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

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