Meningiomas Pathology

Meningiomas, as defined by the 2016 World Health Organization (WHO), are "a group of mostly benign, slow-growing neoplasms that most likely derive from the meningothelial cells of the arachnoid layer." These tumors fall into WHO grade I, with a low risk of recurrence and aggressive behavior; grades II and III indicate a greater likelihood of recurrence and aggressive behavior. ^[1]

Meningioma comprises about one fourth of all primary tumors of the central nervous system (CNS). It is the most common primary intracranial neoplasm and the most diversified in histologic patterns among all primary tumors of the CNS. 

Meningothelial (arachnoidal) cells are believed to be the cell of origin of meningiomas. Based on studies in birds, the telencephalic leptomeninges arise from the neural crest (neuroectoderm) and the leptomeninges of the posterior brain and the spinal cord arises from the mesoderm. ^[2]  The arachnoid cells have several proposed functions, including acting as a structural barrier with cellular wrapping/ensheathing, acting as a conduit for cerebrospinal fluid (CSF) drainage/absorption into dural sinuses/veins (arachnoid villi), epithelial-like/secretory functions, monocytelike functions, trophic support and byproduct detoxification for glial and neuronal cells, and participation in reactive/reparative processes. ^[3]

The histologic patterns and biologic spectrum of meningiomas partially reflect the aforementioned biologic functions and embryogenesis. Both non-neoplastic meningothelial cells and meningiomas possess mixed features of epithelial and mesenchymal cells. In meningiomas, one feature may be dominant over the other, and this phenomenon partly contributes to the rich diversification of histologic patterns in these tumors.

Although some of the observed variants, such as chondroid meningiomas, clear-cell meningiomas, papillary meningiomas, and rhabdoid meningiomas, are associated with unfavorable prognoses, the other histologic patterns are not indicators of unfavorable biologic behavior. Some of the uncommon histologic patterns, such as the lymphoplasmacyte-rich meningioma, may raise concern for lymphoproliferative diseases. Anaplastic meningiomas often shed most of the obvious features of meningiomas, and their diagnosis may be difficult.

With all the above features, it is not difficult to imagine that some meningiomas can be true imposters, histologically mimicking other entities. Although the diagnosis is often straightforward, it can also be challenging.

With the close resemblance between meningiomas and meningothelial cells, these cells are believed to be the cell of origin of meningiomas. This would also explain the high incidence of meningiomas around the sagittal sinus, which has a high concentration of meningothelial cells.

Although meningiomas commonly arise in locations where meningothelial cells are found, the embryonic origin of intraventricular and pulmonary meningiomas are intriguing. Intraventricular meningiomas probably arise from the meningothelial cells of the tela choroidea, where there is an arachnoidal invagination into the stromal base of the choroid plexus. During early embryonic development, the tela choroidea represents a portion of the pia and, together with the adjacent ependyma, forms the roof of the diencephalon. Minute meningothelial pulmonary nodules (MMPNs) ^{[4, 5]} are small perivascular nodules that are histologically and ultrastructurally identical to meningothelial cells of the CNS. These nodules probably represent the origin of primary meningiomas in the lung. Developmental lesions such as heterotopia of meningothelial cells in the scalp are believed to be the origin of meningiomas under the scalp and skin of the head. ^[6]

Similar to other tumors, the risk factors for the development of meningiomas can be divided into those with clearly defined genetic etiology and those that are attributed to environmental and other nongenetic factors. The etiology of most meningiomas, however, remains unclear.

As noted above, meningiomas are more common in women, and the female-to-male ratio has increased over the past several decades. ^{[7, 8]} Rapid growth of meningiomas in pregnant women has also been well documented. ^{[9, 10]} These increases suggest that the more widespread use of hormonal contraceptives may contribute to the tumorigenesis of meningiomas. In tumors obtained from the first operation, 88%, 40%, and 39% of meningiomas are positive for progesterone, estrogen, and androgen receptors, respectively. WHO grade I meningiomas have been reported to have significantly higher incidences of estrogen, progesterone, and androgen receptors than higher-grade meningiomas. However, differences in sex hormone receptor expression alone may not explain the observed increase in incidence in women. ^[11]

NF2 gene (merlin) on chromosome 22 ^[12] and the related cytoskeleton element gene DAL-1/4.1B (EPB41L3) ^{[13, 14]} on chromosome 18 are the two genes known to be associated with meningiomas. Genetically, meningiomas can be subdivided into 3 major genetic groups. The sporadic type, the familial type not related to NF2, and the familial type related to NF2. The sporadic type and familial types not related to NF2 may have different genetic mechanisms. ^{[15, 16]} There is a strong relationship between NF2 and the development of both meningiomas and meningioangiomatosis. ^{[12, 17]} These patients often develop multiple meningiomas. In contrast, patients with NF1 are not at an increased risk for the development of meningiomas.

Radiation at low, moderate, and high doses is a well-described risk factor for the development of meningiomas. ^{[18, 19, 20]} The implicated radiation exposure range spans from dental radiography, low-dose irradiation to the scalp for tinea capitis, radiation therapy for tumors in the head and neck region, and exposure to atomic explosions in Hiroshima and Nagasaki. The mean interval for tumor development is 35, 26, and 19-24 years, respectively. ^[18] Radiation-induced meningiomas tend to occur in younger patients and are more likely to be atypical or aggressive, multifocal, and highly proliferative. ^{[21, 22, 23]}

In the United States, meningiomas comprise about 32% of all primary intracranial tumors, ^[24] with an annual incidence of 5.2 per 100,000 population. ^[24] These tumors are twice as common in women, and there is a regional variation. The overall incidence of meningioma in Norway is 1.5 per 100,000 population among men and 2.8 in women. ^[7] In comparison, the incidence in Italy is 13 per 100,000 population. ^[25] Patients with multiple meningiomas generally comprise less than 10% of cases. Most meningiomas are benign. In general, atypical meningiomas and anaplastic meningiomas comprise less than one fifth of all meningiomas. ^[26]

Meningioma is essentially a tumor of adulthood, with a peak incidence in the sixth decade of life. ^[26] There is a definite predilection for women, with an average male-to-female ratio of 1:2.2. ^[24] Tumors arising in the spinal cord have a distinctly high incidence in women. Atypical and anaplastic meningiomas, however, show a male predominance. ^[27] Childhood meningiomas occur more often in males. ^{[28, 29]} Meningiomas associated with neurofibromatosis type 2 (NF2) tend to occur in younger individuals and with equal distribution between males and females.

With the exception that papillary meningiomas are more common in children relative to adults, meningiomas are rather uncommon in children and almost never occur in infants. When these tumors occur in children, however, they are more often infratentorial, intraventricular, or intraparenchymal than in adults. They also tend to be more aggressive, with an increased frequency of recurrence. ^{[30, 31, 32]} Up to 25% of childhood cases of meningiomas are associated with neurofibromatosis type 1 (NF1) or NF2. Tumors associated with NF2 may also have a more aggressive course. ^[31]

Meningiomas are most commonly dural-based tumors in the brain and, less commonly, the spinal cord. Rare cases occur as intraventricular or pulmonary tumors. Most meningiomas are intracranial extra-axial tumors. About half of these tumors occur in the falcine and parasagittal locations, ^{[33, 34, 35]} and they are often firmly affixed to the sagittal sinus. The majority of the remainder occur in the skull base. Posterior fossa and, in particular, intraventricular meningiomas are relatively uncommon. However, meningiomas in children are more often infratentorial, intraventricular, or intraparenchymal than those in adults. Up to 25% of childhood cases of meningiomas are associated with NF2. ^{[28, 31]}

Most of the spinal meningiomas are firmly affixed to the dura, subdural and laterally situated in close relationship with the spinal nerve roots. The thoracic spine is the most common site, followed by the cervical spine. Meningiomas are rarely seen in the lumbar region. There is a striking female predominance in spinal meningiomas.

Meningiomas outside the central nervous system (CNS) have been described in multiple areas, including the scalp ^[36] and skin and connective tissue covering the head and neck, ^[6] lung, ^{[37, 38]} mediastinum, ^[39] peripheral nerve plexus and ganglion, ^[40] salivary gland, ^[38] mandible, and other odd locations. Primary meningiomas arising in the bone are rare and must be differentiated from meningioma with osseous invasion.

Meningiomas are slow-growing tumors, and smaller ones often remain asymptomatic throughout life. Some of these asymptomatic tumors can be heavily calcified or ossified. For the larger and symptomatic tumors, symptoms result from local compression and peritumoral edema. Headache and newly onset seizures are the most common initial manifestations. The local manifestations result from local compression and irritation of the brain and spinal cord, which lead to focal neurologic symptoms and signs. For the rare tumors that arise in the ventricles, hydrocephalus is often part of the clinical picture. ^[41]

Tumors that arise in the cranial base have a strong tendency to invade the surrounding osseous and nonosseous tissue, and they can be surgically challenging. ^{[42, 43]} Invasion of the cranial base and adjacent structures could cause a spectrum of manifestations, ranging from cranial nerve palsy, symptoms related to involvement of the sinuses and the orbit, ^[44] dental complaints, ^[33] and masses in the forehead. ^[45] Cranial base meningiomas are more likely to recur, but this probably reflects the difficulty in total surgical resection rather than the biologic nature of these tumors. ^[34] Tumors in the anterior visual pathway, such as those occuring along the optic nerve, are more likely to recur. ^[34] Extracranial meningiomas can also be seen in the sinonasal tract ^{[46, 47]} and should be distinguished from extensions from intracranial primaries.

The 5-year recurrence rates of meningiomas, atypical meningiomas, and anaplastic meningiomas are 3%, 38%-40%, and 78%, respectively. ^{[27, 48]} The overall 5-year survival rates for WHO grade I, II, and III meningiomas are approximately 95%, 80%, and 20%, respectively. ^[26] In one study, the median survival of patients with anaplastic meningioma was less than 2 years. ^[49] Gross total resection appears to be one of the most significant factors for favorable prognosis. ^[34]

Imaging characteristics

Most, but not all, meningiomas are hyperdense on computed tomography (CT) scans, and about a quarter of all cases demonstrate calcifications. Large meningiomas may mold the overlying bone.Occasionally, meningiomas invade the cranial vault and cause characteristic hyperostosis.

Typically, meningiomas are almost isodense with the gray matter on T1-weighted magnetic resonance images (MRIs) (see the image below). These tumors vary from hypointense to hyperintense on T2-weighed images.

Contrast-enhanced MRI is the most sensitive method for detecting meningiomas. Meningiomas enhance strongly and often homogeneously. About half of cases have an area of dural enhancement, the so-called "dural tail." Such enhancement is common in all dural-based processes and is not entirely specific for meningiomas. Histologically, the dural tails may be composed entirely of hypervascular, presumably reactive tissue, but not meningioma tumor cells.

On T2-weighted MRI, a crest of cerebrospinal fluid (CSF), the so-called "CSF crest" (see the following image), is often seen around the tumor. The presence of the crest is a good indicator of the extra-axial location of these tumors.

Meningiomas often attach to, encase, or compress adjacent arteries and sinuses. The nature of tumor relationship with the regional vasculature is an important surgical consideration and is best assessed with MRI. Meningiomas are also typically associated with peritumoral edema that is well demonstrated on fluid attenuation inversion recovery (FLAIR) images or T2-weighted MRIs. ^[40] Occasionally, such edema may be disproportionally large relative to the size of the tumor and may suggest an invasive tumor, a metastatic carcinoma, or melanoma. Secretory meningiomas and, to a lesser extent, angiomatous (vascular) and microcystic meningiomas, are well known for inducing a disproportionately large amount of peritumoral edema.

Benign meningiomas often occur as round, bosselated, or lobulated, well-demarcated nodules (see the following image). ^[26] The great majority of these lesions are dural based. Depending on their collagen content, the consistency of the tumors ranges from rubbery to firm. See the following image.

Atypical meningiomas and anaplastic meningiomas are usually larger. The cut surfaces of benign meningiomas are usually granular to homogeneous. Cases with a substantial amount of psammoma bodies are gritty when cut with a knife. Yellow areas resulting from the accumulation of lipid-rich cells may be present. Ossifications may occur. Cysts and spontaneous hemorrhages are uncommon. Necrosis may be present in high-grade tumors. The size of meningiomas varies significantly and ranges from a few millimeters to several centimeters in size. The smallest ones are often asymptomatic, but they can be detected with MRI.

Benign meningiomas can be easily separated from the underlying brain parenchyma without disruption of the cortex. This feature is well reflected by the well-circumscribed appearance and the CSF crest on imaging. The underlying cortex is often compressed and appears gliotic. When invasion is present, the neurosurgeon may have difficulty in establishing a clear cleavage plane between the tumor and the underlying cortex. In contrast, cranial-base meningiomas often invade the surrounding osseous and fibrous structures. Meningiomas that involve the orbit may represent primary tumors arising within the orbit, as well as intracranial meningiomas with extension into the orbit.

En plaque meningiomas refer to tumors with a carpet-like growth pattern along the dura that lead to dural thickening closely apposed to the inner surface of the overlying skull. This pattern is most common in the sphenoid wing and other cranial base locations. Owing to their location and growth pattern, manifestations often refer to the ophthalmic and cranial nerves. ^[44]  En plaque meningiomas should be distinguished from meningioangiomatosis, a task that is not always possible on magnetic resonance images (MRIs). Meninigioangiomatosis, however, is practically impossible to separate from the underlying brain parenchyma.

World Health Organization (WHO) histologic grading of meningiomas

The current (2016, revised 4th edition) WHO grading scheme for meningiomas ^[1] has largely adopted the criteria based on the clinicopathologic data from two large series ^{[48, 49]} ; the validity of these criteria has been subsequently confirmed by two other groups. ^{[50, 51]}

In contrast to many other tumors outside the central nervous system, one of the unique features in meningiomas is that invasion of bone, vascular structures, dura, dural sinus, and paranasal sinuses are not considered evidence of malignancy or aggressiveness. However, invasion of brain parenchyma is considered an indicator of aggressive behavior and is currently classified as WHO grade II.

In the WHO grading system, meningiomas fall into WHO grades I-III. WHO grade I tumors comprise about 80% of all meningiomas. In comparison to WHO grade I tumors, atypical (WHO grade II) meningiomas have histologic features that indicate aggressive behavior, which include an increase in mitotic activity, brain invasion on histology, and at least three of the following five atypical features: spontaneous necrosis, increased cellularity, small cell change, prominent nucleoli, and sheet-like growth. Atypical meningiomas comprise about 15%-20% of all meningiomas and carry a marked increase in local recurrence with reduced long-term survival. Cases with increased mitotic activity may not show impressive nuclear atypia. Careful search for mitotic activity and the mitotic count are important. An elevated mitotic count in atypical meningiomas is defined as four or more mitoses per 10 consecutive high-powered fields (HPFs) (0.16 mm²), ^[48] regardless of whether the increase is focal or diffuse.

Although most histologic patterns do not reflect the tumor’s biologic potential, tumors with clear cell and chordoid histology are considered WHO grade II. Tumors with papillary and rhabdoid features are considered WHO grade III. These components, however, must comprise over 50% of the tumor in order to make a diagnosis of WHO grade II or WHO grade III. In some cases, these features may be focal. There is a tendency for these aggressive components to become the dominant component in recurrent tumors.

Benign meningioma (WHO grade I)

WHO grade I meningiomas are defined by the following:

• Histologic variant other than clear cell, chordoid, papillary, and rhabdoid

• Lacks criteria of atypical and anaplastic meningioma

• No histologic evidence of brain invasion

Atypical meningioma (WHO grade II)

Fulfillment of the any of the following three criteria are sufficient for a diagnosis of WHO grade II meningiomas:

• Mitotic index of ≥4/10 HPFs^*

• At least three of the five following parameters: (1) sheeting architecture (loss of whorling and/or fascicles), (2) small cell formation (high nucleus-to-cytoplasmic [N/C] ratio), (3) macronucleoli, (4) hypercellularity, or (5) spontaneous necrosis (ie, not induced by embolization or radiation)

• Brain invasion^†

^* HPF is defined at 40× magnification of 0.16 mn² or 0.452 mm in field diameter (as adapted from the "Meningiomas" chapter in WHO Classification of Tumours of the Central Nervous System, 4th edition ^[1] ).

^† Brain invasion refers to breaching of the pial barrier but not mere extension or growth of tumor along the Virchow-Robin space. Fingerlike extension of the tumor into the parenchyma is the classic observation. In areas with confluent invasion, immunohistochemistry for glial fibrillary acidic protein (GFAP) may be needed to demonstrate entrapped gliotic parenchymal tissue. In the past, brain invasion was recognized as a definitive sign of malignancy for meningiomas. In the current WHO criteria, however, meningiomas that appear benign but with brain invasion are considered WHO grade II rather than WHO grade III.

Genuine extracranial metastasis or subarachnoid spread is exceptional and most likely originates from anaplastic meningiomas. So-called "benign metastasizing meningioma" represents a stable or slowly growing metastasis from a meningioma exhibiting a typical low-grade histology. In such cases, the metastases are not regarded as evidence of malignancy. They are most often found in the lung and should be distinguished from the equally rare primary pulmonary meningiomas. ^{[52, 53]}

Anaplastic (malignant) meningioma (WHO grade III)

Fulfillment of any of the following two criteria is used for WHO grade III meningiomas:

• Mitotic index ≥20/HPF^*

• Frank anaplasia (histology resembles that of high grade sarcoma, carcinoma, or melanoma)

^* HPF is defined at 40× magnification of 0.16 mn² or 0.452 mm in field diameter (as adapted from the "Meningiomas" chapter in WHO Classification of Tumours of the Central Nervous System, 4th edition ^[1] ).

Histopathology

Meningioma is perhaps the primary neuroepithelial tumor with the widest diversification in histologic pattern. Some of these patterns may suggest a diagnosis other than meningioma, particularly when the biopsy sample is small and during intraoperative consultation. For example, secretory meningiomas can mimic metastatic adenocarcinoma, and lymphoplasmacyte-rich meningiomas may mimic a lymphoproliferative disorder. Some of these patterns carry significant histologic predictive values, whereas the others do not.

It is not common for a meningioma to have a homogeneous histology in all parts of the tumor. This feature is particularly important in the diagnosis of meningiomas with these troublesome patterns and in anaplastic meningiomas, as small areas with typical features of meningioma may be present somewhere on the slides waiting to be discovered.

Components indicative of aggressive behavior, such as chordoid changes, may be focally present initially, but these components may become the dominant component on recurrent tumors and should be identified on the initial specimen. Identification of these focal patterns is important.

Histologic patterns recognized by WHO (as adapted from the "Meningiomas" chapter in WHO Classification of Tumours of the Central Nervous System, 4th edition ^[1] ). are reviewed in this section.

WHO grade I includes the following histologic patterns:

• Meningothelial (syncytial) meningioma

• Transitional (mixed) meningioma

• Fibroblastic (fibrous) meningioma

• Psammomatous meningioma

• Angiomatous (vascular) meningioma

• Microcystic meningioma

• Secretory meningioma

• Lymphoplasmacyte-rich meningioma

• Metaplastic meningioma

WHO grade II includes the following histologic patterns:

• Chordoid meningioma

• Clear cell meningioma (intracranial)

• Atypical meningioma (as per the criteria discussed above)

WHO grade III includes the following histologic patterns:

• Papillary meningioma

• Rhabdoid meningioma

• Anaplastic (malignant) meningioma (as per the criteria discussed above)

Highlights of different histopathologic pattern of meningiomas

The highlights of different patterns are summarized below. Other than atypical and anaplastic meningiomas, these patterns roughly fall into 2 major categories. In the first category, an additional histologic pattern such as a substantial amount of lymphoplasmacytic cells (lymphoplasmacyte-rich meningioma) or specific mesenchymal component (metaplastic meningioma) is present in addition to the classic meningioma component. In the second category, specific cytologic features of the tumor cells, such as clear cell changes (clear cell meningioma), chordoid changes (chordoid meningioma), or rhabdoid changes (rhabdoid meningioma), deviate from the classic histology. Some of these tumors (clear cell, chordoid, papillary, and rhabdoid) are associated with an unfavorable prognosis.

WHO grade I

Meningothelial (syncytial) meningioma histologic highlights are as follows:

• Epithelioid, round to polygonal, with a moderate amount of amphophilic to eosinophilic cytoplasm

• Cells arranged in lobules of cells or whorls

• Syncytial appearance due to fuzzy intercellular border

• Intranuclear clear vacuoles and intranuclear pseudoinclusions are common

Transitional (mixed) meningioma histologic highlights include the following:

• Intermediate features between fibroblastic type or a mixture of both meningothelial and fibroblastic components

• Meningothelial whorls are well developed

• Psammoma bodies are common

Fibroblastic (fibrous) meningioma histologic highlights include the following:

• Spindle cells with bland nuclei arranged in fascicles or storiform pattern

• Collagen fibers are present, and the amount can be substantial

• May be very fibrous

• Diagnostic features that help in the diagnosis include classic nuclear features, meningothelial whorls, and psammoma bodies. Immunohistochemistry and electron microscopy are also helpful. The differential diagnosis includes other low-grade fibrous tumors, such as solitary fibrous tumors.

Psammomatous meningiomas are particularly common in the spinal region of older women and in tumors that are being monitored for a long time before resection. Histologic highlights of these tumors are as follows:

• Numerous meningothelial whorls with psammoma bodies at their centers

• Psammoma bodies should comprise about half of the tumor for this diagnosis to be made. ^[3]  The presences of a few scattered psammoma bodies does not fulfill the diagnostic requirement of a psammomatous meningioma.

Angiomatous (vascular) meningiomas may have disproportionally large peritumoral edema relative to the size of the tumor. Histologic highlights include the following:

• The histologic picture is dominated by blood vessels with small- to medium-sized vascular channels; most of these vessels are small and with hyalinized walls (this hypervascular pattern would suggest a hemangioma)

• Two histologic patterns: Microvascular and macrovascular types ^[54]

• The angiomatous pattern occurs commonly in combination with microcystic meningiomas

• Degenerative nuclear atypia (ancient change) is common and can be striking, thus raising concern for primary or metastatic malignancy and aggressiveness, particularly on frozen sections; however, these tumors are benign

• The differential diagnosis includes vascular tumors, hemangioblastomas, and hemangiopericytomas.

Microcystic meningiomas may also have disproportionally large peritumoral edema relative to the size of the tumor. Histologic highlights are as follows:

• The extracellular microcysts contain pale, eosinophilic mucinous fluid (see the image below)

  Meningiomas Pathology. In this microcystic meningioima, the tumor cells have thin, spidery cytoplasmic processes and numerous microcysts containing mucoid material. A rich vascular network (arrow) is present.

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• The tumor cells have thin, spidery cytoplasmic processes, which may suggest glioma when only small tissues are available or during the interpretation of frozen section diagnosis

• Pleomorphic cells may be present and numerous, but they are not evidence for aggressive behavior

• The differential diagnosis includes hemangioblastomas, gliomas, and, less likely, low-grade metastatic carcinomas.

Secretory meningiomas may have a disproportionally large peritumoral edema relative to the size of the tumor. In addition, these tumors may be associated with elevated carcinoembryonic antigen (CEA) levels in blood. Resection of the tumor would lead to a return of the CEA level to normal. Histologic highlights include the following:

• Tumor cells with intracellular lumina containing eosinophilic (see the following image), periodic acid-Schiff (PAS)–positive secretions

  Meningiomas Pathology. In this secretory meningioma, bright intracellular secretions (black arrows) are present. Note that the size of these vacuoles are several times the size of the nuclei. Intranuclear pseudoinclusions are also present (white arrows).

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• Although these secretory vacuoles are intracellular, they can be several times the size of the nuclei

• These tumors have focal epithelial differentiation, particularly with cells containing the secretory vacuoles; these cells are positive for cytokeratin and CEA (see the image below)

  Meningiomas Pathology. Expression of carcinoembryonic antigen (CEA) is present in the secretory meningioma cells with secretory vacuoles (white arrow) shown. Note that many intranuclear clear vacuoles are present (black arrows).

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• There may be a high number of mast cells

• Secretory meningiomas harbor mutations in KLF4 K409Q and TRAF7 mutations in 93%-100% of cases. However, KLF4 and TRAF7 mutations are mutually exclusive with NF2 mutations. ^{[55, 56]}

• The differential diagnosis includes metastatic and mucin-secreting adenocarcinomas.

Lymphoplasmacyte-rich meningiomas may rarely have systemic findings, such as polyclonal gammopathy and anemia. ^[57] Histologic highlights are as follows:

• This is the least common histologic pattern for meningiomas

• There is extensive, chronic inflammatory cell infiltration, which obscures the meningothelial component; these inflammatory cells may represent a brisk inflammatory response to the tumor

• Plasma cells with Russell bodies may be present

• The differential diagnosis includes Rosai-Dorfman disease (extranodal sinus histiocytosis), Castleman disease, inflammatory pseudotumor, idiopathic hypertrophic pachymeningitis, and rheumatoid nodules; low-grade lymphomas; meningitis and meningeal inflammatory changes secondary to lesions in the skull or adjacent structures.

Metaplastic meningioma histologic highlights include the following:

• Metaplastic components, singly or in combination, including bone, cartilage, myxoid area, and xanthomatous and lipomatous components are present; bone and cartilage are far more commonly found than other components; some of these are reactive changes or mere accumulation of lipids but not genuine metaplasia

• When an osseous component is present, it should be distinguished from bone invasion

• The metaplastic components can be focal or widespread, but classic meningothelial components are often found, and the diagnosis is usually not a serious challenge

• In extreme cases with widespread metaplastic changes, the concern of a primary or metastatic mesenchymal tumor may be raised as part of the differential diagnosis.

WHO grade II

The amount of chordoid component should exceed 50% when a diagnosis of chordoid meningioma is made. Chordoid meningioma's association with the systemic findings of Castleman syndrome, including polyclonal gammopathy and microcystic anemia, has been reported in children. ^{[58, 59]} These are usually large, dural-based, supratentorial tumors with a very high rate of recurrence following subtotal resection. ^{[59, 60]} Histologic highlights are as follows:

• The overall morphology mimics chordoma, featured by epithelioid cells with bubbly cytoplasm (see the first image below) and an Alcian blue–positive myxoid stroma (see the second image below)

  Meningiomas Pathology. In this chordoid meningioma, the background substance resembles those in chordoma, and the meningioma cells have fine bubbly cytoplasm (arrow). The nucleoli shown are also slightly prominent.

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• This tumor is associated with lymphoplasmacytic infiltration that ranges in intensity from patchy to prominent

• The proportion of chordoid component may increase in proportion in subsequent recurrences

• Pure chordoid meningiomas are rare, and most of them are mixed with a variable amount of meningothelial component

• The differential diagnosis includes chordoma and chordoid glioma of the third ventricle. With chordomas, the location is helpful. Chordoid meningiomas are dural-based tumors that occur in a location where chordomas would not be expected. In addition, chordomas are positive for brachyury and diffusely positive for cytokeratin. ^{[61, 62]} Although meningiomas can be focally positive for cytokeratin in some cases, they are never diffusely and strongly positive for cytokeratin. Chordoid gliomas of the third ventricle are positive for glial fibrillary acidic protein (GFAP); knowing the location is also helpful.

Clear cell meningiomas have a predilection for the spinal cord and posterior fossa. Affected patients have a younger age of onset and an aggressive clinical course despite the typically bland histology. ^[63] Histologic highlights include the following:

• Glycogen-rich cytoplasmic clearing but not extracellular secretory vacuoles best demonstrated by PAS with and without diastase digestion; this is an important feature that distinguishes these tumors from microcystic meningioma.

• The tumor is unique in being a pure clear cell tumor with subtle features of classic meningiomas in most cases.

• Dense stromal and perivascular blocky collagen depositions are present.

• SMARCE1 mutations have been identified in clear cell meningiomas. ^{[64, 65]}

• The differential diagnosis includes metastatic clear cell carcinoma, particularly renal cell carcinoma (clear cell meningiomas are negative for cytokeratin), and microcystic meningiomas.

The histologic highlights of atypical meningiomas are as follows:

• When the tumor does not meet the diagnostic criteria of clear cell or chordoid meningioma, the histologic features should meet the criteria listed in WHO Histologic Grading of Meningiomas for the diagnosis of atypical meningioma, as listed above

• Features of atypical changes can occur in any of the variants

• Whole slide imaging appears to have a higher inter- and intraobserver concordance for atypical meningioma relative to use of glass slides, with similar predictive accuracy for recurrence. ^[66]

WHO grade III

Papillary meningiomas are uncommon. The posterior fossa is a common site of predilection. These tumors have an increased frequency in young individuals and children, ^[67] and an aggressive clinical behavior and metastases to the lung is not uncommon. ^{[68, 69]} The amount of papillary component should exceed 50% of the tumor when the diagnosis of papillary meningioma is made. Histologic highlights include the following:

• A perivascular arrangement of tumor cells is the dominant feature

• The papillary or pseudopapillary growth pattern may dominate the histologic picture and results from dyscohesion of the tumor cells

• These tumors often arise from more conventional meningiomas; the proportion of the papillary component may increase in subsequent recurrences

• The differential diagnosis includes ependymomas, astroblastomas, pituitary adenomas, hemangiopericytomas, and medulloblastoma/primitive neuroectodermal tumors.

Rhabdoid meningiomas are similar to many other rhabdoid tumors of adulthood in that this tumor is regarded as a pattern reflecting the malignant transformation of a meningioma. The demographics are similar to conventional meningiomas. The rhabdoid component may occur during recurrence. The amount of rhabdoid component should exceed 50% of the tumor when the diagnosis of papillary meningioma is made. Histologic highlights are as follows:

• The rhabdoid features can be very well recognized on cytologic preparations (see the following image)

  Meningiomas Pathology. The rhabdoid feature of this tumor is well demonstrated in this cytologic preparation. Note the eccentrically located nuclei and the large oval, amphophilic cytoplasm. In this particular case, the nuclear feature is rather bland for a rhabdoid tumor. The nuclei of rhabdoid tumors can be rather bizarre, featuring enlarged, lobulated nuclei with huge, eosinophilic nucleoli.

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• Similar to other rhabdoid tumors, the rhabdoid cells have a discohesive growth pattern and an intracytoplasmic globular, eosinophilic inclusion that displaces the nuclei to the periphery; the nuclei have vesicular nucleoli and prominent nucleoli

• Rhabdoid changes may be superimposed on a papillary meningioma background

• Areas with conventional meningiomas are often present

• The differential diagnosis includes other primary or metastatic rhabdoid tumors, as well as atypical rhabdoid teratoid tumors (ATRTs). Unlike ATRT, SMARCB1 expression is retained in rhabdoid meningioma. Rhabdoid meningiomas are rare in infants and children. ATRTs have a more diversified phenotypic immunohistochemical profile, including loss of expression of the HSNF5/SMARCB1/INI1 protein secondary to heterozygous or homozygous deletion of the INI1 gene. ^[70]

The histologic highlights of anaplastic meningioma include the following:

• There are frank anaplastic changes, and the tumor may mimic metastatic carcinoma, melanoma, and sarcoma

• Mitotic activity is ≥20 mitoses per HPF

Intraoperative cytologic preparations demonstrate helpful diagnostic features. Most meningiomas can be smeared out if an appropriate and sufficient pressure is applied. For meningothelial and transitional meningiomas, the smears are usually composed of large clusters of epithelioid cells mixed with smaller clusters or individual cells in between the large clusters. The degree of rubbery consistency depends heavily on the content of collagen. Fibroblastic meningiomas are a lot more difficult to generate a homogeneous smear than meningothelial or transitional meningiomas. Fibroblastic meningiomas usually yield cluster of spindle cells that tightly adhere to each other, but scattered single cells with epithelioid features are often present.

The scattered single cells typically give clues for the diagnosis of meningiomas. The nuclei are usually oval or slightly elongated and contain open chromatin (see the image below).

For the grade I tumors, a prominent nucleoli should not be seen. A concern for grade II or III tumors, as well as nonmeningeal tumors such as metastatic carcinoma or melanoma, should be raised if prominent nucleoli are noted. Intranuclear pseudoinclusions (invagination of cytoplasm into the nucleus) and intranuclear clear vacuoles vary from scant to abundant. These nuclear features are typical but not unique to meningiomas.

The scattered single cells are usually epithelioid in appearance and in the shape of an elongated triangle with moderate amount of cytoplasm. To the eyes of the authors, these cells look like a veil being blown in the wind. Identification of definitive meningothelial whorl formation (see the first image below) is a clear help. Psammoma bodies are round, concentrically laminated, calcifications (see the second image below) that are commonly seen. Many of the psammoma bodies have a thin rim of meningothelial cells, as illustrated here.

Secretory meningiomas

Secretory meningiomas are featured by large, secretory vacuoles (see the first image below), and rhabdoid meningiomas are featured by rhabdoid cells (see the second image below). These cytologic features are well demonstrated in the cytologic preparations. One of the major features to distinguish secretory meningioma from metastatic adenocarcinoma is that the secretory vacuoles are typically extracellular and are several times or even tens of times of the size of the nuclei. In contrast, cytoplasmic vacules that are often seen in the smears of metastatic adenocarcinoma are rarely larger than the nuclei, with the exception of signet ring cells. However, the bluish mucin content in signet ring cells would not be present in the secretory vacuoles of meningiomas where eosinophilic homogeneous content is usually seen.

Meningothelial cells have features of epithelial and mesenchymal cells, and this mixed feature is well reflected in the histopathology of meningothelial (syncytial), transitional (mixed), and fibroblastic (fibrous) meningiomas. The meningothelial (syncytial) meningioma is perhaps the prototype of meningiomas and the most commonly encountered histologic pattern. In meningiomas with other uncommon histologic patterns, classic meningothelial areas may be focally present, and identification of these areas helps to confirm the diagnosis.

Meningothelial meningiomas

Meningothelial meningiomas are composed of lobules of meningothelial cells, sometimes separated by thin fibrous septa. Meningothelial meningiomas contain tumor cells that have partial phenotypic features of epithelial cells. Sporadic psammoma bodies can be seen (see the first image below), but psammoma bodies should not dominant the field. Meningothelial whorls are present but typically not as well formed as in transitional meningiomas. The intercellular border is typically fuzzy and poorly defined (see the second image below). This feature reflects the interdigitating cytoplasmic border seen at the ultrastructural level. In fact, a well-defined cytoplasmic border in an otherwise typical meningioma raises the suspicion for a more aggressive behavior.

The nuclei are oval to elongated and typically without prominent nucleoli in low-grade cases. Clear intranuclear vacuoles as well as pseudonuclear inclusions are characteristic but not diagnostic nuclear features. Its abundance is rather variable (see the following image).

Fibroblastic meningiomas

At the other end of the spectrum, fibroblastic meningiomas are composed of fascicles of spindle cells mixed with a variable amount of collagen fibers. The tumor cells have partial features of mesenchymal cells. The overall features resemble a benign spindle cell mesenchymal neoplasm (see the image below). Some of these tumors can be densely fibrotic. The nuclear features are helpful hints for the diagnosis, because the cell morphology is not particularly helpful. Pure fibroblastic meningiomas are rather uncommon, and areas with transitional and/or meningothelial components are often present and would help in confirming the diagnosis. When a pure fibroblastic meningioma is encountered, the possibility of a mesenchymal tumor must be entertained.

Transitional meningiomas

Transitional meningiomas are the intermediate version and are composed of areas with intermediate features between meningothelial and fibroblastic components (see the first image below) as well as intermingled areas with distinct meningothelial and fibroblastic features. Meningothelial whorls are often well formed (see the second image below).

Atypical meningiomas

Atypical meningiomas often do not possess impressive atypical nuclear changes. Increased mitotic activity can be seen independent of a significant increase in nuclear atypia (see the first image below). In some atypical meningiomas with a high level of atypia, identification of intranuclear clear vacuoles and pseudoinclusions (see the second image below) can help to confirm the diagnosis. Brain invasion can also be found independent of high-grade atypia (see the third image below). Other features indicative of aggressive biologic potential for atypical meningiomas include loss of whorling and/or fascicles, the so-called sheeting of cells, small cell component, macronucleoli, hypercellularity, and spontaneous necrosis (see WHO Histologic Grading of Meningiomas, 4th edition ^[1] ).

Anaplastic meningiomas

Anaplastic meningiomas have high-grade anaplasia and high-mitotic activity (see WHO Histologic Grading of Meningiomas). These tumors may arise as de novo tumors or result from malignant progression of previously existing meningiomas. Because meningothelial cells have features of both epithelial and mesenchymal cells, it is not surprising to find that their high-grade tumors would span the histologic spectrum, resembling carcinoma at one end to sarcoma at the other. On first look, these tumors may not really suggest meningiomas but raise a consideration of a possible carcinoma, melanoma, or sarcoma. On closer scrutiny, histologic features of meningiomas may be found in some focal areas. Immunohistochemistry, electron microscopy, and genetic studies may be needed to confirm the diagnosis.

Proliferative index

Proliferative markers determined by immunostaining for Ki-67 (MIB-1) or anti-phosphohistone-H3 (PHH3), as well as apoptotic index, have been shown to be correlated with the biologic behavior in meningiomas. In general, there is a high correlation between a high Ki-67 labeling index and histologic grade, but, owing to the differences in techniques used in different laboratories, the cut-off value for meningiomas, atypical meningiomas, and anaplastic meningiomas is not always reproducible, and the sensitivity of Ki-67 may vary among different laboratories. ^{[49, 71, 72, 73, 74]} Increased apoptotic index has also been correlated with increased biologic aggressiveness in meningiomas. ^[73]

An antibody against phosphorylated histone 3 (PHH3) has been used to detect mitotic rates, which has led to some success in distinguishing WHO grade I and grade II meningiomas. ^{[75, 76, 77]}

Immunohistochemistry and electron microscopy

In most current practices, epithelial membrane antigen (EMA) is the most commonly used immunohistochemical stain for meningiomas, in which about 50%-100% of the cases are positive. ^{[43, 62, 78, 79, 80]} Immunohistochemical staining for progesterone receptor (PR) is also helpful. ^[81] However, sensitivity and specificity of EMA and PR are not optimal. The staining pattern of EMA can be weak and patchy rather than a diffuse positivity (see the following image). Somatostatin receptor 2a (SSTR2a) has been described as a more sensitive diagnostic marker of meningioma, includng diagnosing high-grade meningiomas with poor differentiation. ^[82]  Vimentin is typically diffusely and strongly positive in meningiomas.

Meningiomas, with the exception of secretory meningiomas, are usually negative for cytokeratins. Focally positive immunoreactivity for S100 can also be seen. ^[80] Other markers with certain success, but not of wide clinical application, include prostaglandin D synthase, ^[83] E-cadherin, ^[84] claudin-1, ^[85] desmosomal plaque components such as desmoplakin, ^[86] and connexins. ^[87]

Meningiomas are often positive for androgen and estrogen receptors. ^[81] Expression is equally common in males and females, and there is no difference among different histologic subtypes. There is a significant correlation between negative or low expression of progesterone-receptor status and high tumor vascularity with high Ki-67 labeling index. ^{[71, 88]}

The ultrastructural features for meningiomas are highly diagnostic. Regardless of the histologic variants or patterns, the tumor cells have interdigitating cytoplasmic membrane. Intercellular junctions are present (see the image below). ^[89]

 

Monosomy 22 is a unique cytogenetic alteration. ^[90] Mutation and/or deletion of the NF2 gene on chromosome 22q12 is present in most NF2-associated meningiomas and about 50%-80% of sporadic meningiomas. The NF2 gene codes for merlin (schwannomin), and its normal function is poorly understood. This gene is critical in constituting the early tumorigenic event in the 2-hit model of tumor-suppressor inactivation proposed by Knudson. ^[91]

In general, solitary meningiomas are clonal tumors as per X-chromosome inactivation studies. ^[92] In one study, most meningiomas shared the same single mutation, and recurrent tumors had the same clonality as the primary tumor. ^[93] In multiple meningiomas, it has been shown that most of these tumors share the same NF2 gene mutation ^[94] and inactivation of the same copy of X-chromosome. ^[95] Dural spread and peritumoral implants may well be the mechanism in cases with multiple meningiomas. ^[96]

Mutations in TRAF7, KLF4, AKT1 and SMO have been described in meningiomas ^[56] ; mutations in these genes are mutually exclusive of NF2 mutations.

Genetic events in the tumorigenesis and malignant progression of meningiomas

Various genetic alterations have been identified in the malignant progression of meningiomas and are summarized below (as adapted from the "Meningiomas" chapter in WHO Classification of Tumours of the Central Nervous System, 4th edition ^[1] ).

Benign meningioma (WHO grade I)

• -22q (4%-70%)

• NF2 mutation (30%-60%)

• Loss of 4.1B expression (20%-50%)

• Loss of TSLC1 expression (30%-50%)

• PR (50%-90%)

• EGFR, PDGFRB activation

• Combined KLF4 K409Q and TRAF7 mutations in secretory meningioma

Atypical meningioma (WHO grade II)

• -1p (40%-75%)

• -6q (30%)

• -10 (30%-40%)

• -14q (40%-60%)

• -18q (40%)

• +1q, 9q, 12q, 15q, 17q, 20q (30%-50% each)

• Loss of TSLC1 expression (70%)

• Loss of PR expression (60%-80%)

• Telomerase/hTERT activation (60%-90%)

• Notch, WNT, IGF, VEGF activation

• SMARCE1 mutation in clear cell meningioma

Anaplastic meningioma (WHO grade III)

• -1p (100%)

• -6q (50%)

• -9p21 (60-80%)

• -10 (40-70%)

• -14q (60-100%)

• -18q (60-70%)

• NDRG2 hypermethylation (70%)

• Loss of TSLC1 expression (70%)

• Loss of PR receptor (80-90%)

• 17q23 amplification (40%)

The diagnosis of classic, WHO grade I meningothelial, transitional, and fibroblastic meningiomas is usually straightforward. The higher-grade variants and meningiomas of the unusual patterns often pose a diagnostic challenge. Some of the more commonly encountered entities are discussed below.

Meningothelial hyperplasia

Meningothelial hyperplasia refers to meningothelial proliferation over 10 cells thick and associated with an inciting event ^{[97, 98]} and is believed to be caused by reactive changes of meningothelial cells. Such hyperplasia is often prominent in optic nerve gliomas (see the following images). In small biopsy specimens obtained during intraoperative consultation, these clusters may suggest meningiomas.

Meningioangiomatosis

Meningioangiomatosis raises a strong suggestion of NF2, but sporadic cases can present. The initial presentation is usually seizures in a child or young adult. On imaging studies, these lesions may simulate an en plaque meningioma. Classically, this is a plaquelike leptomeningeal thickening that is firmly adhered to the cortex and is believed to be hamartomatous in nature.

Histologically, there is perivascular growth of spindle cells that often demonstrate features of meningothelial cells, including expression of EMA, psammoma bodies, and classic nuclear features of meningothelial cells. Coexisting meningiomas, with some of them presumably arising from the meningioangiomatosis, have been well described.

Schwannomalike cases may also present (meningoangio-neurilemmomatosis). In contrast to benign meningiomas that have a clear cleavage plane, the interface of meningioangiomatosis closely intermingles with the underlying cortex in which impressive gliosis is present. Entrapped neurons are often present.

With all of these features, the diagnosis is often an enigma, particularly when the specimen is small. Meningioangiomatosis may be misinterpreted as a meningioma if meningothelial cells are prominent; as a glioma because of the overall hypercellularity and reactive gliosis; or a ganglion cell neoplasm, due to entrapment of preexisting neurons. A correct diagnosis depends largely on the recognition of the entity as an intracortical perivascular proliferation of meningothelial cells and fibroblasts. ^{[99, 100]} Correlation of clinical and imaging features are important.

Dural-based metastatic clear cell tumors

Dural-based metastatic clear cell tumors with low-grade morphology such as metastatic renal cell carcinoma and prostatic carcinoma may closely mimic clear cell meningioma. Diffuse cytokeratin positivity is present in these tumors, and this contrasts with a mostly negative pattern in classic meningiomas. Specific markers such as CD10 and Pax8 for renal cell carcinoma, as well as NKX3.1, prostatic acidic protein (PSA), prostate-specific antigen (PSA) for prostatic carcinoma, are helpful for confirming the diagnosis of metastatic renal cell carcinoma and prostatic carcinoma, respectively. Neurocytoma may also mimic clear cell meningioma. Neurocytomas occur most commonly within the ventricle and are strongly positive for synaptophysin.

Hemangioblastomas

Hemangioblastomas may mimic microcystic and clear cell meningiomas. Primary dural-based hemangioblastoma is rare, and these tumors are positive for inhibin and D2-40. Renal cell carcinoma is also one of the few carcinomas that are positive both for vimentin and cytokeratin.

Solitary fibrous tumors/hemangiopericytoma

Solitary fibrous tumors/hemangiopericytomas may closely mimic the fibroblastic type of meningiomas. In the past, some of these tumors were termed "sclerotic meningiomas." Solitary fibrous tumors/hemangiopericytomas are rare, slow-growing, spindle cell tumors that affect adults. They are usually dural-based and located in the supratentorial region. A small percentage (about 10%) are located in the spinal region.

Histologically, the degree of cellularity and the amount of collagen vary in different areas of the tumor. The tumor cells show fibroblastic cytomorphology with bland or low-grade, elongated nuclei, and they often insinuate among collagen fibers. These features would suggest a fibroblastic (fibrous) meningioma.

In the latest WHO classification, grading of solitary fibrous tumors/hemangiopericytomas in the central nervous system (CNS) is also different from those occurring outside the CNS. ^[1] In the CNS, a three-tier grading system is used. Grade I solitary fibrous tumor/hemangiopericytoma is considered benign and is treated by surgery alone. Grade I tumors are more hypocellular, with larger amounts of collagen in the background, and they are considered the classic solitary fibrous tumor phenotype. Grade II and II tumors are densely cellular, corresponding to the hemangiopericytoma phenotype; these patients benefit from adjuvant radiotherapy. The distinction between grade II and II is based on the mitotic count (< 5 or >5 mitoses per 10 high-power fields).

Immunohistochemically, solitary fibrous tumors/hemangiopericytomas show diffuse nuclear staining for STAT6 due to presence of NAB2-STAT6 fusion in these tumors. These tumors are also positive for CD34 and Bcl-2 and negative for epithelia membrane antigen (EMA) (see the following images). Faint positive CD34 immunoreactivity may be seen in meningiomas. Fluorescent in situ hybridization (FISH) for the NAB2-STAT6 translocation is also very helpful.

 

Schwannomas

Schwannomas are common in the cerebellopontine angle and in the spinal nerve roots. On rare occasions, meningiomas may have a focal palisading arrangement that would suggest meningioma in these locations. Although uncommon, whorls can be seen in schwannomas.

Meningiomas, particularly those other than fibrous meningioma, typically smear out well: Usually large clusters with small, well-smeared clusters are often admixed with single cells among the large clusters. In contrast, schwannomas typically smear out poorly as large, cohesive, spindle cell clusters with very few or no small, well-smeared clusters or single tumor cells in between the large clusters.

Schwannomas do not routinely contain collagen, and these tumors are strongly positive for S100 and Sox10; reticulin staining may demonstrate deposition of reticulin fibers around individual tumor cells. In contrast, meningiomas are not strongly and diffusely positive for S100 but focal positivity can be seen, and reticulin staining would delineate nests and islands of cells rather than pericellular reticulin fibers.

Gliomas

Although high-grade meningiomas may invade the brain and mimic a glioma, high-grade gliomas may also invade the leptomeninges and mimic meningiomas. Immunohistochemistry would demonstrate positivity for glial fibrillary acidic protein (GFAP) and S100 protein in the glioma component.

Mucin-containing adenocarcinomas

Although anaplastic meningioma may mimic metastatic carcinomas, secretory meningiomas often suggest mucin-containing adenocarcinomas at intraoperative consultation. The exuberant edema associated with secretory meningiomas often suggests metastatic neoplasm on imaging studies. The large vacuoles would fuel this suspicion. Cytologically and histologically, the secretory vacuoles of secretory meningiomas are huge and are several times the size of the nuclei or even the cell (see the first two images below). In contrast, mucin-secreting adenocarcinomas rarely have their vacuoles 2-3 times the size of the nuclei (see the third image below). In addition, they contain bluish mucoid substance rather than the bright eosinophilic substance that are seen in secretory meningiomas.