Last updated: 3/4/2021 Prepared by Kurt Schaberg

Central Nervous System Tumors

General ~1% of tumors in adults, but ~25% of malignancies in children (only 2 nd to leukemia).
Significant increase in incidence in primary brain tumors in elderly.
Metastases to the brain far outnumber primary CNS tumors→ multiple cerebral tumors.
One can develop a very good DDX by just location, age, and imaging.
Differential Diagnosis by clinical information:
Location Pediatric/Young Adult Older Adult
Cerebral/ Ganglioglioma, DNET, PXA, Glioblastoma Multiforme (GBM)
Supratentorial Ependymoma, AT/RT Infiltrating Astrocytoma (grades II-III),
CNS Embryonal Neoplasms Oligodendroglioma, Metastases, Lymphoma,
Infection
Cerebellar/ PA, Medulloblastoma, Ependymoma, Metastases, Hemangioblastoma,
Infratentorial/ Choroid plexus papilloma, AT/RT Choroid plexus papilloma, Subependymoma
Fourth ventricle
Brainstem PA, DMG Astrocytoma, Glioblastoma, DMG, Metastases

Spinal cord Ependymoma, PA, DMG, MPE, Drop Ependymoma, Astrocytoma, DMG, MPE (filum),
(intramedullary) metastases Paraganglioma (filum),
Spinal cord Meningioma, Schwannoma, Schwannoma, Meningioma,
(extramedullary) Metastases, Melanocytoma/melanoma Melanocytoma/melanoma, MPNST
Spinal cord Bone tumor, Meningioma, Abscess, Herniated disk, Lymphoma, Abscess,
(extradural) Vascular malformation, Metastases,
Extra-axial/Dural/ Leukemia/lymphoma, Ewing Sarcoma, Meningioma, SFT, Metastases, Lymphoma,
Leptomeningeal Rhabdomyosarcoma, Disseminated
medulloblastoma, DLGNT,
Sellar/infundibular Pituitary adenoma, Pituitary adenoma, Craniopharyngioma, Rathke
Craniopharyngioma, Rathke cleft cyst, cleft cyst, Pituicytoma, Meningioma,
Pituicytoma, LCH, Germ cell tumors Metastases, Chordoma
Suprasellar/ Germ cell tumors, Craniopharyngioma, Colloid cyst, Craniopharyngioma, Chordoid
Hypothalamic/ PA/optic glioma, LCH glioma,
Optic pathway/
Third ventricle
Pineal Germ cell tumors, Pineocytoma, Pineocytoma, Pineal cyst, PPTID
Pineoblastoma, Pineal cyst,
Thalamus PA, DMG, DMG, GBM, Lymphoma,
Lateral ventricle Central neurocytoma, SEGA, Choroid Central neurocytoma, SEGA, Choroid plexus
plexus papilloma/carcinoma, papilloma, Subependymoma, meningioma
meningioma
Nerve root/ Neurofibroma, Schwannoma, MPNST, Neurofibroma, Schwannoma, MPNST,
Paraspinal Lymphoma, Meningioma
Cerebellopontine Schwannoma, Choroid plexus Schwannoma, Meningioma, Epidermoid cyst,
angle papilloma, AT/RT Choroid plexus papilloma, Endolymphatic sac
tumor
Modified from: Practical Surgical Neuropathology: A Diagnostic Approach. Second Edition. 2018.
 Common Abbreviations
PA→ Pilocytic Astrocytoma MPNST → Malignant Peripheral Nerve Sheath Tumor
PXA→ Pleomorphic Xanthoastroctyoma SFT → Solitary Fibrous Tumor
DNET→ Dysembryoplastic Neuroepithelial Tumor LCH → Langerhans Cell Histiocytosis
GBM→ Glioblastoma (Multiforme) PPTID → Pineal Parenchymal Tumor of Intermediate
AT/RT→ Atypical Teratoid/Rhabdoid Tumor Differentiation
DMG → Diffuse Midline Glioma (H3 K27M mutant) DLGNT→ Diffuse Leptomeningeal Glioneuronal
SEGA → Subependymal Giant Cell Astrocytoma Tumor
MPE → Myxopapillary Ependymoma
DIPG → Diffuse Intrinsic Pontine Glioma

Classic Locations/Correlations
Imaging findings:
Metastases→ Multiple enhancing/rim-enhancing nodules at grey-white junctions in cerebrum
Lymphoma→ Periventricular enhancing lesion
Glioblastoma Multiforme→ Rim enhancing, “Butterfly” mass
Myxopapillary ependymoma→ Filium terminale mass
Meningioma→ Dural lesion with a “dural tail” (enhancing)
Pilocytic astrocytoma→ Circumscribed, cystic brain mass in the cerebellum of a child
Ganglioglioma→ Child with epilepsy and a temporal lobe cystic mass

Classic clinical associations:

Metastases→ Common sites of origin: lung, breast, and kidney
→ Strong prediction: melanoma and choriocarcinoma

A Note on Grading
Grade is part of a continuum and estimates malignancy/aggressiveness.
Brain tumors are pathologically graded, but not staged (as often not resected en bloc).
With increasingly small biopsies, IHC, molecular, and cytogenetics are now critical for Dx and grading!
Some tumors have inherent grades, while others have criteria for grading often depending on mitoses,
necrosis/microvascular proliferation, and atypia.
Generally:
Grade 1 → Low proliferation potential and possibility of cure after surgical resection alone.
Grade 2 → Usually infiltrative in nature and often recur, despite having low levels of proliferation. Some
may progress to higher levels of malignancy. Often survive >5 years.
Grade 3 → Clear histologic evidence of malignancy, including nuclear atypia and sometimes brisk mitotic
activity. Patients with these tumors often receive chemotherapy and/or radiation. Often survive 2-3 years.
Grade 4 → Cytologically malignant, mitotically active, necrosis-prone neoplasms that are often associated
with rapid progression and fatal outcome. Includes GBM (survival < 1 year) and most embryonal
neoplasms (survival depends on treatment and can be long).
Gliomas Tumors derived from glial cells that support for neurons in the CNS, including astrocytes
(form blood-bran barrier) and oligodendrocytes (coat axons forming myelin sheath).
General Most common primary tumors of CNS parenchyma.
Diffuse gliomas (“infiltrative gliomas,” including astrocytomas) → widely invasive into brain parenchyma
→ often not resectable→ often naturally progress to higher grade lesions→ often resistant to therapy.
Other astrocytomas (like pilocytic astrocytoma, PXA, and SEGA) are better circumscribed and have
different molecular pathways.

Diffuse Glioma Molecular Pathways IDHwt

m = mutant
wt = wildtype
EGFR-amp
IDHm
TERTm
TP53m Glioblastoma,
ATRXm Preneoplastic Glial Cell
IDHwt, grade 4
1p19q-codel
Diffuse astrocytoma, IDHm
IDHm, grade 2 TERTm
Diffuse midline glioma,
Oligodendroglioma, H3 K27M, grade 4
grade 2
Diffuse astrocytoma,
9p (CDKN2A/B) LOH
IDHm, grade 3 Diffuse hemispheric glioma,
9p (CDKN2A/B) LOH
H3 G34-m, grade 4
Anaplastic
Diffuse astrocytoma/ Oligodendroglioma, Modified from a talk by Dr. Arie Perry,

Glioblastoma grade 3 University of California, San Francisco

IDHm, grade 4

Is this tumor Glial?

As opposed to metastases, and other non-glial
tumors, glial tumors often have:
Fibrillary processes (→), often also naked nuclei.
Best appreciated on cytology like squash prep.
Infiltrative growth into brain parenchyma with
intra tumoral axons (neurofilament +; primarily
seen with astrocytomas and oligodendroglioma).
(vs non-glial tumors, which are usually well-
demarcated)
Secondary structures, such as perineuronal
satellitosis, subpial density, perivascular
collections.
Eosinophilic cytoplasm with nuclear
hyperchromasia/pleomorphism
IHC: GFAP and/or OLIG2 positive (Warning: broad
spectrum cytokeratins may stain glial filaments
as they are both intermediate filaments!).
Are these glial cells neoplastic? (or is it a mimic?!!)
Gliosis = reactive changes of glial cells in response to injury. Includes both proliferation and hypertrophy.
This can histologically mimic a tumor and pose a diagnostic dilemma, especially intraoperatively.
This is particularly troublesome as gliosis can be found adjacent to tumors or as part of reactive process
that can mimic tumors radiographically.
Early reactive astrocytosis→ hypertrophy with enlarged cytoplasm/processes and open chromatin with
prominent nucleoli (abundant astrocyte cytoplasm is almost always pathologic!)
Longer term reactive astrocytosis → astrocytes become gemistocytic (large amounts of brightly
eosinophilic eccentric cytoplasm) Warning: some tumors can appear gemistocytic too!!
Chronic reactive astrocytosis → often seen around slow-growing lesions → more fibrillar with long
astrocytic processes and Rosenthal fibers → “piloid gliosis”

Gliosis Diffuse Astrocytoma

Gliosis Glioma
Euchromatic, round/ovoid nuclei Large, hyperchromatic, irregular (astrocytoma) to
round nuclei (oligodendroglioma)
Evenly spaced astrocytes Clustering of astrocytes, Hypercellular, Satellitosis
Abundant eosinophilic cytoplasm “Naked” nuclei
Astrocytes with variable atypia Uniform atypia
No mitotic activity Possible mitoses
Radially oriented fibrillary processes Necrosis and/or microvascular proliferation
(usually in high grades)
Can BOTH:
Other bechanges,
reactive cellular, have Rosenthal
such as fibers,
inflammation, Demonstratable mutation (e.g., IDH1, ATRX, etc…)
macrophages, etc…
 Astrocytic Tumors Classic Organization/Grading See more discussion
later for evolving/new
WHO Tumor Histologic criteria Prognosis changes!
Grade
I Pilocytic astrocytoma Excellent
II Diffuse astrocytoma One: Nuclear atypia >5 years
III Anaplastic astrocytoma Two: Atypia + Mitoses 2-5 years Diffuse
Gliomas
IV Glioblastoma multiforme Three: Above + Vascular 1 year
proliferation and/or Necrosis
Modified from a presentation by Dr. Hannes Vogel, Stanford University Medical Center.

Atypia → Variation in nuclear size and shape with hyperchromasia

Mitoses → Must be unequivocal. No strict cut-offs, but a single mitotic figure in a large specimen is
insufficient to upgrade to Grade III.
Microvascular proliferation → Apparent multilayering of endothelium or glomeruloid microvasculature.
Necrosis → Can be any type (does not need to be pseudopalisading).
Order of appearance: Atypia→ Mitoses→ Increased cellularity→ Necrosis and/or microvascular proliferation

Diffuse Astrocytoma WHO grade II

aka “Diffuse astrocytoma, IDH-mutant”
A diffusely infiltrating astrocytoma with a mutation
in either the IDH1 or IDH2 gene (in adults).
NO CDKN2A/B homozygous deletions
Most common in young adults (mid-30s), most
commonly in frontal lobes (but can get anywhere in
CNS). Commonly present with seizures.
Well-differentiated fibrillary astrocytes.
Cellularity is moderately increased.
Moderate nuclear atypia.
Often loose microcystic background.
Mitotic activity is generally absent (A single mitotic
figure in a large specimen is acceptable, but not a Bx)
Molecular/IHC: IDH1 or IDH2 mutations
Most common mutation (~90%) is IDH1 R132H
→ can detect with mutation-specific IHC
ATRX mutation → loss of ATRX IHC staining
TP53 mutation→ strong nuclear p53 IHC staining
Ki67 usually <4%. Express GFAP.
Slow growth. Survival >5yrs (now often >10 yrs!).
Intrinsic capacity for malignant progression → Pediatric Diffuse Astrocytoma: Same histology.
Anaplastic astrocytoma → GBM. Much less common. Most common in cerebrum,
but also thalamus. Rare progression. MYB and
Gemistocytic Astrocytoma: A variant of IDH-mutated
BRAF alterations. ABSENT IDH1&2, ATRX,
astrocytoma with prominent gemistocytic neoplastic
mutations!
astrocytes (>20%). Historically thought to progress
faster, but may not be true.
Anaplastic Astrocytoma
WHO grade III
Diffusely infiltrating astrocytoma with focal or
diffuse anaplasia, significant proliferative activity,
and a mutation in either IDH1 or IDH2.
NO CDKN2A/B homozygous deletions
Can arise from grade II diffuse astrocytoma, but
most of the time no precursor lesion is identified.
Most commonly in the cerebrum (although can
get anywhere in CNS) of young adults (often 30s).
Similar appearance to diffuse astrocytoma, often
with more nuclear atypia and higher cellularity.
→ Increased pleomorphism, coarse chromatin,
prominent nucleoli, multinucleation, atypical
mitoses.
Increased mitotic activity→ must evaluate in
context of sample size. A single mitotic figure on a
biopsy is enough. In resections, need to see
“significant” mitotic activity (often ≥2). Molecular/IHC: IDH1 or IDH2 mutations
By definition: NO necrosis and NO microvascular Most common mutation (~90%) is IDH1 R132H
proliferation (otherwise would be a GBM!) → can detect with mutation-specific IHC
ATRX mutation → loss of ATRX IHC staining
Intrinsic tendency to progress to GBM. TP53 mutation→ strong nuclear p53 IHC staining
Historic survival: 3-5 years (but is increasing!) Ki67 usually 5-10%. Express GFAP.

Glioblastoma WHO grade IV Old name: Glioblastoma Multiforme (GBM)

A high-grade glioma with predominantly astrocytic differentiation with nuclear atypia, mitotic activity,
AND microvascular proliferation, and/or necrosis. Often diffuse growth.
Most common malignant primary brain tumor in adults.
Often diffusely infiltrates adjacent and distant brain structures.
On imaging→ irregularly shaped with ring-shaped enhancement around central dark necrosis.
→ Can grow along corpus callosum into other hemisphere→ “butterfly glioma”
Often present with seizure or neurological deficits.

There are two major molecular pathways with dramatically different prognoses:
IDH-wildtype (primary) → much more common → old patients with no precursor → TERT promoter
mutations→ rapid progression and death, often within 1 year.
IDH-mutant (secondary) → less common → younger patients with precursor astrocytoma →9p
(CDKN2A/B) deletions → slower progression → prolonged survival, up to several years.
To distinguish between the two, perform IHC for IDH1 R132H first, if positive→ IDH-mutant. If negative→
proceed to IDH1&2 sequencing to exclude other mutation. However, this may be unnecessary in older
patients with classic histology.
 Glioblastoma (continued) Palisading necrosis
Variable histology (hence “multiforme”):
Highly cellular with poorly differentiated, sometimes
very pleomorphic tumor cells.
Brisk mitotic activity.
Either necrosis or microvascular proliferation.
→ glomeruloid tufts of multilayered mitotically
active endothelium with smooth muscle and
pericytes. Often near necrosis.
Often regional heterogeneity.
Tumor cells will often migrate/invade around existing
structures, e.g., around neurons (satellitosis), in
subpial zone, etc..
Specific morphologic patterns:
-Small cell glioblastoma Microvascular proliferation
-Glioblastoma with a primitive neuronal component
-Gemistocytic glioblastoma
-Lipidized glioblastoma
-Granular cell glioblastoma
-Adenoid glioblastoma
IHC: Typically (+) GFAP, S100, OLIG2
Ki67 typically ~15-20%, but can be much more
Can grow into multiple lobes/hemispheres →
“gliomatosis cerebri”
Metastases are very uncommon.

IDH-wildtype Glioblastoma IDH-mutant Glioblastoma

(Astrocytoma, IDH-mutant, grade 4)
Synonym Primary glioblastoma Secondary glioblastoma
Precursor lesion None Anaplastic astrocytoma
Proportion of GBMs ~90% ~10%
Mean age at Dx ~60 years ~45 years
Mean length of clinical Hx 4 months (short) 15 months (long)
Survival with treatment < 1 year (short) 2 years (long)
Location Supratentorial Frontal lobe specifically
Necrosis Extensive Limited
TERT promoter mutations 70% 25%
ATRX mutations Rare 70%
EGFR amplifications 35% Rare
PTEN mutations 25% Rare
MGMT promoter methylation status predicts response to alkylating chemotherapy agents

Modified from: WHO Classification of Tumors of the Central Nervous System. 4th Edition. 2016.
 Epithelioid Glioblastoma
High-grade diffuse astrocytic tumor with a dominant
population of closely packed epithelioid cells, some
rhabdoid cells, mitotic activity, microvascular proliferation,
and necrosis.
Predominantly in young adults and children.
IHC/Molecular: (+)GFAP, S100, Vimentin
Frequent expression of CK AE1/AE3 or EMA
Frequent BRAF V600E mutations
IDH-wildtype

Aggressive with short survival (~6 months).

Giant Cell Glioblastoma

Rare variant of IDH-wildtype glioblastoma.
Bizarre, multinucleated giant cells.
Occasionally abundant reticulin network.
Often more circumscribed→ Somewhat
better prognosis
High rate of TP53 mutations (rare EGFR
amplifications)

Consider PXA in differential diagnosis

Gliosarcoma Reticulin
Variant of IDH-wild-type glioblastoma with
biphasic growth displaying glial and
mesenchymal differentiation
→ analogous to epithelial-to-mesenchymal
transition in carcinomas
Sarcomatous component often has a spindle
cell pattern with densely packed long bundles
of spindle cells with abundant reticulin
framework. Also mitoses, necrosis, and atypia.
IHC: Sarcoma component often lacks GFAP

Can have heterologous differentiation (e.g,

cartilage, rhabdomyoblasts, etc…).

Similar prognosis and clinical characteristics

to IDH-wildtype glioblastoma
New Molecular Grading Changes
Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV
Genetic changes that indicate an IDH-wild type astrocytoma will behave aggressively and should be
graded as Glioblastoma, grade IV (even if traditional morphologic findings of glioblastoma aren’t
present): 1)EGFR amplification, or 2) Combined whole chromosome 7 gain and whole chromosome 10
loss (+ 7/− 10), or 3) TERT promoter mutation

Astrocytoma, IDH-mutant, WHO grade IV

Given that IDH-mutant glioblastomas have a better prognosis that IDH-wildtype glioblastomas, there is a
shift to now classify them as grade 4 “astrocytomas” instead. For IDH-mutant tumors, CDKN2A/B
homozygous deletion can also count similar to necrosis and microvascular proliferation for upgrading.

Figures from: Louis DN, et al. cIMPACT-NOW update 6: new entity and
diagnostic principle recommendations of the cIMPACT-Utrecht
meeting on future CNS tumor classification and grading. Brain Pathol.
2020 Jul;30(4):844-856.

Diffuse Glioma, H3.3 G34-mutant WHO grade IV

A diffuse glioma of the cerebral hemispheres with a
missense mutation exchanging glycine for arginine or
valine at position 34 of the mature histone H3.3
protein. IDH-wildtype.
Pediatric and young adult patients.
Cerebral hemispheres.
Diffusely infiltrating atypical astrocytes with features of
anaplasia, including mitotic activity, microvascular
proliferation and/or necrosis.
Sometimes may resemble Embryonal tumor (high N:C
ratio)
Molecular/IHC: (+) H3.3 G34-mutant specific IHC,
p53 overexpression. Loss of ATRX.
(-) IDH, OLIG2.
Poor prognosis.
Diffuse Midline Glioma, H3 K27M-mutant WHO grade IV
Older name: Diffuse Intrinsic Pontine Glioma (DIPG)
An infiltrative high-grade midline glioma with predominantly
astrocytic differentiation and a K27M mutation in the histone
coding genes H3F3A or HIST1H3B/C.
Predominates in children, but can see in adults.
Common locations: Brainstem/Pons, Thalamus, spinal cord.
Tumor cells usually small and monomorphic,
sometimes can be pleomorphic
Diffusely infiltrates adjacent and distant brain structures.
Mitotic activity is often present.
Necrosis and microvascular proliferation may be present, but are
not necessary for Dx.
IHC: (+) S100, OLIG2; (+/-) GFAP, MAP2
(+) Mutation-specific antibody for H3 K27M
Poor prognosis (<2 years)

Subependymal Giant Cell Astrocytoma (SEGA) WHO grade I

Benign, slow-growing tumor
Well-circumscribed. Often calcifications
Composed of large, plump gemistocytic astrocytes
with abundant pink glassy cytoplasm.
Arranged in fascicles, sheets, and nests.
Some areas may have smaller, spindled cells.
Frequently giant ganglion-like cells with prominent
nucleoli. Considerable nuclear pleomorphism.
Typically arises in the wall of the lateral ventricles.
Usually present before age 20, often with seizures.

Very strong association with Tuberous sclerosis.

→ One of the major diagnostic criteria

Good prognosis with totally resected.

Pilocytic astrocytoma (“PA”) Rosenthal Fibers
WHO grade I
An astrocytoma with a biphasic pattern with varying
proportions of 1) compact bipolar cells with Rosenthal
fibers and 2) loose, textured multipolar cells with
microcysts and eosinophilic granular bodies.
Nuclei typically elongate and relatively bland,
may be round (Oligo-like)
Still allowed: Rare mitoses, Hyperchromatic
pleomorphic nuclei, microvascular proliferation,
necrosis, and infiltration of meninges
Most common glioma in children and adolescents.
Preferentially infratentorial, located in the cerebellum
and cerebral midline structures (e.g., optic pathways,
brainstem, etc..).
Often present with neurologic deficits.
Generally circumscribed and slow growing.
Sometimes cystic.
Mutations in MAPK pathway, most commonly BRAF
fusion proteins.
Eosinophilic Granular Bodies
Slow-growing, low-grade with favorable prognosis.
Can be cured with surgical excision (if possible).
Optic nerve tumors are a hallmark of NF1.
Rosenthal Fibers
on smear

Pilomyxoid astrocytoma—variant with angiocentric

arrangement of monomorphous, bipolar cells in a
prominent myxoid background. May grow more
rapidly and have worse prognosis. Not currently
graded.
 Pleomorphic Xanthoastrocytoma (“PXA”) WHO grade II
Astrocytic tumor with large, pleomorphic,
and frequently multinucleated spindled and
lipidized cells.
Frequent intranuclear inclusions and
prominent nucleoli.
Dense reticulin network.
Numerous eosinophilic granular bodies.
Often neuronal differentiation.
Low mitotic activity (<5 mitoses/10 HPF)
IHC/Molecular: Frequent BRAF V600E
(No IDH mutations!)
Majority have combo of BRAFV600E
AND CDKN2A/B homozygous deletion
(+) GFAP, S100
(+/-) Neuronal markers (e.g., MAP2), CD34
Ki67 generally <1%.
Relatively rare.
Most common in children and young adults.
Often superficially located in cerebral
hemispheres (esp. temporal lobe) with
involvement of leptomeninges.
Good prognosis with long survival.

Anaplastic Pleomorphic Xanthoastrocytoma WHO grade III

Same as above, but ≥5 mitoses/10 HPF Mitoses
May have necrosis, but not necessary for Dx.

Lower frequency of BRAF V600E mutation.

Significantly worse prognosis than PXA (but still

better than many high-grade gliomas)
 Oligodendrocyte Tumors
Diffusely infiltrating gliomas morphologically resembling oligodendrocytes.
***Defining genetics: IDH1 or IDH2 mutations AND 1p/19q-codeletions.***
→ An unbalanced translocation between chromosomes 1 and 19 results in loss of the der(1;19)
chromosome, causing codeletion of whole arms of 1p and 19q
→ it’s acceptable if some cells show astrocytic differentiation if these genetic changes are present.
→ IDH1 R132H mutations (present in >90%) can be detected by IHC.
1p/19q-codeletions are usually identified by FISH.
→ Frequent TERT promoter mutations. Unlike in astrocytomas, there is no ATRX loss or p53 mutations
Usually adult patients in the cerebral hemispheres (esp. frontal lobe). Rare in children.
Often present with seizures.
IHC: (+)MAP2, S100, SOX10, OLIG2, ; Usually (+) IDH1 R132H, Intact ATRX, wild-type p53.

Oligodendroglioma WHO grade II

Moderately cellular, diffusely infiltrating.
Monomorphic round nuclei with artifactual
perinuclear halos→ “fried egg” or “honeycomb”
appearance (only seen on formalin-fixed sections)
“Salt and pepper” chromatin
Microcalcifications and cystic degeneration common.
Delicate branching capillary network.
Low mitotic activity (rare mitoses acceptable)
Ki67 proliferation index usually < 5%
Prolonged survival→ can be >11 years!
Generally recur. Malignant progression common (but
much slower than astrocytomas).

Anaplastic Oligodendroglioma Mitosis

WHO grade III
Similar to above, but with focal or diffuse histologic
features of anaplasia (usually shows multiple):
- Brisk mitotic activity (often >6 per 10HPF)
- Microvascular proliferation
- Spontaneous necrosis
(Although some of these findings are also seen in
GBM’s, as long as the defining genetic alterations are Microvascular Proliferation
present, you can still make this Dx).
Can sometimes see marked atypia.
Ki67 often >5%
Progression from grade II → grade III takes ~6 years,
so patients often slightly older (middle-aged)
Shorter survival: ~3.5 years
 Ependymal Tumors
Ependymoma WHO grade II or III
Circumscribed glioma, composed of uniform small cells with
round nuclei and speckled chromatin in a fibrillary matrix

Characteristic pseudorosettes (perivascular anucleate zones)

found in practically every case.
True ependymal rosettes (bland cuboidal cells arranged
around a central lumen) found in ~1/3 of cases.
Variable cellularity. Can hyalinize or have “canals.”
Pseudorosettes
Mainly intracranial, can get in spinal cord.
Can occur in both children and adults.
In children→ usually posterior fossa (often 4th ventricle)

Generally low cell density and mitotic index.

Electron microscopy: shows cilia and microvilli.

IHC: (+) EMA (along lumina surface of rosettes or dot-like

perinuclear), GFAP in pseudorosettes, S100.
Variable outcome depending on resection, therapy, and
molecular group.

True rosettes

Current recommendation is to classify based on Location (e.g., “Supratentorial ependymoma”) and

molecular changes (see below). If there are no molecular changes, say “Not Elsewhere Classified” (NEC).
If can’t do molecular testing, say “Not Otherwise Specified” (NOS)
Can grade as 2 or 3 morphologically (default = 2; brisk mitotic activity and dese cellularity → grade 3)

Morphologic subtypes of ependymoma exist (tanycytic, clear cell, papillary), but do not impact prognosis.
Subependymoma and myxopapillary ependymoma are identified morphologically.

Unique Molecular Subgroups by Location:

Location Molecular Subgroup Age Prognosis Comments

YAP1-fusion Infants and kids Good

Supratentorial
(ST) RELA-fusion Infants to adults Poor IHC: Positive for cyclinD1
(c11orf95) and L1CAM
Methylation group A (PFA) Infants Poor IHC: Loss of H3K27me3
Posterior Fossa
(PF) Methylation group B (PFB) Older children and Good IHC: Retained H3K27me3
adults
Spinal Cord MYCN amplified Older children and Poor Frequent dissemination
(SC) adults
Subependymoma WHO grade I
Slow-growing, exophytic, and intraventricular.
Clusters of mostly bland cells embedded in abundant
fibrillary matrix.
No significant mitotic activity.
Frequent microcystic change. Sometimes calcified.
Rare pseudorosettes.

Often detected incidentally→ often asymptomatic.

All ages. Sharply demarcated grossly.

IHC: (+) GFAP; (-) EMA (unlike ependymoma); Ki67 <1%

Excellent prognosis

Myxopapillary Ependymoma
WHO grade II
Arises almost exclusively in region of conus
medullaris, cauda equina, and filum
terminale.
Elongated to cuboidal cells arranged in
radial patterns around vascularized,
mucoid, fibrovascular cores
Slow-growing.
Typically occurs in young adults.
Stains: Mucin is highlighted by alcian blue
(+) GFAP, S100, CD99, CK AE1/AE3
Thought to have a favorable prognosis, but
sometimes hard to resect with recurrences.
Was previously WHO grade I, but current
data suggests actually grade II.

Anaplastic Ependymoma
WHO grade III
Was a category in the 2016 WHO, but will no longer be
with next edition as WHO grade doesn’t seem to
significantly impact prognosis in ependymomas.

Defined by high cell density and elevated mitotic count.

Also may see widespread microvascular proliferation and
necrosis.
 Other Gliomas
Chordoid Glioma (of the Third Ventricle)
WHO grade II
Slow-growing, non-invasive, glial tumor. Very rare.
Located in 3rd ventricle → obstructive hydrocephalus
Clusters and cords of epithelioid tumor cells within
variably mucinous stroma.
Typically has associated lymphoplasmacytic infiltrate.
IHC: (+) GFAP (strong, diffuse), TTF-1, CD34; (+/-) S100, CK
Usually Adults.
Good prognosis if resected.

Angiocentric Glioma WHO grade I

Stable or slow-growing. Well-circumscribed.

Primarily impacts children and young adults.

Presents with epilepsy.
Superficial cerebrocortical location.
Angiocentric growth pattern.
Monomorphous bipolar cells, oriented around
cortical blood vessels.
Can resemble pseudorosettes of ependymomas.
Other areas can resemble schwannoma with
fibrillary areas.
IHC: (+) GFAP, EMA (like ependymoma)
Molecular: MYB fusions (usually MYB-QKI)
Excellent prognosis→ usually cured by excision

Astroblastoma
Rare. Mainly children and adolescents.
Well-demarcated. Within cerebral hemispheres.
Cells with broad processes radiating towards central
blood vessels (astroblastic pseudorosettes).
Frequent vascular hyalinization.
IHC: (+) GFAP, S100
Molecular: Commonly with MN1-alterations
Biologic behavior varies→ not currently graded.
 Choroid Plexus Tumors Derived from choroid plexus epithelium; Found in Ventricles.
IHC: (+) KIR7.1, CK AE1/AE3, Vimentin, CK7. (+/-) S100. (-) EMA,
Choroid Plexus Papilloma
WHO grade I
Benign ventricular papillary neoplasm.
Most common in lateral ventricle
~2/3 of choroid plexus tumors.
All ages, but more common in kids.
Can present with hydrocephalus.
Delicate fibrovascular fronds covered by a
single layer of cuboidal to columnar
epithelium.
Round to oval, basal, monomorphic nuclei.
Very low/absent mitotic activity (<2/10 HPF)
Ki67 usually <2%
Patients usually cured by surgical resection.

Atypical Choroid Plexus Papilloma WHO grade II

A choroid plexus papilloma that has increased
mitotic activity (≥2 mitoses/10 HPF), but does
not fulfill the criteria of choroid plexus carcinoma.
Often present, but not required: increased
cellularity, nuclear pleomorphism, solid growth,
necrosis.
More likely to recur, but still relatively good
prognosis.

Choroid Plexus Carcinoma WHO grade III

Frankly malignant epithelial neoplasm.
Most commonly in the lateral ventricles of children
At least 4 of the following:
1) Frequent mitoses (>5/10 HPF)
2) Increased cellular density
3) Nuclear pleomorphism
4) Blurring of the papillary pattern with poorly-
formed sheets of tumor cells
5) Necrosis

Frequently invades neighboring brain and

metastasizes via CSF.
Ki67 often >10%
~1/2 have TP53 mutations
Intermediate prognosis/survival
 Neuronal and Mixed Neuronal-Glial Tumors
Dysembryoplastic Neuroepithelial Tumor (“DNET”) WHO grade I
Benign glioneuronal neoplasm.
Usually Children or young adults.
Typically temporal lobe. Often cortical.
Present with early onset epilepsy.
Columns of small round monotonous cells
(oligodendroglioma-like) oriented perpendicular
to the cortical surface formed by axon bundles.
Normal neurons “floating” in mucin pools (→).
Multinodular architecture.
May be associated with cortical dysplasia.
Molecular: Presence of an IDH mutation or
Codeletion of 1p/19q excludes this Dx.
Excellent outcomes

Ganglioglioma WHO grade I

Well-differentiated, slow-growing.
Often in the temporal lobe of young children.
Intracortical, circumscribed, and cystic
Frequently present with early-onset focal epilepsy.
Dysplastic ganglion cells (dysmorphic neuronal
features, without the architectural arrangement or
cytological characteristics of cortical neurons) with
neoplastic glial cells (may resemble astrocytoma,
oligodendroglioma, or pilocytic astrocytoma)
Can be heterogenous within tumor.
Molecular/IHC: BRAF V600E mutation in about ¼
Presence of an IDH mutation or Codeletion of
1p/19q excludes this Dx.
If increased cellularity, pleomorphism, mitotic figures, microvascular proliferation,
Excellent outcomes
and/or necrosis within glial component, consider “Anaplastic Ganglioglioma”
(WHO grade III). Uncertain outcomes.

Gangliocytoma WHO grade I

Rare. Slow-growing. Usually Children with epilepsy
Composed of irregular clusters of mature neoplastic ganglion cells, often
with dysplastic features. Stroma of non-neoplastic glial elements.
May be hard to distinguish from Ganglioglioma in some cases (spectrum).
Dysplastic cerebellar g_angliocytoma (Lhermitte-Duclos Disease)—Rare, benign, cerebellar tumor.
Dysplastic ganglion cells that conform to existing cortical architecture. Major manifestation of Cowden’s
Syndrome (PTEN hamartoma syndrome).
 Papillary Glioneuronal Tumor
2
WHO grade I
Low-grade biphasic neoplasm with:
1) Prominent pseudopapillary architecture with 1
a cuboidal glial cells with round nuclear and
scant cytoplasm around hyalinized blood vessels.
2) Intervening collections of neurocytes with
medium-sized ganglion cells with neuropil.
Can be have fibrillary or microcystic background.
Often in the cerebral hemispheres near the 2
ventricles. 1
Often young adults. Circumscribed.
Molecular: Frequent SLC44A1-PRKCA fusions
Good prognosis.

Desmoplastic Infantile Astrocytoma (DIA) and Ganglioglioma (DIG)

WHO grade I
Rare neoplasms of early childhood.
Always supratentorial. Often large and cystic.
Leptomeningeal component.
Prominent desmoplastic stroma with a
neuroepithelial population of astrocytes (DIA)
possibly with a mature neuronal component
(DIG).
Abundant connective tissue→ Prominent
reticulin → may mimic a mesenchymal tumor!
Good prognosis.

Rosette-forming Glioneuronal Tumor WHO grade I

Two distinct components:
1) Uniform neurocytes forming rosettes
and/or perivascular pseudorosettes
2) An astrocytic component resembling a
pilocytic astrocytoma

Slow-growing. Relatively well-circumscribed.

Most common in the 4th ventricle.
Typically children or young adults.

Molecular: PIK3CA and FGFR1 mutations

Relatively good prognosis.

 Diffuse Leptomeningeal Glioneuronal Tumor
Rare. Usually young children. Spine or Intracranial.
Predominant and Widespread leptomeningeal growth.
Oligodendroglioma-like morphology,
Neuronal differentiation in a subset of cases.
Usually low-grade appearing. Occasional anaplasia.

Molecular: Frequent KIAA1549-BRAF fusions and either

1p deletion or 1p/19q codeletion in the absence of an
IDH mutation.
Not currently graded (too rare).
Slow progression over many years.

Central Neurocytoma
WHO grade II
Uncommon. Intraventricular, often lateral.
Usually young adults.
Uniform round cells with speckled chromatin
and a neuronal immunophenotype
(+Synaptophysin, - GFAP)
Fibrillary areas may mimic neuropil or
ependymal pseudorosettes.
Favorable prognosis.

Extraventricular Neurocytoma
WHO grade II
Present throughout CNS, often cerebrum,
without ventricular association.
Well-circumscribed. Slow-growing.
Histologically similar to central neurocytoma,
but more varied in appearance.
Wide age range, often middle-age.
Must rule out a diffuse glioma→ make sure no
IDH mutations.
Favorable prognosis.

Other
Cerebellar Liponeurocytoma (WHO grade II)—a rare cerebellar tumor with a mixture of small neurocytic
cells with regular round nuclei and focal lipoma-like changes (just lipid in tumor cells, not actual
adipocytes). Adults. Favorable prognosis.
Paraganglioma (WHO grade I)—like elsewhere, “Zellballen” nests of cells surrounded by a delicate
sustentacular network. Most common in cauda equina and jugulotympanic regions.
 Embryonal Tumors
Medulloblastoma WHO grade IV
Most common malignant brain tumor of childhood.
Arise in cerebellum or dorsal brainstem.
Block CSF flow→ increased ICP→ short history of
headaches, nausea, ataxia.
Propensity to spread through CSF.

Embryonal neuroepithelial tumor consisting of

densely packed small round undifferentiated cells.
High N:C ratios. Variable rosettes (Homer-Wright)
Usually mild to moderate pleomorphism.
High mitotic rate.

IHC: Diffuse synaptophysin. Focal NeuN

Currently, can be classified by molecular or histologic

findings (or, ideally, both!).

Commonly altered pathways:

SHH Pathway = “Sonic Hedge Hog”
WNT Pathway—often through CTNNB1 (β-catenin )

WNT-activated SHH-activated Non-WNT/Non-SHH

TP53-Wildtype TP53-Mutant Group 3 Group 4
Age Childhood Infancy or Adult Childhood Infancy/ All
Childhood
Proportion ~10% ~20% ~10% ~20% ~40%

Usual Classic Desmoplastic/ Large cell/ Classic, Large Classic

Histology Nodular Anaplastic cell/Anaplastic
Genetic CTNNB1 PTCH1 TP53 mutation MYC KDM6A, SNCAIP
Changes mutations mutation/loss amplification among others
PVT1-MYC
Monosomy 6 fusions often
Prognosis Excellent Low-risk Poor High-risk Standard
(Standard if classic (Standard if
histology) classic histology)
β-catenin Nuclear + Cytoplasmic Cytoplasmic Cytoplasmic Cytoplasmic
Immunohistochemistry

(WNT pathway)
Cytoplasmic
GAB1 Negative Cytoplasmic Cytoplasmic Negative Negative

FilaminA Cytoplasmic Cytoplasmic Cytoplasmic Negative Negative

YAP1 Nuclear + Nuclear + Nuclear + Negative Negative

Cytoplasmic Cytoplasmic Cytoplasmic
Medulloblastoma Histologic Subtypes: Desmoplastic Nodular
Classic—see prior page (lack features below). Most
common histology.
Desmoplastic/Nodular—nodular reticulin-free zones
(“pale islands”) with intervening densely packed, poorly
differentiated cells that produce an intercellular
network of reticulin fibers.
Significant overlap. Both SHH-pathway, TP53-wt.
Good prognosis. Often considered together.
Extensive Nodularity—many, large, reticulin-free
nodules of neurocytic cells against a neuropil-like Extensive nodularity
matrix. Narrow internodular strands.
Anaplastic—marked nuclear pleomorphism with
particularly numerous mitoses and apoptoses. Frequent
nuclear molding and cell wrapping.
Significant overlap. Often group 3 or SHH, TP53-
mutant. High risk. Often considered together.
Large Cell—Large, monomorphic cells with prominent
nucleoli.

Anaplastic Large Cell

Embryonal Tumor with Multilayered Rosettes, C19MC-altered

WHO grade IV
Includes previous entities of: Medulloepithelioma,
Ependymoblastoma, and Embryonal tumor with
abundant neuropil and true rosettes.
Defining molecular alteration: C19MC (microRNA)
upregulation via amplifications and fusions
Variable morphology, often including:
Multilayered rosettes consisting of pseudostratified
neuroepithelium with a central, round or slit-like lumen.
Numerous mitotic figures.
Fibrillary neuropil-like areas.
Often young children. Most often cerebral.
Aggressive course.
Atypical Teratoid/Rhabdoid Tumor (“AT/RT”) WHO grade IV
Most often in young children. Variable location.
Rhabdoid cells with eccentric nuclei with vesicular
chromatin and prominent nucleoli.
Abundant eosinophilic cytoplasm.
Abundant mitoses. Geographic necrosis.
Most tumors contain other poorly-differentiated
elements with neuroectodermal, epithelial, and/or
mesenchymal differentiation, including a small cell
embryonal component, spindle cell component, or
even gland-like areas.

Molecular/IHC (required for Dx): Loss of SMARCB1

(INI1) [rarely loss of SMARCA4 (BRG1)]—part of
SWI/SNF chromatin remodeling complex.
(+)EMA, SMA, (+/-)GFAP, CK, Synaptophysin.
Ki67 usually >50%
Aggressive course.

If INI1 and BRG1 are intact (or you are unable to test for
these)→ “CNS embryonal tumor with rhabdoid
features”

CNS Embryonal Tumor, NOS WHO grade IV

Poorly-differentiated embryonal tumors of neuroectodermal origin that do not have the
histopathologic/molecular alterations of the tumors listed above.
High-grade with aggressive clinical courses.

Biomarkers that might help in the classification of small cell, embryonal-appearing tumors:
Biomarker Associated Tumor
C19MC amplification or LIN28A expression Embryonal tumor with multilayered rosettes
SMARCB1 or SMARCA4 loss Atypical Teratoid/Rhabdoid Tumor
H3 K27 mutations Diffuse Midline Glioma, H3 K27M-mutant
C11orf95-RELA fusion gene or L1CAM expression Supratentorial ependymoma
IDH1 or IDH2 Adult-type diffuse gliomas
CTNNB1 mutations (nuclear β-catenin) Medulloblastoma, WNT-activated
GAB1 or YAP1 staining Medulloblastoma, SHH-activated
Modified from: WHO Classification of Tumors of the Central Nervous System. 4th Edition. 2016.
 Pineal Tumors Often block aqueduct→ increased intracranial pressure→ Headache,
papilledema, brainstem/cerebellar dysfunction (ataxia), nausea, etc..
Pineocytoma WHO grade I
Uniform, small, mature cells (resembling normal
pineal cells) that grow primarily in sheets and often
form large pineocytomatous rosettes (not in normal
pineal gland) and/or pleomorphic cells showing
gangliocytic differentiation.
Round nuclei with fine chromatin. Lots of processes.
No mitotic activity (<1 per 10 HPF). Ki67 usually <1%.
Rare. Usually adults.
Exclusive localization in pineal region
Well-demarcated, solid mass without infiltration or
dissemination.
Good prognosis.

Pineoblastoma WHO grade IV

Resembles other primitive neuroectodermal tumors
(e.g., medulloblastoma)
Poorly-differentiated, highly cellular embryonal tumor.
Patternless sheets of small immature neuroepithelial
cells.
High N:C ratio. Hyperchromatic.
Frequent mitoses. Ki67 >20%. Necrosis common.
No pineocytomatous rosettes, but may see Homer-
Wright rosettes
Most often young adults/adolescents.
Invade nearby structures and spread via CSF.
Aggressive clinical course.

Pineal Parenchymal Tumor of Intermediate Differentiation (“PPTID”)

Intermediate malignancy between
Pineoblastoma and Pineocytoma.
Diffuse sheets or large lobules of monomorphic
round cells that appear more differentiated
than in pineoblastoma.
Pleomorphic cells may be present.

Mitotic activity low to moderate.

Ki67 elevated (often >5%)

Mainly adults.
Variable outcome, currently without grading
criteria
 Papillary Tumor of the Pineal Region
Papillary tumor of the pineal region with densely
cellular areas exhibiting ependymal-like differentiation
(with true rosettes and tubes). May have solid areas.
Nuclei mostly round and stippled.
Moderate mitoses with moderate Ki67 (median ~7%)
IHC: React with cytokeratins (unique), S100, NSE,
(-)EMA. (+/-) GFAP
No grading criteria (too rare).
Frequent local recurrences.

Dural Tumors
Meningioma
Dural, mostly benign, slow-growing.
Derived from Meningothelial cells of arachnoid layer.
General classic findings:
Oval nuclei with delicate chromatin.
Frequent intranuclear pseudoinclusions.
Syncytial tumor cells with abundant eosinophilic cytoplasm.
Numerous whorls. Occasional psammoma bodies.
Most frequent brain tumor in USA.
Often older adults (risk increases with age).
More common in females.
On imaging have characteristic “dural tail”
Grossly rubbery/firm.
IHC: (+) Somatostatin Receptor 2A (SSTR2A) is likely the most
sensitive/specific. Also, (+) EMA, Vimentin, PR. (+/-) S100.
Ki67 varies often with grade.

Molecular: NF2 mutations common. Cytogenetic alterations.

Variable histologic findings with specific

grades (see next page). The criteria to
diagnose atypical and anaplastic
meningiomas are assigned regardless of
subtype.
Outcome is associated with grade.
Higher grade = more likely to recur/progress
Grades regardless of subtype: Sometimes only focal changes.
Atypical Meningioma (WHO grade II) (Need either 1 of major criteria or 3/5 minor criteria)
A meningioma with either: increased mitotic activity (≥4 per 10 HPF), brain invasion (tongue-like
protrusions), or at least 3 of the following: 1)Increased cellularity, 2)Small cells with high N:C ratios,
3)Sheet-like growth (patternless, uninterrupted), 4)Spontaneous tumor-type necrosis, 5) Macronucleoli.
Anaplastic Meningioma (WHO grade III)
Overtly malignant cytology (resembling carcinoma, melanoma, or sarcoma) and/or markedly elevated
mitotic rate (≥20 per 10 HPF). Often contain necrosis and have Ki67 >20%.
Common Subtypes: Usually want >50% of tumor to have this morphology.
Type Grade Description
Meningothelial Classic (typical) morphology as described
1 on previous page. Most common.
Lobulated architecture.

Fibrous Spindled cells forming parallel to

1 storiform bundles with abundant collagen
matrix.

Transitional (mixed) Meningothelial + Fibrous with

1 conspicuous whorls and psammoma
bodies.

Psammomatous Predominance of psammoma bodies over

1 tumor cells. Often thoracic.

Angiomatous Numerous blood vessels (often more

1 endothelial than meningothelial cells!)

Microcystic Cells with thin, elongated processes and

1 creating a cobweb-like background.

Secretory Focal epithelial differentiation→

1 intracellular lumina with PAS-positive
secretions (“pseudopsamomma bodies”).

Lymphoplasmacyte- Extensive chronic inflammatory infiltrates,

1 often overshadowing meningothelial cells.
rich

Metaplastic Has a mesenchymal component (osseous,

1 cartilaginous, myoid, lipomatous, or
xanthomatous)

Chordoid Cords or trabeculae of eosinophilic, often

2 vacuolated cells, set in mucoid matrix (like
chordoma).

Clear cell Polygonal cells with clear, glycogen-rich

2 cytoplasm and prominent perivascular
and interstitial collagen. Sheet-like.

Papillary Perivascular pseudopapillary pattern. Loss

3 of cell cohesion. Resembles
pseudorosettes.

Rhabdoid Rhabdoid cells (plump cells with eccentric

3 nuclei, open chromatin, prominent
nucleoli, and eosinophilic cytoplasm)
 Solitary Fibrous Tumor/Hemangiopericytoma
Fibroblastic tumor with a histologic spectrum (previously SFT
considered 2 entities, but united by genetics).
Usually Dural and supratentorial.

Solitary Fibrous Tumor (SFT): “Patternless pattern” of

short fascicles with alternating hyper and hypocellular
areas with thick collagen bands.

Hemangiopericytoma: High cellularity and rich network of

reticulin fibers.

BOTH have large, open, branching “Staghorn” vessels. Hemangiopericytoma

Molecular/IHC: NAB2-STAT6 fusion, best identified with

STAT6 IHC. Also, (+) CD34, CD99

Grade based on morphology/mitoses:

Grade I: Solitary Fibrous Tumor→ considered benign→
Treat with surgery only
Grade II: Hemangiopericytoma with <5 mitoses per 10 HPF
Grade III: Hemangiopericytoma with ≥5 mitoses per 10 HPF
→ Considered malignant→ Treat with surgery and
radiation

Unique Mesenchymal Tumors Pretty much any mesenchymal tumor can involve the
CNS, so also refer to separate Soft Tissue/Bone Guides
Hemangioblastoma WHO grade I
Two characteristic components:
1)Large stromal cells that are vacuolated with often
clear cytoplasm.
2) Abundant vascularity
Most common in Adults.
Most common in cerebellum. Can get anywhere.
Associated with Von Hippel-Lindau disease.
Molecular: VHL tumor suppressor inactivated in both
sporadic and VHL-associated cases

IHC: Stromal cells (+) Inhibin, Brachyury. Endothelial

cells express vascular markers (+ CD31, CD34, ERG…)

Important to differentiate from metastatic clear cell

RCC, especially if in setting of VHL disease! In
contrast, RCC stains with: PAX8, AE1/AE3, CD10,
EMA
 Germ Cell Tumors Note: For more info, refer to the Testicle and Ovary guides
Morphologically identical to gonadal counterparts! Germinoma
Usually children/adolescents.
Usually in the midline, most commonly pineal gland.
Symptoms depend on location. Can be “Mixed” GCT.
Germinoma
Large polygonal cells with clear to eosinophilic cytoplasm,
distinct cell membranes, vesicular chromatin, and prominent
nucleoli. Fibrous septae and nested architecture
Lymphocytic infiltrate; Sometimes granulomas
Yolk Sac Tumor
Yolk Sac Tumor
Many patterns/architecture. Often hypocellular myxoid areas
Most common = reticular/microcystic. Hyaline globules.
Classic: Schiller-Duval Bodies; Variable architecture.
Hyaline globules. Elevated Serum AFP
Embryonal Carcinoma
Large “Primitive” cells
Vesicular nuclei with prominent nucleoli Embryonal Carcinoma
Coarse, basophilic chromatin. Amphophilic cytoplasm
Variable architecture (nests, sheets, glands). Aggressive.
Choriocarcinoma
Malignant cytotrophoblasts (mononuclear) and
syncytiotrophoblasts (multinucleated)
Abundant Hemorrhage. Elevated serum or CSF hCG. Choriocarcinoma

Teratoma
Composed of tissues from 2-3 germ layers.
Common elements: Skin (with adnexal structures), Cartilage,
GI, Brain, etc…
Mature→ exclusively mature (adult-type) tissues
Immature→ has immature fetal/embryonic tissue
…with Malignant Transformation→ somatic malignancy Teratoma
developing in a teratoma
Germ Cell Tumor Immunohistochemistry:
IHC Stain Seminoma Embryonal Yolk Sac ChorioCA
Carcinoma Tumor
SALL4 + + + +
OCT 3/4 + + - -
D2-40 + +/- - -
CD117 + - - -
CD30 - + -/+ -
Glypican 3 - - + +/-
 Lymphomas
Perivascular spread of tumor cells
Discohesive cells with scant cytoplasm.
Frequent perivascular infiltration
Diffuse Large B-cell Lymphoma of the CNS: DLBCL
confined to the CNS at presentation. Often older
patients with cognitive dysfunction and a single
supratentorial mass. Need tissue to Dx→ important to
not give steroids before surgery as may cause tumor
waning making it harder to Dx.
Highly cellular, diffuse, patternless growth. Often
necrosis with viable perivascular islands. Perivascular
infiltration of nearby brain. IHC: (+) PAX5, CD20, CD19.
NOT virus related.
Immunodeficiency-associated CNS lymphomas: Most
common in AIDS. EBV-associated. Often multifocal.
Other Lymphomas: Lymphomatoid granulomatosis,
Intravascular Large B cell lymphoma, Extranodal
marginal lymphoma of mucosa-associated lymphoid
tissue (MALT) lymphoma of the dura.

Miscellaneous Other Tumors

Melanocytic tumors:
Presumably arise from leptomeningeal melanocytes. Often contain melanin.
Must consider/exclude metastatic melanoma!
IHC: (+)S100, MelanA, HMB45, MITF; Ki67 usually <2% in melanocytomas
Meningeal Melanocytosis—Diffuse/multifocal benign proliferation of
cytologically bland melanocytes in subarachnoid space. Don’t frankly invade
brain.
Meningeal Melanomatosis—Primary CNS melanoma with diffuse spread
throughout subarachnoid space. Often CNS invasion.
Meningeal Melanocytoma—Well-differentiated, solid, non-infiltrative
melanocytic neoplasm
Meningeal Melanoma—Primary CNS melanoma. Solitary mass with aggressive
growth.

Histiocytic tumors:
Langerhans's Cell Histiocytosis—Clonal proliferation of Langerhans cells.
IHC: (+)S100, CD1a, Langerin. May involve CNS secondarily via extension from
bone or primarily. Usually children. Cells have pale cytoplasm with reniform
nuclei. Classically associated eosinophils. Frequent BRAF V600E mutations.

Erdheim-Chester disease, Rosai-Dorfman disease, Juvenile

Xanthogranuloma, Histiocytic sarcoma
 Sellar Tumors
Pituitary Adenoma
Most common tumor of sella turcica. Usually Adults.
Neoplasm of anterior pituitary hormone-producing cells.
Benign, but can invade adjacent structures.
Monomorphic Neuroendocrine cells. Round nuclei.
Variety of histologic growth patterns, including diffuse,
papillary, and trabecular (like other NE tumors)
May have eosinophilic or basophilic cytoplasm
May have perivascular orientation.
On touch prep see cellular, discohesive, homogeneous
neuroendocrine proliferation
Stains: (+) Synaptophysin, chromogranin; (-)S100
Reticulin shows dissolution of normal network.
(disruption of small normal micro-acini→ larger nests)

Subclassify by hormone secretion, use IHC panel: Growth Hormone (GH), prolactin, TSH-β, ACTH, FSH- β,
LH-β, Alpha subunit (α-SU)
“Functioning” adenomas→ secrete hormone→ often present early with symptoms/tumor syndrome.
“Silent” adenomas do not secrete hormone, but still stain with hormone IHC.
Non-functional ones often present with mass effect. Press on optic chiasm→ bitemporal hemianopsia,
diplopia, headache.
Usually sporadic, but can occur in MEN1, DICER1 syndrome, etc…
Treatment: Usually Transsphenoidal resection is #1; may also consider pharmacotherapy or radiation
Type Hormone IHC
Secreted
Lactotroph Prolactin Prolactin, Most common (up to ½ of all adenomas). Presentation depends on sex:
PIT1, females present with galactorrhea & amenorrhea, men present with
sexual dysfunction and mass effect.

Corticotroph ACTH ACTH, TPIT Excess glucocorticoid→ Cushing’s Disease.

Gonadotroph FSH-β, LH- FSH-β, LH-β, Most are non-functioning and present with mass effect. Can result in
β, and/or α-SU, SF1 menstrual disturbances in women and sexual dysfunction in men.
α-SU,

Somatotroph Growth GH, PIT1, Present with gigantism and/or acromegaly. Eosinophilic.
Hormone

Thyrotroph TSH TSH-β, α-SU, Rare. Present with hyperthyroidism.

PIT1,

Null Cell None None Present due to mass effect

Plurihormonal Multiple Multiple, Some established adenoma subtypes excrete 2 hormones, like
PIT1 mammosomatotrophs (GH and prolactin) and are not considered in this
group. Presentation depends on hormones.
 Pituitary Carcinoma
Defined by metastasis (independent of any histologic finding!)
Very rare. Must have proven primary tumor. Metastases are usually in craniospinal axis.
Resemble pituitary adenoma with histology and IHC.
Often have more abnormal cells and proliferation (e.g., more mitoses, higher Ki67)
Relatively poor prognosis.

Pituitary Blastoma
Rare developmental tumor seen in neonatal period.
Three components:
1) Small chromophobic and undifferentiated blastema-like cells,
2) Larger patternless secretory cells with round nuclei and abundant cytoplasm,
3) Cuboidal to columnar cells forming glandular-like structures.
IHC: (+) ACTH (-)Prolactin, TSH, FSH, LH
Associated with Cushing disease.
Molecular: DICER1 mutations
Relatively poor prognosis.

Craniopharyngioma WHO grade I

Benign, epithelial tumors derived from embryonic
remnants of Rathke’s pouch. K
Usually present with mass effect (visual disturbance,
headache, or endocrine changes).
B
Nearby gliosis and Rosenthal fibers.

Adamantinomatous craniopharyngioma
Bimodal age distribution (1st and 5th decades)
Basal layer with basal palisading (B)
Stellate reticulum (loose background), whorls, “Wet
keratin”(K), Calcifications, Cholesterol clefts.
Multi-Cystic areas.
IHC/Molecular: Nuclear expression of β-catenin
Tumors with frank anaplasia, necrosis, and numerous
mitoses are considered malignant.

Papillary craniopharyngioma
Exclusively in adults
Resembles a squamous papilloma: Non-keratinizing
epithelium and fibrovascular cores. Solid.
NO stellate reticulum, wet keratin, or calcifications
IHC/Molecular: BRAF V600E mutations, (+)p63, CK5/6

Generally favorable prognosis. Treated with surgery.

Nevertheless, can be infiltrative and hard to manage.
 Non-neoplastic lesions of Rathke’s Cleft
No nuclear β-catenin or BRAF V600E staining.
Rathke’s Cleft Cyst: Cyst wall lined by columnar or cuboidal
epithelium, which is often ciliated with mucinous and goblet
cells. May rupture inducing a xanthogranulomatous reaction.

Xanthogranuloma: Cholesterol clefts, foamy macrophages,

multinucleated giant cells, chronic inflammation, necrotic
debris, and hemosiderin. May see scant epithelium from
Rathke’s cleft cyst remnants.

Epidermoid cyst: Unilocular cavity lined by squamous

epithelium and filled with dry, flaky keratin (like elsewhere)

Granular Cell Tumor of the Sellar Region WHO grade I

Epithelioid to spindled cells with abundant
granular eosinophilic cytoplasm (full of lysosomes).
IHC: (+) Diffuse TTF1; (+/-) CD68, S100
Possibly on a spectrum with the two entities below
Arises in posterior pituitary (neurohypophysis) or
infundibulum. Circumscribed.
Usually adults. Rare.
Slow progression and benign clinical course.

Pituicytoma WHO grade I

Low-grade glial tumor composed of bipolar spindled
cells arranged in a fascicular or storiform pattern.
IHC: (+) TTF1, S100; (+/-) GFAP; (-) Synapto
Possibly on a spectrum with the above & below DXs
Circumscribed, Solid. Rare.
In posterior pituitary/infundibulum.
Good prognosis.

Spindle Cell Oncocytoma WHO grade I

Spindled to epithelioid oncocytic non-neuroendocrine
neoplasm of posterior pituitary gland. Variable
pleomorphism.
IHC: (+) TTF1, S100, EMA; (-) Synapto
Possibly on a spectrum with the above two DXs
Good prognosis.
 Metastatic Tumors Metastases are the most common CNS tumors in Adults!
Usually multiple lesions. Usually well-circumscribed (as opposed to an infiltrative diffuse glioma)
80% of metastases are to cerebral hemispheres, particularly in arterial border zones and at the grey-
white junction. Often present with signs of increased intracranial pressure (headache, altered mental
status, ataxia, etc..)
Most common sites of origin:
Men→ 1) Lung, 2)GI, 3)Melanoma, 4)Kidney
Women→ 1) Lung, 2)Breast, 3)GI, 4)Melanoma

Tumor Syndromes AD= Autosomal Dominant

Syndrome Gene Nervous System Tumor(s) Other manifestations

Neurofibromatosis NF1 Optic tract pilocytic Café-au-lait spots, axillary freckles,
Type 1 (NF1) (AD) astrocytomas, Astrocytomas, osseous lesions, Lisch nodules, GIST etc..
Neurofibromas, MPNST’s

Neurofibromatosis NF2 Bilateral vestibular Ocular abnormalities.

Type 2 (NF2) (AD) schwannomas (and elsewhere),
Meningiomas, Gliomas, and
developmental lesions

Schwannomatosis SMARCB1 or Multiple Schwannomas and Rare.

LZTR1 (Sporadic) Meningiomas

Von Hippel— VHL Hemangioblastoma Clear cell renal cell carcinoma,

Lindau Disease (AD) Pheochromocytoma, Pancreas NET, Ear
(VHL) and epididymis tumors.

Tuberous sclerosis TSC1 or TSC2 SEGAs, Cortical hamartomas, Cutaneous angiofibroma, Cardiac
(AD) Subependymal glial nodules rhabdomyomas, Renal angiomyolipoma,
Lung LAM

Li-Fraumeni TP53 Astrocytoma, Glioblastoma, Multiple primary tumors in children and

Syndrome (AD) Medulloblastoma, Choroid young adults including: Breast cancer, Soft
plexus tumors tissue sarcomas, Adrenal cortical
carcinoma, and Osteosarcoma.

Cowden Syndrome PTEN Dysplastic cerebellar Breast, Endometrium, and Thyroid cancer.
(AD) gangliocytoma (Lhermitee- Multiple hamartomas including skin and GI
Duclos disease),

Turcot Syndrome APC Medulloblastoma Colon Cancer, Osteomas, Fibromatosis,

(AD)

Mismatch repair Gliomas Café-au-lait macules, Lymphoma

enzymes (AD)

Nevoid Basal Cell PTCH1 or PTCH2 Medulloblastoma Skin basal cell carcinoma, Odontogenic
Carcinoma (Gorlin) (AD) (desmoplastic/nodular) keratocytes
Syndrome
Rhabdoid Tumor SMARCB1 or AT/RT Kidney malignant rhabdoid tumor
Predisposition SMARCA4
Syndrome
 Pattern-Based Approach Modified from: “Practical Surgical Neuropathology”
by Arie Perry and Daniel Brat
General Comments: Although a pattern-based approach is very useful, in many cases you might have a
good idea of the Dx via “instant pattern recognition.” Nevertheless, it can be helpful to judiciously
consider mimickers and other diagnoses based on a pattern-based approach.

Parenchymal Infiltrate with Hypercellularity

Intact architecture, but with a hypercellular infiltrate
Diffuse gliomas Histiocytic disorders (e.g., Erdheim-Chester disease)
Diffuse large B cell lymphoma of the CNS Infarcts
Angiocentric glioma Metabolic/toxic diseases
Encephalitis (inflammatory/infectious processes) Reactive gliosis
Active demyelinating diseases

Solid Mass A sharply demarcated lesion

Metastases Choroid plexus tumors

Ependymoma Hemangioblastoma
Subependymoma Paraganglioma
SEGA Pituitary adenomas
Neurocytomas Astroblastoma
Pineal parenchymal tumors Chordoid glioma of the 3rd ventricle
Embryonal neoplasms

Solid and Infiltrative Process

A lesion that is mostly solid, but with an ill-defined (infiltrative) margin with the adjacent brain tissue.
Pilocytic astrocytoma Craniopharyngioma
Pilocytic xanthoastrocytoma Diffuse large B-cell Lymphoma
Glioblastoma/gliosarcoma Sarcomas
Ganglioglioma Histiocytic tumors
Disembryoplastic neuroepithelial tumor Abscesses/infection
Embryonal neoplasms (e.g., Medulloblastoma)
Choroid plexus carcinoma
Germ cell tumors

Destructive/Necrotic Process Extensive necrosis and destruction of normal tissue

Infarcts Vasculitis
Glioblastoma Lymphoma
Radiation necrosis/treatment effect Severe demyelinating disease
Infection Metabolic/toxic disease
 Vasculocentric A disease process centered around blood vessels

Diffuse large B-cell lymphoma Amyloid angiopathy

Intravascular lymphoma Arteriosclerosis
Angiocentric glioma Vascular malformations
Ependymoma Infections
Vasculitis Sarcoidosis
Demyelinating diseases Thromboembolic disease

Extra-Axial Mass External to the brain

Meningioma Pituitary adenoma

SFT/Hemangiopericytoma Sarcoidosis
Hemangioblastoma Infection
Peripheral nerve sheath tumors Bone tumors
Metastasis Histiocytic tumors
Melanocytoma/melanoma Leukemia/lymphoma
Paraganglioma

Almost Normal Tissue Very subtle changes

Nonrepresentative biopsy (“they missed”) Neurodegenerative diseases

Subtle diffuse glioma Metabolic/toxic disorders
Cortical dysplasia and other malformations Reactive gliosis
Mesial temporal sclerosis Cerebral edema
Intravascular lymphoma Spongiotic/vacuolar changes
Encephalitis Ischemic changes
Cerebral malaria
Microembolic disease

Meningeal/CSF Infiltrate An expanded subarachnoid space filled with a cellular infiltrate

Meningeal carcinomatosis Histiocytic disorders

Meningeal gliomatosis Meningitis
Meningeal melanocytis/melanomatosis Sarcoidosis
Diffuse leptomeningeal glioneuronal tumor Infection
Metastatic medulloblastoma Collagen vascular disease
Leukemia/lymphoma