Epidemiology, pathology, clinical features, and diagnosis of meningioma

INTRODUCTION — Meningiomas are the most frequent primary brain tumors (table 1 and figure 1). Although most meningiomas are benign, their location in the central nervous system (CNS) can cause serious morbidity or mortality.

The epidemiology, pathology, clinical presentation, and diagnosis of meningiomas will be reviewed here. Other topics on meningioma include:

●Treatment of World Health Organization (WHO) grade 1 (benign) meningiomas (see "Management of known or presumed benign (WHO grade 1) meningioma")

●Treatment of WHO grade 2 and 3 meningiomas (see "Management of atypical and malignant (WHO grade 2 and 3) meningioma")

●Systemic therapy for recurrent meningioma (see "Systemic treatment of recurrent meningioma")

EPIDEMIOLOGY — Meningiomas are the most common primary central nervous system (CNS) tumors and account for approximately one-third of all primary brain and spinal tumors [1,2].

According to the Central Brain Tumor Registry in the United States (CBTRUS), there were 145,916 new cases of meningioma diagnosed from 2011 to 2015 [3]. The estimated number of new cases per year in the United States is nearly 29,000. The incidence rate varies by race, with Black Americans having a 1.2-fold higher incidence than White Americans [3].

The incidence of meningioma increases progressively with age, with a median age at diagnosis of 65 years. Meningiomas are rare in children [4], except in those with hereditary syndromes such as NF2-related schwannomatosis or antecedent therapeutic radiation therapy [5,6]. (See 'Risk factors' below.)

Meningiomas are more common in women, with a female-to-male ratio of approximately two or three to one [7,8]. For spinal meningiomas, which comprise approximately 10 percent of all meningiomas, the female-to-male ratio is even higher, approximately nine to one. This female predominance is highest in middle-aged adults (35 to 54 years) and less pronounced or absent in those with atypical or anaplastic meningiomas, children, and those with radiation-induced meningiomas.

Population-based studies estimate that 80 to 85 percent of meningiomas are World Health Organization (WHO) grade 1, approximately 15 to 18 percent are grade 2, and 1 to 3 percent are grade 3 [3]. Hospital-based studies, particularly from tertiary care centers, have reported a higher proportion of grade 2 and 3 tumors [9,10].

RISK FACTORS — A number of factors have been studied for a possible relationship to the development of meningiomas and other brain tumors. The factors most intensively investigated as having a potential etiologic role in meningioma are discussed here. Factors associated with other types of brain tumors are reviewed separately. (See "Risk factors for brain tumors".)

Ionizing radiation — Exposure to ionizing radiation is the most important acquired risk factor for meningioma [11,12]. Radiation-induced meningiomas have a higher incidence of multiplicity and atypia compared with sporadic meningiomas. An increased risk of meningioma following a lengthy latency period has been established in a variety of situations.

●Radiation therapy for malignancy – Therapeutic use of radiation can result in exposure of the central nervous system (CNS) either as a direct consequence of treatment or by incidental exposure. Clinical situations in which this is particularly important include the following:

•Radiation therapy for primary malignancies of the CNS

•Radiation therapy for tumors in the head and neck region

•Prophylactic craniospinal irradiation to prevent CNS relapse as a component of treatment for acute leukemia or other malignancy

Although the absolute risk associated with radiation therapy is not known, the latency period is more than 20 years in many cases. Long-term follow-up of epidemiologic studies has observed that the incidence continues to rise even after several decades, and that risk may be highest among patients treated at a young age [6,13-17]. In a cohort of over 4000 childhood cancer survivors exposed to cranial radiation, the cumulative risk of meningioma was 5.6 percent by age 40 years [15]. Cumulative incidence was highest among patients younger than five years at initial cancer diagnosis (10 percent); additional risk factors included female sex and increasing dose of radiation. A smaller study found a 12 percent cumulative incidence of meningioma by 40 years after exposure to cranial radiation in childhood [16].

●Incidental radiation exposure – An association between radiation and the subsequent development of meningioma has been observed in a number of other clinical settings:

•Tinea capitis – Until the 1950s, low doses of irradiation were used to treat tinea capitis. An analysis of over 11,000 children treated for tinea capitis found a sevenfold increase in the incidence of meningioma, with a mean latency of 36 years [11,18].

•Dental radiographs – Several studies have reported an increased risk of meningioma associated with frequent dental radiographs [19-24]. Across multiple studies, the reported risk has been highest for multiple radiograph examinations and childhood exposure, primarily in an era when the dose of dental radiographs was higher than with current technology [19,22,23,25]. Importantly, recall bias can influence associations found in case-control studies such as these, and validation of dental records was not performed in most of these studies [26].

•Diagnostic head computed tomography (CT) – Childhood exposure to diagnostic head CTs may also be associated with an increased risk of brain tumors, including meningiomas [27,28]. (See "Radiation-related risks of imaging", section on 'Children and adolescents'.)

•Atomic bomb exposure – An increased incidence of meningiomas has been observed in survivors of the atomic explosions in Japan [29,30]. The increased incidence of meningioma was more pronounced in those who received higher radiation doses and those who were younger at the time of exposure [31].

Genetic predisposition — A genetic predisposition to meningioma is best characterized in patients with NF2-related schwannomatosis (NF2) and other forms of schwannomatosis. Patients with multiple endocrine neoplasia type 1 (MEN1) also have an increased risk of meningioma, although at lower rates compared with neurofibromatosis [32]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Other tumors'.)

NF2-related schwannomatosis — NF2-related schwannomatosis (NF2) is an autosomal dominant disorder predisposing to multiple tumors of the nervous system. This disorder is caused by mutations in the NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor (NF2) gene, a tumor suppressor gene on chromosome 22. (See "NF2-related schwannomatosis (formerly neurofibromatosis type 2)", section on 'Molecular pathogenesis'.)

Approximately one-half of individuals with NF2 have meningiomas, and multiple meningiomas are often present [33]. Most meningiomas are intracranial, although intradural, extramedullary spinal meningiomas are also seen. (See "NF2-related schwannomatosis (formerly neurofibromatosis type 2)", section on 'Meningiomas'.)

The incidence increases with age, and lifetime risk of developing a meningioma may be as high as 75 percent [34]. Patients with NF2 tend to develop meningiomas at an earlier age than those with sporadic meningiomas. The meningiomas seen in patients with NF2 are more frequently atypical or anaplastic compared with sporadic tumors [35,36].

Other schwannomatoses — Meningiomas are recognized as part of the phenotype of other forms of schwannomatosis in some patients. Patients with non-NF2-related schwannomatosis have multiple schwannomas in the absence of bilateral vestibular schwannomas; germline mutations in the tumor suppressor gene SMARCB1 are present in up to 50 percent of familial cases and a small proportion of sporadic cases. (See "Schwannomatoses related to genetic variants other than NF2", section on 'Other tumors'.)

Hormonal factors — Hormonal factors may have a role in the development of meningioma, as suggested by several lines of evidence [1]:

●The incidence of meningioma is higher in postpubertal women compared with men

●The female-to-male ratio is highest during the peak reproductive years and decreases in older adults

●Progesterone and androgen receptors are present in approximately two-thirds of patients, while estrogen receptors have been identified in approximately 10 percent of cases [37-39]

Low-dose estrogens and progestins — Multiple observational studies have explored a possible relationship between low-dose estrogen and progestin exposure (eg, menopausal hormone therapy or oral contraceptive use) and the risk of meningioma, with mixed results [1,40-47]. A meta-analysis of six prospective case-control studies that included over 1600 meningioma cases found that ever-use of hormone therapy was associated with a small but statistically significant increase in the risk of meningioma (relative risk [RR] 1.35, 95% CI 1.2-1.5) [46]. In studies that distinguished between estrogen-only versus combined estrogen-progestin hormone therapy, estrogen, but not combined therapy, was associated with increased risk (RR 1.31). This is equivalent to an approximate absolute excess risk of 2 per 10,000 users over five years.

Some, but not all, studies have also suggested a protective effect of smoking and an increased risk with higher body mass index (BMI), both of which could potentially be mediated through their effects on endogenous estrogen levels [40,43-45,47].

Inhibition of estrogen or progesterone receptors has not been shown to alter the natural history of recurrent meningiomas, however. (See "Systemic treatment of recurrent meningioma", section on 'Hormonal therapy'.)

High-dose cyproterone — Cyproterone, an anti-androgen and progestin, is associated with a small increase in the risk of meningioma with increasing cumulative doses (eg, ≥25 mg per day over several years). It is contraindicated in people with a history of meningioma and should be discontinued if meningioma is diagnosed [48]. (See "Management of known or presumed benign (WHO grade 1) meningioma", section on 'Patients with hormone exposure'.)

Cyproterone is not available in the United States but is used in Europe and elsewhere at high doses (eg, ≥25 mg per day) for conditions that include advanced prostate cancer, severe hypersexuality in males, hirsutism, and androgen suppression in transgender females. Based on a European Medicines Agency (EMA) safety committee review, the occurrence of both single and multiple meningiomas has been reported in association with cyproterone, primarily at doses of 25 mg/day and above [49]. The absolute risk is estimated at between 1 and 10 per 10,000 people, depending on dose and duration of cyproterone. In a case-control study of >1000 resected cyproterone-associated meningiomas in France, the median age at presentation was lower compared with nonexposed resected meningioma cases (47 versus 61 years), and there was a predilection for middle skull base location (39 versus 23 percent) [50]. In a separate French study that included 210 patients exposed to cyproterone or one of two other progestins who underwent MRI screening, the rate of meningioma detection was 7 percent; seven of these patients (47 percent) had multiple meningiomas [51]. The most common tumor locations were convexity (62 percent), middle skull base (21 percent), and anterior skull base (16 percent).

Available data have not shown a risk of meningioma with lower doses of cyproterone (1 to 2 mg alone or in combination with ethinylestradiol or estradiol valerate) used for acne, hirsutism, contraception, or menopausal hormone therapy. As a precaution, the EMA recommends avoiding cyproterone in people with a meningioma, even at these low doses [48].

Others

●Breast cancer – A moderately increased risk of meningioma has been reported in females with breast cancer, and, conversely, an increase in the incidence of breast cancer has been observed in females with a history of meningioma [1,52,53]. The magnitude of risk is not well established. A meta-analysis of 13 observational studies estimated a nearly 10-fold increase in the prevalence of breast cancer in females with meningioma compared with prevalence in the general population (odds ratio 9.87, 95% CI 7.31-13.32), although heterogeneity among studies was high and possible publication bias was identified [53].

Whether the association is due to shared hormonal risk factors, other risk factors causing both diseases, or an underlying genetic predisposition is unclear [1]. Given shared risks, clinicians should emphasize the importance of breast cancer screening in females with meningioma. (See "Screening for breast cancer: Strategies and recommendations".)

●Obesity – A positive association between BMI and meningioma has been reported in several large observational studies, with odds ratios ranging from 1.4 to 2.1 [40,43,47,54-58]. This relationship might be related to endogenous hormonal factors, since obesity is associated with higher levels of estrogens and other growth factors.

High BMI is an established risk factor for a variety of other neoplasms, including esophageal adenocarcinoma, endometrial cancer, colon cancer, and breast cancer [59]. (See "Epidemiology and pathobiology of esophageal cancer", section on 'Obesity and metabolic syndrome' and "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Obesity' and "Factors that modify breast cancer risk in women", section on 'Weight and body fat in postmenopausal women' and "Epidemiology and risk factors for colorectal cancer", section on 'Obesity'.)

●Head trauma – Several studies have analyzed the role of head trauma as an etiologic factor for brain tumors, with conflicting results [25,60-62]. Improved recall of a history of head trauma in patients with meningioma may have contributed to bias in some of these studies.

●Cell phones – Others have looked at a possible link between cell phone usage and the subsequent development of brain tumors. At present, there is no conclusive evidence supporting a causal relationship. However, the prolonged latency period seen with ionizing radiation suggests that longer follow-up is required [1]. (See "Risk factors for brain tumors", section on 'Cellular phones and radiofrequency fields'.)

PATHOLOGY

WHO classification — Meningiomas are classified according to the World Health Organization (WHO) schema, which is based upon morphologic criteria [63-66]. The WHO classification system recognizes three grades, which can be assigned to 15 morphologic subtypes:

●WHO grade 1 – Benign meningiomas (WHO grade 1) (picture 1) span 13 subtypes. WHO grade 1 meningiomas do not meet any of the criteria for a higher-grade lesion based upon morphologic and molecular criteria. The treatment approach is the same for all of the subtypes of benign meningiomas.

●WHO grade 2 – WHO grade 2 meningiomas include specific morphologic subtypes (clear cell and chordoid meningiomas), tumors with increased mitotic activity (4 to 19 mitoses per 10 high-powered fields) or brain invasion, and tumors with three or more of the following features: increased cellularity, small cells with a high nuclear-to-cytoplasmic ratio, prominent nucleoli, uninterrupted patternless or sheet-like growth, and foci of spontaneous or geographic necrosis (picture 1).

●WHO grade 3 – WHO grade 3 (malignant) meningiomas have ≥20 mitoses per 10 high-powered fields; malignant characteristics resembling carcinoma, sarcoma, or melanoma; or a high-risk molecular feature (telomerase reverse transcriptase [TERT] promoter mutation or homozygous cyclin-dependent kinase inhibitor 2A/B [CDKN2A/B] deletion) (picture 1). (See 'Molecular risk stratification' below.)

The WHO grading system correlates with outcome and thus has a major impact on treatment planning. Patients with WHO grade 2 or grade 3 meningiomas are significantly more likely to have invasive disease, a local recurrence following the initial treatment, and, ultimately, a shorter overall survival compared with patients with a WHO grade 1 meningioma.

●Overall reported rates of recurrence for patients with grade 1, 2, and 3 meningiomas are 7 to 25, 30 to 50, and 50 to 94 percent, respectively, in various series [67-71].

●Although WHO grade 3 meningiomas are considered malignant, distant metastasis is rare and the primary issue is local recurrence, which necessitates additional treatment beyond surgery and ultimately can cause death [72]. (See "Management of atypical and malignant (WHO grade 2 and 3) meningioma".)

Among grade 1 tumors, the presence of atypical features may also have prognostic importance, although data are more limited. In a study of 147 patients who underwent resection of a grade 1 meningioma, the five-year recurrence rate was significantly higher for tumors with one or two atypical features compared with tumors with no atypical features (31 versus 14 percent), independent of extent of resection [73].

Molecular risk stratification — A growing number of individual molecular genetic alterations have been identified that are associated with more aggressive biology and worse outcomes, including mutations in the TERT promoter region, CDKN2A/B deletion, and loss of trimethylation of lysine 27 of histone 3 (H3K27me3) [74-77].

●TERT alterations – TERT gene alterations in particular have been associated with an aggressive clinical course. In a multicenter retrospective study of 677 patients with meningioma, the prevalence of TERT gene alterations was 5, 8, and 15 percent for WHO grade 1, 2, and 3 tumors, respectively [78]. Median recurrence-free and overall survival were 14 months and 4.8 years for TERT-mutated tumors, compared with 8.4 and 13.3 years for TERT-wildtype tumors. While this may be partially explained by the higher relative incidence of WHO grade 3 tumors in the TERT-mutated group, the adverse effect on survival appeared to be independent of WHO grade in a multivariable analysis.

●CDKN2A/B deletion – In a study of 528 meningiomas, homozygous deletion of CDKN2A/B was identified exclusively in grade 2 (27 percent) and grade 3 tumors (73 percent) [79]. The median time to progression after surgery was substantially shorter in tumors carrying CDKN2A/B deletion (8 versus 101 months). Co-occurring TERT promoter mutations were present in three of six CDKN2A/B-deleted tumors that were tested for both alterations.

●H3K27me3 loss – Loss of immunohistochemical staining for H3K27me3 is associated with increased risk for recurrence, especially in WHO grade 2 tumors [80-82]. In a large retrospective cohort of over 1100 meningiomas, H3K27me3 loss was observed in 3.1 percent of grade 1 tumors, 10.4 percent of grade 2 tumors, and 17.7 percent of grade 3 tumors [80]. On multivariate analysis, H3K27me3 loss was predictive of decreased recurrence-free survival (risk ratio [RR] 1.80), independent of sex, extent of resection, tumor grade, and proliferation index.

Classification of meningiomas into molecular groups by DNA and RNA profiling as well as the integration of molecular and morphologic features may also improve upon the prediction of biologic behavior and prognosis [83-86]. A three-tiered integrated grading scheme (Integrated Grades 1, 2, and 3) based on mitotic count, chromosomal copy-number data, and CDKN2A deletion status has been proposed, which more accurately predicts risk of recurrence than the WHO grading system [87]. Further validation is necessary, however, before this scheme can be used to guide treatment decisions.

Molecular pathogenesis — The best-characterized genetic alteration is loss of chromosome 22, which in many cases is associated with mutations in the NF2 gene located on the long arm of chromosome 22. (See 'NF2-related schwannomatosis' above.)

NF2 mutations are also present in approximately one-half of sporadic meningiomas, more commonly in those with transitional or fibroblastic histologic subtypes and in higher-grade tumors [88].

Genomic sequencing efforts have identified several oncogenic mutations in a small subset of non-NF2 mutant meningiomas that have potential therapeutic implications. In two separate studies, mutations in Smoothened (SMO), an activator of the Hedgehog pathway that is mutated in many basal cell carcinomas, were found in approximately 5 percent of tumors, and mutations in v-akt murine thymoma viral oncogene homolog 1 (AKT1), an activator of the phosphatidylinositol 3-kinase (PI3K) pathway, were found in up to 13 percent of tumors [89,90]. Mutations in TRAF7, a proapoptotic ubiquitin ligase, were identified in approximately one-quarter of tumors in one study [90]. The role of these mutations in the pathogenesis of meningioma, however, is unclear. Another study found oncogenic mutations in PI3KA in approximately 7 percent of meningiomas [91].

Many of these mutations appear to be most prevalent in anterior skull base tumors. In a series of 62 anterior skull base meningiomas, SMO mutations were present in 7 tumors (11 percent), all but one of which were in the olfactory groove, and AKT1 mutations were present in 12 tumors (19 percent) [92]. Other studies suggest that PI3KA mutations also occur primarily in skull base tumors and might be overrepresented in progestin-exposed tumors [91,93].

Activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway also appears to be a common alteration in meningioma that has potential therapeutic implications [94].

CLINICAL PRESENTATION — Meningiomas can arise anywhere from the dura, most commonly within the skull and at sites of dural reflection (falx cerebri, tentorium cerebelli, venous sinuses) [95]. Other less common sites include the optic nerve sheath and choroid plexus; approximately 10 percent arise in the spine. Very rarely, meningiomas can arise at extradural sites [96].

Symptoms from a meningioma are determined by the location of the mass and by the time course over which the tumor develops. Meningiomas are frequently extremely slow growing and often are asymptomatic. (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Clinical manifestations'.)

Asymptomatic tumors — Many meningiomas are asymptomatic or minimally symptomatic, and are discovered incidentally on a neuroimaging study or at autopsy [97-101]. Follow-up studies on patients with asymptomatic meningiomas suggest that most such tumors either remain the same size or grow slowly over prolonged periods [102,103].

In a systematic review and meta-analysis of incidental findings on brain magnetic resonance imaging (MRI) in nearly 20,000 children and adults, meningioma was the most common incidental tumor, identified on 0.29 percent of MRIs [104]. The prevalence of incidental findings, including meningioma, increases with age. In population-based studies of brain MRI in older adult volunteers (mean age 65 to 70 years), meningiomas are identified in approximately 2.5 percent of participants [105,106]. The most common locations are convexity (62 percent) and falx cerebri (15 percent) [105].

Seizures — Seizures are present preoperatively in approximately 30 percent of patients who are diagnosed with an intracranial meningioma [107]. The risk of seizure is higher in association with non-skull base location (eg, convexity and parasagittal/falcine tumors) and tumors associated with peritumoral edema.

Focal findings — Characteristic focal deficits are caused by tumors in specific locations. Examples of such lesions include:

●Visual changes – Visual changes, which are often unrecognized, are common in meningiomas involving the optic pathways.

•Visual field defects may be caused by parasellar meningiomas

•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, can be caused by optic nerve sheath meningiomas

•Mild weakness of extraocular movements has been associated with cavernous sinus meningiomas

●Loss of hearing or smell – A cerebellopontine angle meningioma can produce sensorineural hearing loss. Olfactory groove or sphenoid ridge meningiomas can cause anosmia due to compression of the olfactory tract.

●Mental status changes – Mental status changes with apathy and inattention may result from surprisingly large subfrontal or sphenoid ridge meningiomas. Similar or even larger-sized tentorial notch and intraventricular meningiomas are at times asymptomatic and diagnosed incidentally.

●Extremity weakness – Meningiomas at different sites can produce characteristic patterns of extremity weakness.

•A parasagittal meningioma growing on the falx and compressing 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, which is followed by contralateral leg and arm weakness that may be misdiagnosed as multiple sclerosis

•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.

NEUROIMAGING — Meningiomas have a very characteristic appearance on both MRI and CT (table 2).

On MRI, a typical meningioma is an extra-axial, dural-based mass that is isointense or hypointense to gray matter on T1 and isointense or hyperintense on proton density and T2-weighted images. There is usually strong, homogeneous contrast enhancement after gadolinium administration (image 1). Most meningiomas show a characteristic marginal dural thickening that tapers peripherally (the "tail" sign) (image 2).

On CT, 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. Isodensity with normal surrounding brain may make diagnosis difficult on a noncontrasted scan, but intravenous contrast administration results in uniformly bright enhancement. Secondary involvement of adjacent bone (reactive sclerosis, invasion, erosion) is uncommon with convexity meningiomas, but occurs in up to one-half of skull base tumors [108].

Differentiating an atypical or malignant meningioma from a benign meningioma purely on the basis of neuroimaging is difficult. Features on MRI that may suggest the presence of a high-grade meningioma rather than a benign meningioma include the following [72,109-112]:

●Intratumoral cystic change

●Hyperostosis of the adjacent skull and/or bone destruction

●Extension of tumor through the skull base

●Peritumoral brain edema

●Low apparent diffusion coefficient (ADC) values

●Elevated cerebral blood volume

However, none of these neuroimaging findings are sufficiently specific to be clinically useful. Furthermore, the initial therapeutic approach for most meningiomas is surgical resection if feasible, depending upon the size and location of the lesion, as well as the patient's overall condition and symptoms. (See "Management of known or presumed benign (WHO grade 1) meningioma".)

18-F Fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning has shown more intense uptake associated with higher-grade meningiomas in some, but not all, studies and is of limited diagnostic value [113]. Novel PET tracers, including specific somatostatin receptor ligands, hold more promise but are not yet widely available for clinical use [114,115].

Prior to the development of MRI and CT, angiography was 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. The use of angiography now is limited to tumor embolization as a component of therapy. (See "Management of known or presumed benign (WHO grade 1) meningioma", section on 'Extent of resection'.)

DIFFERENTIAL DIAGNOSIS — While meningioma is by far the most common cause of a discrete, dural-based enhancing mass lesion, many other disease processes can involve the dura or subdural space, resulting in an appearance on MRI or CT that may suggest meningioma. These include lymphoma, plasmacytoma, metastatic carcinoma, melanocytic neoplasms, solitary fibrous tumor, gliosarcoma, inflammatory lesions such as sarcoidosis and granulomatosis with polyangiitis, and infections such as tuberculosis [95,114,116-118].

In general, MRI, CT, and positron emission tomography (PET) studies cannot reliably distinguish these entities from meningioma. The presence of atypical imaging features, such as large or disproportionate amount of associated edema, extensive bone involvement, or brain or leptomeningeal invasion, may be a clue to an alternative etiology or to a higher-grade meningioma, along with clinical features of systemic disease. These and other clinical clues to rare alternative diagnoses are reviewed in the table (table 3).

DIAGNOSTIC EVALUATION — A definitive diagnosis of meningioma and classification as benign, atypical, or malignant (World Health Organization [WHO] grades 1, 2, and 3, respectively) requires histologic confirmation. However, imaging studies often provide a tentative diagnosis and may be sufficient for empiric treatment when obtaining tissue for pathologic confirmation entails too high a risk of causing further neurologic deficits.

While the differential diagnosis of meningioma includes a wide range of neoplastic and non-neoplastic entities, these are rare and almost always diagnosed after tissue is obtained, due to their clinical and radiographic similarity to meningiomas. The utility of an extensive preoperative evaluation is uncertain.

History — The history in patients with a suspected meningioma should include an assessment of risk factors, especially a history of prior therapeutic radiation. Radiation-induced meningiomas have a higher likelihood of being high grade and of being multiple and recurrent. (See 'Ionizing radiation' above and "Management of known or presumed benign (WHO grade 1) meningioma", section on 'Radiation-induced meningiomas'.)

The history should also probe for conditions that may cause dural-based pathology mimicking meningioma, including hematologic and nonhematologic malignancy, sarcoidosis, and tuberculosis (table 3). (See 'Differential diagnosis' above.)

Genetic syndromes predisposing to meningioma, such as NF2-related schwannomatosis (NF2) and other forms of schwannomatosis, may be apparent by personal and family history by the time a meningioma is identified. Lack of a family history does not rule these syndromes out, however, as de novo mutations frequently occur. (See 'Genetic predisposition' above.)

Physical examination — Most patients with meningioma have a normal physical examination. Occasionally, convexity tumors associated with prominent hyperostosis or direct bony extension may produce a palpable bulge on the skull.

Physical stigmata of NF2 or schwannomatosis may include hearing loss (for NF2) and multiple palpable schwannomas. (See "NF2-related schwannomatosis (formerly neurofibromatosis type 2)", section on 'Clinical features' and "Schwannomatoses related to genetic variants other than NF2", section on 'Clinical features'.)

Laboratories — It seems reasonable to obtain a comprehensive metabolic panel and complete blood count, as findings such as hypercalcemia or anemia might prompt additional testing for multiple myeloma or systemic malignancy. We do not routinely obtain serum protein electrophoresis (SPEP), urinalysis, angiotensin converting enzyme (ACE) level, or tuberculosis screening in otherwise healthy adults. More extensive evaluation should be considered in immunocompromised hosts and in patients with atypical imaging features.

Cerebrospinal fluid analysis does not play a role in the diagnostic evaluation of meningioma but may be indicated if there are atypical imaging features, such as leptomeningeal enhancement, suggesting involvement of the subarachnoid space.

Imaging — MRI with contrast provides the most complete assessment of suspected meningiomas. Dedicated views through the involved region (eg, skull base protocol, orbital sequences) may be needed to adequately image small tumors in certain locations [119]. CT may also be obtained to provide better definition of bony anatomy and the degree of calcification associated with the lesion. (See 'Neuroimaging' above.)

We do not routinely obtain spinal imaging in patients with a suspected intracranial meningioma, but we do advise obtaining a brain MRI in patients with a suspected spinal meningioma to look for intracranial masses that may suggest either a tumor predisposition syndrome or an alternative diagnosis.

We obtain updated cancer staging (eg, chest, abdomen, and pelvis CT) in patients with known cancer but do not routinely obtain these tests in otherwise healthy adults who have undergone age-appropriate cancer screening. The presence of atypical neuroimaging findings, even in a patient without known cancer, may also indicate the need for a more extensive cancer staging.

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Meningiomas account for approximately one-third of primary central nervous system (CNS) tumors, occurring primarily in older individuals with a female predominance (table 1). (See 'Epidemiology' above.)

●Etiology – The etiology of meningioma is not known in most cases. However, there is a clear association with antecedent radiation exposure, which is associated with a latency period that may exceed 30 years. Meningiomas are a frequent manifestation of NF2-related schwannomatosis, and somatic mutations in the NF2 gene may also contribute to the development of sporadic meningiomas. (See 'Risk factors' above and 'Molecular pathogenesis' above.)

●Pathology – Meningiomas are classified according to the World Health Organization (WHO) grading system. WHO grade 1 lesions are benign and generally have a favorable prognosis, while atypical (grade 2) and malignant (grade 3) meningiomas are substantially more likely to recur. (See 'WHO classification' above.)

●Location – Meningiomas can arise anywhere from the dura, most commonly within the skull. Approximately 10 percent arise in the spinal cord. (See 'Clinical presentation' above.)

●Clinical presentation – Many meningiomas are slow growing and discovered incidentally on a neuroimaging study. These may be asymptomatic or minimally symptomatic. Symptoms of large tumors can vary widely, depending upon by the location of the mass. (See 'Clinical presentation' above.)

●Imaging – On MRI, a typical meningioma is an extra-axial, dural-based mass that is isointense or hypointense to gray matter on T1, isointense or hyperintense on proton density and T2-weighted images, and associated with strong, homogeneous contrast enhancement after gadolinium administration (table 2 and image 1). (See 'Neuroimaging' above.)

●Differential diagnosis – The differential diagnosis of meningioma includes a wide range of neoplastic and non-neoplastic entities (table 3). However, these are rare and almost always diagnosed after tissue is obtained, due to their clinical and radiographic similarity to meningiomas. (See 'Differential diagnosis' above.)

●Diagnosis – A definitive diagnosis of meningioma and classification as benign, atypical, or malignant requires histologic confirmation at the time of biopsy or surgery. For small and minimally symptomatic tumors, the diagnosis is based on characteristic imaging findings. (See 'Diagnostic evaluation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Black, MD, PhD, who contributed to an earlier version of this topic review.