Ebook Biopsy interpretation of pediatric lesions Part 2Ebook Biopsy interpretation of pediatric lesions Part 2

6
CENTRAL NERVOUS SYSTEM AND
SKELETAL MUSCLE
Peter Pytel, MD

Most pediatric biopsies encountered in general practice are of lesions in
the central nervous system. In some instances, however, biopsies sampling peripheral nerves, skeletal muscles, or peripheral ganglion cells are
received. These latter biopsies are often referred for specialized processing
and are only discussed briefly in this chapter. Most of the chapter focuses
on CNS tumors and their mimics, which are discussed separately even
though the practicing pathologist will consider both of these in the differential diagnosis of any given case.

CENTRAL NERVOUS SYSTEM TUMORS
In absolute numbers, pediatric central nervous system (CNS) tumors are
relatively rare, but proportionally, they represent the most common solid
neoplasm occurring in the pediatric age group. They are a very diverse
group of tumors complicating the classification as well as the study of
these lesions.1–3 Children more commonly present with infratentorial
tumors in contrast to adults in whom tumors are more often supratentorial. As in adults, the anatomic location is a key consideration in the
process of making a diagnosis (Table 6.1). In many cases, the received
specimen does not provide any clues for determining the anatomic location of a tumor, and in many institutions, the specimen requisition
forms lack detail beyond a generic description of “brain tumor.” The
neuroradiology images, therefore, provide critical information for the
pathologist.
Pediatric CNS tumors are classified according to the World
Health Organization (WHO) classification.1,2 The assigned WHO grade
describes the biology of the lesion, but a low grade does not always
imply a good outcome. In this classification system, pediatric tumors
are stratified according to the same criteria as those used for adults.
As discussed in the following section, there are some limitations to this
approach. Tumors classified as glioblastoma in children may, for example,

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TABLE 6.1 Common Tumors to Consider in the Differential Diagnosis
According to Anatomic Sites
Posterior Fossa/
Brainstem and
Cerebellopontine
Angle

Sellar/
Suprasellar

Pineal Region

Posterior Fossa/
Cerebellum and
Fourth Ventricle

Craniopharyngioma

Pineal parenchymal tumor

Pilocytic
astrocytoma

Intrinsic pontine
glioma

Germ cell
tumor

Germ cell tumor

Medulloblastoma

Pilocytic
astrocytomas

Optic glioma

Papillary tumor
of the pineal
regiona

Ependymoma

Epidermoid

Meningiomaa

Astrocytomaa

Choroid plexus
tumor

Schwannomaa

Pituitary
adenomaa

Hemangioblastomaa

Chordomaa
a

Rare in children.

be different biologically from tumors with similar morphology found in
adults (Table 6.2). Cases that defy accurate classification despite best
efforts may also be more common in children. Systemic metastases from
brain tumors are highly unusual. Thus, in most cases, the main treatment
strategy is focused on preventing or delaying local recurrence or to control growth. In some of the entities discussed in the following section,
however, cerebrospinal fluid (CSF) dissemination is relatively common.
Patients with ependymomas or medulloblastomas therefore will typically
have imaging studies of the entire neuro-axis. Some patients including
those with medulloblastoma will receive radiation treatment to the entire
neuro-axis.
Pilocytic Astrocytoma
Pilocytic astrocytoma is a WHO grade I neoplasm that is most common
in the first two decades of life. Common anatomic sites are the cerebellum, optic nerve/chiasm, and hypothalamus, but these tumors can be
found virtually anywhere within the CNS. In some cases, like a patient

with cerebellar pilocytic astrocytoma, surgery can be curative. In other
patients, a hypothalamic tumor may slowly progress and ultimately be
lethal. This example illustrates that we may consider certain tumors
low-grade but that it can be very misleading to talk about “benign”

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TABLE 6.2 Primary Tumors Commonly Exhibiting the Listed Individual
Morphologic Feature

Tumors with
Desmoplasia

Tumors
with Large
(Nonneuronal)
Cells

Tumors with
Oligodendroglioma-like
Appearance/Clear Cell
Features

PXA

PXA

DNET

SEGA

Clear cell ependymoma

DIA/DIG
a

Gliosarcoma

Giant cell
glioblastomaa

Central neurocytoma
Oligodendrogliomaa

Tumors with
Papillary/
Pseudopapillary
Features
Choroid plexus
tumor

a

Ependymoma
Astroblastoma
Papillary
meningioma
Papillary tumor
of the pineal
regiona

a

Rare in children.
PXA, pleomorphic xanthoastrocytoma; DNET, dysembryoplastic neuroepithelial tumor;
DIA/DIG, desmoplastic infantile astrocytoma/ganglioglioma; SEGA, subependymal giant
cell astrocytoma.

brain tumors. Another uncommon but described phenomenon supporting this same point is the fact that patients with pilocytic astrocytoma
may develop CSF dissemination.
Radiologically and grossly pilocytic astrocytomas are often associated with cyst formation. On enhanced magnetic resonance images,
they typically exhibit enhancement (Fig 6.1). Prototypical cases are
circumscribed with an expansile growth pattern. This can be a helpful diagnostic clue, but cases with more infiltrative edges are reported.
Typical morphologic features (Fig. 6.2) of pilocytic astrocytoma include
variation between dense and loose areas, presence of sometimes prominent hyalinized blood vessels, bipolar spindle cells with long processes,
Rosenthal fibers, and sometimes eosinophilic granular bodies (EGBs).
The presence of random atypical cells, degenerative changes with
thrombosed vessels, organizing hemorrhage, necrosis, and mitotic figures may be worrisome or raise concern for other diagnoses. But these
changes can all be part of the spectrum of pilocytic astrocytomas. Actual
malignant progression in a pilocytic astrocytoma is described but highly
unusual. Some cases may exhibit areas mimicking oligodendroglial
differentiation.

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A

B

C

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FIGURE 6.1 Pilocytic astrocytoma. A: This MRI shows a large
mass lesion in the cerebellum with
enhancement and cystic structures. B: Intraoperative smear
preparations show bland spindle
cells. C: These are associated
with long, delicate “hairlike” (i.e.,
piloid) processes and eosinophilic
Rosenthal fibers (arrow).

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A

FIGURE 6.2 Pilocytic astrocytoma. A: Pilocytic astrocytoma
with microcysts and solid expansile
growth pattern without entrapment
of preexisting structures. B: Rosenthal fibers (arrows) are a helpful
feature if present but are not a
prerequisite.

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Depending on the morphologic features exhibited in a given case,
the differential diagnosis may include the following: 1) Reactive piloid
gliosis adjacent to either another tumor or another lesion such as a
vascular malformation. 2) The glial component of a ganglioglioma may
mimic pilocytic astrocytoma (see the following text). The identification
of lesional dysmorphic ganglion cells allows the distinction. 3) Especially in small biopsy sample, the distinction from a low-grade diffuse
astrocytoma may be challenging or impossible. Relative lack of clearly

permeative invasive growth, presence of hyalinized blood vessels,
Rosenthal fibers, EGBs, and knowledge of the radiologic appearance
can all be helpful. Some small biopsies may, however, be best classified
descriptively as “low-grade astrocytoma.” 4) In some cases, the unusual
differential diagnosis may lie between a pilocytic astrocytoma with necrosis and prominent degenerative changes and a glioblastoma. Rare cases
of “malignant” pilocytic astrocytoma with increased mitotic activity are
described. 5) Pilocytic astrocytomas may have areas mimicking oligodendroglioma. Presence of areas with diagnostic morphologic features
is usually key. Tumors with oligodendroglial differentiation are relatively
rare in children and in infratentorial locations.
Special studies are of limited use in pilocytic astrocytomas. The
lesional cells label for GFAP and S100 but these stains are rarely necessary. In some cases, staining for neurofilament may be helpful by demonstrating the lack of entrapped preexisting axonal processes. But this stain
has to be interpreted with some caution because tumors are not always
completely demarcated. Variants with more distinctly infiltrative growth
are described. MIB-1 labeling is probably best avoided because the results
may be more confusing than helpful. Some cases can go along increased
labeling indices of 10% or more.4,5 Recent studies have shown BRAF
rearrangements with tandem duplication and BRAF-KIAA1549 fusion
in pilocytic astrocytomas.6,7 These are most common in the infratentorial
tumors. The V600E mutation seen in melanomas is unusual in pilocytic
astrocytomas but can be found in pleomorphic xanthoastrocytoma and
ganglioglioma.8 In some unusual cases, fluorescence in situ hybridization
(FISH) studies looking for these rearrangements may be helpful.
Pilomyxoid astrocytoma is closely related to pilocytic astrocytoma.9
It is most commonly found in the hypothalamus or chiasm of very young
children. It is characterized by prominent myxoid matrix and angiocentric
arrangement of lesional cells. Rosenthal fibers and EGBs are typically
absent. These tumors tend to be more aggressive than pilocytic astrocytomas and are graded as WHO grade II.
Infiltrating Astrocytomas
Children, just like adults, develop tumors that are classified and graded in the
WHO system as diffuse astrocytoma (WHO grade II), anaplastic astrocytoma

(WHO grade III), and glioblastoma (WHO grade IV). The growth pattern of
these lesions is characterized by individual cell infiltration between preexisting

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gray and white matter structures (Fig. 6.3). Because of this growth pattern,
these tumors often show up grossly and radiologically as poorly demarcated
areas of mass effect that may appear to be expanding preexisting structures.
Enhancement is thought to often correlate with grade—it is usually absent in
diffuse astrocytomas and associated with higher grade astrocytomas. It is reflective of the tumor containing blood vessels lacking normal blood–brain barrier.
The diagnosis of these lesions often represents a two-step process.
First, the tumor is classified as infiltrating astrocytoma and then the tumor
is graded. The classification as infiltrating astrocytoma is based on the
histologic growth pattern that goes along with the aforementioned entrapment of preexisting tissue elements. The background matrix typically has a
fibrillary appearance representative of processes belonging to preexisting
cells as well as tumor cells. The lesional cells morphologically exhibit features of astrocytic differentiation. In some cases, cells appear to consist of

A

FIGURE 6.3 Infiltrating astrocytoma. A: The MRI scan of this
adolescent patient shows a large
nonenhancing intraaxial mass
lesion. B: The moderately cellular tumor shows focal microcyst

formation. (continued)

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FIGURE 6.3 (continued) C: Neoplastic cells diffusely infiltrate
between preexisting neurons
(arrowhead) and axons (arrow).

C

basically naked-appearing elongated and irregular-shaped nuclei. In other
cases, cells may exhibit distinct eosinophilic and sometimes gemistocytic
cytoplasm that often tapers out into processes.
The grading of these tumors occurs according to the same criteria as in adults. Increased proliferative activity with mitotic figures is
required for a diagnosis of anaplastic astrocytoma. Endothelial proliferation or necrosis is required for classification as glioblastoma. The
necrosis is often but not always pseudopalisading (Figs. 6.4 and 6.19).

A

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FIGURE
6.4 Glioblastoma
multiforme. A: Intraoperative
frozen section shows a cellular
tumor associated with necrosis.
(continued)

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B

FIGURE 6.4 (continued) B: Intraoperative frozen section shows
a cellular tumor associated with
necrosis. C: On the permanent
sections, the tumor is seen as
cellular lesion composed of pleomorphic mitotically (arrows) active
cells. Samples from the center
of the lesion may give the false
impression of a solid neoplasm.
Examination of the edges showing individual cell infiltration similar to that seen in Figure 6.3C can
be helpful.

C

In some cases, MIB-1 labeling and p53 staining may provide some prognostic information.

Special stains are of limited use in establishing the lineage of differentiation. Often, the tumor cells label for GFAP and S100. It is, however,
important to remember that absence of GFAP expression does not exclude
the diagnosis of glioblastoma. Neuronal markers such as neurofilament
stain preexisting tissue elements. In some cases, negative staining for other

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markers can be helpful in excluding other entities that may be considered
in the differential diagnosis, including lymphoma, systemic metastasis, or
neuronal neoplasm.
The differential diagnosis varies depending on the grade of the tumor.
Other high-grade tumors, such as primitive neuroectodermal tumors and atypical teratoid rhabdoid tumor, may be considered in the differential diagnosis of
glioblastoma. In some cases, pleomorphic xanthoastrocytoma and pilocytic
astrocytoma may mimic glioblastoma by showing pleomorphism, necrosis, or
even mitotic activity. The final diagnosis in those cases rests on immunohistochemical and, in some cases, molecular studies. Reactive gliosis and other
low-grade tumors including ganglioglioma may be considered in the differential diagnosis for low-grade lesions. The distinction of reactive gliosis may
be difficult on biopsy samples. A history of disease processes that could illicit
reactive gliosis or morphologic features of the same can be helpful. Uniform
spacing of glial cells, lack of frank atypia, reactive vascular changes, and macrophage infiltration can be suggestive of reactive etiology.
When grading and classifying astrocytomas, we often treat pediatric
patients like little adults. Molecular studies suggest that this approach
has limitations. Glioblastomas in children are associated with different
molecular changes than those typically seen in their adult counterparts.10

There may even be differences between glioblastomas of early childhood
and older children. In adult patients, studies looking for isocitrate dehydrogenase (IDH)1/IDH2 mutations and epidermal growth factor receptor
(EGFR) amplification are sometimes employed. IDH1/IDH2 mutations
and EGFR amplification are rare in pediatric astrocytomas.11 Plateletderived growth factor receptor, ␣-polypeptide (PDGFRA) amplification is
relatively common in pediatric glioblastomas but rare in adult cases. Recent
data suggests that about a third of pediatric glioblastomas show mutations
in the H3F3A gene encoding the replication-independent histone 3 variant H3.3.11,12 This leads to a unique methylation signature in the cancer
genome.11
Oligodendroglioma
In adults, oligodendrogliomas are a well-defined group of tumors that
exhibit an infiltrating growth pattern similar to that seen in infiltrating astrocytomas but distinctly different cytomorphologic features. The
lesional cells show round regular nuclei. On paraffin sections, they often
show perinuclear halos as a processing artifact lacking on frozen sections.
Sometimes, cells with round regular nuclei but distinct eosinophilic cytoplasm are seen, so-called mini-gemistocytes. Oligodendrogliomas show a
strong association with codeletion of 1p and 19q—some would argue they
are defined by these molecular changes.
Sometimes, prototypical oligodendrogliomas with 1p/19q codeletion
are seen in older children. In younger patients, these tumors are uncommon. Rare tumors in these patients with oligodendroglioma morphology
typically lack the 1p/19q codeletion.

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Pleomorphic Xanthoastrocytoma

These are low-grade tumors that present as enhancing superficial lesions.
Clinically, they are often associated with seizures.13,14 Most patients are in
the second or third decade of life. In some cases, surgical resection can be
curative. Pleomorphic xanthoastrocytomas (PXAs) are most often seen in
the hemispheres as superficial lesions that may exhibit striking extension
into the subarachnoid space resulting in a meningocerebral distribution.
These tumors are appropriately named for some of their key morphologic
features (Fig. 6.5). 1) They are composed of cells exhibiting features of
astrocytic differentiation. 2) Often, they show marked pleomorphism.
3) Some cells may show distinct vacuolated foamy xanthomatous cytoplasm attributable to cytoplasmic lipid. EGBs are found in virtually all
cases. Other features are an overall expansile growth pattern and at least
focal distinct pericellular reticulin. PXAs are typically classified as WHO
grade II despite the pleomorphism and often high cellularity that may at
first glance be worrisome features. Higher grade variants are very unusual
but described. Rare ganglion cells may be found, and in some cases, the
distinction from ganglioglioma may be difficult.
Subependymal Giant Cell Astrocytoma
Subependymal giant cell astrocytomas (SEGAs) arise in the wall of the
lateral ventricles and are virtually always tuberous sclerosis–associated
discrete tumors.15 They are most common in the second decade of life.

FIGURE 6.5 Pleomorphic xanthoastrocytoma. This image illustrates several of the
key features of PXA that can be seen to variable extent in individual cases: Pleomorphic
and tumor giant cells are present as well as xanthomatous changes (arrows) and admixed
mononuclear inflammatory cells.

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FIGURE 6.6 Subependymal giant cell astrocytomas. SEGAs can exhibit variable features. They are typically demarcated lesions and, by definition, arise in the wall of the ventricle. The lesional cells may vary from spindled to more plumb. Calcifications seen here in
the lower left corner (arrow) and necrosis can be prominent.

Because of their location, these tumors may cause obstruction of CSF
flow at the level of the foramen of Monroe. Radiologically, these are
solitary or bilateral demarcated enhancing tumors. The lesional cells
vary in appearance from spindled to plumb and from small to large
(Fig. 6.6). Calcifications are common. Necrosis, increased cellularity,
and nuclear atypia can be seen in this WHO grade I tumor. The lesional
cells may express GFAP or neuronal markers such as synaptophysin.
Sometimes, markers of both lineages may be expressed in an individual
cell. Because of the mixed differentiation, these tumors are sometimes
referred to as subependymal giant cell tumor. The histologic features
are indistinguishable from those found in the subependymal nodules of
tuberous sclerosis that may form multinodular changes in the ventricular wall likened to candle drippings. Size is the distinguishing feature.
The underlying molecular alteration driving the growth of these tumors
is activation of the mammalian target of rapamycin (mTOR) signaling
pathway. Therefore, patients are often treated with rapamycin to control
tumor growth.
Astroblastoma
This is a well-demarcated solid or cystic tumor that presents as contrastenhancing superficial hemispheric lesion.16 Despite the name, these tumors are not immature blastic but exhibit some ependymal features. The
lesional cells show perivascular arrangement that may mimic ependymal
pseudorosettes but typically goes along with shorter, more plumb stubby

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A

FIGURE 6.7 Astroblastoma.
A: This image illustrates variation
between more cellular and more
hyalinized areas. B: The tumor
cells line up around hyalinized
blood vessels with short plumb
processes, focally in a radiating pattern. Other tumors may
exhibit more papillary features.

B

cell processes (Fig. 6.7). Often, there is distinct vascular/perivascular
hyalinization. GFAP and S100 are strongly positive, and epithelial membrane antigen (EMA) staining may also be seen. Intercellular junction and
microvillous processes as found in ependymomas may be present. Often,
these tumors behave as low-grade lesions, but more aggressive cases are
reported, and a definitive grade has not been assigned in the WHO system.
Ependymoma and even papillary meningioma may be considered in the
differential diagnosis.
Desmoplastic Infantile Ganglioglioma/Astrocytoma
Desmoplastic infantile ganglioglioma/astrocytomas (DIG/DIAs) is a

WHO grade I tumor that usually presents as large hemispheric lesion in
early childhood.17,18 The tumor is contrast enhancing on magnetic resonance imaging (MRI) and is often associated with cystic changes. A key
morphologic feature is the desmoplasia that appropriately has become part
of the entity’s name. Prominent collagen bundles are seen admixed with
the tumor and may in places crowd out tumor cells. They are highlighted

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FIGURE 6.8 Desmoplastic infantile astrocytomas. Bundles of collagen separate nests
and islands of bland astrocytic cells placed in a fibrillary neuropil-like background.

on a trichrome stain. Nestled between the desmoplastic collagenous areas
are nests, strands, or islands with fine fibrillary background (Fig. 6.8). The
lesional cells are small astrocytes with bland plump oval nuclei. The presence of a neuronal component distinguishes DIG from DIA. Sometimes,
the neuronal component can at least in part take the form of larger ganglion cells, but often, the neuronal cells are small and therefore difficult to
distinguish from lesional astrocytes on the hematoxylin and eosin (H&E)
stain. Staining for neuronal markers can therefore be helpful. The glial
component is positive for GFAP. In rare cases, a cellular mitotically active
small cell component can be present. This may mimic primitive neuroectodermal tumor–like differentiation. This latter feature does, however,
not clearly indicate poor outcome and is at the moment of undetermined
significance.
Dysembryoplastic Neuroepithelial Tumor
These are WHO grade I glioneuronal lesions that typically arise superficially

in the hemispheres early in life.19,20 Seizures are a common presenting feature. Grossly and radiologically, the tumor often appears as multinodular,
superficial, and, at least partly, intracortical lesion. The histologic appearance is that of a tumor that may mimic oligodendroglioma because the
dominant cell population is composed of small cells with round nuclei
often surrounded by perinuclear halos on paraffin sections. These cells tend
to be arranged in rows around vessels and bundles of processes leaving
small paucicellular spaces filled with mucinous material. Larger ganglion
cells floating in these mucinous pools are termed “floating neurons” and

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FIGURE 6.9 Dysembryoplastic neuroepithelial tumor (DNET). Small, bland tumor cells
with rounded nuclei are arranged in rows or columns. Larger cells with neuronal features
are seen in the loose spaces separating these columns.

represent a helpful feature (Fig. 6.9). Sometimes, more complex patterns
with areas mimicking pilocytic astrocytomas or diffuse astrocytomas are
described. The low-power multinodular appearance, the arrangement of
the small oligodendroglioma-like cells in rows or columns, and the presence of floating neurons are key features for the diagnosis. The absence
of 1p/19q codeletions can be helpful at times to exclude the possibility of
oligodendroglioma.
Ganglioglioma
Ganglioglioma is typically classified as WHO grade I tumor. These are
most frequently seen as hemispheric tumors, often in the temporal lobes,21

but they can be found virtually anywhere in the CNS. Seizures are a common presenting feature. Grossly and radiologically, they may be solid or
cystic. Gangliogliomas are one of a set of low-grade tumors that can present with an MRI showing a cystic lesion with an enhancing mural nodule
(e.g., as also seen in pilocytic astrocytomas or hemangioblastomas). Typically, these are tumors with solid expansile growth pattern. The neuronal
component of this glioneuronal tumor consists of large, often dysmorphic,
ganglion cells (Fig. 6.10). The spacing of the neurons is haphazard, and
abnormally clustered “kissing” neurons may be seen. The glial component can be more variable and may mimic pilocytic astrocytoma, diffuse
astrocytoma, or even oligodendroglioma. EGBs, calcifications, and perivascular lymphocytes are common features and helpful clues. Immunohistochemical studies for neuronal markers can confirm the differentiation of

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FIGURE 6.10 Ganglioglioma. Haphazardly arranged dysmorphic ganglion cells (arrows)
are admixed in a background of fibrillary astrocytic cells with spindled nuclei. Calcifications
and perivascular lymphocytes are present.

the neuronal component. In some cases, the distinction between lesional
neurons and neurons entrapped by an infiltrating glioma may be difficult.
Dysmorphic ganglion cells in cortical dysplasia may mimic those of ganglioglioma but more closely follow normal anatomic distribution.
Central Neurocytoma
Central neurocytoma is a WHO grade II tumor that typically arises in
or around the lateral ventricles—usually in the vicinity of the foramen
of Monroe. Most commonly, it is seen in young adults. It is composed
of small but mature neuronal cells that may at times mimic a sheetlike
infiltrate of oligodendroglioma cells. These cells are, however, positive for

neuronal markers including synaptophysin and NeuN.
Ependymoma
Ependymomas are composed of cells exhibiting features of ependymal differentiation that can be found at any age but are especially common during the
first decade of life. Their anatomic distribution differs in different age groups.
The fourth ventricle is the most common site and is the site that is associated
with pediatric age cases. Adult cases are most common in the spinal cord.
Supratentorial tumors are encountered in children and adults. Radiologic
studies typically show a demarcated contrast-enhancing tumor. A demarcated
expansile growth pattern is also appreciated grossly and on histologic studies.
The tumor can appear quite cellular. The lesional cells contain
monomorphic bland nuclei placed in a fibrillary background (Fig. 6.11).
Ependymal pseudorosettes with radiating perivascular arrangement of

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A

FIGURE 6.11 Ependymoma.
A: A low-power view shows a
fairly cellular tumor with perivascular nuclear-free areas. B: At
higher power, distinct perivascular ependymal pseudorosettes
are seen. The nuclear-free zones
correspond to a zone of radially

arranged long fibrillary processes.

B

cells are a characteristic feature. The radiating perivascular cells leave a
perivascular “nuclear-free” zone of fibrillary processes around the vessel.
True rosettes with arrangement of cells around small central lumina and
formation of larger spaces with cells exhibiting distinct ependymal surface
differentiation are sometimes seen.
In many cases, the presence of (micro)lumina formation can be
highlighted by staining for EMA and D2-40 (Fig. 6.12) even in cases
where these are not appreciated on the H&E stain.22 These same lumina
can also be found on ultrastructural studies on which microvilli, cilia,
and intercellular junctions are found as correlates of the distinct surface
differentiation. Ependymal cells are of glial lineage and typically GFAP
positive. This stain often highlights the radial perivascular arrangement of
glial processes associated with perivascular pseudorosettes.
Ependymomas are classified as WHO grade II. An anaplastic grade III
variant characterized by high mitotic activity and typically microvascular proliferation is recognized (see Fig. 6.12). Often, these tumors exhibit necrosis.
Necrosis can, however, be found in grade II ependymomas, and reproducible

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A

B

C

D
FIGURE 6.12 Anaplastic ependymoma. A: This low-power image shows a cellular demarcated tumor. B: The tumor exhibits microvascular/endothelial proliferation. C: Focal perivascular nuclear-free zones are seen and focal pseudopalisading necrosis is present. D: D2-40
staining highlights focal dot-like expression corresponding to microlumina that were also
visualized on EMA staining and ultrastructurally.

grading is difficult in some cases.23 In additional to local recurrence, CSF
dissemination is a frequent problem in the management of these patients.
The clear cell variant of ependymoma may be a mimic of other tumors with
oligodendroglioma like appearance.
Choroid Plexus Tumors
These arise from the choroid plexus and are most commonly seen in the
first decade of life. The lateral ventricles are a common site of disease in
young patients, whereas older patients are more likely to have involvement
of the fourth ventricle. Sometimes, choroid plexus tumors can present as
cerebellopontine angle lesions. Choroid plexus tumors are classified as
WHO grade I. Choroid plexus carcinomas (WHO grade III) usually occur
in the first 3 years of life. An intermediate category of atypical choroid
plexus papilloma (WHO grade II) is recognized.
Tumors often present with enlarged ventricles and hydrocephalus from
CSF pathway obstruction and/or from overproduction of CSF. Imaging
studies show an intraventricular enhancing mass. These are highly vascular tumors. Significant intraoperative blood loss can complicate surgical

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resection, particularly in the youngest patients. In many cases, the papillary
growth pattern can already be suspected at the time of gross examination.
Some tumors may closely mimic normal choroid plexus, but most are composed of cells with taller columnar shape and more nuclear pleomorphism
than seen in normal choroid plexus (Fig. 6.13). Most tumors are positive for

A

B

FIGURE 6.13 Choroid plexus
papilloma. A: H&E-stained preparations typically show a tumor
with distinct papillary architecture.
The cells tend to be tall columnar.
Focal calcification may be present
(lower right corner). B: Choroid
plexus tumors are positive for cytokeratins (Cam5.2 shown here).
C: D2-40 is often expressed by the
lesional cells as seen here.

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D2-40, cytokeratins, and S100.24 Sometimes they express GFAP. Choroid
plexus carcinomas show complex architecture and often, sheetlike solid
growth with cells that exhibit high mitotic figures, marked pleomorphism,
and necrosis. They may be associated with invasive growth into adjacent
brain tissue. Atypical choroid plexus papillomas are characterized by
increased mitotic figures. Complete surgical resection is often curative in
choroid plexus papillomas.
Medulloblastomas
Medulloblastomas are WHO grade IV neoplasms that by definition arise
in the cerebellum. They usually present in the first two decades of life as
a contrast-enhancing mass that often leads to compression of the fourth
ventricle and a presentation attributable to increased intracranial pressure.
Biologically, the tumor cells can be linked back to populations of normal
neuronal precursor cells that contribute to cerebellar development. The
histology is typically that of a small blue cell tumor. The lesional cells
exhibit neuronal differentiation confirmed through staining for neuronal
markers such as synaptophysin and NeuN. The most common associated
cytogenetic abnormality is isochromosome 17q.
Medulloblastomas are one of the CNS tumors that often spread
along CSF pathways. Imaging of the entire neuro-axis and CSF sampling
looking for tumor cells is therefore part of the staging workup for affected patients. The treatment includes the most radical resection feasible,
radiation to the entire neuro-axis with a boost to the posterior fossa,
and chemotherapy. The 5-year survival with this approach is over 70%.

Treatment-related morbidity with secondary tumors, endocrine dysfunction, short stature, and lowered intelligence are big challenges facing
survivors.
Data from different sources suggest that medulloblastomas are a heterogeneous group of tumors that can be subclassified.10,25–28 1) Different
histologic variants are recognized (Figs. 6.14 and 6.15) including nodular/
desmoplastic medulloblastoma, large cell/anaplastic medulloblastoma,
and medulloblastoma with extensive nodularity. 2) Different familial
tumor predisposition syndromes can be associated with medulloblastoma
development and point toward involvement of different pathways including Gorlin syndrome (abnormalities in sonic hedgehog [SHH] signaling),
Li-Fraumeni syndrome (p53 mutations), and Turcot syndrome type 2
(adenomatous polyposis coli [APC] gene mutations). 3) Different pools
of neuronal stem cell found during development are linked to different
medulloblastoma subtypes. 4) Different molecular markers characterize
tumor subgroups. Some subtypes are associated with distinct prognostic
implications as illustrated by the following three examples:
• Nodular desmoplastic medulloblastomas tend to be lateral hemispheric lesions in young children that are associated with SHH
pathway activation, good prognosis, and a derivation from external

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A

FIGURE 6.14 Medulloblastoma.
A: This image illustrates the appearance of a classic medulloblastoma with sheetlike arrangement

of mitotically active small blue
cells. Image (B) is taken at the
same magnification as (A). It shows
the morphologic appearance of
the large cell/anaplastic variant of
medulloblastoma associated with
nuclear enlargement, pavement
stone–like nuclear wrapping, and
prominent mitotic activity.

B

granular neurons. These typically lack MYC amplification and chromosome 17 aberrations.
• A group of medulloblastomas with classic morphologic are associated with ␤-catenin mutations and good prognosis. These typically
lack MYC amplification and chromosome 17 aberrations and instead
may show monosomy 6 as good prognostic marker. These tumors
may be associated with cells derived embryologically from the lower
rhombic lip.
• Medulloblastomas with large cell/anaplastic morphology are associated with poor prognosis, MYC amplification, isochromosome 17q,
and gain of 6q.
In the future, targeted therapies (e.g., SHH inhibitors) may also be
the reason to subclassify medulloblastomas. Immunohistochemical staining for ␤-catenin is thought to correspond well the molecular signature
of the tumor and is easy to do. Confirmation of other alterations such as

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FIGURE 6.15 Medulloblastoma. Medulloblastomas with extensive nodularity are cases in
which the tumor is almost entirely composed of cells arranged in nodules that are outlined
by vascular septations.

those affecting the SHH signaling pathway or myc rearrangements have to
be confirmed by molecular studies.
Central Nervous System/Supratentorial Primitive
Neuroectodermal Tumors
Tumors with morphologic features similar to those found in medulloblastoma can be seen outside the cerebellum.10,29 Pineoblastoma (discussed
in the following section) and retinoblastoma are two that also occur at
defined anatomic locations. CNS/supratentorial primitive neuroectodermal tumors (PNETs) occur outside these specific anatomic sites and
are often found in the hemispheres. In the past, all of these tumors have
at times been lumped together as PNETs. Molecular studies suggest that
there are differences between medulloblastomas and CNS/supratentorial
PNETs. The nomenclature is unfortunate because the term of primitive
neuroectodermal tumor could be interpreted as erroneously suggesting
a relationship to PNET/Ewing sarcoma. The CNS/supratentorial PNET,
however, lack the typical EWSR rearrangement/t(11;22) associated with
PNET/Ewing sarcoma.
Atypical Teratoid/Rhabdoid Tumor
Atypical teratoid/rhabdoid tumors (AT/RTs) are WHO grade IV lesions
that usually occur in the first few years of life.30–34 In the CNS, they are
often seen in the posterior fossa. Histologically, these may resemble small
blue cell tumors, but the morphology can be somewhat variable (Fig. 6.16).

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A

B

FIGURE 6.16 Atypical teratoid/rhabdoid tumor. A: These
may mimic medulloblastoma on
the H&E-stained sections as seen
here when they have the appearance of a small blue cell tumor.
B: Loss of INI1 expression with
preserved normal staining in vascular structures helps to establish
the correct diagnosis. C: Synaptophysin may be positive as seen
in this case.

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Cells with rhabdoid appearance are often scant and more difficult to find
than implied by the entity’s name. Some cases may contain more spindled
cells that mimic a mesenchymal neoplasm. The immunoprofile of these
tumors is also complex. They often stain for EMA and may exhibit variable
staining for GFAP, synaptophysin, cytokeratins, vimentin, and actin. This
tumor is associated with loss of chromosome 22 or part of chromosome
22 that goes along with deletion of INI1 on 22q11.2. Nowadays, the more
common diagnostic test is immunohistochemical staining for INI1. AT/
RTs show loss of the normal nuclear staining. Blood vessels in the tumor
provide a good internal positive control. AT/RTs are often considered in
the differential diagnosis of medulloblastoma and supratentorial PNET.
INI1 stain is, therefore, used relatively liberally in the context of a pediatric intracranial small blue cell tumor.
Meningiomas
Meningiomas typically arise as dural-based well-demarcated mass lesions
in adults. In typical cases, these are cellular tumors in which monomorphic meningothelial cells are arranged into lobules and whorls. The
lesional cells stain for EMA and Glut-1. Focal S100 staining may be seen.
Sometimes, meningiomas are found in children. These tumors are graded
according to the same WHO criteria established for adult patients. The rare
variant of papillary meningioma (by definition WHO grade III) is more
common in children and may be considered in the differential diagnosis
of other tumors exhibiting papillary or pseudopapillary features such as
astroblastomas and ependymoma. Meningiomas can be radiation-induced
tumors, for example, in the context of a patient who received radiation in
early childhood for a diagnosis of medulloblastoma or ependymoma. They
can also be associated with familial tumor syndromes, most importantly
neurofibromatosis type 2. In that context, they may arise earlier than in
the general population.
Schwannoma
Schwannomas in the CNS are most commonly encountered as vestibular schwannomas and as lesions arising in the posterior nerve roots.

Usually, schwannomas are seen as adult age lesions. Sometimes, however,
schwannomas are encountered in pediatric-range patients, in particular
in the context of neurofibromatosis type 2 (Fig. 6.17).
Hemangioblastomas
Hemangioblastomas are well-demarcated vascular lesions (see Fig. 6.17)
that can be found anywhere in the CNS but commonly arise in the
cerebellum. They present as an enhancing lesion on imaging studies
and may appear as a cystic lesion associated with an enhancing mural
nodule. The presumed lesional stromal cells are admixed between a
dense network of vascular channels. Typically, the stromal cells show

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FIGURE 6.17 Schwannoma/
hemangioblastoma. A: Schwannoma in a teenager with neurofibromatosis type 2. As often
in vestibular schwannomas, this
tumor exclusively shows dense
Antoni A areas. Fasciculated arrangement of spindle cells and
focal nuclear palisading are seen.
B: Hemangioblastoma in a patient
with von Hippel-Lindau syndrome.
A demarcated cerebellar tumor
with prominent vascular channels

is seen in this low-power image.
The prominence of the lesional
stromal cells and their morphologic appearance can be variable.

A

B

cytoplasmic lipidization. Their nuclei may at least in part be hyperchromatic and atypical. These are typically adult age tumors. In the context
of von Hippel-Lindau (VHL) disease, they may present in pediatric
patients. In the context of VHL the possibility of metastatic renal cell
carcinoma is sometimes considered. Hemangioblastomas stain for inhibin A but are negative for PAX8 and cytokeratins. Staining for S100,
CD56, and GFAP can be seen. The actual lineage of differentiation of
the lesional stromal cells is unknown.
Pineal Parenchymal Tumors
The pineal region is a typical location for germ cell tumors. By definition, it is the site for pineal cysts and pineal parenchymal tumors.
Because of the anatomic location, it may at times be difficult to differentiate a true pineal lesion from a mass arising in the posterior midbrain or the quadrigeminal cistern. Pineal parenchymal lesions include
pineocytoma (WHO grade I) and pineoblastoma (WHO grade IV).33,34

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