Neuropathology 1,2,3 Flashcards

Question

Which one of the following is most likely based on the image shown below? a. Alobar holoprosencephaly b. Arhinencephaly c. Lobar holoprosencephaly d. Semilobar holoprosencephaly e. Syntelencephaly

Answer 1

c. Lobar holoprosencephaly ## Footnote Two distinct cerebral hemispheres have formed, but there is fusion of inferior-medial structures including the thalamus and mammillary bodies. There is no septum pellucidum. Holoprosencephaly represents a spectrum of midline patterning defects that involve the fore- brain and midline facial structures; brain mal- formation results from failure of prosencephalon to develop into two telencephalic vesicles. Rare: 1 per 10,000 live births (but 1 in 250 spontaneous abortions); equal gender distribution. Genetic abnormalities (25-50%): trisomy 13 and 18, deletion/duplication 13q, SHH (sonic hedgehog), ZIC2 (zinc finger protein of the cerebellum 2), SIX3, TGIF. Non-genetic: maternal diabetes, retinoic acid, drug/alcohol abuse, hypercholester- olemia. Genetic counseling: risk of recurrence after affected sibling estimated 6%. Presentation variable: arhinencephaly least severe (anosmia, single central incisor), cleft lip/palate, hypotelor- ism, flat single nostril nose/cebocephaly, micro- cephaly, hydrocephalus, most severe cyclopsia with proboscis-like structure emanating from forehead. Prognosis depends on type and associ- ated anomalies—high incidence of fetal demise in severe cases, cognitive delay, epilepsy, mental retardation, endocrine abnormalities; less severe cases have normal brain development with mild facial anomalies. Classification: 1. Alobar—complete failure in forebrain sep- aration resulting in single holospheric cerebrum. 2. Semilobar—frontal and parietal lobes appear fused but posterior interhemi- spheric fissure present. 3. Lobar—only rostral most areas of cerebral hemispheres show fusion. 4. Syntelencephaly (middle hemisphere vari- ant)—hemispheres separated rostrally and caudally except near posterior frontal lobe/ parietal lobe. 5. Arrhinencephaly—absent olfactory bulbs, olfactory tracts and gyri recti.

Answer 2

b. Chiari II malformation ## Footnote Chiari malformations are structural defects of the cerebellum and brain stem associated with reduced volume posterior fossa. Incidence 1 per 1000 live births; commoner in females; Chiari type 1 com- monest. Presentation: neck pain, balance/incoordi- nation, weakness, numbness, swallowing, hearing, vomiting, insomnia, depression, high pressure headache; asymptomatic (incidental); syringomye- lia. Type I is usually asymptomatic—surgery only to reduce symptoms/halt CNS injury, shunting for hydrocephalus in Chiari II. Classification: 1. Type I (commonest): extension of tonsils through FM without brainstem involve- ment; synringomyelia. 2. Type II (“Arnold-Chiari” malformation): small posterior fossa (low lying torcular herophili; unlike Dandy-Walker) with downward herniation of cerebellar vermis/ brainstem into foramen magnum and upward herniation of midbrain (tectal beak- ing—prominent inferior colliculus) with aqueduct compression causing hydroceph- alus (clival hypoplasia). Associated with lumbosacral myelomeningocele. 3. Type III (rare): cerebellar vermis, cerebel- lar hemisphere and brain stem 1⁄4/ part of fourth ventricle protrude through fora- men magnum; associated with occipital encephalocele. 4. Type IV (rare): cerebellar hypoplasia.

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c. Dandy-Walker malformation ## Footnote Dandy-Walker malformation is charac- terized by loss of cerebellar vermis with dilatation of fourth ventricle. Incidence 1 in 25,000-30,000. Genetics: possible loci on chromosomes 3 (ZIC1), 6 (ZIC4), 9, partial trisomy 13q, 18, autosomal dominant 2q36; possible association with first trimester infec- tions and warfarin. Presentation: delayed motor development, increasing head circum- ference, raised ICP, abnormal breathing pat- terns, associated congenital heart defects, visual problems (nystagmus, cataracts, retinal dysgenesis, coloboma). Prognosis depends on severity of brain and systemic manifesta- tions. Imaging—posterior fossa cyst. Gross pathology: partial or complete absence of cer- ebellar vermis, posterior fossa cyst continuous with fourth ventricle and congenital hydro- cephalus. Other cerebellar vermian malforma- tions include Joubert syndrome (autosomal recessive; vermis agenesis, molar tooth sign as deep interpeduncular fossa with thick- ened/elongated superior cerebellar peduncles) and rhombencephalosynapsis (fused cerebel- lar hemispheres, no vermis, associated septo- optic pituitary dysplasia, poly/syndactyly).

Answer 4

d. Pachygyria ## Footnote Neuronal migration defects result in abnormal cortical development due to abnormal migration of young neurons from periventricular sites of production to the cortex, but also likely to involve dysfunctional stem cell generation, neuronal differentiation, synaptogenesis and functional duced in subventricular zones migrate to cortex in inside out fashion—neurons forming deep cor- tical layers migrate first then more superficial ones; most migration defects have genetic basis. Presentation: seizures, poor muscle tone/func- tion, developmental delay, mental retardation, failure to grow/thrive, feeding difficulty, micro- cephaly. Associated dysmorphic facial features or syndactyly depending on cause. Gross classifi- cation though can occur in combination: 1. Abnormal proliferation (megancephaly) or apoptosis (microcephaly). 2. Neuronsdonotmigrateawayfromsubven- tricular zone—subependymal/periventri- cular heterotopias. 3. Neurons only migrate half way to cortex— subcortical band heterotopias. 4. Neurons reach cortex but abnormal cortical lamination—lissencephaly type 1/pachygyria. 5. Neurons overshoot cortex and end up in subarachnoid space—marginal zone hetero- topia (leptomeningeal glioneuronal hetero- topia) and lissencephaly type 2 (cobblestone cortex). 6. Latestagemigrationdefectswithabnormal cortical organization or neuronal morphol- ogy—polymicrogyria and focal cortical dysplasia/microdysgenesis. Histological classification: 1. Periventricular heterotopia—unorganized nodules of neurons under the ependyma of lateral ventricles; mutation in FNLA gene at Xq28 producing filamin A1 actin binding protein (fatal in males, heterogeneous in females). 2. Lissencephaly type 1 (agyria/pachygyria)— smooth hemispheric surface lacking sulci/ gyri and only four cortical layers; mutation in LIS1 gene (17p13), complete loss fatal, partial 1⁄4 seizures + retardation. 3. Lissencephaly type 2 (cobblestone cor- tex)—neuroglial tissue interrupts pia as it enters subarachnoid space resulting in fine stippling; marked disorganization of neu- rons, glia and blood vessels. 4. X-linked lissencephaly (double cortex syn- drome): subcortical band heterotopia within centrum ovale; mutation of double-cortin gene (DCX; X22.3-q23). 5. Pachygyria—broad gyri and thick cortex with abnormal cryoarchitecture; metabolic CNS disorders. 6. Polymicrogyria—hemispheric surfaces have multiple festoon-like convolutions with four cortical layers only; diffuse or focal, unilateral or bilateral and symmetric or asymmetric; acquired cases CMV infection, hypoxic injury, in utero vascular occlusion (in association with schizencephaly); mutation of SRPX2 (bilateral sylvian polymicrogyria), PAX6, TBR2, GPR56. 7. Focal cortical dysplasia-microdysgenesis— focally thickened cortex with disordered cryoarchitecture (large abnormally ori- ented neurons, hypertrophic astrocytes); for example, cortical tubers (TSC); intrac- table epilepsy.

Answer 5

b. Periventricular nodular heterotropias

Answer 6

a. Acute diffuse hypoxia ## Footnote Acute diffuse hypoxia/anoxia. A ribbon effect is produced under conditions of acute hypoxia where the white matter appears dif- fusely dusky while cortical ribbon appears pale. Periventricular leukomalacia (PVL) encompasses focal necrotic lesions and dif- fuse white matter gliosis resulting from selec- tive ischemic injury of periventricular white matter during the fetal/perinatal period. Commonest ischemic brain injury in pre- mature infants (4-25%); greatest risk <32/40; hypotension, sepsis, congenital car- diac disease, diaphragmatic hernia, acute chorioamnionitis. Pathophysiology: periven- tricular white matter is watershed perfusion zone, increased metabolic demand of mye- linating white matter, poorly developed autoregulatory mechanisms. Presentation: cerebral palsy (fixed or nonprogressive motor disorder resulting from lesions acquired dur- ing fetal/perinatal period; spastic diplegia), quadriplegia in severe PVL, poor suck reflex, developmental delay, coordination problems, vision and hearing impairment. Prognosis depends on severity of brain injury; out- come/cerebral palsy difficult to predict in neo- natal period. Emphasis on prevention: good prenatal care, prompt treatment of maternal infection/other conditions. Gross pathology: ribbon effect in acute diffuse hypoxia, cavities in periventricular deep white matter, periven- tricular lesions may become hemorrhagic.

Answer 7

**a. Germinal matrix hemorrhage** ## Footnote Germinal matrix zone is a fetal periventricular structure that forms between the developing deep cerebral nuclei and ependymal lining; 13-36 weeks gestation; composed of immature neuroe- pithelial cells and thin walled blood vessels with little supportive stroma. Germinal matrix hemor- rhage refers to bleeding into the subependymal germinal matrix zone with or without subsequent intraventricular extension. Classification: Grade I—subependymal hemorrhage Grade II— IVH without HCP Grade III— IVH with HCP Grade IV— IPH

Answer 8

e. Periventricular leukomalacia ## Footnote Neuromuscular spindles are stretch receptor organs within skeletal muscles which are respon- sible for the regulation of muscle tone via the spinal stretch reflex. They lie parallel to the mus- cle fibers, embedded in endomysium or perimy- sium. Each spindle contains 2-10 modified skeletal muscle fibers called intrafusal fibers, which are much smaller than skeletal extrafusal fibers. The intrafusal fibers have a central non- striated area in which their nuclei tend to be con- centrated. The two types of intrafusal fibers are nuclear bag fiber and nuclear chain fiber. Asso- ciated with the intrafusal fibers are branched non-myelinated endings of large myelinated sen- sory fibers which wrap around the central non- striated area, forming annulospiral endings. Additionally, flower-spray endings of smaller myelinated sensory nerves are located on the striated portions of the intrafusal fibers. These sensory receptors are stimulated by stretching of the intrafusal fibers, which occurs when the (extrafusal) muscle mass is stretched. This stim- ulus evokes a simple two-neuron spinal cord reflex, causing contraction of the extrafusal mus- cle mass. This removes the stretch stimulus from the spindle and equilibrium is restored (e.g., knee jerk reflex). The sensitivity of the neuro- muscular spindle to stretch is modulated via small gamma motor neurons controlled by the extra-pyramidal motor system. These gamma motor neurons innervate the striated portions of the intrafusal fibers; contraction of the intra- fusal fibers increases the stretch on the fibers and thus the sensitivity of the receptors to stretching of the extrafusal muscle mass. During a normal movement, both alpha and gamma motor neu- rons are co-activated. If only the alpha motor neurons were activated the muscle would con- tract and the central non-contractile portion of intrafusal muscle fibers would become slack and unable to monitor changes in muscle length. However, where descending inhibition on gamma motor neurons is impaired (e.g., UMN lesion), this can result in exquisitely sensitive stretch receptors and hyperreflexia.

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d. Right PCA infarct ## Footnote Remote infarct in region of right posterior cerebral artery appears as a depressed, cavitated area.

Answer 10

c. Malignant infarction ## Footnote A massive right cerebral infarct (recent) resulted in hyperemia, swelling, and right cingulate gyrus herniation.

Answer 11

c. Mycotic aneurysm ## Footnote Vasoinvasive fungi are revealed by Gomori methenamine silver (GMS) stain.

Answer 12

d. Developmental venous anomaly ## Footnote DVA—congenital venous malformation consisting of dilated but fully functional veins of the superficial or subcortical cerebral vascu- lature. Most common vascular malformation (2% people); accounts for 60% of all CNS vas- cular malformations; 30% associated with another vascular malformation (typically AVM). Dilated-appearing superficial veins may arise in the region of the Sylvian fissure as shown in the image. Benign lesion not requiring intervention.

Answer 13

b. Contrecoup contusion ## Footnote Contrecoup contusions. The orbital frontal gyri and inferior lateral surfaces of the temporal lobes are typical sites of contre- coup contusional injury.

Answer 14

a. Kernicterus ## Footnote Kernicterus. Yellow discoloration of the subthalamic nuclei with lighter yellow stain- ing of the thalamus and basal ganglia. Neuro- nal necrosis and yellow staining of deep cerebral and brain stem nuclei associated with infantile hyperbilirubinemia.

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e. Porencephalic cyst ## Footnote Porencephaly (“hole in brain”; porence- phalic cysts) refers to a spectrum of cystic lesions resulting from loss of neural tissue (encephalomalacia) between the subpial cor- tical surface and ependymal lining of ventri- cles. Prevalence <1 per 200,000; thought to result from large vessel occlusion/spasm dur- ing gestation (emboli, lupus, maternal cocaine), but familial version due to mutation in COL4A1 gene. Presentation: delayed growth and development, spastic paresis, hypotonia, poor or absent speech, epilepsy, hydrocephalus, mental retardation. Progno- sis depends on the size and location of the cyst, and the presence of other abnormalities. Gross pathology: Basket brain—bilateral severe porencephaly with persistence of mesial structures. Porencephalic cysts are lined with white matter, in contrast to schi- zencephaly, where the cyst is lined with het- erotopic gray matter. They are intra-axial, in contrast to arachnoid cysts, which are extra- axial.

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e. Schizencephaly ## Footnote Schizencephaly is a rare cortical malfor- mation in which gray-matter lined clefts arise near the sylvian fissure, often with adjacent polymicrogyria in the lining dysplastic gray matter. Ependyma and pia mater meet in the cleft at the pial-ependymal seem. Presen- tation is with seizures, motor and develop- mental delay. Gross/imaging: may be unilateral or bilateral; open lip/type II (com- monest type in bilateral) cleft walls separated and filled with CSF; closed-lip/type I (com- monest in unilateral cases) cleft walls are in apposition; frequently associated with septo-optic dysplasia, gray matter heteroto- pia, absent septum.

Answer 17

a. Astrocytoma ## Footnote Astrocytoma. Gross specimen showing an ill-defined lesion with loss of gray-white matter demarcation toward the left of the image.

Answer 18

b. Gliomatosis cerebri ## Footnote Gliomatosis cerebri. Gross brain section showing subtle effacement of gray and white matter structures. Compare the affected right basal ganglia and surrounding structures with the unaffected left side. Tumor cells were found in contiguous frontal, temporal, and parietal lobes.

Answer 19

b. NF-1 ## Footnote NF-1 associated optic nerve glioma. Pilocytic astrocytoma causing fusiform enlargement of the optic nerve (left) in a patient with neurofibromatosis type I.

Answer 20

d. Tuberous sclerosis ## Footnote Tuberous sclerosis. This gross image is from a patient with tuberous sclerosis that shows a sharply circumscribed subependymal giant cell astrocytoma (SEGA) arising from the lateral wall of the left lateral ventricle. A cortical “tuber” is present in the lower left side of the image.

Answer 21

a. Fourth ventricular subependymoma ## Footnote Fourth ventricular subependymoma. Grossly, subependymomas are lobular neo- plasms that are well demarcated from adjacent CNS tissue as in this fourth ventricular example situated between cerebellum and medulla. Focal hemorrhage is present

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a. Atypical teratoid/rhabdoid tumor ## Footnote Atypical teratoid/rhabdoid tumor. Grossly, tumors are soft gray, tan, and demarcated from the surrounding brain (right side of image).

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c. Meningioma ## Footnote Meningioma. Meningiomas are typically firm, solid, well-circumscribed neoplasms that are attached to the dura (upper right).

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e. Meningioma ## Footnote This intraventricular meningioma arose from the choroid plexus on the left side. It had histologic features of a fibrous meningioma.

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e. Schwannoma ## Footnote Schwannoma. This inferior view of the brain shows a large solid tumor (left) com- pressing the brain stem at the cerebellopontine angle.

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e. Primary CNS lymphoma ## Footnote Primary CNS lymphoma. Grossly, tumors are located deeply within the cerebral hemispheres in periventricular locations and may contain extensive necrosis.

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e. Hemangioblastoma ## Footnote Hemangioblastoma. This image shows a classic gross appearance of a large cerebellar cyst with a hyperemic mural tumor nodule.

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d. Pituitary adenoma

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e. Rathke's cleft cyst ## Footnote .Grossly,Rathke'scleft cysts have a thin cyst wall and may be adher- ent to the adjacent infundibular stalk or infe- rior hypothalamus.

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a. Colloid cyst ## Footnote Colloid cyst of third ventricle. This col- loid cyst fills the third ventricle and obstructs both foramina of Monro causing significant hydrocephalus.

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d. Multiple metastasis ## Footnote Multiple metastasis. Grossly, metastatic tumors are found at the junctions between cortical gray and white matter.

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d. Melanoma ## Footnote Melanoma.Hemorrhagicmetastasesmay be associated with significant mass effect. Metastatic tumors that tend to undergo hem- orrhage include renal cell carcinoma, mela- noma, and choriocarcinoma.

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c. Ecchordosis physaliphora ## Footnote Ecchordosis physaliphora. Gross image of skull base showing the optic chiasm (left center), basilar artery (left), and a focal gelat- inous mass adjacent to the basilar artery. Such incidental notochordal rests (remnants) can be seen in 1-2% of autopsies usually located in the retroclival prepontine region, but can be found anywhere from the skull base to the sacrum. Ecchordosis physaliphora arise from remaining notochord cells along the axis of the spine after embryogenesis. Unfortunately, ecchordosis physaliphora and chordoma are histologically indistinguishable, other than by examining the margins, the later demonstrating infiltrative growth.

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d. Purulent meningitis ## Footnote Purulent meningitis. A purulent exudate covers the frontal region of the brain in this superior view. Hyperemia of the superficial blood vessels is also typical.

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e. Ventriculitis ## Footnote Ventriculitis. The acute purulent lepto- meningeal exudate can extend into the ven- tricular system to cause ependymitis (ventriculitis) that can lead to obstructive hydrocephalus.

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a. Mycobacterium Tuberculosis ## Footnote Mycobacterium Tuberculosis. Thick, grayish exudates are typically located at the base of the brain. Basilar meningitis is com- monly TB or cryptococcal, and less com- monly syphilis, spirochetes and autoimmune conditions. Risk factors include AIDS and other causes of immunocompromise.

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c. Cryptococcosis ## Footnote Cerebral cryptococcosis. The presence of multifocal gelatinous cysts within the bilat- eral basal ganglia is a classic pattern of CNS involvement by Cryptococcus in the immunocompromised host.

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a. Aspergillosis ## Footnote Aspergillosis. Multiple hemorrhagic in- farcts resulting from vasoinvasive Aspergillus arose in a child with severe combined immu- nodeficiency syndrome. Typical lesions are circumscribed, hemorrhagic, and softened.

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d. Neurocysticercosis ## Footnote Neurocysticercosis. Grossly two thin- walled cysts (arrows) with scolex present in the larger cyst.

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a. Amoebic meningoencephalitis ## Footnote Amoebic meningoencephalitis. Gross pathology shows hemorrhagic necrosis of basal frontal lobes, destruction of olfactory bulbs/tracts, cerebral edema, diffuse hemor- rhagic meningeal exudate.

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a. CMV ventriculitis ## Footnote Cytomegalovirus ventriculitis and encephalitis. Grossly, the ventricular surfaces are discolored and necrotic.

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d. Progressive multifocal leukoencephalopathy ## Footnote Progressive multifocal leukoencephalo- pathy—CNS demyelinating disease caused by the ubiquitous JC virus (John Cunning- ham virus; papovavirus/polyomavirus), usu- ally affecting immunocompromised patients (80% HIV; also hematological malignancy, post-transplant, other malignancy). Gross image showing confluence of multiple areas of demyelination to forma unifocal lesion on the right. The adjacent cortical ribbon is spared.

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a. Alzheimer's disease ## Footnote Alzheimer's disease. Most cases show dif- fuse cerebral atrophy with widening of the sulci and narrowing of the gyri. There is also symmetrical ventriculomegaly with blunting of the lateral ventricular angles (ex vacuo hydrocephalus).

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e. Pick disease ## Footnote Pick disease. Characterized by sulcal wid- ening and gyral atrophy in frontal and tem- poral lobes, but sparing of parietal and occipital lobes.

Answer 45

a. Amyotrophic lateral sclerosis ## Footnote Amyotrophic lateral sclerosis. Lateral cor- ticospinal tract—degeneration manifest by pallor on myelin-stained sections is typical. Motor neuron disease (or amyotrophic lateral sclerosis) is a progressive neuromuscular disease characterized by degeneration of upper and lower motor neurons resulting in progressive skeletal muscle wasting and weakness leaking to respira- tory failure and death. Genetics: most common familial form is AD ALS associated with mutation of copper/zinc superoxide dismutase (SOD1) gene on chromosome 21. Classification: primary lateral sclerosis affects predominantly UMNs, while progressive muscular atrophy affects LMNs. Incidence 2 per 100,000 per year; preva- lence 5 per 100,000; mean age of onset for sporadic 60 years; familial cases make up 10%. Presenta- tion: asymmetric extremity weakness, dysphagia and dysarthria; signs of UMN (weakness, hyperre- flexia, spasticity) and LMN degeneration (weak- ness, atrophy, hyporeflexia, fasciculations). Median survival 3-5 years after symptom onset; glutamate inhibitor may slow disease. MRI usually normal but T2 hypointensity of motor cortex. Histology: loss of anterior horn cells, lateral and anterior corticospinal tract degeneration, Bunina bodies, Skein-like inclusion, Lewy-like inclu- sions, loss of Betz cells in M1/cranial nerve nuclei. Immunohistochemistry: Bunina bodies cystatin-C positive and ubiquitin negative; Dif- ferential: spinal muscular atrophy, hereditary spastic paraplegia, myasthenia gravis.

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d. Huntington's disease ## Footnote Huntington's disease. Huntington's dis- ease is an autosomal dominant neurodegener- ative disease characterized by choreiform movements, psychiatric symptoms, dementia and genetic expansion of the trinucleitide (CAG) repeat in the HD gene (chromosome 4p). IAgre range 2-85 (mean 40); incidence 2-4 per 1,000,000 per year, prevalence 5-8 per 100,000; no gender predilection; inter- action of mutated Huntington protein with other proteins results in neuronal death. Presentation: insidious onset of chorea, psy- chiatric symptoms (irritability, depression, anxiety) and cognitive impairment; successive generations have expanded repeats leaded to earlier onset and more severe phenotype (anticipation). Eventually fatal disease. Imaging: striatal and cortical atrophy. Gross appearance: marked atrophy of the caudate nucleus and putamen is associated with enlarged lateral ventricles (“ex vacuo hydro- cephalus”). Histology shows striatal atrophy (caudate/putamen) due to degeneration of medium spiny neurons, and reactive gliosis.

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c. Friedreich's ataxia ## Footnote Friedreich's ataxia. Sections of spinal cord typically show degeneration (pallor) of the posterior columns and lateral corticospinal tracts as shown in this lumbar level. Frie- dreich's ataxia is an autosomal recessive spino- cerebellar degeneration due to mutation of FRDA (frataxin) gene on chromosome 9q— trinucleide repeat (GAA) expansion results in reduced frataxin protein (involved in oxida- tive phosphorylation and iron homeostasis). Longer repeat size associated with earlier age of onset, increased severity/progression rate and increased neurologic impairment (shows genetic “anticipation”). FA is the commonest hereditary ataxia (50% cases); children and young adults; mean 15 years, 85% before age 20; incidence 2 per 100,000 per year; preva- lence 1 in 30,000; rare in Black/Asian popula- tions. Presentation: progressive lower limb and gait ataxia, sensory loss, areflexia, dysar- thria; progression of the disease leads to loss of vibration/JPS, areflexia of all extremities, foot deformity, scoliosis, diabetes mellitus, hypertrophic cardiomyopathy/myocardial fibrosis. Prognosis—loss of ambulation within 15 years onset, life expectancy 30-40 years after onset; coenzyme Q and vitamin E may slow disease progression. Gross appearance: brain usually appears normal, but possibly atrophy of cerebellar vermis and dentate nucleus; diffuse atrophy of spinal cord, partic- ularly dorsal and lateral columns. Differential: other hereditary ataxias, hereditary spastic paraplegia, ataxia telangiectasia, acquired ataxias.

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e. Vascular dementia ## Footnote Vascular dementia. Foci of complete white matter cavitation (upper left) may be evident. There is also marked thinning of the corpus callosum and symmetrical widening of the lat- eral ventricles because of widespread white matter disease.

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d. Rosenthal fibers ## Footnote These are intracytoplasmic aggregates of glial fibrillary acidic protein (GFAP) and chaperone pro- teins. They are bright eosinophilic in H&E-stained sections and cork-screw-like or beaded. Eosino- philic granular bodies are related to Rosenthal fibers and they often occur together. RFs occur most commonly in pilocytic astrocytoma, but may also be seen in Grade I ganglioglioma or Grade II pleomorphic xanthoastrocytoma, and Alexander's disease. They can also be seen in reactive gliosis (piloid gliosis), particularly around chronic lesions in the hypothalamus, spinal cord or cerebellum (e.g., craniopharyngioma, AVM, syrinx, or granulomatous inflammation).

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d. Posterior pituitary ## Footnote Posterior pituitary is formed by axonal projec- tions of neurons from the hypothalamus together with primary glial cells and pituicytes, and Her- ring bodies (eosinophilic axonal dilatations that store neurosecretory peptides) can be seen throughout the posterior gland.

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b. Gemistocytic astrocytoma ## Footnote Diffuse astrocytomas are infiltrating glial neoplasm with astrocytic features. WHO grade II. Peak inci- dence in fourth decade, accounting for 5% of all pri- mary intracranial tumors (10-15% of astrocytic tumors). Genetics: 60% have p53 mutation (90% in gemistocytic) and subset have IDH-1 mutations. Commonly present with seizures and progress to higher grade lesions. Management is surgical resec- tion and radiotherapy. Favorable prognosis with younger age, complete resection, and seizure at pre- sentation. Mean survival 6-8 years. Worse progno- sis if older, large size and focal neurological deficit. MRI appearances T1 hypointense, T2/FLAIR hyperintense. Gross appearances of ill-defined lesion with blurring of gray-white matter junction, colored gray/yellow-white without tissue destruc- tion, possibly cystic. Histologically may be fibrillary or gemistocytic. Fibrillary astrocytoma commonest and consists of neoplastic astrocytes in dense fibril- lary background, cells often have inconspicuous cytoplasm: “naked” nuclei which can be atypical, with elongation and irregular nuclear contours and often has extensive microcyst formation. Gemistocytic astrocytoma tumor composed of plump, angular cells with eosinophilic, glassy cyto- plasm and short, haphazardly arranged processes (gemistocytes; at least 20% are neoplastic) with eccentrically located, round, hyperchromatic nuclei; perivascular lymphocytic infiltrates are common; higher rate of malignant transformation. Immunohistochemistry: GFAP in 100% (not spe- cific), TP53 in >50%, S-100, Ki-67 mitotic index <4%. Histologic differential: reactive gliosis, oligodendroglioma.

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a. Anaplastic astrocytoma ## Footnote Intermediate-grade infiltrating glioma derived from malignant astrocyte-like cells; may arise from lower- grade diffuse astrocytoma, and may progress to glio- blastoma. Peak incidence in fifth decade, slight male preponderance; 10% of astrocytic tumors. Genetics: 60% TP53 mutations, 40-60% loss of chromosome 10q, 10-20% PTEN losses, 30-50% p16 losses. Pro- gression from diffuse to anaplastic astrocytoma accompanied by increased seizures and neurologic deficits. Management is biopsy or resection, fol- lowed by chemotherapy and radiotherapy. Mean survival 3 years from diagnosis; mean transformation time to GBM is 2 years; better prognosis if young and complete resection; worse prognosis with larger size. MRI: T1 hypointense, T2 hyperintense, but may have foci of gadolinium enhancement. Gross appearances ill-defined without associated tissue destruction. Histology similar to diffuse astrocytoma (fibrillary or gemistocytic) but with increased cellu- larity and cellular atypia; most important distin- guishing feature is presence of mitotic figures. May represent undersampled glioblastoma multi- forme in some cases. Staining positive for GFAP, S100, p53 (60%), Increased Ki-67 (MIB1) labeling index 5-10%; mutated IDH-1 in subset of cases. His- tologic differential: diffuse astrocytoma, glioblas- toma multiforme.

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c. Glioblastoma multiforme ## Footnote This image shows pseudopalisading necrosis. Nuclear palisades may be considered “primary” when they reflect a natural tendency of the nuclei to develop this distinctive pattern of growth or “secondary” when the alignment forms as a response to external influences such as necrosis. The latter have been termed “pseudopalisades”: garland-like array of nuclei surrounding a region of necrosis. Palisades are most often seen in (but are not pathognomonic) of schwannomas whereas pseudopalisades are pathognomonic of GBM.

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c. Glioblastoma multiforme ## Footnote This is the most malignant of gliomas, and has astrocytic differentiation; WHO grade IV.Commonest primary brain tumor in adults (15% of all intracranial); accounts for 70% of astrocytic tumors. Mean age at presentation 60 years old, slight male preponderance, rare in children. Most arise rapidly de novo (95%; pri- mary GBM) but some arise from progressive transformation of lower-grade gliomas in youn- ger patients (5%; secondary GBM). Genetics: Primary GBMs show loss of heterozygosity chro- mosome 10 (70%), epidermal growth factor receptor (EGFR) amplification (40%), p16 dele- tion (30%), p53 mutation (30%), PTEN muta- tion (25%), mutated isocitrate dehydrogenase-1 (IDH-1) (<10%); secondary GBMs show mutated isocitrate dehydrogenase-1 (IDH-1) (>80%), loss of heterozygosity chromosome 10 (63%), p53 mutation (60%), EGFR amplification (8%), PTEN mutation (5%). Most occur in sub- cortical white matter, and may cross corpus callo- sum into contralateral hemisphere (butterfly glioma). Symptoms present abruptly and progress rapidly, with symptoms of raised ICP, and sei- zures in 30%. Poor prognosis even with maximal therapy, including surgical resection (complete resection usually impossible given extensive infil- tration of tumor) and chemoradiotherapy (Stupp protocol). Prognosis is better in younger patients, those with secondary GBM and tumors with methylated MGMT promotor (respond better to alkylating chemotherapy agents like temozolo- mide). MRI shows ring/heterogenous enhance- ment on T1+GAD, central hypointense lesion with zone of surrounding edema on T2. Gross appearance of poorly defined lesion, gray periph- erally and yellow/tan necrosis centrally with occa- sional hemorrhage/cyst. Histology: nuclear atypia, pleomorphism (Figure 1), mitoses, micro- vascular proliferation (multilayered plump endo- thelial cells with increased mitotic activity, often forming “glomeruloid tufts”), thrombosis and necrosis (pseudopalisading necrosis is pathogno- monic but not always present); “multiforme” indicates, there can be a marked variability between tumors which may be composed of small monotonous cells (small cell glioblastoma), giant cells, gemistocytes, granular cells, and they may rarely have metaplastic epithelial or mesenchymal elements. Immunohistochemistry: GFAP- positive with a high KI-67 (MIB-1) labeling index; p53 immunostaining is positive in tumors with TP53 mutation; mutated isocitrate dehydrogenase-1 (IDH-1)—positive in second- ary GBM. Histological differential: anaplastic oli- godendroglioma, metastatic carcinoma, lymphoma, radiation necrosis.

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d. Mitotic figure ## Footnote Mitosis is a continuous process that is tradition- ally divided into five phases, prophase, prometa- phase, metaphase, anaphase and telophase, each stage being readily recognizable with the light microscope (see figure below).

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e. Oligodendroglioma ## Footnote Oligodendrogiomas are diffuse infiltrating glio- mas with cells resembling oligodendroglia— WHO grade II. Account for 3% of primary brain tumors and 10% of gliomas; peak in fourth and fifth decades; usually arise in cortex; slight male predominance. Genetics: Isocitrate dehydrogenase-1 (IDH-1) mutations in 75%; 80% have loss of 1p and 19q associated with better prognosis. Presentation: seizures, head- ache, focal deficit. Imaging: T1 hypointense without contrast enhancement, T2 hyperin- tense with ill-defined edges; calcification on CT. Gross appearance: soft pink-gray, blurring of gray-white junction; gritty if calcifications. Histology: monomorphic tumor cells with ten- dency to form small clusters, perinuclear haloes (fried egg appearance) are an artefact of forma- lin fixation; delicate chicken wire capillary vasculature; perineuronal satellitosis. Immuno- histochemistry: GFAP variably reactive, S100 positive, p53 negative, IHD-1 reactive in 75%, Ki67 labeling index variable. Differential: DNET, diffuse astrocytoma, clear cell ependy- moma. It should be noted that DNET has cells similar in histology to oligodendroglioma how- ever are arranged in cords and have more superstructure.

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b. Anaplastic oligodendroglioma ## Footnote Anaplastic oligodendroglioma is an oligoden- droglial tumor with malignant features— WHO grade III. Accounts for 1% of primary brain tumors and 20-30% of oligodendroglial tumors; peak age 45-50; commonly frontal then temporal cerebrum. Genetics: IDH-1 mutation present in majority; 1p/19q loss in 80% and offers better prognosis. Presentation: seizures; average progression from oligodendroglioma (WHO II) to anaplastic variant is 7 years. Treatment involves surgical resection, radio- therapy and chemotherapy; increased survival in younger patients; median survival 7 years in those with 1p/19q loss, while 3 years in those without. Imaging: as oligodendroglioma but may enhance with contrast. Gross appearance: Well-defined soft pink-gray tumors, may have focal necrosis. Histology: as oligodendroglioma but increased cellularity and pleomorphism, increased mitotic activity, microvascular prolif- eration, necrosis, gliofibrillary oligodendrocytes and minigemistocytes, focal microcalcifications. Immunohistochemistry: GFAP highly variable, negative p53, mutated IDH-1 positive. Differ- ential: oligodendroglioma (WHO II), anaplastic astrocytoma, small cell glioblastoma.

Answer 58

b. Gliomatosis cerebri ## Footnote Gliomatosis cerebri is an extensively infiltrating glioma involving at least three lobes of the brain; typically resembles diffuse astrocytoma but occasionally oligodendroglioma—WHO grade III. Peak in fifth decade; bilateral in 75% cases; can arise de novo or secondary to diffuse infiltra- tion by locally infiltrative glioma. Genetics: unclear, some have p53 mutation. Present with seizures, gait disturbance or dementia. Treat- ment is chemotherapy or whole brain radiother- apy—poor prognosis; favorable factors are young age, good performance status, lower WHO grade and histological subtype. Imaging: diffuse T2 hyperintense lesion, foci of contrast enhancement (multifocal glioma). Gross: blur- ring/effacement of gray-white junction, gyral wid- ening. Histology: diffusely infiltrating tumor with irregular pleomorphic nuclei consistent with astro- cytoma, can have other glial morphologies within same tumor, typically no necrosis/microvascular proliferation. Immunohistochemistry: variable GFAP and S100. Differential: diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, pro- gressive multifocal leukoencephalopathy.

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e. Pilocytic astrocytoma ## Footnote Pilocytic astrocytomas are WHO grade I circum- scribed, well-differentiated tumors usually pre- senting as a cystic cerebellar mass but also arise in hypothalamus, optic pathway and brainstem (midbrain tectum or exophytic). Commonest childhood brain tumor; overall accounts for 2% of brain tumors and 6% of gliomas. Average age of diagnosis is 13 years old. Genetics: BRAF gene duplications on chromosome 7q34 lead to KIAA1549:BRAF fusions in 80% of cerebellar, 60% of optic pathway/hypothalamic and 15% of cerebral pilocytic astrocytomas; tumors arising in NF1 have distinct alterations, with loss or mutation in NF1 gene. Presentation can be hydrocephalus (fourth ventricle or aqueduct compression), visual loss (optic pathway) or endo- crine dysfunction (hypothalamic). Prognosis is good with approximately 80% survival at 20 years; better prognosis in context of NF1 and worse if supratentorial location. Imaging appearance in cerebellum is a cystic mass with enhancing mural nodule; diffusely enhancing or cystic in hypothal- amus; fusiform in optic pathway. Gross appear- ance is well-demarcated lesion with large cyst and pink-tan, soft mural tumor nodule; may be calcified. Histological appearance is biphasic (dense microfibrillar areas vs loose, microcystic areas), bipolar piloid cells (elongated hair-like cytoplasmic processes), round to oval nuclei, oli- godendrogliomatous appearance in some areas, multinucleate cells with clustering of nuclei (pennies on a plate), eosinophilic granular bodies, Rosenthal fibers, microvascular hyperplasia, mitoses are rare. Immunohistochemistry: GFAP positive, S-100 variable, PAS (identifies eosino- philic granular bodies and Rosenthal fibers). Differential: Pilomyxoid variant, diffuse astrocy- toma, oligodendroglioma, reactive piloid gliosis (craniopharyngioma, hemangioblastoma, syrin- gomyelia, pineal cysts).

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c. Pleomorphic xanthoastrocytoma ## Footnote Pleomorphic xanthoastrocytoma is a circum- scribed astrocytic neoplasm with reticulin depo- sition and significant pleomorphism (variability of cell/nuclear size, shape and staining) usually found in superficial cortex and involving the meninges. Most are WHO grade II (anaplastic PXA is WHO III). Accounts for <1% all CNS tumors; two thirds occur in those under 18 years. Genetics: BRAF gene (7q34) point mutation (V600E) in two thirds of cases; 50% of lesions will have loss of chromosome 9; multiple other genetic alterations can be found but are not spe- cific. Usually present with prolonged history of seizures. Surgical excision often curative, adju- vant therapy indicated if incomplete resection, recurrent or anaplastic features. Malignant transformation occurs in 15-20%. Favorable prognosis with 80% 5-year and 70% 10-year survival. Imaging appearance is cystic mass with enhancing mural nodule (or solid mass) and meningeal involvement. Gross appearance is firm, well-demarcated solid or cystic mass, often with calcification. Histological appearance: sig- nificant cellular and nuclear pleomorphism, spindled cells with astrocytic features, stori- form/fascicular growth pattern, multinucleated cells, lipidized tumor cells (in 25%), eosinophilic granular bodies and perivascular lymphocytes; usually very low mitotic rate (no microvascular proliferation or necrosis)—increased mitotic rate (>5 mitoses per high power fields) and necrosis suggestive of anaplastic PXA. Immuno- histochemistry: GFAP and S100 positive, neuro- nal markers (synaptophysin/neurofilament) positive in 25%, Ki67 mitotic index <3%, PAS staining shows eosinophilic granular bodies, reticulin deposition surrounds small groups of tumor cells. Differential: ganglioglioma, glio- blastoma variants.

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e. Subependymal giant cell astrocytoma ## Footnote Subependymal giant cell astrocytomas (SEGA) are benign intraventricular neoplasms with astro- cytic and neuronal features associated with tuber- ous sclerosis complex—WHO grade I. Rare (<1% of all brain tumors); seen in 5-15% of TSC patients, usually in first two decades of life. Genetics: TSC is autosomal dominant (but 50% cases arise de novo), 50-90% cases due to TSC2 gene mutation (chromosome 16p13; codes for tuberin) and 10% due to TSC1 mutation (chro- mosome 9q34; codes for hamartin). Presentation may be due to hydrocephalus as SEGAs arise in lateral ventricle near foramen of Monro (or sometimes third ventricle); seizures are due to cortical hamartomas (tuber) not SEGA; other fea- tures of TSC include facial angiofibromas, ungula fibroma, cardiac rhabdomyoma, renal angioli- poma, lymphangiomatosis, retinal hamartomas and hypomelanotic macules. Management is sur- gical excision (often curative) for primary tumor or recurrence—malignant transformation is rare. Prognosis depends on severity of other TSC manifestations. Imaging appearance is solitary, circumscribed intensely enhancing intraventricu- lar mass. Gross appearance is solid well- circumscribed mass, calcification, spontaneous hemorrhage. Histological appearance: astrocyte- like tumor cells can appear polygonal with glassy eosinophilic cytoplasm, spindled, or epithelioid; cells typically arranged in fascicles or nests sepa- rated by fibrillary areas; “ganglioid” cells with neuronal-like features also seen; nuclei with finely granular chromatin and distinct nucleoli; perivas- cular pseudorosette-like arrangement of tumor cells is frequent; nuclear pleomorphism and multi- nucleated cells often present; mitotic figures can be present but have no impact on prognosis. Immunohistochemistry: Strong GFAP in subset, S100 reactive, individual cells or processes may be positive for neuronal markers. Differential: central neurocytoma, subependymoma, ependy- moma, choroid plexus tumor.

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c. Tuberous sclerosis complex ## Footnote Cerebral cortical hamartomas (tubers): circum- scribed areas of disorganized CNS tissue; dystro- phic neurons and “balloon cells”; highly associated with seizures. The other CNS lesions seen in TSC are subependymal giant cell astrocy- toma (SEGA) and subependymal hamartomatous nodules (candle gutterings).

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b. Ependymoma ## Footnote Ependymomas are a slowly growing tumor arising in the central region of the spinal cord in adults or intraventricular in children—WHO grade II. Rep- resent 5-7% of all CNS tumors. Most common intra-axial spinal cord tumor in adults and third most common posterior fossa tumor in children. Infratentorial ependymomas have bimodal age dis- tribution with first peak in childhood (2-16 years) and second peak at 30-40 years; supratentorial ependymomas have no age predilection. Genetics: 30% incidence of aberration involving chromo- some 22, associated with neurofibromatosis type 2 involving tumor suppressor NF2 gene located at 22q12 (distinct from the 22q mutation found in many incidental ependymomas of the spinal cord). Presentation depends on location: infratentorial (hydrocephalus/visual disturbances, ataxia), supra- tentorial (seizures, focal deficits), spinal cord (motor and sensory deficit). Prognosis is good with overall 60-70% 5-year survival with surgery; best prognosis in adults with spinal cord ependymoma; recurrence is common in children hence goal is gross total resection. Imaging shows well- demarcated masses with variable enhancement on MRI. Gross appearance is soft pink-tan well- circumscribed tumor with occasional hemor- rhage/necrosis; fourth ventricular tumors may extend out of foramen of Luscka laterally into sub- arachnoid space/cistern. Histological appearances: uniform appearance of cells (salt and pepper chro- matin), distinctive perivascular pseudorosettes (radially arranged tapering cell processes extending to intratumoral blood vessels) are commoner than true ependymal rosettes (tumor attempting to form little ependymal canal-like channels with central lumen). Variants by location and histology include papillary ependymomas, clear cell ependymomas, tanycytic ependymomas, myxopapillary ependy- momas (WHO grade I) and anaplastic ependymo- mas (WHO grade III). Immunohistochemistry: GFAP-positive perivascular cell processes, dot-like EMA reactivity within inner lining of ependymal rosettes, CD99 (nonspecific), Ki67 mitotic index low <5%. Electron microscopy: luminal cilia and microvilli in ependymal rosettes, zipperlike junc- tional complexes. Differential diagnosis by loca- tion—fourth ventricle tumor in child (medulloblastoma, pilocytic astrocytoma, choroid plexus tumor), adult intra-axial spinal cord tumor (diffuse astrocytoma), supratentorial (central neu- rocytoma, choroid plexus tumor, astroblastoma). A fourth type of rosette is the perivascular pseudorosette. In this pattern, a spoke-wheel arrangement of cells with tapered cellular pro- cesses radiates around a wall of a centrally placed vessel. Perivascular pseudorosettes are encoun- tered in most ependymomas regardless of grade or variant. As such, they are significantly more sensitive for the diagnosis of ependymomas than true ependymal rosettes. Unfortunately, perivas- cular pseudorosettes are also less specific in that they are also encountered in medulloblastomas, PNETs, central neurocytomas, and less often in glioblastomas, and a rare pediatric tumor, mono- morphous pilomyxoid astrocytomas.

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c. Ependymoma ## Footnote In contrast to the Homer Wright and the Flexner-Wintersteiner rosettes, the empty- appearing lumen of the true ependymal rosette resembles a tubule lumen and contains no fiber-rich neuropil or central cytoplasmic projec- tions. These tubule-like structures, as well as more elongated versions known as ependymal canals, may represent an attempt by the tumor cells to recapitulate the formation of ventricles with ependymal linings. This rosette provides strong evidence of ependymal differentiation at the light microscopic level. Unfortunately, true ependymal rosettes and canals are found in only a minority of the most well-differentiated epen- dymomas and most commonly in infratentorial examples.

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e. Retinoblastoma ## Footnote Flexner-Wintersteiner Rosette-retinoblastoma tumor cells surrounding central lumen containing cytoplasmic extensions. The tumor cells that form the Flexner-Wintersteiner rosette circumscribe a central lumen that contains small cytoplasmic extensions of the encircling cells; however, unlike the center of the Homer Wright rosette, the central lumen does not contain the fiber-rich neuropil. Like the Homer Wright rosette, the Flexner-Wintersteiner rosette signifies a specific form of tumor differentiation. This con- tention is supported by electron microscopy where the tumor cells forming the Flexner-Wintersteiner rosette have ultrastructural features of primitive photoreceptor cells. In addition, special staining properties of the rosette lumen resemble those seen in rods and cones. Although this type of rosette is particularly characteristic of retinoblas- tomas, it may also be seen in pineoblastomas and medulloepitheliomas, where it is similarly thought to represent retinal differentiation.

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c. Homer Wright rosette ## Footnote James Homer Wright (1869-1928), recognized a group of adrenal and sympathetic nervous system tumors, which became known as neuroblastomas. The typical Homer Wright rosette with its central lumen or hub filled with fiber-like processes can also be found in medulloblastomas and histologi- cally similar tumors occurring outside of the cere- bellum, designated PNETs. Although the cellular mechanisms responsible for the formation of rosettes within medulloblastomas and the signifi- cance of these rosettes are not fully understood, most investigators believe that their presence indi- cates neuronal differentiation. The delicate fibril- lary material found within the central lumen of the Homer Wright rosette is composed of neuropil, which contains primitive neuronal processes or neurites. Although the identification of Homer Wright rosettes in a posterior fossa tumor is nearly pathognomonic of the diagnosis of medulloblas- toma, the rosettes are encountered in only a third of these tumors. Moreover, Homer Wright rosettes may be found in other tumors such as supratentorial PNETs and pineoblastomas. Pineocytomas and central neurocytomas repre- sent well-differentiated neuronal neoplasms with small rounded nuclei, analogous to those nor- mally encountered in the internal granular layer of the cerebellum or the dentate fascia of the hip- pocampus. Although they likely originate from slightly different precursors, the histologic fea- tures of these two tumors are virtually identical, including their tendency to form neuropil-rich rosettes, referred to as pineocytomatous rosettes in pineocytomas and neurocytic rosettes in cen- tral neurocytoma. Both are quite similar to the Homer Wright rosette, but they are generally larger and more irregular in contour. As in the other types of rosettes discussed, the presence of pineocytomatous or neurocytic rosettes is generally thought to reflect differentiation of the tumor, in this case neuronal. The cells of the pine- ocytomatous and neurocytic rosettes are also considered to be much more differentiated than the cells forming Homer Wright rosettes in that the nuclei are slightly larger, more rounded, much less mitotically active, and paler or less hyperchromatic.

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d. Papillary ependymoma ## Footnote Papillary ependymomas is a rare variant with uni- form epithelial surfaces along the border with CSF with papillary (nipple-like) or pseudopapil- lary architecture. Differential: choroid plexus tumor, metastasis.

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c. Clear cell ependymoma ## Footnote This is a mimic of oligodendroglioma but has well-demarcated border with adjacent brain; usu- ally located in cerebral hemisphere of young adults; may behave more aggressively. Electron microscopy shows deep nuclear invaginations in the clear cell variant.

Answer 69

e. Tanycytic ependymoma ## Footnote These usually arise in the spinal cord as a discrete mass that is well demarcated from the adjacent neural tissue; forms fascicles of highly fibrillated bipolar spindle cells; mimic of diffuse astrocy- toma; ependymal rosettes usually absent with only vague pseudorosettes.

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a. Anaplastic ependymoma ## Footnote Anaplastic ependymoma is an malignant ependy- mal tumor seen most commonly in posterior fossa in children—WHO grade III. Treatment included surgical resection (extent is key predic- tor of outcome), chemotherapy and radiotherapy. Worse prognosis if <3 years old, incomplete tumor resection and CSF dissemination at pre- sentation. Ependymomatous features (e.g., peri- vascular pseudorosettes) present, but also malignant features such as increases cellularity, mitoses, microvascular proliferation and pseudo- palisading necrosis. Differential: ependymoma, poorly differentiated embryonal tumors, astrocy- toma, anaplastic oligodendroglioma.

Answer 71

c. Myopapillary ependymoma ## Footnote Myxopapillary ependymoma is a slow growing ependymal tumor commonly arising in the conus medullaris, cauda equina and filum terminale— WHO grade I. Represents 10% of all ependymo- mas, and 50% of all spinal cord ependymomas; twice as common in men. Presents as chronic back pain, sciatica, sensorimotor deficit and sphincter disturbance. Management is surgical resection (high cure rate), greater than 10-year survival; recurrence may be seen in tumors with nerve root invasion. Imaging shows enhancing, well-demarcated ovoid masses attached to filum terminale. Gross appearance is soft, lobulated, white-tan tumor easily separable from surround- ing structures. Histological appearance cuboidal/ spindled tumor cells arranged radially around papillary vascular cores, myxoid matrix with microcystic structures. Immunohistochemistry: GFAP positive, S100 and vimentin reactivity, absent cytokeratin activity. Differential: filum terminale region tumors (schwannoma, meningi- oma, paraganglioma), sacral tumors (chordoma, chondrosarcoma), metastatic adenocarcinoma.

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e. Subependymoma ## Footnote Subependymoma is a benign glial neoplasm usu- ally attached to wall of lateral ventricles near the foramen of Monro or floor of fourth ventricle— WHO grade I. Mean age of presentation approx- imately 60, mostly incidental on imaging or autopsy, though can present with hydrocephalus. Treatment is total or subtotal resection, with low recurrence. Imaging shows small, nodular, dis- crete mass (<2 cm), occasional foci of calcifica- tion/hemorrhage/cystic change. Grossly distinct from adjacent brain tissue. Histology shows nod- ular growth pattern, clusters of small bland nuclei within background of eosinophilic fibrillary pro- cesses, microcystic change (if in lateral ventricle), vague perivascular pseudorosette-like pattern. Immunohistochemistry shows GFAP-positive cell processes, negative for synaptophysin, low mitotic index. Differential: ependymoma, central neurocytoma, astrocytoma.

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c. Choroid plexus papilloma ## Footnote Choroid plexus papilloma (CPP) is an intraventric- ular papillary neoplasm—WHO grade I. Repre- sents 0.3-0.6% of brain tumors and 2-4% of pediatric brain tumors (10-20% of brain tumors in <1 year olds). Most common in children <15 years; fourth ventricular CPP shows no age predilection while lateral ventricular CPPs arise in younger patients (<20 years). Location is lateral ventricle (50%) > fourth (40%) > third ventricle (5%). Genetics: Association with SV-40 T antigen; May arise in Aicardi syndrome (sporadic mutation linked to X chromosome; partial or total agenesis of corpus callosum, chorioretinal lacunae, infantile spasms); no mutations in p53 gene unlike choroid plexus carcinoma. Presentation is with increasing head circumference or hydrocephalus. Manage- ment is surgical resection and prognosis is good. Imaging appearances of well-circumscribed intra- ventricular mass, enhancing with gadolinium and T2 hyperintense. Gross appearance of well- defined cauliflower-like mass that may adhere to ventricular wall. Histological appearance: resem- bles normal choroid plexus but has increased cellularity, nuclear crowding, solid areas and strat- ification; fibrovascular tissue core surrounded by single layer of columnar-cuboidal epithelium with basally oriented nuclei; atypical CPP (WHO grade II) has increased mitoses, pleomorphism and foci of necrosis. Immunohistochemistry: Immunoreac- tive to transthyretin, cytokeratins (CK), and synap- tophysin; 75% are CK7-positive and CK20- negative; Ki-67 (MIB1) labeling range from 0% to 6%; S-100 staining in 55% to 90% of reported cases; Focal glial fibrillary acidic protein (GFAP) reactivity. Differential: normal/hypertrophy of choroid plexus, choroid plexus carcinoma; ependy- moma; metastatic carcinoma.

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a. Choroid plexus carcinoma ## Footnote Choroid plexus carcinoma is a malignant cho- roid plexus neoplasm (WHO grade III; 80% arise in children). Genetics: Reported associa- tion with p53 germline mutation or Li- Fraumeni syndrome; nearly all demonstrate p53 immunoreactivity; no INI-1 mutations despite histologic resemblance to atypical tera- toid/rhabdoid tumors. Present with hydroceph- alus and focal neurology. Management is surgical resection, chemotherapy and irradia- tion. Poor prognosis due to CSF dissemination. Imaging: large ventricular poorly defined lesion, edema of adjacent brain. Gross appearance: gray-tan tumor with areas of hemorrhage and necrosis, brain invasion may be evident. Histo- logical criteria (at least four of the following): frequent mitoses (>5 of 10 high power fields), increased cellularity, nuclear pleomorphism, blurring of papillary pattern, necrosis. Immuno- histochemistry: Cytokeratin reactivity, less reac- tive than CPP to S100 and transthyretin, GFAP 20%, EMA negative. Differential: AT/RT, met- astatic carcinoma.

Answer 75

d. Medulloblastoma ## Footnote edulloblastomas are malignant embryonal tumors (PNET) arising in the posterior fossa of children—WHO grade IV. Commonest PNET—0.5/100,000; peak incidence 5-10 years (adults cluster in 30s); accounts for 20% of brain tumors in children, and is the commonest malig- nant brain tumor in children. Genetics: * Classic medulloblastoma: most common genetic alteration: 17p loss with isochromo- some 17q formation * Large cell/anaplastic medulloblastoma associated with C-MYC oncogene amplifications * Desmoplastic medulloblastoma: PTCH gene mutations (sonic hedgehog pathway) * Gorlin syndrome (nevoid basal cell carci- noma): autosomal dominant germline muta- tions of patched gene at 9q22.3 with odontogenic keratocysts, pitting of palms and soles, skeletal anomalies, lamellar calcium deposition in falx cerebri and diaphragma sellae, calcifying ovarian fibromas, and multi- focal, early-onset basal cell carcinomas * Li-Fraumeni syndrome/p53 mutation syndromes * Turcot syndrome (Type 2): medulloblas- toma arises in setting of autosomal domi- nant adenomatous polyposis of colon resulting from APC mutations on chromo- some 5q21 APC * Rubinstein-Taybi syndrome (with menin- giomas and oligodendrogliomas): mutations in CREB-binding protein gene on chromo- some 16p13 with cognitive impairment, growth retardation, microcephaly, facies Presentation is with raised ICP or cerebellar signs—75% arise from vermis and fill the fourth ventricle; 30% show CSF spread with spinal drop metastases at presentation. Manage- ment is maximal surgical resection followed by chemotherapy and craniospinal irradiation— overall 5-year survival 65%. Good prognostic factors: 3-22 years old at presentation, gross total excision, no CSF spread, WNT signaling activation (nuclear b-catenin immunoreactiv- ity), TrkC neurotrophin receptor overexpres- sion, balanced 17q, monosomy chromosome 6, nodular/desmoplastic and extensively nodular variants. Poor prognostic factors: <3 years old, subtotal resection, CSF dissemination at pre- sentation, C-MYK/N-MYC amplification, iso- chromosome 17q (unbalanced), 17p loss, large cell/anaplastic variant (aggressive and extra- neural metastasis has been reported). Imaging: solid heterogenous enhancing mass adjacent or extending into fourth ventricle; nodular/ desmoplastic variant location in cerebellar hemisphere; extensively nodular variant has enhancing nodules which cluster (look grape- like). Gross appearances: solid masses of friable gray-white tissue involving cerebellar folia and leptomeninges. Histological appearance: small round blue cell tumor composed of sheets of undifferentiated cells with indistinct cytoplasm, hyperchromatic angulated nuclei (molding); frequent mitoses; Homer Wright rosettes in about 40% of cases; apoptosis or necrosis may be present but more prominent in large cell/a- naplastic variants; overall architecture may be swirling, fascicular, diffuse; scanty stroma con- taining small blood vessels (occasional micro- vascular proliferation). Immunohistochemistry: Most are synaptophysin immunoreactive; nodular foci of neuronal differentiation (synap- tophysin, neurofilament); GFAP-positive ele- ments appear to be focally entrapped; positive for INI-1 (hSNF5/SMARCB1) using BAF47 antibody to exclude AT/RT; S-100 may be seen in melanocytic variant; Desmin and myo- globin positivity in myogenic cells; Ki-67 index is variable, but generally >20%. Differential: AT/RT, ependymoma, lymphoma, small cell carcinoma, metastasis, high-grade glioma.

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c. Large cell/anaplastic medulloblastoma ## Footnote Large cell/anaplastic medulloblastomas are typi- cally grouped together and probably represent a spectrum; they share frequent mitoses, apoptotic cells, pleomorphism, cell “wrapping” (seen in sec- tion). Large cell medulloblastoma: cells are large with rounded vesicular nuclei, prominent nucle- oli, and conspicuous eosinophilic cytoplasm; discohesive with numerous mitotic and apop- totic cells. Anaplastic medulloblastoma: marked variation in nuclear size and shape with some bizarre forms: multinucleated, giant cells, cell wrapping/molding. Nodular/desmoplastic medulloblastoma: reti- culin rich, proliferatively active cellular tumor with nodular reticulin-free “pale islands” Neuro- nal differentiation in nodules (synaptophysin, neurofilament immunoreactive) Reduced mitotic activity in nodules. Medulloblastoma with extensive nodularity (previously called “cerebellar neuroblastoma”): more advanced neurocytic maturation with more lobular (nodular), pale areas with neuropil-like stroma. * Predilection for children <3 years of age with a more favorable prognosis than other subtypes * Greatly decreased proliferation index, lin- ear pattern of tumor cell nuclei * Rarematurationtobenignganglioneurocy- tic or gangliogliomatous elements * “Neuroblastic” foci: may be found in any given tumor case

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d. Supratentorial primitive neuroepithelial tumor (PNET) ## Footnote Supratentorial/CNS-PNET area heterogenous group of embryonal tumors composed of primitive-appearing neuroepithelial cells expres- sing neuronal or glial antigens and most com- monly arise in cerebral hemispheres. Represent 1-3% of pediatric CNS neuroepithelial tumors; age range 4 weeks to 20 years; in older patients may be mistaken as PNET-like areas within GBM. Present with raised ICP, localizing signs or seizures. Management is chemotherapy (stem cell rescue) and radiotherapy as usually large and non-resectable. Overall 5-year survival 20-30%. Imaging: large enhancing lesions with mass effect, restricted diffusion, calcification. Gross—large soft, tan-gray tumors with areas of necrosis or calcification. Histological appear- ance: highly cellular with scant cytoplasm, hyperchromatic nuclei with granular chromatin, frequent mitoses, necrosis. Immunohistochemis- try: variably positive for neuronal antigens (NF, synaptophysin, NSE, beta-III tubulin), high Ki67 labeling index, positive for INI-1. Differen- tial: AT/RT, germ cell tumors, GBM.

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a. Atypical teratoid/rhabdoid tumor ## Footnote Atypical teratoid/rhabdoid tumors (AT/RT) are high-grade embryonal tumors expressing epithe- lial, neuronal and mesenchymal lineage anti- gens—WHO grade IV. Represent 1-2% of all pediatric brain tumors (10% of infant brain tumors); >90% cases in under 5 year olds (mean age 20 months); 1.5-2:1 male preponderance; supratentorial location (cerebrum, suprasellar) slightly more common than infratentorial (cerebel- lar, CPA with brainstem involvement). Genetics: monosomy/deletions or mutations of INI1 (hSNF5/SMARCB1) gene on chromosome 22q11.2 (INI1 protein functions in chromatin remodeling); rhabdoid predisposition syndrome: germline loss or inactivation of INI1 gene. Presen- tation usually nonspecific irritable, vomiting, lethargic, headache. Management influenced by CSF dissemination (present in 1/3 at presentation) and age (risks of radiotherapy if <3 years); surgery can confirm diagnosis but is not curative; chemo- therapy is mainstay. Poor survival 50% at 6 months; survival >2 years is exceptional. Imaging: T1 hypointense, variable enhancement, diffusion restricting, large, partly cystic/hemorrhagic. Gross: large, soft demarcated mass. Histology: Heteroge- neous lesion; rhabdoid cells (large, distinct cell bor- ders with eccentric nuclei, macronucleoli, and prominent pink cytoplasmic inclusions); occasional vacuolization; some areas have overlapping histol- ogy with other embryonal tumors (such as medullo- blastoma or CNS-PNET); spindled mesenchymal or even myxoid-like components may be promi- nent; overall architecture can be nested, spindled, sheet-like, or even glandular. Immunohistochemis- try: INI1 protein negative (BAF47 antibody), immunoreactive for vimentin and EMA, variably positive for SMA, neurofilament, GFAP, synapto- physin, and cytokeratins (AE1/3; CAM 5.20; Ki- 67 [MIB-1] labeling index is typically high [>50%]). Differential: medulloblastoma, supraten- torial PNET, choroid plexus tumors, germ cell tumors, high-grade glioma.

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b. Ganglioglioma ## Footnote These are well-differentiated CNS tumors with mature neurons (ganglion cells) as a defining feature: 1. Ganglioglioma—ganglion cell tumor with a low grade glial element (WHO grade I) 2. Gangliocytoma—ganglion cell tumor with- out a glial element (WHO grade I) 3. Anaplastic ganglioglioma—ganglion cells and anaplastic glial elements (WHO grade III) Represent 4% of primary brain tumors (incidence 0.2/100,000 per year); commoner in children and temporal lobe. Presentation with seizures or loca- tion specific symptoms. Management is surgery (>90% 10-year survival), while combination with radiotherapy for inoperable or anaplastic (WHO III) cases. Imaging: variably enhancing solid or cystic tumor, possibly calcified. Gross appearance: demarcated tumor mass with or without cystic change or calcification. Histology: disorganized collection of mature ganglion cells with variable glial background; clusters of mature neurons, with large nuclei, prominent nucleoli in disordered/ haphazard arrangements; ganglion cells may exhibit binucleation or have bizarre-appearing nuclei; Rosenthal fibers, eosinophilic granular bodies; perivascular lymphocytes, microcalcifica- tions also can be present; exclude anaplastic fea- tures. Immunohistochemistry: synaptophysin, chromogranin, neurofilament reactive neoplastic ganglion cells but NeuN negative; GFAP-positive in astrocytic elements; Ki-67/MIB1 usually low, <2%. Differential: pilocytic astrocytoma, diffuse astrocytoma, DNET, developmental lesion, cor- tical dysplasia, tuberous sclerosis.

Answer 80

b. Dysembryoplastic neuroepithelial tumor ## Footnote This is a benign neuronal-glial neoplasm arising from gray matter—WHO grade I. Accounts for <1% primary brain tumors; affects children/ young adults (mean age 9 years); first seizure usu- ally <20 years of age; supratentorial and cortical origin (temporal > frontal). Present with seizures. Excellent prognosis with surgery—recurrence is rare. Imaging: T1 hypointense, T2 hyperintense non-enhancing lesion located within expanded cortical ribbon. Gross appearance: multinodular or cystic; gelatinous/mucoid mass with discrete margins. Histological: specific glioneuronal ele- ment consisting of oligodendrocyte-like cells arranged along bundled axons separated by a myxoid matrix that contains floating neurons; cortical dysplasia may be found adjacent to the neoplasm; eosinophilic granular bodies, bipolar astrocytes; no mitotic figures, necrosis, or endo- thelial hyperplasia. Immunohistochemistry: floating neurons are positive for synaptophysin/ NF/neuron specific enolase; GFAP in astrocytes; S100 in oligodendrocyte-like cells; mucin is Alcian blue positive; Ki67 index <1-2%. Differ- ential: oligodendroglioma, astrocytoma with microcystic change, ganglioglioma/cytoma, pap- illary glioneuronal tumor, rosette-forming glio- neuronal tumor of the fourth ventricle.

Answer 81

a. Central neurocytoma ## Footnote This is an intraventricular tumor composed of uniform round cells with neuronal differentia- tion—WHO grade II. Rare 0.25-0.5% of intracranial tumors; peak age 20-40 (rare <10 years or >70 years). Presentation is with raised ICP/hydrocephalus; tumor typically attached to septum pellucidum near foramen of Monro. Good prognosis with complete sur- gical excision—incomplete excision associated with recurrence/progression; radiotherapy used in some cases. Imaging: enhancing intra- ventricular mass attached to septum pelluci- dum (calcified/cystic). Gross appearance: well demarcated, gray friable tumor—calcified/ cystic/hemorrhagic. Histology: monomorphic bland appearing cells with oval nuclei and salt and pepper chromatin, background fibrillary neuropil is eosinophilic, mimic of oligodendroglioma, rare Homer Wright rosettes and ganglion cells, perivascular pseudorosettes, perinuclear haloes, rarely ana- plastic features. Immunohistochemistry: Synaptophysin/NeuN positive, GFAP for astrocytes, Ki67 low <2%, unlike oligoden- drogliomas do not show loss of 1p/19q. Differ- ential: oligodendroglioma, ependymoma, pineocytoma, DNET.

Answer 82

c. Hemangiopericytoma ## Footnote These are rare dural-based mesenchymal tumors—WHO grade II or III. Account for 0.4% of primary CNS tumors; common between second and sixth decades (mean age 45). Presenta- tion is due to local compression/invasion, com- monly headache and seizures or myelopathy (10% arise as spinal lesions). Primary treatment is surgical resection but 90% recurrence rate and metastasis in up to 20%; radiotherapy/radiosur- gery in some cases. Imaging: dural-based contrast-enhancing masses. Gross appearance: solid, gray to red/brown tumors with tendency to bleed excessively during surgery. Histological appearance: monomorphous cellular spindle cell tumor with staghorn-like blood vessels, focally storiform architecture, no intranuclear inclusions, no whorls/psammoma bodies, necrosis uncom- mon; WHO III have >5 mitoses per 10 HPF with moderate to high cellular atypia and cellularity. Immunohistochemistry: tumor cells negative for CD34 but blood vessels positive for CD34, Ki67 index mean 5-10% (up to 40%), reticulin rich, vimentin positive but negative for S100 and EMA. Differential: meningioma, solitary fibrous tumor (positive for CD34, Bcl-2, CD99) menin- geal sarcoma, metastasis, meningeal lymphoid tumors.

Answer 83

c. Meningothelial meningioma ## Footnote These are tumors arising from meningothelial (arachnoidal) cells attached to the inner surface of the dura mater—most are WHO grade I. Rep- resent 25-30% of primary intracranial tumors; 1.4% at autopsy; most common in fifth to seventh decades, commoner in females 3:1 (10:1 for spinal meningiomas); multiple in 10%. Genetics: many arise secondary to radiation exposure, deletion of chromosome 22, multiple meningiomas seen in NF2 (22q11-13.1 mutation; Merlin peptide pro- duction), DAL-1 loss (18p11.3). Presentation: headache and seizures commonest, but local com- pression related also. Location: intracranial, intraspinal or orbital; intracranial locations are convexity (half of these parasaggital), olfactory groove, sellar/parasellar (cavernous sinus), petrous ridge, tentorium, posterior fossa; rarely in intraventricular/extradural location. Manage- ment is gross total resection; recurrence if not completely excised; radiotherapy/radiosurgery for recurrence or small surgically inaccessible lesions (cavernous sinus). Imaging: circumscribed, isodense/isointense contrast-enhancing lesion with dural tail sign; peritumoral edema due to vas- cular compromise; calcification or bone forma- tion/hyperostosis on CT. Gross appearance: well-demarcated, firm, rubbery, yellow-tan, round/lobulated mass compressing adjacent brain/spinal cord, invasion of skull/hyperostosis. Histology (commonest meningothelial variant): lobules of uniform cells in a syncytium, whorls and psammoma bodies, bland oval nuclei, fine chromatin with central clearing, nuclear pseudoinclusions. Immunohistochemistry: Posi- tive for vimentin and EMA, S100 variable, 60% progesterone receptor positive (mostly females). Differential: Metastatic carcinoma, schwannoma, solitary fibrous tumor, sarcoma.

Answer 84

c. Fibrous fibroblastic meningioma ## Footnote Fibrous (fibroblastic) meningioma: spin- dled cells forming interlacing, parallel fasci- cles with surrounding collagenous stroma; psammoma bodies and whorls uncommon. Differential: Schwannoma (versus fibroblas- tic meningioma).

Answer 85

e. Psammomatous meningioma ## Footnote Psammomatous meningiomas are typi- cally found in thoracic spinal region of middle-aged women. Psammomatous menin- gioma: variant having abundant psammoma bodies; most common in the thoracic spinal cord of middle-aged women. Differential: Reactive process with calcification (psammo- matous meningioma).

Answer 86

e. Secretory meningioma ## Footnote Secretory meningioma: “classic” appear- ing tumor cells with numerous interspersed intracellular lumina containing eosinophilic secretions (pseudopsammoma bodies); may have abundant mast cells; may have peritu- moral edema. Pseudopsammoma bodies of secretory variant are carcinembryonic anti- gen (CEA) immunoreactive (and periodic acid-Schiff [PAS] positive). Differential: Metastatic adenocarcinoma (versus secretory meningioma).

Answer 87

a. Angiomatous meningioma ## Footnote Angiomatous meningioma: predomi- nance of small hyalinized blood vessels; back- ground tumor cells may demonstrate marked degenerative nuclear atypia. Differential: Vascular malformation, hemangioblastoma (versus angiomatous meningioma).

Answer 88

a. Atypical meningioma ## Footnote These are those dural-based meningothelial tumors which are WHO grade II (includes atypi- cal, chordoid and clear cell variants). Account for 5-20% of meningiomas; clear cell and chordoid usually affect younger individuals (third decade). Genetics (in addition to classic mutations) losses on 1p, 6q, 10q, 14q, 18q; gains on 1p, 9q, 12q, 15q, 20q. Surgical resection is primary treatment; 30-40% recurrence; radiotherapy/radiosurgery in some cases; 80% 10-year survival; 25% may pro- gress to malignant (anaplastic) meningioma WHO grade III. Gross appearance: larger than benign variants, necrosis and adherence to adja- cent brain tissue. Histological appearance: high mitotic index (>4 per 10 HPF) or 3 of hypercellularity/sheet-like growth pattern/small cell formation/macronuclei/necrosis/brain inva- sion/chordoid features/clear cell features. Immu- nohistochemistry: Vimentin positive but less consistent EMA. Differential: meningioma (WHO I or III), schwannoma, solitary fibrous tumor, chordoma, metastatic clear cell carcinoma.

Answer 89

b. Chordoid meningioma ## Footnote This affects younger individuals (mean age 35); slight female predominance; rare association with Castleman disease, iron-refractory anemia, bone marrow plasmacytosis with dysgammaglobuline- mia. Chordoid meningioma: usually in supraten- torial location; rarely found intraventricular, near the foramen jugulare, and intraorbital; most com- mon presenting symptoms are headache, mental or visual disturbances, and seizures. Chordoid meningioma: chordoma-like tumor with cords, nests, or trabeculae of epithelioid and spindled tumor cells with eosinophilic, often vacuolated cytoplasm; myxoid stroma; foci of typical menin- gotheliomatous features; foci of chronic inflamma- tion may be prominent. Chordoid meningiomas are typically PAS positive. Differential: Chordoma, other meningioma (versus chordoid meningioma).

Answer 90

b. Clear cell meningioma ## Footnote Rare variant also affecting children and young adults (mean age 29 years old) although reported at all ages; slight female predominance. Clear cell meningioma: tendency to arise in the cerebello- pontine angle or cauda equina; also found along cerebral convexities; may have headache and cra- nial nerve palsies. Histology: Clear cell meningi- oma: sheets of polygonal tumor cells with abundant clear cytoplasm, bland round to oval nuclei, separated by bands of collagen and inter- spersed vessels with perivascular hyalinization; rare mitoses; nuclear pleomorphism and necrosis uncommon. Differential: Metastatic clear cell carcinoma, microcystic meningioma (versus clear cell meningioma).

Answer 91

a. Anaplastic meningioma ## Footnote Anaplastic meningiomas (WHO grade III; malig- nant, papillary or rhabdoid) have markedly increased mitotic activity or frank anaplasia. Account for 1-3% of meningiomas; 50% papil- lary meningiomas occur in children. Genetics: gains on 17q, losses on 9p (CDKN2A, p14ARF, CDKN2B), losses on 1p, 6q, 14q, 18q. Can occur de novo, in tumor recurrence or post-radiation; commonly located at falx or convexity. Treat- ment is with surgical resection followed by radiotherapy; high recurrence rate (50% in pap- illary meningioma and 90% in rhabdoid meningi- oma); extracranial metastasis (20% in papillary meningioma, 10% in rhabdoid). Similar imaging and gross appearance to meningioma, but inva- sion of adjacent brain/skull and hemorrhage/ necrosis. Histopathology: high mitotic rate (>20 per 10 HPF) or frank anaplasia with areas resembling carcinoma/sarcoma/melanoma.

Answer 92

e. Rhabdoid meningioma ## Footnote >50% of tumor composed of loosely cohesive sheets of large cells with eosinophilic inclusion-like cyto- plasm sometimes appearing as globular or whorled filamentous inclusions; vesicular nuclei with prominent nucleoli; other histo- logic features of malignancy—including increased mitoses, high proliferative indices, and necrosis—should be present; foci of con- ventional meningioma morphology may be present; concurrent papillary features may be present. * Focal rhabdoid-like histology in otherwise typical meningioma not sufficient for diag- nosis of rhabdoid variant * Metastatic carcinoma/melanoma, rhabdo- myosarcoma, gemistocytic astrocytoma (versus rhabdoid meningioma)

Answer 93

e. Papillary meningioma ## Footnote Papillary meningioma: discohesive menin- gothelial tumor cells around fibrovascular pap- illary or pseudopapillary cores; perivascular pseudorosettes may be apparent; increased mitoses, necrosis, and pleomorphism; brain invasion common. Ependymoma, metastatic carcinoma, astroblastoma, choroid plexus tumor (versus papillary meningioma).

Answer 94

b. Neurofibroma ## Footnote These are peripheral nerve sheath tumors com- posed of differentiated Schwann cells, perneurial-like cells (epithelioid myofibroblasts in perineurium), fibroblasts and nerve fibers— WHO grade I. Relatively common sporadic tumor that affects all ages and both genders equally; multiple and plexiform neurofibromas associated with NF1 (mutation on 17q). Presen- tation: localized painless cutaneous nodule/mass (commonest; sporadic); diffuse cutaneous nod- ules (extraneural types); plexiform neurofibromas in NF1 (multinodular tangles “bag of worms,” enlargement/deformity of plexus or nerve trunk, multiple neurofibromas, >5 café-au-lait spots, axillary/inguinal freckling, optic glioma, Lisch nodules, sphenoid dysplasia). Treatment is surgical resection—sporadic neurofibromas are benign, 3-5% of NF1 plexiform neurofibromas undergo malignant transformation. Gross appearance: firm to soft tan pink with variable myxoid stroma; intraneural tumors are well- circumscribed fusiform shape vs diffusely infil- trating extraneural tumor. Histology: delicate spindle cells in matrix of collagen fibers, mucus, axons; Schwann cells have wavy nuclei; expansion of multiple nerve fascicles in plexiform neurofi- broma; vascular unlike schwannomas; nuclear atypia and increased cellularity but mitoses rare; uncommon—pseudo-Meissnerian bodies, mela- nin pigmentation, dense aggregations of hyperchromatic nuclei. Immunohistochemistry: S100 and vimentin positive, EMA for perineu- rium, CD34 positive cells (non-Schwann).

Answer 95

c. Neurofibroma

Answer 96

a. schwannoma ## Footnote These are encapsulated nerve sheath tumor com- posed of differentiated Schwann cells—WHO grade I. Represent 8-10% of intracranial tumors and 30% of spinal tumors; peak incidence in fourth to sixth decade; most are sporadic and sol- itary; 4% are associated with NF2 or schwannomatosis; no gender predilection. Genetics: bilateral vestibular schwannomas involving CN VIII are pathognomonic for NF2 (22q frameshift mutation of gene coding for tumor suppressor merlin found in 60% of schwannomas); Schwannomatosis syndrome characterized by multiple painful schwannomas in a segmental distribution in absence of other NF2 features; psammomatous/melanotic schwannomas associated with Carney complex (mutation of PRKAR1A gene on chromosome 17q; autosomal dominant disorder characterized by lentiginous facial pigmentation, cardiac myx- oma, and endocrine disorders). Presentation: Account for 85% of cerebellopontine angle tumors (most arise from vestibular branch of VIII [acoustic neuroma], occasionally V, VII); intraspinal schwannomas arise from sensory roots. Management is surgical resection for large tumors, radiosurgery possible for small (<2.5 cm); malignant transformation is rare. Imaging: intracranial circumscribed/cystic enhancing mass with extension into the internal auditory canal; spinal schwannomas are generally intradural extramedullary (but occasionally extend into extradural space creating dumbbell shape). Gross appearance: well-circumscribed, occasion- ally cystic mass, heterogenous cut surface will yellow or hemorrhagic foci. Histology: encapsu- lated, differentiated Schwann cells form two architectural patterns Antoni A (closely apposed spindled tumor cells with palisading, elongated nuclei; Verocay bodies are alternating parallel rows of nuclear palisades with areas devoid of nuclei occurring within Antoni A) and Antoni B (less cellular areas of loosely arranged tumor cells with indistinct processes and microcystic change); nuclear inclusions, nuclear pleomorphism; hyalinized vessels; larger schwan- nomas may undergo degenerative change and necrosis. Variants: cellular Schwannoma (hyper- cellular, Antoni A without Verocay bodies, low mitoses, paravertebral and cranial nerve locations), plexiform Schwanomma (affect skin/ subcutaneous tissues of extremities in schwanno- matosis) and psammomatous/melanotic schwan- noma (50% associated with Carney complex; 10% undergo malignant transformation). Immu- nohistochemistry: Reactive for S100, Leu-7, calretinin; basement membrane type IV collagen and laminin. Differential by location: CPA— meningioma/epidermoid/ependymoma, spinal— meningioma/myxopapillary ependymoma, skin—neurofibroma, large nerve root—MPNST.

Answer 97

a. Antony B schwannoma

Answer 98

e. Verocay bodies

Answer 99

d. Malignant peripheral nerve sheath tumors ## Footnote hese are high-grade sarcomas arising from peripheral nerve or extraneural soft tissue with nerve sheath differentiation. Represent 5% of malignant soft tissue tumors; over half arise from neurofibromas in NF1 (usually plexiform); spo- radic cases peak fifth decade, NF1 associated ear- lier (second and third decades). Genetics: MPNSTs associated with NF-1 have both NF1 alleles inactivated; alterations in p53, p16, and p27; RB and p53 pathways are altered. Presenta- tion: progressively enlarging painful mass on an extremity; medium to large nerves, sciatic nerve commonest; radicular pain with spinal cord lesions; cranial nerves rare (spontaneously from schwannoma/neurofibroma). Treatment is surgi- cal resection with irradiation, but poor prognosis: 60% mortality (80% for paraspinal lesions), local recurrence 40-65%, metastasis 30-80% (usually lungs), overall 16-39% 5-year survival. Imaging: Inhomogenous contrast enhancement with irreg- ular contours and invasion. Gross appearance: fusiform/globoid, thick pseudocapsule, light tan fleshy tumor with necrosis and hemorrhage. His- tology: cellular/hypercellular bipolar spindle cells arranged in herringbone pattern, hyperchromatic nuclei, moderate to marked pleomorphism, mito- ses and necrosis. Variants: Epithelioid MPNST, MPNST with mesenchymal differentiation (including Triton tumor), MPNST with glandu- lar differentiation, melanotic MPSNT. Immuno- histochemistry: scattered S100 reactivity in 50-70%, p53 reactive, Leu-7 focally positive, Ki67 5-65%. Differential: fibrosarcoma, synovial sarcoma, leiomyosarcoma, melanoma.

Answer 100

d. Primary CNS lymphoma ## Footnote Primary CNS lymphoma is a malignancy arising independently within the CNS with- out evidence of systemic lymphoma. Com- prise 1-5% of primary brain tumors; peak incidence is in immunocompetent individ- uals age 55-77 years; increased risk in inher- ited or acquired immunodeficiency (AIDS, transplant patients, Wiskott-Aldrich syn- drome) where it is associated with EBV; HAART therapy has reduced incidence in AIDS patients; 50% of post-transplantation PCNSL occur in first year. Present as focal or multifocal neurologic deficit, neuropsy- chiatric symptoms, seizures, raised ICP. Sur- vival without therapy is 6 months; treatment is systemic and intrathecal methotrexate che- motherapy with or without whole brain radiotherapy; also rituximab (anti-CD20 monoclonal antibody) and autologous stem cell transplantation. Five-year survival in immunocompetent individuals is 75% (under 60 years) and 20% (over 60)—in general approaches 48 months. HIV-infected patients undergoing HAART and radiation reported median survival 36 months. Imag- ing: highly variable appearance, usually deep and periventricular location; iso- hyperintense T2, less peritumoral edema than metastasis/abscess, in context of AIDS diffi- cult to distinguish from opportunistic infec- tions, steroids may cause disappearance (glucocorticoids are lymphocytic) but usually returns. Gross appearance: single or multifo- cal (commoner in immunocompromised) deep lesions, necrosis is present, lymphomato- sis cerebri. Histology: 92-98% are aggressive non-Hodgkin B-cell lymphoma (95% are large cell), express pan-B-cell lineage antigens (CD20, CD79a), atypical lymphoid cells, angiocentric growth pattern, mitotic activity, necrosis, background reactive astrocytes; low grade B-cell lymphoma and T cell lymphoma less common. Immunohistochemistry: CD 20, CD79a (CD19 flow cytometry); majority express BCL-6 and BCL-2 (but not indica- tive of t(14;18) translocation); 90-100% express MUM-1; high Ki 67 index 80%. Differential: glioma, opportunistic infection in immunocompromised individuals, metas- tasis of systemic lymphoma (meningeal> cerebral).

Answer 101

e. Pineocytoma ## Footnote Pineocytoma is a primary pineal paren- chymal tumor composed of small, uniform pinealocyte-like cells—WHO grade I. Accounts for 14-60% of pineal parenchymal tumors; mean age 38. Presentation: raised ICP/hydrocephalus from aqueduct com- pression, Parinaud's syndrome (upgaze palsy, light-near dissociation, convergence/ retraction nystagmus, lid retraction/sun set- ting), brainstem/cerebellar dysfunction, hypothalamic dysfunction. Treatment is surgical resection; 5-year survival 85% (debulking), does not metastasize. Imaging: contrast enhancing, T2 hyperintense. Gross: gray-tan tumor, well demarcated. Histology: pineocytomatous rosettes, sheets of well-differentiated pinealocyte-like cells, low mitotic rate, no necrosis, occasional multinucleate giant cells, ganglion cells. Immunohistochemistry: positive neural markers (synaptophysin, NF, NSE), positive retinal S-antigen and rhodopsin, Ki67 <3%. Differential: normal pineal gland tis- sue (lobular and contains calcifications), pineal cyst, pineal tumor of intermediate differentiation or pineoblastoma, germ cell tumors, metastasis.

Answer 102

d. Pineal parenchymal tumor of intermediate differentiation ## Footnote Pineal parenchymal tumors of intermedi- ate differentiation define those intermediate- grade malignancies between pineocytoma and pineoblastoma. Account of 20% of pineal parenchymal tumors. Similar presentation and imaging features to pineocytoma. Treat- ment is resection with 40-75% 5-year sur- vival rate. Gross: solid gray-tan tumor. Histology: diffuse or lobular architecture, moderate/high cellularity, mitotic index <15%, occasional giant cells and Homer Wright rosettes. Immunohistochemistry: positive for neuronal markers, variable for NF, chromogranin, retinal S-antigen and S100. Ki67 index 3-10%. Differential: other pineal parenchymal tumors, germ cell tumors, metastasis, normal pineal gland.

Answer 103

d. Pineoblastoma ## Footnote Pineoblastoma is an aggressive embryo- nal tumor of pineal region—WHO grade IV. Accounts for 40% of all pineal parenchy- mal tumors; present in first two decades of life. Genetics: 3% of patients with bilateral retinoblastoma have pineoblastoma (“trilat- eral retinoblastoma”; RB1 mutation; pineo- blastoma must be concurrent/sequential rather than pineal retinoblastoma metasta- sis). Treatment is resection and radiotherapy; infiltration into adjacent brain and CSF dis- semination is common; median postsurgical survival 24-30 months; prognosis for trilat- eral retinoblastoma is <1-year survival from diagnosis. Imaging: ill-defined lobular mass >3 cm, heterogenous contrast enhancement. Histology: sheets of densely packed small blue cells, no pineocytomatous rosettes but occasional Homer Wright or Flexner- Wintersteiner rosettes; necrosis/calcification common; high nuclear/cytoplasmic ratio; increased mitotic index. Immunohistochem- istry: positive for neuronal markers and retinal-S-antigen. Differential: pineal paren- chymal tumors, medulloblastoma metastasis, AT/RT, germ cell tumors, metastasis.

Answer 104

c. Germinoma ## Footnote Germinoma is a germ cell tumor (resem- bling testicular seminoma and ovarian dys- germinoma) arising in the pineal or suprasellar region. Account for 3% of pediat- ric intracranial tumors; 65% of CNS germ cell tumors are germinomatous (i.e., germi- nomas; lack cellular differentiation), 35% are non-germinomatous (display tissue type differentiation; teratoma, yolk sac, embryo- nal carcinoma, choriocarcinoma); male pre- dominance; present teens/early 20s. Presentation: 80% are midline pineal (hydro- cephalus, Parinaud's) or suprasellar lesions (visual field defect, panhypopituitarism, dia- betes insipidus). Given the lack of differenti- ation in germinomas serum and CSF markers may often be negative. Primary treatment is radiotherapy—10-year survival 85% or more; poorer prognosis with mixed germi- noma (germinoma with syncytiotrophoblas- tic giant cells, mixed germinoma/teratoma). Imaging: hyperdense, enhancing lesions.Gross: solid, soft tan-white tumor. Histol- ogy: biphasic with large neoplastic cells with abundant cytoplasm intermixed with fibrovascular septae harboring lymphocytic infiltrate, occasional granulomas/syncytio- trophoblastic cells/foci of other germ cell tumor. Immunohistochemistry: positive CD117 (c-kit), OCT3/4, SALL4, placental alkaline phosphatase (PLAP); if syncytiotro- phoblasts present betaHCG or human placental lactogen may be present. Differen- tial: primary pineal/suprasellar tumor, non- germinomatous germ cell tumors.

Answer 105

e. Teratoma ## Footnote Numerous germ cell ele- ments are present including cartilage (upper left), squamous epithelium with skin adnexal structures (upper right), bone (lower right), and neuroepithelial elements (center). Non-germinomatous germ cell tumors (NGGCTs) include teratomas, embryonal carci- nomas, yolk sac tumor (endodermal sinus tumor) and choriocarcinomas. Prognosis depends on his- tological subtype of GTC: good prognosis (pure germinoma, mature teratoma), intermediate prog- nosis (germinoma with syncytiotrophoblasts, immature teratoma, teratoma with malignant transformation, mixed germinoma/teratoma), and poor prognosis (choriocarcinoma, yolk sac tumor, embryonal carcinoma, mixture of these). Surgical resection of mature teratoma can be curative. Teratomas are comprised of cells originating from usually all three of endoderm, mesoderm and ectoderm. Intra-axial teratomas are rare but are the commonest cause of fetal brain tumors (25-50%); located in cerebral hemi- spheres presenting antenatally or in the neonatal period with increased head circumference. Extra-axial (suprasellar or pineal) teratomas are commoner and present in childhood/early adult- hood. Mature teratoma contain differentiated skin, brain, cartilage, fat, respiratory/enteric epi- thelium and may be cystic (n.b. dermoids are ectodermal in origin only hence will not contain fat). Immature teratomas have foci of incom- pletely differentiated tissue elements including immature neuroepithelium, embryonal mesen- chymal tissue, abortive retinal epithelium; malig- nant transformation of any component can occur. Immunohistochemistry: cytokeratin posi- tive in epithelial elements.

Answer 106

e. Yolk sac tumor ## Footnote Yolk sac tumors may have gelatinous appearance Yolk sac (endodermal sinus) tumors: highly vari- able histology with cuboidal/elongated epithelial cells surrounding fibrovascular cores (Schiller- Duval bodies) or having eosinophilic hyaline globules within cytoplasm. Immunoreactive for AFP, SALL4, glipican-3.

Answer 107

b. Embryonal carcinoma ## Footnote Embryonal carcinoma. This highly malignant neoplasm consists of large cells with prominent nucleoli and abundant clear to eosinophilic cytoplasm forming solid sheets, nests, or lining glandlike spaces; fre- quent mitoses and necrosis. Embryonal car- cinoma: positive for cytokeratins, CD30, OCT4, SALL4, PLAP.

Answer 108

a. Choriocarcinoma ## Footnote Choriocarcinoma. These highly hemor- rhagic tumors contain neoplastic cytotropho- blastic (left) and syncytiotrophoblastic giant cells (right center). Choriocarcinoma: com- posed of both neoplastic cytotrophoblastic and syncytiotrophoblastic giant cells with extensive hemorrhagic necrosis. Choriocar- cinoma: syncytiotrophoblastic cells positive for β-HCG, HPL, PLAP (variable).

Answer 109

b. Hemangioblastoma ## Footnote Hemangioblastoma is a highly vascular- ized tumor composed of stromal cells and cap- illaries. Accounts for 1-2% of intracranial tumors; peaks in third to fifth decade (affects children as part of VHL); mostly sporadic; 25% associated with von Hippel-Lindau disease (autosomal dominant inherited defect in VHL gene on 3p25-p26; multiple hemangioblastomas, renal cell carcinoma, phaeochromocytoma, pancreatic/liver cysts, endolymphatic sac tumor). Presentation: spo- radic hemangioblastomas commonest in cere- bellum, while those in VHL in cerebellum, brain stem, spinal cord (associated with syr- inx), cerebrum, leptomeninges, retina and peripheral nerves; 10% associated with sec- ondary polycythemia (stromal EPO produc- tion). Surgical resection is treatment of choice for these benign lesions; can bleed extensively hence may require preop emboli- zation; multiple lesions and recurrence seen in VHL. Imaging: commonly cystic lesion with contrast-enhancing mural nodule in cerebel- lum. Gross: circumscribed, non-encapsulated usually cystic with vascularized red mural nodule or yellow from lipid cells. Histology: lipid rich stromal cells with vacuolated cyto- plasm ovoid nuclei surrounded by network of capillaries; intratumoral sclerosis/hemor- rhage; mitoses/necrosis rare; Rosenthal fibers and reactive gliosis in cyst wall. Immunohisto- chemistry: Stromal cells positive for NSE, inhibin A, aquaporin 1, S100, CD56, vimen- tin, GFAP; unlike renal cell carcinoma also negative for CD10, EMA, cytokeratin; capil- laries positive for CD31, CD34, and reticulin. Differential: metastatic RCC, pilocytic astro- cytoma, endocrine neoplasm.

Answer 110

c. Pituitary adenoma ## Footnote Pituitary adenomas are tumors of the anterior pituitary gland. Represent 10-15% of all intracranial tumors; incidence 0.2-2.8 per 100,000 per year; 20-30% non-function- ing, 25% prolactin-secreting, 20% growth hormone, 10% ACTH, 10-15% secrete FSH/LH, 1-3% secrete TSH; occasional bihormonal adenomas, usually prolactin and GH. Genetics: most sporadic; 3% associ- ated with multiple endocrine neoplasia type 1 (11q13 mutation; pituitary, pancreatic and parathyroid tumors). Presentation: 1. General: headache, facial pain, fatigue, weight loss 2. Mass effect: bitemporal hemianopia, cranial nerve palsy, stalk effect (prolactin rise with- out prolactinoma) 3. Pituitary apoplexy: hemorrhagic necrosis of adenoma—sudden headache, visual loss, Addisonian crisis 4. Prolactin excess: amenorrhoea, irregular periods, galatorrhoea, infertility in women; hypogonadism, loss of libido, impotence in men 5. Growth hormone excess: gigantism in chil- dren, acromegaly in adults 6. ACTH excess: Cushing disease 7. TSH excess: thyrotoxicosis 8. Gonadotrophins (FSH/LH): amenorrhoea in females, impotence in males Medical treatment of prolactinomas with dopa- mine receptor agonist (bromocriptine or caber- goline) and GH-secreting tumors with somatostatin analogs (octreotide). Transphenoi- dal resection for symptomatic non-functioning lesions or resistant to medical therapy. Radio- therapy for residual tumor, recurrence or inva- sive. Management of pituitary apoplexy includes glucocorticoids, close monitoring and surgical decompression if vision deteriorating. Imaging: circumscribed, variably enhancing compared to adjacent pituitary, macroadenomas expand the sella. Gross: circumscribed, non- encapsulated tan-brown tumor (microadenoma <10 mm, macroadenoma >10 mm). Histology: loss of normal lobar architecture of anterior pituitary; sheets and cords of monomorphic cells; basophilic granules in ACTH secreting types; eosinophilic cytoplasmic granules (cytokeratins; CAM5.2) in GH-secreting types. Immunohistochemistry: reticulin staining demonstrates loss of architecture; chromogra- nin, cytokeratin, EMA positive; hormone stains. Differential: pituicytoma, craniopharyn- gioma, granular cell tumor, sellar meningioma/ schwanomma, Rathke cleft cyst, germ cell tumor, metastasis, hypothalamic hamartoma/ glioma, carotid cavernous fistula/aneurysm.

Answer 111

a. Adamantinomatous craniopharyngioma ## Footnote Craniopharyngiomas are epithelial tumors derived from Rathke's pouch. Accounts for 3% of intracranial tumors; Incidence is 0.5-2.5 per million/year; no gender predilection; adamanti- nomatous subtype (children; 5-10% of pediatric intracranial tumors) and papillary subtype (exclusively adults). Presents due to local com- pression in suprasellar region: hypothalamus (endocrine dysregulation/diabetes insipidus), third ventricle (hydrocephalus), optic chiasm (bitemporal hemianopia). General symptoms: cognitive impairment, N&V, somnolence. Man- agement is surgical resection, with >90% 10- year recurrence free survival depending on extent of resection (limited by adherence to adja- cent structures); rare reports of malignant trans- formation to SCC post-radiotherapy. May need hormone replacement if hypopituitarism. Imag- ing: suprasellar cystic mass (T1 hyperintense) but occasionally solid enhancing tumor (T1 hypointense). Gross: solid and cystic mass with calcification, motor-oil like material in adaman- tinomatous type. Histology: 1. Adamantinomatous:nestsandtrabeculaeof epithelium in lose fibrous stroma, palisad- ing at periphery of tumor, stellate reticulum (loosely arranged epithelium), wet keratin (eosinophilic), cysts, calcification, xantho- granulomatous reaction (cholesterol clefts, foreign body giant cells, inflammation), gliosis/Rosenthal fibers at lesion edges 2. Papillary: circumscribed papillary tumor with fibrovascular cores lined by well- differentiated monotonous squamous epi- thelium (i.e., no stellate reticulum, wet ker- atin, calcification, xanthogranulomatous change). Immunohistochemistry: cytokeratin and focal HCG, CK7, CK20; adamantinomatous subtype associated with beta-catenin mutations resulting in nuclear reactivity. Differential: xanthogranulo- matous inflammation, Rathke cleft cyst, epider- moid cyst, metastasis, pilocytic astrocytoma.