NEUROPATHOLOGY

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CHAPTER 16 NEUROPATHOLOGY

Intracranial and spinal tumors

Primitive/embryonal tumors

Medulloblastoma

Supratentorial PNET/CNS-PNET

Atypical teratoid/rhabdoid tumor

Medulloepithelioma

Ependymoblastoma

Pineal tumors

Pineal parenchymal tumor of intermediate differentiation

Papillary tumour of the pineal region

Miscellaneous tumors

Hemangioblastoma

CNS germ cell tumors

Glial hamartias of neurofibromatosis type 2

Metastatic tumors of the CNS

Peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumor

Progressive myoclonic epilepsy

Lafora body disease

Neurodegenerative disorders of childhood

Infantile neuroaxonal dystrophy

Neuronal intranuclear inclusion disease

Neural tube defects, encephaloceles and related disorders

Cranial meningocele/encephalocele

Spinal meningocele and myelomeningocele

Miscellaneous spinal defects

Miscellaneous disorders

Neurosarcoidosis

Radiation necrosis

INTRACRANIAL AND SPINAL TUMORS

Overview

• Tumors of the central nervous system are the commonest solid tumors of childhood

• Typing and grading of brain tumors is prescribed by the WHO classification of Tumors of the Central Nervous System

• Tumors are graded using the WHO grading system

scale of I (low grade) to IV (high grade)

in most cases a specific tumor diagnosis carries a specific grade

– eg medulloblastoma is always grade IV

• H&E morphology remains the cornerstone of the classification

increasing emphasis on prognostic stratification in pediatric neuro-oncology based on a combination of histological and molecular techniques

• CNS tumors need to be reported in the context of a multidisciplinary team

in particular radiological input is critical for a number of diagnoses

Specimen handling

• Best practice for specimen sampling is as described for pediatric soft tissue tumors (see Chapter 6)

• The completeness of resection is an important prognostic factor in many pediatric brain tumors but is usually assessed by postoperative radiology

complete resections are more common than in adult practice

in most cases, the tissue received will be fragments and may represent only a part of the tumor

– particularly if the cavitron ultrasonic surgical aspirator (CUSA) is used (see below)

assessment of margins by histology is usually not possible

– assessment of completeness of resection is made radiologically

• Macroscopic findings in most cases add little specific diagnostic information

• Handling of lobectomy specimens is considered in the epilepsy surgery section (below)

Role of intraoperative diagnosis

• Intraoperative assessment is very common in neurosurgical practice

should be available in all centers undertaking neuro-oncological surgery

• Intraoperative samples can be assessed by frozen sections or by smear (crush) cytology

Crushing or smearing a small sample of fresh tissue between two glass slides followed by rapid alcohol fixation and staining with hematoxylin and eosin or toluidine blue

• Most CNS tumors can be smeared unless the texture prevents adequate spread of the tissue

eg some gliotic tissue, mesenchymal tumors

• The choice of frozen section versus smear is

determined in part by the nature of the tissue

determined in part by the preference and experience of the pathologist

• Overall accuracy of intraoperative diagnosis in predicting the final diagnosis is in the range of 85–95%

• In this chapter, only the smear findings of the major tumor types are given

mostly, frozen section findings parallel those in paraffin sections

GLIOMAS

PILOCYTIC ASTROCYTOMA

• Commonest glial tumor in children

• Many alternative, predominantly clinical, terms refer to the same tumor

optic nerve glioma, juvenile cerebellar astrocytoma etc

the term ‘pilocytic astrocytoma’ is preferable

WHO grade

• Pilocytic astrocytoma is WHO grade I

• Pilomyxoid astrocytoma is WHO grade II

Genetics

• Pilocytic astrocytoma is more common in neurofibromatosis type 1

tumors in this context have better prognosis and radiotherapy is often avoided

• Tandem duplications leading to BRAF activation are common (Jones et al 2008, Forshew et al 2009)

Intraoperative findings

• Uniform bipolar cells

• Minimal or absent atypia

• Fibrillary stroma

• Rosenthal fibers and eosinophilic granular bodies

appear cyan on toluidine blue

• Vascular proliferation may be present

Histopathological features

Diagnostically useful features

• Architecture (Figs 16.1–16.3)

– stellate cells in a loose or microcystic stroma

– compact fibrillary stroma containing spindle cells

• Cytology (Fig 16.4)

stellate or bipolar with thin elongated (hair-like or ‘piloid’) process

small nuclei with uniform nuclear chromatin

lack prominent nucleoli

mitotic activity may be present but is not usually prominent

• Microvascular proliferation (Fig 16.5)

often are arranged in extensive arcades

other vascular change

– hyaline change

– thrombosis and fibrinoid change

evidence of previous hemorrhage

• Rosenthal fibers (Figs 16.6, 16.7)

irregular carrot shaped eosinophilic inclusions

• Eosinophilic granular bodies (Figs 16.8, 16.9)

brightly eosinophilic and coarse granularity

eosinophilic structures lacking granularity may also be seen

Fig 16.1 Photomicrograph demonstrating a pilocytic astrocytoma with a mixture of loose microcystic areas and compact fibrillary areas.

Fig 16.2 Photomicrograph demonstrating a compact fibrillar area of a pilocytic astrocytoma with frequent Rosenthal fibers.

Fig 16.3 Photomicrograph demonstrating loose microcystic areas of a pilocytic astrocytoma.

Fig 16.4 Photomicrograph demonstrating the typical ‘piloid’ cytology of a pilocytic astrocytoma.

Fig 16.5 Photomicrograph demonstrating microvascular proliferation in a pilocytic astrocytoma.

Fig 16.6 Photomicrograph demonstrating clusters of Rosenthal fibers in a pilocytic astrocytoma.

Fig 16.7 Photomicrograph demonstrating high power image of Rosenthal fibers.

Fig 16.8 Photomicrograph demonstrating an eosinophilic granular body in a pilocytic astrocytoma.

Fig 16.9 Photomicrograph demonstrating an eosinophilic granular body in a pilocytic astrocytoma.

Morphological variations

Anaplastic pilocytic astrocytoma

• Some pilocytic astrocytomas show a more aggressive clinical pattern

• No well-defined and agreed histological criteria

some authors suggest the combination of a high mitotic count, vascular proliferation and necrosis

Differential diagnoses and pitfalls

• In most cases the diagnosis is clear

biphasic tumor of piloid cells containing Rosenthal fibers or eosinophilic granular bodies

• Differential diagnosis of eosinophilic granular bodies

pleomorphic xanthoastrocytoma

pilocytic astrocytoma

• Reactive (‘piloid’) gliosis

dense fibrillary gliosis containing multiple Rosenthal fibers surrounding often a slow growing or well-circumscribed lesion

– eg craniopharyngioma, a syrinx or a capillary hemangioblastoma

– particular problems occur when a small biopsy doesn’t include the primary lesion but the surrounding tissue

• In small biopsies, differential diagnosis from a low-grade diffuse astrocytoma (grade II) may be difficult

features favoring diffuse astrocytoma

– lack of a true biphasic architecture

– absence of Rosenthal fibers and eosinophilic granular bodies

correlation with the radiology may be helpful

– well-circumscribed enhancing lesions favor a pilocytic astrocytoma

• Microvascular proliferation and necrosis may prompt the consideration of a high-grade glioma

for correct interpretation of vascular proliferation

– first make the differential between the distinctive features of pilocytic and diffuse glioma

• The absence of Rosenthal fibers or EGBs does not preclude a definite diagnosis of pilocytic astrocytoma with classic architectural and cytological features

DIFFUSE ASTROCYTOMA (Fig 16.14)

• Diffusely infiltrating astrocytoma of low grade but with the potential to undergo transformation

• Mean survival is very variable

usually 6–8 years

Fig 16.14 Photomicrograph demonstrating a diffuse (fibrillary) astrocytoma (WHO grade II).

WHO grade

• WHO grade II

Genetics

• Described in Li–Fraumeni (p53 mutations) and Ollier’s disease (inherited multiple enchondromatosis type 1)

Histopathological features

• Diffusely infiltrating architecture with poorly defined margins

• Low cellularity

• Mild pleomorphism

• Mitosis absent unless sampling is extensive

• Necrosis and microvascular proliferation are absent

• Nuclei are slightly angular, hyperchromatic and show occasional atypia

• Stroma is variably microcystic and fibrillary

Morphological types

Protoplasmic astrocytoma

• Rare controversial tumor

• Younger patients

• Superficial location

• Small astrocytic nuclei with thin flaccid processes

within a mucoid stroma

• Mitosis absent

Granular cell astrocytoma

• A rare variant of astrocytoma with prominent granular cell change

granules are PAS positive

• May be grade II, III, IV using the same criteria for other diffusely infiltrating astrocytoma

Molecular diagnosis

• No routine use for molecular studies in the diagnosis of diffuse astrocytoma

• If overlap with oligodendroglial tumors is a problem 1p19q studies may be helpful in predicting outcome

ANAPLASTIC ASTROCYTOMA (Figs 16.15, 16.16)

• Diffuse astrocytoma showing more cellularity and pleomorphism than a grade II diffuse astrocytoma with clear mitotic activity

• By definition lacks necrosis or microvascular proliferation

• Transformation to glioblastoma is frequent with a mean interval of 2 years

Fig 16.15 Photomicrograph of an anaplastic astrocytoma demonstrating increased cellularity and pleomorphism compared with a grade II tumor. (see Fig 16.14)

Fig 16.16 Photomicrograph of an anaplastic astrocytoma demonstrating increased cellularity, pleomorphism and mitotic activity compared with a grade II tumor. (see Fig 16.14)

WHO grade

• WHO grade III

Clinical features

• Similar to grade II diffuse astrocytoma

• May be a previous history of a grade II diffuse astrocytoma

Intraoperative diagnosis

• Similar to grade II diffuse astrocytoma but

mitotic activity and more nuclear atypia are present

• Necrosis and microvascular proliferation are absent

• Precise grading of astrocytoma on smear is not necessary and is not reliable

Histopathological features

• Similar to diffuse astrocytoma (WHO grade II) but

increased cellularity

mitotic activity

• No necrosis or microvascular proliferation

Immunohistochemical staining

• Similar to grade II astrocytoma

• Ki67 labeling indices are about 5–10%

Molecular diagnosis

• Molecular diagnosis is not necessary for the diagnosis

• In the differential diagnosis with anaplastic oligodendroglioma 1p19q deletion may be useful

Differential diagnoses and pitfalls

• Grade II diffuse astrocytoma

• Gliomatosis cerebri

• Glioblastoma

• Ganglioglioma

• Pleomorphic xanthoastrocytoma

• Oligodendroglioma

GLIOBLASTOMA (Figs 16.17–16.19)

• Archetypal malignant glial tumor

Fig 16.17 Photomicrograph demonstrating a glioblastoma with anaplastic cytology and pseudo-palisading necrosis.

Fig 16.18 Photomicrograph demonstrating a glioblastoma with extensive tracks of pseudo-palisading necrosis.

Fig 16.19 Photomicrograph demonstrating microvascular (‘glomeruloid’) proliferation.

WHO grade

• WHO grade IV

Genetics

• Can arise in the context of familial colonic carcinoma (Turcot’s syndrome)

• Also in Li–Fraumeni syndrome

Intraoperative diagnosis

• Vascular proliferation

• Pleomorphic angular nuclei

• Fine metachromatic fibrillary stroma

Morphological variants

Giant cell glioblastoma (WHO grade IV)

• A variation of glioblastoma with frequent multinucleate giant tumor cells

• Occasional abundant reticulin-positive stroma

• Tend to be more circumscribed than conventional glioblastoma

• Usually poor prognosis

may be slightly better than conventional glioblastoma

• Frequent p53 mutations

Molecular diagnosis

• 1p19q deletion studies may be undertaken if the differential diagnosis includes an anaplastic oligodendroglial tumor

• Methylation of the MGMT promoter is associated with a better prognosis and a better response to alkylating drugs (Hegi et al 2005, Donson et al 2007) and high levels of MGMT expression may be a poor prognostic factor (Pollack et al 2006)

GLIOMATOSIS CEREBRI (Figs 16.20, 16.21)

• Diffusely infiltrative tumor defined by infiltration of at least 3 lobes

type 1 (classical) gliomatosis

– absence of a discrete tumor mass

type 2 gliomatosis

– extensive diffuse infiltration and a discrete tumor mass

Fig 16.20 Photomicrograph demonstrating gliomatosis cerebri at low power exhibiting diffuse infiltration of tumor cells.

Fig 16.21 Photomicrograph of gliomatosis cerebri demonstrating diffuse infiltration by tumor cells.

WHO grade

• Similar criteria can be used to grade gliomatosis as would be used for diffuse astrocytomas

majority correspond to WHO grade III

Intraoperative diagnosis

• Similar to diffuse or anaplastic glioma

Immunohistochemical staining

• GFAP and S100 may be positive or negative

• Ki67 labeling variable

not required for the diagnosis

• If there is confusion between a reactive microgliosis, markers of microglia (CD68) may be helpful in excluding the latter

Molecular diagnosis

• Similar genetic changes to diffuse glioma

not currently used diagnostically

PLEOMORPHIC XANTHOASTROCYTOMA

• Tumor of relatively favorable prognosis presenting with a superficial mass in the cerebrum or meninges (Weber et al 2007)

WHO grade

• WHO grade II

• Some tumors may show a more aggressive behavior

tumors with increased mitosis (at least 5/10 hpf) or necrosis should be called ‘pleomorphic xanthoastrocytoma with anaplastic features’ (Giannini et al 1999, Hirose et al 2008)

Genetics

• Rare cases have been associated with neurofibromatosis type 1

Clinical features

• Presentation is typically in childhood or early adulthood

often there is a history of seizures

• Most are supratentorial with a superficial location that may involve the meninges

• Rare cases in the spinal cord, cerebellum and retina

• Imaging may reveal a cyst

Intraoperative diagnosis

• Marked pleomorphism with giant bizarre cells

• Relatively little mitosis

Histopathological features (Fig 16.22)

• Pleomorphic astrocytic tumor

may include spindle cells, epithelioid cells and multinucleate cells

nuclear inclusions may be present

a few cells may appear ganglioid

• Variable xanthomatous change

not required for the diagnosis

• Pericellular reticulin

• Cortical and meningeal location

• Eosinophilic granular bodies

• Relatively well-demarcated margin

• Mitotic figures are typically rare at presentation

• Ganglion or ganglion-like cells

• Perivascular inflammation

• Recurrence may be associated with

raised mitotic counts (>5/10 hpf)

vascular endothelial proliferation

loss of pleomorphism

• overlap with ganglioglioma, oligodendroglioma and dysembryoplastic neuroepithelial tumor has been reported

• rare cases with prominent angiomatous change

Fig 16.22 Photomicrograph demonstrating a pleomorphic xanthoastrocytoma.

Special stains

• Fat stains on frozen tissue may highlight the xanthomatous change

• Pericellular reticulin (Fig 16.23)

not always prominent

Fig 16.23 Photomicrograph demonstrating the dense reticulin staining in a pleomorphic xanthoastrocytoma.

Differential diagnoses and pitfalls

• Ganglioglioma

• Giant cell glioblastoma

EPENDYMOMA

• One of the commonest and most problematic tumors of childhood (Metellus et al 2007)

• Prognostication on histological grounds is difficult

major predictor of clinical outcome is the extent of surgical excision (judged radiologically and surgically)

Genetics

• Most sporadic

• Increased frequency in neurofibromatosis type 2

Histopathological features (Figs 16.26–16.28)

• Uniform round cells

speckled nuclear chromatin

inconspicuous mitotic activity

• Necrosis is common

should not be regarded as a prognostic feature when isolated

• Calcification is common

Fig 16.26 Photomicrograph demonstrating the architecture of an ependymoma with diffuse sheets of uniform cells interrupted by nuclear free zones around the vessels (perivascular pseudorosettes).

Fig 16.27 Photomicrograph demonstrating perivascular pseudorosettes in an ependymoma.

Fig 16.28 Photomicrograph demonstrating true ependymal rosettes in an ependymoma.

Special diagnostic investigations (including EM)

• EM is not routinely required in the diagnosis of ependymoma but may be helpful in difficult cases

cilia (with a 9+2 arrangement) and microvilli lining ependymal canals

blepharoplasts at the luminal surface

junctional complexes (zonulae adherentes)

zonulae occludentes

ANAPLASTIC EPENDYMOMA (Figs 16.30, 16.31)

• Ependymoma with features of malignancy

• Diagnostic criteria poorly defined (Metellus et al 2007)

Fig 16.30 Photomicrograph demonstrating an anaplastic ependymoma. There is increased cellularity, atypia and vascular proliferation.

Fig 16.31 Photomicrograph demonstrating an anaplastic ependymoma with marked cytological atypia.

WHO grade

• WHO grade III

Clinical features

• Anaplasia is relatively common in childhood ependymomas

• Clinical presentation is similar to those of ependymoma (WHO grade II)

• Uncertainty whether the prognosis differs from that of ependymoma (WHO grade II)

Intraoperative diagnosis

• Similar to ependymoma but may show

increased nuclear atypia

vascular proliferation

Immunohistochemical staining

• As ependymoma but

Ki67 labeling index increased

Special diagnostic investigations (including EM)

• Electron microscopy confirm evidence of ependymal differentiation (see above)

SUBEPENDYMOMA

• A low-grade glial tumor with ependymal differentiation

WHO grade

• WHO grade I

Immunohistochemical staining

• Positive for GFAP

• Ki67 labeling index very low (<1%)

Differential diagnoses and pitfalls

• Occasional ependymomas will show evidence of subependymoma in parts

may be regarded as mixed ependymoma / subependymoma

graded according to the highest-grade component

• Morphological overlap with low-grade astrocytoma and tanycytic ependymomas

MYXOPAPILLARY EPENDYMOMA

• Distinctive histological and clinical low-grade tumor that shows a predilection for the caudal end of the spinal cord

WHO grade

• WHO grade I

Clinical features

• Typically presents with long standing back pain.

• MRI reveals a well-circumscribed lesion at the distal end of the spinal cord

• Excellent prognosis in most cases

occasional cases do show subarachnoid dissemination

Intraoperative diagnosis

• Uniform cells with rounded nuclei

• Perivascular pseudorosette

tumor cells separated from the vessels by thin cellular processes and dense deposits of myxoid material

myxoid material shows a dramatic metachromasia on toluidine blue staining

Histopathological features (Figs 16.32–16.34)

• Architecture

arrangement of tumor cells around thin blood vessels in a ‘papillary’ pattern

– separated from the vessels by prominent collections of Alcian blue-positive myxoid material

may be rather cuboidal and appear separated from the vessel or

more elongated extending thin processes in a radial pattern towards the vessels

– accumulation of myxoid material between the processes

uniform nuclei without conspicuous mitotic activity

• In some cases the perivascular arrangement may be less prominent

dominant feature is microcystic pattern containing myxoid material

Fig 16.32 Photomicrograph demonstrating typical architecture of a myxopapillary ependymoma.

Fig 16.33 Photomicrograph demonstrating the typical perivascular arrangement of a myxopapillary ependymoma.

Fig 16.34 Photomicrograph of a myxopapillary ependymoma demonstrating the presence of collections of poorly staining myxoid material separating the cellular processes as they run toward the vessel.

Special stains

• Alcian Blue stains the myxoid stroma (Fig 16.35)

Fig 16.35 Photomicrograph demonstrating the accumulation of myxoid material between tumor cells and the vessels in a myxopapillary ependymoma (Alcian blue-DPAS).

Immunohistochemical staining

• Positive for GFAP (Fig 16.36)

• Dot-positivity for EMA

• Negative for cytokeratin

• Ki67 proliferation index is usually low

Fig 16.36 Photomicrograph demonstrating GFAP immunoreactivity in a myxopapillary ependymoma.

Differential diagnoses and pitfalls

• The distinctive clinical and morphological features of this tumor rarely cause problems

• On occasion, other papillary or multicystic tumors such as carcinoma or germ cell tumor may enter the differential diagnosis if the site is not clearly known but the absence of significant cytological atypia and lack of staining for cytokeratins favor ependymoma

• A small sample may cause confusion with pilocytic astrocytoma

• Differential diagnosis from a conventional ependymoma (WHO grade II) may cause problems if the papillary pattern is not prominent

ANGIOCENTRIC GLIOMA

• A distinct grade I cortical tumor described in 2005 and also named angiocentric neuroepithelial tumor (Lellouch-Tubiana et al 2005, Wang et al 2005, Preusser et al 2007)

Histopathological features (Figs 16.37–16.40)

uniform spindle cells

granular chromatin

mitotic activity may be seen

• Microcyst formation may be seen

• Microvascular proliferation and necrosis are not typical features

Fig 16.37 Photomicrograph from the solid part of an angiocentric glioma.

Fig 16.38 Photomicrograph demonstrating a perivascular arrangement of an angiocentric glioma.

Fig 16.39 Photomicrograph demonstrating a perivascular arrangement of an angiocentric glioma. Trapped host neurones can be seen in between tumor cells.

Fig 16.40 Photomicrograph of an angiocentric glioma demonstrating the typical pattern of subpial accumulation.

Differential diagnoses and pitfalls

• Other angiocentric tumors including ependymoma, meningioangiomatosis and pilomyxoid astrocytoma

• A number of the reported cases were originally diagnosed as diffuse astrocytoma

• Distinction from ependymoma is dependent on

typical clinical and radiological features

– cortically based lesion in a patient with epilepsy

typical histological features of angiocentric glioma

– spindle cell cytology and prominent subpial and cortical invasion

– while the tumor may have regions that closely resemble ependymoma, these do not consist the majority of the tumor

• Some perivascular tumor cells may resemble the onion-skin arrangement of meningioangiomatosis

in other areas a more orientated perivascular arrangement points away from this diagnosis

subpial accumulation is not typical of meningioangiomatosis

cytology of the cells in angiocentric glioma shows coarser chromatin

presence of extensive GFAP-positivity not typical of meningioangiomatosis

CHOROID PLEXUS PAPILLOMA AND ATYPICAL CHOROID PLEXUS PAPILLOMA

• Well-differentiated papillary tumor of the choroid plexus

WHO grade

• Choroid plexus papilloma – WHO grade I

• Atypical choroid plexus papilloma – WHO grade II

Intraoperative diagnosis

• Papillary architecture

• Uniform epithelial cells

Histopathological features

• Architecture (Fig 16.43)

may form tubules

solid dedifferentiated areas if present favor a choroid plexus carcinoma (see below)

• Cuboidal or columnar epithelium overlying a delicate fibrovascular core

• Secondary changes, eg

xanthomatous change

• Cytology (Fig 16.44)

flattened cuboidal cells, columnar cells or pseudostratified

may be ciliated

cells may be very bland or showing varying degrees of nuclear atypia

mitotic activity varies

– scattered mitoses are usual

• Atypical choroid plexus papilloma (Fig 16.45)

increased proliferation and cytological atypia

– >2 mitoses/10 hpf has been suggested (Jeibmann et al 2006)

· possibly too stringent

• Brain invasion may occur

less common than in carcinomas

not useful in distinction of papilloma versus carcinoma

• Other variants

neuropil islands (Hasselblatt et al 2008)

psammomatous (Morgan et al 2007)

Fig 16.43 Photomicrograph demonstrating the papillary architecture of a choroid plexus papilloma.

Fig 16.44 Photomicrograph demonstrating the cytology of a choroid plexus papilloma.

Fig 16.45 Photomicrograph demonstrating the increased mitotic activity of an atypical choroid plexus papilloma.

Immunohistochemical staining

• Positive for epithelial markers (cytokeratins, EMA) and transthyertin (prealbumin)

• May show positivity for GFAP and variably synaptophysin

CHOROID PLEXUS CARCINOMA

• Malignant tumor of choroid plexus (Gopal et al 2008)

WHO grade

• WHO grade III

Clinical features

• Most arise in early childhood

• See papilloma above but 5-year survival is 41%

Intraoperative diagnosis

• May resemble a papilloma or an undifferentiated epithelial tumor

Immunohistochemical staining

• Similar to papillomas

• Some reports claim that choroid plexus carcinoma may lose INI-1 staining (Bourdeaut et al 2007) whereas others regard INI-1 as useful diagnostic markers of ATRT (Judkins et al 2005)

poorly differentiated tumors without INI-1 staining best regarded as AT/RT unless there is very good evidence to the contrary

Differential diagnoses and pitfalls

• Choroid plexus papilloma and atypical choroid plexus papilloma

• Primary poorly differentiated tumor (glioblastoma, AT/RT, PNET)

• Metastatic papillary tumors

OLIGODENDROGLIOMA (Fig 16.49)

• Predominantly a tumor of adulthood consisting of cells resembling oligodendroglial cells (Aldape et al 2007)

• Median survival >10 years

Fig 16.49 Photomicrograph demonstrating an oligodendroglioma in an infant composed of uniform rounded cells with perinuclear haloes.

WHO grade

• WHO grade II

Genetics

• Deletion of 1p and 19q present in up to 80% of cases

but is less common in children

Intraoperative diagnosis

• Smears show uniform rounded cells arranged near thin branching capillaries

• Calcium may be present

• Distinction from astrocytoma suggested by the paucity of a fibrillary stroma

Histopathological features

• Infiltrative edge shows diffuse infiltration of cortex and white matter

infiltrating tumor cells may accumulate around neurones (satellitosis), around vessels and in a subpial location

• Mini-gemistocytes may be present

small astrocytic cells with eccentric eosinophilic cytoplasm

• A variety of other cell types have been described: mucocytes, signet ring cells (rarely extensive-signet ring cell oligodendroglioma), eosinophilic granular cells

Immunohistochemical staining

• No immunohistochemical marker in routine diagnostic use identifies oligodendroglioma with any specificity

• GFAP may stain mini-gemistocytes but usually spares the typical tumor cells

• Neuronal markers may be present in the tumor cells and MAP-2 staining is typical

• Ki67 labeling is usually below 5%

high levels are associated with a worse prognosis

Molecular diagnosis

• Deletion of 1p and 19q by FISH or PCR is associated with a better prognosis and a better response to treatment

less common in children

ANAPLASTIC OLIGODENDROGLIOMA

• Oligodendroglial tumor with features of malignancy (Aldape et al 2007)

WHO grade

• WHO grade III

Intraoperative diagnosis

• Similar to oligodendroglioma but

increased nuclear pleomorphism

mitoses may be noted

• Necrosis and vascular proliferation may be seen

Immunohistochemical staining

• As oligodendroglioma

Molecular diagnosis

• Deletion of 1p19q in 60–70% by FISH or PCR

associated with a better prognosis and response to adjuvant therapy

less common in children

Differential diagnoses and pitfalls

• Oligodendroglioma

• Mixed astrocytic-oligodendroglial tumors

• High-grade astrocytomas (anaplastic astrocytoma or glioblastoma)

• Primitive neuroectodermal tumors (PNET)

OLIGO-ASTROCYTOMA AND ANAPLASTIC OLIGO-ASTROCYTOMA

• Tumors consisting of a well defined oligodendroglial and astrocytic components

• Both unusual in childhood

• Clinically not distinguishable from the equivalent single lineage tumors

• Two components may be

intermixed (diffuse variant)

separated (compact variant)

Oligoastrocytoma

• Lacks cytological anaplasia, necrosis and vascular proliferation

• WHO grade II

• May have a 1p19q deletion

• 5-year survival 58%

Anaplastic oligoastrocytoma

• Shows cytological atypia, increased cellularity, proliferation and may show necrosis and microvascular proliferation

• WHO grade III

• May have 1p19q deletion

• 5-year survival 36%

• Presence of mini-gemistocytes or non-neoplastic astrocytes in an oligodendroglioma does not justify the diagnosis of oligoastrocytoma

• Proportion of astrocytic cells necessary to make the diagnosis is not well defined

OTHER MIXED TUMORS

• Other combinations of glial differentiation are occasionally encountered in diffuse gliomas

eg combinations of astrocytic, ependymal and oligodendroglial differentiation

SUBEPENDYMAL NODULES/SUBEPENDYMAL GIANT CELL ASTROCYTOMA

• Benign intraventricular tumor in tuberous sclerosis complex (TSC)

• Subependymal nodules are multiple lesions in the ventricles of TSC patients (candle wax guttering).

• Subependymal giant cell astrocytomas (SEGAs) are defined radiologically as >1 cm

WHO grade

• WHO grade I

Genetics

• In practice, SEGAs are a tumor of TSC patients

6–14% of TSC patients develop SEGA

SEGA is one of the major criteria for the diagnosis of TSC

Clinical features

• First two decades

rare infantile and congenital cases

• Local pressure symptoms or obstruction to CSF flow

• Very rare drop lesions may occur

• Worsening seizures

Intraoperative diagnosis

• Smears contain plump cells

abundant cytoplasm

eccentric nuclei

sometimes multinucleate

perivascular arrangement

• Calcification

Immunohistochemical staining

• Variable expression of glial markers (GFAP, S100) and neuronal markers (neurofilament, synaptophysin, tubulin beta III) (Figs 16.51, 16.52)

• Ki67 index is low (usually <8%)

Fig 16.51 Photomicrograph demonstrating a subependymal giant cell astrocytoma with rather patchy staining for GFAP.

Fig 16.52 Photomicrograph demonstrating a subependymal giant cell astrocytoma with positive staining for synaptophysin.

Differential diagnoses and pitfalls

• Perivascular pseudorosettes may occasionally raise the possibility of ependymoma

cytology and clinical context allow diagnosis

ASTROBLASTOMA

• Rare and controversial tumor consisting of cells with broad non-tapering processes arranged around blood vessels

WHO grade

• Not specified

Clinical features

• Mostly young adults and children

• Usually present in the cerebral hemispheres

• Nodular and often cystic

Immunohistochemical staining

• Patchy staining for a GFAP, S100 and Vimentin

• Variable staining for epithelial markers eg EMA and cytokeratin

• Ki67 labeling index varies

NEURONAL AND MIXED GLIONEURONAL TUMORS

GANGLIOGLIOMA AND GANGLIOCYTOMA

• Usually low grade tumors containing neoplastic ganglion cells with (ganglioglioma) or without a glial component (gangliocytoma)

WHO grade

• Gangliocytoma – WHO grade I

• Ganglioglioma

most are WHO grade I

anaplastic ganglioglioma – WHO grade III

a grade II ganglioglioma is recognized by some authors but is not well defined

Genetics

• Rare cases have been described in neurofibromatosis type 1 and type 2 and in Peutz–Jeghers syndrome

Clinical features

• Presentation is most often in childhood or early adulthood

• Localization to anywhere in the CNS

70% are in the temporal lobe

• Cerebral ganglioglioma most commonly presents with chronic seizures

Intraoperative diagnosis

• Presence of dysplastic/binucleate cells with/without astrocytic cells

Histopathological features (Figs 16.54–16.57)

• Anaplastic ganglioglioma

ganglioglioma where the glial component resembles a malignant astrocytoma

Fig 16.54 Photomicrograph demonstrating ganglion cell clustering in a ganglioglioma.

Fig 16.55 Photomicrograph demonstrating a binucleate ganglion cell in a ganglioglioma.

Fig 16.56 Photomicrograph demonstrating eosinophilic granular bodies in a ganglioglioma.

Fig 16.57 Photomicrograph demonstrating perivascular inflammation in ganglioglioma.

DESMOPLASTIC INFANTILE ASTROCYTOMA AND GANGLIOGLIOMA (Fig 16.61)

• Large cystic tumors of early childhood defined by the presence of neuroglial cells in a desmoplastic stroma

Fig 16.61 Photomicrograph of the small cell component of a desmoplastic infantile ganglioglioma.

WHO grade

• WHO grade I

Clinical features

• Presentation usually first 1–2 years of life

occasional cases have been described later

• Short history with mass effect

• Occasional presentation with seizures or neurological deficit

• Very good prognosis

Special stains

desmoplastic component

– pericellular

Differential diagnoses and pitfalls

• Small cell component, which may be confused with a high-grade small cell tumor (eg PNET)

• Ganglioglioma

DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR (Figs 16.62–16.64)

• A low grade tumor associated with focal epilepsy

Fig 16.62 Photomicrograph demonstrating the specific glioneuronal element in a dysembryoplastic neuroepithelial tumor.

Fig 16.63 Photomicrograph demonstrating the specific glioneuronal element in a dysembryoplastic neuroepithelial tumor.

Fig 16.64 Photomicrograph demonstrating a floating neurone in a dysembryoplastic neuroepithelial tumor.

WHO grade

• WHO grade I

Clinical features

• Typically present with focal epilepsy

may be drug-resistant

• Age of presentation is very variable

typically teenagers and young adults

Intraoperative diagnosis

• Relatively uniform population of small round cells that spread relatively well

• Metachromatic stroma

• Scattered ganglion cells may be seen

• Calcification

Macroscopic features

• Cortically based

• Nodular architecture

Histopathological features

• Architecture

’specific glioneuronal element’

– OLCs arranged in a line along axonal processes

– myxoid stroma in which there are architecturally normal neurones

• Calcification and hemosiderin may be present

• Features of a high-grade tumor (pleomorphism, mitotic activity, vascular proliferation, necrosis) are typically absent

• Subpial accumulation of OLC may occur

• ’Simple’

single nodules of typical DNT histology

– OLCs and the specific glioneuronal element

• ‘Complex’ DNT

nodules of simple DNT

nodules of less distinct features

– resembling a glioma or a ganglioglioma

• Non-specific form of DNT

recent addition to classification

lacks ‘typical’ features such as the specific glioneuronal element

• May be ‘dysplasia’ in the adjacent cortex

often resembles additional nodules of tumor

well-developed focal cortical dysplasia of the type II is very unusual

Special stains

• The mucinous material is positive for Alcian blue

Immunohistochemical staining

• OLC are typically GFAP-negative, S100 positive

• Floating neurones will stain with standard neuronal markers (NeuN, Neurofilament etc)

• CD34 may be positive (Blümcke et al 1999)

• Ki67 proliferation index is low

Differential diagnoses and pitfalls

• Other tumors with a prominent round cell component (eg ependymoma, neurocytoma, oligodendroglioma) and the round cell component of a pilocytic astrocytoma

• Ganglioglioma

• Many cases of low-grade glioneuronal tumors in epilepsy contain an OLC component without a well-developed specific glioneuronal element

classification of these tumors is difficult

CENTRAL AND EXTRAVENTRICULAR NEUROCYTOMA (Figs 16.65–16.67)

• Low-grade tumor composed of uniform round cells with neuronal differentiation

Fig 16.65 Photomicrograph demonstrating an extraventricular neurocytoma composed of diffuse sheets of rounded cells, not unlike an oligodendroglioma.

Fig 16.66 Photomicrograph demonstrating an extraventricular neurocytoma composed predominantly of uniform rounded cells with perinuclear haloes and patches of neuropil. There are occasional ganglion cells.

Fig 16.67 Photomicrograph demonstrating ganglion-cell differentiation in an extraventricular neurocytoma.

WHO grade

• WHO grade II

Genetics

• Most show no genetic predisposition

Intraoperative diagnosis

• Well spread uniform tumor

rounded cells with speckled nuclear chromatin

Immunohistochemical staining

• Synaptophysin +ve

• Some cases NeuN +ve

• Usually GFAP negative

• Ki67 labeling indices usually very low

values >2–3% associated with a worse prognosis

Electron microscopy

• Thin cellular processors rich in microtubules

• Dense core and clear vesicles

• Synapses may be present

Differential diagnoses and pitfalls

• Oligodendroglioma

• Pineocytoma

• Dysembryoplastic neuroepithelial tumor

PAPILLARY GLIONEURONAL TUMOR (Figs 16.68–16.70)

• Low grade biphasic tumor consisting of neurocytes and pseudo-papillae lined by GFAP-positive astrocytes

Fig 16.68 Photomicrograph of a papillary glioneuronal tumor demonstrating the papillary component.

Fig 16.69 Photomicrograph of a papillary glioneuronal tumor demonstrating the neurocytic component.

Fig 16.70 Photomicrograph of a papillary glioneuronal tumor demonstrating the papillary component stained with GFAP.

WHO grade

• WHO grade I

Clinical features

• Most common in the cerebral hemispheres

• Presentation

raised intracranial pressure

neurological deficit

Immunohistochemical staining

• Glial cells in the papillae are GFAP-positive

• Neurocytic cells are synaptophysin positive

• Ganglion cells are NeuN positive

ROSETTE-FORMING GLIONEURONAL TUMOR OF THE FOURTH VENTRICLE (Fig 16.71)

• Rare low grade tumor of the fourth ventricle consisting of a component resembling a pilocytic astrocytoma and a rosette-forming neurocytic component (Komori et al 2002, Jacques et al 2006)

Fig 16.71 Photomicrograph demonstrating rosette formation in a rosette-forming glioneuronal tumor of the fourth ventricle.

WHO grade

• WHO grade I

Clinical features

• Presents as slow growing lesions of the fourth ventricle

obstructive hydrocephalus

cranial nerve signs

cerebellar signs

Intraoperative diagnosis

• Features of low-grade astrocytoma

may include a round cell component arranged in perivascular rosettes or Homer Wright rosettes

Histopathological features

component indistinguishable from a low grade/pilocytic astrocytoma

component consisting of uniform round (‘neurocytic’) cells arranged in perivascular rosettes and Homer Wright type rosettes

Immunohistochemical staining

• Astrocytic component is positive for GFAP and S100

• Neurocytic component is positive for neuronal markers

synaptophysin, MAP2 and variably NeuN

• Center of the rosettes will stain for MAP-2 and synaptophysin

• Ki67 index is typically low

Differential diagnoses and pitfalls

• Pilocytic astrocytoma

• Extraventricular neurocytoma

• Papillary glioneuronal tumor

• Rosetted glioneuronal tumor / glioneuronal tumor with neuropil like islands

GLIONEURONAL TUMOR WITH NEUROPIL-LIKE ISLANDS

• Rare tumor composed of a diffuse type of astrocytoma (of grade II or III) with islands of neuropil surrounded by uniform rounded cells

• The round cells may form loose rosettes or cross the neuropil islands

• Occasional more mature neuronal cells may be included and there may be occasional staining for mature neuronal markers

• Tumors may arise throughout the neuroaxis

• Prognosis follows the grade of the diffuse astrocytoma component

DYSPLASTIC GANGLIOCYTOMA OF THE CEREBELLUM / LHERMITTE–DUCLOS DISEASE

• Benign dysplastic mass arising in the cerebellum

Genetics

• Association with Cowden disease and mutations in PTEN gene

PTEN mutations may be less common in childhood cases

Immunohistochemical staining

• Abnormal ganglion cells are positive for neuronal markers

• Most are negative for Purkinje cell markers

Differential diagnoses and pitfalls

• Morphological features are typical without a significant differential diagnosis

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