Neuropathology II

1. Neuropathology II

2. Vascular brain diseases

3. 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)

4. 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

5. 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

6. 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

7. 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

8. 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

9. Trauma of CNS

10. 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

11. 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

12. 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

13. 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)

14. 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

15. Neoplasms of CNS

16. 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

17. 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

18. 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

19. 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%

20. 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)

21. 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

22. 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

23. 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

24. 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

25. 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%

26. 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

27. 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

28. 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

29. 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)

30. 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%

31. 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)

32. 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

33. Mesenchymal, non-meningothelial neoplasms lipoma liposarcoma solitary fibrous tumor/hemangiopericytoma fibrosarcoma MFH leiomyoma leiomyosarcoma rhabdomyosarcoma chondroma chondrosarcoma osteosarcoma hemangioma angiosarcoma

34. 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

35. 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

36. 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

37. 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

38. 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