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

(BQ) Part 2 book Biopsy interpretation of pediatric lesions presentation of content: Central nervous system and skeletal muscle, hematopoietic system, the heart, the lung, pancreas, adrenal, thyroid, parathyroid, and selected head and neck, breast and reproductive system, skin.

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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

sam-pling 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

dif-ferential 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

tumors in contrast to adults in whom tumors are more often

supraten-torial 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

lo-cation 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

describes the biology of the lesion, but a low grade does not always

imply a good outcome In this classification system, pediatric tumors

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

Sellar/

Suprasellar Pineal Region

Posterior Fossa/

Cerebellum and Fourth Ventricle

Posterior Fossa/

Brainstem and Cerebellopontine Angle

Craniopha-ryngioma

Pineal chymal tumor

paren-Pilocytic astrocytoma

Intrinsic pontine glioma

Germ cell

tumor

Germ cell tumor Medulloblastoma Pilocytic

astrocytomas Optic glioma Papillary tumor

of the pineal regiona

Hemangio-Chordomaa

aRare 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

con-trol 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

cerebel-lum, 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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174 ——— BIOPSY INTERPRETATION OF PEDIATRIC LESIONS

brain tumors Another uncommon but described phenomenon

support-ing this same point is the fact that patients with pilocytic astrocytoma

may develop CSF dissemination

Radiologically and grossly pilocytic astrocytomas are often

asso-ciated 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

help-ful 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

promi-nent 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

fig-ures 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

Tumors with Oligodendroglioma-like Appearance/Clear Cell Features

Tumors with Papillary/

papillary Features

tumor

Gliosarcomaa Giant cell

glioblastomaa

Central neurocytomaa Astroblastoma

Oligodendrogliomaa Papillary

meningioma Papillary tumor

of the pineal regiona

aRare in children.

PXA, pleomorphic xanthoastrocytoma; DNET, dysembryoplastic neuroepithelial tumor;

DIA/DIG, desmoplastic infantile astrocytoma/ganglioglioma; SEGA, subependymal giant

cell astrocytoma.

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FIGURE 6.1 Pilocytic

astrocy-toma A: This MRI shows a large

mass lesion in the cerebellum with enhancement and cystic struc-

tures B: Intraoperative smear

prep arations show bland spindle

cells C: These are associated with long, delicate “hairlike” (i.e., piloid) processes and eosinophilic Rosenthal fibers (arrow).

A

B

C

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A

B

FIGURE 6.2 Pilocytic

astrocy-toma A: Pilocytic astrocytoma

with microcysts and solid expansile

growth pattern without entrapment

of preexisting structures B:

Rosen-thal 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)

Espe-cially in small biopsy sample, the distinction from a low-grade diffuse astrocytoma may be challenging or impossible Relative lack of clearly

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

necro-sis 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

oligo-dendroglioma 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 neces-

sary In some cases, staining for neurofilament may be helpful by

demon-strating 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

rearrangements with tandem duplication and BRAF-KIAA1549 fusion

tumors The V600E mutation seen in melanomas is unusual in pilocytic

astrocytomas but can be found in pleomorphic xanthoastrocytoma and

(FISH) studies looking for these rearrangements may be helpful

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 astrocyto-

mas 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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FIGURE 6.3 Infiltrating

astro-cytoma A: The MRI scan of this

adolescent patient shows a large

nonenhancing intraaxial mass

lesion B: The moderately

cellu-lar tumor shows focal microcyst

formation (continued)

A

B

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

reflec-tive 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

entrap-ment of preexisting tissue eleentrap-ments 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

fea-tures of astrocytic differentiation In some cases, cells appear to consist of

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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 ria as in adults Increased proliferative activity with mitotic figures is required for a diagnosis of anaplastic astrocytoma Endothelial prolif-

crite-eration or necrosis is required for classification as glioblastoma The necrosis is often but not always pseudopalisading (Figs 6.4 and 6.19)

Neo-plastic cells diffusely infiltrate between preexisting neurons (arrowhead) and axons (arrow).

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B

C

Intra-operative frozen section shows

a cellular tumor associated with

necrosis C: On the permanent

sections, the tumor is seen as

cellular lesion composed of

pleo-morphic mitotically (arrows) active

cells Samples from the center

of the lesion may give the false

impression of a solid neoplasm

Examination of the edges

show-ing individual cell infiltration

simi-lar to that seen in Figure 6.3C can

be helpful.

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

prog-nostic information

Special stains are of limited use in establishing the lineage of

differ-entiation 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

atypi-cal 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

immunohis-tochemical and, in some cases, molecular studies Reactive gliosis and other

low-grade tumors including ganglioglioma may be considered in the

differ-ential 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

mac-rophage 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

There may even be differences between glioblastomas of early childhood

and older children In adult patients, studies looking for isocitrate

dehy-drogenase (IDH)1/IDH2 mutations and epidermal growth factor receptor

(EGFR) amplification are sometimes employed IDH1/IDH2 mutations

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

show perinuclear halos as a processing artifact lacking on frozen sections

Sometimes, cells with round regular nuclei but distinct eosinophilic

cyto-plasm 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 uncom-

mon 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

3) Some cells may show distinct vacuolated foamy xanthomatous

cyto-plasm attributable to cytocyto-plasmic 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

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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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

ventricu-lar 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

tu-mors 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

FIGURE 6.6 Subependymal giant cell astrocytomas SEGAs can exhibit variable

fea-tures They are typically demarcated lesions and, by definition, arise in the wall of the

ven-tricle The lesional cells may vary from spindled to more plumb Calcifications seen here in

the lower left corner (arrow) and necrosis can be prominent.

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cell processes (Fig 6.7) Often, there is distinct vascular/perivascular

hyalinization GFAP and S100 are strongly positive, and epithelial

mem-brane 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

reso-nance 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

A

B

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

radiat-ing pattern Other tumors may

exhibit more papillary features.

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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

pres-ence of a neuronal component distinguishes DIG from DIA Sometimes,

the neuronal component can at least in part take the form of larger

gan-glion 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

neuro-ectodermal 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

fea-ture Grossly and radiologically, the tumor often appears as multinodular,

superficial, and, at least partly, intracortical lesion The histologic

appear-ance 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

FIGURE 6.8 Desmoplastic infantile astrocytomas Bundles of collagen separate nests

and islands of bland astrocytic cells placed in a fibrillary neuropil-like background.

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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

pres-ence of floating neurons are key features for the diagnosis The abspres-ence

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

but they can be found virtually anywhere in the CNS Seizures are a

com-mon presenting feature Grossly and radiologically, they may be solid or

cystic Gangliogliomas are one of a set of low-grade tumors that can

pre-sent with an MRI showing a cystic lesion with an enhancing mural nodule

(e.g., as also seen in pilocytic astrocytomas or hemangioblastomas)

Typi-cally, 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

compo-nent can be more variable and may mimic pilocytic astrocytoma, diffuse

astrocytoma, or even oligodendroglioma EGBs, calcifications, and

peri-vascular lymphocytes are common features and helpful clues

Immunohis-tochemical studies for neuronal markers can confirm the differentiation of

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.

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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

gan-glioglioma 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

differ-entiation 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

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.

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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

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

pro-liferation is recognized (see Fig 6.12) Often, these tumors exhibit necrosis

Necrosis can, however, be found in grade II ependymomas, and reproducible

A

B

FIGURE 6.11 Ependymoma

A: A low-power view shows a

fairly cellular tumor with

peri-vascular nuclear-free areas B: At

higher power, distinct

perivas-cular ependymal pseudorosettes

are seen The nuclear-free zones

correspond to a zone of radially

arranged long fibrillary processes.

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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 vascu-

lar tumors Significant intraoperative blood loss can complicate surgical

B A

D C

FIGURE 6.12 Anaplastic ependymoma A: This low-power image shows a cellular

demar-cated tumor B: The tumor exhibits microvascular/endothelial proliferation C: Focal

perivas-cular 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.

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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

com-posed of cells with taller columnar shape and more nuclear pleomorphism

than seen in normal choroid plexus (Fig 6.13) Most tumors are positive for

FIGURE 6.13 Choroid plexus

papilloma A: H&E-stained

prepa-rations 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

cy-tokeratins (Cam5.2 shown here)

C: D2-40 is often expressed by the

lesional cells as seen here.

A

B

C

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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

af-fected 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

dysfunc-tion, short stature, and lowered intelligence are big challenges facing survivors

Data from different sources suggest that medulloblastomas are a erogeneous group of tumors that can be subclassified.10,25–28 1) Different

het-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

includ-ing Gorlin syndrome (abnormalities in sonic hedgehog [SHH] signalinclud-ing),

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:

hemi-spheric lesions in young children that are associated with SHH pathway activation, good prognosis, and a derivation from external

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granular neurons These typically lack MYC amplification and

chro-mosome 17 aberrations

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

associ-ated 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

of the tumor and is easy to do Confirmation of other alterations such as

A

B

FIGURE 6.14 Medulloblastoma

A: This image illustrates the

ap-pearance of a classic

medulloblas-toma 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.

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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

in the following section) and retinoblastoma are two that also occur at

defined anatomic locations CNS/supratentorial primitive

neuroecto-dermal 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)

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.

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A

B

C

FIGURE 6.16 Atypical

tera-toid/rhabdoid tumor A: These

may mimic medulloblastoma on

the H&E-stained sections as seen

here when they have the

appear-ance of a small blue cell tumor

B: Loss of INI1 expression with

preserved normal staining in

vas-cular structures helps to establish

the correct diagnosis C:

Synap-tophysin 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 pediat-

ric 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

mono-morphic 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

vestib-ular 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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cytoplasmic lipidization Their nuclei may at least in part be

hyperchro-matic 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

in-hibin 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

defi-nition, it is the site for pineal cysts and pineal parenchymal tumors

Because of the anatomic location, it may at times be difficult to

dif-ferentiate a true pineal lesion from a mass arising in the posterior

mid-brain or the quadrigeminal cistern Pineal parenchymal lesions include

FIGURE 6.17 Schwannoma/

hemangioblastoma A:

Schwan-noma in a teenager with

neu-rofibromatosis type 2 As often

in vestibular schwannomas, this

tumor exclusively shows dense

Antoni A areas Fasciculated

ar-rangement 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

morpho-logic appearance can be variable.

A

B

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Pineal parenchymal lesions are positive for neuronal markers including

synaptophysin Expression of retinal proteins may be found but is rarely

used as diagnostic marker Pineocytomas are most commonly

encoun-tered in adults Their morphology may mimic normal pineal

paren-chyma The presence of pineocytomatous rosettes is a key distinctive

feature Pineoblastomas are typically pediatric age tumors that have the

appearance of a high-grade small blue cell tumor with mitotic activity,

Homer-Wright rosettes, Flexner-Wintersteiner rosettes, and necrosis Pineal parenchymal tumors of intermediate differentiation are recog-

nized Mitotic count and neurofilament staining have been suggested as

helpful diagnostic markers

Craniopharyngioma/Differential Diagnosis of Suprasellar Tumors

The sellar/suprasellar area can be the site for many different neoplasms

including pituitary adenomas, pituicytomas, meningiomas,

craniopha-ryngiomas, astrocytomas with the clinical appearance of “optic glioma,”

germ cell tumors, and chordomas Many of these lesions are uncommon

in children, but germ cell tumors, optic gliomas, and craniopharyngiomas

are not infrequent in the pediatric age group

Craniopharyngiomas are classified as either papillary or nomatous The former is more common in older patients, whereas the latter tends to be more common in younger patients These WHO grade

adamanti-I tumors are thought to arise from Rathke pouch remnants Local

recur-rence is the main management problem Surgical resection is challenging

because of the anatomic location Radiation can be helpful to control growth Radiologically and grossly, these tumors may be cystic Some-

times, mass effect can be controlled by draining cysts The cyst fluid is

thick brown, likened to machine oil, and characteristically contains

polar-izing cholesterol crystals The adamantinomatous variant consists of nests

and central loose stellate reticular areas with spindled cells (Fig 6.18) Wet keratin pearls—anuclear, often rounded aggregates of keratinocytes

maintaining a polygonal rather than a flattened shape—are typical The

papillary variant, in contrast, consists of more ordinary well-differentiated

squamous epithelium

Epidermoid Cyst

Germ cell tumors and dermoids are typically seen as midline lesions Epidermoids are most commonly encountered in the cerebellopontine angle region (Fig 6.19)

Congenital Brain Tumors

Sometimes, brain tumors are diagnosed before or around birth In contrast

to the overall pattern of distribution seen with pediatric brain tumors,

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FIGURE 6.19 Epidermoid cyst These often arise off the midline in the cerebellopontine

(CP) angle This patient presented with a meningitis-like presentation including

meningis-mus and CSF pleocytosis Further workup revealed this ruptured epidermoid cyst Spillage

of keratin debris into the CSF can cause chemical meningitis.

FIGURE 6.18

Craniopharyn-gioma A: The hallmarks of

adamantinomatous

craniopha-ryngioma are the peripheral

pali-sading of the nuclei, the central

stellate reticular appearance, and

the often rounded aggregates

of wet keratin seen here in the

left lower corner B: Parenchyma

at the edge of a

craniopharyn-gioma may show piloid gliosis

with Rosenthal fibers (arrows) as

seen here.

A

B

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FIGURE 6.20 Congenital brain

tumors A: This biopsy of a

congenital brain lesion shows a glioblastoma An area of pseudopalisading necrosis is seen in the

upper half of the image B: This

specimen is from a patient with

a congenital brain tumor that exhibits the typical features of

an immature teratoma

includ-ing cartilage (lower left corner)

and immature neural elements.

A

B

these cases are most commonly supratentorial Common entities in this

setting are teratomas, medulloblastomas/CNS supratentorial PNETs, astrocytomas/glioblastomas, and choroid plexus tumors (Fig 6.20)

TREATMENT EFFECT

Sometimes, patients who were previously treated for a known neoplasm

present with new imaging abnormalities that may mimic tumor recurrence

but turn out to be explained by treatment-related changes/necrosis One

example is children treated with fractionated radiation for a diagnosis of

an infiltrating glioma (Fig 6.21) Another example is patients who were

treated with radiation and methotrexate for acute leukemia These

pa-tients may develop necrotizing white matter lesions Correct classification

of the imaging changes as treatment effect rather than recurrent disease

can be critical for decisions on patient management

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A

B

C

FIGURE 6.21 Treatment-

related changes A: This

en-hanced MRI scan shows the

patient from Figure 6.3 months

after resection, radiation therapy,

and chemotherapy New

enhanc-ing areas were worrisome for

recurrent disease B: Resected

tissue showed hyalinization with

reactive blood vessel and focal

mineralization (lower right

cor-ner) C: Radiation necrosis with

typical vascular changes, patchy

foamy macrophages, and

mum-mified necrotic debris.

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BIOPSIES AND RESECTIONS IN THE CONTEXT OF

CHRONIC SEIZURES

Surgical resection of ictal foci can help to control seizure activity in

chil-dren with intractable disease Various morphologic changes can be seen

in these surgical specimens

• Some cases lack distinctive morphologic changes on H&E preparations

grids prior to resection

may be found in resections from the medial temporal lobe area

from the patient’s clinical history, such as encephalomalacia able to prior trauma

attribut-• Some specimens exhibit cortical dysplasia with disruption of normal

lay-ered cortical architecture These often have an admixture of dysmorphic neurons In some cases, large neuronal cells with glassy, pale pink cyto-plasm are seen These are referred to as “ballooned neurons” (Fig 6.22)

ganglio-glioma, PXA, or pilocytic astrocytomas

conditions such as Rasmussen encephalitis

INFECTIONS, DEMYELINATING DISEASES, VASCULAR DISEASES

All of these are relatively rare in biopsy material received from children In

principal, the associated morphologic findings are not different than those

seen in affected adults An abscess, a demyelinating lesion, or an organizing

infarct may all present in a way that mimics a tumor clinically In many cases,

correctly identifying macrophages and differentiating them from primary

neu-roglial cells is a first clue that should at least lead to the consideration of

non-neoplastic conditions Demyelinating disease goes along with loss of myelin

but relative preservation of axons These features are often best highlighted

by performing Bodian or neurofilament staining to visualize axons and Luxol

fast blue staining to demonstrate myelin loss In the case of infections, the

biopsy tissue can sometimes give useful clues to the underlying organism Immunohistochemical studies or in situ hybridization can identify the pres-

ence of viral particles in progressive multifocal leukoencephalopathy (PML),

Herpes simplex infection, or cytomegalovirus infection Sometimes, fungal stains or acid-fast staining can help to establish a diagnosis

METABOLIC DISEASES

In most cases, the question of a metabolic disease is clearly submitted

to-gether with a biopsy specimen A muscle biopsy may be taken to look for

features of a metabolic disease or a rectal suction biopsy may be obtained

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to look at mucosal ganglion cells in search of alterations suggesting ceroid

lipofuscinoses (Fig 6.23) These types of specimens sometimes require

appropriate tissue handling to ensure a meaningful analysis Some

stor-age products, for example, require the availability of frozen sections to

confirm the presence of abnormal metabolites on special studies A rectal

suction biopsy looking for inclusions of ganglion cells is usually processed

for Epon embedding and electron microscopy

In pediatric biopsies, storage material may rarely be encountered as

an unexpected finding—either because of clinical information the

pathol-ogist is lacking at the time of biopsy or because the findings are indicative

of a new diagnosis

NERVE BIOPSIES

Peripheral neuropathies are relatively uncommon in children as

A

B

FIGURE 6.22 Focal cortical

dysplasia Some variants include

cortex with altered

architec-tural arrangement of neurons

combined with the presence of

dysmorphic neurons (A) and/

or ballooned neurons with pale

pink cytoplasm (arrows) (B).

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considered in the differential diagnosis In certain settings, other forms

such as chemotherapy-induced toxic damage may occur Most of the biopsies are taken from the sural nerve to sample peripheral nerve tis-

sue while avoiding secondary motor deficits A good peripheral nerve biopsy consists of a segment of at least 3 cm The nerve is fixed in a gently

stretched state Tissue can subsequently be triaged for paraffin sections

and Epon embedding A saved segment of nerve can be used for teased

fiber preparations looking for features of demyelinating disease whenever

appropriate

MUSCLE BIOPSIES

In most cases, muscle biopsies are performed because the patient

pre-sents with weakness, hypotonia, muscle pain, or elevated creatine kinase

levels Sometimes, a muscle biopsy is part of a workup looking for a systemic disease process such as mitochondrial disease In the pediatric

FIGURE 6.23 Neuronal ceroid lipofuscinoses These electron micrographs illustrate the appearance of fingerprint bodies

(A) and curvilinear bodies (B) as

they can be found in mucosal ganglion cells of rectal suction biopsies from affected patients.

A

B

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population, the differential diagnosis often includes inherited as well as

acquired diseases Muscle biopsy specimens require special processing of

the fresh tissue that at least in part is often snap frozen in cooled

isopen-tane The frozen tissues allows a wide range of special studies that could

not be performed on fixed tissue including certain immunohistochemical

studies, enzyme histochemical studies, biochemical testing, and

some-times, immunoblot analysis Many pathologists elect to send their muscle

biopsy specimens out for processing This chapter therefore discusses this

specialized area only briefly

During skeletal muscle development, muscle fibers or myofibers

develop as syncytium through fusion of mononucleated precursor cells

Some of these so-called myoblasts remain as satellite cells to form a

pool of tissue stem cells that aid in muscle regeneration after injury

Normal muscle function is dependent on a number of specialized

proteins including those contributing to the formation of sarcomeres,

those establishing the dystrophin–glycoprotein complex, and those

important for energy metabolism Deficiency in any of these can lead

to inherited disease of skeletal muscle Many of the proteins are also

expressed in cardiac muscle, and inherited defects therefore often result

in a presentation that is characterized by skeletal and cardiac muscle

involvement

Inflammatory Myopathies

The most common inflammatory myopathy in children is

dermato-myositis This autoimmune disease goes along with a type I interferon

response and leads to damage of endothelial cells as well as drop-out of

reflective, at least in part, of poor perfusion related to vascular injury

The muscle damage that typically presents as weakness in proximal

muscle groups is associated with skin manifestations as suggested by

the name of the disease These include violaceous facial rash and

peri-ungual telangiectasias Calcinosis is an associated manifestation that is

fairly common in pediatric cases of dermatomyositis In most cases, the

disease responds to therapy with corticosteroids and other

immuno-modulatory agents Complications such as interstitial lung disease and

association with systemic malignancy are less common in children than

adults Polymyositis and muscle involvement by other systemic

connec-tive tissue diseases may be in the differential diagnosis but are relaconnec-tively

uncommon in children

Like other inflammatory myopathies, dermatomyositis goes along

with inflammatory infiltrates and features of degeneration/regeneration

of myofibers Morphologic features that are more suggestive of

derma-tomyositis are perifascicular atrophy, prominent capillary staining for

ultrastructural studies (Fig 6.24)

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Muscular Dystrophies

These are diseases that are associated with ongoing degeneration and

re-generation of myofibers Skeletal muscle has a high regenerative potential

But in muscular dystrophy, the continuous damage typically outpaces the

regenerative potential leading to increasing chronic remodelling through

endomysial fibrosis and fatty replacement In children, this type of chronic

remodelling suggestive of a long-standing disease process is therefore often indicative of an inherited disease process (Fig 6.25) Inflammatory

infiltrates are typically absent in muscular dystrophies The basic

morpho-logic features found in a patient with muscular dystrophy are often fairly

nonspecific In some cases, additional special staining can establish a specific diagnosis including staining for dystrophin (Duchenne or Becker

muscular dystrophy), sarcoglycans (limb-girdle muscular dystrophy 2C to

A

B

FIGURE 6.24 Dermatomyositis

A: The H&E-stained section of this

muscle shows preferential tribution of small atrophic and partly basophilic myofibers at the edge of the fascicles—a pattern described as perifascicular

Trang 35

mutations), merosin (congenital muscular dystrophy with merosin

defi-ciency), collagen IV (congenital muscular dystrophy/Ullrich disease), and

dysferlin (limb-girdle muscular dystrophy 2B) In other cases, the

diagno-sis rests on genetic studies (e.g., myotonic dystrophy, Emery-Dreifuss

mus-cular dystrophy, fascioscapulohumeral musmus-cular dystrophy, limb-girdle

Congenital Myopathies

These are diseases characterized by early onset but more static course than

the relentlessly progressive muscular dystrophies Many of the diseases

included in this group are associated with distinctive morphologic

of nemaline myopathy, central cores of central core disease, and central

nuclei in centronuclear myopathy The genetics of congenital muscular

dystrophies are complex A disease phenotype as for example nemaline

myopathy may be the result of several different mutations, and sometimes,

mutations in a single gene can have variable clinical manifestations

Metabolic Myopathies

Diseases of glycogen metabolism, lipid metabolism, or mitochondrial

function are often associated with changes on muscle biopsies These

include abnormal aggregates of lipid or glycogen in the cytoplasm of

FIGURE 6.25 Duchenne muscular dystrophy This muscle biopsy from a young boy

shows focal myofiber degeneration (arrows)/regeneration These myopathic changes are

associated with focal deposition of collagen between the muscle fibers of the visualized

fascicles (arrow tip) This endomysial fibrosis is a feature of disease chronicity and typical

but not specific for muscular dystrophies In the setting of a dystrophy, endomysial fibrosis

and fatty replacement tend to progress as the patient gets older.

Trang 36

B

FIGURE 6.26 Congenital myopathies Congenital myopathies are often associated with

distinct structural changes in the muscle A: The severe X-linked form of central nuclear

myopathy is also referred to as myotubular myopathy because myofibers show an

appear-ance that is normal at an earlier developmental stage of muscle development termed the

myotubular phase As during that normal developmental phase, the muscle in these cases

shows myofibers with large rounded nuclei placed in the geometric center of the fiber

(arrow) Other fibers show central lack of pink cytoplasmic staining in the corresponding

location (arrow tip) B: Central core disease This NADH reaction highlights disruption of

normal internal sarcoplasmic architecture with numerous fibers that contain demarcated

central zones of decreased reactivity (arrows) These central cores can be visualized on

other studies including by electron microscopy They are typically associated with mutations

in the ryanodine receptor Mutations in RYR1 are also linked to malignant hyperthermia.

myofibers, absent enzyme reactivity on histochemical testing, or

abnor-mal lysosoabnor-mal activity in the case of acid abnor-maltase deficiency

Mitochon-drial myopathies can be associated with the presence of ragged red fibers

(Fig 6.27) or cytochrome oxidase negative fibers It is, however,

impor-tant to remember that a normal-appearing muscle biopsy does not

nec-essarily exclude the possibility of a metabolic myopathy In some cases,

Trang 37

A

B

FIGURE 6.27 Mitochondrial

myopathy Mitochondrial

dis-eases can affect multiple organ

systems and lead to diverse

manifestations that may include

cardiomyopathy, seizures,

endo-crinopathy, and peripheral

neu-ropathy Skeletal muscle is often

involved A: The H&E-stained

section shows subtle increased

subsarcolemmal purplish staining

(arrow) B: This is confirmed on

the modified Gomori trichrome

stain that shows granular

thick-ened subsarcolemmal staining

(arrows) in a pattern often

de-scribed as “ragged red fiber.”

biochemical testing on muscle biopsy tissues or genetic testing is required

to confirm a diagnosis

Neurogenic Changes

Sometimes muscle biopsy specimens may simply show changes that

are reflective of disruption of normal muscle innervation rather than a

primary myopathic process These neurogenic changes include grouped

atrophy, fiber type grouping, and the presence of target formations Spinal

muscular atrophy is one of many possible causes of severe neonatal

hypotonia Muscle innervation is abnormal in these cases, but the pattern

of the associated changes differs somewhat from that seen in acquired

grouped atrophy because the atrophic myofibers never received proper

innervation and trophic input This results in a biphasic appearance with

numerous small polygonal myofibers and scattered clustered normal to

hypertrophied fibers that represent the rare fibers that received

innerva-tion by a surviving motor neuron (Fig 6.28)

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