13 
Meningiomas
Introduction and Proposed Etiologies  259
Definition and Analogies With Meningothelial Cells  259
Brief Historical Overview of Nomenclature and Histogenetic
Notions 260
Incidence and Demographics  260
Localization and Clinical Manifestations  260
Radiologic Features and Gross Pathology  263
Histopathology 266
Histologic Variants and Grading  267
Differential Diagnosis  289
Ancillary Diagnostic Studies  292
Genetics 294
Treatment and Prognosis  296
Introduction and Proposed Etiologies
Meningiomas are among the most common of central nervous system
(CNS) neoplasms and are by far the most common of the extra-axial
tumors. Our understanding of meningioma classification, grading, and
molecular genetics has evolved greatly over time and continues to be
refined.1 Both environmental and genetic factors have been implicated
in meningioma formation, although most examples are idiopathic.
Meningioma genetics is covered later in this chapter, whereas the
meningioma-associated syndrome NF2 is discussed further in Chapter
22. Proposed environmental factors include irradiation (discussed later),
hormone exposures (discussed later), and head trauma, although only
the first of these has been unequivocally established. The latter is
occasionally the basis for medicolegal cases, though it is hardly a proven
cause. In Cushing and Eisenhardt’s 1938 monograph, a surprising 32%
of intracranial meningiomas had a prior history of head injury,2 and a
modern epidemiologic study estimated a 4.33 odds ratio for developing
meningiomas 10 to 19 years after head trauma.3 Rare case reports feature
Arie Perry, MD
meningiomas arising at sites of prior skull fracture, cranioplasty, or
lodged foreign material, such as shrapnel, implicating wound healing
and arachnoidal proliferation as a possible mechanism.4 However, most
epidemiologic studies have not found a significant correlation.5,6 Similarly,
evidence to date argues against the common notion that cell phones
cause meningiomas and other brain tumors, although admittedly this
is a relatively new technology and more follow-up may still be needed.7,8
In contrast, meningiomas caused by irradiation are well documented,
and this is an irrefutable risk factor. As with other radiation-associated
neoplasms (see Chapter 21), these tumors must arise in the prior radiation
field, develop after long latency (typically years), differ histologically
from the originally irradiated disease process, and arise more frequently
in irradiated than in control patients. Radiation-induced meningiomas
are sometimes divided into low-dose (<10 Gy), medium-dose and
miscellaneous (10 to 20 Gy), and high-dose (>20 Gy) categories. The
low-dose group has been most extensively studied, mostly in children
receiving scalp irradiation for tinea capitis in Israel during the 1960s,1
although recent studies have similarly implicated prior exposures to
computed tomography (CT) imaging and dental x-rays (mostly the
older and somewhat higher dose Panorex films in young children).9–11
The miscellaneous group includes direct application of radium, thorotrast
ventriculography, and myelography, whereas high-dose examples mostly
follow therapeutic irradiation for cancer. Radiation-induced meningiomas
typically afflict younger patients, with median onset being 45, 32, and
34 years for the high-, medium-, and low-dose groups, respectively.
The average latencies are 35, 26, and 19.5 years, respectively. Children
appear to be particularly sensitive (“window of vulnerability”), with
the latency often being shorter than in adults. Providing further evidence,
atomic bomb survivors are also at increased risk of developing menin-
giomas, the distance from the epicenter of the explosion being inversely
associated with overall risk.
Lastly, it is of interest that allergic diseases, such as asthma and
eczema, have been confirmed in epidemiologic studies as protective
(i.e., lower risk) for subsequent meningioma development.12
Definition and Analogies With
Meningothelial Cells
Meningiomas are a clinicopathologically diverse group of neoplasms
with morphologic, immunohistochemical, and ultrastructural features
259
 Meningiomas

Abstract
Accounting for over a third of all primary CNS neoplasms, meningiomas
are amongst the most common diagnoses encountered in neurosurgical
practice. Like their non-neoplastic counterparts, meningiomas show
some overlapping features with both epithelial and mesenchymal cell
types. As such, many histologic variants are recognized, some of which
commonly engender diagnostic confusion due to their mimicry of other
tumor types. It has long been appreciated that the two most important
prognostic variables are extent of surgical resection and tumor grade.
While most are histologically and clinically benign, 20%–30% show
aggressive features. Current grading criteria within the 2016 WHO
13
scheme largely derive from the findings in two large Mayo Clinic series,
which have been subsequently validated. Nevertheless, predicting clinical
behavior in individual patients can still be challenging. As such, this
revised chapter incorporates (and illustrates) recent immunohistochemical
and molecular advances that enhance our diagnostic accuracy and our
understanding of meningioma tumorigenesis and malignant progression,
including some of the rarer variants.

Keywords
meningioma
classification
grading
immunohistochemistry
molecular genetics

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 Practical Surgical Neuropathology
resembling normal meningothelial cells. More specifically, the majority
resemble the arachnoidal cap cell, although rare variants such as the
microcystic meningioma resemble other cell types (arachnoidal trabecular
cell). Like their normal meningothelial counterparts, meningiomas can
display a wide range of epithelial- and mesenchymal-like properties.
Mesenchymal features include a prominent spindled morphology in the
fibroblastic and sarcoma-like meningiomas, an ability to produce collagen
and other extracellular matrix proteins, and the finding of mesenchymal
“metaplasia” in a subset of otherwise classic meningiomas (discussed
further under Histologic Variants and Grading). Epithelial features include
epithelioid morphology in meningothelial (and other variant) menin-
giomas, the presence of desmosomes and other intercellular junctions,
epithelial membrane antigen (EMA) positivity, the capacity for papillary
growth, the formation of gland-like lumens in the secretory variant,
and occasional carcinoma-like histology in anaplastic meningiomas.
As an appropriate candidate cell of origin, arachnoidal cap cells are
essentially found in the same locations as meningiomas (see Chapter
2). These include
• the external layer of the leptomeninges and arachnoid granulations
attaching loosely to the inner surface of the dura (e.g., dural-based
and, less often, leptomeningeal-based meningiomas);
• extensions along perivascular Virchow-Robin spaces into the
underlying brain (rare intracerebral meningiomas);
• the tela choroidea (meningeal invagination) at the stromal base
of the choroid plexus (intraventricular meningiomas); and
• rare meningothelial rests/heterotopias, traumatic displacements,
metaplasias/aberrant differentiation, and perineural extensions
(calvarial/intraosseous, scalp, sinonasal, pulmonary, and other
extradural meningiomas).
The light- and electron-microscopic similarities include frequent
intranuclear inclusions, interdigitating cell membranes, intercellular
junctions, and cytoplasmic filaments. Arachnoidal cap cells are unique
cell types that are also functionally similar to meningiomas. Their known
functions include:
• ensheathing or wrapping around each other, the surface of
the CNS, and proximal portions of nerve roots, forming part
of the CNS–cerebrospinal fluid (CSF) and blood-CSF barriers
(recapitulated in the whorls of meningiomas);
• helping to maintain CSF homeostasis, both in terms of protein
secretion (recapitulated in the pseudopsammoma bodies of secre-
tory meningiomas) and the regulation of intracranial pressure;
• providing trophic support for migrating neuroglial cells during
development; and
• taking on macrophage-like functions rarely, including some limited
capacity for phagocytosis and rheumatoid nodule formation;
the most macrophage-like meningioma is the metaplastic-
xanthomatous subtype.
Brief Historical Overview of Nomenclature and
Histogenetic Notions
The wide-ranging biologic and histologic continuum of meningiomas
has fascinated physicians since the beginning of the 20th century. One
of the greatest single advances in our understanding of these tumors
came in 1938 when Drs. Harvey Cushing and Louise Eisenhardt published
their detailed monograph on 313 meningiomas accumulated over nearly
30 years.2 Over the next few decades, variants became better characterized
and new techniques such as karyotyping, electron microscopy, and
immunohistochemistry were subsequently applied. In 1982, a second
major monograph by John Kepes summarized the many advances of
that time, along with personal observations obtained from a review of
approximately 1300 cases.13 Since then, a few more aggressive variants
have been described or clarified, hemangiopericytomas (now termed
260
solitary fibrous tumor/hemangiopericytoma) have been removed as a
biologically distinct tumor type (see Chapter 14), grading criteria have
been extensively revised, our understanding of the molecular pathology
has greatly increased, and therapeutic modalities have evolved. The
classification scheme utilized by most pathologists today is the World
Health Organization (WHO) 2016 edition.1
As with other neoplasms, the issue of meningioma histogenesis has
long been debated.13 The earliest terms attempted to lump these tumors
in with better known extracranial categories, resulting in clumsy and
inaccurate diagnoses, such as fungus of the dura mater, sarcoma, car-
cinoma, mesothelioma, endothelioma, meningoexothelioma, and
arachnoidal/meningeal fibroblastoma. In 1922, recognizing that these
tumors were distinct from systemic tumor types, Cushing proposed
the term meningioma, a clinically practical alternative based primarily
on anatomy, rather than unsubstantiated histogenetic notions. Various
hypotheses on the cell of origin were posited nonetheless, including
dural, endothelial, fibroblastic, and epithelial cell types. In 1831, Dr.
Richard Bright raised the possibility that they might originate from the
inner arachnoidal lining of the dura, rather than the dense fibrous tissue
of the dura proper. Similarly, Cleland and, later on, Schmidt emphasized
the similar histology of most meningiomas with the cell clusters that
line arachnoid villi. Since then, these arachnoidal cap cells have been
considered the most likely, though still unproven, cell of origin for
meningiomas.
Incidence and Demographics
Meningioma accounts for about 36% of over 356,000 primary brain
tumors reported to the Central Brain Tumor Registry of the United
States in the 2008 to 2012 census; it is the single most common tumor
subtype overall and also accounts for over half of all nonmalignant
CNS tumors.14 The incidence is roughly 7.86 per 100,000 person-years
(4.68 in males and 10.62 in females), with a mean diagnostic age of 65
years. Meningioma incidence figures have progressively risen over time,
possibly reflecting ever-increasing radiologic detection of incidental
tumors. In fact, incidental meningiomas are quite common, especially
in the elderly where they are reported in up to 2.3% of autopsies.15 The
prevalence of meningioma is much higher in families with NF2 and
rarely in those with Gorlin, Cowden, Li-Fraumeni, Turcot, or von
Hippel-Lindau syndromes as well (see Chapter 22). It also occasionally
runs in families without any well-established tumor predisposition
syndromes.
Meningiomas are most common in middle-age to elderly adults and
vary in incidence with race in the United States, affecting Blacks, Whites,
and Asians/Pacific Islanders in decreasing order, respectively.14 However,
they are considerably more common in women than men, with a roughly
2 to 1 female–male ratio. This sex predilection is even higher in thoracic
spinal meningiomas, where the ratio is nearly 9 to 1.13 Pediatric menin-
giomas are distinctly rare, but are more likely than adult counterparts
to present with large tumor size, cyst formation, lack of dural attachment,
high-grade histology, aggressive behavior, and/or aggressive variant
histology, particularly the clear cell or papillary subtypes.16–18 They lack
any female predominance and are more likely to present in unusual
locations, such as lateral ventricles, posterior fossa, and spinal epidural
regions. Predisposing factors often include NF2 or a history of prior
radiation, although over half are still sporadic. In comparison to adult
cases, the clinical behavior is more difficult to predict.
Localization and Clinical Manifestations
Localization
Meningiomas occur all along the craniospinal axis (Fig. 13.1). Intracrani-
ally, they are most common over the convexity and parasagittal regions,
with approximately half extending to the superior sagittal sinus and
 Meningiomas

Olfactory groove

Tuberculum 13
sellae

Lateral Cavernous
sphenoid sinus
Medial
wing
sphenoid
wing

A Foramen magnum B Petroclival

Parasagittal
Falcine

Convexity

C D
Fig. 13.1  Common locations for meningiomas. Common sites of tumor growth in relationship to adjacent skull, brain, and dural reflections (A–D). Illustrations created by MedPIC
at Washington University School of Medicine with additional input from Dr. Michael Chicoine, Department of Neurosurgery.

half affecting more lateral areas (Fig. 13.2A). Falcine meningiomas attach
to the dense fibrous tissue of the falx rather than the sinus per se, while
parasagittal meningiomas are located slightly more laterally (Fig. 13.1C
and D). “Skull base meningiomas” are often technically challenging to
resect and variably involve olfactory groove, parasellar region, lateral
or medial sphenoid wing (Fig. 13.2B), foramen magnum, cavernous
sinus, or tuberculum sella (Fig. 13.1A and B). Orbital (optic pathway)
meningiomas or those that involve the anterior visual pathway in general
are often highly invasive and frequently recur, despite a benign histologic
appearance. Recent studies suggest some heterogeneity in this location,
with those involving the spheno-orbital region being most clinically
aggressive, especially those with 1p and 6q chromosomal losses.19,20
Nevertheless, advances in radiation therapy have generally improved
local control for these tumors.21 In the posterior fossa, they arise in
regions such as the petrous bone, tentorium cerebelli, and foramen
magnum. Tentorial meningiomas may be supratentorial, infratentorial,
or both.
Spinal meningiomas occur mostly in the thoracic region (Fig. 13.2C),
although males are less likely to show this regional predilection. Cervical
and thoracic examples mostly present anterior and posterior to the
cord, respectively. Most cover multiple segments and present as intradural
extramedullary tumors similar to schwannomas. Less commonly, however,
they present as leptomeningeal or epidural masses.
Intraventricular meningiomas are relatively rare (0.5% to 3%) and
most likely originate from the tela choroidea of the choroid plexus (Fig.
13.2D). Lateral ventricles are most often involved, and there is an
unexplained left-sided predilection. Most reach a large size by the time
they present, making complete resection difficult.
Extracranial or extradural meningiomas have been reported in the
orbit (see previous discussion), scalp, paranasal sinuses, nasal cavities,
and the skull (“intraosseous meningioma”). In the latter, one must first
rule out the possibility of bone invasion from a thin en plaque or carpet-
like dural-based meningioma (Fig. 13.3).22 The origin of other extracranial
meningiomas is controversial. In cases where extension of intracranial
meningioma has been ruled out, meningothelial heterotopias or rests
seem most plausible. Peripheral nerve, lung, salivary gland, and the
soft tissue of the little finger are even rarer sites of supposed involvement.
In the lung, minute meningothelial pulmonary nodules are thought to
arise from reactive or metaplastic changes and provide one viable
histogenetic explanation (Fig. 13.4).23 The function of these unusual
structures is unclear, but may involve drainage of pulmonary edema
fluid. Some of the older case reports could also include misdiagnosed

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A B

C D
Fig. 13.2  Common meningioma sites and appearances on MRI. (A) Convexity meningioma on contrast T1-weighted MRI. Note the extra-axial location, uniform contrast enhancement,
and “dural tail” sign, with mass effect causing compression of occipital horn of lateral ventricle. (B) Sphenoid wing meningioma on contrast T1-weighted MRI. Uniformly contrast-
enhancing extra-axial mass centered on sphenoid wing and pushing adjacent frontal and temporal lobes. (C) Spinal cord meningioma on T2-weighted MRI. This thoracic cord
meningioma (lower image) pushes and compresses the spinal cord posteriorly. The normal rim of bright CSF is displaced by the tumor and compressed cord. (D) Intraventricular
meningioma on contrast T1-weighted MRI. A large homogeneously enhancing intraventricular meningioma fills the left lateral ventricle.

perineuriomas, given the extensive morphologic and immunohistochemi-
cal overlap of this rare entity (see Chapter 15).
Clinical Manifestations
Clinical manifestations of meningiomas vary with location and may
also include nonspecific symptoms of mass effect. Headaches, seizures,
personality changes, and localizing signs such as hemiparesis, sensory
deficits, and ataxia are most common. Parasagittal meningiomas may
cause leg weakness combined with urinary incontinence. Parasellar
and orbital meningiomas often produce visual symptoms that occa-
sionally lead to blindness. Similarly, hearing loss is common in the
cerebellopontine angle meningiomas. Spinal examples compress the
cord, leading to motor and sensory deficits. Those in locations with
greater room for growth (e.g., lateral ventricles) can be asymptomatic for
years, finally reaching a critical mass that brings it to clinical attention.
It is also well known that patient morbidity and mortality increase
with peritumoral cerebral edema, as does the likelihood of psychiatric
manifestations.
The WHO grade II meningiomas (atypical, clear cell, chordoid)
are characterized by considerably increased risks of recurrence when
compared with the benign (WHO grade I) counterparts, even after a
gross total resection. They also have a modest but statistically significant
increased mortality rate. Their accurate identification is therefore of
critical importance. The estimated 5-year recurrence rate for atypical
meningiomas is 40% even after gross total resection, as compared with
5% for similarly treated benign meningiomas.24 After subtotal resection,
the vast majority of atypical meningiomas recur. At a minimum, these
tumors require careful radiologic follow-up; whether they should be
treated with ancillary radiation therapy remains controversial and often
depends on other variables as well, such as patient age and extent of
resection.25,26
In addition to increased recurrence rates, WHO grade III tumors
(anaplastic, papillary, rhabdoid) are associated with significant risks
of highly aggressive local disease, widespread dissemination, and
tumor-related patient death. As such, they are considered malignant
meningiomas. They lack the usual female predominance of benign

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 Meningiomas

13

1
LAH

PFL
A 5cms B C
Fig. 13.3  (A) En plaque meningioma on contrast T1-weighted MRI. Thin, carpet-like meningioma involving a large portion of the left convexity. There is marked associated cerebral
edema with midline shift. (B) Skull x-ray from a meningioma specimen with bone invasion. Note the extensive hyperostosis associated with bone thickening and a “sunburst”
pattern of new bone formation. (C) Hyperostotic bone. Thickened lamellar bone with replacement of marrow space by aggregates of meningioma.

Fig. 13.5  “Multicentric meningioma” resection specimen. This large dural resection
specimen showed a primary tumor nodule (far right) with a nearby satellite nodule,
likely representing intradural spread of tumor.

Fig. 13.4  Minute meningothelial pulmonary nodules. Interstitial lung nodules with
aggregates of meningothelial-like cells.
meningiomas and present either as anaplastic from the outset (de novo)
or via progression from atypical or benign meningiomas. Either way,
the prognosis is poor with median survival of 2 to 5 years.27 Roughly
a quarter of patients live considerably longer, and most of their tumors
lack 9p21 deletions (see Molecular Genetics section).1,28
Multiple Meningiomas
Multiple meningiomas are typical of NF2, but are also seen in sporadic
adult patients, representing roughly 3% of surgical and up to 8% of
postmortem cases. In some patients, there is one predominant menin-
gioma with one or more satellite masses (Fig. 13.5), either in close
proximity or at a distance; they often show the same variant type
morphology, many being transitional or psammomatous. The number
of multiple meningiomas varies, with as many as 47 histologically similar
tumors reported in one non-NF2 patient.29 Often, the same NF2 gene
mutation is found in multiple meningioma patients in all the tumors
removed from a single patient, consistent with a monoclonal origin
despite the multicentricity.30 This suggests intradural spread as a
mechanistic explanation (see Fig. 13.10C and D), which is further
supported by the common finding of microscopic tumor foci in otherwise
grossly unremarkable dura samples from meningioma patients.31 In the
rarer case of a child with multiple meningiomas, this is nearly pathog-
nomonic for NF2.
Radiologic Features and Gross Pathology
Radiology and Cerebral Edema
Neuroimaging plays a critical role in the diagnosis of meningiomas and
their therapeutic planning. Meningiomas are commonly isodense to
gray matter on noncontrast CT and T1-weighted magnetic resonance
imaging (MRI) studies, making it difficult to appreciate their borders.
However, they are avidly contrast enhancing, such that meningiomas
as small as 3 mm are often detectable. Radiologists use the “dural tail”
sign as a helpful feature to diagnose meningioma or to confirm that the
lesion is indeed extra-axial, rather than parenchymal in origin (see Fig.
13.2A). This refers to the tail-like extension of contrast enhancement into

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 Practical Surgical Neuropathology
adjacent dura. In fact, this is a nonspecific finding commonly encountered
in nearly all dural-based masses, but given that meningioma is so much
more common, it often leads to the correct diagnosis. Microscopically, this
dural tail often consists merely of reactive hypervascular dura, although
small foci of tumor can also be seen occasionally.1 T2-weighted images
vary with tumoral consistency, such that firm, fibroblastic meningiomas
often appear hypointense, whereas hyperintensity is often associated
with soft, vascular, and/or meningothelial meningiomas.32 Calcifications
appear dark on T1 MRI and bright on CT. Necrosis is typically also
dark on T1, but bright on T2.
Most meningiomas display a smooth, rounded edge that appears to
compress rather than invade the adjacent brain (Fig. 13.6). An irregular
tumor–brain interface has been associated with increased risk of finding
brain invasion and other high-grade features on histology (Fig. 13.7).
Other features that have been associated with more aggressive menin-
giomas include increased signals on both T1- and T2-weighted MRI,
“mushrooming” into the adjacent brain (i.e., irregular contour), extensive
edema, lack of calcifications, central necrosis, and low apparent diffusion
coefficient (ADC) values on diffusion-weighted imaging.33–35 However,
these radiopathologic correlations are far from perfect and there are
many exceptions.
Extent of radiologically detected peritumoral cerebral edema (dark
on T1, bright on T2 MRI) is highly variable, and, not surprisingly, it is
often more prominent in symptomatic versus incidentally detected
meningiomas. Extensive edema has also been associated with large
tumor size, recruitment of pial vascular supply, location in the convexity
or middle fossa, an irregular (often “mushroom-like”) brain–tumor
interface, T2 bright signal intensity, microscopic brain invasion, histologic
malignancy, and variant histology that includes secretory, microcystic
angiomatous, and/or lymphoplasmacyte-rich features (see Histologic
Variants and Grading section).
Gross Pathology
Meningiomas show a diverse range of gross appearances, depending
mostly on their locations, growth patterns, and histologic subtypes (see
Histologic Variants and Grading section). Most are rubbery, well

A B

C D
Fig. 13.6  (A) Incidental meningioma on T2-weighted MRI. The extra-axial appearance of this meningioma is well demonstrated by the thin layer of T2 bright CSF between the
tumor and the adjacent indented, but noninvaded brain parenchyma. (B) Benign meningioma on autopsy. This meningioma showed a classic attachment to the inner surface of
the dura, with the adjacent compressed brain molded to the rounded contours of the slowly growing tumor. (C) Resected meningioma. The tumor is attached to the resected sleeve
of dura and shows a smooth external surface. (D) Resected meningioma. The tumor shows central attachment to the dura below and a bosselated cut surface.

264
 Meningiomas

13

A B

C D
Fig. 13.7  (A) Atypical meningioma on contrast T1-weighted MRI. The enhancing extra-axial mass with dural tail sign is typical of meningioma, although the irregular brain–tumor
interface is worrisome for a more aggressive subtype. (B) Anaplastic meningioma on contrast T1-weighted MRI. The irregular contour, inhomogeneous signal characteristics, and
central hypodensity suggestive of necrosis are worrisome for higher grade. (C) Atypical meningioma. The soft fleshy appearance with focal papillary (cauliflower-like) configuration
is worrisome for higher grade meningioma. (D) Anaplastic meningioma. Features worrisome of high grade include the soft, almost gelatinous cut surface suggesting high cellularity
and the large yellow region of tumor necrosis evident in the upper fragment.

circumscribed, spherical, and firmly attached to the inner surface of the
dura (see Fig. 13.6). The tumor surface is usually smooth or bosselated,
like cauliflower. The cut surface is white, yellow, or tan, often with
intersecting white streaky bands of fibrous tissue. Xanthomatous or
lipomatous “metaplasia” imparts a yellow color, whereas foci of metaplastic
cartilage and bone appear white. Psammoma bodies (“sand-like” from
the Greek word psammos) impart a gritty cut surface. Decalcification
is often needed for the psammomatous variant, ossified tumors, and
those with bone invasion. The microcystic variant has a moist glistening
cut surface, consistent with Masson’s original name of “meningioma
humide.” Secretory meningiomas have a tan-red gland-like appearance.
Hemorrhage and necrosis are relatively rare findings in benign menin-
giomas, but are seen more commonly after therapeutic embolization.
More cellular tumors such as atypical and anaplastic meningiomas tend
to be softer and more fleshy, the latter often being extensively necrotic
on cut surface (see Figs. 13.5, 13.7C and D).
The cerebral cortex adjacent to meningiomas often appears com-
pressed and distorted, sometimes forming a cavity that molds perfectly
around the protuberant surface of the meningioma (see Fig. 13.6B).
Nevertheless, the brain–tumor interface is typically distinct, with most
meningiomas easily peeling away. Those that don’t are either brain
invasive or merely adherent to the leptomeninges. In contrast to true
brain invasion, infiltration of adjacent dura, venous sinuses, bones, and
soft tissue is relatively frequent, even in benign examples. For example,
orbital meningiomas are often highly invasive of adjacent bone and
soft tissue, typically surrounding and compressing the optic nerve with
resulting loss of vision (Fig. 13.8). Other cranial and spinal nerves/
ganglia are occasionally invaded by meningioma as well.

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 Practical Surgical Neuropathology

A B C
Fig. 13.8  Optic pathway meningioma in a patient with progressive visual loss/blindness. (A) Eye and optic nerve resection specimen. The optic nerve was markedly expanded by
a circumferentially placed meningioma. (B) Eye and optic nerve resection specimen. Cross sections reveal a large meningioma surrounding and compressing a central atrophic optic
nerve. (C) Optic nerve resection specimen. The optic nerve on the left is compressed, but not directly invaded by the meningioma on the right.

Some meningiomas are dumbbell shaped with tumor masses growing

out on both sides of a dural reflection, such as the falx or tentorium.
Intraventricular meningiomas are often large, potentially expanding and
distorting the ventricular cavity, often with resultant obstructive
hydrocephalus (see Fig. 13.2D). The en plaque meningiomas are defined
by a carpet-like growth pattern, resulting in long stretches of thickened,
sometimes rough or shaggy dura (see Fig. 13.3A). They are most com-
monly encountered in the skull base, especially the sphenoid wing,
where they tend to invade the adjacent bone, with associated hyperostosis
(Fig. 13.3B and C).
Cystic meningiomas represent 2% to 4% of all cases (Fig. 13.9). They
are mostly benign and are seen more commonly in children.36 Any
meningioma can develop grossly evident cysts, although the microcystic
variant is most frequent, with macrocysts likely forming from coalescence
of microscopic ones. In some of these cases, the dural attachment is
subtle and there may even be ring enhancement, mimicking glioblastoma.
Cystic elements are intratumoral and/or peritumoral with suspected
etiologies including secretory, reactive, and degenerative changes. In
rare cases, a cystic meningioma may form within a preexisting malforma-
tion, such as an arachnoid cyst.

Histopathology
The histopathologic spectrum of meningiomas is extremely wide (see
next section), although there are several characteristic features, seen in
most tumors regardless of subtype or grade. Key features include whorl
formation, psammoma bodies, and characteristic cytologic features such
as nuclear clearings (“holes”) and pseudoinclusions. As stated earlier,
one of the common characteristics of meningothelial cells is to wrap
around various structures including themselves, resulting in cellular
whorls (Fig. 13.10A). Over time, the cells within these whorls deposit
intercellular collagen, progressively leading to hyalinized whorls, typically
with concentric laminations. As these structures mineralize, one sees
concentric calcifications known as psammoma bodies. Cytologically,
most meningioma cells are moderately sized with ample eosinophilic
Fig. 13.9  Cystic meningioma on contrast T1-weighted MRI. This cystic meningioma
was difficult to distinguish from a primary CNS neoplasm.
cytoplasm and oval nuclei with delicate chromatin, often displaying
numerous clear vacuoles (“holes”) and pseudoinclusions (Fig. 13.10B).
The latter represent cytoplasmic invaginations into the nuclei, such that
on cross section, they appear membrane bound with identical tinctorial
qualities to that of the cytoplasm (i.e., eosinophilic, rather than clear).
These cytologic features are by no means specific to meningiomas, but
are helpful for the differential diagnosis nonetheless, particularly in

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13

A B

C D
Fig. 13.10  Common histology in meningiomas. (A) Prominent whorl formation gives way to concentric rings of hyalinization and psammoma bodies. (B) Meningioma with frequent
clear nuclear holes and pseudoinclusions (eosinophilic like the cytoplasm). (C, D) Foci of dural invasion with aggregates of meningioma cells between bands of dense collagen.

variants that do not otherwise show classic architectural features, such Table 13.1  WHO 2016 Classification Scheme for Meningiomas
as whorling. The vast majority of meningiomas, even the most benign, Meningioma Variants That Are
invade the dura, and this likely represents a common mode of spread Mostly Benign (WHO Grade I) WHO Grade II Meningiomas
beyond the point of dural attachment (Fig. 13.10C and D). Other Meningothelial Atypical (any variant plus criteria)
histologic features such as cytoplasmic characteristics, degree of col-
lagenization, stromal background, architectural growth patterns, vascular Fibrous (fibroblastic) Clear cell
changes, and invasiveness into bone, soft tissue, and brain are highly Transitional (mixed) Chordoid
variable and discussed in greater detail in the next section.
Psammomatous
Histologic Variants and Grading Angiomatous (vascular)
The vast histopathologic spectrum encountered in meningiomas is
Microcystic WHO Grade III Meningiomas
astonishing and has led to several complex classification schemes
with numerous variants described over the years. In 1938, Cushing Secretory Anaplastic (any variant plus criteria)
and Eisenhardt stratified meningiomas into 9 main types and 20
Lymphoplasmacyte rich Papillary
subtypes.2 Since that time, several variants have been reclassified as
distinct entities. For example, the meningeal solitary fibrous tumor/ Metaplastic Rhabdoid
hemangiopericytoma is now considered a distinct form of sarcoma
(see Chapter 14). However, in the WHO 2016 classification scheme,
there remain nine mostly benign (WHO grade I), three intermediate (clear cell, chordoid, papillary, rhabdoid), it has been suggested that the
category (WHO grade II), and three malignant (WHO grade III) subtypes WHO grade II or III designation only be assigned if the majority of
(Table 13.1).37 For the more aggressive subtypes, it remains unclear what the tumor (>50%) shows the appropriate morphology38; nevertheless,
percentage of the variant histology must be present before the higher a study of rhabdoid meningiomas lacking overt features of malignancy
grade is automatically assigned. For the four subtypes in this category was associated with a mostly favorable prognosis even when more than

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Table 13.2  WHO 2016 Grading Criteria for Meningioma
Benign Meningioma (WHO Grade I)

• Any predominant histology other than clear cell, chordoid, papillary, or rhabdoid
• Lacks criteria of atypical and anaplastic meningioma

Atypical Meningioma (WHO Grade II) (Any of Three Major Criteria)

• Mitotic index ≥4 mitoses/10 HPF

• Brain invasion
• At least three of the following five parameters:
Sheeting architecture (two-dimensional sheets with loss of whorls and fascicles)
Small cell formation (clusters of lymphocyte-like cells with high N/C ratio)
Hypercellularity
Macronucleoli
Spontaneous necrosis (i.e., not induced by embolization or radiation)

Anaplastic (Malignant) Meningioma (WHO Grade III) (Either of Two Criteria)

• Mitotic index ≥20 mitoses/10 HPF
• Frank anaplasia (sarcoma-, carcinoma-, or melanoma-like histology)
A

50% of cells appeared rhabdoid.39 In contrast to these rare variants,

any of the more common meningioma subtypes may qualify as either
atypical (WHO grade II) or anaplastic (WHO grade III) if diagnostic
criteria are met even focally (Table 13.2), either at initial presentation
or in subsequent recurrences. These subtypes are discussed in greater
detail in this chapter.

Meningiomas That Are Mostly Benign (WHO Grade I)

Meningothelial Meningioma
These are defined by lobulated, nested, or whorled aggregates of polygonal
to epithelioid cells with fuzzy or indistinct cell borders (Fig. 13.11A).
The latter imparts a syncytial appearance, explaining the older term,
“syncytial meningioma.” Large nests or islands of cells are often surrounded
by variable quantities of collagen or fibrous septae. Nuclear atypia may
occur and by itself has no prognostic bearing. Occasional examples of
meningothelial meningoma (or other subtypes) feature bizarre mono-
nucleated or multinucleated giant cells with dark smudgy chromatin
and abundant cytoplasm (Fig. 13.11B). This type of nuclear atypia is
likely degenerative in nature, analogous to that encountered in “ancient
schwannomas.”
Fibrous (Fibroblastic) Meningioma
These fibroblast-like spindle cell tumors predominantly form intersecting
fascicles and storiform growth patterns, with variable but often prominent
collagen deposition (Fig. 13.12). The nuclei are oval to elongate, but
retain the overall features of meningothelial cells, including the presence
of clear holes and pseudoinclusions. Whorls and psammoma bodies
are often only present focally, but are helpful in excluding schwannoma
(see Differential Diagnosis section).
Transitional Meningioma
This variant is perhaps the most common and readily recognized form
of meningioma; it contains a mixture of the meningothelial and the
fibrous types, as well as cells with intermediate features (see Fig. 13.10A).
Syncytial islands intermix with fascicles of collagen-rich, spindle-shaped
cells. Whorl formation is prominent and well developed, often with
numerous psammoma bodies.
Psammomatous Meningioma
These tumors manifest commonly in the spinal cord of older women,
where they are usually slow growing and biologically indolent. The
marked calcifications are readily evident on both plain x-rays and CT
scans (Fig. 13.13A). They likely start out as transitional meningiomas
B
Fig. 13.11  (A) Meningothelial meningioma. Large nests of epithelioid cells with fuzzy
intercellular borders imparting a syncytium-like growth pattern. There are also numerous
nuclear clear holes. (B) Meningothelial meningioma with “ancient changes.” The bizarre
nuclei in this meningioma are most likely degenerative in nature, since there are no
mitoses or other associated high-grade features.
that develop so many individual and confluent psammoma bodies over
time that the calcifications obscure the underlying meningothelial cells.
Psammoma bodies should constitute over half of the tumor mass (Fig.
13.13B–D), with eventual dystrophic ossification (“osseous metaplasia”)
also being common.
Angiomatous (Vascular) Meningioma
This subtype is defined by its hypervascularity, with tumoral blood
vessels exceeding 50% of the total volume40 (Fig. 13.14). Larger vessels
are often markedly hyalinized (Fig. 13.14B), while smaller, capillary-sized
vessels are often surrounded by bubbly or foamy tumor cells with
degenerative nuclear atypia (Fig. 13.14C), closely mimicking the histology
of hemangioblastoma (see Differential Diagnosis section). This variant
often coexists with the microcystic subtype and is often associated with
cerebral edema beyond that expected for its size (Fig. 13.14A).40,41 Special
studies are occasionally needed to confirm the meningothelial nature
of this variant, including somatostatin receptor 2a (SSTR2a; see later
sections) (Fig. 13.14D). Genetic studies also suggest that these tumors
frequently harbor polysomies (chromosomal gains), especially polysomy
5, rather than the losses of chromosome 22 more commonly encountered
in conventional meningiomas.42

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13

A B

C D
Fig. 13.12  Fibrous meningiomas. (A, B) Fibrous meningiomas with intersecting fascicles of spindled cells and variable collagen deposition. (C) Verocay-like bodies in a fibrous
meningioma, mimicking schwannoma. Other regions had whorls and occasional psammoma bodies. The tumor was also EMA positive. (D) Patchy EMA immunoreactivity in a fibrous
meningioma.

Microcystic Meningioma Secretory Meningioma

Microcystic meningiomas are typically T1 hypodense, T2 bright tumors
on MRI, often with marked cerebral edema.43,44 Grossly, they are soft
and occasionally form macrocysts. They have a “wet” glistening cut
surface, justifying the original name of humid meningioma. Microscopi-
cally, the tumor has a “cobweb-like” appearance due to intercellular clear
fluid collections (sometimes containing blue to pale eosinophilic mucin)
between spider-like cells with long thin processes (Fig. 13.15). In fact,
this morphology (and ultrastructural features) more closely resembles
the normal arachnoidal trabecular, rather than the cap cells.45 The
pathogenesis of microcyst formation remains unclear, with proposed
mechanisms including secretory activity by the tumor, cystic degenera-
tion, ischemia, and penetration of the CSF into the tumor. Tumor
cytoplasm appears faintly eosinophilic or finely vacuolated. Whorls and
psammoma bodies are rare. Scattered bizarre nuclei and hypervascularity
are relatively common, as they are with the angiomatous variant; in
fact, these two meningioma subtypes are often seen together in the
same tumor. In cases where EMA expression is weak or absent (given
wispy processes), an SSTR2a immunostain can be helpful in establishing
the meningothelial nature.
This morphologic variant virtually never occurs in pure form, but most
often develops within an otherwise meningothelial or transitional
meningioma. It represents an advanced form of epithelial differentiation
characterized by the formation of gland-like lumens with eosinophilic
secretions (Fig. 13.16). Female predominance is even more pronounced
in secretory meningioma than that of more common subtypes. They
are most commonly encountered in the frontal convexity or sphenoid
ridge. Like the angiomatous and microcystic subtypes, secretory
meningiomas often induce cerebral edema out of proportion to their
size.46,47 The gland-like spaces contain brightly eosinophilic, smooth or
granular PAS-positive secretions known as pseudopsammoma bodies
due to their superficial resemblance to calcifications at first glance (Fig.
13.16B–F). They vary in size and may be single or multiple. Pseudopsam-
moma bodies may be evenly distributed, but are more often concentrated
in smaller foci. The tumor cells associated with the gland-like spaces
are usually strongly immunoreactive for cytokeratin, while carcinoem-
bryonic antigen (CEA) is found within the pseudopsammoma bodies
and/or the tumor cells surrounding them (Fig. 13.16E and F). Occasion-
ally, there is sufficient production of CEA to elevate serum levels. When

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A B

C D
Fig. 13.13  Psammomatous meningioma. (A) This heavily calcified upper cervical meningioma appears hyperintense on this CT scan and was also visible on plain x-ray. (B, C) The
majority of the tumor mass was composed of psammoma bodies, which appear red rather than purple due to acid decalcification. (D) Meningioma cells in between the psammoma
bodies are EMA positive.

compared with other meningiomas, studies have found increased
pericytic, mast cell, and histiocytic elements, as well as extracellular
matrix proteins in the secretory subtype.46,48–50 Of additional interest,
nearly all cases are associated with combined KLF4 K409Q and TRAF7
gene mutations.51
Lymphoplasmacyte-Rich Meningioma
Of all meningiomas, this one is the most enigmatic and controversial.
It is characterized by dense infiltrates of lymphocytes and plasma cells
that partially obscure the underlying meningioma (Fig. 13.17).52,53 Using
criteria similar to other variants, the inflammatory component should
comprise over half of the tumor cells; in some cases, it’s entirely intermixed
with the meningioma, whereas in others, the inflammation is mainly at
the periphery of the tumor. Some of the previously reported patients
have had associated monoclonal gammopathies and/or anemia. Other
common features reminiscent of an inflammatory process include young
age of onset, en plaque growth pattern, multicentricity, spontaneous
regression, and recurrence over multiple sites. Therefore, it is likely that
some examples diagnosed as “lymphoplasmacyte-rich meningioma”
are actually inflammatory disorders with associated meningothelial
hyperplasia. Features favoring meningioma over the latter include a
definite mass on imaging (rather than en plaque or pachymeningitis
pattern), larger meningothelial aggregates, and dural invasion by the
tumor. In the absence of these features, one should always exclude
other lymphoplasmacyte-rich meningeal disorders, such as infection,
Rosai-Dorfman disease, IgG4-associated pachymeningitis, inflammatory
myofibroblastic tumor, Castleman disease, collagen vascular disorders,
and either primary or secondary low-grade lymphomas. Also, given

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13

A B

C D
Fig. 13.14  Angiomatous meningioma. (A) This angiomatous meningioma was associated with abundant cerebral edema (increased signal) on FLAIR MRI, despite its relatively small
size. (B, C) Marked hypervascularity with extensive hyalinization of both large and small vessels. As is often the case, the intervening tumor cells are only subtly meningothelial with
foamy spider-like cells (overlaps with microcystic) and often prominent degenerative atypia. (D) The meningioma cells are strongly and diffusely positive for somatostatin receptor 2a.

A B C
Fig. 13.15  Microcystic meningioma. (A, B) A small nest of more classic meningothelial cells is seen within this predominantly microcystic meningioma (A). The latter is characterized
by thin tumor processes and a cobweb-like lattice. (C) Focal EMA positivity outlines the thin tumor processes surrounding microcystic spaces. 271
 Practical Surgical Neuropathology

A B

C D

E F
Fig. 13.16  Secretory meningiomas. (A) Secretory meningioma with a tan, gland-like appearance on cut surface. (B, C) Gland-like spaces with brightly eosinophilic pseudopsammoma
bodies seen on both intraoperative smear (B) and permanent sections (C). The latter range from smooth to granular or particulate. (D) The pseudopsammoma bodies are strongly
PAS positive. (E) The epithelioid cells forming gland-like spaces are strongly cytokeratin positive. (F) The pseudopsammoma bodies and, sometimes, the cells surrounding them show
CEA positivity.

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13

A B

C D
Fig. 13.17  (A–D) Lymphoplasmacyte-rich meningioma. On postcontrast T1-weighted MRI, the tumor appears heterogeneous, possibly representing pockets of inflammation (A).
The meningothelial component is partially obscured by dense inflammation (B). The lymphoid and meningothelial components are highlighted by the CD45 (C) and somatostatin
receptor 2a (D) stains, respectively.

that macrophages often predominate and plasma cells are not always
conspicuous, “inflammatory-rich meningioma” has been proposed as
an alternate term.52
Metaplastic Meningiomas
Virtually any type of meningioma (most often meningothelial, transi-
tional, or fibroblastic) can develop areas of mesenchymal “metaplasia,”
including cartilaginous/chondroid, osseous, lipomatous, xanthomatous,
and myxoid patterns that alternate with more classic histology (Fig.
13.18). However, careful scrutiny suggests that in most examples, it is
not true metaplasia per se, but rather cytoplasmic fat accumulation,
vacuolization, dystrophic ossification, or other changes within otherwise
EMA (Fig. 13.18D) and/or SSTR2a (Fig. 13.18E) immunoreactive
meningothelial cells that also retain their characteristic meningothelial
features ultrastructurally. As such, Roncaroli et al. have proposed alternate
terms, such as lipidized rather than lipomatous meningioma.54 Also, in
the rare cases of myxoid and chondroid meningiomas, one must take
care to distinguish them from chordoid meningiomas (see upcoming
discussion), given some overlapping features.55,56
WHO Grade II Meningiomas
WHO grade II meningiomas are characterized primarily by a significantly
increased risk of tumor recurrence, but also a small yet statistically
significant decrease in survival. Difficulties with local control of these
tumors account for their higher morbidity and mortality.
Atypical Meningioma
Atypical meningioma may either arise in a recurrence of one of the
more commonly benign histologic patterns already described or de
novo. Clinical risk factors include male sex, nonskull base location, and
prior surgery.57 The diagnosis is based on the presence of one or more
established microscopic criteria (see Table 13.2). These 2016 WHO
criteria1 are based mostly on data from two large clinicopathologic
series from the Mayo Clinic.24,27 In these series, the estimated 5-year
recurrence rate for gross totally resected atypical meningiomas was
40%, as compared to 5% for similarly treated benign meningiomas. This
considerably increased risk of recurrence justifies the WHO grade II
designation. Despite the name “atypical meningioma,” cytologic atypia
is neither required nor reliable given that benign meningiomas may

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A B

C D

E F
Fig. 13.18  “Metaplastic meningiomas.” (A) Dystrophic ossification or “bone metaplasia” in the center of an otherwise typical meningioma. (B–E) Lipidized meningioma (or
“lipomatous metaplasia”) with accumulation of large globules of fat within meningioma cells, many of which still demonstrate EMA (D) and somatostatin receptor 2a (E) positivity.
(F) Chondroid (cartilaginous) metaplasia with islands of cells containing basophilic matrix resembling cartilage.

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13

G H
Fig. 13.18, cont’d  (G, H) Meningioma with “xanthomatous metaplasia” due to accumulations of lysosomes and/or small lipid vacuoles. The similarity to macrophages is highlighted
in G, whereas H demonstrates earlier metaplasia consisting of clear vacuoles but retained spindled cytology of fibrous meningioma.

A B
Fig. 13.19  (A, B) Embolized meningioma. In this case, the meningioma was embolized with polyvinyl alcohol (PVA) imparting a striped “tigroid” appearance in dural (A) and
intratumoral (B) vessels, due to intermixed PVA and fibrin thrombus. The induced tumor necrosis often appears acute with nuclear debris (B) and should not be used for meningioma
grading.

show considerable degenerative nuclear atypia (see Fig. 13.11B), while
mitotically active meningiomas can be completely monomorphic and
cytologically bland. Likewise, although it makes the surgery more chal-
lenging, invasion of adjacent dura, bone, and soft tissue do not warrant
a higher grade. Lastly, embolization-induced necrosis (Fig. 13.19) should
not be utilized as evidence of higher grade, since it is iatrogenically
induced. The same applies to radiation-induced ischemia. In other words,
only “spontaneous necrosis” is considered when grading meningiomas
(Table 13.2). Instead, atypical meningiomas are currently defined by
at least focal presence of either high mitotic index (≥4 mitoses per 10
high powered fields [HPF]), brain invasion (discussed later), or at least
three of the following five features: hypercellularity (originally defined
as >53 nuclei/HPF diameter, but mostly a subjective impression in daily
practice), small cell formation (clusters of lymphocyte-like tumor cells
with high nuclear/cytoplasmic ratio), macronucleoli (e.g., visible at 100×),
sheeting architecture (loss of whorled or fascicular growth patterns),
and spontaneous necrosis (Fig. 13.20). Often, the two-dimensional
sheeting and small cell formation are evident at low magnification,
whereas the other features require greater time spent at medium to
high magnifications.
Based on these WHO criteria, the diagnosis of atypical menin-
gioma has become more common. Whereas most studies before
2000 quoted frequencies of 5% to 7%, they comprise 15% to 25% in
modern series.24,58,59 For instance, increased mitotic count was the most
common reason for “upgrading” in a careful review of 314 previously
diagnosed meningiomas, emphasizing the importance of review at
higher magnification, even when “worrisome features” are not seen on
initial scan.58
Clear Cell Meningioma
Clear cell meningiomas are rare (<1% of meningiomas), have a strong
predilection for the spinal cord and posterior fossa, and often present at a
younger age, with many reported cases encountered in infants, children,
and young adults (Fig. 13.21A and B). They are composed of sheets
of polygonal cells with clear cytoplasm (Fig. 13.21C), resulting from
glycogen accumulation which can be demonstrated as diastase-digestible

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A B

C D

E F
Fig. 13.20  Atypical meningiomas. (A) Sheeting architecture with loss of whorl and fascicle formation. (B) Small cell formation (and sheeting) with clusters of lymphocyte-like tumor
cells that have lost most of their cytoplasm (i.e., high NC ratio). (C) Macronucleoli. (D) Focus of “spontaneous necrosis.” Note the lack of nuclear debris that is more commonly
seen in embolization-induced necrosis (see Fig. 13.19B). (E) Increased proliferative index (>4% labeling index) on Ki-67 immunostaining. (F) Only a rare PR positive cell is seen,
providing further (albeit nonspecific) support for high-grade histology.

276

PAS positivity (Fig. 13.21E and F).60,61 Whorl formation is often subtle
and psammoma bodies are typically absent, making it more difficult
to recognize the meningothelial nature of this tumor. A distinctive
feature, however, is the often prominent interstitial and perivascular
hyalinization. In some, this collagenization becomes confluent, forming
large acellular zones of hyalinization, overlapping with reported cases of
the so-called “sclerosing meningioma” (Fig. 13.21D).62 Thick, brightly
eosinophilic amianthoid-type fibers may also be seen. Despite a bland
cytology in most cases, the behavior is surprisingly aggressive, justifying
its WHO grade II designation. For instance, Zorludemir and colleagues
Meningiomas
originally reported 61% recurrence and 23% mortality rates in their 14
cases, with one also showing CSF dissemination (Fig. 13.21B).61 Others
have similarly reported both local and distant forms of progression.63 Rare
13
examples have featured prominent inflammatory components.64 Both
familial and sporadic clear cell meningiomas have strong associations
with SMARCE1 mutations and loss of protein expression.65,66
Chordoid Meningioma
As one might guess, chordoid meningioma was named for its striking
resemblance to the bone tumor, chordoma. It is a rare subtype, accounting

A B

C D
Fig. 13.21  Clear cell meningiomas. (A, B) Postcontrast MR images showing a large posterior fossa/cervicomedullary junction primary (A) and a spinal drop metastasis (B). (C)
Predominantly clear cytoplasm and only vague whorling. (D) Focus of advanced interstitial and perivascular hyalinization forming hypocellular sclerotic zone on trichrome stain.
Continued

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E F

G H

Fig. 13.21, cont’d  (E, F) Increased cytoplasmic glycogen confirmed by PAS without (E) and with diastase (F) treatment, the latter eliminating PAS staining. (G, H) The tumor shows
patchy EMA (G) and diffuse somatostatin receptor 2a (H) expression.

for roughly 0.6% of meningiomas in one large series.67 Most cases present
as large, difficult to resect, supratentorial masses (Fig. 13.22A).68–71 The
tumor is often vaguely lobulated with abundant basophilic mucin and
epithelioid to spindled cells arranged in ribbons or cords (Fig. 13.22B–D).
The mimicry of chordoma is further enhanced by the presence of foamy
or vacuolated “physaliferous-like” cells. A prominent lymphoplasmacytic
infiltrate is occasionally seen and was stressed in the original descrip-
tion in 1988.70 Foci of conventional meningothelial or transitional
meningioma may be seen, although others are composed entirely of
chordoid morphology, making it difficult to recognize the tumor as
meningioma, especially since psammoma bodies are also uncommon. The
original series of seven cases reported children with Castleman disease,
anemia, and a prominent inflammatory response to the tumor; systemic
findings disappeared upon tumor resection and reappeared with tumor
recurrence.70 However, larger series have found these clinicopathologic
associations to be relatively rare.69 Nonetheless, chordoid meningiomas
are particularly likely to recur, particularly following subtotal resection
(nearly 100% in this setting), justifying the WHO grade II designation.
As with other meningiomas, however, the prognosis is considerably
better with complete resection.72 Rare examples of CSF dissemination
have been reported.73
Brain Invasive Meningioma
The issue of brain invasion in meningioma grading has been a contro-
versial one for many decades. It is histologically defined as extension of
tumor cells beyond the pial surface into the adjacent brain parenchyma
(Fig. 13.23). It is typically found at the periphery of larger meningio-
mas, as irregular tongue-like protrusions associated with gliosis in the
adjacent brain, and especially in entrapped fragments of brain within
the tumor. Extension of tumor along leptomeningeal Virchow–Robin
spaces is occasionally seen, particularly in pediatric examples with or
without associated meningioangiomatosis; however, this should not
be misconstrued as true brain invasion. The previously published view
that brain invasion in meningiomas represents the most reliable sign
of malignancy is no longer tenable.27 Careful studies of brain invasive
meningiomas that were otherwise benign or otherwise atypical showed
recurrence and mortality rates that were virtually identical to those of
atypical meningiomas (WHO grade II) defined by other criteria. As such,
the 2016 classification scheme now considers brain invasion to represent
another criterion for atypical meningioma, WHO grade II, even in the
absence of any other worrisome features.1 Nevertheless, this remains a
controversial issue given that some studies still suggest that such cases are
less aggressive than conventionally defined atypical meningiomas.74 This

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13

A B

C D

E F
Fig. 13.22  Chordoid meningiomas. (A) Large supratentorial chordoid meningioma (clinically recurrent) with extensive frontal sinus invasion on contrast T1-weighted MRI. (B) Gross
pathology shows mucoid and glistening cut surface, which may be similar to that seen in microcystic meningiomas. (C, D) Chordoma-like histology with cords of small epithelioid
cells and bubbly physaliferous-like clear vacuoles (C), set within an Alcian blue–positive mucin-rich stroma (D). (E, F) Meningothelial features include EMA (E), somatostatin receptor
2a (not shown), and, sometimes, progesterone receptor (F) expression.

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 Practical Surgical Neuropathology
A B
Fig. 13.23  (A–C) Brain invasive meningioma. Brain invasion is characterized by tongue-like protrusions of meningioma into adjacent often gliotic brain (A, B), with entrapped
parenchyma highlighted on GFAP stains (C).
distinction between brain invasive and other high-grade meningiomas
is also based in part on molecular genetic observations, showing that
otherwise benign brain invasive meningiomas less commonly harbor
classic “progression-associated alterations” (see Genetics section).75 As
such, additional studies with larger numbers and longer follow-up times
are still needed to resolve the remaining controversies.
WHO Grade III (Malignant) Meningiomas
The WHO grade III meningiomas are those that have a considerably
increased risk of not only recurrence, but also metastatic dissemination
and patient death from disease. As such, they are considered overtly
malignant.
Anaplastic (Malignant) Meningioma
These highly aggressive WHO grade III neoplasms are defined primarily
by the presence of cellular anaplasia and/or excessive mitotic activity
(see Table 13.2). Earlier definitions of anaplastic meningioma were
problematic, since they were often vague, sometimes depended mainly
on the presence of brain invasion (see prior discussion), and were not
always associated with a particularly poor prognosis. However, since
the 2000 version, the WHO schemes adopted stricter criteria based on
previously published statistical associations with overall patient survival:
either at least 20 mitoses per 10 HPF or overtly malignant sarcoma-,
carcinoma-, or melanoma-like cytology (Fig. 13.24A and B).1,27 These
features may be encountered focally or diffusely. In the latter case, a
firm diagnosis of meningioma requires additional supporting evidence,
such as:
• History of prior meningioma at the same site (often better
differentiated)
• Immunohistochemical features of meningioma (see later
discussion)
• Strong diffuse vimentin positivity (Fig. 13.24C)
• Strong diffuse SSTR2a immunoreactivity
• Patchy EMA expression (Fig. 13.24D)
• Progesterone receptor usually negative or only focally expressed
• Limited or no cytokeratin expression
• Lack of nuclear STAT6 staining (i.e., rule out SFT/HPC)
280
C
• Ultrastructural features of meningioma
• Imbricating cellular processes
• Intercellular junctions, including desmosomes
• Genetic features of high-grade meningioma (see later discussion)
• 22q, 1p, 6q, 10, 14q, 18q, and/or 9p (p16 gene) deletions (Fig.
13.24F–H)
• NF2 and TERT promoter region mutations
Other common features in anaplastic meningiomas include extensive
zones of geographic necrosis, brain invasion, atypical mitotic figures,
and Ki-67 labeling indices exceeding 20% (Fig. 13.24E). Whereas
the revised WHO criteria have led to increased numbers of atypical
meningiomas, the more stringent definition of malignancy has led to a
less dramatic but noticeable decrease in anaplastic meningiomas, with
current estimates for the latter being 1% to 6%.1,27,58,76 They should
not be confused with a variety of true meningeal sarcomas; thus,
the older term “sarcomatous meningioma” should not be used for
anaplastic meningiomas that are predominantly spindled or collagen
rich (Fig. 13.24B). Nevertheless, there are rare anaplastic meningiomas
with compelling carcinoma-like (e.g., malignant glands) or sarcoma-
like (e.g., rhabdomyoblastic, myofibroblastic) foci of metaplasia
(Fig. 13.25).77–79
Papillary Meningioma
Papillary meningiomas are rare (<1% of all meningiomas) cellular
tumors characterized, at least in part, by (1) a papillary or more often
a pseudopapillary pattern resulting from discohesive tumor cells (Fig.
13.26B), and (2) a perivascular arrangement of epithelioid tumor cells
resembling the pseudorosettes of ependymoma (Fig. 13.26C and E). When
the architectural features are well developed, it may appear grossly or
radiologically similar to other papillary neoplasms with a cauliflower-
like growth pattern (Fig. 13.26A). In cases with abundant cytoplasm,
tumor cells often appear epithelioid (Fig. 13.26E and F) to rhabdoid (see
upcoming discussion), suggesting metastatic carcinoma, melanoma, and
other malignancies, but nevertheless maintaining immunoprofiles typical
of meningioma. This variant was originally described by Cushing and
Eisenhardt in a patient who underwent 17 operations, and eventually
died with pulmonary metastases.2 Tumor nuclei often resemble those
 Meningiomas

13

A B

C D

E F
Fig. 13.24  Anaplastic meningioma. (A) Carcinoma-like region with excessive mitotic activity (>20/10 HPF). (B) Fibrosarcoma-like spindled region in the same tumor. (C) Strong
and diffuse vimentin positivity. (D) Patchy EMA positivity and lack of cytokeratin (not shown) supported a meningothelial derivation. (E) The Ki-67 labeling index in this case was
similarly more than 20%. (F–H) FISH studies showed typical genetic features of high-grade meningioma, including 22q loss (F: BCR gene in red, NF2 gene in green; only one signal
Continued

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G H
Fig. 13.24, cont’d  in most cells) and 1p deletion (G: 1p32 in green, 14q32 in red; most nuclei have one green and two red signals). FISH also showed 9p21 deletion (centromere
9 in green and 9p21 in red; one red and two green signals in most nuclei), consistent with the more aggressive subset of anaplastic meningioma.

A B

C D
Fig. 13.25  Anaplastic meningiomas with metaplastic features. (A, B) Anaplastic meningioma with adenocarcinoma-like foci. This case had CK7 immunoreactive (B) epithelioid cells
forming gland-like structures intermixed with anaplastic meningioma. Both components showed classic meningioma-associated deletions by FISH (not shown). (C–F) Anaplastic
meningioma with rhabdomyosarcoma-like foci. Predominantly spindled anaplastic meningioma with scattered brightly eosinophilic cells suggestive of rhabdomyoblasts (C, D).

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13

E F
Fig. 13.25, cont’d  The latter were positive for desmin (E), whereas larger meningioma-like nests expressed vimentin most avidly (F). Both components showed classic meningioma-
associated deletions by FISH (not shown).

A B

C D
Fig. 13.26  (A–F) Papillary meningiomas. Occasional examples where papillary architecture is well developed will show a “cauliflower-like” gross or postcontrast MRI appearance
(A). This tumor was characterized by a pseudopapillary growth pattern due to poor tumor cohesion (B). Remaining cells cling to blood vessels with perivascular nuclear-free zones
reminiscent of ependymal pseudorosettes (C). The Ki-67 labeling index was elevated (D). Continued

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E F
Fig. 13.26, cont’d  Another example shows papillary architecture combined with epithelioid cytology (E) and strong vimentin positivity (F).
of meningothelial cells, and regions of more classic variant histology are
commonly found; in fact, the papillary pattern predominates in only
about a fourth of cases. However, the diagnosis of “papillary meningioma,
WHO grade III” should only be rendered when this architectural pattern
predominates (i.e., >50% of tumor). Otherwise, normal grading criteria
should be applied followed by “with focal papillary features” in the
diagnostic line and a comment regarding the need for close clinical
follow-up due to a potential for more aggressive behavior. In cases
with multiple recurrences, the papillary morphology often becomes
more prominent over time. The vascular walls may occasionally show
hyaline thickening. Mitotic activity is variable, although some high-grade
histologic features are seen in the majority of cases (Fig. 13.26D).
Papillary meningiomas correspond to WHO grade III; they are highly
aggressive and have a propensity to invade, recur, and metastasize.80,81
In one review of 46 cases, 75% invaded the brain or other adjacent
structures, 55% recurred, and 20 metastasized.82 Roughly half of the
patients die of disease. They also tend to occur in younger patients,
roughly half presenting in children.80 Occasional examples combine
papillary architecture with rhabdoid cytology (Fig. 13.27A).83
Rhabdoid Meningioma
Representing another rare variant (<1%), rhabdoid meningiomas contain
discohesive aggregates of classic rhabdoid cells (see Fig. 13.27).84,85 When
fully developed, the latter contain large eccentric vesicular nuclei, variably
prominent nucleoli, and densely eosinophilic cytoplasm with paranuclear
globular or whorled filamentous inclusions (Fig. 13.27B and C). Ultra-
structurally, the paranuclear inclusions correspond to whorled bundles
of intermediate filaments, the latter most commonly being vimentin
(Fig. 13.27C), although GFAP and desmin immunoreactivity have also
been reported occasionally.85–87 Most meningiomas with fully developed
rhabdoid cells have additional features of malignancy, such as high
mitotic indices, cellular anaplasia, and necrosis. Such examples are highly
aggressive clinically and have therefore been assigned a WHO grade of
III. In one series of 15 cases, 13 (87%) had recurrences, 2 (13%) had
extracranial metastasis, and 8 (53%) had died of disease.85 Occasionally,
though, rhabdoid cells are seen focally in otherwise benign (or atypical)
meningiomas, and often the rhabdoid features are not fully developed
(e.g., still cohesive, eccentric eosinophilic cytoplasm without paranuclear
inclusions). Such cases do not automatically behave more aggressively;
284
therefore, it is recommended such cases be designated as “meningioma
with focal rhabdoid features, WHO grade I,” with a comment that closer
follow-up may be warranted given at least a potential for more aggressive
behavior.39 As mentioned previously, rhabdoid cytology is occasionally
combined with papillary architecture. Most recently, it has been shown
that the most aggressive rhabdoid meningiomas often lose BAP1 expres-
sion (Fig. 13.27D), a finding that can be associated with germline as
well as somatic BAP1 mutations.88 Lastly, it should be noted that rare
“pseudo-rhabdoid” meningiomas show complex interdigitating cell
processes on electron microscopy, rather than whorled bundles of
intermediate filaments; the significance of this rare variant is unknown
at this time.89
Other Meningioma Patterns Not Included in the WHO
A small series of six oncocytic meningiomas was initially reported in
1997.90 Histologically, these were characterized by granular eosinophilic
cytoplasm that corresponded to mitochondrial accumulations (Fig.
13.28). These tumors had both aggressive histologic features and frequent
recurrences. However, a second group subsequently reported benign
histology and clinical behavior in five additional cases.91 Therefore,
additional experience is needed and, to date, it has not been officially
recognized by the WHO. Meningiomas with granular cytoplasm due
to lysosome accumulation or other cellular structures are even rarer92,93
and perhaps overlap somewhat with the metaplastic-xanthomatous
variant. Similarly, a “sclerosing” or “sclerosing whorling” variant has been
reported and is defined by extensive hyalinization that obscures
the underlying meningothelial cytology (Fig. 13.29).62,94–96 Originally
described as a pediatric variant, it has subsequently been reported in
adults, sometimes associated with more conventional variant histology
and sometimes with the clear cell variant. A few have shown the unusual
feature of GFAP positivity in meningothelial cells. Therefore, it remains
unclear whether this is truly a distinct variant or merely an exaggerated
form of the normal hyalinization encountered to lesser degrees in nearly
all types of meningioma. Another rare histologic pattern reported in
the literature is the mucinous meningioma, although it overlaps with
both the chordoid and metaplastic-myxoid subtypes.97 Occasionally,
meningiomas will form diagnostically confusing structures such as
nuclear palisades resembling the Verocay bodies of schwannoma (Fig.
13.30) or meningothelial rosettes simulating those of embryonal neoplasms
 Meningiomas

13

A B

C D
Fig. 13.27  (A–D) Rhabdoid meningiomas. Rhabdoid features include large cells with vesicular nuclei, variably prominent nucleoli, eccentrically placed eosinophilic cytoplasm, and
globular paranuclear inclusions (A, B), the latter of which are often vimentin immunoreactive (C). A subset of rhabdoid meningiomas show loss of BAP1 expression, often accompanied
by aggressive clinical behavior (D, Complements of Dr. Sandro Santagata, Brigham and Women’s Hospital, Boston, MA.)

A B
Fig. 13.28  (A, B) “Oncocytic meningioma.” Enlarged cells with coarsely granular cytoplasm (A) due to accumulation of mitochondria, the latter highlighted on an antimitochondrial
immunostain (B).

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A B

C D
Fig. 13.29  (A–D) “Sclerotic whorling meningioma.” This meningioma had small foci of classic cytology, but was predominantly composed of large hypocellular zones replaced by
dense collagenization (A–C). Meningothelial cells showed strong PR positivity (D).

A B C
Fig. 13.30  (A–C) Meningioma with extensive nuclear palisades. Nuclear palisades in meningioma (A) may mimic the Verocay bodies of schwannoma, but retain expression of
meningothelial markers such as EMA (B) and progesterone receptor (C).

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13

A B C
Fig. 13.31  (A–C) Meningothelial rosettes. Meningothelial rosettes feature central fibrillar material (A) or lumens (not shown) and are primarily composed of vimentin-positive cell
processes (B) and/or collagen (C; trichrome).

A B C
Fig. 13.32  (A–C) Granulofilamentous inclusions. Granulofilamentous meningiomas feature eosinophilic inclusions (A) that may superficially resemble those of rhabdoid meningioma,
but are more irregular and contain clear vacuoles with one or more central granules. The inclusions appear red on trichrome stain (B) and the vacuoles can be vimentin positive (C).

(Fig. 13.31); the central zones of the latter may be variably composed
of cell processes and/or collagen.98 Finally, there are rare meningiomas
with unusual inclusions or extracellular deposits, such as the granulo-
filamentous meningioma, containing eosinophilic cytoplasmic inclusions
with one or more vacuoles (Fig. 13.32), or the meningioma with tyrosine
crystals (Fig. 13.33)99; the granulofilamentous variant may be confused
with rhabdoid meningiomas but has generally been considered benign
in the few cases reported to date.100,101
Metastasis of and to Meningiomas
Metastasis is an exceedingly rare event, estimated to involve only 0.1%
of meningiomas. Forms of spread include both systemic and CSF
(e.g., drop metastases). Most metastatic meningiomas are histologi-
cally malignant, although in up to 34% of all examples (especially if
including incidentally identified metastases), it occurs in tumors
without any aggressive histologic features. These “benign metastasiz-
ing meningiomas” spread to the lungs and pleura most often (Fig.
13.34), followed in frequency by the musculoskeletal system, CSF,
liver, reticuloendothelial system, and kidneys; the prognosis for such
patients can be surprisingly favorable; and, in some, the metastatic foci
are clinically silent.102,103 In general, factors associated with increased
risk of metastasis include prior craniotomy, venous sinus invasion, local
recurrence, WHO grade III, and papillary and/or rhabdoid variant
morphology.102
For reasons that remain enigmatic, meningioma is also one of the
most common receptor neoplasms for systemic metastases. Breast and
lung carcinomas are particularly common primaries to metastasize to
meningioma, although other malignancies have also been reported.104 In
most cases, the meningioma is histologically benign, although sometimes
the cytology of the metastasis and the meningioma are similar enough

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A B
Fig. 13.33  (A, B) Tyrosine crystals. These rare deposits feature petal-shaped eosinophilic crystals (A) that appear red on trichrome stain (B).

A B

C D
Fig. 13.34  (A–D) Benign metastasizing meningioma. This patient with a previously resected intracranial meningioma was found to have multiple lung nodules years later, one of
which was PET avid (A; arrow) and underwent needle biopsy. The histology resembled a benign meningioma (B) with patchy EMA positivity (not shown), lack of keratin expression
(not shown), diffuse somatostatin receptor 2a expression (C), extensive progesterone receptor positivity (D), and a low Ki-67 labeling index (not shown).

288

that only careful inspection reveals the malignant component (Fig. 13.35).
Immunohistochemical studies are useful in this scenario.
Differential Diagnosis
Most meningiomas are readily diagnosed from routine H & E–stained
sections alone. However, the remarkably wide morphologic spectrum
that can be encountered causes considerable diagnostic difficulties in
selected cases (Table 13.3), particularly with some of the rarer or higher
grade variants. The majority of differential diagnoses can be resolved
using immunohistochemistry (see Ancillary Diagnostic Studies section),
although in rare and often poorly differentiated meningiomas, ultra-
structural or genetic studies may be required to establish the diagnosis.
The differential between fibrous meningioma and schwannoma is a
common one, especially in the cerebellopontine angle and in the spinal
cord, where both tumors are regularly encountered. This is also a common
differential in the setting of NF2, where patients are predisposed to
both tumor types (see Chapter 22). Whorls and psammoma bodies are
found at least focally in most fibrous meningiomas, but one is occasionally
surprised by schwannomas that contain well-developed whorls and
meningiomas with Verocay body–like structures (see Figs. 13.12C and
A B
C D
Fig. 13.35  Benign meningioma with metastatic lung carcinoma. (A, B) Typical dural-based meningioma (A) with slightly enlarged, mitotically active epithelioid cells in central
portion of tumor (B; left side). (C) Strong cytokeratin was seen in the central focus of metastatic carcinoma, as well as CK7, CEA, and TTF-1 (not shown). (D) In contrast, the
peripheral zones of benign meningioma were strongly vimentin positive.
Meningiomas
13.30). Of note, up to 70% of fibrous meningiomas are S-100 positive,
although this is often patchy, rather than the diffuse pattern encountered
in schwannomas. A similar pitfall is that SSTR2a can be positive in
13
both.105,106 Unlike meningothelial cells, Schwann cells lay down a continu-
ous basement membrane. Therefore, reticulin histochemical and type
IV collagen immunohistochemical stains are useful to highlight the
widespread peritumoral basement membrane network of schwannomas.
The basal lamina expression is also demonstrable by electron microscopy,
whereas fibrous meningiomas show classic ultrastructural features of
meningiomas in general (see Ancillary Diagnostic Studies section). Also,
schwannomas are strongly SOX10 positive, while meningiomas are
typically negative.107 Lastly, schwannomas are consistently negative for
EMA, whereas most fibrous meningiomas will show at least focal
immunoreactivity.
In small tumors, the differential diagnosis between meningothelial
meningioma and meningothelial hyperplasia can occasionally be chal-
lenging, though the latter never invades into the dura and is often
associated with other pathologic features, such as hemorrhage, inflam-
mation, or the presence of another neoplasm.108 Most cases of hyperplasia
are also detected incidentally.
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Table 13.3  Differential Diagnoses for Meningioma Variants The primary diagnostic consideration for psammomatous meningioma
Variant DDx is a rare entity known as calcifying pseudoneoplasm of the neuraxis
(CAPNON). This lesion is considered an unusual reactive process that
Meningothelial or Transitional Metastatic Carcinoma
Meningothelial Hyperplasia
involves the meninges and/or adjacent bone of the skull or spine.109–111
Pituitary Adenoma/Neuroendocrine Tumor MR imaging often reveals a lobulated, rim-enhancing mass, the center
of which is hypodense on all sequences, suggesting calcification (Fig.
Fibroblastic Schwannoma 13.36A and B). An older term for this lesion was fibro-osseous lesion of the
Solitary Fibrous Tumor/Hemangiopericytoma (SFT/HPC)
neuraxis, and some have amusingly referred to this lesion as “CRUDoma”
Psammomatous Reactive Process With Calcification due to its distinctive basophilic “crud” (Fig. 13.36C). Most reported cases
Calcifying Pseudoneoplasm of the Neuraxis have been sporadic and idiopathic in nature. The basophilic material is
Calcium Pyrophosphate Deposition Disease (Tophaceous nonetheless fairly distinctive in terms of a fibrillated quality at least focally,
Pseudogout) which resembles “chicken feet or footprints.” It is variably calcified or
Angiomatous (Vascular) Hemangioblastoma even ossified. The etiology of this material remains a mystery, but often
Vascular Malformation is associated with reactive epithelioid macrophages and meningothelial
cells (Fig. 13.36D). When arranged in multilayered nests or whorls, the
Microcystic Diffuse or Pilocytic Astrocytoma
latter constitutes a form of meningothelial hyperplasia and should not
Clear Cell Meningioma
be mistaken for an underlying meningioma. Inflammation and foreign
Secretory Metastatic Adenocarcinoma body reaction may also be encountered, as well as crystalline deposits
resembling the calcium pyrophosphate of pseudogout (see upcoming
Lymphoplasmacyte Rich Inflammatory/Infectious Process
IgG4 Disease/Collagen Vascular Disorders
discussion).112 Surgery is usually curative. Another rare differential
Marginal Zone (MALT) Lymphoma with psammomatous meningioma is indeed tophaceous pseudogout or
Meningothelial Hyperplasia calcium pyrophosphate disease (CPPD) (Fig. 13.37); such cases have
Angiomatoid Fibrous Histiocytoma (AFH) been reported primarily in the spine, though the distinctive rhomboidal
calcium pyrophosphate crystals (Fig. 13.37B) appear quite different than
Metaplastic (Osseous, Soft Tissue Tumors
the concentric layers of calcium in psammoma bodies.113,114
Cartilaginous, Xanthomatous, Histiocytic Disorders
Myxoid, Lipidized, etc.)
Of the rare benign histologic variants, the secretory, microcystic,
lymphoplasmacyte-rich, and chordoid meningiomas are most likely to
Clear Cell (WHO Grade II) Metastatic Renal Cell Carcinoma cause diagnostic difficulties. Secretory meningiomas may be confused with
Microcystic Meningioma adenocarcinomas, since they form gland-like spaces with both cytokeratin
Hemangioblastoma
and CEA positivity (see Fig. 13.16). However, the pseudopsammoma
Chordoid (WHO Grade II) Chordoma bodies are fairly distinctive and regions of more typical meningioma
Chordoid Glioma of Third Ventricle are usually also present. Microcystic meningiomas superficially resemble
Epithelioid Hemangioendothelioma low-grade astrocytomas (see Fig. 13.15B), a mimicry that may actually be
Papillary (WHO Grade III) Papillary Ependymoma
more than just superficial at the time of frozen section. However, the dural
Astroblastoma attachment is an important clue and areas of more classic meningioma
Meningeal SFT/HPC are often found as well (Fig. 13.15A). Nonetheless, if it remains unclear
Metastatic Malignancy even on permanent sections, the lack of GFAP, OLIG2, and SOX10
immunoreactivities argue against this diagnostic consideration. The
Rhabdoid (WHO Grade III) Metastatic Malignancy
controversial nature of the lymphoplasmacyte-rich meningiomas has
Atypical Teratoid/Rhabdoid Tumor
GBM/Gliosarcoma
already been discussed. Care is needed to avoid misinterpretation of
Granulofilamentous Meningioma scattered hyperplastic meningothelial nests as being neoplastic and a
Rhabdoid-like Meningioma With Complex Interdigitating number of other lymphoplasmacyte-rich disorders should be excluded,
Cell Processes (Inclusions) including various infections, sarcoidosis, IgG4-associated pachymeningitis
(Fig. 13.38), inflammatory myofibroblastic tumor, meningeal rheumatoid
Anaplastic (WHO Grade III) Metastatic Carcinoma/Melanoma
nodules, Wegener granulomatosis, Rosai-Dorfman disease (extranodal
Meningeal SFT/HPC
Other Meningeal Sarcomas
sinus histiocytosis), Castleman disease, and low-grade lymphomas, such
as marginal zone lymphoma (see also Chapters 14, 17, and 23).
The differential between chordoid meningioma and chordoma may
The occasional difficulty with the differential diagnosis with astro- be problematic in diagnosing a midline, skull base tumor. However, this
cytoma can usually be resolved by immunostaining for glial markers is rare and most chordoid meningiomas present as large, dural-based
such as GFAP, OLIG2, and SOX10, which are typically positive in supratentorial masses (see Fig. 13.22A), without involvement of the sites
astrocytomas and nearly always negative in meningiomas. Meningiomas, most commonly implicated in chordoma, such as the clivus or sacrum.
particularly the meningothelial type, may superficially mimic metastatic In addition to neuroimaging, immunocytochemistry may be helpful.
carcinoma, especially in higher grade examples (see Fig. 13.24A). EMA Chordomas are typically much more strongly and diffusely cytokeratin
is positive in both, although usually stronger in carcinomas, most of and S-100 positive than chordoid meningiomas, as well as expressing
which also strongly express various cytokeratins (see Fig. 13.35C). In the more specific marker, brachyury.115
contrast, even poorly differentiated meningiomas are typically strongly Clear cell meningiomas may superficially resemble metastatic renal
and diffusely positive for vimentin, a nonspecific finding that would cell carcinoma (see Fig. 13.21), although they have a fairly unique
nevertheless be uncommon in metastatic carcinomas (see Fig. 13.30D). pattern of dense perivascular and interstitial collagen deposition that
Lastly, SSTR2a is typically diffusely positive in even the most anaplastic is not a feature of classic renal cell carcinoma.61 Both tumors may
meningiomas, whereas metastatic carcinomas lack this pattern with have abundant cytoplasmic PAS-positive diastase digestible glycogen,
the exception of neuroendocrine tumors.106 although this is not true of microcystic meningioma, which also

290
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13

A B

C D
Fig. 13.36  Calcifying pseudoneoplasm of the neuraxis. T1-weighted MRI with gadolinium shows a meningeal-based ring-enhancing mass with a hypodense center (A). This center
remains hypodense on other modalities, including T2-weighted images (B). On histology, the center of the lesion consists of variably calcified, fibrillated basophilic material (C),
which is surrounded by epithelioid macrophages and reactive meningothelial cells (D).

A B C
Fig. 13.37  (A–C) Calcium pyrophosphate deposition disease (tophaceous pseudogout). This spinal contrast-enhancing mass was favored to represent a meningioma on MRI (A).
Histology showed typical rhomboid crystalline deposits (B, C) that were birefringent on polarized light (not shown).
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 Practical Surgical Neuropathology

A B

C D
Fig. 13.38  (A–D) IgG4-associated pachymeningitis. Postcontrast MR images showed both diffuse dural thickening and meningioma-like tumor masses (A). On histology, there is
a lymphoplasmacytic infiltrate as well as meningothelial hyperplasia (upper half), which does not invade the underlying dura (B). Germinal centers and numerous plasma cells were
evident (C), with many of the latter staining for IgG4 (D).

occasionally enters the differential. Renal cell carcinomas are more
likely to be positive for carbonic anhydrase IX (CA IX), cytokeratin,
CD10, and RCC and negative for progesterone receptor than clear cell
meningiomas.61,116,117
Papillary meningioma should be distinguished from other papillary
neoplasms, including ependymoma, choroid plexus tumors, and astro-
blastoma (see Fig. 13.26). Strong GFAP positivity should aid in establish-
ing a diagnosis of ependymoma or astroblastoma. Choroid plexus tumors
are strongly cytokeratin reactive. Rhabdoid meningioma (see Fig. 13.27)
may look similar to other rhabdoid neoplasms; however, atypical teratoid/
rhabdoid tumors (AT/RTs) are almost exclusively encountered in infants,
whereas rhabdoid meningiomas mostly afflict adults. The latter also do
not inactivate the INI1/hSNF5 (SMARCB1) gene, and, therefore, nuclear
protein expression is retained in rhabdoid meningiomas and lost in
AT/RTs118; in contrast, a subset of rhabdoid meningiomas lose BAP1
expression.88
Occasionally, anaplastic meningiomas develop branching, thin-walled
gaping blood vessels, similar to those of solitary fibrous tumor/
hemangiopericytoma (SFT/HPC; Fig. 13.39). In the past, such cases
were used as evidence that these two tumor types were related
(“angiomatous meningiomas”). However, the clinicopathologic features
of these two tumor types differ greatly (see Chapter 14) and those with
otherwise classic features of meningioma should be diagnosed as such.
Most cases of SFT/HPC do not express EMA or show diffuse SSTR2a
positivity, although occasional examples are encountered with focal
staining of these markers.119 In contrast, only the SFT/HPCs feature
nuclear STAT6 positivity,120 often in addition to extensive positivity for
both CD99 and bcl-2. Lastly, these tumors are associated with NAB2-
STAT6 fusions,120,121 rather than the typical genetic features of menin-
giomas (see Genetics section).
Ancillary Diagnostic Studies
Immunohistochemistry
Immunohistochemistry supports the dual mesenchymal and epithelial-
like features of meningothelial cells. The vast majority of meningiomas are
strongly positive for vimentin (see Figs. 13.24C, 13.25F, 13.26F, 13.27C,
13.31B, 13.32C, 13.35D) and show patchy, often modest EMA expres-
sion, the latter representing the most commonly utilized antibody for
supporting a meningioma diagnosis (see Figs. 13.12D, 13.13D, 13.15C,
13.18D, 13.21G, 13.22E, 13.24D, 13.30B). Nevertheless, it has long been

292

A be as biologically relevant as more diffuse ones.126
B
Fig. 13.39  (A, B) Anaplastic meningioma. Focal hemangiopericytoma-like vascular pattern
in an anaplastic meningioma (A). Other regions showed classic features of meningioma (B).
appreciated that EMA suffers from insufficient sensitivity and specificity.
As such, another marker, somatostatin receptor 2a (SSTR2a), has been
reported as a more sensitive and relatively specific marker (see Figs.
13.14D, 13.17D, 13.18E, 13.21H, 13.34C), an exception being its strong
immunoreactivity in neuroendocrine tumors.106 Cytokeratin is usually
negative or only focally positive, with the exception of secretory menin-
gioma, which strongly expresses cytokeratin in the cells surrounding the
pseudopsammoma bodies (see Fig. 13.16E). The latter structures (and
sometimes the cells surrounding them) are also immunoreactive for
CEA (Fig. 13.16F), CA 19-9, alpha-1-antitrypsin, and immunoglobulins,
which are typically negative in other types of meningioma.122 Variable
S-100 protein expression is seen most commonly in the fibrous subtype.
Except in very rare cases (most often rhabdoid meningiomas), GFAP
is negative; however, this stain is useful for highlighting foci of brain
invasion in equivocal cases (see Fig. 13.23C). Additional meningothelial
markers that may be useful and are commonly positive include cathepsin
D, E-cadherin, claudin-1, and platelet-derived growth factor receptor
beta.123 Unfortunately, most of these markers are not terribly specific.
Other particularly useful ancillary markers for grading and prognosis
include progesterone receptor (PR; see Hormone Studies section) and
Ki-67 (see Figs. 13.20E, 13.24E, 13.26D). As with many other tumor
types, Ki-67 labeling provides additional information regarding the
proliferation index. Whether or not this labeling index (LI) represents
Meningiomas
an independent prognostic variable has been debated, since it usually
increases proportionally to both the mitotic index and the histologic
grade in general.124,125 Another difficulty comes from interlaboratory
13
variability in staining and counting methods, making it difficult to
extrapolate cutoff values from one lab to the next. Nonetheless, the
Ki-67 LI is particularly useful in borderline cases falling between either
benign and atypical or atypical and anaplastic meningioma; it is mainly
in these borderline cases that Ki-67 and PR studies add value. Those
with higher than expected LI may behave more aggressively and those
with lower than expected LI more indolently. Although it is not formally
used in histologic grading, this information may nonetheless be useful
in guiding patient management. For instance, a patient with a “benign
meningioma with increased proliferative index, WHO grade I” may need
to be followed more carefully for potential tumor recurrence, especially
if subtotally resected. Of interest (yet perhaps not surprisingly), one
study suggests that very focal elevations in proliferative index may not
Hormone Studies
The study of sex hormones and their receptors in meningiomas has
been of great interest for many years, particularly given the well-known
female patient predominance, reports of rapidly worsening visual
symptoms during pregnancy, and modest epidemiologic links between
the incidence of meningioma and breast carcinoma, another hormone-
associated tumor of women.127,128 In terms of enhanced pregnancy-
associated growth, this is probably more the exception than the rule.
Nonetheless, these rare examples can be clinically dramatic with
symptoms presenting typically in the third trimester most often from
optic nerve compression; of interest, the symptoms often resolve
postpartum and recur in subsequent pregnancies.129–132 Based on this
unusual behavior and a general lack of increased mitotic figures on
histology, the “growth” is thought to primarily result from pregnancy-
associated vascular congestion and cytotoxic edema, rather than true
tumor cell proliferation due to hormone stimulation, a finding supported
by the increased vascularity, hemorrhage, and intracellular/extracellular
edema found histologically in some of the resected cases.131 Nevertheless,
reports of PR expression in 50% to 80% of meningiomas (see Figs.
13.22F, 13.29D, 13.30C, 13.34D) have generated great interest in both
the clinical and scientific (not to mention medicolegal) communities.
In comparison, estrogen receptor expression is relatively rare and, typically,
low level.133
Degrees of PR expression are highly variable, but they are roughly
inversely proportional to grade, such that the majority of benign menin-
giomas and even reactive meningothelial proliferations are strongly
immunoreactive. A patchy or mosaic pattern of staining is also common
and the significance of this intratumoral heterogeneity remains unclear
(Fig. 13.40A and B). In contrast, most atypical, anaplastic, and other
clinically aggressive meningiomas are completely negative or show only
focal staining (see Fig. 13.20F).123,134,135 Unfortunately, there remains a
great overlap in PR status among WHO grades and clinical subsets.
Whether or not PR status is an independent prognosticator remains
uncertain. Therefore, its routine use is not warranted. Nonetheless, it
may be particularly useful in borderline atypical cases, especially when
utilized in combination with MIB-1 (Ki-67) labeling indices. In other
words, “loss of expression” is worrisome for more aggressive behavior.
The precise biologic role of PR also remains unclear. Arguing in
favor of a tumorigenic or growth stimulatory function is the female
predominance of meningiomas and epidemiologic data suggesting a
minimally increased risk of meningioma for women using oral contracep-
tives or hormone replacement therapy.1 Against a critical role, however,
is the common presence of PR in the meningiomas of men and children,
a lack of compelling growth stimulation by progesterone in vitro, and
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 Practical Surgical Neuropathology
A lipid, lysosomes, and more.54
B within these paranuclear inclusions.85 As the name implies, oncocytic
Fig. 13.40  (A, B) Progesterone receptor (PR) immunohistochemistry. Meningiomas that
are positive for PR often display a mosaic or heterogeneous pattern of immunoreactivity
with clusters of strongly positive nuclei alternating with negative ones.
a peak incidence in women at roughly 60 years of age (i.e., beyond
childbearing years or periods of life when circulating progesterone levels
are normally high). Despite these observations, it was hoped that therapy
with antiprogestational agents such as mifepristone (RU-486) might be
useful as an ancillary therapy for unresectable meningiomas; unfortu-
nately, this has not borne out clinically, perhaps because the most biologi-
cally aggressive meningiomas are the ones least likely to express PR.136
Additional hormone receptors detected in meningiomas include the
androgen, prolactin, growth hormone, thyroid hormone, and cholecys-
tokinin receptors.137–141 The potential biologic and therapeutic roles for
these receptors have yet to be fully elucidated.
Electron Microscopy
Electron microscopy (EM) has mostly been replaced by immunohis-
tochemistry (see earlier discussion) for the diagnosis of meningioma
and its variants. Nevertheless, classic ultrastructural features of menin-
gioma, regardless of subtype, include complex intercellular junctions,
interdigitating cell processes, and abundant intracellular filaments. The
syncytium-like pattern of meningothelial meningiomas seen at the light
microscopic level is due to an abundance of interdigitating cell processes,
creating fuzzy rather than sharp intercellular borders. Ultrastructurally,
they have been likened to the interlocking pieces of a jigsaw puzzle.
294
Like normal arachnoidal cap cells, meningioma cells are interconnected
by intercellular junctions, including desmosomes, hemidesmosomes,
and gap junctions. The abundance of 10-nm intermediate filaments is
usually due to abundant vimentin expression. The intermediate filaments
tend to converge on the cytoplasmic side of desmosomes or form a
tight whorling pattern in the cytoplasm, most commonly in the rhabdoid
variant. As with routine light microscopy, nuclear pseudoinclusions are
often prominent and represent cytoplasmic invaginations. In contrast,
the clear intranuclear vacuoles occasionally contain glycogen particles,
but most often represent empty nonmembrane bound spaces.142 The
presence of classic meningothelial features by EM is particularly useful
in establishing the lineage in poorly differentiated meningiomas, such
as the anaplastic and papillary subtypes, each of which often generates
extensive differential diagnostic considerations.27,143 Lastly, “metaplastic
meningiomas” typically do not show evidence of true metaplasia, but
rather retain meningothelial features; they simply accumulate cytoplasmic
In addition to the nearly universal ultrastructural features described,
some meningioma variants may show distinctive features. For instance,
spider-like cytoplasmic processes line the intercellular spaces of microcystic
meningiomas. There are also scattered desmosomes, and the widened
extracellular spaces are filled with finely granular material, reminiscent
of the EM findings in normal arachnoidal trabecular cells.45 Despite
the presence of xanthoma-like cells by light microscopy, they typically
do not contain lipid droplets. The pseudopsammoma bodies of secretory
meningiomas are seen within gland-like spaces lined by microvilli.144 The
inclusions may appear amorphous, particulate, vesicular, or lamellar.
The cells surrounding the inclusions appear epithelial-like with electron
dense cytoplasm, abundant filaments, and numerous desmosomes. The
glycogen-rich cytoplasm of clear cell meningiomas is easily confirmed
by EM, and occasional amianthoid-type collagen fibers may be encoun-
tered.60 Rhabdoid meningiomas have the classic whorled bundles of
intermediate filaments, although entrapped organelles are also common
meningiomas have cytoplasm stuffed with mitochondria,90 whereas the
even rarer granular subtypes have lysosomal accumulations93 or other
membrane bound inclusions.92
Genetics
A detailed discussion of meningioma genetics is beyond the scope of
this book, and the interested reader is referred to recent reviews of this
topic.75,145 Nonetheless, much has been learned over the last few decades
and a putative model of molecular tumorigenesis and malignant progres-
sion of meningiomas is illustrated in Fig. 13.41.
Cytogenetics
Consistent cytogenetic abnormalities are found in most meningiomas
and mostly involve common chromosomal losses that result in a progres-
sive state of hypodiploidy.146,147 The most frequent chromosomal
abnormality is monosomy 22 or, less often, a partial 22q deletion; these
changes are encountered in about 40% to 70% of cases. Following
monosomy 22, losses involving chromosomes 6, 10, 14, and 18 are most
common and often seen in higher grade tumors. In terms of structural
alterations, loss of chromosome 1p is by far the most common, again
being associated with more aggressive meningiomas. In general, the
more aggressive and higher grade the meningioma, the more abnormal
the karyotype becomes.
Molecular Genetics
Molecular genetic and molecular cytogenetic techniques, such as loss of
heterozygosity (LOH) or fluorescence in situ hybridization (FISH), have
also demonstrated frequent 22q losses in benign meningiomas, with
 Meningiomas

Meningothelial Hyperplasia Arachnoid Cap Cells

13

Gain of PR expression (65%)

Benign Meningioma Atypical Meningioma Anaplastic Meningioma

Chromosome 22q loss (40–70%)
NF2 mutations (30–60%)
TRAF7 and KLF4 mutations (10–25%;
skull base and secretory subtype)
AKT1 mutations (10%; skull base)
SMO mutations (5%; skull base)
PIK3CA mutations (5%; skull base)
SMARCB1 mutations (rare;
schwannomatosis)
SUFU or PTCH1 mutations (rare; Gorlin
/nevoid basal cell carcinoma syndrome)
Gain of PR expression (50–90%)
Loss of TSLC1 expression (30–50%)
EGFR activation
PDGFRB activation
TERT promoter mutation (5–10%)
SMARCE1 mutation (clear cell subtype)
Chromosome 1p loss (40–75%)
Chromosome 6q loss (30%)
Chromosome 10 loss (30–40%)
Chromosome 14q loss (40–60%)
Chromosome 18q loss (40%)
Gains of 1q, 9q, 12q, 15q, 17q, 20q
(30–50% each)
Loss of TSLC1 expression (70%)
Loss of PR expression (60–80%)
Activation of Notch, WNT, IGF, or
VEGF pathways
TERT promoter mutation (20–30%)
Chromosome 1p loss (70–100%)
Chromosome 6q loss (50%)
9p21 (CDKN2A/B, p14ARF) loss (60–80%)
Chromosome 10 loss (40–70%)
Chromosome 14q loss (60–100%)
Chromosome 18q loss (60–70%)
NDRG2 hypermethylation (70%)
Loss of TSLC1 expression (70%)
Loss of PR expression (80–90%)
17q23 amplification (RPS6KB1, others)

Fig. 13.41  Genetic model of meningioma tumorigenesis and malignant progression (modified from WHO 2016 scheme). Pathways that are almost certain are shown with solid
arrows, whereas those that are less certain are displayed using dashed arrows. The most common alterations and their frequencies are shown at each stage of development.

deletions of other chromosomal regions as meningiomas progress to
WHO grades II and III.1 As such, this provides a potential ancillary test
to support a suspicion of meningioma, as opposed to a meningothelial
hyperplasia or nonmeningothelial neoplasm (see Fig. 13.24F). Deletions
of 1p, 10, and 14q are especially frequent in the high-grade meningiomas,
potentially providing ancillary support for the likelihood of aggressive
behavior in a known meningioma or for the diagnosis of high-grade
meningioma versus other malignant neoplasms (Fig. 13.24G). Of interest,
such deletions in recurrent high-grade meningiomas are often already
detectable in the original tumors at a time when they may have appeared
otherwise benign.148 In fact, a comparison of benign meningiomas with
and without subsequent recurrences revealed a statistically increased
likelihood of 14q deletions.149
These common chromosomal losses strongly suggest the presence
of meningioma tumor suppressor genes. The most studied has been
chromosome 22q, with the NF2 gene being well established as the main
target of inactivation for both sporadic and NF2-associated meningiomas.1
Genetic studies suggest that other chromosome 22q loci may also play
a role in rare examples. In atypical and anaplastic meningiomas, NF2
gene mutations occur in approximately 70% of cases, consistent with a
role for NF2 inactivation in the formation, rather than progression, of
meningiomas. Interestingly, the frequency of NF2 gene mutations varies
somewhat among the three most common variants of meningioma. The
fibroblastic and transitional meningiomas have detectable NF2 gene muta-
tions in roughly 70% to 80%, whereas they are found in only about 25% of
meningothelial meningiomas, particularly those encountered at the skull
base.150,151 This suggests that many meningothelial meningiomas could
arise from alternate (i.e., non-NF2 associated) tumorigenic pathways.
Recently, a number of other driver mutations have also been identified,
mostly in skull base meningiomas lacking NF2 mutations. Notably,
mutations of TRAF7 and KLF4 are nearly always combined, are present
in nearly all of the secretory meningiomas, and are found in roughly
10% to 25% of meningiomas overall.1,51,152 AKT1, SMO, and PIK3CA
mutations are each detected in about 5% to 10% of meningiomas and
are of additional interest due to the possible use of targeted therapies
for patients with mutant-specific meningiomas that have failed con-
ventional surgical and radiation approaches.1,152–155 SMARCB1, SUFU,
and PTCH1 mutations are each rare, but associated with familial tumor
predisposition syndromes such as schwannomatosis and Gorlin (nevoid
basal cell carcinoma) syndromes (see Chapter 22).145,156–158
For most of the progression-associated losses, the relevant tumor
suppressor genes have yet to be identified (see Fig. 13.41). However,
an important association has been found with promoter region mutations
of the TERT gene (same mutations as seen in glioblastomas and oligo-
dendrogliomas) and aggressive clinical behavior.159–161 As such, testing
may be useful in grade II and III meningiomas, as well as clinically
worrisome grade I examples. Additionally, mutations of SMARCE1
(another member of the SWI/SNF chromatin remodeling complex with
SMARCB1) have been identified in both familial and sporadic clear
cell meningiomas.65,66,145 Investigations of known tumor suppressor genes
have revealed only rare alterations in meningiomas. Of interest, however,
losses of the CDKN2A/p16 region on 9p21 are seen in the majority of

295
 Practical Surgical Neuropathology
anaplastic meningiomas (see Fig. 13.24H), where they are known to be
associated with poor survival.28,162 The alternate (“optimist”) viewpoint
is that the roughly one-third of patients whose anaplastic meningiomas
lack 9p21 deletions have surprisingly long survival times, with tumor
biology more closely resembling that of atypical meningioma. For this
reason, there may be prognostic value in the analysis of 9p21 by FISH
in anaplastic meningiomas.
Treatment and Prognosis
Given the slow growth and indolent behavior of most meningiomas,
a “watch and wait” approach is commonly utilized for many patients,
especially the elderly and those who had their meningioma identified as
an incidental finding on neuroimaging. For patients with symptomatic
disease or evidence of tumor growth on serial imaging, however, definitive
therapy is often necessary. Surgery is the standard and most effective
therapy for meningiomas, although radiation is also a major treatment
modality, particularly for patients where surgery carries high risk.25,163
Adjuvant radiotherapy has been shown to significantly reduce recurrence
rates in subtotally resected or higher grade meningiomas. Additionally,
newer forms of delivery have become increasingly popular, especially for
smaller tumors or postsurgical residual masses. These include stereotactic
radiosurgery (e.g., “gamma knife”), as well as fractionated stereotactic,
intensity modulated, and proton beam forms of radiotherapy. As with
any form of radiation therapy, however, the potential benefits must
be weighed against the low but significant risks of side effects, such
as radiation-induced secondary neoplasms and leukoencephalopathy-
associated cognitive decline, particularly in younger patients with long
life expectancies (see Chapter 21).
Using the 2016 WHO scheme (see Table 13.1), roughly 75% to 80%
of meningiomas are benign (WHO grade I), 15% to 25% are WHO grade
II, and 1% to 3% are malignant (WHO grade III). Gross totally resected
WHO grade I meningiomas are appropriately designated “benign,” since
they show no increased mortality when compared with age- and sex-
matched controls, but have a roughly 5% recurrence rate at 5 years, which
continues to increase steadily with longer follow-up times.24,27 In subtotally
resected cases, this risk of recurrence increases considerably (~30% to
40% at 5 years), with extent of resection itself being highly linked to
tumor location, such that meningiomas in surgically challenging regions
(e.g., skull base) are more likely to be limited to subtotal resection. The
high-grade variants are associated with statistically significant increased
risks of both recurrence and death, although in general, the WHO grade
II meningiomas often recur even with gross total resection, while the
WHO grade III tumors have high mortality rates.
Meningiomas that can no longer be treated with any additional
surgery or radiation constitute a considerable therapeutic challenge.
Standard chemotherapy and hormonal therapy approaches have been
disappointing to date, although potential strategies currently being
explored in early stages include targeted therapies and immunother-
apy.155,164–169 Additional experience in large clinical trials will be needed
to further assess their efficacies.
Suggested Readings
Perry A, Louis DN, Budka H, et al. Meningioma. In: Louis DN, Ohgaki H, Wiestler OD, et al., eds.
WHO Classification of Tumours of the Central Nervous System. Revised 4th ed. Lyon: IARC;
2016:232–245 [Chapter 10].
Perry A, Scheithauer BW, Stafford SL, et al. “Malignancy” in meningiomas: a clinicopathologic study
of 116 patients, with grading implications. Cancer. 1999;85:2046–2056.
Rogers CL, Perry A, Pugh S, et al. Pathology concordance levels for meningioma classification and
grading in NRG Oncology RTOG Trial 0539. Neuro Oncol. 2016;18:565–574.
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