Pathology of CNS

Eric M. Mirandilla MD, DPSP

Emilio Aguinaldo College of Medicine
 Objectives
• To understand the functional anatomy and physiology of the nervous
system and how these apply to common pathological presentations.
• To understand the pathology of cerebral infarction and haemorrhage.
• To describe traumatic injuries to the CNS and their effects.
• To recall the main causes of dementia and have a basic understanding of
the pathological changes.
• To recall the distribution and effects of common infections of the CNS.
• To have a basic understanding of demyelinating and degenerative disease
of the CNS.
• To briefly describe the effect of metabolic disorders and toxins on the CNS.
• To describe the mechanisms of hydrocephalus and the common causes.
• To recall neoplasms that affect the central and peripheral nervous system.
 Cerebral Edema
• Vasogenic:
– Increased vascular permeability leads to the focal or
generalized accumulation of intercellular fluid; the absence
of lymphatics impairs resorption.
• Cytotoxic:
– Increased intracellular fluid secondary to endothelial,
neuronal, or glial injury (e.g., after anoxia or toxic and
metabolic disturbances).
• Interstitial:
– Fluid from the ventricular system transudates across the
ependymal lining secondary to increased intraventricular
pressure.
 Hydrocephalus
• When hydrocephalus occurs before cranial
suture closure, the head is enlarged;
• hydrocephalus after bone fusion leads to
ventricular expansion and increased
intracranial pressure.
– Noncommunicating hydrocephalus refers to
enlargement of only a portion of the ventricle
system (e.g., due to blockage of the third
ventricle); in communicating hydrocephalus the
entire system is expanded.
 Raised Intracranial Pressure and
Herniation
• Subfalcine (cingulate) herniation
– compromise branches of the
anterior cerebral artery.
• Transtentorial (uncinate, mesial
temporal) herniation
– distort the adjacent midbrain and
pons; third cranial nerve
compromise causes papillary
dilation, and compression of the
posterior cerebral artery can cause
visual cortex ischemia.
– Substantial herniation causes
ipsilateral hemiparesis and is often
accompanied by tearing of feeding
vessels (Duret hemorrhages).
 Neural Tube Defects
• Spina bifida
– can be an asymptomatic bony defect
(spina bifida occulta) or a severe
malformation with a flattened,
disorganized cord segment with
overlying meningeal outpouching.
• Myelomeningocele
– represents CNS outpouching through a
vertebral column defect; most occur in
the lumbosacral region associated with
lower extremity motor and sensory
deficits and disturbed bowel and
bladder control.
• Encephalocele
– is a malformed CNS diverticulum
extending through a defect in the
cranium, typically in the occiput or
posterior fossa.
• Anencephaly
– is a malformation of the anterior neural
tube, resulting in failure of cerebral
development.
 Forebrain Anomalies
• Brain size
– microencephaly (small brain)
– (lissencephaly)
– complete absence of gyri (agyria)
– Megalencephaly (large brain)
 Forebrain Anomalies
• Gyral formation
– Polymicrogyria are small, overabundant cerebral
convolutions due to focal injury near the end of
neuronal migration
– Neuronal heterotopias are abnormal clusters of
neurons in inappropriate locations along normal
migratory routes;
– Holoprosencephaly is characterized by incomplete
separation of the cerebral hemispheres;
– In agenesis of the corpus callosum, normal white
matter interhemispheric bundles are not formed
 Posterior Fossa Anomalies
• Arnold-Chiari malformation
(Chiari II malformation)
– consists of a small posterior fossa,
a malformed midline cerebellum
with extension of the vermis
through the foramen magnum,
hydrocephalus, and a lumbar
myelomeningocele.
• Chiari I malformation
– is associated with low-lying
cerebellar tonsils extending into
the vertebral canal;
– it is often clinically silent, but can
present with CSF flow obstruction.
• Dandy-Walker malformation
– is characterized by an enlarged
posterior fossa, absent cerebellar
vermis, and large midline cyst,
with brainstem nuclei dysplasias.
 Syringomyelia and Hydromyelia
• These are expansions of the central canal
(hydromyelia) or formationof a cleftlike cavity
(syringomyelia) in the spinal cord.
• Histologically there is associated gray and
white matter destruction, surrounded by
reactive gliosis.
• Patients present with loss of pain and
temperature sensation in the upper
extremities
 Perinatal Brain Injury
• Cerebral palsy is the broad term for
nonprogressive motor deficits related to prenatal
and perinatal neurologic insults
– Intraparenchymal hemorrhage
– Ischemic infarcts can occur in the periventricular
white matter (periventricular leukomalacia) or within
the hemispheres (multicystic encephalopathy).
– Ulegyria is the term for thin, gliotic gyri due to
perinatal cortical ischemia
– Injury during gestation can destroy brain tissue
without evoking any reactive gliosis
Parenchymal Injuries
 Spinal Cord Injury
• Cord injuries are associated with displacement
of the spinal column; the level of injury
determines the neurologic outcome:
• Thoracic vertebrae or below: paraplegia
• Cervical vertebrae: quadriplegia; with lesions
at C4 and above, respiratory compromise due
to diaphragm paralysis
 Hypoxia, Ischemia, and Infarction
• Loss of the membrane potential necessary for
neuronal electrical activity
• Elevation of cytoplasmic calcium levels, activating
an enzymatic cascade that causes cellular injury
• Inappropriate release of excitatory amino acid
neurotransmitters (e.g., glutamate) that cause
cell damage via calcium influx through N-methyl-
D-aspartate (NMDA)-type glutamate receptors
 Global Cerebral Ischemia
• Severe global ischemia leads to widespread neuronal
cell death;
• patients who survive can remain in a persistent
vegetative state or meet “brain death” criteria: “flat”
electroencephalogram and absent reflexes, respiratory
drive, and cerebral perfusion.
• When maintained on mechanical ventilation, the brain
of such patients eventually autolyzes (“respirator
brain”).
• If oxygenation is only incompletely compromised,
watershed (border zone) infarcts can occur at the
interface between major vascular supplies
 Focal Cerebral Ischemia
• Thrombosis (usually due to underlying atherosclerosis)
most frequently affects the extracerebral carotid system
and the basilar artery.
• Embolism most commonly involves the intracerebral
arteries and particularly the middle cerebral artery
distribution.
• Inflammatory lesions, including infectious vasculitis (e.g.,
syphilis or tuberculosis) and vasculitides (e.g., polyarteritis
nodosa) can also cause luminal narrowing and cerebral
infarction.
• Venous infarcts occur after occlusion of the superior
sagittal sinus, other sinuses, or deep cerebral veins, and are
characteristically hemorrhagic.
Hypertensive Cerebrovascular Disease
• Lacunar Infarcts
– are small (<15 mm) cystic infarcts resulting from
cerebral arteriolar sclerosis and occlusion
• Slit Hemorrhages
– occur when hypertension causes small vessel
rupture; these eventually resorb, leaving residual
hemosiderinladen macrophages and associated
gliosis.
 Hypertensive Encephalopathy
• Acute hypertensive encephalopathy
– is a clinicopathologic syndrome caused by increased
intracranial pressure and manifesting as diffuse
cerebral dysfunction
• Chronic hypertensive injury.
– Recurrent small infarcts (hypertensive,
atherosclerotic, and/or embolic) can lead to vascular
(multi-infarct) dementia, a syndrome characterized by
dementia, gait abnormalities, pseudobulbar signs, and
other focal neurologic deficits.
 Intraparenchymal Hemorrhage
• Hypertension is the predisposing factor in half,
accounting for 15% of deaths among patients
with chronic hypertension
• Cerebral amyloid angiopathy (CAA) is the
second most common etiology
 Subarachnoid Hemorrhage and Ruptured Saccular
Aneurysms
• Berry aneurysms occur in 2% of the
population, with 20% to 30% of
patients having multiple aneurysms;
– 90% of berry aneurysms occur in the
anterior circulation near arterial branch
• Although most are sporadic,
aneurysms are also associated with
autosomal dominant polycystic
kidney disease, hypertension, aortic
coarctation, connective tissue
disorders (Ehlers-Danlos syndrome
type IV, Marfan syndrome),
neurofibromatosis type 1 (NF1), and
fibromuscular dysplasia.
• The aneurysms are not typically
present at birth but develop over
time due to an underlying weakness
in the vessel media
Infections
Infections
 Demyelinating Diseases
Multiple Sclerosis
• an autoimmune demyelinating disorder
characterized by distinct episodes of
neurologic deficit separated in time and
attributable to white matter lesions that are
separated in space
 Demyelinating Diseases
• Multiple Sclerosis
• Active plaques show myelin
breakdown, lipid-laden
macrophages, and relative
axonal preservation.
– Lymphocytes and
mononuclear cells are
prominent at plaque edges
and around venules.
• Inactive plaques lack the
inflammatory cell infiltrate
and show gliosis;
– most axons within the lesion
persist but remain
unmyelinated.
 Neuromyelitis Optica
• This disorder is characterized by near-
synchronous, bilateral optic neuritis and spinal
cord demyelinating lesions.
• White matter lesions exhibit necrosis with
acute inflammation and vascular
immunoglobulin and complement deposition
– antibodies directed against aquaporins, which are
important in maintaining astrocyte foot processes
and thus blood-brain barrier integrity.
 Acute Disseminated Encephalomyelitis and
Acute Necrotizing Hemorrhagic
Encephalomyelitis
• Acute disseminated encephalomyelitis (ADEM) is a
diffuse demyelinating disease occurring after viral
infection (or rarely, a viral immunization);
– patients present with headache, lethargy, and coma but no
focal deficits.
• Acute necrotizing hemorrhagic encephalomyelitis
(ANHE) is a more fulminant, frequently fatal,
demyelinating syndrome typically affecting children
and young adults after an upperrespiratory tract
infection.
– Lesions are similar to ADEM but more severe and often
confluent, with small vessel destruction and disseminated
CNS necrosis.
 Central Pontine Myelinolysis
• This disorder is characterized by myelin
damage (with axonal preservation) without
inflammation in the basis pontis and portions
of the pontine tegmentum, often leading to
rapidly evolving quadraplegia.
• It is most commonly associated with a rapid
correction of a hyponatremic state (damaging
oligodendroglial cells), although it can occur
with other electrolyte abnormalities.
 Alzheimer Disease
• AD is the most common dementing illness of
the elderly, reaching a prevalence of >40% in
the 85- to 89-year-old cohort
• Aβ and tau accumulations constitute the
fundamental biochemical AD abnormality;
plaques and tangles are the pathologic
hallmarks.
 Alzheimer Disease
• Role of Aβ.
– Aβ derives from the processing of
amyloid precursor protein (APP), a
normal transmembrane protein
– Aβ is highly prone to
aggregation—first into small
oligomers (which may be the toxic
form responsible for neuronal
dysfunction) and eventually into
large aggregates and fibrils.
– An initial cleavage in the
extracellular domain of APP
determines the outcome:
• Nonamyloidogenic pathway: α-
secretase cleavage at the cell
surface
• Amyloidogenic pathway: Surface
APP is endocytosed and undergoes
cleavage by β-secretase
 Alzheimer Disease
• Role of tau:
– Tangles formation in AD is associated with tau
hyperphosphorylation and inability to bind to and
stabilize microtubules; hyperphosphorylated tau
aggregates also elicit a stress response.
• Other genetic risk factors:
– Apolipoprotein E (ApoE) alleles (ε2, ε3, and ε4)
influence AD risk; ε4 increases AD risk and lowers
the age of onset by promoting Aβ generation and
deposition.
 Alzheimer Disease
• Role of inflammation: Aβ elicits an inflammatory response
from microglia and astrocytes that can assist in aggregate
clearance but can also stimulate the secretion of potentially
deleterious mediators.
• Basis for cognitive impairment: A large burden of plaques
and tangles is highly associated with severe cognitive
dysfunction.
– The degree of dementia also correlates with loss of choline
acetyltransferase, synaptophysin immunoreactivity, and amyloid
burden.
• Biomarkers:
– Aβ deposition can be imaged using 18F-labeled amyloid-binding
compounds, and neuronal degeneration correlates with
increased phosphorylated tau and reduced Aβ in the CSF.
Alzheimer Disease
 Frontotemporal Lobar Degeneration-
Tau
• FTLD-Tau is associated with aggregates of either wild-
type or mutant tau, a phosphoprotein that normally
interacts with microtubules; when
hyperphosphorylated, it has a propensity to aggregate
• Some missense mutations affect tau phosphorylation,
whereas others influence splicing.
• Neuronal injury is a combination of aggregate toxicity
as well as tau depletion through aggregation.
• Severe selective lobar atrophy with inclusions is the
hallmark of Pick disease.
Frontotemporal Lobar Degeneration-
TDP
• Some FTLDs have inclusions that contain TDP-43, an
RNA-binding protein; there are three associated
mutations:
– An expansion of a hexanucleotide repeat in the 5′ UTR of
C9orf72 (a gene encoding a protein of unknown function)
is most common.
• The spectrum of disease also includes amyotrophic lateral
sclerosis (ALS).
– Mutations in the gene encoding the TDP-43 protein are
less common; these can also be seen in some cases of ALS.
– Mutations in the gene encoding progranulin, a secreted
glial and neuronal protein that is cleaved into multiple
small peptides implicated in regulating CNS inflammation;
these mutations are not associated with ALS.
 Parkinson Disease
• Parkinson disease (PD) is the principal
neurodegenerative disease in this category and is
diagnosed in individuals with the triad of tremor,
rigidity, and bradykinesia in the absence of toxic or
other known etiology
• Autosomal dominant forms of the disease include
mutations causing overexpression of α-synuclein (a
lipid-binding protein associated with synapses) or gain
of function in the LRRK2 gene (encoding a kinase).
• A juvenile recessive form of PD is caused by loss-of-
function mutations in the parkin gene (encoding an E3
ubiquitin ligase).
 Parkinson Disease
• There is pallor of the
substantia nigra and locus
ceruleus, with loss of
pigmented,
catecholaminergic
neurons and gliosis;
• Lewy bodies
(intracytoplasmic,
eosinophilic inclusions,
containing α-synuclein)
occur in the remaining
neurons.
Atypical Parkinsonism Syndromes
• Progressive Supranuclear Palsy
– is a tauopathy (associated with aggregates of tau)
characterized by loss of vertical gaze, truncal rigidity,
dysequilibrium, loss of facial expression, and mild
progressive dementia.
• Corticobasal Degeneration
– is a tauopathy of the elderly characterized by
extrapyramidal rigidity, asymmetric motor
disturbances,
– and sensory cortical dysfunction;
– this disorder is associated with the same SNP as are
found in PSP
Atypical Parkinsonism Syndromes
• Multiple System Atrophy
– reflects a group of disorders characterized by atrophy in
specific CNS regions associated with glial (predominantly
oligodendrocyte) tubular cytoplasmic inclusions containing
α-synuclein and ubiquitin.
• Huntington Disease
– an autosomal dominant movement disorder clinically
manifesting between ages 20 and 50.
– Patients develop chorea (jerky, hyperkinetic, dystonic
movements) that can evolve into parkinsonism
– HD is associated with expansion of a CAG trinucleotide
repeat encoding a polyglutamine tract in huntingtin.
 Spinocerebellar Degenerations
• Spinocerebellar Ataxias
– are a group of more than 30 different autosomal
dominant diseases involving the cerebellum,
brainstem, spinal cord, and peripheral nerves.
– Some forms are caused by unstable expansions of
CAG repeats, encoding polyglutamine tracts in
different protein
 Spinocerebellar Degenerations
• Friedreich Ataxia
– autosomal recessive; patients present with gait
ataxia, hand clumsiness, dysarthria, depressed
tendon reflexes, and sensory loss rendering most
wheelchair bound within 5 years
– caused by expansion of an intronic GAA repeat in
the gene encoding frataxin
 Spinocerebellar Degenerations
• Ataxia-Telangiectasia
– autosomal recessive;
– patients present in childhood with cerebellar
dysfunction, telangiectatic lesions in the skin and
conjunctiva (and CNS), and immunodeficiency
(lymph nodes and thymus are hypoplastic).
– The relevant ATM gene encodes a kinase involved
in repairing double-stranded DNA breaks
 Spinocerebellar Degenerations
• Amyotrophic Lateral Sclerosis
– characterized by progressive loss of both lower
motor neurons and upper motor neurons, with
ensuing profound weakness.
– due to adverse gain-of-function mutations in the
copper-zinc superoxide dismutase (SOD1) gene,
believed to yield misfolded proteins that engender
an injurious unfolded protein response
 Toxic and Acquired Metabolic
Diseases / Neurologic Sequelae of Metabolic
Disturbances
• Thiamine (Vitamin B1) Deficiency
• Vitamin B12 Deficiency
• Hypoglycemia
• Hyperglycemia
 Toxic Disorders
• Carbon Monoxide
• Methanol
• Ethanol
• Radiation
TUMORS
 Astrocytoma
• Infiltrating Astrocytomas
– account for 80% of adult primary brain tumors;
typically arising between ages 30 and 60, most
occur in the cerebral hemispheres
– Tumors range from diffuse astrocytoma (grade
II/IV) to anaplastic astrocytoma (grade III/IV) to
glioblastoma (grade IV/IV)
 Astrocytoma
• Infiltrating Astrocytomas
– Diffuse astrocytomas (grade II)
are poorly defined, gray-white,
infiltrative tumors that expand
and distort a region of the brain
– Anaplastic astrocytomas (grade
III) exhibit increased nuclear
anaplasia with numerous mitoses.
– Glioblastomas (grade IV;
previously called glioblastoma
multiforme [GBM]) are composed
of a mixture of firm white areas,
• softer yellow foci of necrosis, cystic
change, and hemorrhage; there is
also increased vascularity. Increased
tumor cell density along the
necrotic edges is termed
pseudopalisading.
 Astrocytoma
• Pilocytic Astrocytoma
– occurs in children and young adults, usually in the
cerebellum but also in the floor and walls of the
third ventricle, the optic nerves, and occasionally
the cerebral hemispheres; they are WHO grade
I/IV.
– These tumors have a relatively benign behavior;
they grow slowly and are rarely infiltrative.
 Astrocytoma
• Pilocytic Astrocytoma
• Gross: Lesions are often
cystic with a mural nodule
in the wall of the cyst.
• Microscopic: Tumors are
composed of bipolar cells
with long, thin hairlike
processes;
– Rosenthal fibers and
microcysts are often present.
– There is a narrow infiltrative
border with the surrounding
brain.
Pleomorphic Xanthoastrocytomas
• Pleomorphic xanthoastrocytomas typically
occur in the temporal lobes of young patients,
often with a history of seizures.
• The tumor (usually WHO grade II/IV) exhibits
neoplastic, occasionally bizarre astrocytes,
abundant reticulin and lipid deposits, and
chronic inflammatory cell infiltrates;
• 5-year survival nears 80%.
 Brainstem Glioma
• Brainstem glioma occurs mostly in the first two
decades of life.
• Their course depends on location, with pontine
gliomas (most common) having an aggressive
course, tectal gliomas with a relatively benign
course, and corticomedullary junction tumors
somewhere intermediate.
• These tumors often have a specific histone
mutation affecting acetylation and methylation
events that influence chromatin structure and
gene expression.
 Oligodendrogliomas
• constitute 5% to 15% of gliomas and are most
common in middle life.
• The most common genetic alterations involve
mutations of IDH1 and IDH2;
 Oligodendrogliomas
• Gross:
– Tumors have a white matter
predilection; they are
wellcircumscribed, gelatinous,
gray masses, often with cysts,
focal hemorrhage, and
calcification.
• Microscopic:
– Tumors consist of sheets of
regular cells with round nuclei
containing finely granular
chromatin, often surrounded by a
clear halo of cytoplasm and sitting
in a delicate capillary network.
– Calcification is present in 90% and
ranges from microscopic to
massive.
 Ependymomas and Related Paraventricular Mass
Lesions

• Ependymomas and related paraventricular

mass lesions are tumors arising from the
ependymal lining.
• In the first two decades of life, the fourth
ventricle is the most common site;
• the spinal cord central canal is a common
location in middle age and in NF2, where the
NF2 gene is mutated
 Ependymomas and Related Paraventricular Mass
Lesions
• Gross:
– Tumors are moderately well-
demarcated solid or papillary
lesions.
• Microscopic:
– Lesions have regular, round-
oval nuclei with abundant
granular chromatin; they can
form elongated ependymal
canals or perivascular
pseudorosettes.
– Most are WHO grade II/IV;
anaplastic lesions (grade
III/IV) exhibit greater cell
density, mitoses, and necrosis
with less evident ependymal
differentiation.
 Ependymomas and Related Paraventricular Mass
Lesions

• Myxopapillary
ependymomas are
distinct but related
lesions arising in the filum
terminale of the spinal
cord.
• Cuboidal cells, sometimes
with clear cytoplasm, are
arranged around papillary
cores; myxoid areas
contain neutral and acidic
mucopolysaccharides.
Related Paraventricular Mass Lesions
• Subependymomas
– are solid, sometimes calcified, slowgrowing nodules attached to
the ventricular lining and protruding into the ventricle; they are
usually asymptomatic butcan cause hydrocephalus.
• Choroid plexus papillomas
– recapitulate the normal choroid plexus; they exhibit connective
tissue papillae covered with a cuboidal-columnar ciliated
epithelium.
• Choroid plexus carcinomas are rare; they are typically
adenocarcinomas arising in children.
• Colloid cysts of the third ventricle are non-neoplastic lesions
of young adults; they are located at the foramina of Monro
and can result in noncommunicating hydrocephalus,
sometimes rapidly fatal
 Neuronal Tumors
• Ganglioglioma is the most common CNS tumor of matureappearing
neurons (ganglion cells);
– it is slow growing, although the glial component can become frankly
anaplastic and the tumor more aggressive.
– One fifth of these tumors have activating BRAF mutations; most occur
in the temporal lobe and have a cystic component.
• Dysembryoplastic neuroepithelial tumor is a rare, low-grade
childhood neoplasm often presenting as a seizure disorder;
– prognosis after resection is good.
– Features include intracortical location, cystic changes, nodular growth,
“floating neurons” in a pool of mucopolysaccharide-rich fluid, and
surrounding neoplastic glia without anaplastic features.
• Central neurocytoma is a low-grade neuronal neoplasm within the
ventricles consisting of evenly spaced, round, uniform nuclei and
islands of neuropil.
 Medulloblastomas
• account for 20% of childhood brain
tumors; they occur exclusively in
the cerebellum.
• Gross:
– Tumors are well circumscribed, gray,
and friable.
• Microscopic:
– Lesions are usually extremely
cellular, with sheets of anaplastic
cells exhibiting hyperchromatic
nuclei and abundant mitoses;
– cells have little cytoplasm and are
often devoid of specific markers of
differentiation, although glial and
neuronal features (e.g., Homer-
Wright rosettes) can occur.
– Extension into the subarachnoid
space can elicit prominent
desmoplasia.
Atypical Teratoid-Rhabdoid Tumor
• a highly malignant tumor of the posterior
fossa and supratentorium of young children;
survival is usually <1 year.
• Chromosome 22 deletions occur in >90%
• These are large, soft tumors that spread over
the brain surface;
– they are highly mitotic lesions histologically
characterized by rhabdoid cells, resembling those
seen in rhabdomyosarcoma.
 Primary Central Nervous System
Lymphoma
• Primary CNS lymphoma accounts for 2% of extranodal
lymphomas and 1% of intracranial tumors;
– it is the most common CNS neoplasm in
immunocompromised hosts.
• Most primary brain lymphomas are of B-cell origin and
nearly all are latently infected by EBV;
– the most common histologic group is diffuse large-cell B-
cell lymphomas.
• These are aggressive tumors and respond poorly to
chemotherapy compared with their peripheral
counterparts.
 Germ Cell Tumors
• Germ cell tumors occur along the midline in
adolescents and young adults; they constitute
0.2% to 1% of CNS tumors in European
populations but up to 10% of Japanese.
• Tumors most commonly occur in the pineal
(male predominance) and suprasellar regions.
• The histologic classification and therapeutic
responsiveness of CNS germ cell tumors
mirror those of their non-CNS counterparts
 Pineal Parenchymal Tumors
• Pineal parenchymal tumors derive from
pineocytes; they range from well-
differentiated lesions with neuronal
differentiation (pineocytomas) to high-grade
tumors (pineoblastomas) that spread
throughout the CSF.
• High-grade pineal tumors tend to affect
children, whereas lower-grade lesions are
found more often in adults.
 Meningiomas
• benign tumors of adults that arise from
arachnoid meningothelial cells and are
attached to the dura
• These are often associated with loss of
chromosome 22 (especially the long arm,
22q), leading to deletions of the NF2 gene
encoding the protein merlin, and associated
with greater chromosomal instability
 Meningiomas
• Gross:
– Tumors are usually rounded
masses with well-defined dural
bases that compress
underlying brain but easily
separate from it;
• Microscopic:
– Several histologic patterns exist
(e.g., synctytial, fibroblastic,
transitional, psammomatous,
secretory, and microcystic) all
with approximately
comparable favorable
prognoses (WHO grade I/IV);
– among these, proliferation
index is the best predictor of
biologic behavior.
 Meningiomas
• Anaplastic (malignant) meningiomas (WHO grade
III/IV) are aggressive tumors that resemble
sarcomas;
• mitotic rates are high (>20 per 10 high-powered
fields).
• Papillary meningiomas (pleomorphic cells
arranged around fibrovascular cores) and
rhabdoid meningiomas (sheets of cells with
hyaline eosinophilic cytoplasm composed of
intermediate filaments) also have a high
recurrence rate (WHO grade III/IV tumors).
 Familial Tumor Syndromes
• Cowden syndrome: Dysplastic cerebellar
gangliocytomas due to PTEN mutation
• Li-Fraumeni syndrome: Medulloblastomas due
to p53 mutation
• Turcot syndrome: Medulloblastomas or
glioblastomas due to APC or mismatch repair
gene mutation
• Gorlin syndrome: Medulloblastomas due to
PTCH mutation
 Tuberous Sclerosis Complex
• Tuberous sclerosis complex is an autosomal
dominant disorder occurring in 1 in 6000
births; it is characterized by autism, seizures,
and mental retardation
– leads to CNS hamartomas, including cortical
tubers (haphazardly arranged neurons and cells
expressing phenotypes intermediate between glia
and neurons) and subependymal hamartomas
(large astrocytic and neuronal clusters forming
subependymal giant cell astrocytomas).
 von Hippel-Lindau Disease
• von Hippel-Lindau disease is an autosomal
dominant disorder; affected individuals
develop hemangioblastomas in the
cerebellum, retina, or brainstem and spinal
cord, as well as cysts involving the pancreas,
liver, and kidney.
• There is also a propensity for renal cell
carcinoma and pheochromocytomas
• END