BRAIN

SPINE

Meningiomas (Ms) are generally slow-growing benign tumors attached to the dura mater and composed of neoplastic meningothelial (arachnoidal) cells. They typically manifest in adults and are more predominant in women.

Ms account for approximately 20% of all intracranial tumors in male and 38% in females. The prevalence of Ms is estimated to be 97.5 in 100,000 with over 138,000 individuals diagnosed with this tumor. Rates for Caucasians, African-American, and Hispanics are similar and the age-specific incidence reveals an increasing risk with age.

At present, the two risk factors for which strongest evidence exists with respect to an association with M risk are exposure to ionizing radiation and hormones. The most recent case control study of 200 meningioma patients reported that the full-mouth dental radiograph series was associated with a significantly increased risk of meningioma (odds ratio 2.06,95% confidence interval 1.03,4.17). Radiation therapy is also associated with increased meningioma risk since ionizing radiation can induce intracranial tumors by damaging DNA, with resultant single-strand or double strand-breaks. Jhawar et al. (2003) found an overall positive association between the use of hormone replacement therapy and meningioma risk.

The relative risk of meningioma associated with hormone use for premenopausal women was 2.48 (95% confidence interval 1.29, 4.77) when compared with postmenopausal women who had never used hormones. Donnel et al. (1979) first described the presence of an estrogen receptor (ER) protein in four out of six meningiomas. Carrol et al. (1999) indicate that there are some differences in the prevalence of ER isoforms, alpha and beta, with 44% of meningiomas expressing ER-alpha mRNA and 68% expressing ER-beta mRNA in a series of 34 Brigham and Women’s Hospital cases. Since the two different ERs may elicit different bioresponses ,the resistance to tamoxifen therapy could be related to the different isoforms of the two ERs. The majority of Ms (40-100%) have progesterone receptors (PR). Hsu et al. (1997) observed that benign meningiomas were more likely to be PR positive (96% versus 40%) than malignant ones, with PR status being inversely related to mitotic index and grade and therefore associated with better prognosis. Across currently existing studies, the relative risk association between breast cancer and Ms range between 1.5 and 2.0 with the majority statistically significant.

Ms typically occur intracranially (cerebral convexities, olfactory grooves, sphenoid ridges, parasellar regions, optic nerve, petrous ridges, tentorium cerebelli, cerebellopontine angle, posterior fossa and within the ventricles (28%). Spinal Ms represent 25% to 46% of primary spinal neoplasms and account for 7.5% to 12.7% of all meningiomas. They are the second most common intradural spine tumors after neuromas. Spinal localization most often (70-80%) affects middle-aged women (mean age 49 - 62 yrs), with an F:M between 3:1 and 4:1. Spinal meningiomas are thought to occur more frequently in women because of a possible dependence on sex hormones. The most frequent location of spinal Ms is the thoracic region, followed by the cervical region and, only rarely in the lumbar region. Most spinal Ms are located lateral to the spinal cord or have a laterally extending component. A posterior location occurs more frequently than an anterior location. They are rarely completely extradural.

Molecular genetics of Ms

The NF2 gene product (a protein called merlin, belonging to the protein family 4.1) acts as a recessive tumor suppressor. Apparently, inactivation of both NF2 alleles is necessary for M formation. In patients with neurofibromatosis (NF) Type 2, Ms are commonly diagnosed, and most are multiple. NF2 gene (locus on chromosome 22) inactivation is considered an important initiation step but probably plays no role in malignant M progression. This inactivation is less frequent in meningothelial tumors than in fibroblastic and transitional variants and a recent study found high numbers of NF2 mutations in psammomatous and no alterations in secretory Ms. These data can support the hypothesis that NF2 mutations may play a role in M variants with a mesenchymal-like morphology, rather than in a tumor with an epithelial phenotype.

Another gene alteration is present in Ms. DAL1 (18p11.32) mutation is described in up to 76% of cases but there is no evidence that this mutation has the propensity to develop tumors.
Mutations of SMARCB1/INI1/hSNFS are found in rhabdoid tumors, atipical teratoid/rabdoid tumors and epithelioid sarcomas and may contribute to M formation.
Ms are associated with many abnormal genetic conditions such as: NF1; Gorlin/nevoid basal cell carcinoma syndrome; Rubinstein-Taybi syndrome; Li-Fraumeni syndrome; von Hippel-Lindau syndrome; Werner syndrome; Gardner syndrome; melanoma/astrocytoma-brain tumor syndrome; Cowden disease; syndromes related to PTEN mutations. A recent work suggests an association also with multiple endocrine neoplasia Type I syndrome (MEN1).
In radiation-induced Ms many chromosomes 1p11, 6q, and 7p are lost. These losses could play a critical role in radiation-induced Ms.


Grading

Most Ms are benign and may be graded into World Health Organization (WHO) I. Other types have a worse outcome and correspond to WHO grades II (atypical M, clear cell M, chordoid M) and III (rhabdoid M, papillary M, anaplastic M). Specifically, Ms not showing increased mitotic activity may be termed atypical when exhibiting at least three of the following five features: increased cellularity (4 or more mitoses per 10 high-power fields (0.16 mm2), prominent nucleoli, small cell cytology, sheet-like or patternless growth, and spontaneous or geographic necrosis (in the absence of prior embolization). Metastases are rare, even for anaplastic Ms. The most common site for seeding is the lungs, but lesions have been seen in the liver, bone, skin, and subcutaneous tissue. Atypical Ms constitute between 4.7 - 7.2% of all Ms, whereas anaplastic Ms account for 1 - 2.8%. In some series there is evidence that up to 2% of all benign Ms transform into malignant forms, whereas up to 28.5% of all recurrent benign Ms will be found to be atypical or anaplastic. The atypical and anaplastic types are more common in the cerebral convexities and more prevalent in male patients.

Treatment: The treatment chosen for all types of Ms is surgery . Surgery resection allows definitive diagnosis, reduces mass effect, and alleviates signs and symptoms. Excision should be as complete as possible to allow a possible cure. Embolization of Ms with polyvynyl alcohol, gelatin foam, coils/microcoils, and Avitene are currently used as an adjunct to surgery, and have been for several decades. This procedure minimizes blood loss, it can reduce tumor volume, and it makes surgical excision easier. The decision to embolize is often made on a case-by case basis. Ms supplied by branches of internal carotid artery are usually not amenable to embolization due to the risk of stroke. The efficacy of radiation therapy in preventing recurrence is controversial. Proton beam therapy has also been considered for primary and recurrent atypical and anaplastic Ms. Some studies reported that a proton boost, combined with > 60 Gy prothon therapy, can improve survival and local control with a 5-year survival rate of 89% for atypical tumors and 51% for anaplastic tumors. Currently there is no role for chemotherapy, but in future, one for both anti-PDGF and anti-EGF compounds could be established by Phase 2 protocols in patients with atypical or anaplastic Ms that are resistant to other therapy.

Outcome: analyses based on information from the National Cancer Data Base report overall 2 and 5 year survival rates for patients with Ms of 81% and 69%, respectively.

References