiomas (1 chondrosarcoma, 2 metastatic carcinomas), so the rate of a documented false diagnosis when radiosurgery was done as primary treatment in suspected meningioma was 2% ( Flickinger 2003). However, the tumour control rate at 5 and 10 years was 93% (Flickinger 2003). As imaging techniques such as MR Spectroscopy (MRS) become more widely used, it appears possible, that stereotactic radiosurgery will expand its role as primary treatment option for small meningiomas, as it has not only been proven to be safe and effective (Pollock 2003), but also more cost effective when logistically feasible, for example when transportation and hospitalization costs are considered along with surgery and radiotherapy costs, as recently demonstrated by a Swiss study (Wellis 2003). Several centers combine surgery and radiosurgery for individual optimal treatment of patients with skull base meningiomas in order to achieve growth control even after incomplete resection and preservation or improvement of neurological function (Maruyama 2004).

Table 6a: Radiosurgery for newly diagnosed meningiomas: outcome and complications

CS: cavernous sinus

Table 6b: Radiosurgery for meningiomas: outcome and complications in series including patients with recurrent and/or previously resected meningiomas

CS: cavernous sinus

6.3 Medical therapy

After repeated surgery and radiotherapy, the number of patients affected by recurrent, progressive and symptomatic meningiomas is indeed small, but these patients represent a great therapeutic challenge. Medical therapy for these patients is investigational on a type R basis.

6.3.1 Hormonal therapy
There is sufficient evidence that the expression of progesterone receptors (PgR) by meningioma cells is a prognostically favorable sign and that loss of this expression is accompanied by a more aggressive behaviour. Mifepristone is a potent anti-gestagen, established in the eighties, which is mainly used to terminate early pregnancy. Mifepristone inhibits the transcriptional activity of PgR by complex mechanisms at concentrations much lower than the progestins ( Edwards 2000).
The use of progesterone antagonists in the palliation of meningioma has been discussed repeatedly for at least ten years. There are some small series describing mostly successful management of meningioma patients using mifepristone (Lamberts 1992; Haak 1990).
The only prospective study on this topic was conducted by SWOG on 193 patients, however, it was prematurely closed and is yet to be published. Progesterone receptor status was unknown in 138/160 patients, 80 patients were treated with mifepristone 200 mg, 80 patients were treated with placebo for a median of 10 months. Grade IV toxicities were experienced by 6 patients in the mifepristone arm and one patient in the placebo arm. Grade III toxicities were seen in 30 patients in the mifepristone arm and in 24 patients on the placebo arm. Reported toxicities were mostly fatigue (72% versus 54%), headache (44% vs 41%), and hot flushes (38% vs 26%). A significant number of female patients developed endometrial hyperplasia ( Newfield 2001).
There was no trend and no difference in results between the two arms. CR was not confirmed in any patient. PR and unconfirmed responses were noted in 1% of patients of both arms, and SD was observed in 55% of patients. TTP did not differ significantly in both arms, median OAS has not yet been reached. These data suggest that the postulated antiproliferative effect of mifepristone would appear in patients with highly differentiated meningothelial meningiomas, probably not in patients that who experienced multiple recurrences or with atypical or anaplastic meningiomas, and that this effect if it exists, is modest.

6.3.2 Chemotherapy
There are only few reports on chemotherapy in patients with meningiomas. The burden of side effects of most cytotoxic drugs appears not to be justifiable for long treatment periods. To date, no effective chemotherapy has been found. There have been some attempts of treatment with anthracyclines and cisplatin and CPT-11, but a definite response could not be obtained ( Stewart 1995).
Schrell et al have described that hydroxyurea (HU) inhibits the growth of meningioma cells in vitro and induces apoptosis. They were able to describe a dose dependent shrinkage of meningiomas in four patients with recurrent meningiomas after radiotherapy including stabilization for two years in a patient with malignant meningioma. There are several small series of patients with recurrent or progressive meningiomas (Cusimano 1998; Newton 2000; Newton 2004; Mason 2002; Rosenthal 2002; Hahn 2005), treated with hydroxyurea orally at 20 mg/kg/day, thus half the dose usually used in the treatment of chronic myelogenous leukemia (CML). In the most recent update, Newton et al stated that 18/20 evaluable patients responded to Hydroxyurea for a median of more than 3 years (176 weeks), 2 of them with partial response for a median duration of 80 weeks. Some patients experienced minor haematological toxicity, mainly neutropenia. Mason et al observed 12/20 patients with stable disease for a median of two years treatment duration and 1/20 minor response in a cohort of 20 patients. There was also mention of mild myelosuppression. Rosenthal et al describe a clinical benefit in most patients treated with hydroxyurea, 11/15 had stable disease for a median of 11 months, 2 patients discontinued therapy because of skin rashes. Hahn et al combined concomitant radiation of 55.8 to 59.4 Gy with Hydroxyurea for three months. They observed disease stabilizations in 14/21 patients, with radiological minor response in three patients. The median time of response was 13 months. Thus, hydroxyurea appears as suitable and active drug in the treatment of recurrent meningiomas that provides clinical benefit by delaying progression of the disease.

6.3.3 Antiangiogenic therapy
Some meningiomas are characterized by a prominent neo-angiogenesis. There is extensive in vitro evidence that interferon (IFN) is active against the proliferation of meningioma cells (Muhr 2001; Zhang 1996a; Wöber-Bingol 1995). The antitumoral effect of IFN has been demonstrated to be exerted mainly via inhibition of angiogenesis. The effect of IFN-± on progression and metabolism of recurrent, inoperable meningioma has been documented in case reports, as well as in small patient series. Kaba et al observed disease stabilization in 5/6 treated patients, Muhr et al report disease stabilizations in 9/12 patients, two patients being treated for more than eight years. Of note, Muhr noticed that the response to IFN could be demonstrated as early as 7 days after the start of treatment or dose change as a decrease of C-11 methionine uptake by the meningiomas on PET scan. IFN in combination with 5-fluorouracil in vitro has shown promising effects on cultured meningioma cells ( Zhang 1996b; Park 2000; Lamszus 2000). The side effects of IFN observed in meningioma patients were mostly those previously described (fever, flu-like symptoms, fatigue, leukopenia, and psychiatric symptoms) and were tolerable for long treatment periods. Therefore, in patients with progressive meningiomas interferon alpha in low to moderate dose emerges as a promising treatment option. The decrease of TGF - beta in serum could be used as a surrogate marker for tumour response during IFN therapy.

6.3.4 Other therapeutic approaches
Some promising in vitro results using meningioma cell lines might be developed into useful clinical tools in the future.Transfection of tumoral cells with a vector expressing the wild type of NF2 cDNA results in growth suppression and normalization of cellular morphology in cultivated meningioma cells (Lutchman 1995 ; Sherman 1997). The inhibition of meningioma cell growth in vitro by the cytokine recombinant oncostatin M could emerge as new therapeutic issue (Schrell 1998). As meningiomas can be visualized in nuclear medicine using their somatostatin receptor expression, the therapeutic use of octreotide has been incidentally reported and might be increasingly used (Jaffrain-Rea 1998; Prat 1997). Most meningioma cells, also atypical and malignant meningiomas, express insulin-like growth factor I (IGF-1) (Friend 1999). Blockade of the IGF-1 receptor by pegvisomant, a genetically engineered protein was found efficacious in a meningioma mouse model (McCutcheon 2001). Another potentially successful intervention could result from antagonizing the platelet derived growth factor (PDGF-ß) which stimulates mitoses in meningioma cells in an autocrine manner by trapidil, a drug mostly used to prevent vascular restenosis after angioplasty ( Johnson 2001). A growing number of small molecules interfering with the enzyme pathways activated in proliferating meningioma cells have shown activity in vitro. However, for the "orphan disease" as recurrent, inoperable and "radiation exhausted meningioma", however, up to now, these concepts have not yet been translated in human clinical studies (Johnson 2005).

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7. LATE SEQUELAE

7.1 Long term sequelae

Cognitive and focal neurological deficits may have a great impact on long term survivors of brain tumors, regardless of the histology and grade of the tumors. Memory loss, apathy, concentration difficulties and personality changes may have a profound effect even in those patients who appear to have a Karnofsky performance status of 100. Surgery in the so called silent areas may contribute to cognitive deficits. Less clear are the late effects of radiation therapy on cognitive function. Radiotherapy is known to cause an early somnolence syndrome but may also cause late sequelae, in particular a delayed leuko-encephalopathy with cognitive dysfunction and radiation necrosis ( Corn 1994; Crossen 1994; Kumar 2000). In individual patients it is difficult however to entangle the direct effects of the tumor on cognition from late effects of treatment. A recent survey on cognitive deficits in progression free survivors of low grade glioma failed to confirm the generally assumed relation between radiotherapy and cognitive deficits (Klein 2002). Only in those patients who had been treated with fraction of more than 2 Gy evidence of increased cognitive dysfunction was observed. The only other association with cognitive deficits was treatment with anti-epileptic drugs. Prior studies have suggested that whole brain radiotherapy may be associated with more cognitive deficits than involved field irradiation, but today involved field radiotherapy is standard practice (Gregor 1996). Radiation therapy may also affect cranial nerves, or induce endocrine dysfunction even in case of tumors distant from the hypothalamus-pituary region ( Brandes 2000). Seizures may have a great impact on the quality of life even in patients with well controlled tumors. Newer anti-epileptic drugs may have less side-effects and should be considered, especially in those patients that are on a multi-drug regimen. Apart cognitive deficits a risk of death of 2.5% at 2 years has been reported for doses of 50.4 Gy. A risk of radionecrosis up to 5% in 5 years may occur after 60 Gy to one third or 50 Gy to two thirds of the brain volume or with 50-53 Gy to brain stem. Similar risk for blindness with 50 Gy to the optic chiasm. Also chemotherapy may induce late sequelae such as lymphoma or leukemia or solid tumors, lung fibrosis, infertility, renal failure, and neurotoxicity.

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8. FOLLOW-UP

No general guidelines for the follow-up can be given, these should be tailored to the individual patient taking tumor grade, previous treatments and remaining treatment options into account.

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Contributors

Dr. Marco Hassler (Author)
University of Vienna - Vienna, Austria

Dr. Christine Marosi (Author)
University of Vienna - Vienna, Austria
mail: christine.marosi@meduniwien.ac.at

Dr. Michele Reni (Associate Editor)
Ospedale San Raffaele - Milan, Italy
mail: reni.michele@hsr.it

Dr. Karl Roessler (Author)
University of Vienna - Vienna, Austria

Dr. Milena Sant (Consultant)
Istituto Nazionale per lo Studio e la Cura dei Tumori - Milan, Italy
mail: milena.sant@istitutotumori.mi.it

Prof. Charles Vecht (Reviewer)
Neurology Medical Center - The Hague, The Netherlands
mail: c.vecht@mchaaglanden.nl

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