4/15/2016

RESIDENT BASIC SCIENCE I: NEUROPATHOLOGY

BASIC NEUROPATHOLOGY I
08:00-09:40
AAN Annual Meeting 2016
C1

Increased Intracranial Pressure

Tumors
Cerebrovascular Disease
J. Clay Goodman, M.D. FAAN
Associate Dean of Undergraduate Medical Education
Walter Henrick Moursund Chair in Neuropathology
Professor of Pathology & Immunology and Neurology
Baylor College of Medicine

This course is dedicated to

Sydney S. Schochet, Jr, M.D.
1937-2008

Neuropathologist
Teacher
Mentor
Friend

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Necrosis
Apoptosis
Degeneration
Inflammation
Death
Stroke
Trauma

Life
Growth

Neoplasm
Developmental

TrappedinaBoneBox

Threeconstituentsoftheintracranial
space:brain tissue, blood and CSF

Intracranialvolumeisfixed anincreasein
thevolumeofoneconstituentdecreases
theothers

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Cerebri fungoides

Cingulate Herniation

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Uncal Herniation

Kernohans Notch

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PCAStrokeDuetoIncreasedICP

Posterior cerebral artery

territory infarcts

May result from emboli

or thrombosis

May also result from

compression of PCA in
increased ICP false
localizing finding!

FalseLocalizingFindingsinICP
PCAinfarcts
CN6weakness
Kernohansnotch
Papilledema(nonlocalizing)

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Tonsilar Herniation

Cerebellar tonsils
Compressed
Necrotic

Pressure on medulla

Fragments of
cerebellum may be
seen in CSF

Duret Hemorrhages

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RESIDENT BASIC SCIENCE I: NEUROPATHOLOGY

BASIC NEUROPATHOLOGY I
08:00-09:40
AAN Annual Meeting 2016
C1

Tumors

J. Clay Goodman, M.D. FAAN

Associate Dean of Undergraduate Medical Education
Walter Henrick Moursund Chair in Neuropathology
Professor of Pathology & Immunology and Neurology
Baylor College of Medicine

NervousSystemTumors
KeyConcept#1:
Cellproliferation,differentiation,andprogrammedcell
deathareundergeneticcontrol.

KeyConcept#2:
Atthemostfundamentallevel,cancerisasetofdisorders
characterizedbymutationsofgenesregulatingcellgrowth,
differentiation,anddeath.

KeyConcept#3:
Tumorprogressionresultsfromthesequentialacquisition
ofnewmutationswhichconferselectiveadvantage.

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KeyConcept#4:
Nervoussystemtumors,liketumors
elsewhere,arenamedaccordingtothe
similarityofthetumorcellstoarchitectureof
normaltissuesduringdevelopment.

KeyConcept#5
CNStumorsaregradedbutnotgenerally
staged
Extraneural spreadrare
Parenchymalinfiltrationcommoninglioma
CSFdisseminationaltersrx andprognosis

KeyConcept#6:
Nervoussystemtumorsproducesymptomsby
compressingorinvadingadjacentneuraltissue;
therefore,focalsignsandsymptomsare
commoninpatientswiththesetumors.

KeyConcept#7
InadditiontofocaleffectsCNStumorsproduce
increasedintracranialpressurewithits
attendantsignsandsymptoms.

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WHO2016BrainTumorClassification
ComingSoon!
Histologyisstillfoundational
Incorporationofclinicallycriticalmolecular
signaturesintothedefinitionofthetumorentity
Ifhistologyonlyisavailablethediagnosisis:
Xxx,NOS(Histologicaltype,nototherwisespecified)
Example:Oligodendroglioma,NOS
IfhistologyANDmolecularsignaturesareknown:
Xxx,molecularsignature
Example:Oligodendroglioma,1p/19qcodeleted,IDH
mutated
Somenewtumorshavebeendefined

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CNS Tumor Types That Will in WHO

2016 Have Molecular Signature Data for
Definitive Integrated Diagnosis

Medulloblastoma
Atypical Teratoid / Rhabdoid Tumor
Diffuse Gliomas
Diffuse Intrinsic Pontine Glioma
Ependymoma

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CellularConstituentsoftheNervous
System
NeuroectodermalElements
Neurons
Astrocytes
Oligodendroglia
Ependymocytes
MesenchymalElements
Meninges
Microglia&lymphocytes
Bloodvessels
NeuralCrest
Schwanncells

Germinal Matrix
Primitive Neuroectodermal
Tumors
(PNET: medulloblastoma)

IV Neuroglial
Precursors
Glioblastoma Multiforme

Ependyma Astrocyte Oligodendrocyte

III Anaplastic Anaplastic Anaplastic
Ependymoma Astrocytoma Oligodendroglioma

II Ependymoma Astrocytoma Oligodendroglioma Neuron

Juvenile pilocytic Gangliocytoma

Choroid Plexus astrocytoma Central Neurocytoma
I Papilloma Pleomorphic Dysembryoplastic
Colloid Cyst III xanthoastrocytoma neuroectodermal
Ventricle Subependymal giant tumor (DNET)
Myxopapillary cell astrocytoma
ependymoma

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Medulloblastoma

Common childhood
brain tumor

Second peak in young

adults

Medulloblastoma

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Medulloblastoma

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

Homer Wright

Flexner-
Wintersteiner

Slide and Images Courtesy of Dr. G.N. Fuller,

M.D. Anderson Cancer Center

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MIB-1 (Ki67): labels nuclei in cell cycle

MIB-1

Medulloblastoma

Medulloblastoma in CSF

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Medulloblastoma Metastatic to Bone Marrow

Medulloblastoma HistologicalSubtypes

Classic
Desmoplastic/nodular
Medulloblastoma withextensivenodularity
Largecell/anaplastic

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Molecular Classification of
Medulloblastoma : 4 Groups

WNT Classic Morph Monosomy 6 Nuclear beta-catenin Better prog.

SHH Desmopl/Class Loss of 9q GAB1 + SHH inhib.

Gp C Classic/Anapl Isochr 17q MYC act. Worse prog.

Gp D Classic/Anapl Isochr 17q ? Worse prog.

Slide and Images Courtesy of Dr. G.N. Fuller,

M.D. Anderson Cancer Center

CLINICAL Molecular Class. of

Medulloblastoma : 3 Groups

WNT Classic Morph Monosomy 6 Nuclear beta-catenin Better prog.

SHH Desmopl/Class Loss of 9q GAB1 + SHH inhib.

Non-Gp A/B Worse prog.

Slide and Images Courtesy of Dr. G.N. Fuller,

M.D. Anderson Cancer Center

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Medulloblastoma WHO2016
DiagnosticreportingwithbothHistological
subtypeANDGenetic subtypeisencouraged

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The Other Primitive Posterior Fossa Tumor:

Atypical Teratoid/Rhabdoid Tumor (AT/RT)

Primarily infants and young children

75% in cerebellum, remaining 25% in cerebrum

Cells generally larger and more pleomorphic than

those of typical PNET

Gestalt is that of a malignant neoplasm that doesnt

quite fit with either medulloblastoma or glioblastoma,
but often misdiagnosed as medulloblastoma

Slide and Images Courtesy of Dr. G.N. Fuller,

M.D. Anderson Cancer Center

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Atypical Teratoid /
Rhabdoid Tumor
(AT/RT)

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center

Houston TX

Atypical Teratoid/Rhabdoid Tumor

(AT/RT)

Always immunoreactive for vimentin

95% are immunoreactive for epithelial membrane

antigen (EMA); 75% for smooth muscle actin
(SMA)

Variable immunoreactivity for other antigens,

including cytokeratins and neuroectodermal
markers (GFAP and neurofilament proteins)

Slide and Images Courtesy of Dr. G.N. Fuller,

M.D. Anderson Cancer Center

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Atypical Teratoid/Rhabdoid Tumor

(AT/RT)
Genetic studies show mutation/deletion
of the putative rhabdoid tumor
suppressor gene:

INI1 (hSNF5) on chromosome 22q11.2

INI1 gene product loss detectable as

absence of BAF47 immunoreactivity
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center
Houston TX

ClassificationofGliomas
Diffuse
Lowgradeastrocytomaoroligodendroglioma
Anaplasticastrocytomaoroligodendroglioma
Glioblastoma

Circumscribed
Pilocyticastrocytoma
Pleomorphicxanthoastrocytoma(PXA)
Subependymalgiantcellastrocytoma(SEGA)
Desmoplasticcerebralastrocytomaofinfancy
Ependymoma(allgrades)

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WHO2007
DiffuseAstrocytomas
Lowgradeastrocytoma(WHOgradeII)
Nuclearpleomorphism,mitoticfiguresrare

Anaplasticastrocytoma(WHOgradeIII)
Nuclearpleomorphism,mitoticfiguresprominent
NOvascularproliferationornecrosis

Glioblastoma (WHOgradeIV)
Nuclearpleomorphism,mitoticfiguresprominent
Vascularproliferationand/ornecrosis

WHO2007
DiffuseAstrocytomas
Lowgradeastrocytoma(WHOgradeII)
Mediansurvival:6.58years

Anaplasticastrocytoma(WHOgradeIII)
Mediansurvival:22months
Age<40yr:37monthsAge>40yr:15months

Glioblastoma (WHOgradeIV)
Mediansurvival:14months
Age<40yr:24monthsAge>40yr:12months

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Glioblastoma multiforme
crossing the midline via the
corpus callosum

40
Days

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Diffuse intrinsic pontine

glioma (DIPG)
Histone H3F3A Gene
Mutations

WHO 2016
Diffuse Midline Glioma
H3 K27M-Mutated

Glioblastoma of pons in
an adult

Diffuse intrinsic glioma DIG of the pons

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Diffuse intrinsic glioma DIG of the pons

Glioblastoma

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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Glioblastoma: Pseudopallisading
Necrosis

Glioblastoma multiforme
Glial Fibrillary
Acidic Protein

GFAP

Intermediate filament
of glia

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PathwaystoGlioblastoma
PrimaryGlioblastoma SecondaryGlioblastoma
Glioblastoma arisesdenovo Glioblastoma arisesfrom
withoutprogressionfrom lowergradeglioma
lowergradeglioma Sequentialacquisitionof
IDH1mutationsrare newmutations
Heterozygosity 10q(70%of IDH1andp53common
cases),EGFR amplification gliomagenic mutations
(36%),p16INK4a deletion Temozolamide therapy
(31%),andPTEN mutations leadstohypermutation
(25%). DrivermutationsinRBand
AktmTOR pathways*

*Johnson BE et al. Mutational analysis reveals the origin and therapy-driven evolution of
recurrent glioma. Science 343 (10 Jan 2014): 189-193.

Molecular Classification of Glioblastoma

MGMT Promoter Methylation Status
O-methylguanine DNA methyl transferase (MGMT)
gene silencing by methylation

Tumor cannot repair DNA damage from alkylating

agents such as temozolomide

Better survival but still poor

3 yr survival 30% with methylated MGMT promoter

3 yr survival 10% with unmethylated MGMT

promoter

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Anaplastic astrocytoma

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

Low grade astrocytoma

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Gliomatosis cerebri
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

Glioma Therapy

Surgicaldebulking
Debulkbutdonotproducemajornewdeficits
Rarelycurative
XRT
StereotacticfractionatedhasreplacedwholebrainXRT
Chemotherapy
Temazolamide
Nitrosoureas

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MolecularBiologyofAstrocytomas
Astrocyte
Loss of heterozygosity 17p
P53 Anti-oncogene

Astrocytoma
Loss of heterozygosity 13q,
16p, 9p, 19q

Anaplastic Astrocytoma
Loss of heterozygosity 10
Loss of Anti-oncogene
Amplification of 7
Epidermal growth factor
receptor amplification Glioblastoma

Oligodendroglioma
ClassicLowGradeOligodendroglioma
Friedeggartifact

Chickenwirevascularpattern

Calcifications

Corticalinvasionwithperineuronalandperivascular
satellitosis(secondarystructuresofScherer)

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Oligodendroglioma

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MolecularBiologyofOligodendroglioma

Oligodendrocyte
Loss of heterozygosity 19q
and 1p

Oligodendroglioma

Loss of heterozygosity 10
Loss of Anti-oncogene

Amplification of 7 Anaplastic
Epidermal growth factor Oligodendroglioma
receptor amplification

Oligodendroglioma Grading

Lowgradeoligodendroglioma(WHOgradeII)

Anaplasticoligodendroglioma(WHOgradeIII)
Densecellularity
Microvascularproliferation
Necrosis

Anaplasticoligodendrogliomawithnecrosis=GradeDoligodendroglioma=
Oligodendroglialglioblastoma

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Anaplastic
Oligodendroglioma

Dense cellularity
Microvascular proliferation
Necrosis

Oligodendroglioma Prognosis

A clinically significant subset (85%) of classical

oligodendroglial tumors show LOH for chromosomes
1p and 19q

Response to therapy and survival are better in

patients with combined LOH for chromosomes 1p and
19q (mean survival 12 mo wild-type vs 124 mo in co-
deletors)

RX: combination chemo-therapy with regimens such

as PCV (procarbazine, lomustine/CCNU and
vincristine) OR temazolamide

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AnaplasticOligodendroglioma
Impactof1p/19qStatus
1p
Absent Present
19q
Absent Present

Response 100% 100% 18%

Rate

Survival > 123 mo 71 mo 16 mo

Adapted from JNEN 62(2):111-126, 2003

Molecular Classification of
Grade II and III Diffuse Gliomas
1p / 19q Co-deletion
IDH Mutation
FAVORABLE GENETIC SIGNATURES
in Diffuse Gliomas

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center

Houston TX

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Molecular Classification of
Grade II and III Diffuse Gliomas
Isocitrate Dehydrogenase Mutation
IDH1 (R132H) point
mutation accounts for
95% of all IDH mutations
in diffuse gliomas and
can be detected by
immunohistochemistry
Other IDH mutations
require sequencing

image Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center

Houston TX

IDH Mutation in Primary CNS Tumors

IDH1 (R132H) mutation is present in about
75% of grade II and III diffuse gliomas
(astrocytomas, oligodendrogliomas, mixed
oligoastrocytomas) and secondary
glioblastomas
NOT PRESENT in primary glioblastomas
VERY RARE in other types of primary CNS
tumors.
Not present in gliosis (glioma vs gliosis)
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center
Houston TX

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Molecular Classification of
Grade II and III Diffuse Gliomas
Isocitrate Dehydrogenase Mutation
IDH Mutation Status can be used to
substratify Non-1p19q Co-deleted
Diffuse Gliomas (Astrocytomas) into
Favorable (mutation Present) and
Unfavorable (mutation Absent)
prognostic groups
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center
Houston TX

Strong Prognostic Marker

Absence of IDH1-R132H Mutation
Predicts Rapid Progression of Non-
enhancing Diffuse Gliomas in Older
Adults

Olar A, et al. Annals Diag Pathol, 2012 (in

press)

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center

Houston TX

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Glioma Versus Gliosis

IDH1-R132H immunohistochemistry is currently
the most helpful marker for distinguishing low-
grade diffuse glioma from gliosis
Glioma: Positive
Gliosis: Negative

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center

Houston TX

Molecular Classification - Summary

1. If the H&E shows classic oligodendroglioma features,
there is an 85% probability of combined 1p/19q
deletion (and 100% of 1p/19q co-deleted gliomas also
exhibit IDH mutation) and the diagnosis is
Oligodendroglioma
2. If the morphologic features are NOT classical oligo, the
trend is to classify the tumor as an Astrocytoma
3. FISH testing for combined deletion of 1p and 19q has
become standard of care, and co-deletion constitutes
the molecular definition of oligodendroglioma
4. IHC for IDH1 mutation (and sometimes sequencing for
less common IDH1 and IDH2 mutations) permits
substratification of non-co-deleted diffuse gliomas
(astrocytomas) into favorable and unfavorable groups
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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Trend
The trend in glioma classification (already
well in place for clinical trials) is to give less
weight to traditional morphologic
subclassification in favor of patient
stratification based on the presence or
absence of predictive molecular markers,
specifically: 1p/19q codeletion status and
IDH mutation status.
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center
Houston TX

Example of Objective Diffuse Glioma

Diagnosis Using Combined Morphologic-
Molecular Criteria (MDACC Format)

ANAPLASTIC DIFFUSE GLIOMA

WHO Grade III
IDH1-R132H Mutation: POSITIVE
1p/19q: CO-DELETED

(anaplastic oligodendroglioma)
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center
Houston TX

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Example of Objective Diffuse Glioma

Diagnosis Using Combined Morphologic-
Molecular Criteria (MDACC Format)

DIFFUSE GLIOMA
WHO Grade II
IDH1-R132H Mutation: NEGATIVE
1p/19q: INTACT

(low-grade diffuse astrocytoma)

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center
Houston TX

WHOS NEXT

Haarlem
May 1-3 2014

A Colloquium
to Guide the
Next Steps in
Brain Tumor
Classification
and Grading

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center

Houston TX

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ISN-Haarlem Colloquium Participants

28 Oncologic Neuropathologists

Dr. Kenneth Aldape Dr. Bea Lopes

Dr. Daniel Brat
Dr. Peter Burger
Dr. Peter Collins
Dr. Andreas von Deimling
Dr. Charles Eberhart
Dr. David Ellison
Dr. Dominique Figarella-Branger
Dr. Gregory Fuller
Dr. Felice Giangaspero
Dr. Caterina Giannini
Dr. Cynthia Hawkins
Dr. Paul Kleihues
Dr. J. Max Kros
Dr. David Louis
Dr. Ho-Keung Ng
Dr. Andray Korshunov
Dr. Hiroko Ohgaki
Dr. Werner Paulus
Dr. Arie Perry
Dr. Torsten Pietsch
Dr. Guido Reifenberger
Dr. Marc Rosenblum
Dr. Elizabeth Rushing
Dr. F. Soylemezoglu
Dr. Pieter Wesseling
Dr. Otmar Wiestler

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What Does an Integrated

Diagnosis Pathology Report Look
Like at MDACC?
DIAGNOSIS
(A) BRAIN, LEFT FRONTAL LOBE, CRANIOTOMY AND RESECTION:

INTEGRATED DIAGNOSIS: DIFFUSE ASTROCYTOMA

WHO GRADE II

Histologic phenotype: Mixed oligoastrocytoma

Mitotic index (PHH3): 3 mitoses / 10 HPF

Ki-67 index (MIB1): 3.8%

IDH status (IHC): POSITIVE FOR MUTANT p.IDH1 Arg132His

1p/19q status (FISH): NEGATIVE FOR CODELETION

(SEE COMMENT)

CircumscribedAstrocytomas
Sharedfeaturesofthesetumors:
Astrocyticdifferentiation(GFAPpositive)

Relativelycircumscribedgrowthwithverylimited
infiltrationofadjacentneuralparenchyma
comparedtothediffuseastrocytomas

Commonlyinvadeoverlyingleptomeningesand
subarachnoidspace(JPA,PXA) NOTanegative
prognosticfactor!

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CircumscribedAstrocytomas
Histologicfeaturesmimichighgradeastrocytomaandcanresult
inovergradingthatresultsininappropriatetherapy(XRT,
chemotherapy)
Goodprognosiscomparedtodiffuseastrocytoma
Treatmentofchoiceisgrosstotalresectionwhenanatomically
possible
Inasmallpercentageofcases,especiallyforPXA,progressionto
highgradeastrocytomaoccurs

Pilocytic Astrocytoma

20%ofchildhoodbraintumors
Cerebellum,hypothalamic/thirdventricularregion,
opticnerves,cerebrum,brainstemandspinalcord
MRI:oftenacystwithanenhancingmuralnodule
Histology:biphasicarchitecture,pilocyticastrocytes,
Rosenthalfibersandeosinophilicgranularbodies(EGBs)

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Pilocytic Astrocytoma

Microvascularproliferation(contrastenhancing)
Nuclearatypia
Commonlyinvadeoverlyingleptomeninges
Theabovethreefeaturescanleadtoovergradingasa
malignantastrocytoma!
Mitoticfiguresarerare
Treatment:grosstotalresectionwhenpossible

Image Courtesy of the Sydney S. Schochet, Jr. Collection with Permission

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Optic nerve glioma

Pilocytic astrocytoma

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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BrainStemGliomas
DiffuseInfiltratingPontine
Glioma:Classicpontineglioma
(malignantinfiltratingfibrillary
astrocytoma;diffuselyexpandsthepons
andengulfsthebasilarartery,thus
ventrally exophytic)

Dorsallyexophytic glioma
(lowgrade;pilocytic;relatively
circumscribedmargin;preferredRxis
grosstotalresection;prognosisgood
comparedtoclassicpontine glioma)
Slide and Images Courtesy of Dr. G.N. Fuller, M.D. Anderson Cancer Center

BRAF V600E MUTATION

Pleomorphic xanthoastrocytoma 66%
Ganglioglioma 40-60%
Epithelioid glioblastoma 50%
Extra-Cerebellar Pilocytic Astrocytoma 33%
Dysembryoplastic neuroepithelial tumor 30%
Cerebellar Pilocytic Astrocytoma 2%
Diffuse Gliomas 2%

(KIAA1549:BRAF FUSION in Pilocytic astrocytoma: 70%)

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center
Houston TX

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PleomorphicXanthoastrocytoma
(PXA)
Densecellularity
Extremepleomorphism andbizarreatypical
cellsmimickinggiantcellGBM
ProminentEGBs
Mayhavexanthomatous (lipidladen)tumor
cells
Densereticulin pattern
65%haveBRAFmutations

Pleomorphic xanthoastrocytoma (PXA)

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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Subependymal GiantCell
Astrocytoma(SEGA)

Intraventricularlocation(lateralventricles)
Resemblesgemistocyticastrocytoma,anaplastic
astrocytomaorganglioncelltumor
Spindlecellmorphologyalsocommon
Mitoticfiguresrare

SEGA

Slide and Images Courtesy of Dr. G.N. Fuller, M.D. Anderson Cancer Center

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Subependymal giant cell astrocytoma (SEGA)

Images Courtesy of Dr. G.N. Fuller, M.D. Anderson Cancer Center

Subependymal GiantCell
Astrocytoma(SEGA)

Althoughcommonlyassociatedwith
tuberoussclerosis,maybepresenting
problemandinsomecasesnostigmataof
TSarefound
Requiresahighindexofsuspicionasa
historyofTSmaybeabsent
Treatmentisgrosstotalresection

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Ependymoma

Image Courtesy of the Sydney S. Schochet, Jr. Collection with Permission

ClassicEpendymoma
Perivascularpseudorosettes arethemost
distinctivefeature;muchmorecommonthantrue
ependymalrosettes(centrallumen)
Cellprocessesofperivascularpseudorosettes
oftenstronglypositiveforGFAP
Ultrastructuralfeatures:Intercellularlumenswith
microvilli,+/ ciliaandprominentcelljunctions

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Ependymoma

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

Ependymoma Clincogenetic Subtyping

Supratentorial Infratentorial
Adolescentandadult TypeA
Intermediateprognosis Infantandadolescent
Fewchromosomaldefects Intermediateprognosis
Intrachromosomal defect Fewornochromosomalor
C11orf95RELAfusion genedefects
WHO2016 Epigeneticchanges
Ependymoma,RELAfusion
positive TypeB
Adolescentandadult
Goodprognosis
Extensivechromosomal
defects
Nogeneticorepigenetic
defects

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Myxopapillary Ependymoma
of the Filum Terminale

Subependymoma

Lateralventricle,4th ventricle,andspinal
cord

Distinctivelobules withclusters ofbenign

nucleiwithinanabundantfibrillarymatrix

Grosstotalresectioniscurative!

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Subependymoma

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

Ependymoblastoma

Subtypeof
primitive
neuroectodermal
tumor(PNET)

Profuse numbers of true ependymal

rosettes (with central lumens)
Malignant tumor with aggressive
behavior
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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ChoroidPlexusTumors

Choroidplexuspapilloma
Choroidplexuscarcinoma
Choroidplexusmeningioma
XanthogranulomaoftheCP
MetastasistotheCP

Normal Choroid
Plexus

Papilloma

Carcinoma
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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Xanthogranuloma ofthe
ChoroidPlexus
Non-neoplastic masscomposedofcholesterol
crystals(cholesterolclefts)engulfedby
macrophagesandmultinucleatedgiantcells

Etiologyuncertain;possiblyintrachoroid

hemorrhage

Unilateralor,morecommonly,bilateral!

CanbemistakenformetastasisonMRIscan

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

ChoroidPlexusMetastases
Fairlycommon
Inadults,amalignantneoplasmofthe
choroidplexusismuchmorelikelytobe
metastaticcarcinomathanchoroidplexus
carcinoma!
Bilateral CPmassesareusually
xanthogranulomas!

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NeuronalTumors
WellDifferentiatedNeuronalTumors
Gangliocytoma
Dysplasticgangliocytoma(LhermitteDuclos)
Centralneurocytoma
Cerebellarliponeurocytoma
Paragangliomaofthefilumterminale

HighGradeNeuronalTumors
Ganglioneuroblastoma
Cerebralneuroblastoma

Gangliocytoma

Quasihamartomatous
benigntumorcomposed
exclusivelyoflarge
matureganglioncell
neurons

The presence of smaller, less mature,

mitotically-active neuroblasts changes the
diagnosis to ganglioneuroblastoma
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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DysplasticGangliocytoma ofCerebellum
(LhermitteDuclos)

Matureganglioncellsofgranularcellneuronorigin
(oldmisnomer Purkinjeoma)

Borderlinelesionbetweenmalformationandlow
gradeneoplasm

Grosstotalresectioniscurative

50%ofpatientshaveCowdenSyndrome(multiple
hamartomasyndrome)

DysplasticGangliocytoma ofCerebellum
(LhermitteDuclos)

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Central Neurocytoma

Mature neuronal tumor

Intraventricular
Young adults
Good prognosis with gross
total resection

Tumors of the Filum Terminale

Paraganglioma

Myxopapillary
Ependymoma

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Ganglioglioma (GG)
MRI:oftenclassiccystwithenhancingmuralnodule

Thegliomacomponentisalmostalwaysastrocytic;
veryrarelyoligodendroglial

Glioma componentfrequentlyhasahighlyspindled
pilocyticmorphology

Eosinophilic granularbodies(EGBs)prominent!

Ganglioglioma (GG)

Ganglioncellsmaybeverysparse

Ofteninvadeoverlyingsubarachnoidspace

Treatmentisgrosstotalresectionifpossible

Diagnosticpitfall:dontmistakeentrappednormal
neuronsincortexinfiltratedbyadiffuseastrocytomafor
neoplasticganglioncells!

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Ganglioglioma

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

Dysembryoplastic Neuroepithelial
Tumor(DNET)
Clinicalpresentationin
childrenwithahistory
ofseizures

Low-grade, intra-
cortical location,
multinodular
Prominent
oligodendroglia-like
cells (OLCs) mimic
oligodendroglioma

56
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Dysembryoplastic Neuroepithelial Tumor

(DNET)
Prominentmucinouschangeinintracortical
nodulesresultsinfloatingneurons

Maybeassociatedwithdysplasticchangesin
surroundingcortex

Grosstotalresection(andoftenevenpartial
resection)iscurative

Meningiomas

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Image Courtesy of the Sydney Schochet, Jr. Collection with Permission

58
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Galea

Scalp
Skull

Tumor

Image Courtesy of the Sydney Schochet, Jr. Collection with Permission

Two Tumors
of the Optic Nerve

Meningioma of the optic nerve arises from the

dural sheath of the nerve

Optic nerve pilocytic astrocytoma in NF

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Images Courtesy of Dr. Gregory N. Fuller

MD Anderson Cancer Center

Meningiomas

Epithelial
Membrane
Antigen Desmosomes
Interdigitating
processes

Slide and Images Courtesy of Dr. G.N. Fuller, M.D. Anderson Cancer Center

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Meningiomas
Fourvariants associatedwithaggressivebehavior
(increasedrecurrenceandmetastasisrates;WHOgrades
IIandIII)
Chordoid (WHOgradeII) cordsofcellsinmucinousmatrix;mimics
chordoma
Clearcell(WHOgradeII) prominentcytoplastmic clearing,maybemore
aggressive
Papillary (WHOgradeIII) aggressivevariant,perivascularpseudorosettes
thatmimicependymoma;morecommoninyoungerpatients
Rhabdoid (WHOgradeIII) aggressivemeningiomawithrhabdoid
morphology

C2PR

HighGradeMeningioma

Twocategories:Atypical(WHOgradeII)andAnaplastic
(Malignant;WHOgradeIII)

Braininvasionnolongerqualifiesasacriterionforupgrading
toAnaplastic(Malignant)Meningioma tumorswiththis
featureareclassifiedasAtypicalMeningioma

MajorcriterionforAnaplastic(Malignant)Meningioma20or
moremitoticfiguresper10HPF(Perryetal.,Cancer 85:2046
56,1999)

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AtypicalMeningioma
(WHOgradeII)

Braininvasionwarrants
upgradingtoAtypical
Meningioma(WHOgradeII)

Invasionofaduralvenoussinus
ortheoverlyingcranialbone
doesNOTwarrantupgrading!

Anaplastic(Malignant)Meningioma

GradeasAnaplasticMeningiomaif:

Mitoticrateof20mitoses/10HPF(400x)or
greater,OR

Highlyanaplasticfeatures(resemblingsarcoma,
carcinomaormelanoma)present

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FeaturesSuggestingIncreasedRateof
RecurrenceWarrantingaDiagnosisofAtypical
Meningioma(WHOgradeII)
Braininvasion,or

Maximalmitoticrateof4mitoticfiguresper10HPF
(400x)orgreater,or

Threeormoreofthefollowing:
Sheeting(patternless)architecture
Hypercellularity (>53nucleiperHPFdiameter)
Macronucleoli
Smallcellformation
Micronecrosis

CaveatforBenignMeningioma

Significantmorbidityandmortalitycanbe
seeninhistologicallybenign(WHOgradeI)
meningiomassecondarytounfavorable
LOCATION

(e.g.,enplaque skullbasemeningiomas)

63
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PrimaryCNSLymphoma(PCNSL)

TwoCommonClinicalSettings

Immunocompromised patients

Elderlypatients

Primary CNS Lymphoma: Angiocentric & Infiltrative

64
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Primary CNS Lymphoma: Angiocentric & Infiltrative

CD20
B-Cell

EBV in PCNSL in AIDS

65
 4/15/2016

PCNSL
SystemicNHLusuallyinvolvesleptomeninges
whilePCNSLisintraparenchymal
SystemicworkupinPCNSLiscontroversial;
extraneuraldiseaseidentifiedinonly3%
Ifpossibleavoiduseofcorticosteroidspriorto
bx
RX:HighdoseMTX+cytarabine

Tumorsthat
Diffusely Infiltrate
BrainParenchyma

Gliomas

Lymphoma

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 4/15/2016

Intravascular Lymphomatosis

Slide and Images Courtesy of Dr. G.N. Fuller, M.D. Anderson Cancer Center

Craniopharyngioma

Slide and Images Courtesy of Dr. G.N. Fuller, M.D. Anderson Cancer Center

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 4/15/2016

Craniopharyngioma
Adamantinomatous variant
Palisading,plumpnodulesofwetkeratin,prominentcalcification,
machineryoilcystfluid
Childrenandadults
Papillaryvariant
WelldifferentiatedsquamousepitheliumwithNOkeratin,
pallisading orcalcifications
Adultsonly(doesNOToccurinchildren!)
Betterprognosis(lessinfiltrativeandthereforemoreamenableto
grosstotalresection)

Fluid in a Craniopharyngioma

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Craniopharyngioma with Adjacent Compressed

Brain with Rosenthal Fibers

Craniopharyngioma

Adamantinomatous
variant

Papillary

Papillary variant
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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PituitaryAdenoma
Oldtinctorialclassificationsystem(acidophil,basophil,
chromophobe)hasbeensupplantedby
immunohistochemistryforpituitaryhormones

Commonpropertiesofalladenomas:
Shedcellsprofuselyontouch(imprint)
preparations(shouldbeperformedonALL
specimens,ESPECIALLYmicroadenomas!)
Lossofnormallobulararchitecturebestappreciated
withareticulinstain

Sellar Region Coronal Section MRI: Pituitary Mass

70
 4/15/2016

Normal

Adenoma

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

Normal Acinar Pattern Effacement of Acinar Pattern

in Pituitary Gland (Reticulum in Pituitary Adenoma
Stain) (ReticulumStain)

71
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Immunohistochemical Staining of Hormone

Overproduction in Pituitary Adenoma

Effacement of Acinar Pattern

in Pituitary Adenoma

Tiny ACTH Pituitary Adenoma

Capable of Producing a Lethal
Endocrinopathy

72
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Crookes Hyalin Change: ACTH Secreting Adenoma

CrookesHyalineChangein
NormalAdjacentPituitaryGlandwithAcinar
PreservationNearACTHSecretingAdenoma

73
 4/15/2016

CrookesHyalineChange
Accumulationofpolymerizedcytokeratinforming
aninclusionoftennearthenucleus
Mayoccurinpituitarycellsbearingcorticosteroid
receptors
Normalcellsinresponsetohighcorticosteroidsfrom
ACTHsecretedbyanadenoma
Normalcellsinresponsetocorticosteroidsfromother
sources(adrenaltumors,ACTHsecretingsmallcell
carcinomaoflung,exogenousoriatrogenicsteroids)

CrookesHyalineChange
Classicalteachingisthatnormal ornonneoplasticpituitary
cellsdevelopCHC
MostcellswithCHCprobablyarenonneoplasticcells
Corticotrophadenomacells,however,mayhaveenough
steroidreceptorstoalsohavethischange
IfCHCisveryabundantinadenoma,thetermCrookescell
adenoma hasbeenappliedbutdiagnositiccriteriaisstill
underdiscussion
Crookescelladenomamaybemorelocallyaggressive

74
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Rathkes Cyst
Intrasellarorsuprasellar
mass

MRI:cystwithsignal
characteristicssimilarto
thoseofCSF

Lining:ciliated
pseudostratifiedcolumnar
epitheliumwithGoblet
cells
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

Epidermoid
Cyst

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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Dermoid
Cyst

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

Arachnoid cyst versus epidermoid/dermoid

Use diffusion weighted MRI

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 4/15/2016

PinealRegionTumors
Germinoma
PinealParenchymalTumors(PPTs)
Astrocytomas
OtherGermCellTumors
Meningiomas(arisefromsurrounding
arachnoidcellnestsofthevelum
interpositum)

Pineocytoma
Large rosettes

Pineoblastoma
Small blue cell tumor

77
 4/15/2016

Germinoma: Large Germ Cells + Lymphocytes

Hemangioblastoma
NegativeforEMA(incontrasttometastaticrenalcell
carcinoma,whichisalsoseeninvonHippelLindau)

Positiveforalphainhibin
SporadicorassociatedwithvonHippelLindau
Syndrome
Treatment surgicalresection

78
 4/15/2016

Hemangioblastoma

Hemangioblastoma Foamy
Stromal Cell

Derived from pluripotential mesenchymal stem cell (hemangioblast)

capable of hematopoietic and endothelial differentiation

79
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ColloidCystofthe3rd Ventricle

Images Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

Colloid cyst of the 3rd ventricle: positional hydrocephalus

80
 4/15/2016

CiliatedPseudostratified Columnar
EpitheliumwithGobletCells

ColloidCyst

RathkesCyst

NeurentericCyst
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

TumorsofPeripheralNerve
Schwannoma

Neurofibroma

Perineuroma

MalignantPeripheralNerveSheathTumor

TritonTumor

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SCHWANNOMA Antoni B

Antoni A NF2
Bilateral CPA
tumors
Chromosome 22

Verocay Body

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

NF2
Cervical ependymoma
Thoracic schwannoma
Bilateral CN8 schwannomas

82
 4/15/2016

NF2
Multiple meningiomas

Neurofibroma
SporadicorNFassociated(more
commoninNF1thanNF2)

Diffusefusiformexpansionofthe
nerve

Intermixed axons throughout tumor (more dense in

center)

Tumor composed of Schwann cells, fibroblasts and

perineurial cells

Plexiform neurofibroma is pathognomonic for NF1 at

risk for progression to malignant peripheral nerve
sheath tumor (MPNST)
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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Neurofibroma

NF1: neurofibromas Chromosome 17 neurofibrobin

84
 4/15/2016

Chordoma

Physaliferous
(Bubble-Bearing)
cells

Ecchordosis
Physaliphora

85
 4/15/2016

Metastatic Tumors

Multiple

Grey-white
junction

Can occur
anywhere

Metastatic Tumors

Multiple

Grey-white
junction

Can occur
anywhere

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 4/15/2016

Metastatic Tumor To Midbrain

MetastaticTumors

Mostcommonmetastatictumorsin
olderadults:
Lung
Breast
Melanoma
Renal
Gastrointestinal

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MetastaticTumors
Inyoungeradults,consider:
Choriocarcinomainwomen
Alveolarsoftpartsarcoma(ASPSisthemost common
sarcomatometastasizetotheCNS)

Commontumors withUncommonCNSmets:
Prostate,Cervicalca,Sarcomasingeneral,Squamouscell
carcinoma

Hemorrhagicmets:
Renal,Melanoma,ChoriocarcinomaandLung

Hemorrhagic Metastases

Renal, Melanoma, Choriocarcinoma

and Lung

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 4/15/2016

BrainMetastasisRX
Multiple:WBXRT
Solitaryorfew
N<3considersurgicalremoval
MovementawayfrompostopWBXRT
Forsmall(<3cm)lesionsconsiderstereotactic
radiosurgery
Corticosteroidsveryhelpful
Patientsusuallydieofsystemiccomplicationsof
cancernotbrainmets

Meningeal
Carcinomatosis

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Dural Metastases
Same as Bone Mets
Prostate
Breast
Kidney
Thyroid
Lung

MRI:CystwithEnhancingMural
Nodule

PilocyticAstrocytoma

Pleomorphic
Xanthoastrocytoma

Ganglioglioma

Hemangioblastoma

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

90
 4/15/2016

Intraventricular Tumors
Choroidplexuspapilloma/carcinoma
Ependymoma
Subependymoma
Subependymalgiantcellastrocytoma
Centralneurocytoma
Intraventricularmeningioma
Chordoidgliomaofthe3rdventricle
Fetus(IntracranialFetusinFetu)

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

MassLesionsthatMimicNeoplasms
onMRI

DemyelinatingDisease
(PseudotumorofKepes)

Abscess
Infarct
ParasiticCyst

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SpinalCordSpaces

Extraduralspace
Intradural
extramedullary
Intramedullary

SpinalEpiduralMasses

Neoplasms:usuallymetastatictospine
Abscess
Herniatedintervertebraldisc

Local pain
Radicular pain
Myelopathy

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Intradural Extramedullary Masses

Neoplasms:arisefromnerverootsand
meninges
Schwannoma
Neurofibroma
Meningioma

Radicular pain
Myelopathy

IntramedullaryMasses
Neoplasms:arisefromcellsindigenoustothe
CNS
Astrocytoma
Ependymoma
Oligodendroglioma

Myelopathy

93
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WHO2007:GradeITumors
Subependymal giant cell astrocytoma
Pilocytic astrocytoma
Subependymoma
Myxopapillary ependymoma
Choroid plexus papilloma
Angiocentric glioma

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

WHO2007:GradeITumors
Gangliocytoma
Ganglioglioma
Desmoplastic infantile astrocytoma / Desmoplastic
infantile ganglioglioma (DIG)
Dysembryoplastic neuroepithelial tumor (DNET)
Paraganglioma of the spinal cord
Papillary glioneuronal tumor (PGNT)
Rosette-forming glioneuronal tumor of the fourth
ventricle (RGNT)
Pineocytoma
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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WHO2007:GradeITumors
Schwannoma
Neurofibroma
Meningioma
Hemangioblastoma
Craniopharyngioma
Granular cell tumor of the neurohypophysis
Pituicytoma
Spindle cell oncocytoma of the adenohypophysis

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

WHO2007:GradeIITumors
Pilomyxoid astrocytoma
Diffuse astrocytoma
Pleomorphic xanthoastrocytoma
Oligodendroglioma
Oligoastrocytoma (MOA)
Ependymoma
Atypical choroid plexus papilloma
Chordoid glioma of the third ventricle
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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WHO2007:GradeIITumors
Central neurocytoma
Extraventricular neurocytoma
Cerebellar liponeurocytoma
Pineal parenchymal tumor of intermediate
differentiation (PPTID)
Atypical meningioma (including chordoid
and clear cell variants)
Hemangiopericytoma

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

WHO2007:GradeIIITumors
Anaplastic astrocytoma
Anaplastic oligodendroglioma
Anaplastic oligoastrocytoma (AMOA)
Anaplastic ependymoma
Choroid plexus carcinoma
Anaplastic ganglioglioma
Anaplastic (malignant) meningioma
(including papillary and rhabdoid variants)
Anaplastic hemangiopericytoma
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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WHO2007:GradeIVTumors
Glioblastoma
Giant cell glioblastoma
Gliosarcoma
Pineoblastoma
Medulloblastoma (including desmoplastic/nodular, MB
w/ extensive nodularity, anaplastic, and large cell variants)
CNS primitive neuroectodermal tumor (CNS
PNET) (including medulloepithelioma,
ependymoblastoma, CNS neuroblastoma, and
ganglioneuroblastoma)
Atypical teratoid/rhabdoid tumor (AT/RT)
Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

WHO2007:Tumorswithmultiplegrades
dependingonvariousfeatures

Pineal parenchymal tumor of intermediate differentiation

(PPTID) grade II or III

Papillary tumor of the pineal region (PTPR) grade II or III

Perineurioma grade I, II, or III

Malignant peripheral nerve sheath tumor (MPNST) grade

II, III, or IV

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

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WHO2007:Tumorswithnoassignedgrade

Astroblastoma
Dysplastic gangliocytoma of the cerebellum
(Lhermitte-Duclos disease) - benign

Slide Courtesy of Dr. Gregory N. Fuller MD Anderson Cancer Center Houston TX

RESIDENT BASIC SCIENCE I: NEUROPATHOLOGY

BASIC NEUROPATHOLOGY I
08:00-09:40
AAN Annual Meeting 2016
C1

Cerebrovascular Disorders

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Infarction

Globalhypoxiaorhypoperfusion
Arterialinfarctssecondarytoocclusionor
embolus
Arterialandarteriolarinflammation
vasculitis
Venousinfarctssecondarytosuperiorsagittal
thrombosis

Atherosclerosis

99
 4/15/2016

Carotid Endarterectomy
WithUlcerated
(Complicated)Plaques

CarotidArteryDissection

100
 4/15/2016

SelectiveVulnerability
Neurons>>Glia>Endothelium

Purkinjecellsofcerebellum
PyramidalneuronsofCA1 Sommerssector ofthe
hippocampus
Middlelayersofthecerebralcortex Laminarnecrosis

Majorcontributionfromexcitotoxicity secondaryto
releaseofaspartateand glutamate

101
 4/15/2016

HistopathologyofInfarction
Earliestclassicalfinding:
Redneuron
Eosinophilic shrunkencytoplasmwithobscurationof
Nissl
Hyperchromatic nucleus
Thedeadredneuronmorphologytakes6 18hours
todevelop notseeninsuddendeath
Ultrastructural changesincludingmitochondrial
swellinganddissolutionofroughendoplasmic
reticulumoccurwithinminutesofdamage

AcuteInfarct:RedNeurons

Images Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

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AcuteInfarct:RedPurkinjeNeurons

Image Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

HistopathologyofInfarction:Temporal
Evolution
Day1
Redneuronandrarefactionofneuropil
Day2 Weeks
Neuronaldropout
Rarefactionofneuropil
Influxofmacrophagesandfewerlymphocytesandpolys
Astrogliosis
Vascularproliferation(Bewareofcontrastenhancement!)
Weeks Months
CysticcavitycontainingmacrophagesthenCSF
Wallofreactiveastrocytes

103
 4/15/2016

HypotensiveIschemicInjury

Watershedorarterialborderzoneinfarcts:
dorsolateralaspectsofthecerebralhemispheres
maninabarrelweakness
rimsofthecerebellarhemispheres
Ifsufficientlysevere,globaldamagewith
atrophyofneuroncontainingstructures
Laminarnecrosis
Basalgangliashrinkage
Hydrocephalusexvacuo

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Depth of Crown of
Sulcus Gyrus

Ischemia Contusion

105
 4/15/2016

WatershedInfarcts
Watershed infarcts result from global
hypoperfusion

They involve the border zones between the

anterior, middle and posterior cerebral
arteries

Most severe at high parietal occipital area

Depths of sulci are less well perfused than

crowns of gyri

GrossPathology ArterialDistribution
Infarct

Softeningoftissue
Maybepaleorhemorrhagic
Associatedwithcerebraledema
Liquifactivenecrosiswithevolutionto
cavitationandcystformation
Radiologicallycorrespondstoavascular
territory

106
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AcutePCAStroke

Posterior cerebral
artery territory infarcts

May result from emboli

or thrombosis

May also result from

compression of PCA in
increased ICP false
localizing finding!

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 4/15/2016

RemoteCystic
MCAInfarct

Secondarytract
degeneration
withatrophyof
cerebral
peduncleand
medullary
pyramid
6monthsrequired

RemoteCysticPontineInfarct

Image Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

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Wallenburg Infarct
Gross

Image Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

LateralMedullaryInfarct
Wallenburg Infarct

109
 4/15/2016

WallenburgStroke

Image Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

110
 4/15/2016

EmbolicStroke
Embolitendtocausehemorrhagicinfarcts
Processisduetoreestablishmentofbloodflowto
necrotictissue
Septicembolimaycausemicroabscessformation
Mycoticaneurysmmaydevelopinavesselinfected
byasepticembolus
Mycoticaneurysmsaredistal
Berryaneurysmsareproximal

MultipleEmbolicHemorrhagicInfarcts

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Normal Mitral Valve

MCA Embolic Infarct

Marantic Mitral Valve

Pancreatic Carcinoma

SourcesofEmboli
Complicatedatheroscleroticplaques
Cardiacvalves
Hypokineticmyocardium
Atrialmyxoma
Paradoxicalemboli
Fatemboli
Amnioticfluidemboli

112
 4/15/2016

MycoticAneurysm

Vasculitis
Maybepartofasystemicvasculitisormaybe
confinedtoCNS
InflammatoryinfiltrateMUSTinvolvethe
entirethicknessofthevesselwall
transmuralinflammation
Granulomatousvasculitis
Temporalarteritis
IsolatedCNSvasculitis

113
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VasculitidesAreClassifiedPathologicallybytheSizeof
theInvolvedVessels
Capillaries
Arterioles Venules

Arteries Veins

Aorta
Vena cava

Large Vessel Medium Vessel Small Vessel

Vasculitis Vasculitis Vasculitis

114
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Capillaries
Arterioles Venules

Arteries Veins

Aorta
Vena cava

Granulomatous Inflammation
Large Vessel
Giant cell arteritis
Vasculitis Takayasu arteritis

LargeVesselVasculitis
Granulomatousinflammation
Giantcell(temporal)arteritis
Mostcommonvasculitis inolderindividuals
Temporal,ophthalmic&vertebralarteries
Mayinvolveaortaandotherarteries
Tcellattackonunknownvascularwallcomponents
Segmental(longbiopsyneeded!)
Rarebeforeage50
Headache:6090%
Constitutionalsx:fever,weightloss,fatigue
Ophthalamic sx:in30%andisabruptonsetin50%of
those
Jawclaudication
Rx:corticosteroids
AntiTNFrx forcasesnotresponsivetocorticosteroids

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GiantCellArteritis
Temporalarterybiopsy
Sensitivity50%
Contralateralbiopsydoesntaddtosensitivity
Ifvisualsx arealreadypresentyieldis80%
Treatment
Initialdose4060mg/dayprednisone
Ifblindness,highdosepulsemethylprednisolone
1000mg/dayfor35days
Treatfor1monthbeforetaper
Taperat1020%doseevery2weeks
Prolongedtreatmentisusuallyneeded

Images Courtesy of Dr. Paty Cavez-Barrios Houston Methodist Hospital, Houston, TX

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GiantCellArteritis
Outcome
Increasedriskofcardiovasculardeath
17xincreaseinriskofthoracicaorticaneurysm
1in5patientswithGCA
50%ofpatientswhodevelopthoracicaorticaneurysm
havedissectionorrupture
Serialaorticimagingrecommended
Mostremainoncorticosteroidsand60%develop
complicationsofrx
Calcium,vitaminDandantiosteoclastic rx for
osteoporosis

PolymyalgiaRheumatica andGiant
CellArteritis
PMRandCGAareextremesofsamedisease
process
PMR:proximalmusculoskeletalpainand
stiffness
Age>50
ElevatedESR
Otherserologies (RA)negative
Veryresponsivetocorticosteroids
1620%ofPMRprogresstoGCA

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LargeVesselVasculitis
Granulomatousinflammation
Takayasu arteritis(pulselessdisease)
Largevesselsincludingaorticarchandaorticbranches
Pulmonaryarteryinvolvedin50%
Globaldistribution
Age
Age<50years:Takayasu arteritis
Age>50years:Giantcellaortitis
Constitutionalsx:fever,weightloss,fatigue
Largevesselinvolvement
Myocardialinfarcts
Largeischemicstrokes
Rx:corticosteroids
AntiTNFrx forcasesnotresponsivetocorticosteroids
Usuallyprogressesrapidlybutmaybecomequiescentafter
12years

Takayasu arteritis (pulseless

disease)
Large vessels including
aortic arch and aortic
branches
Pulmonary artery
involved in 50%

Age < 50 years:

Takayasu arteritis
Age > 50 years: Giant
cell aortitis

SlideCourtesyoftheSydneyS.Schochet,Jr.M.D.NeuropathologyImageCollection

118
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SlideCourtesyoftheSydneyS.Schochet,Jr.M.D.NeuropathologyImageCollection

Capillaries
Arterioles Venules

Arteries Veins

AortaMedium Vessel
Vena cava
Vasculitis

Immune Complex Anti-endothelial

Mediated Antibodies
Polyarteritis nodosa Kawasaki disease

119
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Primary CNS Angiitis: PCNSA

SlideCourtesyoftheSydneyS.Schochet,Jr.M.D.NeuropathologyImageCollection

MediumVesselVasculitis
Antiendothelialcellantibodies
Kawasakidisease
Leadingcauseofacquiredcardiacdiseasein
infantsandchildren
Age<4yearsin80%
Pathology
Transmuralinflammation:neutrophils,eosinophilsand
mononuclearcells
Fibrinoidnecrosis
Fibrosisandthickeningofvesselwall
Rx:IVIGandaspirin

120
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SmallVesselVasculitis
Immunecomplexvs nonimmunecomplex
Nonimmunecomplex
OftenassociatedwithANCAantibodies
Syndromes
ChrugStrausssyndrome
Eosinophilia+asthma+granulomas
Wegenergranulomatosis
Granulomasbutnoasthma
Microscopicpolyangitis
Nogranulomasorasthma

SmallVesselVasculitis
Immunecomplexvsnonimmunecomplex
Immunecomplexmediated
Syndromes
Systemiclupus
IgAcomplexes:HenochSchonleinpurpura
Cryoglobulinemia
Goodpasturedisease

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SmallVesselVasculitis withImmune
Complexes
Microscopicpolyangitis
Necrotizingvasculitis
Mostlycapillariesbutmayextendtoarteriolesandvenules
Uniformageoflesions(unlikepolyarteritis nodosa)
Skin,mucousmembranes,lungs,brain,heart,GItract,
kidneysandskeletalmuscle
Renalinvolvementin90%
Pulmonaryinvolvementcommon
Mononeuritis multiplexin55%
CNSinvolvementin10%
MPOANCA(myeloperoxidaseantineutrophil
cytoplasmicantibodies)

SmallVesselVasculitis withImmune
Complexes
Wegenergranulomatosis
Necrotizingandgranulomatousvasculitis
Acutenecrotizinggranulomasofupperrespiratory
tract
Lungsandairwayinvolvement
10%35%neurologicalinvolvementPNS>>CNS
PR3ANCAin95%(antiproteinase3ANCA)
Malesunder40years

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PrimaryAngiitisoftheCNS

Calabrese&Malleck 1988
Unexplainedacquiredneurologicaldeficit
Classicalangiographicorhistopathological
evidenceofangiitis intheCNS
Noevidenceofsystemicvasculitis ordisorders
thatmimick vasculitis
Severalvariantshavebeensubsequently
recognized
Rare!(lessthan1%ofallvasculitides)

PCNSA
Confinedtosmallandmediumsizedcerebral
vessels
Classicalformhasgranulomatousvasculitis
GranulomatousCNSangiitis (GCNSA;20%ofall
PCNSA)
Atypicalformdoesnothavegranulomatous
vasculitis (80%ofPCNSA)
Atautopsy,classicalandatypicalfeatures
usuallycoexist

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PCNSAClinical
Middleagedmen
Meanage50
Menx2>women
Subacute insidiousheadache
Encephalopathy
Transientfocalneurologicaldeficit3050%
Fixedfocalneurologicaldeficit20%
Seizures<25%

PCNSA
Laboratorytestingresultsarenonspecific
AbnormalESR,CRPorserologiesindicatea
systemicprocessratherthanPCNSA
Laboratorytestingandothertestsaredirected
primarilyatEXCLUDINGalternativediagnoses

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PCNSA:BrainBiopsy
Limitedbylowsensitivity(36%)
Openwedgebiopsyoftipofnondominanttemporal
cortexandwhitematterwithleptomeninges
Alternativediagnosesisoftenfound(39%)
Lymphoma
MS
Infections
Nodiagnosis(25%)
Completeevaluationforneoplasticandinfectious
causesofvasculopathy required

RCVS:MajorMimicker
Reversiblecerebralvasoconstrictionsyndromes
Oncecalledbenignangiopathy oftheCNS
OutcomeusuallybetterthanPCNSbutnotalways
benign
Vascularnarrowingduetovasospasmnotinflammation
Causes
Migraine
Postpartumangiopathy
Eclampsia
Druginducedarteritis
Pheochromocytoma

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HypertensiveSmallVesselDisease

40900microndiametervessels
Chronichypertensionleadstosmallarteryand
arteriolarstructuralchanges
Atherosclerosis
Fibrinoidnecrosis
Arteriosclerosis
Microaneurysms

Thesevesselshavethickbutweakwalls
Lumenalcompromise lacunarinfarcts
Wallormicroaneurysmrupture hypertensivehemorrhage

HypertensiveSmallVesselDisease

Chronichypertensionleadstosmallarteryand
arteriolarstructuralchanges
Thickenedeosinophilicwalls
Fibrinoidchange:depositionofplasmaproteinswithdegenerationof
smoothmusclecells
Fibrosis:fibroblastsdepositcollagen
Hyalinosis:fibroblastsdepartleavingfeaturelessthickenedwalls
Lipidsareaveryminorcomponentsolipohyalinosisshouldprobably
beabandoned

Thesevesselshavethickbutweakwalls
Lumenalcompromise lacunarinfarcts
Wallrupture hypertensivehemorrhage

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WhiteMatterIschemicDisorders
Subacute arterioscleroticleukoencephalopathy
(Binswangersdisease)
Cribriformchange:wideningofperivascularspacearoundsmall
vesselswithmyelinlossandaxonalthinning
Hypertensivechangesinsmallvessels

CADASIL(Cerebralautosomaldominantarteriopathy with
subacute infarctsandleukoencephalopathy)
Notchmutation
Concentricarteriolarfibrosis/hyalinethickeningwithPAS+deposits
GranulardepositsonEM
Changespresentinskin,nerve,andmuscle

CADASIL

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SickleCellDisease

VenousInfarctduetoSuperiorVenousSinusThrombosis

Image Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

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IntraparenchymalHemorrhage

Hypertensivehemorrhage
Amyloidangiopathy
Hemorrhagictumors
Vascularmalformations
Hemorrhagicinfarcts

Intraparenchymal Hypertensive
Hemorrhage

Hypertension
Basalganglia,pons,cerebellum,cerebral
hemispheres(lobar)
Precursorlesionmaybetortuoussmallvessel
dilatationstermedCharcotBouchard
aneurysms thereissomecontroversyabout
theexistenceofthese

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CharcotBuchardMicroaneurysm

Image Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

Basal Ganglionic
Intracerebral Hematoma

Image Courtesy and with Permission of the

Sydney S. Schochet, Jr. Collection

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CerebellarVascularCatastrophes
Treatable!

Cerebellar hemorrhages or
infarcts are neurosurgical
emergencies!

They can be evacuated with

limited morbidity

Sudden onset occipital

headache, vertigo, ataxia,
nausea and vomiting

Image Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

Pontine Hemorrhage

Image Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

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AmyloidAngiopathy
Majorcauseoflobarhemorrhageinelderly
patients
Identifywitheithercongoredorbeta
amyloidimmunohistochemicalstain
MaycoexistwithAlzheimersdisease

AmyloidAngiopathy
Majorcauseoflobarhemorrhageinelderly
patients

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AmyloidAngiopathy

HemorrhageInTumors
Hemorrhagicmetastases
Renalcell
Melanoma
Choriocarcinoma
Lungcarcinoma
Hemorrhagicprimarytumors
Glioblastomamultiforme
Oligodendroglioma

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Hemorrhagic metastases:

Renal, Melanoma, Choriocarcinoma and Lung

MultipleHemorrhagicAMLDeposits

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VascularMalformations
Arteriovenous Venous
Malformation Angioma

Cavernous Capillary
Angioma Telangectasia

AVMs

Composedofanastamosedabnormalarteriesand
veins(nointerveningcapillarybed)
Arterialcomponentcontainsinternalelasticlamina
(elasticstain)
Interveningneuropilisgliotic(sometimeswith
Rosenthalfibers)
Hemosiderindepositionandgranularbodies
AVMsgreatestpotentialforsignificanthemorrhage2
4%peryear

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ArteriovenousMalformations
LargeAVMSareoftenwedgeshaped
(triangular)oncoronalsections
Broadestportiononcorticalsurface,tapering
towardtheventricle
Smallerlesionsmaybespherical,superficial
corticalorelsewhere

Image courtesy of Dr. S. Powell

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Images Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

SpinalDuralAVM
FoixAlajouanineSyndrome(necrotizing
myelopathy)
Progressiveparesisandultimatelyparalysisof
thelowerextremitiessecondarytoAVM
Producesengorgedandtortuousspinalveins
andprogressiveischemiccordnecrosis

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CavernousAngioma (Cavernous
Hemangioma orCavernoma)

Clusterofvascularchannelswithhyalinized
walls
Varyingcaliber
Maycontainfibrinthrombi
Nointerveningneuropil
Noarterialcomponent
PopcornappearanceonMRwith
hemosiderindeposition
CCM1:krit mutation

CavernousAngioma

Images Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

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Cavernous Angioma Interface with Brain

Cavernous angioma core

hyalinized vascular channels
without intervening neuropil

Cavernous angioma rim

Hemosiderin laden
macrophages

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Cavernous angioma core hyalinized vascular channels

without intervening neuropil

Cavernous angioma rim

Hemosiderin laden
macrophages

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CapillaryTelangectasia
Smalllesions
Oftenincidentalinpons
Littletendencyforhemorrhage
Capillarysizedvesselswithnormal
interveningparenchyma

VenousAngioma
Clusterofvenouschannels
Verythinwalledofvariouscalibers
Interveningnormalneuropil
Solitaryenlargedvenouschannel=varix

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VeinofGalenAneurysm
ActuallyanAVM
Symptomscorrelatewithageof
presentation
Neonates:cyanosisandhighoutput
heartfailureduetoshunting
Infants:seizures,obstructive
hydrocephalus
SAHinolderchildren
Infarctswithperiventricular
leukomalacia

Image Courtesy of Dr. Suzanne Z. Powell Houston Methodist Hospital

Berry(Saccular)Aneurysms

Presentwithworstheadacheoftheirlives
Radiologic/angiographicdetection
Maybeincidentalfindingatautopsy
Mostcommoncomplicationisspontaneousrupture
butmaypresentwithcompressionofadjacent
structures
Hemorrhagemaybemassiveandfatal;whenfatal
ruptureusuallyhasbeenintoventricularspace
45%ofpatientsdiewithin8weeksofrupture

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SubarachnoidHemorrhage
Saccularaneurysmsites:
Anterior(internalcarotid)circulation90%
Junctionofanteriorcerebralandanteriorcommunicating
arteries
Junctionofposteriorcerebral/posteriorcommunicating
arteries
TrifurcationofmiddlecerebralarteryinSylvianfissue
Aneurysmsarenotsimpleballoons thereis
complexpartiallygeneticallydetermined
remodelingofvascularwall

SubarachnoidHemorrhage
Wallofaneurysm composedonlyofadventitiaand
intimanoMEDIA (justlikeatthebifurcationpoints
wheretheaneurysmsarise!)
Cerebralinfarctsafterruptureofberryaneurysms
mayoccursecondarytoarterialvasospasmcaused
bybloodproducts(maximalriskat7dayspost
hemorrhage)

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Most saccular or berry aneurysms Mycotic aneurysms are also on

are on the anterior circulation the anterior circulation
15-20% may be multiple but they are distal
They are proximal Bacterial or fungal

Saccular Aneurysm:MiddleCerebral

Image Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

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TipofBasilarArteryAneurysm

Image Courtesy and with Permission of the Sydney S. Schochet, Jr. Collection

Giant Aneurysm
25 mm or greater

Critical diameter
For rupture 7-8 mm

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ICA Aneurysm
may extend into
sellar region

Add this to your

list
of sellar
masses

Best not to
biopsy!

35 year old with sudden onset of the worst headache in her life

Coiled but neck

ruptured

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Intracavernous ICA Aneurysm Rupture:

Cavernous AV Fistula

SubarachnoidHemorrhage

1030%ofpatientswithadultpolycystic
kidneydisease haveberryaneurysms
Berryaneurysmsareassociatedwith
fibromusculardysplasia,coarctationofthe
aorta,moyamoyadisease

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AneurysmTypes

Saccular(Berry,Congenital)
Fusiform(Atherosclerotic;
Dolichoectasia)
Dissecting
Mycotic

Fusiform(Atherosclerotic)Aneurysms

5thdecade
Maycausepressuresymptoms,particularly
whenthebasilararteryisinvolved
Maybeasymptomatic

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