P e d i a t r i c N e u ro - O n c o l o g y

Fatema Malbari, MD

KEYWORDS
 Pediatric brain tumors  Gliomas  Medulloblastoma  ATRT  Ependymoma
 Craniopharyngioma  Cancer predisposition syndromes

KEY POINTS
 Central nervous system (CNS) tumors are the most common solid tumor in pediatrics and
represent the largest cause of childhood cancer–related mortality.
 With the advances in molecular characterization of tumors considerable developments
have occurred impacting diagnosis, management and refining prognostication of pediat-
ric CNS tumors.
 Therapeutic approaches targeting the biology of these tumors are being investigated to
improve overall survival and decrease treatment-related morbidity.

INTRODUCTION

Central nervous system (CNS) tumors are the most common solid tumor in pediatrics
and represent the largest cause of childhood cancer–related mortality.1 The incidence
of CNS tumors in children and young adults, 0 to 19 years of age, is 6.06 per 100,000
population. Gliomas are the most common tumor histology reported in this age group
and embryonal tumors have the highest incidence in children 0 to 4 years of age. Pi-
tuitary and craniopharyngeal duct tumors are the most common tumor location. The
different pediatric CNS tumor types by histology and location are shown in Fig. 1.
Risk factors for developing these tumors remain unknown aside from prior ionizing ra-
diation exposure and genetic predisposition syndromes, such as neurofibromatosis
(NF), tuberous sclerosis (TSC), Li Fraumeni syndrome (LFS), Gorlin syndrome, familial
adenomatous polyposis (FAP) syndrome, and constitutional mismatch repair defi-
ciency (CMMRD).
With the advances in molecular characterization of tumors, considerable advances
have occurred in the field of pediatric neuro-oncology.2 The understanding of the
biology has impacted diagnosis and management, and refined prognostication of pe-
diatric CNS tumors. Advances in management have led to better survival, but mortality
remains high and significant morbidity persists. Patients often have deficits from the

Department of Pediatrics, Division of Pediatric Neurology and Developmental Neurosciences,

Texas Children’s Hospital, Baylor College of Medicine, 6701 Fannin Street, Suite 1250, Houston,
TX 77030, USA
E-mail address: malbari@bcm.edu

Neurol Clin 39 (2021) 829–845

https://doi.org/10.1016/j.ncl.2021.04.005 neurologic.theclinics.com
0733-8619/21/ª 2021 Elsevier Inc. All rights reserved.
830 Malbari

Fig. 1. Distribution in children and young adults (0–19 years of age) with primary CNS tu-
mors based on (A) histology and (B) location from the Central Brain Tumor Registry in the
United States. a All others include oligodendrogliomas, including anaplastic oligodendro-
gliomas, other neuroepithelial tumors, tumors of the pineal region, choroid plexus tumors,
other tumors of cranial and spinal nerves, other tumors of the meninges, hemangioma,
mesenchymal tumors, melanocytic lesions, hematopoietic neoplasms, and neoplasms un-
specified. b Other astrocytomas includes diffuse astrocytoma, anaplastic astrocytoma and as-
trocytoma variants. c All other embryonal tumors include ICD-O3 histology codes 8963/3,
9364/3, 9480/0, 9480/3, 9490/0, 9490/3, 9500/3, 9501/3, 9502/3. (Modified from Ostrom, Q.,
Cioffi, G., Gittleman, H., Patil, N., Waite, K., Kruchko, C. and Barnholtz-Sloan, J., 2019.
CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diag-
nosed in the United States in 2012–2016. Neuro-Oncology, 21(Supplement_5), pp.v1-v100.)

tumor or secondary to therapy. These include neurocognitive impairment, neuro-

endocrine dysfunction, and focal neurologic deficits, such as seizures; cranial nerve,
motor, or sensory deficits; ataxia; and stroke. Molecular profiling of tumors has
become incorporated in the most recent World Health Organization (WHO) 2016 clas-
sification and novel therapeutic approaches targeting the biology of these tumors are
being investigated to improve overall survival (OS) and decrease treatment-related
morbidity.3 Further molecular understanding of pediatric CNS tumors will lead to
continued refinement of tumor classification, management, and prognostication.

LOW-GRADE GLIOMA

Low-grade gliomas (LGG), the most common pediatric CNS tumor, represent 30% to
40% of all CNS tumors.4,5 Histologically LGGs (WHO grade I and II) are composed of
both astrocytic and mixed glial-neuronal tumors, with PA being the most common of
all LGGs. Other histologies include pilomyxoid astrocytoma, pleomorphic xanthroas-
trocytoma (PXA), diffuse astrocytoma, ganglioma, dysembryoplastic neuroepithelial
tumor (DNET), and subependymal giant cell astrocytoma (SEGA).6 Clinical presenta-
tion is dependent on tumor location, which can arise anywhere in the CNS. Cortical
tumors typically manifest with focal neurologic deficits, seizures, and headache. Cere-
bellar signs and increased intracranial pressure are most commonly seen with tumors
in the posterior fossa. Diencephalic tumors can present with failure to thrive. Although
LGGs are often localized, approximately 5% of patients at initial diagnosis and up to
12% of patients at time of progression will have disseminated disease.7
 Pediatric Neuro-oncology 831

Management of LGG is dependent on tumor location and age of the patient. Gross
total resection (GTR) can be curative and patients can be followed with serial imaging,
with a low risk of recurrence, 5-year posterior fossa syndrome (PFS) of 94%.8 Subtotal
resection is also beneficial as tumors can become quiescent for extended periods. For
patients in whom surgical resection cannot be achieved or if LGGs are progressive,
chemotherapy, radiation, and targeted therapy are other treatment options with 10-
year OS reported at approximately 90%.9 Patients with residual or progressive dis-
ease often have a decrease in quality of life (QOL) due to the chronic nature of the
disease and associated morbidity from the tumor and treatment. Radiation therapy
(RT) can achieve comparable results, with 5-year PFS and OS of 87% and 96%,
respectively.9 However, due to potential adverse effects from RT, including neurocog-
nitive effects, vasculopathies, secondary malignancies, endocrine and growth defi-
ciencies, radiation is often reserved for children older than 10 in whom
neurocognitive effects are not as significant, in children who have exhausted multiple
treatment options, or in patients in whom RT may cause the least toxicity.10 For these
reasons, chemotherapy is usually the preferred treatment option when GTR is not
feasible, although this may change with the recent advances in molecular character-
ization of pediatric CNS tumors and the availability of targeted therapy. Chemotherapy
is not as effective as surgery or radiation but can achieve approximately 50% PFS at
5 years.11,12 The most common chemotherapy regimens used are carboplatin and
vincristine or single-agent vinblastine.
Pediatric LGG (pLGG) molecular alterations involve the RAS-MAPK pathway, with
most involving the BRAF oncogene13–19 (Table 1). In 70% to 80% of pediatric PAs,
there is a tandem duplication on chromosome 7q34 resulting in a BRAF-KIAA1549
fusion, which is almost universally found in midline and infratentorial PAs.5 The other
common alteration seen in 15% to 20% of pLGGs is a BRAF V600E mutation, which is
frequently found in supratentorial hemispheric PAs, PXAs, gangliogliomas, and
DNETs.20 It suggests a poorer prognosis with an increased risk of tumor progres-
sion.4,20 IDH mutations often observed in adults with LGG infrequently occur in ado-
lescents with diffuse astrocytomas and the clinical significance in this population
remains unclear. MAP/ERK kinase (MEK) inhibitors and BRAF inhibitors have shown
promising results in patients with these alterations.9,14 Results from phase I and II clin-
ical trials using MEK and BRAF inhibitors in patients with recurrent or refractory pLGG
has led to the development of upfront phase III clinical trials randomizing standard of
care chemotherapy to these targeted therapies in patients with newly diagnosed or
previously untreated pLGG with BRAF fusion alterations (NCT04166409) or mutations
(NCT02684058).21,22
Patients with NF1 AND TSC have an increased risk of developing pLGGs (Table 2).
PA of the optic pathway can occur in 15% to 20% of patients with NF1.23–26 Treatment
for symptomatic tumors are similar to non NF-1 PAs, with chemotherapy as the first
option because surgery is generally not feasible and RT can cause an increased
risk for secondary malignancies and vasculopathy; it is therefore reserved for patients
with progressive tumors who have exhausted other therapeutic options. Targeted
therapy with MEK inhibitors has shown promising results leading to a phase III clinical
trial randomizing standard of care chemotherapy versus a MEK inhibitor
(NCT03871257).9 SEGAs can occur in 20% of patients with TSC. If a patient is symp-
tomatic with acute focal neurologic deficits or obstructive hydrocephalus, surgical
resection is indicated. Otherwise, targeted therapy with mammalian target of rapamy-
cin inhibitors is recommended for unresectable tumors or multisystem involvement of
TSC.25,27,28
832 Malbari

Table 1
Molecular alterations of specific pediatric central nervous system tumors

Tumor Molecular Alterations

Low-grade glioma BRAF KIAA1549 fusion, BRAF V600E
FGFR1
NTRK
MYB, MYBL1
CDKN2A/B
IDH
NF1
TSC1/2
High-grade glioma H3.1 and H3.3 K27M, H3.3 G34R/V
Diffuse intrinsic pontine glioma IDH1, IDH2, MYCN, PDGFRA, EGFR, BRAF V600E, TP53, NF1,
ATRX
PI3-kinase/Akt/mTOR
H3.1 and H3.3 K27M, ACVR1, PDGFRA, MYCN, ID2
PI3-kinase/Akt/mTOR
Medulloblastoma Monosomy 6, CTNNB1, TP53, DDX3X, APC and SMARCA4
Wingless PTCH1, SUFU, SMO, GLI1, GLI2, TP53, PI3K, MYCN, TERT, loss
Sonic hedgehog (SHH) of chromosome 9q and 10q
Group 3 MYC, MYCN, OTX2, SMARCA4, KBTBD4, CTDNEP1, KMT2D,
Group 4 GFI1, GFI1B
Isochromosome 17q gain of chromosomes 1q and 7, loss of
chromosomes 8, 10q and 16q
KDM6A, ZMYM3, KMT2C (MML3), MYCN, CDK6, OTX2
isochromosome 17
Gain of chromosome 7, 17
Loss of chromosomes 8, 11 and 17 p
Atypical teratoid SMARCB1, SMARCA4,SMARCB4
rhabdoid tumors (ATRT)
ATRT-SHH
ATRT-MYC
ATRT-TYP
Ependymoma C11ORF95-RELA, YAP1, CDKN2A/B loss of either 9p or the
Supratentorial (excluding entire chromosome 9
subependymoma) CXorf67, Gain of chromosome 1q, histone 3 variants (H3.1
Posterior Fossa-A and H3.3 K27M)
Posterior Fossa-B Loss of chromosome 6 and 13q
Craniopharyngioma CTNNB1
Adamantinomatous BRAF V600E
Papillary

HIGH-GRADE GLIOMA

High-grade gliomas (pHGG) in children represent approximately 15% to 20% of pedi-

atric CNS tumors. These include anaplastic astrocytoma (WHO grade III), glioblas-
toma (WHO grade IV) and diffuse intrinsic pontine glioma (DIPG). Other less
common histologies include anaplastic PXA, anaplastic ganglioglioma, and pilocytic
astrocytoma with anaplasia. Despite advances in management, it still has a poor
outcome, with OS at 5 years less than 20%.29 Clinical presentation is dependent on
tumor location. Patients can present with signs of increased intracranial pressure or
focal neurologic deficits. Seizures are less common in pHGG.
Management of pHGG is maximal safe surgical resection followed by focal RT. The
extent of resection is a predictor of overall outcome, with near to GTR associated with
Table 2
Hereditary cancer predisposition syndromes associated with central nervous system (CNS) tumors

Cancer Predisposition Syndrome Germline Mutation CNS Tumor Type

Neurofibromatosis 1 Chromosome 17q11, NF1 Pilocytic astrocytoma
Low-grade glioma
Tuberous sclerosis Chromosome 9q34, TSC1 Subependymal giant cell astrocytoma, Low-
Chromosome 16p13, TSC2 grade glioma
Gorlin syndrome Chromosome 9q22, PTCH1 chromosome 10q24, Medulloblastoma, SHH subgroup
SUFU
Constitutional mismatch repair deficiency Biallelic mutations mismatch repair genes: High-grade glioma
Lynch syndrome Chromosome 7p22, PMS2
Chromosome 3p22, MLH1
Chromosomes 2p21–16, MSH2
Chromosome 2p16, MSH6
Monoallelic mutations in mismatch repair genes
Familial adenomatous polyposis syndrome Chromosome 5q21–22, APC Medulloblastoma, WNT subgroup
(Turcot syndrome 2)

Pediatric Neuro-oncology
Li Fraumeni Syndrome Chromosome 17p13, TP53 High-grade glioma, choroid plexus carcinomas,
medulloblastoma SHH subgroup
Neurofibromatosis 2 Chromosome 22q12, NF2 Ependymoma, meningioma, schwannoma

833
834 Malbari

a greater than 5-year PFS.30,31 Infants and very young children with HGG have better
OS outcomes than older children.32,33 Multiple chemotherapy regimens have been
tried in pHGG without any significant improvement in OS.14,34–36 Molecular profiling
of pHGG has identified potential targetable therapeutic options that are currently be-
ing investigated.
Molecular characterization of pHGG has led to the discovery of unique characteris-
tics that separate these tumors from adult HGG and has allowed for further subgroup-
ing.14,18 pHGGs have a novel oncogenic mutation in histone 3 variants including H3.1
K27M and H3.3 K27M as well as H3.3 G34R/V (see Table 1). The H3.1 and H3.3 K27M
mutation are classically seen in diffuse midline HGGs.14 Within the K27M mutated
pHGG, the H3.3 K 27M mutation can be seen in all midline HGGs and in most DIPG
tumors and is associated with a poorer outcome, whereas the H3.1 K27M mutation
is unique to DIPG, frequently co-occurs with an ACVR1 mutation, and portends a
slightly better prognosis. H3.3 G34R/V mutations are seen in up to a third of hemi-
spheric HGGs. As opposed to adult HGG, less than 5% of pHGGs have somatic mu-
tations in IDH1 or IDH2.14,29,37–40 pHGG with wild-type Histone 3 and IDH1/2 GBM can
be subdivided further into 3 additional groups: (1) receptor tyrosine kinase, (2) mesen-
chymal, and (3) PXA-like, distinguished by BRAF V600E mutation and deletion of
CKDN2A.14,18,37,39 PXA-like pHGG, which represents 5% to 10% of pHGGs, have
BRAF V600E mutations similar to LGGs and tend to have a better prognosis with
slightly prolonged survival. They can be treated with targeted BRAF inhibitors.14,29,39
The discovery of these somatic mutations in pHGG has led to clinical trials using tar-
geted agents to different molecular alterations. Histone deacetylate inhibitors, dopa-
mine receptor 2 antagonist, and GD2 chimeric antigen therapy are being investigated
in H3K27M mutated tumors (NCT02717455, NCT04196413, NCT03416530,
NCT04099797).41–43 Tyrosine kinase inhibitors targeting epidermal growth factor re-
ceptor, platelet-derived growth factor receptor, vascular endothelial growth factor re-
ceptor, and c-met are being explored in addition to PD-1 inhibitors for hypermutant
gliomas.20 Other treatment options include immune therapy using vaccines with
glioma-associated antibodies and other different delivery approaches of novel agents
to bypass the blood brain barrier (intra-arterial, convection enhanced delivery, intra-
nasal, intracavitary).29

Diffuse Midline Glioma and Diffuse Intrinsic Pontine Glioma

Diffuse midline gliomas are a distinct entity of pHGG, with most of these tumors arising
in the pons (DIPG). Other common locations include the thalamus and spinal cord.
DIPG typically occurs in school-aged children and is universally fatal. Patients present
with rapid onset of cranial nerve deficits, long tract signs, ataxia, and obstructive hy-
drocephalus in a third of patients. DIPGs are radiologically defined as an expansile
diffusely infiltrative T1 hypointense and T2 hyperintense mass involving the pons.44
Histologically, these tumors can be WHO grade II-IV but prognosis remains dismal,
with median survival of 11 months.45 Diagnosis is generally a combination of both clin-
ical symptoms and radiographic appearance, although biopsies are being offered
more routinely and are required for enrollment on some clinical trials. RT is standard
of care and only provides transient relief of symptoms without any significant improve-
ment in OS. Multiple therapeutic strategies have been investigated, including radio-
sensitizers and chemotherapy, but all have been ineffective.46–48
LFS, CMMRD, and Lynch syndrome are genetic cancer predisposition syndromes
associated with the development of HGGs (see Table 2). Patients with LFS are predis-
posed to a variety of childhood malignancies including HGGs, choroid plexus carci-
nomas, and sonic hedgehog (SHH) medulloblastoma (MB).29,49,50 Treatment is
 Pediatric Neuro-oncology 835

generally the standard therapy for sporadic cases. CMMRD and Lynch syndrome are
associated with the development of glioblastoma. Patients with pHGG due to
mismatch repair deficiencies are treated similar to patients with sporadic GBM but
are often resistant to therapy. However, clinical responses have been seen to check-
point inhibition.14,29,49,51

MEDULLOBLASTOMA

MB is the most common CNS embryonal tumor, representing approximately 64% of

all pediatric embryonal tumors.1,52 It generally arises from the cerebellum, can invade
the fourth ventricle, and can present with CNS metastases in a third of patients at diag-
nosis. As part of tumor staging, patients will get an MRI of the spine and lumbar punc-
ture for CSF cytology. Clinically, patients will present with symptoms concerning for
increased intracranial pressure and cerebellar dysfunction.
Management of MB is initiated with maximal safe surgical resection followed by risk
adapted craniospinal irradiation (CSI) and adjuvant chemotherapy in children older
than 3 years. Risk stratification is based on age of the patient, extent of surgical resec-
tion, and the presence of metastatic disease. In patients with average-risk MB, defined
as GTR with no evidence of metastatic disease, 5-year OS is approximately 80% in
comparison with 60% for high-risk MB, defined as residual tumor measuring larger
than 1.5 cm2 and the presence of metastatic disease.52 In general, patients with
average-risk MB will receive 23.4 Gy CSI with a boost to the tumor bed of 54 Gy fol-
lowed by chemotherapy consisting of a combination of cisplatin, carboplatin, vincris-
tine, cyclophosphamide, and lomustine. Patients with high-risk MB will receive 36 Gy
CSI with a boost to the tumor bed of 54 Gy followed by the same conventional chemo-
therapy. In infants with MB (younger than 3 years), radiation sparing therapy is the
standard of care due to potential devastating effects; this often leads to inferior sur-
vival. Infants will receive myeloablative chemotherapy followed by autologous stem
cell rescue (ASCR).
Treatment of MB is not without toxicity. Approximately 25% of patients develop PFS
after surgical resection of MB.53 PFS is a constellation of symptoms including
emotional lability, paucity of speech (mutism), cerebellar syndrome, and cranial nerve
dysfunction. The underlying mechanism for the development of this syndrome is not
completely understood but is felt to be secondary to disruption of the dentate-
rubro-thalamic pathway. Patients with posterior fossa syndrome will eventually have
some recovery of speech and cerebellar dysfunction, but most without a full recovery.
They also have significant neurocognitive impairment, worse than their counterparts
with MB without posterior fossa syndrome.53 CSI can cause neurocognitive impair-
ment in patients with MB in addition to secondary malignancies, vasculopathy, and
endocrine deficiencies. The conventional chemotherapy used for MB can cause neu-
ropathy and ototoxicity. Because of these toxicities, MB survivors often have an
increased risk of poor QOL. Molecular characterization of MB has allowed for identi-
fication of different prognostic groups and molecular risk stratification is now being
incorporated into clinical management (Table 3). Previously, classification of medullo-
blastoma was dependent on histopathology; however, now DNA methylation profiling
has identified 4 molecular subgroups of MB.3 The 4 different subgroups are wingless
(WNT), SHH, group 3, and group 4.52,54–56
The WNT subgroup represents 10% of all MBs and are typically seen in older chil-
dren. These tumors are centrally located near the brainstem, are nonmetastatic, and
most frequently have classic histology. Patients classified as the WNT subgroup
have the best prognosis, with 5-year OS of 95%, and are stratified as low risk (see
836 Malbari

Table 3
Clinical risk groups for medulloblastoma

Intermediate-Risk 5-
Low-Risk 5-Year OS >90% Year OS 75%–90% High-Risk 5-Year OS <60%
WNT, M0, M1 SHH, TP53 wild type Group 3, MYC and non MYC
amplified Group 3, M1
SHH, MBEN SHH, not MBEN SHH b/I
SHH g/II Group 4 SHH, TP53 mutant
Group 4 with Group 4, M1
chromosome 11 loss or 17 gain

Abbreviations: M0, no evidence of metastases in MRI or CSF cytology; M1, microscopic tumor cells
in CSF; M2, gross intracranial metastasis beyond primary site; M3, gross metastasis in subarachnoid
space; M4, metastasis outside cerebrospinal axis; MBEN, medulloblastoma with extensive nodular-
ity; OS, overall survival; SHH, sonic hedgehog.
Data from Northcott PA, Robinson GW, Kratz CP, et al. Medulloblastoma. Nature reviews. Disease
primers. 2019;5(1):11.

Table 3).57 Molecular alterations specific to WNT include monosomy 6 and a mutation
in CTNNB1 (Fig. 2; see Table 1).56 APC mutations are often associated with FAP (see
Table 2). De-escalation of therapy consisting of decreased doses of both CSI and
chemotherapy are being investigated in this subgroup, given the overall excellent
prognosis, in attempt to decrease toxicity and late effects.52

Fig. 2. MB subgroups and risk adapted management. (Data from Northcott PA, Robinson
GW, Kratz CP, et al. Medulloblastoma. Nature reviews. Disease primers. 2019;5(1):11.)
 Pediatric Neuro-oncology 837

The SHH subgroup accounts for approximately 30% of all MBs and has a bimodal
age distribution, occurring more frequently in children younger than 3 or older than
16 years. These tumors usually arise from the cerebellar hemispheres and present
with appendicular ataxia.18 The most common histology seen is desmoplastic or
MB with extensive nodularity.18 SHH MB can be further categorized into 4 different
subtypes: SHH b/I, SHH g/II, SHHa, and SHHd.20,52,58 SHH b/I and SHH g/II are the
2 predominant subtypes in infants. SHH b/I is associated with poorer outcomes, often
with metastatic disease and molecularly have PTEN loss and SUFU mutations,
whereas infants with SHH g/II subtype have excellent outcomes and SMO muta-
tions.59 SHHa is the most common subtype in older children and when associated
with germline p53 mutation, portend a significantly worse prognosis. SHHd is most
commonly seen in adults and adolescents and is associated with PTCH, SMO, and
TERT promoter mutations (see Fig. 2, Table 1).56,60 SHHa and SHHd patients will
receive surgery, CSI, and chemotherapy with the addition of an SHH inhibitor in the
setting of a clinical trial (NCT01878617).
Group 3 MB represents approximately 25% of all MBs and are seen in young infants
and children. Tumors are often midline near the fourth ventricle and metastatic in 40%
of patients at initial diagnosis.61 This subgroup is associated with the worst prognosis,
with 5-year OS less than 60%.52 Histology is frequently large cell, anaplastic, or
classic. Three different subtypes of group 3 are being proposed based on genetic al-
terations and outcomes.52,56,61 MYC amplification can be seen in 20% of patients,
which is associated with poor outcomes (see Table 3). Isochromosome 17q is also
seen frequently in this subgroup (see Fig. 2, Table 1). Treatment for high-risk patients
includes surgery, CSI, and chemotherapy, with the addition of novel agents through a
clinical trial (NCT01878617) and high-dose chemotherapy with ASCR for
infants.59,62,63
Group 4 MB, the most common subgroup, represents 35% of all MB and is seen in
late childhood, early adolescence. These tumors typically arise from the midline adja-
cent to the fourth ventricle and are metastatic in a third of patients. Histology is often
classic and based on molecular features, and can be further subdivided into 3 sub-
types. Prognosis is intermediate, with 5-year OS reported at 70%. The low-risk group
has chromosome 11 loss or 17 gain and the high-risk group has metastatic disease at
diagnosis (see Table 3).57 Isochrome 17q is seen in 80% of patients in this subgroup
(see Fig. 2, Table 1).20 MYCN amplification can be seen in a small subset and is asso-
ciated with poorer outcomes. Treatment includes surgery, CSI, and chemotherapy
with the potential addition of novel agents for high-risk patients (NCT01878617).
Gorlin, FAP, and LFS are cancer predisposition syndromes associated with the
development of MB. SHH MB typically develops in infants with Gorlin syndrome.
Treatment is the same as infant SHH MB, specifically avoiding radiation, as there is
a significantly higher risk for developing secondary basal cell carcinoma in the radia-
tion field. FAP is characterized by the development of multiple adenomatous polyps
and WNT MB in adolescence (see Table 2).24,64,65 Patients are treated the same as
sporadic cases of WNT MB.

ATYPICAL TERATOID RHABDOID TUMORS

Atypical teratoid rhabdoid tumors (ATRT) are highly aggressive tumors that affect chil-
dren younger than 3 years, with a 5-year OS of 30% to 40%.66 These tumors represent
about 15% of all CNS embryonal tumors (see Fig. 1).1,67 They can arise most
commonly in the infratentorial region, followed by supratentorial and rarely in the spi-
nal cord. Approximately 20% to 40% of patients will have metastatic disease at the
838 Malbari

time of diagnosis and require extent of disease evaluation with CSF analysis and MRI
of the spine. Clinical presentation is dependent on tumor location, with infratentorial
tumors presenting with increased intracranial pressure and cranial nerve deficits
and supratentorial tumors with headaches and focal deficits.
Management of ATRT has been challenging due to the aggressive nature and young
age of patients. Multimodal therapy with surgery, conventional chemotherapy, high-
dose chemotherapy with ASCR, and focal radiation has shown dramatic improvement
in OS compared with historical therapies that included dose-intensive multi-agent
chemotherapy without radiation.66 RT has been avoided due to age; however, some
studies have shown that focal RT may not have as significant neurocognitive affects.68
A recent Children’s Oncology Group (COG) trial used this multimodal approach in
addition to age-stratified RT, which resulted in a 4-year OS of 43%.
Mutations associated with ATRT include biallelic inactivation of SMARCB1 on chro-
mosome 22, which histologically can be identified as loss of INI1 nuclear staining. Less
frequently you can see a SMARCB4 mutation.69 In addition to these somatic muta-
tions, a third of patients will have germline mutations in SMARCB1 and less commonly
SMARCA4.70 Further molecular analyses of ATRT has identified 3 main subgroups.69
Targeted therapies are under investigation through clinical trials (NCT02114229).

EPENDYMOMA

Ependymoma is the third most common malignant CNS tumor and represents
approximately 5% of all pediatric CNS tumors.1 They can arise anywhere in the neuro-
axis, but 90% of pediatric cases occur intracranially, with two-thirds in the posterior
fossa and one-third supratentorially. There is a peak incidence in early childhood.
Fewer than 10% of patients will present with metastatic disease at diagnosis and
therefore require MRI spine and CSF analyses for further evaluation.71,72 Clinical
symptoms are dependent on tumor location with infratentorial tumors often presenting
with signs of increased intracranial pressure, cranial nerve palsies, and ataxia and
supratentorial tumors presenting with focal neurologic deficits, headaches, and sei-
zures. Histologically, ependymomas can be WHO grade I (myxopapillary ependy-
moma, subependymoma), grade II (classic ependymoma), or grade III (anaplastic
ependymoma).73
Treatment is similar for all tumor locations, with maximal safe surgical resection fol-
lowed by focal RT in children older than 1. Chemotherapy is currently used for children
younger than 1, as a bridge to focal RT. A Phase III COG study was recently completed
to determine if chemotherapy provides any additional benefit after surgery; these data
are currently being analyzed. The 10-year OS is approximately 60%, but patients diag-
nosed in infancy have the lowest survival.74
Nine molecular subgroups of ependymoma have been identified, 3 in each anatomic
location: supratentorial, posterior fossa, and spinal cord (Fig. 3). Sub-ependymomas,
which primarily occur in adults, represent one molecular subgroup in each anatomic
region. The other 2 molecular subgroups for spinal cord ependymomas are distin-
guished by pathology: myxopapillary, and WHO grade II/III ependymomas. Supraten-
torial ependymomas (ST-EPN) can be subdivided by the presence of fusion
oncoproteins: C11ORF95-RELA and YAP1 (ST-EPN-RELA and ST-EPN-YAP1,
respectively) (see Table 1). The ST-RELA subgroup represents 85% of supratentorial
ependymomas and occurs in all ages, whereas the ST-YAP1 subgroup is found mostly
in pediatric patients.73,74 The ST-RELA subgroup is believed to have a poorer prog-
nosis but prospective studies did not show any differences in event-free survival be-
tween the different subgroups.72–76 The ST-YAP1 subgroup is said to have an
 Pediatric Neuro-oncology 839

Fig. 3. Ependymoma molecular subgroups. (Data from Pajtler KW, Witt H, Sill M, et al. Mo-
lecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological
Grades, and Age Groups. Cancer cell. 2015;27(5):728-743.)

excellent prognosis while homozygous deletion of CDKN2A/B is associated with infe-

rior outcomes in ST-RELA tumors.20,74,76 Posterior fossa ependymomas (PF-EPN)
have 2 additional subgroups identified as PF-EPN Group A (PF-EPN-A) and PF-EPN
Group B (PF-EPN-B). PF-EPN-A tumors primarily occur in infants and young children,
whereas PF-EPN-B ependymomas are predominant in adolescents and young
adults.73,74 PF-EPN-A subgroup is associated with a poorer prognosis and in a small
proportion of tumor mutations in CXorf67 and histone 3 variants have been
described.77,78 Gain of chromosome 1q in the PF-EPN-A subgroup and loss of chro-
mosome 13q in the PF-EPN-B subgroup are also associated with poorer outcomes in
PF-EPN.74,76 Management is standard for all subgroups; however, observation-only
clinical trials will be implemented for PF-EPN-B without loss of chromosome 13q
and ST-EPN-RELA after GTR.20,73
Approximately 50% of patients with NF2 can develop ependymomas in addition to
meningiomas, gliomas, schwannomas, and neurofibromas.79 Treatment of NF2 CNS-
associated tumors are similar to sporadic counterparts; however, molecularly targeted
therapies are currently being investigated (NCT04374305, NCT04283669,
NCT03095248).

CRANIOPHARYNGIOMA

Craniopharyngiomas occur in the sellar/parasellar region and represent 2% to 6% of

all pediatric brain tumors.80 There are 2 histologic subtypes, adamantinomatous (ACP)
and papillary (PCP). In childhood and adolescence, the predominant histologic sub-
type is ACP, with peak age of incidence at 5 to 15 years (bimodal peak with second
peak at 45–60 years). PCP is most frequently seen in adults. Children with ACP often
present with visual disturbances, headaches, and endocrine deficiencies. Current
treatment options for craniopharyngioma include GTR or partial resection followed
by RT. Both treatment options achieve comparable results and decrease the risk of
tumor recurrence. Although histologically these tumors are considered benign, they
are associated with significant morbidity and poor QOL. Overall, mortality is also 3
to 5 times greater than the general population in patients with CP.80 As such, more
effective, novel therapeutic strategies are being investigated.
ACP tumors frequently carry mutations in CTNNB1, whereas PCP subtypes carry
BRAF V600E mutations. In addition, activation of the MAPK, immune, and
840 Malbari

inflammatory pathways has been demonstrated, such as elevation of interleukin-6 and

increased expression of PD-1, PD-LI, and CTLA-4.81–85 Clinical trials using targeted
therapy to address some of these pathways are currently ongoing, whereas others
are being designed (NCT03224767, NCT03970226).

CLINICS CARE POINTS

 Molecular profiling of CNS tumors are changing the current tumor classification,
management, and prognostication of these patients.
 The goal of management of pediatric brain tumors is to continue to improve survival,
decrease morbidity, and improve QOL.
 In patients who have received RT, recommend monitoring for potential neurologic side
effects, including neurocognitive outcomes, radiation vasculopathy, and secondary CNS
malignancies.
 Targeted therapy for pediatric brain tumors is currently being investigated for different
tumor types and may be the future direction of care for these patients.

DISCLOSURE

None.

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