NEUROPATHOLOGY

CHAPTER 16 NEUROPATHOLOGY



Intracranial and spinal tumors

Gliomas
Pilocytic astrocytoma

Diffuse astrocytoma

Anaplastic astrocytoma

Glioblastoma

Gliofibroma

Gliomatosis cerebri

Pleomorphic xanthoastrocytoma

Ependymoma

Anaplastic ependymoma

Subependymoma

Myxopapillary ependymoma

Angiocentric glioma

Choroid plexus papilloma and atypical choroid plexus papilloma

Choroid plexus carcinoma

Oligodendroglioma

Anaplastic oligodendroglioma

Oligo-astrocytoma and anaplastic oligo-astrocytoma

Other mixed tumors

Subependymal nodules/subependymal giant cell astrocytoma

Astroblastoma

Chordoid glioma of the third ventricle

Neuronal and mixed glioneuronal tumors
Ganglioglioma and gangliocytoma

Desmoplastic infantile astrocytoma and ganglioglioma

Dysembryoplastic neuroepithelial tumor

Central and extraventricular neurocytoma

Cerebellar liponeurocytoma

Papillary glioneuronal tumor

Rosette-forming glioneuronal tumor of the fourth ventricle

Glioneuronal tumor with neuropil-like islands

Spinal paraganglioma

Dysplastic gangliocytoma of the cerebellum / Lhermitte–Duclos disease

Primitive/embryonal tumors
Medulloblastoma

Supratentorial PNET/CNS-PNET

Atypical teratoid/rhabdoid tumor

Medulloepithelioma

Ependymoblastoma

Pineal tumors
Pineocytoma

Pineal parenchymal tumor of intermediate differentiation

Pineoblastoma

Papillary tumour of the pineal region

Meningeal tumors
Meningioma

Meningioangiomatosis

Meningeal hemangiopericytoma

Mesenchymal tumors of the central nervous system

Diffuse meningeal melanocytosis and melanomatosis

Meningeal melanocytoma

Primary malignant melanoma

Miscellaneous tumors
Hemangioblastoma

CNS germ cell tumors

Glial hamartias of neurofibromatosis type 2

CNS lymphomas

Metastatic tumors of the CNS

Benign cystic lesions of the nervous system
Rathke’s cleft cyst

Pineal cysts/glial cysts of the pineal

Epidermoid cysts

Dermoid cysts

Colloid cysts

Neurenteric cysts (enterogenous cysts)

Ependymal cysts

Choroid plexus cysts

Peripheral nerve sheath tumors
Schwannoma

Neurofibroma

Perineurioma

Malignant peripheral nerve sheath tumor

Schwannosis

Pituitary and hypothalamic lesions
Craniopharyngioma

Rathke’s cleft cyst

Pituitary adenoma

Pituitary carcinoma

Granular cell tumor of the neurohypophysis

Pituicytoma

Spindle cell oncocytoma of the adenohypophysis

Pituitary/hypothalamic gangliocytomas/ganglioneuromas

Hypothalamic hamartoma

Inflammatory disease of the pituitary/hypothalamus

Histiocytosis in the central nervous system
Langerhans cell histiocytosis

Rosai–Dorfman disease

Erdheim–Chester disease

Hemophagocytic lymphohistiocytosis

Juvenile xanthogranuloma

Xanthoma disseminatum

Malignant histiocytic disorders

Surgical pathology associated with epilepsy
Focal cortical dysplasia

Cortical tubers

Hemimegalencephaly

Polymicrogyria

Cerebral heterotopias

Perivascular oligodendrocyte clustering/hyperplasia

Classical hippocampal sclerosis

Granule cell dysplasia

End folium sclerosis

Old ischemic injuries

Chaslin’s gliosis

Rasmussen’s encephalitis

Progressive myoclonic epilepsy
Lafora body disease

Vascular pathology of the nervous system
Cavernous hemangioma (cavernoma)

Arterio-venous malformation

Venous angiomas

Vascular malformations of the leptomeninges

Vascular malformations of the dura

Sturge–Weber syndrome

Berry/saccular aneurysms

Sinus pericranii

Vasculitis

Moyamoya disease

White matter disease
Multiple sclerosis

Acute disseminated encephalomyelitis

Multiphasic disseminated encephalomyelitis

Acute hemorrhagic leukoencephalitis (Hurst’s disease)

Alexander’s disease

Metachromatic leukodystrophy

Other inherited white matter 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

Infectious disease
Meningeal viral infection (lymphocytic/aseptic meningitis)

Grey matter viral infection (polioencephalitis/poliomyelitis)

White matter viral disease

Necrotizing viral diseases of grey and white matter (panencephalitis)

Non-necrotizing viral diseases of grey and white matter (panencephalitis)

HIV-associated pathology

Miscellaneous virus associated with CNS infection/encephalitis

Cerebral abscess

Other pyogenic bacterial infections

Tuberculosis

Cerebral Whipple’s disease

Actinomycosis

Nocardia

Miscellaneous bacterial CNS infections

Toxoplasmosis

Amebiasis

Microsporidia

Nematodes

Filaria

Cestodes

Miscellaneous parasitic CNS infections

Aspergillosis

Blastomycosis

Candidiasis

Coccidioidomycosis

Crypotococcosis

Histoplasmosis

Chromomycoses

Zygomycosis (mucormycosis)

Other fungal infections

Miscellaneous disorders
Neurosarcoidosis

Radiation necrosis

CSF cytology


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

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

• In routine pediatric practice, a relatively restricted group account for the majority of tumors
image astrocytomas
– esp. pilocytic astrocytoma

image primitive neuroectodermal tumors
– esp. medulloblastoma

image ependymoma

image choroid plexus tumors

image germ cell tumors

image epilepsy associated tumors
– dysembryoplastic neuroepithelial tumors

– ganglioglioma

• The tumor location can also restrict the diagnostic possibilities, the following are the more common diagnosis by site in children
image posterior fossa
– pilocytic astrocytoma

– medulloblastoma

– ependymoma

– choroid plexus tumors

image spine
– astrocytoma

– ependymoma

image pineal gland
– pineoblastoma

– germ cell tumor

image pituitary fossa / hypothalamus
– craniopharyngioma

– germinoma

– pilocytic astrocytoma (hypothalamic)

– pituitary adenoma

– Rathke’s cleft cyst

• CNS tumors need to be reported in the context of a multidisciplinary team
image 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
image complete resections are more common than in adult practice

image 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)

image 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)

• The use of CUSA is common in neurosurgical practice to remove tumor mass
image in some centers, the material aspirated is sent as a pathological specimen
– advantage
· increased amount of tissue available

– disadvantage
· the tissue may be subject to artefact


Role of intraoperative diagnosis



• Intraoperative assessment is very common in neurosurgical practice
image should be available in all centers undertaking neuro-oncological surgery

• Intraoperative samples can be assessed by frozen sections or by smear (crush) cytology
image 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
image eg some gliotic tissue, mesenchymal tumors

• The choice of frozen section versus smear is
image determined in part by the nature of the tissue

image determined in part by the preference and experience of the pathologist

• Intraoperative diagnosis has specific purposes
image to assess whether tissue is pathological

image to assess tissue viability and therefore its sufficiency for diagnosis

image to identify diagnoses that may change intraoperative management
– diagnoses for which a complete resection may be attempted
· eg ependymoma, medulloblastoma

– diagnoses for which a biopsy may be preferred over a complete resection
· eg lymphoma, germinoma

• 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
image 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
image optic nerve glioma, juvenile cerebellar astrocytoma etc

image 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
image 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)


Clinical features



• Can present at any age

• Can occur at any site but common sites include
image optic nerve

image cerebellar hemisphere

image thalamus

image spinal cord

image hypothalamus/optic chiasm

• Symptoms are those of a slowly growing mass lesion
image related to the site

• Leptomeningeal dissemination is described
image should not discourage the diagnosis

• Often regarded as benign tumors but
image rate of morbidity is high
– reflecting particularly the difficulty with tumors in the hypothalamus and optic pathway

image whilst 5-year survival is high, progression free survival is more modest


Intraoperative findings



• Uniform bipolar cells

• Minimal or absent atypia

• Fibrillary stroma

• Rosenthal fibers and eosinophilic granular bodies
image appear cyan on toluidine blue

• Vascular proliferation may be present


Histopathological features



Diagnostically useful features



• Architecture (Figs 16.1–16.3)
image biphasic
– stellate cells in a loose or microcystic stroma

– compact fibrillary stroma containing spindle cells

• Cytology (Fig 16.4)
image stellate or bipolar with thin elongated (hair-like or ‘piloid’) process

image small nuclei with uniform nuclear chromatin

image lack prominent nucleoli

image mitotic activity may be present but is not usually prominent

• Microvascular proliferation (Fig 16.5)
image common

image often are arranged in extensive arcades

image other vascular change
– hyaline change

– thrombosis and fibrinoid change

image evidence of previous hemorrhage

• Rosenthal fibers (Figs 16.6, 16.7)
image irregular carrot shaped eosinophilic inclusions

• Eosinophilic granular bodies (Figs 16.8, 16.9)
image brightly eosinophilic and coarse granularity

image eosinophilic structures lacking granularity may also be seen

image

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


image

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


image

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


image

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


image

Fig 16.5 Photomicrograph demonstrating microvascular proliferation in a pilocytic astrocytoma.


image

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


image

Fig 16.7 Photomicrograph demonstrating high power image of Rosenthal fibers.


image

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


image

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



Associated features



• Subpial invasion and spread in the meningeal space are frequent histologically

• Margin may be better circumscribed than diffuse gliomas
image relative rather than absolute

image presence of diffuse microscopic invasion is fairly common

• Degenerative changes may be seen
image hyaline or cystic degeneration

image degenerative nuclear atypia

image occasional necrosis

• Some tumors contain areas of uniform rounded cells that may mimic an oligodendroglioma or DNT (Fig 16.10)

• Ribbons of aligned nuclei

image

Fig 16.10 Photomicrograph demonstrating a small rounded component to a pilocytic astrocytoma (compare with the oligodendroglioma in Fig 16.49).



Morphological variations



Anaplastic pilocytic astrocytoma



• Some pilocytic astrocytomas show a more aggressive clinical pattern

• No well-defined and agreed histological criteria
image some authors suggest the combination of a high mitotic count, vascular proliferation and necrosis


Pilomyxoid astrocytoma (WHO grade II) (Figs 16.11, 16.12)



• Hypothalamus/optic chiasm
image cases have been described elsewhere

• Usually very young children

• Uniform bipolar cells set against a prominent myxoid stroma

• Prominent perivascular arrangement of tumor cells

• Rosenthal fibers and eosinophilic granular bodies usually absent

• Tendency to leptomeningeal spread

• Worse prognosis than conventional pilocytic astrocytoma

image

Fig 16.11 Photomicrograph demonstrating the perivascular orientation of cells in a pilomyxoid astrocytoma.


image

Fig 16.12 Photomicrograph demonstrating the cytological features of a pilomyxoid astrocytoma.



Immunohistochemical staining



• Diagnosis is essentially morphological

• GFAP positive (Fig 16.13)

• Ki67 labeling index usually <1% but may be up to 10%

• There is some evidence that WT-1 staining may help to distinguish neoplastic astrocytes from reactive astrocytes (Schittenhelm et al 2008, 2009)

image

Fig 16.13 Photomicrograph demonstrating GFAP-immunoreactivity in a pilocytic astrocytoma.



Differential diagnoses and pitfalls



• In most cases the diagnosis is clear
image biphasic tumor of piloid cells containing Rosenthal fibers or eosinophilic granular bodies

• Differential diagnosis of Rosenthal fibers
image reactive (‘piloid’) gliosis

image pilocytic astrocytoma

image ganglioglioma

image pleomorphic xanthoastrocytoma

image focal cortical dysplasia and hemimegalencephaly

image Alexander’s disease

image giant axonal neuropathy

image fucosidosis

• Differential diagnosis of eosinophilic granular bodies
image pleomorphic xanthoastrocytoma

image pilocytic astrocytoma

image ganglioglioma

• Reactive (‘piloid’) gliosis
image 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
image features favoring diffuse astrocytoma
– lack of a true biphasic architecture

– absence of Rosenthal fibers and eosinophilic granular bodies

image 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
image 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
image usually 6–8 years

image

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)


Clinical features



• Peak age of onset is young adults
image 10% <20 years

• May arise at any site
image most frequently supratentorial
– especially frontal and temporal lobes

image rare in the cerebellum

• Seizures are a common presentation

• Subtle behavioral changes may be present for many years

• Imaging shows a diffuse ill-defined tumor
image calcification may be present

image contrast enhancement is absent


Intraoperative diagnosis



• Smears show a fibrillary stroma
image metachromatic with toluidine blue

• Slightly angular cells with fine processes
image partially spread but often stay in the regions of vessels

• Mitosis is usually absent

• No necrosis or vascular proliferation


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



Fibrillary astrocytoma



• Commonest type of diffuse astrocytoma

• Nuclear features are diagnostic
image irregular, cigar shaped, hyperchromatic nuclei

• Nuclear atypia may be severe but mitoses are absent

• Cytoplasm not visible or minimally present

• Fibrillary stroma

• Microcysts and mucinous stroma

• Metaplasia may occur
image cartilage formation is described


Gemistocytic astrocytoma



• >20% of the tumor cells are gemistocytes
image plump astrocytes with glassy eosinophilic cytoplasm

image eccentric nuclei (with distinct nucleoli and clumped chromatin)

image short, randomly orientated processes

• Fibrillary stroma

• Perivascular inflammation may be present

• Prone to transformation


Protoplasmic astrocytoma



• Rare controversial tumor

• Younger patients

• Superficial location

• Small astrocytic nuclei with thin flaccid processes
image within a mucoid stroma

• Mitosis absent


Granular cell astrocytoma



• A rare variant of astrocytoma with prominent granular cell change
image granules are PAS positive

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


Immunohistochemical staining



• Most diffuse astrocytomas show GFAP positivity in cell bodies and stroma
image may be sparse in protoplasmic type

• May be S100 and vimentin positive

• p53 nuclear staining may be present
image not prognostic

• There is some evidence that WT-1 staining may help to distinguish neoplastic astrocytes from reactive astrocytes (Schittenhelm et al 2008, 2009)

• Ki67 indices are generally low (<4%); values >5% predict a shorter survival


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


Differential diagnoses and pitfalls



• Reactive astrocytosis
image particularly in circumstances in which pleomorphism is prominent
– eg acute demyelination, progressive multifocal leukoencephalopathy

• Oligodendroglial and oligoastrocytic tumors

• Pilocytic and pilomyxoid astrocytoma

• Anaplastic astrocytoma


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

image

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


image

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
image 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
image increased cellularity

image nuclear atypia

image 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

image

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


image

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


image

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


Clinical features



• May arise anywhere in the neuroaxis
image frequently deep white matter of the cerebrum or brain stem

• Clinical features depend on site
image focal neurological deficit

image seizures

image raised intracranial pressure

• Rapid clinical progression


Intraoperative diagnosis



• Necrosis

• Vascular proliferation

• Pleomorphic angular nuclei

• Mitoses

• Fine metachromatic fibrillary stroma


Histopathological features



• Diagnostic criteria
image malignant astrocytic tumor with necrosis or microvascular proliferation

• Necrosis
image pseudo-palisading or coagulative

• Cytology is very variable
image pleomorphic cells with angular hyperchromatic nuclei

image eccentric eosinophilic nuclei

• Mitotically active

• Additional features may include
image small cell component (’small cell glioblastoma’)

image granular cells

image epithelial component

image gemistocytes

image lipidized cells

image perivascular lymphocytes

image metaplasia

image multinucleation

image epithelioid morphology


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
image may be slightly better than conventional glioblastoma

• Frequent p53 mutations


Gliosarcoma (WHO grade IV)


Related posts:

  1. METABOLIC DISEASE PATHOLOGY
  2. BONE PATHOLOGY
  3. DERMATOPATHOLOGY
  4. RENAL PATHOLOGY

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Jun 18, 2016 | Posted by in PEDIATRICS | Comments Off on NEUROPATHOLOGY

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