CNSCNS

Pattern of CNS Diseases

Congenital Malformation &Perinatal Brain

Injury

Trauma

Cerebrovascular diseases

Infections

Tumors

Degenerative Diseases

Learning objectives

To discuss

Benign and malignant tumours of the CNS and Familial tumour

syndromes in terms of genetics, clinical features, associated

lesions, and complications, clinical course

Learning outcomes

At the end of the lecture the student will be able to

Classify the tumours of the brain

Discuss types, age and sex predominance, incidence, clinical

presentation, morphology and clinical course-prognosis of common brain

tumours

Discuss the common familial tumour syndromes associated with brain

tumours

CNS Tumors

CNS Tumors

Tumors of the CNS are a larger proportion of

cancers of childhood

CNS tumors in childhood differ from those in

adults both in histologic subtype and location

In childhood tumors are likely to arise in the

posterior fossa

In adults - supratentorial

CNS

Normal

Neurons

Glia

Astrocytes, Oligodendrocytes, Ependymal

Cells, Microglia

Tumors of the nervous system may arise

from

Cells of the coverings

Cells intrinsic to the brain

Other cell populations within the skull

Metastases (spread from elsewhere in the

body )

CNS Tumors

CLASSIFICATION OF CNS TUMOURS

1. TUMOURS OF THE GLIAL TISSUE – (GLIOMAS)

2. TUMOURS OF NEURONS

3. MIXED TUMOURS WITH GLIAL & NEURONAL COMPONENTS

4. POORLY DIFFERENTIATED AND EMBRYONAL TUMOURS

5. TUMOURS OF THE MENINGES6. PERIPHERAL NERVE SHEATH TUMOURS

7. METASTATIC TUMOURS

8. PRIMARY CNS LYMPHOMA9. Miscellaneous TUMOURS

CLASSIFICATION MIXED TUMOURS WITH

GLIAL & NEURONAL COMPONENTS

Ganglioglioma

Dysembryoplastic Neuroepithelial tumour (DNT)

POORLY DIFFERENTIATED AND EMBRYONAL TUMOURS

Medulloblastoma

Atypical teratoid/rhabdoid tumour

Medulloepithelioma

Dysplastic Gangliocytoma of the cerebellum (Lhermitte –Duclos disease)

Polar spongioblastoma

TUMOURS OF THE GLIAL TISSUE – (GLIOMAS)

Astrocytoma

Oligodendroglioma

Ependymoma 

TUMOURS OF NEURONS

Gangliocytoma

Neuroblastoma

Ganglioneurocytoma

Gliomatosis cerebri

Cerebral neuroblastoma

Central neurocytoma

TUMOURS OF THE MENINGES Meningioma PERIPHERAL NERVE SHEATH TUMOURSSchwannomaNeurofibromaMalignant nerve sheath tumour-MPNST (Malignant Schwannoma))

Miscellaneous TUMOURSHemangioblastomaCraniopharyngiomaPituitary tumoursMesenchymal tumours

METASTATIC TUMOURS

PRIMARY CNS LYMPHOMA

Tumors of the nervous system have unique characteristics

Histologic distinction between benign and

malignant lesions

The pattern of growth

The anatomic site of the neoplasm

The pattern of spread

CNS-Tumours• Incidence of CNS tumors ranges from 10 to 17 per

100,000

• Half to three-quarters are primary tumors, rest are

metastatic

• 70% of childhood CNS tumors arise in the

posterior fossa

• In adults tumours arise within the cerebral

hemispheres above the tentorium.

• Distinction between benign & malignant lesions is

less evident

CNS-Tumours• Ability to surgically resect infiltrating glial

neoplasms without compromising neurologic

function is limited

• Anatomic site of the neoplasm can have lethal

consequences irrespective of histologic

classification

CNS-Tumours

• Pattern of spread of primary CNS neoplasms

differs -Even the most highly malignant Gliomas

rarely metastasize outside the CNS

• The subarachnoid space provides a pathway for

spread - occur in highly anaplastic as well as in

well-differentiated neoplasms that extend into the

CSF pathways.

The criteria used to determine malignancy

1. Even highly malignant intracranial neoplasms

generally do not metastasize

2. Destructive infiltration of the brain is the major

criterion of malignancy for intracranial neoplasms.

Neurologic deficits resulting from destructive

invasion by malignant neoplasms are irreversible.

Benign neoplasms, on the other hand, cause

neurologic deficits due to compression; these

often reverse when the neoplasm is removed

The criteria used to determine malignancy

3. The rate of growth of neoplasms also correlates

well with malignant behavior .

4. Recurrence after treatment is almost invariable with

malignant intracranial neoplasms.

5. The term benign for any intracranial neoplasm is

probably implies rather that they are slow growing

and do not infiltrate the brain substance.

Intracranial

neoplasm

space occupying

Raised ICP

Obstruction to CSF flow

hydrocephalous

oedema

Raised ICP

destruction

neurological deficit

compression

neurological deficit

irritation

seizures

Patho- physiological Patho- physiological affects of intracranial affects of intracranial neoplasmsneoplasms

TUMOURS OF THE GLIAL TISSUE – (GLIOMAS)

Astrocytoma

Oligodendroglioma

Ependymoma 

Astrocytoma

Fibrillary astrocytoma

Glioblastoma

Pilocytic astrocytoma, and

Pleomorphic xanthoastrocytoma

WHO Grading system for astrocytomas

Variables such as nuclear atypia/mitosis/

endothelial proliferation & necrosis are

scored as

Grade 1 if none = pilocystic astrocytoma

Grade 2 if any one = diffuse astrocytoma

Grade 3 if any two= anaplastic astrocytoma

Grade 4 if three or all = glioblastoma multiforme

Fibrillary (Diffuse) Astrocytomas (grade II/IV)

• Most common adult CNS tumour

• 80% of adult primary brain tumors

• Location: cerebral hemispheres, also occur in the

cerebellum, brainstem, or spinal cord

• Fourth through sixth decades

• most common presenting signs and symptoms

are seizures, headaches, and focal neurologic

deficits related to the anatomic site of involvement

Fibrillary (Diffuse) Astrocytomas (grade II/IV)

Gross

Poorly defined gray infiltrative

tumor that expands and

distorts the brain

C/S of the tumor - firm or soft and gelatinous; cystic degeneration

few centimeters - enormous lesions

Low-grade astrocytoma is seen as expanded white matter of the left cerebral hemisphere thickened corpus callosum and fornices

MICROMild to moderate increase in the number of glial cell nucleiTumor cells - stellate, spindle-shaped with fiber like processesIntervening feltwork of fine, GFAP-positive astrocytic cell processes that give the background a fibrillary appearance

Fibrillary (Diffuse) Astrocytomas (grade II/IV)

Other types

• Anaplastic astrocytomas (Grade III/IV)

• Gemistocytic astrocytoma :predominant

neoplastic astrocyte shows a brightly eosinophilic

cell body from which emanate abundant, stout

processes

Glioblastoma (grade IV/IV)

• Older age group

Morphology

• show variation in the gross appearance : Some

areas are firm and white, others are soft and yellow (the

result of tissue necrosis), and yet others show regions of

cystic degeneration and hemorrhage

• well demarcated from the surrounding brain

tissue, but infiltration beyond the outer margins is

always present

• Gliomatosis cerebri- multiple regions of the brain

are infiltrated by neoplastic astrocytes

Glioblastoma multiforme GROSS

appearing as a necrotic, hemorrhagic, infiltrating mass

variation in the gross appearance of the tumor from region to region is

Characteristic

Some areas are firm and white,others are soft and yellow (the result of tissue necrosis), and still others show regions of cystic degeneration and hemorrhage

Glioblastoma- morphology MICRO:•Densely cellular with nuclear pleomorphism •Necrosis in a serpentine pattern•Tumour cells crowded along the edges of necrosis referred to as pseudopalisading• When vascular cell proliferation is extreme, the tuft forms a ball-like structure, the glomeruloid body

Nuclearpalisading

Serpentine necrosis

Glioblastoma multiforme

Pilocytic Astrocytoma (Grade 1)

• Have relatively benign behavior

• They typically occur in children and young adults

• Located in the cerebellum but may also appear in

the floor and walls of the third ventricle, the optic

nerves, and occasionally the cerebral

hemispheres

Pilocytic Astrocytoma (Grade 1)

Grosslywell circumscribed cystic, with a mural nodule in the wall of the cyst

 cystic astrocytoma of the cerebellum in a child

The tumor is composed of bipolar cells with long, thin “hairlike”processes that are GFAP-positive

Rosenthal fibers,eosinophilic granular bodies, and microcysts are often present; necrosis and mitoses are rare

Pilocytic Astrocytoma (Grade 1)

Oligodendrogliomas (Grade II/IV)

• Constitute 5% to 15% of gliomas ,Fourth and fifth decades.• Cerebral hemispheres, with a predilection for white matter.

Morphology • Grossly they are well-circumscribed, gelatinous, gray

masses, often with cysts, focal hemorrhage, and calcification

• Microscopically the tumors are composed of sheets of regular cells with spherical nuclei containing finely granular chromatin surrounded by a clear halo of cytoplasm (fried egg appearance)

• The tumor typically contains a delicate network of anatomizing capillaries(chickenwire)

• Calcification seen in 90% of cases

Oligodendrogliomas (Grade II/IV)

fried egg appearance

chickenwire

Oligodendrogliomas (Grade II/IV)

fried egg appearance

chickenwire

Calcification

Ependymomas- (Grade II/IV)

Gross:• Solid/papillary masses extending from the floor of

the ventricle • Variant :Myxopapillary ependymomas occurs in

the filum terminale of the spinal cord

•Arise next to the ependyma - lined ventricular system

•First two decades of life - - they typically occur near the

fourth ventricle

•In adults, the spinal cord is their most common location;

tumors in this site are frequent in the setting of

neurofibromatosis type 2

ependymoma arising from the ependymal lining of the fourth ventricle above the brainstem and bulging toward the cerebellum

CT scan

horizontal section of the brain reveals a large ependymoma of the fourth ventricle

Ependymomas- (Grade II/IV)

Cells with regular, round to oval nuclei with abundant granular chromatin in a dense fibrillary background

Tumor cells may form gland-like round or elongated structures (rosettes, canals) that resemble the embryologic ependymal canal

• Subependymomas are solid, sometimes calcified,

slow-growing nodules attached to the ventricular

lining and protruding into the ventricle

• Choroid plexus papillomas can occur anywhere

along the choroid plexus and are most common in

children (lateral ventricles). In adults, they are

found in the fourth ventricle.

• There are rare cases of choroid plexus carcinoma

NEURONAL TUMORSTUMOURS OF NEURONS Gangliocytoma Neuroblastoma Ganglioneurocytoma Gliomatosis cerebri Cerebral neuroblastoma Central neurocytoma

NEURONAL TUMORS

• Central neurocytoma: low-grade neoplasm found

within and adjacent to the ventricular system characterized

by evenly spaced, round, uniform nuclei and often islands

of neuropil

• Gangliogliomas are tumors with a mixture of glial

elements, usually a low-grade astrocytoma, and mature-

appearing neurons

• Dysembryoplastic neuroepithelial tumor is a distinctive,

low-grade childhood tumor

Embryonal (Primitive) Neoplasms

Medulloblastoma•neuroectodermal origin, retain cellular features of

primitive, undifferentiated cells.

•accounts for 20% of the brain tumors in children

•Location :exclusively in the cerebellum.

Morphology

•Grossly : well circumscribed, gray, and friable

•Microscopically : highly cellular and are composed of

diffuse masses of small, undifferentiated oval or round

cells, like a lymphoma

Rosette formation- are groups of tumor cells

arranged in a circle around a fibrillary center

Embryonal (Primitive) Neoplasms

Medulloblastoma

Medulloblastoma small round blue cells withRosette formation

Sagittal section of brain showing medulloblastoma destroying the superior midline cerebellum

Medulloblastoma

small round blue cells withRosette formation

Medulloblastoma

 posterior fossa mass

cerebellum

fourth ventricle

brainstem 

MENINGIOMAS (mostly Grade I/IV)• predominantly benign tumors of adults, usually

attached to the dura• That arise from the meningothelial cell of the

arachnoid.

Common sites of involvement • Parasagittal aspect of the brain convexity• Dura over the lateral convexity• Wing of the sphenoid• Olfactory groove, sella turcica• Foramen magnum• Ectopic meningiomas

MENINGIOMAS (mostly Grade I/IV)

Macro:• usually rounded masses, bosselated or polypoid

appearance• Extension into the overlying bone may be present• The surface of the mass is usually encapsulated• Usually, they displace brain tissue without invading it• Some meningiomas grow flat on the surface of the brain

– en plaque variant

Morphology-Micro - types

• Syncytial appropriately named for the whorled clusters of

cells that sit in tight groups without visible cell membranes

• Fibroblastic with elongated cells and abundant collagen

deposition between them

• Psammomatous with numerous psammoma bodies,

apparently forming from calcification of the syncytial nests

of meningothelial cells

• Secretory with PAS-positive intracytoplasmic droplets and

intracellular lumens by electron microscopy

• Transitional which share features of the syncytial and

fibroblastic types

• Microcystic with a loose, spongy appearance

• Atypical, Anaplastic ,Papillary and Rhabdoid

Morphology

whorled nests of meningothelial cells

Morphology

whorled nests of meningothelial cells

numerous psammoma bodies

METASTATIC TUMORS• Metastatic lesions, mostly carcinomas, account

for approximately a quarter to half of intracranial tumors

• The five most common primary sites are lung, breast, skin (melanoma), kidney, and gastrointestinal tract, accounting for about 80% of all metastases.

• The Meninges are also a frequent site of involvement by metastatic disease.

• Intraparenchymal metastases form sharply demarcated masses, often at the gray matter-white matter junction

• The boundary between tumor and brain parenchyma is well defined microscopically as well; melanoma is one tumor that does not always follow this rule

METASTATIC TUMORS

Carcinomas that metastasize to the brain parenchyma reach the brain via arterial channels most commonly encountered in the territory of the middle cerebral artery, often implant at gray-white junctions, typically well circumscribed

Metastatic melanomamulticentricity and well-demarcated marginsThe dark pigment in the tumor nodules in this case is characteristic of most malignant melanomas

PERIPHERAL NERVE SHEATH TUMORS

arise from cells of the peripheral nerve, including

Schwann cells

perineurial cells

fibroblasts

Many express Schwann cell characteristics, including the presence of S-100 antigen

MPNST -Malignant Peripheral Nerve Sheath Tumor (MPNST, Malignant Schwannoma) :Are highly malignant sarcomas that are locally invasive

Schwannoma• These benign tumors arise from the neural crest-

derived Schwann cell and are associated with neurofibromatosis type 2.

• common location - cerebellopontine angle usually attached to vestibular branch of the eighth nerve

• Elsewhere within the dura, sensory nerves are preferentially involved, including branches of the trigeminal nerve and dorsal roots

• When extradural, most commonly found in association with large nerve trunks, where motor and sensory modalities are intermixed

Schwannomas

extra-axial, circumscribed and encapsulated and range from small and solid to large, irregular, cystic, and hemorrhagic tumors

Site: in the acoustic (eighth cranial) nerve at the cerebellopontine angle

Patients may present with hearing loss

Micro : Two growth patterns Antoni A pattern elongated cells with cytoplasmic processes arranged in fasciclesRegions of nuclear palisading The "nuclear-free zones" are termed Verocay bodies

Antoni B PatternThe tumor is less densely cellular

With a loose meshwork of cells- looser, myxoid regions

Neurofibromas

Two forms

cutaneous neurofibroma

• The most common form occurs in the skin

(cutaneous neurofibroma) or in peripheral nerve

(solitary neurofibroma).

• These arise sporadically or in association with

neurofibromatosis type 1

• The risk of malignant transformation from these

tumors is extremely small, and cosmetic concerns

are their major morbidity

•

Neurofibromas

Plexiform neurofibroma

•occur only in patients with neurofibromatosis

type 1

•frequently multiple and the nerve is irregularly

expanded

•difficulty in surgical removal of these plexiform

tumors when they involve major nerve trunks

•have a significant potential for malignant

transformation

MorphologyGross:• Present in the dermis and subcutaneous fat or arise anywhere along a

nerve• not encapsulated

On microscopic examination

- a loose, myxoid background with a low cellularity

A number of cell phenotypes are present

- Schwann cells, Inflammatory cells, Larger

multipolar fibroblastic cells

- areas of collagen bundles, which have a

“shredded carrot" appearance

OTHER TUMORS • Atypical Teratoid / Rhabdoid Tumor - highly

malignant tumor of young child• Primary CNS lymphoma (PCNSL) It is the most

common CNS neoplasm in immunosuppressed ,are high grade Non-Hodgkin's B-cell ,Poor prognosis

• Hemangioblastoma :Arises in the cerebellum Important component of VHL

• Germ Cell Tumors :Occur along the midline, most commonly in the pineal and the suprasellar regions. Teratomas are common

Pineal Parenchymal Tumors –well-differentiated lesions (pineocytomas) high-grade tumors (pineoblastomas)

FAMILIAL TUMOR SYNDROMES

• These are a group of inherited diseases

characterized by the development of

hamartomas and neoplasms throughout

the body with particular involvement of the

nervous system

• Many of the disorders are inherited in an

autosomal-dominant pattern and have

been linked to tumor-suppressor genes

FAMILIAL TUMOR SYNDROMES 1)Neurofibromatosis Type 1 (NF1) Autosomal-dominant characterized by Neurofibromas Gliomas of the optic nerve Pigmented nodules of the iris (Lisch nodules) Cutaneous hyperpigmented macules (café au lait spots)

2)Neurofibromatosis Type 2 (NF2) Autosomal-dominant disorder Commonly bilateral VIII nerve schwannomas and multiple meningiomas & Gliomas

Neurofibromatosis

an inherited disorder Affected individual develop multiple benign neurofibromas

that arise within or are attached to the nerve trunks in the skin

On the right side of the neck and shoulder of this patient, extensive subcutaneous neurofibromas have formed pendulous masses called plexiform neurofibromas

an increased risk of developing neurofibrosarcomas

This condition arises from mutations in the NF1 tumor suppressor gene

. This patient shows another typical feature of neurofibromatosis: cafe' au lait spots. These spots on the skin (macules) have light brown pigmentation. Neurofibromas are not seen well in this picture.  

FAMILIAL TUMOR SYNDROMES 3)Tuberous Sclerosis • Autosomal-dominant syndrome

• Characterized by hamartomas and benign neoplasms involving the brain and other tissues.

• other lesions include renal angiomyolipomas, retinal glial hamartomas, and cardiac rhabdomyomas

• Cysts found in the liver, kidneys, and pancreas• Cutaneous lesions include angiofibromas, leathery thickenings in

localized patches (shagreen patches), hypopigmented areas (ash-leaf patches), and subungual fibromas

4) Von Hippel-Lindau Disease • Autosomal-dominant disease • Individuals develop capillary hemangioblastomas

within the cerebellum ,retina, & the brainstem and spinal cord.

• cysts involving the pancreas, liver, and kidneys are present

• may develop renal cell carcinoma of the kidney .

5) Others • Turcot syndrome (APC)– Medulloblastoma• Gorlin’s syndrome (PTCH)- Medulloblastoma• MEN syndrome – Schwannomas• Retinoblastoma (RB1) –

Retinoblastoma,pineoblastoma• Li FRAUMENI –(P53) Malignant glioma