Biology and clinical features of meningioma

INTRODUCTION Meningiomas arise from the arachnoid cap cells of the arachnoid villi of the meninges; 90 percent are benign.

EPIDEMIOLOGY AND RISK FACTORS  In a 1995 analysis of data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, meningioma was the second most frequent primary brain tumor . Overall, the incidence is approximately six per 100,000, and meningiomas account for 13 to 26 percent of primary intracranial tumors . Meningiomas are most common between the ages of 40 and 70 and are two to three times more prevalent in females than in males except in children.

An etiologic relationship between ionizing radiation and the subsequent development of meningiomas has been established in a variety of clinical situations. Higher doses of irradiation are associated with both an increased incidence of meningiomas and a shorter latency period.

Genetic factors are also implicated in the development of meningiomas . The incidence of meningioma is increased in patients with breast cancer, for whom shared risk factors may be important (see below) . Patients with a history of parathyroid adenoma have been reported to have a twofold increased risk for developing an acoustic neuroma

BIOLOGY  Like many tumors, meningiomas are thought to arise from a multistep progression of genetic changes in a cell. These alterations may involve activation of oncogenes or inactivation of tumor suppressor genes. It is likely that the total accumulation of genetic changes rather than the sequence in which they are acquired is important in neoplastic transformation.

Growth factors and receptors  Meningiomas occur more commonly in women, may increase in size during pregnancy , and are increased in incidence in women who use postmenopausal hormones. These data, and the association of meningiomas with breast cancer (see above) suggest the potential involvement of steroid hormones and their receptors in the growth and/or development of meningioma. Meningiomas express receptors that are associated with a proliferative response to steroid hormones, such as progesterone and androgen receptors and estrogen alpha and beta receptors.

The function of these proteins in meningiomas is unknown but their synthesis and expression may have prognostic significance. Benign meningiomas that express progesterone receptors appear to be less likely to recur.

Meningiomas also express receptors for peptide growth factors such as insulin-like growth factors I and II, platelet-derived growth factor, vascular endothelial growth factor, and epidermal growth factor. In some cases, there is expression of the growth factor as well, leading to the possibility of cell growth via an autocrine loop mechanism.

Tumor suppressor genes  There are two genes that are each mutated in approximately 50 percent of meningiomas, the NF2 gene, and the DAL-1 gene. These mutations are thought to represent an early event in tumorigenesis.

The NF2 gene is a presumptive tumor suppressor gene, located on chromosome 22q12, that encodes a membrane cytoskeletal protein called merlin or schwannomin, that appears to be involved in actin-cytoskeleton organization. Mutations in this gene presumably lead to decreased expression or dysfunction of this protein.The merlin protein itself may also have tumor-suppressive properties in vitro
As noted previously, patients with NF2 have an increased incidence of meningioma

The possibility of a second meningioma susceptibility gene was initially suggested in familial meningioma, a rare disorder with fewer than 20 families described in the literature. The NF2 gene is not deleted in these tumors, while mutations in DAL-1, which is located on chromosome 18p, were identified . Furthermore, DAL-1 mutations have also been identified in a subset of the approximately 40 percent of sporadic meningiomas that have neither NF2 gene mutations nor allelic loss of chromosome 22q.

PATHOLOGY  Menigiomas are heterogeneous, and there is no single characteristic morphologic appearance. Several histologic growth patterns have been described including syncytial, fibroblastic, transitional, psammomatous, secretory, microcystic, and papillary .

WHO classification  Of the several histologic classification schemes for meningiomas, the most commonly used is that of the World Health Organization (WHO), which groups tumors morphologically, and according to their estimated risk of recurrence and/or aggressive growth. Benign meningiomas are classified as WHO grade I tumors and account for 90 percent of cases.

The differing prognosis according to WHO grade can be illustrated in one report that included 42 cases of atypical meningioma (see below) and 29 malignant meningiomas, survival was significantly higher in the patients with atypical meningioma at both five (95 versus 64 percent) and ten years (79 versus 35 percent) . However, 26 percent of the recurrent atypical meningiomas behaved clinically as malignant tumors.

In a typical meningioma, expression of vimentin is common, while glial fibrillary acidic protein and anti-leu-7 expression are not. Fatty degeneration, hemorrhage, calcification and cyst formation can also occur. Features that support the diagnosis of malignant meningioma include the loss of usual meningioma growth patterns, infiltration of underlying brain, abundant mitoses with atypical forms, and multifocal microscopic foci of necrosis

  Atypical meningioma  The term atypical meningioma refers to a tumor that contains increased mitotic activity (4 mitoses per high powered field) compared with a benign meningioma and three or more of the following features: increased cellularity, small cells with a high nuclear:cytoplasmic ratio, prominent nucleoli, uninterrupted patternless or sheet-like growth, or foci of spontaneous or geographic necrosis .

  Malignant meningioma Malignant (anaplastic) meningiomas are characterized by the same histologic features as atypical meningiomas, but abnormalities are present to a much higher degree.

The classification of a meningioma as benign, atypical or malignant does not correlate perfectly with prognosis, nor does any individual histologic criterion. As an example, invasion of the brain is more common in malignant meningiomas, but may also be seen in benign and atypical lesions, and is independently associated with an increased risk of recurrence.

This concept was illustrated in one study of 116 patients with meningioma which were classified as malignant due to brain invasion, anaplasia (20 mitoses per high-powered field or histology resembling carcinoma, sarcoma, or melanoma), and/or extracranial metastasis. Survival time for all patients was highly variable, ranging from 10 days to 24 years. Of the 89 cases with brain invasion, 23 percent were otherwise morphologically benign, 61 percent were otherwise atypical, and 17 percent were frankly anaplastic. Despite the presence of brain invasion, tumors without anaplasia behaved similarly to atypical meningiomas while anaplastic meningiomas were usually fatal, with a median survival of 1.5 years. The authors concluded that brain invasion constituted an additional criterion for the diagnosis of atypical meningioma (WHO grade II) whereas frank anaplasia indicated a higher grade malignancy (WHO grade III) with a worse prognosis.

Angioblastic meningiomas must be distinguished from hemangiopericytomas which should be considered malignant neoplasms.

Other classification schema  Other classification schemes have been used for meningiomas, the main goal of which is to predict which tumors are destined to recur. One method devised a point system to predict the clinicopathological behavior. Loss of architecture, increased cellularity, nuclear pleomorphism, mitotic figures, focal necrosis, and presence or absence of brain infiltration were all considered in the distribution of points:

  • Grade I (benign tumors) had 0 to 2 points
  • Grade II ("atypical" tumors) had 3 to 6 points
  • Grade III ("anaplastic" tumors) had 7 to 11 points
  • Grade IV (sarcomatous) had 12 to 18 points

By these criteria, 94 percent of 657 meningiomas were benign, 5 percent were atypical, and 1 percent were anaplastic. This grading scheme appeared to adequately predict behavior in that the five year recurrence rate was 3, 38, and 78 percent for benign, atypical, and anaplastic tumors, respectively.

Others have used tumor histopathology (WHO grade 1 versus 2 or 3), the presence of chromosome 14 abnormalities (losses or gains), and patient age (45 versus older) to construct a point-based prognostic stratification scheme. In an initial report, which was based upon 70 patients with meningioma, all patients with two or more adverse prognostic features had experienced relapse by five years compared to none of those who lacked any of the three adverse factors.

CLINICAL PRESENTATION Meningiomas can arise from the dura at any site, most commonly the skull vault, and at sites of dural reflection (eg, falx cerebri, tentorium cerebelli, and dura of the adjacent venous sinuses). Other less common sites include the optic nerve sheath and choroid plexus; approximately 10 percent arise in the spine.

Many meningiomas are asymptomatic and discovered incidentally on a neuroimaging study or at autopsy, where incidence rates are 1 to 2 percent . The prevalence of asymptomatic meningioma increased with age and was highest in one study in patients 80 years of age or older.

The most common presentation of a symptomatic intracranial meningioma is with a focal or generalized seizure or gradually worsening neurologic deficit. Seizures are present preoperatively in 30 to 40 percent of patients with intracranial meningioma. The median duration of preoperative seizures was one month in one contemporary series, considerably shorter than that observed prior to the CT/MRI era. In one retrospective review, preoperative epilepsy was more common in patients with supratentorial meningiomas, tumors located at the convexity, and tumors associated with severe peritumoral edema.

Focal findings Characteristic focal deficits are caused by tumors in specific locations:

  Visual changes  Visual changes, often unrecognized, are common in meningioma. In one series of 80 patients, approximately one-third had ophthalmologic symptoms including visual loss, field defects, and diplopia. Visual field defects in particular may be caused by parasellar meningiomas. In addition, optic atrophy in one eye and papilledema in the other, the so-called Foster-Kennedy syndrome, can be produced by parasellar or subfrontal meningiomas; progressive unilateral visual loss, which may be mistaken for optic neuritis, by optic nerve sheath meningiomas; and mild extraocular movement weakness by cavernous sinus meningiomas.

  Hearing loss A cerebellopontine angle meningioma can produce sensorineural hearing loss.

  Mental status changes  Mental status changes with neglect and inattention may result from surprisingly large subfrontal or sphenoid ridge meningiomas. In comparison, similar or larger sized tentorial notch and intraventricular meningiomas are at times asymptomatic and diagnosed incidentally.

  Extremity weakness  Meningiomas at different sites can produce often characteristic patterns of extremity weakness. A parasagittal meningioma growing on the falx against the motor strip can lead to bilateral leg weakness in the absence of a spinal cord lesion; foramen magnum meningiomas may produce a subtly progressive sequence of ipsilateral arm, then leg weakness followed by contralateral leg and arm weakness that may be misdiagnosed as multiple sclerosis; and spinal meningiomas frequently present with progressive leg weakness and numbness.

  Obstructive hydrocephalus  Large tumors in the posterior cranial fossa can cause obstructive hydrocephalus, and present with papilledema and classic early morning headache.

DIAGNOSIS  The diagnosis of intracranial tumor is suggested by the clinical presentation and confirmed radiographically with computed tomography (CT) or magnetic resonance imaging (MRI). Angiography has traditionally been used to suggest the diagnosis of meningioma by demonstrating arterial supply from meningeal vessels and the delayed vascular blush that is characteristic of these lesions. However, angiography is not necessary in most cases unless tumor embolization is being considered for therapy.

On CT scan, the typical meningioma is a well-defined extra-axial mass that displaces the normal brain. They are smooth in contour, adjacent to dural structures, and sometimes calcified or multilobulated. Isointensity with normal surrounding brain may make diagnosis difficult on a non-contrasted scan, but intravenous contrast administration results in uniformly bright enhancement. In about 15 percent of cases, there is an atypical pattern with necrosis, cyst formation (sometimes mimicking schwannoma), or hemorrhage. Indistinct margins, marked edema, mushroom-like projections from tumor, deep brain parenchymal infiltration, and heterogeneous enhancement all suggest, but do not prove aggressive behavior .

Secondary involvement of the underlying bone (reactive sclerosis, invasion, erosion) is uncommon with convexity meningiomas, but occurs in up to one-half of skull base tumors.

MRI is the preferred imaging method because it can show the dural origin of the tumor in most cases. The typical meningioma is isointense or hypointense to gray matter on T1 and isointense or hyperintense on proton density and T2 weighted images; there is strong homogeneous enhancement with gadolinium. Most meningiomas show a characteristic marginal dural thickening that tapers peripherally (the "tail" sign).

PET scanning may have a role in predicting the aggressiveness of a meningioma and the potential for recurrence. In one study, tumors that did not recur after surgery had a significantly lower mean rate of glucose utilization than did recurrent tumors (1.9 versus 4.5 mg/dL per min). In addition, FDG-PET may also permit preoperative estimation of the malignant potential of a meningioma. In one series, PET correctly identified 8 of 9 atypical meningiomas and 58 of 66 grade I tumors; the specificity was much higher in fasting patients. The degree of aggressiveness may also be suggested by a high retention index on thallium 201 SPECT imaging. These tests are not currently in routine use because maximal surgical resection is the goal for all grades of meningioma.

Differential diagnosis  Several other disease processes have a propensity for involving the dura or subdural space, resulting in an appearance that may suggest meningioma. These include lymphoma, metastatic carcinoma, inflammatory lesions such as sarcoidosis and Wegener's granulomatosis, and infections such as tuberculosis .