Epidemiology of meningiomas

The prevalence of pathologically confirmed meningiomas is estimated to be approximately 97.5 in 100,000 in the United States, with more than 170,000 individuals currently diagnosed. There is a 2:1 female/male ratio. There have been an increasing number of diagnosed patients in the past several decades. It is unclear whether this is a real trend or a bias from increasingly accurate and more easily obtainable imaging studies.

Pathophysiology of meningiomas

Meningiomas are believed to arise from the meningothelial cap cells that are normally distributed through the arachnoid trabeculations. The greatest concentration of meningothelial cells is found in the arachnoid villi at the dural sinuses, cranial nerve foramina, middle cranial fossa, and the cribriform plate. Subsequently, meningiomas are commonly found over the convexity, along the falx, and at the skull base. The tumors are generally encapsulated and attached to dura. The dura provides some blood supply, but OGMs primarily receive their vascular supply from the anterior and posterior ethmoidal arteries. Histologically, they appear benign, presenting with typical features, including whorls of arachnoid cells surrounding a central hyaline material that eventually calcifies to form psammoma bodies. The cells are arranged in sheaths separated by connective tissue trabeculae.

There are several meningioma subtypes, including meningotheliomatous, fibrous, and transitional types (also known as psammomatous tumors). The subtype provides little prognostic value. The only subtypes that have true clinical relevance are clear cell meningiomas, because they behave more aggressively; secretory meningiomas, which secrete vascular endothelial growth factor (VEGF) and are associated with marked edema; and papillary or rhabdoid variants, which are treated as malignant tumors. Norden and colleagues describe the recurrence rate and median survival based on WHO classification system. Meningiomas are classified based on the World Health Organization grading system ( Table 1 ). Malignant meningiomas are rare, but half of these patients develop distant metastases, most commonly to bone, liver, or lung ( Fig. 1 ).

( A ) Coronal T1-weighted postcontrast magnetic resonance imaging (MRI). This patient previously had a resection of an OGM. He was disease free for greater than 5 years but, in a period of 6 months, rapidly developed a malignant meningioma and ultimately died without additional treatment. ( B ) Sagittal T1-weighted postcontrast MRI of malignant meningioma from ( A ).

( Images courtesy of Dr Richard Harvey.)

Meningiomas are typically associated with 1 or more focal chromosomal deletion(s), and atypical and malignant grades tend to have multiple chromosomal copy number alterations consistent with the acquisition of mutations that foster genomic instability.

Deletion and inactivation of NF2 on chromosome 22 is a predominant feature in sporadic meningiomas. Additional genes are likely involved as well, because loss of NF2 occurs in only one-third of patients who exhibit loss of heterozygosity of chromosome 22. Additional genomic regions that are recurrently lost in meningiomas include 14q, 1p, 6q, and 18q. Meningiomas with increased tumor grade are found to have increased genetic alterations. In general, a small number of mutations may be necessary for most meningiomas. The difficulty with meningiomas is the long latency periods of the tumors, which lead to the challenges in identifying the source and timing of the initiating mutations.

Pathophysiology of meningiomas

Meningiomas are believed to arise from the meningothelial cap cells that are normally distributed through the arachnoid trabeculations. The greatest concentration of meningothelial cells is found in the arachnoid villi at the dural sinuses, cranial nerve foramina, middle cranial fossa, and the cribriform plate. Subsequently, meningiomas are commonly found over the convexity, along the falx, and at the skull base. The tumors are generally encapsulated and attached to dura. The dura provides some blood supply, but OGMs primarily receive their vascular supply from the anterior and posterior ethmoidal arteries. Histologically, they appear benign, presenting with typical features, including whorls of arachnoid cells surrounding a central hyaline material that eventually calcifies to form psammoma bodies. The cells are arranged in sheaths separated by connective tissue trabeculae.

There are several meningioma subtypes, including meningotheliomatous, fibrous, and transitional types (also known as psammomatous tumors). The subtype provides little prognostic value. The only subtypes that have true clinical relevance are clear cell meningiomas, because they behave more aggressively; secretory meningiomas, which secrete vascular endothelial growth factor (VEGF) and are associated with marked edema; and papillary or rhabdoid variants, which are treated as malignant tumors. Norden and colleagues describe the recurrence rate and median survival based on WHO classification system. Meningiomas are classified based on the World Health Organization grading system ( Table 1 ). Malignant meningiomas are rare, but half of these patients develop distant metastases, most commonly to bone, liver, or lung ( Fig. 1 ).

( A ) Coronal T1-weighted postcontrast magnetic resonance imaging (MRI). This patient previously had a resection of an OGM. He was disease free for greater than 5 years but, in a period of 6 months, rapidly developed a malignant meningioma and ultimately died without additional treatment. ( B ) Sagittal T1-weighted postcontrast MRI of malignant meningioma from ( A ).

( Images courtesy of Dr Richard Harvey.)

Meningiomas are typically associated with 1 or more focal chromosomal deletion(s), and atypical and malignant grades tend to have multiple chromosomal copy number alterations consistent with the acquisition of mutations that foster genomic instability.

Deletion and inactivation of NF2 on chromosome 22 is a predominant feature in sporadic meningiomas. Additional genes are likely involved as well, because loss of NF2 occurs in only one-third of patients who exhibit loss of heterozygosity of chromosome 22. Additional genomic regions that are recurrently lost in meningiomas include 14q, 1p, 6q, and 18q. Meningiomas with increased tumor grade are found to have increased genetic alterations. In general, a small number of mutations may be necessary for most meningiomas. The difficulty with meningiomas is the long latency periods of the tumors, which lead to the challenges in identifying the source and timing of the initiating mutations.

Risk factors for meningioma

Currently, the primary environmental risk factor identified for meningiomas is exposure to ionizing radiation. Studies have shown a sixfold to tenfold increase in meningioma formation. The best example is atomic bomb survivors who displayed a significantly increased risk for meningioma. Evidence also shows increased risk at lower dose levels. Between 1948 and 1960, children in Israel were treated with ionizing radiation for tinea capitis. They have a relative risk of almost 10 for meningioma development.

There is also an association between hormones and the risk for meningioma development. This association was initially suggested because of the observation of increased incidence of postpubertal disease in women versus men. As previously mentioned, there is a 2:1 female/male ratio with a peak ratio of 3.15:1 during peak reproductive years. In addition, some meningiomas present histologically with estrogen, progesterone, and androgen receptors. Studies have shown progesterone receptors on 80% of meningiomas in woman and in 40% of those in men. Furthermore, there is an association between breast cancer and meningiomas. In conjunction with studies showing that some meningiomas change size during different phases of the menstrual cycle and pregnancy, and the regression of multiple meningiomas in patients following cessation of estrogen agonist therapy, this has led to numerous investigational trials.

Despite the data correlating hormones with meningiomas, they have not been consistently associated with meningioma incidence. The significance of hormone receptors expressed on meningiomas is still a matter of debate and its significance is still unclear. Several future studies are dedicated to evaluating these hormone receptors with a goal of improving treatment, much as hormone receptor treatment has revolutionized breast cancer therapy.

Head trauma has also been suggested by some as a risk factor for meningiomas. Small case-control studies have reported an increased risk of meningioma associated with head trauma to both men and women. Conversely, there have been other studies that have found no such association.

With several reports identifying a relationship between glial brain tumors and allergic disease such as asthma and eczema, this corollary has been studied with meningiomas. Little evidence has been found to support this. In addition, no occupationally or industrially exposed groups of patients have identified any clear association.

There have been some studies of the relationship between meningioma risk and family history. Between 1% and 3% of the adult population may have a meningioma. Despite this, families with multiple members diagnosed with meningioma are rare. If families have any association, this is believed to be caused by inherited NF2 mutations. Currently, no family-based genetic linkage has been reported.

Anatomy

OGMs arise in the midline over the cribriform plate and frontosphenoidal suture. Although they generally arise in the midline, they may extend predominantly to one side. Most of these tumors occupy the floor of the anterior cranial fossa extending from the crista galli to the tuberculum sella. Extension into the ethmoid sinuses have been shown in 15% of cases ( Fig. 2 ). Further extension into the nasal cavity and orbit has been reported. Similarities exist between posteriorly extending OGMs and tuberculum sellae meningiomas. The main difference between the 2 is the location of the optic apparatus in relationship to the tumor. OGMs push the optic nerves and the chiasm downward and posteriorly as they grow. Conversely, tuberculum sellae meningiomas elevate the chiasm and displace the optic nerve superolaterally because these neoplasms occupy the subchiasmal position. The blood supply to OGMs is commonly derived from the anterior and posterior ethmoidal arteries. In addition, they receive contributions from the anterior branches of the middle meningeal artery and the meningeal branches of the ophthalmic artery. If the tumor is extensive in size, vascular supply from small branches of the anterior communication artery are common.

( A ) Coronal T1-weighted postcontrast MRI of an OGM with paranasal sinus extension. ( B ) Sagittal T1-weighted postcontrast MRI showing the same OGM with paranasal sinus extension.

( Images courtesy of Dr Richard Harvey.)

Presentation and work-up

Because of the slow growth and the location of OGMs, clinical presentation is generally delayed. The most common presenting symptom is olfactory impairment (58.8%), followed by headache, visual impairment, and mental status changes ( Box 1 ).

Diagnosis is generally made based on radiographic imaging. Magnetic resonance imaging (MRI) is the imaging modality of choice. Before the widespread use of MRI, angiography was used to suggest the diagnosis based on showing arterial supply from anterior and posterior ethmoidal arteries and the delayed vascular blush that is characteristic of OGMs. MRI is generally preferred because it can show the dural origin of the tumor in most cases. OGMs are typically isointense or hypointense to gray matter on T1-weighted images and isointense or hyperintense on T2-weighted images. In addition, they have a strong homogeneous enhancement with gadolinium. Most meningiomas show a characteristic marginal dural thickening that tapers peripherally (often termed the dural tail). On computed tomography (CT), OGMs typically appear as a well-defined extra-axial mass that displaces the normal brain. They are smooth in contour, adjacent to dural structures, and often are calcified or multilobulated. Noncontrast CT shows isointensity with normal surrounding brain parenchyma and makes diagnosis difficult. With intravenous contrast, OGMs present with uniform enhancement. Approximately 15% of cases present with an atypical pattern of necrosis, cyst formation, or hemorrhage.

Management of meningiomas

Treatment options for OGMs are similar to other skull base tumors. For small tumors in elderly or medically ill patients, observation with serial imaging may be acceptable. Definitive therapy for OGMs is surgical, but other options include radiation therapy (RT), and SRS. Investigational studies in chemotherapy and targeted molecular therapy are ongoing.

OGMs are often large at the time of presentation because of their slow, indolent growth. In some series, 50% to 60% of OGMs were larger than 6 cm in diameter at the time of surgery. Despite the large size, complete resection is generally possible. OGMs have an arachnoid membrane separating the tumor from nearly all critical neurovascular structures, which facilitates a complete resection.

Surgical therapy

Since Cushing described surgical resection of OGMs using a unilateral frontal craniotomy, numerous approaches have been described for definitive therapy. Today, commonly described approaches include wide bifrontal craniotomy with subfrontal approach, unilateral frontal craniotomy with subfrontal approach, pterional approach, and endoscopic approach.

This article outlines the advantages and disadvantages of all the neurosurgical approaches, but focuses on the technical aspects of the endoscopic approach.

The bifrontal craniotomy with subfrontal approach provides wide exposure for radical tumor resection, drilling of hyperostosis in the cribriform plate area of the planum sphenoidale and tuberculum sellae, and unroofing the optic nerves if necessary. The disadvantages to this procedure include significant brain retraction. With large tumors, brain edema can result in the brain herniating into the craniotomy window, often requiring partial resection of the frontal lobe. In addition, critical anatomic structures, including the optic apparatus, carotids, and the anterior communicating complex, present late in the dissection.

The unilateral frontal craniotomy with subfrontal approach has the advantage compared with the previously mentioned procedure that it spares the contralateral frontal lobe and superior sagittal sinus. The disadvantages are similar to the bifrontal craniotomy. In addition, this approach provides a smaller opening with a narrow view via a unilateral approach.

The pterional approach is considered a new approach to OGMs. This approach provides several advantages compared with other open approaches. It is less invasive than a bifrontal craniotomy. In addition, it avoids cerebrospinal fluid (CSF) leaks, because the frontal sinus is not transected. The optic nerve can also be localized and secured before tumor manipulation. The ipsilateral internal carotid artery also comes into view early in the dissection. The major disadvantage to this approach is that it uses a narrow working angle. In patients with a high-riding tumor, the upper portion is in a relatively blind area, and may require significant brain retraction for visualization.