Neuropathology II
Vascular brain diseases
Global cerebral ischaemia (hypoxic encephalopathy)
decrease of cerebral perfusion pressure below 45mmHg
cardiac arrest, shock, severe hypoxia
various sensitivity to hypoxia: neurons > glial cells
most susceptible: neurons of the hippocampus, Purkinje cells, pyramidal neurons
of the neocortex
clinical outcome depends on the severity of ischemic insult:
mild ischaemia → transient postischemic confusion
severe prolonged ischaemia → deep coma with neurological impairment
(„persistent vegetative state“), „brain death“ (isoelectric
electroencephalogram, no perfusion in angiography)
patients with brain death mantained on mechanical ventilation → „respirator brain“
(softening of the whole brain due to autolysis)
Morphology
Acute changes (12-24h)
neuronal cell death (red cell change), later glial cell death
neutrophilic infiltration
Subacute changes (24h to 2 weeks)
tissue necrosis, macrophages, vascular proliferation
reactive gliosis
Reparative changes (after 2 weeks)
removal of necrotic tissue, gliosis → disorganisation of normal architecture
neocortex: some layers preserved → laminar necrosis
Focal cerebral ischaemia
short duration, incomplete → transitory ischaemic attack (TIA) → full recovery
prolonged, complete → cerebral infarction (encephalomalacia, „stroke“)
occlusion of cerebral artery:
thrombosis (arteriosclerotic plaques)
thrombotic embolisation (mural thrombi from the hearth – myocardial
infarction, valve diseases, atrial fibrillation)
emboli of other material (tumor, fat, air) - rare
extent of infarction depends on collateral flow (circle of Willis, cortical-meningeal
anastomoses)
Macro
First 12 hours: no gross changes
12-48 hours: pale, soft, swollen area, blurred corticomedullary junction
2-10 days: gelatinous and friable, distinct boundary between infarction and normal
brain
10 days – 3 weeks: liquefaction and resorption of necrotic area → postmalatic
pseudocyst
Micro
12-48 hours: red cell change, edema, swelling of astrocytes and endothelial cells,
loss of myelinated fibers, neutrophils
48 hours and later: mononuclear phagocytic cells (myelin breakdown products) →
gitter cells; reactive astrocytic gliosis at the edge → gemistocytes
Intracerebral hemorrhage
mid and late adult life
arterial hypertension
rupture of small intraparenchymal artery
basal ganglia, thalamus, internal capsule → contralateral hemiparesis
clinical presentation depends on the extent and site
Morphology
central area of clotted blood
rim of hypoxic changes and perifocal edema
later resorption of blood → cavity surrounded by gitter cells, siderophages and
reactive astrocytes → posthemorrhagic pseudocyst
Complications
hematocephalus
herniation
Subarachnoid hemorrhage
rupture of saccular („berry“) aneurysm
thin-walled outpouching of cerebral artery
development from the focal defect of the media
↑risk in adult type polycystic kidney disease
micro
absence of elastic fibres
clinical presentation
sudden severe headache, loss of consciousness
death in 25-50%, in survivors ↑risk of repeated bleeding
complication
fibrous adhesions of subarachnoid space → block of CSF flow → hydrocephalus
Vascular malformations
Arteriovenous malformation (AVM)
subarachnoid space and adjacent brain parenchyma
meshwork of malformed arteries and veins surrounded by gliotic tissue with
siderophages
clinical presentation
peak incidence 10-30 years
seizures, subarachnoid or intracerebral bleeding
Cavernous hemangioma
dilated thin-walled vascular spaces without intervening parenchyma
peak incidence 30-50 years
seizures, intracranial bleeding, focal neurological deficits
Trauma of CNS
Trauma
Primary (result of tissue deformation at the moment of injury)
diffuse
diffuse axonal injury
diffuse vascular injury
focal
contusion
laceration
intracranial hemorrhage (epidural, subdural)
Secondary (complications of the primary traumatic damage)
ischemia/hypoxia
edema
herniations
hydrocephalus
infection
Diffuse axonal injury
widespread traumatic damage of axons throughout the brain
rapid angular acceleration/deceleration (traffic accidents)
only small portion of axons torn at the moment of injury (primary axotomy)
large majority of axons deformed mechanically → focal disruption of axonal
membrane → influx of Ca2+ → activation of Ca-dependent proteolytic systems →
cytoskeleton breakdown → disconnection of axon after 6-12 hours (secondary
axotomy)
macro: no gross changes or small hemorrhages (CC, brainstem)
micro: axonal swellings, retraction spheroids (balls)
silver stains, amyloid precursor protein (APP)
clinical picture: unconsciousness, coma
Concussion
mild reversible axonal injury
temporary unconsciousness, amnesia for the traumatic event
Diffuse vascular injury
patients who die within minutes after head injury
numerous small hemorrhages throughout the brain, especially in white matter
endothelial injury (small vessels) → extravasation of erythrocytes
Contusion
focal injury of brain parenchyma due to head impact
brain surface (crests of gyri)
frontal and temporal lobes
coup contusion (beneath the site of impact)
contrecoup contusion (on the opposite side)
wedge-shaped hemorrhagic lesion
combination of hemorrhage and necrosis in variable proportions
mass effect, perifocal edema → ↑ICP → herniations
healing: resorption of necrosis and hemorrhage + gliosis + hemosiderin
pigmentation → „plaque jaune“ (shallow depressed yellowish-brown pigmented
area)
Laceration
brain tissue tearing
Epidural hematoma (EDH)
arterial bleeding (middle meningeal artery)
usually combined with skull fracture
temporoparietal region
small children: deformable skull → hematoma without fracture
separation of dura from the skull, compression of the brain → ↑ICP →
herniations
20% of EDH: lucid interval (between trauma and development of neurologic
symptoms)
Subdural hematoma (SDH)
rapid acceleration/deceleration → tearing of bridging veins → venous bleeding into
subdural space
older people (brain atrophy, veins stretched out), infants (thin-walled veins)
lateral aspect of hemispheres
bilateral in 10%
signs of ↑ICP, often only headchache and mental confusion
Morphology
Acute SDH: clotted blood
Subacute SDH: lysis of clot, ingrowth of fibroblasts and capillaries (granulation
tissue)
Chronic SDH: connective tissue capsule (subdural neomembrane), common
rebleeding from dilated thin-walled vessels present in neomembrane
Neoplasms of CNS
CNS neoplasms
unique features:
anatomic site can have fatal consequences even in benign lesions (e.g.
meningioma compressing vital brainstem centers)
mass effect, CSF flow obstruction → intracranial hypertension → herniations
malignant tumors produce metastases within CSF pathways, systemic metastases
extremely rare
current WHO classification: more than 100 entities, many rare
most common CNS neoplasms:
adults: glioblastoma, meningioma, metastases
children: pilocytic astrocytoma, medulloblastoma, ependymoma
Glial neoplasms
Low-grade diffuse astrocytoma (WHO grade II)
young adults (peak incidence 30-40 years)
any region of CNS, most common in hemispheres (frontal and temporal lobe), brain
stem, spinal cord
clinical presentation: seizures, intracranial hypertension
slow growth, but intrinsic tendency to progression to more malignant forms
(anaplastic astrocytoma, glioblastoma)
median survival time 7-12 years
morphology:
diffusely infiltrative nature → blurring of anatomic boundaries, enlargement and
distortion, but not destruction of involved structures
poorly demarcated greyish area
well differentiated fibrillary astrocytes
only moderate cytologic atypia, no mitoses
Anaplastic astrocytoma (WHO grade III)
diffusely infiltrating malignant astrocytic tumor
mean age 45 years
sites and clinical presentation similar as in low-grade astrocytoma
tendency to transformation into glioblastoma
median survival time: 2-4 years
morphology:
diffusely infiltrating neoplasm
increased cellularity, mitotic activity
Glioblastoma multiforme (WHO grade IV)
most frequent primary CNS tumor in adults
primary glioblastoma
de novo
secondary glioblastoma
evolution from low-grade diffuse and/or anaplastic astrocytoma
adults (peak incidence 45-75 years)
sites: cerebral hemispheres (temporal, parietal, frontal lobe)
clinical presentation
short history (3 months)
intracranial hypertension, focal neurologic deficits, seizures, mental change
very poor prognosis: median survival time 12 months, 5-years survival rate 5%
Macro and MRI
large mass with central necrosis (MRI: ring-shaped contrast enhancement)
highly infiltrative spread along white matter tracts
common extension through corpus callosum into contralateral hemisphere
(„butterfly glioma“)
Histopathology
poorly differentiated cells with extremely variable appearance: marked
pleomorphism, bizzare hyperchromatic nuclei, multinucleated cells, monotonous
small cells
high cellularity, mitotic activity, microvascular proliferations, necrosis (with
palisading)
Pilocytic astrocytoma (WHO grade I)
benign astrocytic neoplasm completely different from low-grade diffuse
astrocytoma
children and adolescents (first two decades)
cerebellum, hypothalamus, thalamus, basal ganglia, brainstem, optic nerve
clinical presentation
slowly evolving intracranial hypertension, focal neurological deficits, cerebellar
symptoms
good prognosis
morphology
well circumscribed, often associated with cyst
biphasic pattern
compact areas with bipolar cells, common Rosenthal fibres
loose areas with multipolar cells, microcysts and eosinophilic granular
bodies
Oligodendroglioma (WHO grade II)
cells resembling oligodendrocytes
adults (peak incidence 40-45 years)
cerebral hemispheres
Clinical presentation
seizures, intracranial hypertension
prognosis better than low-grade diffuse astrocytoma
Morphology
diffusely infiltrating tumor
monomorphic cells, uniform round nuclei, perinuclear halo (fixation artifact),
plexiform („chicken-wire“) capillary network
common microcalcifications
infiltration of cortex: perineuronal satellitosis
no specific IHC marker
Cytogenetics
deletion of chromosomal arms 1p and 19q
Ependymoma (WHO grade II)
children and young adults
ventricular system (most common in 4th ventricle), spinal cord
Clinical presentation
hydrocephalus, intracranial hypertension
prognosis: 5-year survival rate 50%
Morphology
well circumscribed intraventricular soft tan mass
moderately cellular, monomorphic oval nuclei
low mitotic activity
perivascular pseudorosettes, true ependymal rosettes
Myxopapillary ependymoma (WHO grade I)
slowly growing ependyma tumor
young adults
back pain
conus medullaris, cauda equina, filum terminale (exclusive location)
cuboidal to elongated ependymal cels arranged in a papillary manner around
myxoid cores
Subependymoma (WHO grade I)
benign neoplasm
middle-aged and elderly adults
4th ventricle, lateral ventricles
incidental finding, ventricular obstruction, intracranial hypertension
subependymal firm nodules, variable size
clusters of isomorphic nuclei embedded in dense fibrillary matrix
Choroid plexus papilloma (WHO grade I)
children and young adults
intraventricular cauliflower-like mass
block of CSF pathways → hydrocephalus, intracranial hypertension
monolayer of cuboidal to columnar epithelium covering delicate fibrovascular
cores
benign
Choroid plexus carcinoma (WHO grade III)
frequent mitoses, hypercellularity, loss of papillary pattern (solid growth),
necrosis, invasion to adjacent brain
5-year survival rate 40%
Neuronal and glioneuronal neoplasms
Gangliocytoma and ganglioglioma (WHO grade I)
well diferentiated tumors consisting of large neurons (gangliocytoma) or admixture
of neurons and glial cells (ganglioglioma)
children and young adults
temporal lobe
Clinical presentation
seizures
good prognosis
Morphology
well circumscribed, often cystic component
large multipolar neurons with dysplastic features (loss of cytoarchitectural
organisation, variation in size and shape, binucleation)
glial component resemble diffuse or pilocytic astrocytoma, oligodendroglioma
calcifications, perivascular lymphocytic infiltrates
Central neurocytoma (WHO grade II)
young adults (20-40 years)
lateral ventricle near foramen of Monro
Clinical presentation
CSF flow obstruction
5-year survival 80%
Morphology
discrete intraventricular mass
uniform round cells (neurocytes), fibrillary nucleus-free areas of neuropil
Pineal neoplasms
Pineocytoma (WHO grade I)
slowly growing well demarcated tumor
adults
neuro-ophthalmologic dysfunctions (Parinaud syndrome), obstruction of CSF flow
small uniform pineocytes, large pineocytomatous rosettes
excellent prognosis (5-year survival rate 86-100%)
Pineoblastoma (WHO grade IV)
children
soft, friable and poorly demarcated mass, infiltration of adjacent structures
high cellularity, patternless sheets of primitive small cells with dark nuclei, loss of
pineocytomatous rosettes, high mitotic activity
highly malignant tumor with poor prognosis (death usually within 2 years), CSF
pathways dissemination
Embryonal neoplasms
Medulloblastoma (WHO grade IV)
children (peak incidence 7 years)
cerebellum (vermis 75%)
Clinical presentation
cerebellar ataxia, intracranial hypertension
highly malignant tumor, 5-year survival rate 50-60%
Morphology
pink or grey mass, often filling 4th ventricle
densely packed primitive cells with round-to-oval carrot-shaped hyperchromatic
nuclei
Homer-Wright neuroblastic rosettes in 40%
neuronal differentiation (synaptophysin)
Meningeal neoplasms
Meningioma (WHO grade I, II, III)
meningothelial (arachnoidal) cell neoplasm
middle-aged and elderly adults, predominance of women
intracranial, intraspinal and orbital localization
intracranial: over hemispheres, parasagittal, olfactory groove, sphenoid ridges,
suprasellar region, petrous ridges, tentorium, posterior fossa
very rare extracranial examples
Clinical presentation
headache, seizures, signs from compression of adjacent structure (depend on the
site)
prognosis case-dependent
5-year survival rates
WHO grade II: 95%
WHO grade III: 64%
Morphology
rubbery or firm, well-demarcated, lobulated mass broadly attached to dura
flat carpet-like mass (en plaque meningioma)
invasion into the dura → higher recurrence rate (wide excision)
wide range of histologic appearances, several subtypes (majority of them without
prognostic significance)
Meningothelial
most common
lobules divided by thin fibrous septa
uniform cells vith oval nuclei with delicate chromatin, sometimes central clearing
inconspicuous cell borders (syncytial appearance)
Fibrous: spindle cells in bundles
Transitional: whorls, psammoma bodies
Psammomatous: multiple psammoma bodies
Angiomatous: predominance of blood vessels
Microcystic: microcysts containing pale mucinous fluid
Secretory: intracellular lumina containing PAS-positive secretion
Clear cell: patternless sheats of polygonal cells with clear cytoplasm (glycogen),
greater likelihood of recurrence and/or aggresive behaviour (WHO grade II)
Atypical meningioma (WHO grade II)
either higher mitotic activity (more than 4 mitoses/10HPF)
or at least 3 from following 5 features:
increased cellularity
sheeting (patternless growth)
foci of necrosis
small cells with high N/C ratio
prominent nucleoli
Anaplastic meningioma (WHO grade III)
features of frank malignancy („meningeal sarcoma“)
nuclear pleomorphism and hyperchromasia
markedly elevated mitotic activity
necrosis
Mesenchymal, non-meningothelial neoplasms
lipoma
liposarcoma
solitary fibrous tumor/hemangiopericytoma
fibrosarcoma
MFH
leiomyoma
leiomyosarcoma
rhabdomyosarcoma
chondroma
chondrosarcoma
osteosarcoma
hemangioma
angiosarcoma
Melanocytic lesions
from leptomeningeal melanocytes
Melanocytoma
all ages, peak incidence 50 years
intradural extramedullary compartment of cervical and thoracic spine, posterior
fossa
compression of spinal cord
black or non-pigmented mass
uniform oval-shaped or spindled cells, melanin, mitoses occasional
benign, rare recurrences
Diffuse melanocytosis/melanomatosis
children
diffuse pathologic proliferation of leptomeningeal melanocytes without
(melanocytosis) or with (melanomatosis) malignant features
poor prognosis
Malignant melanoma
adults
slight predilection for spinal cord and posterior fossa
variable pigmented mass
anaplastic spindle or epithelioid cells, variable content of melanin, numerous
mitoses, invasion of the adjacent tissue, necrosis
highly aggressive neoplasm, poor prognosis
Malignant lymphoma
primary or secondary infiltration
Primary CNS lymphoma
predisposing factor: inherited or acquired immunodeficiency (AIDS,
immunosuppressive therapy)
Clinical presentation
focal neurological deficits
psychiatric symptoms
intracranial hypertension
prognosis poor, especially in AIDS patients
Morphology
single or multiple masses in the hemispheres
often deep-seated and periventricular
several types of B-lymphomas (over 90%) and T-lymphomas
diffuse large B-cell lymphoma (95%)
perivascular and diffuse parenchymal infiltration, necroses
Germ cell neoplasms
homologues of gonadal tumours
pineal and suprasellar region
types
germinoma (corresponds to seminoma and dysgerminoma)
mature and immature teratoma
yolk sac tumour
embryonal carcinoma
choriocarcinoma
Craniopharyngioma
from Rathke pouch epithelium
children and adolescents, adults
Clinical presentation
visual disturbances, endocrine deficiencies (GH, LH/FSH, ACTH, TSH), diabetes
insipidus, cognitive impairment, personality changes
benign, recurrences after incomplete resection
Morphology
lobulated solid mass with cysts containing brownish fluid („machinery oil“)
lobules and cords of squamous epithelium
peripheral palisading, stellate reticulum
keratinous masses with remnants of nuclei („wet keratin“), cholesterol clefts,
calcifications
Metastatic tumours
most common CNS neoplasms
cerebral hemispheres (80%), cerebellum (15%)
usually multiple, less then half single
adults: lung carcinoma (small cell, adenocarcinoma), breast carcinoma,
melanoma, renal cell carcinoma, colorectal carcinoma
children: leucaemia, lymphoma, osteosarcoma, rhabdomyosarcoma, Ewing
sarcoma
Clinical presentation
focal neurological deficit
intracranial hypertension
death usually within 1 year
Morphology
rounded well-circumscribed masses, central necrosis, perifocal edema
carcinomatous leptomeningitis: diffuse infiltration, multiple nodules