Neuropathology II

Vascular brain diseases

Global cerebral ischaemia (hypoxic encephalopathy)

decrease of cerebral perfusion pressure below 45mmHgcardiac arrest, shock, severe hypoxiavarious sensitivity to hypoxia: neurons > glial cellsmost 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 confusionsevere 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 deathneutrophilic infiltration

Subacute changes (24h to 2 weeks)tissue necrosis, macrophages, vascular proliferationreactive gliosis

Reparative changes (after 2 weeks)removal of necrotic tissue, gliosis → disorganisation of normal architectureneocortex: some layers preserved → laminar necrosis

Focal cerebral ischaemiashort duration, incomplete → transitory ischaemic attack (TIA) → full recoveryprolonged, 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)MacroFirst 12 hours: no gross changes12-48 hours: pale, soft, swollen area, blurred corticomedullary junction2-10 days: gelatinous and friable, distinct boundary between infarction and normal brain10 days – 3 weeks: liquefaction and resorption of necrotic area → postmalatic pseudocystMicro12-48 hours: red cell change, edema, swelling of astrocytes and endothelial cells, loss of myelinated fibers, neutrophils48 hours and later: mononuclear phagocytic cells (myelin breakdown products) → gitter cells; reactive astrocytic gliosis at the edge → gemistocytes

Intracerebral hemorrhage

mid and late adult lifearterial hypertensionrupture of small intraparenchymal arterybasal ganglia, thalamus, internal capsule → contralateral hemiparesisclinical presentation depends on the extent and site

Morphologycentral area of clotted bloodrim of hypoxic changes and perifocal edemalater resorption of blood → cavity surrounded by gitter cells, siderophages and reactive astrocytes → posthemorrhagic pseudocyst

Complicationshematocephalusherniation

Subarachnoid hemorrhage

rupture of saccular („berry“) aneurysmthin-walled outpouching of cerebral arterydevelopment from the focal defect of the media↑risk in adult type polycystic kidney disease

microabsence of elastic fibres

clinical presentationsudden severe headache, loss of consciousnessdeath in 25-50%, in survivors ↑risk of repeated bleeding

complicationfibrous adhesions of subarachnoid space → block of CSF flow → hydrocephalus

Vascular malformations

Arteriovenous malformation (AVM)subarachnoid space and adjacent brain parenchymameshwork of malformed arteries and veins surrounded by gliotic tissue with siderophagesclinical presentationpeak incidence 10-30 yearsseizures, subarachnoid or intracerebral bleeding

Cavernous hemangiomadilated thin-walled vascular spaces without intervening parenchymapeak incidence 30-50 yearsseizures, intracranial bleeding, focal neurological deficits

Trauma of CNS

Trauma

Primary (result of tissue deformation at the moment of injury)diffuse

diffuse axonal injurydiffuse vascular injury

focalcontusionlacerationintracranial hemorrhage (epidural, subdural)

Secondary (complications of the primary traumatic damage)ischemia/hypoxiaedemaherniationshydrocephalusinfection

Diffuse axonal injurywidespread traumatic damage of axons throughout the brainrapid 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

Concussionmild reversible axonal injurytemporary unconsciousness, amnesia for the traumatic event

Diffuse vascular injurypatients who die within minutes after head injurynumerous small hemorrhages throughout the brain, especially in white matterendothelial injury (small vessels) → extravasation of erythrocytes

Contusionfocal injury of brain parenchyma due to head impactbrain surface (crests of gyri)frontal and temporal lobescoup contusion (beneath the site of impact)contrecoup contusion (on the opposite side)wedge-shaped hemorrhagic lesioncombination of hemorrhage and necrosis in variable proportionsmass effect, perifocal edema → ↑ICP → herniationshealing: resorption of necrosis and hemorrhage + gliosis + hemosiderin pigmentation → „plaque jaune“ (shallow depressed yellowish-brown pigmented area)

Lacerationbrain tissue tearing

Epidural hematoma (EDH)

arterial bleeding (middle meningeal artery)usually combined with skull fracturetemporoparietal regionsmall children: deformable skull → hematoma without fractureseparation of dura from the skull, compression of the brain → ↑ICP → herniations20% 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 spaceolder people (brain atrophy, veins stretched out), infants (thin-walled veins)lateral aspect of hemispheresbilateral in 10%signs of ↑ICP, often only headchache and mental confusion

MorphologyAcute SDH: clotted bloodSubacute 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 → herniationsmalignant 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, metastaseschildren: 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 cordclinical presentation: seizures, intracranial hypertensionslow growth, but intrinsic tendency to progression to more malignant forms (anaplastic astrocytoma, glioblastoma)median survival time 7-12 yearsmorphology:diffusely infiltrative nature → blurring of anatomic boundaries, enlargement and distortion, but not destruction of involved structurespoorly demarcated greyish areawell differentiated fibrillary astrocytesonly moderate cytologic atypia, no mitoses

Anaplastic astrocytoma (WHO grade III)

diffusely infiltrating malignant astrocytic tumormean age 45 yearssites and clinical presentation similar as in low-grade astrocytomatendency to transformation into glioblastomamedian survival time: 2-4 years

morphology:diffusely infiltrating neoplasmincreased cellularity, mitotic activity

Glioblastoma multiforme (WHO grade IV)

most frequent primary CNS tumor in adultsprimary glioblastomade novosecondary glioblastomaevolution from low-grade diffuse and/or anaplastic astrocytoma

adults (peak incidence 45-75 years)sites: cerebral hemispheres (temporal, parietal, frontal lobe)

clinical presentationshort history (3 months)intracranial hypertension, focal neurologic deficits, seizures, mental changevery poor prognosis: median survival time 12 months, 5-years survival rate 5%

Macro and MRIlarge mass with central necrosis (MRI: ring-shaped contrast enhancement)highly infiltrative spread along white matter tractscommon extension through corpus callosum into contralateral hemisphere („butterfly glioma“)

Histopathologypoorly differentiated cells with extremely variable appearance: marked pleomorphism, bizzare hyperchromatic nuclei, multinucleated cells, monotonous small cellshigh cellularity, mitotic activity, microvascular proliferations, necrosis (with palisading)

Pilocytic astrocytoma (WHO grade I)

benign astrocytic neoplasm completely different from low-grade diffuse astrocytomachildren and adolescents (first two decades)cerebellum, hypothalamus, thalamus, basal ganglia, brainstem, optic nerve

clinical presentationslowly evolving intracranial hypertension, focal neurological deficits, cerebellar symptomsgood prognosis

morphologywell circumscribed, often associated with cystbiphasic pattern

compact areas with bipolar cells, common Rosenthal fibresloose areas with multipolar cells, microcysts and eosinophilic granular

bodies

Oligodendroglioma (WHO grade II)

cells resembling oligodendrocytesadults (peak incidence 40-45 years)cerebral hemispheres

Clinical presentationseizures, intracranial hypertensionprognosis better than low-grade diffuse astrocytoma

Morphologydiffusely infiltrating tumormonomorphic cells, uniform round nuclei, perinuclear halo (fixation artifact), plexiform („chicken-wire“) capillary networkcommon microcalcificationsinfiltration of cortex: perineuronal satellitosisno specific IHC marker

Cytogeneticsdeletion of chromosomal arms 1p and 19q

Ependymoma (WHO grade II)

children and young adultsventricular system (most common in 4th ventricle), spinal cord

Clinical presentationhydrocephalus, intracranial hypertensionprognosis: 5-year survival rate 50%

Morphologywell circumscribed intraventricular soft tan massmoderately cellular, monomorphic oval nucleilow mitotic activityperivascular pseudorosettes, true ependymal rosettes

Myxopapillary ependymoma (WHO grade I)slowly growing ependyma tumoryoung adultsback painconus 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 neoplasmmiddle-aged and elderly adults4th ventricle, lateral ventriclesincidental finding, ventricular obstruction, intracranial hypertensionsubependymal firm nodules, variable sizeclusters of isomorphic nuclei embedded in dense fibrillary matrix

Choroid plexus papilloma (WHO grade I)children and young adultsintraventricular cauliflower-like massblock of CSF pathways → hydrocephalus, intracranial hypertensionmonolayer of cuboidal to columnar epithelium covering delicate fibrovascular coresbenign

Choroid plexus carcinoma (WHO grade III)frequent mitoses, hypercellularity, loss of papillary pattern (solid growth), necrosis, invasion to adjacent brain5-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 adultstemporal lobeClinical presentationseizuresgood prognosisMorphologywell circumscribed, often cystic componentlarge multipolar neurons with dysplastic features (loss of cytoarchitectural organisation, variation in size and shape, binucleation)glial component resemble diffuse or pilocytic astrocytoma, oligodendrogliomacalcifications, perivascular lymphocytic infiltrates

Central neurocytoma (WHO grade II)

young adults (20-40 years)lateral ventricle near foramen of Monro

Clinical presentationCSF flow obstruction5-year survival 80%

Morphologydiscrete intraventricular massuniform round cells (neurocytes), fibrillary nucleus-free areas of neuropil

Pineal neoplasms

Pineocytoma (WHO grade I)slowly growing well demarcated tumoradultsneuro-ophthalmologic dysfunctions (Parinaud syndrome), obstruction of CSF flowsmall uniform pineocytes, large pineocytomatous rosettesexcellent prognosis (5-year survival rate 86-100%)

Pineoblastoma (WHO grade IV)childrensoft, friable and poorly demarcated mass, infiltration of adjacent structureshigh cellularity, patternless sheets of primitive small cells with dark nuclei, loss of pineocytomatous rosettes, high mitotic activityhighly 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 presentationcerebellar ataxia, intracranial hypertensionhighly malignant tumor, 5-year survival rate 50-60%

Morphologypink or grey mass, often filling 4th ventricledensely packed primitive cells with round-to-oval carrot-shaped hyperchromatic nucleiHomer-Wright neuroblastic rosettes in 40%neuronal differentiation (synaptophysin)

Meningeal neoplasms

Meningioma (WHO grade I, II, III)meningothelial (arachnoidal) cell neoplasmmiddle-aged and elderly adults, predominance of womenintracranial, intraspinal and orbital localizationintracranial: over hemispheres, parasagittal, olfactory groove, sphenoid ridges, suprasellar region, petrous ridges, tentorium, posterior fossavery rare extracranial examples

Clinical presentationheadache, seizures, signs from compression of adjacent structure (depend on the site)prognosis case-dependent5-year survival rates

WHO grade II: 95%WHO grade III: 64%

Morphologyrubbery or firm, well-demarcated, lobulated mass broadly attached to duraflat 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)Meningothelialmost commonlobules divided by thin fibrous septauniform cells vith oval nuclei with delicate chromatin, sometimes central clearinginconspicuous cell borders (syncytial appearance)Fibrous: spindle cells in bundlesTransitional: whorls, psammoma bodiesPsammomatous: multiple psammoma bodiesAngiomatous: predominance of blood vesselsMicrocystic: microcysts containing pale mucinous fluidSecretory: intracellular lumina containing PAS-positive secretionClear 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 cellularitysheeting (patternless growth)foci of necrosissmall cells with high N/C ratioprominent nucleoli

Anaplastic meningioma (WHO grade III)features of frank malignancy („meningeal sarcoma“)nuclear pleomorphism and hyperchromasiamarkedly elevated mitotic activitynecrosis

Mesenchymal, non-meningothelial neoplasmslipomaliposarcomasolitary fibrous tumor/hemangiopericytomafibrosarcomaMFHleiomyomaleiomyosarcomarhabdomyosarcomachondromachondrosarcomaosteosarcomahemangiomaangiosarcoma

Melanocytic lesionsfrom leptomeningeal melanocytesMelanocytomaall ages, peak incidence 50 yearsintradural extramedullary compartment of cervical and thoracic spine, posterior fossacompression of spinal cordblack or non-pigmented massuniform oval-shaped or spindled cells, melanin, mitoses occasionalbenign, rare recurrencesDiffuse melanocytosis/melanomatosischildrendiffuse pathologic proliferation of leptomeningeal melanocytes without (melanocytosis) or with (melanomatosis) malignant featurespoor prognosisMalignant melanomaadultsslight predilection for spinal cord and posterior fossavariable pigmented massanaplastic spindle or epithelioid cells, variable content of melanin, numerous mitoses, invasion of the adjacent tissue, necrosishighly aggressive neoplasm, poor prognosis

Malignant lymphomaprimary or secondary infiltration

Primary CNS lymphomapredisposing factor: inherited or acquired immunodeficiency (AIDS, immunosuppressive therapy)Clinical presentationfocal neurological deficitspsychiatric symptomsintracranial hypertensionprognosis poor, especially in AIDS patientsMorphologysingle or multiple masses in the hemispheresoften deep-seated and periventricularseveral types of B-lymphomas (over 90%) and T-lymphomasdiffuse large B-cell lymphoma (95%)perivascular and diffuse parenchymal infiltration, necroses

Germ cell neoplasms

homologues of gonadal tumourspineal and suprasellar region

typesgerminoma (corresponds to seminoma and dysgerminoma)mature and immature teratomayolk sac tumourembryonal carcinomachoriocarcinoma

Craniopharyngioma

from Rathke pouch epitheliumchildren and adolescents, adults

Clinical presentationvisual disturbances, endocrine deficiencies (GH, LH/FSH, ACTH, TSH), diabetes insipidus, cognitive impairment, personality changesbenign, recurrences after incomplete resection

Morphologylobulated solid mass with cysts containing brownish fluid („machinery oil“)lobules and cords of squamous epitheliumperipheral palisading, stellate reticulumkeratinous masses with remnants of nuclei („wet keratin“), cholesterol clefts, calcifications

Metastatic tumours

most common CNS neoplasmscerebral hemispheres (80%), cerebellum (15%)usually multiple, less then half single

adults: lung carcinoma (small cell, adenocarcinoma), breast carcinoma, melanoma, renal cell carcinoma, colorectal carcinomachildren: leucaemia, lymphoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma

Clinical presentationfocal neurological deficitintracranial hypertensiondeath usually within 1 year

Morphologyrounded well-circumscribed masses, central necrosis, perifocal edemacarcinomatous leptomeningitis: diffuse infiltration, multiple nodules