= Low grade

CNS TUMOR MAP, 2020 REVISION WITH 2016 WHO

E = EGBs = Enhancing b = BRAF alteration * Tumor summaries below may not necessarily state the formal WHO Prepared by C. Krishnan, MD
= Grade III preferred terminology, in the name of brevity. Ref: WHO Tumors of the CNS
= Seizures = Cyst+mural nodule i = IDH1/2 mutation

LEGEND
(4th rev 2020)
DESIGNATIONS AND MOLECULAR INTEGRATION
= Grade IV # Not all CNS tumors are described here. Specifically, this chart will not
R = Rosenthals = Calcifications o = 1p/19q co-del = Ungraded address meningiomas, CNS lymphomas or mesenchymal tumors.

INFANT HIGH-GRADE GLIOMA I ANGIOCENTRIC GLIOMA ASTROBLASTOMA II PLEOMORPHIC XANTHOASTROCYTOMA III GLIOBLASTOMA, EPITHELIOID GLIOBLASTOMA (IDH MUT) GLIOBLASTOMA (IDH WT)
Usually embryonal “PNET-like” histology. Subtly infiltrative, spindle cell tumor with elongated Well defined tumor arranged in radial “rosettes” with Cellular tumor with epithelioid cells, sometimes lipidized Infiltrative tumor with epithelioid eosinophilic cells +/- Infiltrative glial tumor with: hypercellularity, mitoses, Infiltrative glial tumor with: hypercellularity,
cells radially arranged around vessels - akin to broad bases. Prominent vascular hyalinization. Can have and vascular proliferation. Less pronounced necrosis. mitoses, pseudopalisading necrosis and vascular

MX
MX
Sometimes papillary, rosetted or spindled growth with multinucleation & nuclear inclusions. Frequent rhabdoid change. May have lipidzed cells, ala PXA. Zonal

MX

MX
MX

MX

MX
patterns. Occasionally lower-grade glial pattern. E ependymomatous rosettes papillary like formation. Occasional necrosis. perivascular lymphocytes and reticulin. necrosis and +/- MV proliferation. E Often arising from lower grade glioma proliferation. Small cell var = minimal atypia

E
POS (if mutated): ALK1, panNTRK, ROS1 POS: GFAP, MYB, EMA (dot-like) POS: GFAP (var), S100, Ki67 (<20%), Ker (var) POS: GFAP, BRAF V600E, MAP2 (var), CD34 (var) POS: S100, GFAP (patchy), EMA/CK (focal), BRAF POS: GFAP, IDH1 R132H, p53 POS: GFAP, IDH1 R132H, p53, S100, focal INI-1 loss
R R

IHC

IHC
IHC
IHC
IHC

IHC

IHC
NEG: retained INI1/BRG1 NEG:Ki67 (<5%), Synap, p53, IDH1 NEG: IDH1 NEG: p16 null (usually), IDH1 NEG: H3K27M, CK5/6, retained INI1/BRG1 NEG: H3K27M, ATRX, IDH1 (if alternative mutation) NEG: H3K27M, CK5/6

HGG pattern: ALK / ROS / NTRK / MET alterations IDH1 wildtype. BRAF V600E (50%) IDH1 R132X mutated or IDH2 R172K mutated IDH1 wildtype, TERT promoter mut., EGFR alterations
MYB (6q23) alterations or rearrangements aCGH: gains of 19 and 20q

MOL

MOL
MOL
BRAF mut (80%), CDKN2A del (60%)

MOL
MOL

MOL

MOL
LGG pattern: ALK alterations only No H3K27M or SMARCB1/B4 mutations Additionally: TP53 mut, ATRX mut, MGMT hypermeth (esp in small cell var.), TP53 mut

Usually don’t have H3K27M or BRAF mutations Ependymoma, pilomyxoid astrocytoma, astroblastoma Malignant var: anaplastic, >5 mites, palisading necr. Grade 3 = >5 mitoses & necrosis | Epithelioid GBM Related to anaplastic PXA or may arise from Gr2PXA IDH-wt GBM, IDH-mut anaplastic astro Epithelioid GBM, Oligodendroglioma (small cell var)

DDX
DDX
i

DDX

DDX

DDX
DDX

DDX
b i i
S
U PEDIATRIC LOW-GRADE GLIOMA, ALK
FUSION I
DESMOPLASTIC INFANTILE
ASTRO/GANGLIO
I DNET
Glioneuronal tumor with oligo-like cells in vertical
?I PLNTY I PAPILLARY GLIONEURONAL TUMOR
Low-grade biphasic glioneuronal tumor arranged in

P
Glial tumor with piloid cells, set among prominent

MX
Glial or glio-neuronal tumor with moderate rows, mucoid microcysts and “floating” neurons. pseudopapillae surrounding hyalinzed vessels. Intervening

MX

MX
Triphasic tumor: glial cyst wall, desmoplastic vasculature and heavy calcification
cellularity and mild atypia. High-grade Can have distinct glioma areas & separate FCD (IIIa) ganglionic cells with neuropil.
MX

embryonal mural nodule +/- ganglion cell

MX
R
versions also exist. component.
Oligo-like: POS: S100, OLIG2, CD34 (focal) POS: Synap, CD34 (strong) POS: GFAP and S100 (glial); OLIG2 (var), Synap

IHC
IHC

IHC
NEG: GFAP (in oligo-like), IDH1 NEG: Cga, IDH1, GFAP (mostly) , Ki67 usu low NEG: CgA
POS: GFAP, Alk,

A
POS GFAP, reticulin fibres, Synap (neurons),
IHC

IHC
NEG: Ki67 (very low) desmin (rare)
i FGFR2-CTNNA3 fusions

MOL
BRAF mut (30%), Chr 5 and 7 gains (30%) SLC44A1-PRKCA fusion in most

MOL

MOL
T
Alk-fusions: PPP1CB-Alk and rare other Rare aneuploidy. Rare BRAF V600E mutations.
MOL

MOL

partners No BRAF-fusions or TP53 mutations Pilocytic astrocytoma, DNET, ganglioglioma

o

DDX
Pilocytic astro, oligodendroglioma, ganglioglioma Ependymoma, AVM

DDX

DDX
i II III II III EXTRAVENTRICULAR NEUROCYTOMA
E PLNTY, Ganglioglioma ASTROCYTOMA OLIGODENDROGLIOMA II
DDX

Embryonal tumors, ganglioglioma, pilocytic astro

DDX

Cellular astrocytic, fibrilar neoplasm with mild to moderate Infiltrating gliomas with round, “fried-egg” cells in Round cell neurocytic tumor with prominent

N intralesional vessels and pseudorosettes.

MX
nuclear atypia, angulated nuclei + hyperchromasia. No necrosis delicate chicken-wire vasculature background. Grade 3

MX

MX
DICER1-ASSOCIATED CNS SARCOMA allowed. = Incr. mitoses + Microvasc prolif + necrosis Oligo-like with occasional gangliod differentiation.
GANGLIOGLIOMA
I
T CNS EMBRYONAL TUMORS, GENETICALLY High-grade spindle cell neoplasm with PPB-like
III
Disorganized, variably cellular lesion with glial and neuronal POS: GFAP, TP53, IDHR132H (80%) POS: IDHR132H (90%), ATRX (retained), S100, OLIG2 POS: Synap

IHC
IHC

IHC
NEG: Cga, IDH1, GFAP (mostly) , Ki67 usu low

MX
component. Look for binucleated and dysplastic neurons. NEG: ATRX (loss) NEG: GFAP (mostly)

MX
pattern, eosinophilic globules and ~ rhabdo cells.

O DEFINED Perivascular lymphocytes.

POS: Desmin (focal), nyogenin (focal) (80%) IDH1/2 mut & TP53 mut + ATRX mut
o IDH1/2 mut + co-del 1p/19q | Often: CIC & TERT mut. o Rarely co-del 1p/19q. FGFR1-TACC1 fusions
E

MOL
MOL

MOL
POS (Neuron): MAP2, Synap, BRAF V600E, CD34 Never IDH1/2 mutation or BRAF V600E mutation
MGMT promoter methylation (50%) NEG: mutations in ATRX or TP53

IHC
R

IHC
Many genetically defined embryonal tumors look similar to one NEG: GFAP, Olig2, Synap, INI1 (retained) Rarely: H3K27M in non-infiltrative, temporal cases
another: Oligodendroglioma, DNET, ganglioglioma, PGNT
i Grade 3 = Hypercellular + increased mitoses Neurocytoma, clear cell ependymoma, DNET, Pilocytic

DDX
DDX

DDX
Bi-allelic DICER1 mutations BRAF V600E (~50%), BRAF fusions (rarely)
i i i

MOL

MOL
I
NO IDH1/2 mutations (excludes this diagnosis)
1. CNS NB-FOXR2: Resembles CNS neuroblastoma, ganglionic nodules
Embryonal tumors, GBM, AT/RT

DDX
DNET, Oligodendroglioma, co-existing FCD (type IIIb)

DDX
b
A
2. CNS HGNET-MN1: Solid + pseudopapillary tumor, resembles
MX

astroblastoma

L
3. CNS HGNET-EFT-CIC: Can resemble EWS ATYPICAL TERATOID/RHABDOID TUMOR EMBRYONAL TUMOR WITH MULTILAYERED
4. CNS HGNET-BCOR: Glial looking w/ rosettes or ependymoma-like ROSETTES
5. CNS HGG-ALK/ROS/NTRK Supratentorial > infratentorial & midline Cerebellar > Midline/Posterior fossa.
Polyphenotypic, hypercellular embryonal tumor with
II EPENDYMOMA (SUPRATENTORIAL)
MX

Embryonal tumor with layered rosettes and islands of

MX
rhabdoid and ocasional anaplastic cells. nucleus free neuropil
Can be papillary or clear cell morphology. Clear cell =
CNS NB-FOXR2: Olig2, Synaptophysin, GFAP POS: LIN28 (strong & diffuse), Synap (neuropil) III arranged in cellular groups with perinuclear halos, focal

MX
POS: INI1 or BRG1 (aberrant loss), GFAP (foca)
IHC

IHC
CNS HGNET-MN1: GFAP NEG: INI1 (retained), GFAP perivascular rosettes.

CNS HGNET-EFT-CIC: NUT1 SMARCB1 > SMARCA4 alterations. Mut >> deletions POS: FOXJ1, GFAP, S100, EMA (dot-like)

IHC
IHC

C19MC-altered
MOL

In SP-RELA: Cyclin-D1, L1CAM, p16 null

MOL
33% germline
CNS HGNET-BCOR: GFAP, B-cat (nuc), BCOR
ST-EPN-RELA: C11orf95-RELA fusion, Chromothripsis

MOL
All embryonal tumors in children
DDX

Embryonal tumors, anaplastic ependymoma, CPC

DDX
CNS HGG-ALK/ROS/NTRK: ALK1, ROS1, NTRK ST-EPN-YAP1: YAP1 fusions

Oligodendroglioma, neurocytoma, hemangioblastoma

DDX
PINEOCYTOMA PINEAL PARENCHYMAL TUMOR OF
PAPILLARY TUMOR OF PINEAL REGION
PINEOBLASTOMA ? II I ? II INTERMEDIATE DIFFERENTIATION
H3G34R mut

CNS NB-FOXR2: Intrachromosomal rearrangement, FOXR2 upreg.

More often

Embryonal, hypercellular tumor of pineal region ? III Biphasic solid and papillary tumor with Moderately cellular round cell tumor growing in
? III
Two patterns: Diffuse neurocytoma-like and
CNS HGNET-MN1: Various fusion partners ependymoma-like pattern, hyalinized vessels and sheets and multilayered (pineocytomatous) lobulated/nested pattern w/ distinct vessels. More

MX
MX

MX
with focal rosette formation. Often invasive and

MX
occasional PAS+ cytoplasmic globules neuropil rosettes, set among rich vasculature. cellular and occasional dysplastic gangloid cells.
CNS HGNET-EFT-CIC: CIC-NUTM1 fusion disseminated.
MOL

CNS HGNET-BCOR: BCOR ITD exon 15 DIFFUSE MIDLINE HIGH-GRADE GLIOMA, H3K27M POS: Synap (var), NF (focal), CgA (focal) POS: Keratins (AE1/3, CAM5/2, CK18), GFAP (var) POS: Synap, NF, MAP2 (var), CgA (var) POS: Synap, NF, CgA (var)

IHC

IHC

IHC
IHC
M
NEG: INI1 & BRG1 (retained) NEG: NF, Syanp (focal), CgA (focal) NEG: GFAP, S100 NEG: GFAP, S100, NeuN
CNS HGG-ALK/ROS/NTRK: Various fusion partners across all
E
Infiltrative tumor involving midline nuclei or brainstem.

I
Monomorphic tumor cells with variable morphology RB1 deletion, DICER1 mutation

MOL
MX

aCGH: del 10, + 4. PTEN alteration occasional No relevant diagnostic molecular genetic profile aCGH: gains of 4q, 12q and loss of 22

MOL

MOL
MOL
resembling pilocytic astro to GBM.
R
D
All embryonal tumors of childhood, AT/RT

DDX

DDX
Ependymoma, Germ cell tumor, Metastasis PPTID, EV neurocytoma, Germinoma Pineoblastoma, Germinoma,

DDX
DDX
POS: GFAP (var), H3K27M, OLIG2, MAP2
IHC

NEG: retained INI1/BRG1, CGA, ATRX, OLIG2

LI H3K27M mutation (midline), H3G34R (hemispheric) i

N
MOL

PILOMYXOID ASTROCYTOMA TP53 (50%), PDGRFA amp. PILOCYTIC ASTROCYTOMA

I
Astrocytic tumor with elongated processes, biphasic
E Piloid astrocytic tumor with subtle angiocentric growth, Related to anaplastic PXA or may arise from Gr2PXA density, microcysts and occasional multinucleation. Low ANAPLASTIC ASTROCYTOMA WITH
DDX

MX

myxoid background & microcysts.

E PILOID FEATURES
MX

mitoses. +/- Vasc prolif, Leptomening. spread

Variable mitotic activity. +/- Pilocytic-like areas
Cellular, moderately pleomorphic infiltrative tumor
I
POS: GFAP, ~OLIG2, BRAF (hemispheric)
with pilocytic morphology, vascular proliferation
IHC

MX
POS: GFAP, S100, ~CD34, Ki67 (up to 20% labeling)
R
NEG: p53, IDH1/2
R and focal areas of necrosis.
N
IHC

NEG: BRAF V600E, H3K27M Posterior fossa; KIAA1549-BRAF fusion

MOL

F
Cortex/Midline: BRAF mut, FGFR1 (5%), NTRK (~5%)
E POS: GFAP

IHC
Rarely can have BRAF rearrangement NEG: ATRX (loss), IDH1, H3K27M
MOL

R Pilomyxoid (no EGBs/ Rs), Oligodendo., DNET

DDX

b Defined by methylation studies. Characteristic:

A

MOL
DDX

Pilocytic astrocytoma, Angiocentric glioma NF1/BRAF alterations + del ATRX + del CDKN2A

T MEDULLOBLASTOMA EPENDYMOMA (PF) Pilocytic astrocytoma, IDH-wt GBM

DDX
II i
E Embryonal tumor with variable nodules of neuronal
Monomorphic glioma arranged in rosettes with ?I DYSPLASTIC CEREBELLAR GANGLIOCYTOMA

III CEREBELLAR LIPONEUROCYTOMA

N perivascular anuclear zones. Can have dense Expansion of molecular and internal granule layers
II
MX

MX

differentiation. Cerebellum and 4th ventricle

cellularity, focal necrosis and hemorrhage with variably sized ganglionic cells that preserves

MX
T overall architecture. Cerebellar version of neurocytoma with prominent

MX
POS: Synap, MAP2, p53, B-Cat (WNT),, GAB1 (SHH) POS: FOXJ1, GFAP, S100, EMA (dot-like) neoplastic adipocyte-like component.
O
IHC
IHC

NEG: GFAP, INI1 (retained) H3K27me3: Lost in EPN-A, Retained in EPN-B POS: Syna

IHC
NEG: PTEN (loss in adult cases) POS: Synap, NeuN, MAP2, GFAP (focal)
R

IHC
4 molecular groups: PF-EPN-A: Few copy # changes, CpG-me + NEG: Ki67 (usu <10%)
MOL

WNT - Older children, some adults. PF-EPN-B:Chromosomal instability, Cpg-me - Adult: PTEN mutations (Cowden syndrome)
I
TP53 mutation (20%),

MOL
SHH - Often hemispheric & Desmoplastic/EN. TP53 Children: no PTEN mutations

MOL
MOL

mut confers worse prognosis No BRAF or IDH mutations

A
Choroid plexus tumor, Medulloblastoma, Metastasis
DDX

G3/4 - Infants/children. Large/anaplasia & MYC amp

DDX
Ganglioglioma, Glioneuronal tumors Astrocytomas, lipid-rich SFT?

DDX
i
L
B I
MYXOPAPILLARY EPENDYMOMA
II EPENDYMOMA (SPINAL CORD)
R & ?II
Typically found in distal spinal cord. Radially arranged
tumor cells in papillary / balloon arrangement around III
Often Tanycytic morphology: Monomorphic glioma in

A
MX

spinal cord growing as spindle cell fascicles with

MX
myxoid substance. elongated nuclei. Rosettes typically subtle.

I C POS: GFAP, S100, CD99, Ker AE1/3 POS: FOXJ1, GFAP, S100, EMA (dot-like)
IHC

IHC
NEG: CK5/6, CK7, CK20, EMA, Ki67 (<1%) NEG:
N O Whole chromosome aneuploidy Frequent NF2 mutations, del Chr 22
S R

MOL
MOL

MYCN amplification (more aggressive variant)

T D Metastatic papillary tumors (adult), Chordoma Pilocytic astrocytoma, Schwannoma, Met.

DDX
DDX

E
M
V I CHOROID PLEXUS TUMOR MYXOID GLIONEURONAL TUMOR DIFFUSE LEPTOMENINGEAL TUMOR CENTRAL NEUROCYTOMA SUBEPENDYMOMA
CHOROID PLEXUS CARCINOMA I SUBEPENDYMAL GIANT CELL TUMOR I ROSETTE FORMING GLIONEURONAL TUMOR
I II CHORDOID GLIOMA OF 3RD VENTRICLE
E II Intraventricular round cell neurocytic tumor with
N Malignant intraventricular tumor w/ sheet-like II Papillary tumor with delicate fronds with crowded
cuboidal cells. Atypical = >2/10 mits + incr.
Circumscribed glio-neuronal tumor with large
gemistocyic or ganglion-type cells. Mitoses, tumor
DNET-like tumor arising in septum
E
Oligodendroglial-like tumor with predominant
leptomeningeal growth pattern and lesser
Biphasic solid-cystic, tumor: neurocytic rosettes
and piloid astrocytic components. Neurocytic
prominent intralesional vessels and pseudorosettes.
Ventricular tumor. Clusters of small nuclei
arranged in fibrillar matrix with occasional
Solid neoplasm w/ cords and nests of epithelioid
tumor cells. Lymphoplasmacytic infiltrates present.
MX
MX

MX
MX

MX

MX

MX
growth, focal papillary formation, necrosis and brain pellucidum > lateral ventricles.
MX

T
Anaplastic cytology = “atypical central
invasion. Usu freq. Mitoses. cellularity, pleomoprh., solid growth and/or necrosis. lymphocytes and hyalinized vessels present. ganglion cell / neuropil component
R rosettes surround neuropil core. b microcysts. Rarely forming rosettes. Mucinous stroma common. Rarely fibrotic.
R
MX

R
Myxoid stroma, microcysts and neurocytoma”.

R POS: CK7, p53 (50%) POS: CK7, TTR, S100 (var) POS: GFAP, S100, Synap (var), NeuN (var) rosette-formations. POS: OLIG2, MAP2, S100, GFAP (focally) POS: Neurocytic = Synap, MAP2; Glial = GFAP POS: Synap, NeuN, MAP2 POS: GFAP POS: GFAP, TTF-1, CD34, Ker (var), S100 (var)
IHC
IHC

IHC
IHC

IHC

IHC

IHC
IHC

NEG: EMA, NeuN, IDH1

I NEG: S100, TTR, EMA, INI1 (Retained) NEG: CK20, EMA (weak) NEG: CD34 NEG: BRAF V600E, IDH1/2 NEG: Cga, GFAP, Ki67 usu <2%. If >2% = “atypical” NEG: EMA, Ki67 (<1%) NEG: P53 (weak), Synapto, IDH1
POS: OLIG2, MAP2, S100, GFAP (focal)
i
IHC

C TSC1 and TSC2 mutations common NEG: CD34, NeuN, IDH1 KIAA-BRAF fusion (75%), del 1p (50%), rare FGFR1 mut, PIK3CA mut in some aCGH: 11q13 and 9p21 losses.
MOL

Germline TP53 mut (40%) aCGH: hyperdiploidy. MGMT promoter methylation aCGH: copy # alterations, MYCN amplification Not really relevant
MOL

MOL
MOL

MOL

MOL

MOL
MOL

60% sporadic, 40% TS syndromic 1p/19q del. No BRAF V600E or IDH1/2. No BRAF alterations or IDH1/2 mutations No TP53 mutations
L
DDX

E
Defined by PDGFRA K385I/L mutation Oligodendroglioma, Pilocytic astro, PXA
b i
MOL

Anaplastic ependymoma, Embryonal tumors CP carcinoma, Endolymphatic sac tumor, Metastasis Ganglioglioma, PXA (if not obviously near ventricle) Pilocytic astro, neurocytoma, Oligodendroglioma Ependymoma, Pineocytoma Ependymoma variants Metastasis, Chordoma.
DDX

DDX

DDX
DDX

DDX

DDX

DDX
o o
S

0 - 24 months 2- 20 years 20-50 years > 50 years