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Pediatric Pathology > CNS > Flashcards

CNS Flashcards

1
Q

What syndromes are associated with

Pilocytic Astrocytomas

A

NF-1

Possibly Li-Fraumeni, Noonan & TS?

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2
Q

What syndromes are associated with choroid papillomas?

A

Aicardi

Li-Fraumeni

&

Hypomelanosis of Ito

(tX;17(q12;p13))

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3
Q

What syndromes are associated with ependymomas?

A

NF2

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4
Q

What syndromes are associated with Medulloblastoma?

A

Gorlin

Turcot Type 2

&

Li-Fraumeni

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5
Q

What tumor belongs to this pathway?

A

Pilocytic astrocytoma

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6
Q

A duplication of results in KIAA1549-BRAF fusion protein with KIAA1549 replacing the BRAF N-terminal regulatory domain is associated with what tumor and how often?

A

Pilocytic astrocytoma:

70%

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7
Q

What is unique about pilocytic astrocytoma with loss of wild type NF1?

A

Grow in association with optic nerve

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8
Q

BRAF V600E mutation is associated with what CNS tumors?

A

Supratentorial pilocytic astrocytomas, gangliogliomas, PXA & DNET

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9
Q

What are the WHO grades for ganglioglioma and anaplastic ganglioglioma

A

WHO I

&

WHO III

(There is no WHO II)

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10
Q

What syndrome is associated with cerebellar ganglioglioma?

A

Cowden syndrome.

Bonus: gangliogloma in this location warrants genetic testing for Cowden syndrome.

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11
Q

What is the most common pediatric CNS malignancy?

2nd most common?

A
  1. Pilocytic astrocytoma
  2. Medulloblastoma
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12
Q

Assuming appropriate histology and stains, what required feature is necessary to make a diagnosis of medulloblastoma?

A

Primary tumor present in the cerebellum.

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13
Q

What is the immunoprofile of medulloblastoma?

What is in the differential?

A

Synaptophysin, GFAP, INI-1 retained.

Other embryonal tumors (medulloepithelioma, pineoblastoma, CNS neuroblastoma, embryonal mutated or NOS) and high grade gliomas.

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14
Q

What are the 4 (or 5) different diagnostic categories of medulloblastoma?

Other molecular associations, syndrome, histologic type and risk?

A
  1. WNT activated - beta catenin/CNNTB1; Turcot (T2); DN/classic; low risk/100% survival.
    2a. SHH activated w/p53 WT - PTCH/LOH 9q22; Gorlin; DN/MBEN; intermediate; *bimodal age
    2b. SHH activated w/p53 mutated - Li Fraumeni; LCA; high risk
  2. Group 3 - MYC amplified, p53 & i17q; LCA; high risk, worst Px; CD133+
  3. Group 4 - i17q, MYCN; classic; intermediate risk
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15
Q

What is the most common subtype of medulloblastoma?

2nd, 3rd, 4th?

A
  1. Group 4 - 40%
  2. SHH p53WT - 26-27%
  3. Group 3 - 20%
  4. WNT activated - 10%
  5. SHH p53 mutated - 3-4%
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16
Q

What ages do the various medulloblastoma subtypes present?

A
  1. WNT - child to young adult
  2. SHH p53WT - bimodal: <4, teens/young adults
  3. SHH p53 mutated: 14-17 years old
  4. Group 3: infants
  5. Group 4: all ages
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17
Q

Large cerebellar mass in a 5 yo female.

A

Medulloblastoma, classic histology

(Probably WNT activated or Group 4)

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18
Q

Large cerebellar mass in a 2 year old male.

What is it? What is likely mutation? What syndrome to screen for? What is Px?

A

Medulloblastoma

SHH p53WT (PTCH1, SUFU)

Gorlin syndrome

Excellent px/low risk

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19
Q

What is the definitive treatment for medulloblastoma?

A

Complete surgical resection.

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20
Q

What is the ddx for medulloblastoma based on location?

Based on histology?

A

Location: Cerebellar astrocytoma, ependymom, hemangioblastoma, CNS Embryonal tumors

Histology: CNS Embryonal tumors, ATRT

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21
Q

C5-C6 nerve root damage

A

Erb palsy

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22
Q

Klumpke paralysis

A

Paralysis of wrists and digits due to trauma a C9-T1 nerve roots

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23
Q

What is this?

A

Area cerebrovasculosa: histologic appearance of anencephalic brain w/primitive superficial neural layer and subadjacent vascular layer.

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24
Q

Describe the types of Chiari malformations

A

Type 0: syringohydrocele without herniation

Type I: >5mm tonsilar herniation +/-syringocele; syndromic ass’n - Marfan, EDS

Type 1.5: >5mm herniation w/persistent syringomyelia

Type II: Arnold Chiari - <5mm tonsilar herniation w/low lying torcular herophili, tectal beaking, hydrocephalus w/clival hypoplasia & lumbosarcal meningomyelocele.

Type III: variable herniated elements w/occipital encephalocele

Type IV: ~cerebellar agenesis/hypoplasia

25
Q

What is the Meckel Gruber Syndrome triad?

BQ: what is the mode of inheritance and what 3 genes are implicated?

A
  1. Occipital encephalocele (& other CNS malform)
  2. Cystic dysplasia b/L kidneys
  3. Duct-plate malformation liver

Mode: AR

Genes: MSK1 (Chr 17), MSK2 (Chr 11) & MSK3 (Chr 8)

26
Q

What is this?

A

Alexander Disease - GFAP mution –>failure to myelinate –> wide spread white matter destruction

*Note the perivascular Rosenthal fibers

27
Q

What is this?

A

Krabbe disease (aka Globoid Cell Leukodystrophy)

An AR lysosomal storage disease caused by galactosylceramidase deficiency

Presents in infancy

Fatal

28
Q

What is this?

A

Metachromatic Leukodystrophy:

Arylsulfatase A deficiency –>accumulation of myelin toxic sulfatides stain pink on H&E & brown w/acid cresyl violet

Presents as peripheral neuropathy, psychomotor retardation & blindness beginning 1-2yo

*Asx inclusions can be seen throughout other tissues

29
Q

What is this?

A

X-linked Adrenoleukodystrophy:

Xq28 peroxisomal storage disease affecting ALD transporter –> inability to process/accumulation of VLCFA –> demyelination & adrenal atrophy

*Note perivascular lymphocytes and aggregates of foamy histiocytes, & trilaminar lipids on EM

30
Q

What defect in Smith-Lemli-Opitz syndrome results in holoprosencephaly?

A

Defective cholesterol synthesis - required for SHH cleavage (cholesterol binds corboxy-terminus allowing for autocleavage)

31
Q

What is ass’d w/batwing ventricles or moose-head ventricles?

A

Agenesis/dysgenesis of corpus callosum leads to superior displacement of lateral ventricles and “batwing” shape.

Joubert Syndrome

32
Q

Describe 3 types of holoprosencephaly

A
  1. Lobar
  2. Semilobar
  3. Alobar
33
Q

Describe features of alobar holoprosencephaly

A

MC form in neuropath/autopsy service

Absent longitudinal fissure, horseshoe shaped holosphere, absent sylvian fissue, gyrus rectus and olfactory structures.

Can see dorsal cyst at membranous attachment at tentorium

34
Q

What risk factors are associated with agenesis of the corpus callosum?

A
  1. Aicardi syndrome: retinal abns & seizures
  2. Ciliopathies: primary ciliary dyskinesia, Bardet–Biedl syndrome, Alström, Meckel–Gruber
  3. nonketotic hyperglycemia (inborn errors)
35
Q

What is lissencephaly? What are the types?

A

Abnormality of cerebral surface

Type I - failed migration; agyric w/thickened neocortical grey matter & thin white

Type II - overmigration; focal agyric pattern with thickened grey matter

36
Q

What genes and syndromes are ass’d w/Lissencephaly Type I?

A

LIS1 (17p13.3) - Miller-Dieker syndrome - facies, respiratory

XLIS (Xq22) - males = lissenceph; females = subcortical heterotopia

RELN (7q22) - cerebellar malformations

ARX (Xp21) - ambiguous genitalia

37
Q

What syndromes are associated w/ lissencephaly Type II?

What is the cause?

A
  1. Fukuyama congenital muscular dystrophy - MC
  2. Walker-Warburg
  3. Muscle-eye-brain disease
  4. Congenital muscular dystrophy (MDC) 1D
  5. MDC-1C

*Defective glycosylation (O-mannosylation) - necessary in post-translational protein modification

38
Q

What are the risk factors for polymicrogyria?

A

TORCH infections, metabolic disease (e.g. Zellweger), intrauterine ischemia, family hx, & FGFR3 mutation (thanotophoric dwarphism)

39
Q

Describe the types of focal cortical dysplasia

A

Type I: Distortion of tangential layers w/heterotopic neurons in white matter.

Ia: w/o giant neurons

Ib: w/ giant neurons

Type II: w/dysmorphic neurons

IIa: +Type Ia; TSC2 gene

IIb: +Type 1a +balloon cells; TSC1 gene - indistinguishable from tubers

Type III: FCD w/ass’d lesion (low grade glioma)

40
Q

When does microcystic encephalopathy occur? What is the associated infection?

A

Late in gestation: brain formation normal but with multiple foci of necrosis & cystic change

Ass’d w/HSV

41
Q

What stains distinguish various cysts/cell types of CNS?

A

Neurenteric/dermoid: respiratory/GI w/BM substance - CK & EMA+, usually CK20 neg. Col-IV for BM

Rathke: same w/xanthogranulomatous inflam

Colloid: PAS+ contents, CK & EMA lining

Ependymal: GFAP & S100

Choroid: CK & S100

Pineal: 3 layers - GFAP (inner); pineal - synaptophysin (middle); CT (outer)

Blake pouch - meninges, ependyma & choroid

Arachnoid - EMA

42
Q

What are the 4 categories of lysosommal storage disorders?

A
  1. Neuronal lipidoses-lipofuscin, cherry red ; accumulates in cytoplasm; Niemann Pick
  2. Leukodystrophies-demyelinating peripheral neuropathy; MLD, Krabbe, ALD
  3. Storage histiocytoses-Gaucher, Pompe, Niemann-Pick
  4. Mucopolysaccharidoses- accumulation in extracellular matrix too; CVD, cloudy corneas, skeletal abns, organomegaly -Hurler
43
Q

What is Zellweger spectrum and what 3 disorders are categorized as Zellweger spectrum?

A

Peroxisomal biogenesis disorders involving PEX genes, w/VLCFA accumulation identifiable in plasma

  1. Zellweger syndrome - aka cerebrohepatorenal syndrome
  2. Neonatal ALD
  3. Infantile Refsum disease - less severe than Zellweger
44
Q

What are the 6 leukodystrophies?

A
  1. Metachromatic: metachromatic material in CNS, PNS and viscera; herringbone, prismatic & tuft stone inclusions
  2. X-linked adrenoleukodystrophy: trilaminar inclusions; perivascular lymphocytes; foamy histiocytes
  3. Krabbe: perivascular globoid cells; hypertrophic “onion bulb” neuropathy; tubular inclusions
  4. Alexander disease: grossly cavitated; intermediate filaments
  5. Canavan disease (oligodendroglial & axonal sparing): NO macrophages/gliosis; vacuolation at gray-white junction; ladder-like cristae; aspartate accumulation
  6. Pelizaeus-Merzbacher disease: X-linked; perivascular, tigroid dysmyelination
45
Q

What are 6 neuronal lipidoses?

A
  1. GM1 gangliosidosis: B-galactosidase (MPS)
  2. GM2 gangliosidosis: Tay-Sachs & Sandhoff (SH); hexosaminidase A &/or B
  3. Niemann-Pick A/B: Sphingomyelinase (SH)
  4. Niemann-Pick C: Cholesterol transport; axonal swell & neurofibrillary tangles; no cherry-red spot
  5. Farber Granulomatosis: ceramidase; hoarsness, arthropathy, SQ nodules
  6. Neuronal ceroid lipofuscinosis: osmiophilic deposits & fingerprint bodies; no cherry-red spot

*MPS: mucopolysaccharidosis; SH:storage histiocytosis

46
Q

What are the sphingolipidoses?

A
  1. GM1 gangliosidosis: B-galactosidase
  2. GM2 gangliosidosis: Tay-Sachs, Sandhoff; hexosaminidase
  3. Niemann-Pick A/B: sphingomyelinase
  4. Gaucher: glucocerebrosidase
  5. Fabry: alpha-galactosidase; PN, CVD, bathing trunk telangiectasias, renal & eye dz
  6. Farber granulomatosis: ceramidase; lipid granulomas
47
Q

What is this?

What is MELAS?

A

Ragged Red Fiber

M-Mitochondrial

E-Encephalopathy with

L-Lactic acidosis

A-And

S-Strokes

*Paracrystaline “Parking lot” inclusions

48
Q

What is Pompe disease and what are its features?

A

Glycogen storage disease (glycogenosis type2) from alpha-glucosidase deficiency

Vaculor myopathy, cardiomegaly & macroglossia

Accumulation of membrane bound and free glycogen

49
Q

Name and describe the 4 most common mitochondrial diseases

A
  1. MELAS - brain infarcts w/o vascular pattern in occipital lobes, cerebellum & deep gray; young-variable onset
  2. Myoclonic epilepsy w/raged red fibers (MERRF) - neuronal loss & gliosis in dentorubroolivary region, substania nigra & dorsal column; young
  3. Leigh: subacute necrotizing encephalopathy; symmetrical vasculonecrotic lesions in substantia nigra, brain stem & inferior colliculi - histology=Wernicke w/o hemorrhage; <2yo; AR inheritance
  4. Kerns-Sayre: eye findings, fatal cardiomyopathy /conduction, GI, renal & endocrine manifestations; chronic progressive external opthalmoplegia; deletion of mtDNA
50
Q

What is the proposed cause of mitochondrial disorders?

How do these disorders cause dz?

What are the signs and sx of mitochondrial dz?

A
  1. Defects in assembly/formation of e-transport chain or in maintenance of mitochondrial DNA (mtDNA)
  2. Dysfunction of e-transport causes energy deprivation, free radical formation & apoptosis
  3. Encephalomyopathies; increased blood/CSF lactate and lactate to pyruvate ratio.
51
Q

What are the microscopic features of mitochondrial dz/ragged red fiber muscle dz?

A

Ischemic-like changes, intramyelin edema, sestem degenerations & vascular mineralization in deep gray, adjacent white matter, dentate nucleus & brain stem.

Modified Gomori trichrome or SDH highlights proliferation of abnormal mitochondria in muscle (RRF)

EM: mitochondrial in concentric spirals, rectangular parcrystalline arrays (“parking lot” inclusions)

52
Q

What dz categories are included in the amino acid disorders?

A
  1. Urea cycle
  2. Phenylketonuria
  3. Maple syrup urine dz
  4. Organic acidemias (propionic, methylmalonic)

Most sporadic/AR

53
Q

What is the most common type of Congenital Disorders of Glycosylation?

A

CDG1a - psychomotor impairment, ataxia & alternating strabissmus; early stages often fatal, but can be survived.

  • Olivaropontocerebellar atrophy
  • Dysmorphic features: inverted nipples, subcutaneous buttock fat pads, contractures, MSK

EM: myelin-like lysosomal inclusions

54
Q

What dz is characterized by POLG mtDNA depletion/mutation with CJD-like histology (spongiformencephalopathy) and shows neutral fat deposition in diseased brain tissue w/Oil Red-O?

A

Alpers-Huttenlocher Syndrome

55
Q

What are the more common neurodegenerative disorders?

AR?

AD?

A

AR:

  1. Friedreich Ataxia
    - Frataxin gene on 9q13 - iron transport
    - Pes cavus, scoliosis, DM, cardiomyop
    - Histology: DRG: neuronal depletion w/nodules of Nageotte; loss of sensory fibers in PNS
  2. Ataxia Telangiectasia

AD:

  1. Spinocerebellar atrophies:
    - Often trinucleotide repeats, or pentanucleotide repeats
  2. dentatorubropallidoluysian atrophy, episodic ataxia 1 & 2
56
Q

What is the gene responsible for Friedreich Ataxia?

What is affected?

A
  • Frataxin gene on 9q13
  • iron transport
57
Q

What is the most common pathologic feature of autism?

A

Megaencephaly

Microscopically: neuronalmegaly in young, atrophy and drop-out in older patients

58
Q

What is mesial temporal sclerosis?

Histology?

Stains?

Associations?

A
  1. Idiopathic - ass’d w/refractory seizures
  2. Identical to hypoxic ischemic injury - changes in CA1 & CA4 (endofolium) of hippocampus
  3. NeuN1 highlights neuronal loss and dispersion
  4. Ass’d w/prolonged febrile seizures in infancy

Pediatric Pathology (37 decks)

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