PIR2020004499_proof.pdf

Central Nervous System Tumors

in Children

Katherine C. Pehlivan, MD,* Megan R. Paul. MD,

†

and John R. Crawford, MD, MS

†,‡

*Department of Pediatrics, Division of Hematology-Oncology, New York Medical College, Valhalla, NY

†

Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego and Rady Children’s Hospital, San Diego, CA

‡

Department of Neurosciences, University of California and Rady Children’s Hospital, San Diego, CA

EDUCATION GAP

The role of the pediatrician is crucial in both the diagnosis and

management of pediatric brain tumors, the most common solid tumor of

childhood. Awareness of the presenting signs and symptoms of brain

tumors can lead to timely diagnosis, and understanding the late effects of

brain tumor treatment improves long-term management of childhood

brain tumor survivors.

OBJECTIVES After completing this article, readers should be able to:

1. Recognize the presenting symptoms and physical examination ﬁndings

suggestive of a childhood brain tumor and how these ﬁndings depend

on tumor location.

2. Review common brain tumor pathologies affecting children.

3. Understand how molecular genetics plays a role in the diagnosis and

treatment of childhood brain tumors.

4. Recognize the late affects associated with the treatment of childhood

brain tumors.

INTRODUCTION

Brain tumors are the most common solid malignancy in children and represent

the leading cause of pediatric cancer-related deaths. Five thousand new brain

tumors are diagnosed yearly in the United States in children ages 0 to 19 years,

with an incidence of approximately 6 per 100,000 children. (1) Childhood brain

tumors, more than half of which are malignant, vary in terms of biology, prog-

nosis and treatment. Presenting signs and symptoms depend on tumor location,

growth rate, and presence of obstructive hydrocephalus. Making the initial diag-

nosis of a brain tumor can be difﬁcult because early symptoms, such as head-

aches or vomiting, are nonspeciﬁc to brain tumors and more frequently are

associated with other etiologies, leading to delays in diagnosis. The pediatrician

plays a crucial role in the timely diagnosis of patients with brain tumors as well

AUTHOR DISCLOSURE: Drs Pehlivan,

Paul, and Crawford have disclosed no

ﬁnancial relationships relevant to this

article. This commentary does contain a

discussion of an unapproved/

investigative use of a commercial

product/device.

ABBREVIATIONS

ATRT atypical teratoid rhabdoid tumor

CNS central nervous system

CN cranial nerve

CSF cerebrospinal ﬂuid

CT computed tomography

HGG high-grade glioma

ICP intracranial pressure

LGG low-grade glioma

MRI magnetic resonance imaging

NF neuroﬁbromatosis

NGGCT nongerminomatous germ cell

tumor

OS overall survival

WHO World Health Organization

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ARTICLE

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as recognizing late effects resulting from tumor therapies.

This review summarizes the presenting features on history

and physical examination, tumor classiﬁcation of common

tumor types, genetic brain tumor predisposition syndromes,

general management strategy, and late ef fects of therapy.

PRESENTATION OF BRAIN TUMORS IN CHILDREN

Signs and symptoms of a pediatric brain tumor can be non-

speciﬁc, insidious , inter mittent , and dependent on locatio n

within the central nervous system (CNS) and the anatomical

pathways affected. Although headache is the most common

presenting complaint overall, it is present in only approxi-

mately one-third of the children presenting with brain

tumors, and, in the absence of other symptoms or physical

examination ﬁndings, is not in itself predictive of a brain

tumor. Elevated intracranial pressure (ICP) is present in

approximately half of all children with brain tumors. In addi-

tion to headache, it can cause nausea/vomiting, abnormali-

ties of gait and coordination, and papilledema. Vital sign

abnormalities associated with increased ICP, known as the

Cushing triad (bradycardia, hypertens ion, ab normal respira-

tions), are late signs of acutely increased ICP but can be

absent in those with chronically elevated ICP. In young chil-

dren with an open fontanelle, macrocephaly, especially when

progressive, can be suggestive of hydrocephalus and a poten-

tial mass-occupying lesion. (2)

Presenting symptoms depend on tumor location (Fig 1),

and certain constellations of symptoms can point to speciﬁc

lesion locations. Table 1 lists commonly overlooked signs

and symptoms that can lead to a delayed diagnosis . Wilne

et al analyzed presenting features of more than 4,000 child-

hood brain tumors and found that for posterior fossa

tumors, three-quarters presented with nause a and vomiting,

two-thirds with headache, three-ﬁfths with abnormal gait

and coordination, and one-third with papilledema. (2) In

contrast, headache, nausea, and vomiting were rare in

patients presenting with supratentorial tumors. Instead, seiz-

ures were present in one-third of patients, along with focal

neurologic deﬁcits such as weakness or sensory deﬁcits on

the contralateral side if there is involvement of the cortical

motor or sensory regions, respectively . (2) In cases of brain-

stem tumors, children can present with crossed ﬁndings of

ipsilateral facial weakness and contralateral hemiparesis.

More than 75% of patients with brainstem tumors presen t

with abnormal gait and coordination, whereas cranial nerve

(CN) palsies are present in more than half. Headache, how-

ever, is not common in patients with brainstem tumors and

is present in less than one-quarter at the time of diagnosis.

Thalamic tumors can cause coordination and motor difﬁcul-

ties or hemiple gia. (2)

Patients with pituitary tumors or optic pathway tumors

often present with visual deﬁcits. It is not uncommon for

even severe visual deﬁcits in children to go unrecognized by

the patient, parents, or pediatrician. (3) Because patients

with neuroﬁbromatosis (NF) type 1 are at increased risk for

optic pathway glioma, they should have yearly ophthalmol-

ogy evaluations. Children with pituitary or hypothalamic

tumors often present with endocrine abnormalities, such as

failure to thrive, excessive thirst, or central obesity.

Figure 1. Presenting features of childhood brain tumors based on tumor

location. The presenting symptoms in the child with a brain tumor differ

based on the anatomical location of the tumor. Here, various anatomical

regions of the brain are highlighted and correlated to common constella-

tions of presenting symptoms suggestive of a lesion in that region of the

brain.

Table 1. Initial Presenting Signs and Symptoms Leading to Diagnosis of Brain Tumors in Various Locations

SIGNS AND SYMPTOMS TUMOR LOCATION

Early-morning vomiting, recurrent vomiting, enlarging head

circumference

Posterior fossa, ventricular system

Failure to thrive, anorexia Suprasellar region, hypothalamic

Visual complaints, abnormal eye movements Optic pathway, suprasellar region, brain stem, posterior fossa

Tics, tremors, movement disorder Basal ganglia, thalamus, midbrain

Early handedness Cortex, subcortical, brain stem, spinal cord

Facial nerve palsy Brain stem, cerebellar pontine angle

Hearing loss Cerebellar pontine angle

Precocious puberty, nocturnal enuresis Suprasellar region

Head tilt, torticollis Cerebellar pontine angle, cervicomedullary junction

Reproduced with permission from American Academy of Pediatrics, adapted from Crawford J. Childhood brain tumors. Pediatr Rev.

2013;34(2):63–78.

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Children with spinal cord tumors most commonly pre-

sent with back pain, present at diagnosis in approximately

two-thirds of cases. Spinal cord tumors may occur in extra-

dural, intramedullary, and extramedullary intradural loca-

tions. Although some children may present with scoliosis,

most will not. Spinal cord compression causes signs such

as gait and coordination abnormalities, focal weakness, or

bowel and bladder dysfunction. (2)

ROLE OF THE NEUROLOGIC EXAMINATION

A comprehensive neurologic examination (summarized in

Table 2) is crucial to identify abnormalities that might be

suggestive of a CNS tumor. A normal neurologic examina-

tion does not exclude the diagnosis of a brain or spinal

cord tumor and must be correlated with symptoms.

Mental Status

Patients with acute hydrocephalus can display dramatic

changes in their mental status, with increased sleepiness,

decreased energy, and decreased responsiveness. How-

ever, those with chronic hydrocephalus might show only

subtle signs, such as slowly declining school performance.

Cranial Nerves

A fundoscopic examination of the optic nerve, CN II, is

crucial to assess for papilledema and optic nerve pallor,

which can reveal information about hydrocephalus or

tumors along the optic pathways. A fundoscopic examina-

tion can be difﬁcult in young or uncooperative children,

warranting referral to ophthalmology for a dilated exami-

nation. Vision should be assessed by confrontation in the

4 quadrants of each eye because different patterns of

visual ﬁeld deﬁcits will suggest varying tumor locations.

In younger children, assessment of visual ﬁelds can be

performed using a colorful object for central ﬁxation and

introducing a second object in the periphery and watching

for the eyes to track to that object.

Eye movements are controlled by CNs III, IV, and VI.

The nuclei of CNs III and IV are located in the midbrain,

whereas the nucleus of CN VI is in the pons, and brainstem

tumors can lead to abnormalities of extraocular movements.

Large pineal tumors can cause Parinaud syndrome, charac-

terized by upgaze palsy, convergence-retraction nystagmus,

and poorly reactive pupils due to compression of the rostral

midbrain. Nystagmus can also be seen in patients with cere-

bellar tumors or optic pathway tumors.

CN V, the trigeminal nerve, has 3 divisions that give sensa-

tion to the face. The trigeminal nucleus is located in the pons,

as is the nucleus of CN VII (the facial nerve), which controls

facial movement. Facial asymmetry or decreased facial sensa-

tion should raise concern for a mass in this region. Hearing in

each ear should be assessed to look for CN VIII dysfunction.

The lower CNs (CNs IX, X, XII) exit from the medulla

and are involved in phonation, swallowing, and tongue

Table 2. Key Components of the Neurologic Examination in a Child with Suspected Central Nervous System

Tumor

EXAMINATION PERTINENT FINDINGS SUGGESTIVE OF TUMOR

Mental status (alertness, speech) Encephalopathy, progressive neurocognitive decline

Cranial nerve II (visual ﬁelds, fundoscopic examination) Visual ﬁeld deﬁcit, papilledema, optic nerve pallor

Cranial nerves III, IV, VI (extraocular movements, efferent pupillary

function)

Nystagmus (upgaze in particular), gaze paralysis in any direction,

mid-position, poorly reactive pupils

Cranial nerve V (facial sensation) Asymmetry or change in facial sensation in anatomical distribution

of V1, V2, V3

Cranial nerve VII (facial symmetry, movement) Facial weakness (upper vs lower motor neuron distribution)

Cranial nerve VIII (hearing, balance) Decreased hearing to ﬁnger rub (unilateral or bilateral), vertigo

Cranial nerves IX, X, XII (palate elevation, swallowing, tongue

movements)

Drooling, dysphagia, asymmetrical palate

Motor examination (bulk, tone, proximal and distal strength) Early handedness, delayed motor milestones, pronator drift, focal

changes in tone with associated atrophy

Sensory examination Sensory deﬁcits in a focal anatomical distribution

Reﬂexes (biceps, triceps, brachioradialis, patellar, Achilles) Hyperreﬂexia with Babinski sign

Coordination (ﬁnger to nose testing, mirror testing, rapid ﬁnger

and toe tapping)

Dysmetria, overshoot on mirror testing, marked asymmetry of ﬁnger

and/or toe tapping (must be differentiated from weakness)

Gait (heel, toe, tandem straight line) Wide-based unsteady gait, inability to perform straight-line test,

circumduction of gait

A thorough neurologic examination includes assessment of mental status, cranial nerves, motor and sensory function, reﬂexes, coordination,

and gait. Examples of abnormal ﬁndings according to each examination component that might suggest a central nervous system mass or

lesion are listed. These abnormalities should be interpreted within the clinical context but can suggest a need for imaging or further

evaluation.

Reproduced with permission from American Academy of Pediatrics, adapted from Crawford J. Childhood brain tumors. Pediatr Rev.

2013;34(2):63–78.

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movement. Palatal asymmetry, change in voice quality, or

unilateral glossal atrophy raises suspicion for a medullary

lesion. CN XI, the accessory nerve, has the most distal

nucleus, also in the medulla, and innervates the trapezius

and sternocleidomastoid musculature.

Motor Function, Sensation, Reflexes

Motor function, sensation, and reﬂexes should be assessed

with special attention to comparison with the contralateral ﬁnd-

ings. Asymmetry can indicate a lesion affecting corticospinal

tracts (motor), spinothalamic tracts (temperature, pain, light

touch), or dorsal columns (proprioception, vibratory sense).

Asymmetric al hypo reﬂexia can indicate lower motor neuron

injury, whereas hyperreﬂex ia and the presence of a Babinski

reﬂex are indicative of upper motor neuron dysfunction. In

acute upper motor neuron injury, reﬂexes may be absent.

Gait and Coordination

Patients with cerebellar tumors can present with a wide-

based ataxic gait and difﬁculty with tandem gait. A hemipa-

retic gait can suggest a tumor involving cortical motor areas,

the thalamus, or the brain stem. Patients with cerebellar or

brainstem tumors may exhibit abnormal coordination, eli-

cited by testing rapid alternating movements, ﬁ nger to nose

testing, or ﬁnger (pointer to thumb) and toe tapping (on the

ﬂoor) or asking a child to mirror the examiner's ﬁnger as

the examiner moves the ﬁnger laterally and/or vertically.

Skin Examination

Although not technically part of the neurologic examinati on, a

skin examination is importa nt to ass ess for dermatologic man-

ifestations of underlying tumor predispositions such as NF

type 1 (predisposed to low-grade gliomas [LGGs], especially in

optic pathways), NF type 2 (predisposed to acoustic schwanno-

mas and meningiomas), tuberous sclerosis complex (predis-

posed to subependymal giant cell tumors), or, more rarely,

constitutional mismatch repair deﬁciency syndrome. Patients

with constitutional mismatch repair deﬁciency syndrome have

a genetic defect in genes responsible for repairing a speciﬁc

type of DNA damage known as mismatch repair. Abnorma li-

ties in these genes (MLH1, MSH2, MSH5, PMS2) make it

more difﬁcult for the body to repair normally occurring DNA

damage, leading to mutations and predisposing these patients

to many types of cancers at an early age, including brain

tumors, most commonly high-grade gliomas (HGGs). (4)

ACUTE MANAGEMENT

The child with a suspected brain tumor might require

urgent interventions. Those with unstable vital signs,

altered mental status, or concern for increased ICP war-

rant expedited evaluation, best managed initially in the

emergency department. Although magnetic resonance

imaging (MRI) with and without contrast is the gold stan-

dard imaging technique for optimal visualization for brain

tumors and is often needed for neurosurgical planning, in

the unstable child, a computed tomographic (CT) scan

may be the best initial imaging choice. CT scans can pro-

vide information regarding acute hydrocephalus, impend-

ing herniation, or acute hemorrhage, all of which

represent neurosurgical emergencies. They can also show

the anatomical location of a mass, lesion size, presence of

hydrocephalus, and whether the mass is compressing

other brain structures, thereby helping to triage and plan a

timeline for MRI, surgery, or other sedated procedures.

When choosing the optimal initial imaging study for a

young child who would require anesthesia to complete an

MRI, the relative risks of anesthesia compared with the

risk of exposure to ionizing radiation from a CT scan,

which could be completed without sedation, must be

weighed while taking into account the degree of suspicion

for an abnormality and individual risk factors speciﬁcto

that patient. (5)

MRI with and without contrast is generally the pre-

ferred imaging modality for diagnosis and follow-up of

brain tumors. MRI allows for more detailed characteriza-

tion of the tumor itself and the surrounding anatomy,

with more specialized sequences for visualization of

edema, relationship to CNs, blood vessels, and perfusion.

Furthermore, MRI does not expose children to ionizing

radiation so is preferred over CT for repeated studies, as

would be needed to follow a brain tumor. Most patients

with a brain tumor require a spinal MRI to evaluate for

evidence of leptomeningeal disease.

When a diagnosis of a brain tumor is made based on

imaging, in the absence of a neurosurgical emergency,

patients should be managed in concert with neuro-oncol-

ogy teams preoperatively. Early neuro-oncology consulta-

tion allows for additional baseline neurologic examination,

can help inform surgical planning based on the working

differential diagnosis and postoperative treatment options,

and facilitates an opportunity for clinical trial enrollment

where presurgical consent may be required.

TREATMENT OVERVIEW OF PEDIATRIC BRAIN

TUMORS

The care of the pediatric neuro-oncology patient requires a

multidisciplinary team–based approach. In addition to an

excellent primary care pediatrician, this team includes

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neuro-oncology, neuro-surgery, neurology, neuro-radiol-

ogy, radiation oncology, genetics, endocrinology, ophthal-

mology, audiology, neuropsychology, physical medicine

and rehabilitation, palliative care, and social work.

Upfront treatment of pediatric brain tumors generally

includes surgery, radiotherapy, chemotherapy, or a combina-

tion of these modalities. For most tumor types, maximal

safe surgical resection is pursued to obtain diagnosis and as

the ﬁrs t step in deﬁnitive treatment. Some notable excep-

tionstothisincludetumorsineloquentlocationswhere

resection would result in signiﬁcant morbidity or mortality.

These locations include the brain stem, optic pathways, thal-

amus, internal capsule, sensory and motor cortices, visual

cortex, or Broca and Wernicke areas, which are important

for receptive and expressive language. In some cases, a small

needle biopsy of these areas can be performed to obtain tis-

sue for diagnostic purposes. For germ cell tumors, tumor

markers can be diagnostic, obviat in g the need for upfront

surgery. Some patients with low-grade–appearing lesions are

followed with observation alone.

Although some low-grade tumors can be treated with

resection only, many low-grade and most high-grade tumors

require additional postsurgical treatment. The standard of

care for postsurgical management of pediatric brain tumors

is constantly evolving based on emerging preclinical and

clinical data. In many cases, enrollment in an open clinical

trial is considered the standard of care. There are a variety of

clinical trial consortia and cooperative groups with open pro-

tocols focused on pediatric brain tumo rs. A complete list of

open clinical trials can be found on clinicaltrials.gov.

CLASSIFICATION AND TREATMENT OF

PEDIATRIC BRAIN TUMORS

There are more than 30 unique pathologies of CNS

tumors in children. MRI characteristics of some common

childhood brain tumors are shown in Fig 2. The advent of

molecular genetics has enhanced our understanding of

the biologic behavior of brain tumors, has changed tumor

classiﬁcation systems, and has had treatment implications.

Medulloblastoma

Medulloblastoma is the most common malignant brain

tumor in children and is of embryonal origin. It generally

presents as a posterior fossa mass and, due to its location,

is often associated with obstructive hydrocephalus. Staging

includes an MRI of the spine and a lumbar puncture look-

ing for malignant cells in the cerebrospinal ﬂuid (CSF).

Histologically it is classiﬁed as classic, large cell anaplastic,

or nodular desmoplastic. Overall, medulloblastoma has 5-

year overall survival (OS) of approximately 70%. (6)

Treatment depends on age at presentation, extent of

resection, and presence of metastatic disease. Recent trials

are accounting for molecular subtype in treatment deci-

sions. Generally, treatment involves maximal tumor resec-

tion, craniospinal radiotherapy, and chemotherapy. Young

patients undergo high-dose chemotherapy with autologous

stem cell rescue to avoid or delay irradiation.

Figure 2. Magnetic resonance imaging (MRI) features of pediatric brain

tumors with associated clinical presentatio n. A. MRI with contrast reveals a

heterogeneously enhancing mass of the posterior fossa. The patient pre-

sented with several days of early-morning vomiting. Examination demon-

strated papilledema, ataxia, and dysmetria. Diagnosis: medulloblastoma. B.

Fluid-attenuated inversion recovery MRI sequence demonstrates a right-

sided, posterior, cortically based tumor. The patient presented with a new-

onset focal seizure. Neurologic examination was normal. Diagnosis: dysem-

broplastic neuroepithelial tumor. C. MRI with contrast demonstrates an

enhancing mass involving the optic chiasm and tracts. The patient pre-

sented with several months of blurred vision. Examination revealed multiple

caf



e au lait macules, axillary freckling, bilateral pale optic nerves, and poor

visual acuity. Diagnosis: optic pathway glioma, neuroﬁbromatosis type 1. D.

Noncontrast MRI reveals a large hypointense mass involving the pons. The

patient presented with several weeks of double vision, facial weakness, and

poor coordination. Examination revealed bilateral sixth and seventh nerve

palsies, bilateral dysmetria, and diffuse hyperreﬂexia with clonus. Diagnosis:

diffuse intrinsic pontine glioma. E. Postcontrast MRI reveals a large suprasel-

lar tumor and hydrocephalus. The patient presented with several months of

headaches, double vision, and increasing difﬁcult y seeing objects on the

television. Examination revealed bitemporal hemianopsia and papilledema.

Diagnosis: craniopharyngioma. F. T2-weighted MRI reveals a large right fron-

tal mass with mass effect. The patient presented with 2 weeks of headache

and left-sided weakness. Examination demonstrated left hemiparesis and

acute encephalopathy. Diagnosis: high-grade glioma.

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Medulloblastoma has been classiﬁed into 4 principle

molecular subgroups: WNT (wingless), SHH (sonic hedge-

hog), group 3, and group 4 (Table 3). (7) WNT-driven

medulloblastomas are rarely metastatic and have the best

overall prognosis, with greater than 90% OS. Current clin-

ical trials are focused on reducing therapy in this subtype.

SHH-driven tumors have a bimodal distribution present-

ing most commonly in infants or adolescents and young

adults. They have an intermediate prognosis, although

association with p53 mutations portends a poor prognosis.

(9) Group 3 and group 4 tumors are known as non-WNT,

non-SHH medulloblastoma subtypes. Although immuno-

histochemical studies can differentiate WNT and SHH

medulloblastoma from the non-WNT and non-SHH

medulloblastoma subtypes, other molecular methods,

such as methylation studies, are needed to distinguish

group 3 from group 4 tumors. Group 3 tumors can pre-

sent in very young children, often have MYC ampliﬁca-

tion, are commonly metastatic at presentation, and have

the poorest outcomes overall of any subgroup. Recent data

suggest that group 3 tumors might beneﬁt from intensi-

ﬁed chemotherapy concurrent with radiotherapy. Group 4

tumors are the most common subgroup overall, present-

ing in children and adults and, similar to group 3 tumors,

more commonly present in males than in females. (7)

Group 4 tumors have an intermediate prognosis.

Atypical Teratoid Rhabdoid Tumor

Atypical teratoid rhabdoid tumors (ATRTs) are also embry-

onal tumors but can present in the posterior fossa or

supratentorial region. These tumors have a very poor prog-

nosis, with 3-year OS of approximately 25%. Survival

trends improve with older age at diagnosis, with those

older than 3 years faring better than younger patients. (10)

Histologically, the loss of INI1, encoded by SMARCB1, is

pathognomonic. Up to 35% of patients with ATRT have a

germline mutation in SMARCB1 (or rarely SMARCA4),

which predisposes them to the development of malignant

rhabdoid tumors in other locations, most commonly the

kidneys. Germline variants are more common in younger

patients, and approximately two-thirds are sporadic. (11)

Staging includes MRI of the brain and spine and lumbar

puncture for CSF cytology. Treatment involves surgical resec-

tion, radiotherapy, and chemotherapy, with or without triple

tandem autologous stem cell transplant. Recent clinical trial

data showed improved survival outcomes compared with his-

torical controls achieved with a regimen including radiotherapy

for patients as young as 6 months and 3 cycles of high-dose

chemotherapy with autologous stem cell rescue for all patients.

(12) A meta-analysis including 130 patients with ATRT saw that

survival correlated most strongly when patients were treated

with regimens that included high-dose chemotherapy with

autologous stem cell rescue. Treatment modalit ies of radiother-

apy and intrathecal chem othera py als o lead to a statistica lly sig-

niﬁcant improvement in OS in this cohort. (10)

ATRT tumors have also been classiﬁed based on molec-

ular characteristics into 3 subgroups: ATRT–tyrosine

(ATRT-TYR), ATRT–sonic hedgehog (ATRT-SHH), and

ATRT–myelocytomatosis oncogene (ATRT-MYC), but fur-

ther research is needed to delineate the prognostic and

clinical implications of these subgroups. (13)

Ependymoma

Ependymoma represents the third most common brain

tumor in children and arises from the ependymal cells lin-

ing the ventricles or the central canal of the spinal cord.

Two-thirds of ependymomas present in the posterior

fossa, with the remainder in the supratentorial region or

spinal cord. For pediatric ependymoma as a whole, OS at

10 years is approximately 64%, but cases achieving gross

total resection followed by radiotherapy fare signiﬁcantly

better. Molecular subtype and gain of chromosome 1q has

important prognostic implications as well. (14)

Ependymoma is treated with maximal surgical resec-

tion followed by focal radiotherapy, except for spinal dis-

ease, in which gross total resection without adjuvant

Table 3. The Four Major Consensus Molecular Subgroups of Medulloblastoma

VARIABLE

SUBGROUP

WNT SHH GROUP 3 GROUP 4

Frequency 10% 30% 25% 35%

5-y overall survival 95% 75% 50% 75%

Rate of metastases 5%–10% 10%–15% 40%-45% 30%–50%

Age group Children Infants, adults Infants, children Children, adults

Medulloblastoma is divided into 4 major molecular subgroups with clinical and prognostic implications. These subgroups are beginning to

be integrated into clinical trial designs to impact risk stratiﬁcation and treatment considerations. However, there is molecular and clinical

heterogeneity even within these subgroups. (7)(8)

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radiotherapy can be curative. The role of chemotherapy in

ependymoma remains under clinical investigation. Studies

have also explored the use of postoperative chemotherapy

to delay or omit radiotherapy in patients younger than 3

years, but outcomes were inferior to regimens involving

radiotherapy for children older than 12 months. (15)

Ependymoma has been divided into 9 molecular sub-

groups, with 3 subgroups for each anatomical location:

spinal, supratentorial, and posterior fossa. Only 6 of the

molecular subtypes generally affect children. Pediatric

ependymoma of the spine is divided into the SP-MPE sub-

type (myxopapillary, usually World Health Organization

[WHO] grade I) and the SP-EPN subtype (anaplastic,

WHO grade II/III). Both spinal subtypes have a relatively

good prognosis. In the posterior fossa, patients with PF-

EPN-A have a worse prognosis than those with PF-EPN-B,

and in the supratentorial compartment, those with RELA

fusion-driven disease (ST-EPN-RELA) have poorer OS than

those with YAP1 fusion-positive disease (ST-EPN-YAP1).

Both PF-EPN-A and ST-EPN-RELA are associated with

10-year OS less than 50% and 10-year progression-free

survival of approximately 20%. (14)

Low-Grade Gliomas

Pediatric LGGs are a heterogenous group of tumors that

encompass several distinct WHO histologies, including

astrocytic tumors (juvenile pilocytic astrocytoma being the

most common), oligodendroglial tumors (such as oligo-

dendroglioma), and mixed glioneuronal tumors (including

dysembryoblastic neuro-epithelial tumors). When grouped

together, LGGs represent the most common brain tumor

in children and can present in many anatomical locations.

LGGs are less likely to metastasize to other parts of the

CNS axis than their malignant counterparts, and in some

cases gross total resection can be curative. However, resec-

tion is not always possible in certain anatomical locations,

such as in the brain stem or with optic pathway gliomas,

common in patients with NF type 1. LGGs have a relatively

favorable prognosis, with OS of 92.5% and progression-

free survival of 67% reported in a study of 1,000 LGGs

with median follow-up of 15.9 years. (16)

Classically, when medical therapy is needed for LGGs,

the ﬁrst-line regimen consists of traditional chemotherapy

with either carboplatin/vincristine or procarbazine, lomus-

tine, vincristine, and thioguanine, although other chemo-

therapy regimens have demonstrated responses as well. (17)

Radiotherapy is not routinely used in the upfront manage-

ment of LGG due to concerns for late effects. Study of the

molecular landscape of LGGs has demonstrated that most

are driven by alterations in the mitogen-activated protein

kinase pathway, most commonly KIAA1459-BRAF fusions

(33%), BRAF V600E single-nucleotide variants (17%), and

NF type 1 alterations (17%). (16) MEK inhibitors have shown

activity against mitogen-activated protein kinase–activated

pediatric LLGs, and BRAF inhibitors have shown promise

in BRAF V600E–altered tumors. (18)(19)

High-Grade Gliomas

In contrast to LGGs, pediatric HGGs have a dismal prog-

nosis. HGGs include hemispheric high-grade tumors (ana-

plastic pleomorphic xanthoastrocytoma, glioblastoma),

brainstem tumors (diffuse intrinsic pontine glioma), and

nonbrainstem diffuse midline gliomas.

Treatment of pediatric HGGs is challenging. Hemi-

spheric tumors may be amenable to surgical resection.

Resection is typically followed by radiotherapy and chemo-

therapy for these tumors, as a Children’s Cancer Group

study showed improved survival when chemotherapy was

added to radiotherapy compared with radiotherapy alone.

Nonetheless, no speciﬁc chemotherapy regimen has

emerged as a clearly superior standard of care for upfront

pediatric HGGs. (20) In contrast, for midline tumors such

as diffuse intrinsic pontine glioma, adding chemotherapy

to radiotherapy has not been shown to prolong survival

beyond the median 9- to 12-month OS and the 10% two-

year OS achieved with radiotherapy alone. Several open

molecularly based and immunotherapy-driven clinical tri-

als are currently accruing patients, hoping to improve out-

comes for these patients. (21)(22)

Molecular studies in pediatric HGGs demonstrate that

the biology of pediatric HGGs differs from that of adult glio-

blastomas. Histone mutations H3.1K27M and H3.3 K27M

in midline tumors, and H3.3G34R.V in hemispheric

tumors, highlight the inﬂuence of epigenetics in pediatric

HGGs and portend a poor prognosis. Infant HGGs are bio-

logically distinct from HGGs in older children, with signi ﬁ-

cantly improved survival. NTRK fusions are more common

in children younger than 1 year, and TRK inhibitors under

investigation are showing promising results. (23)(24)

Germ Cell Tumors

CNS germ cell tumors represent approximately 1% of

pediatric brain tumors and are categorized as pure ger-

minomas and nongerminomatous germ cell tumors

(NGGCTs). They most commonly arise in the pineal re-

gion but can also present in the suprasellar region, fourth

ventricle, thalamus, or basal ganglia. NGGCTs secrete

a-fetoprotein (yolk sac) or human chorionic gonadotropin

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(choriocarcinoma) or both (immature teratomas or mixed),

which can be detected in peripheral blood and/or CSF.

Pure germinomas can cause modest elevation of human

chorionic gonadotropin in the CSF but do not secrete

a-fetoprotein. In some cases, diagnosis can be made based

on CSF and serum tumor markers, whereas biopsy is

required when tumor markers are inconclusive. Germino-

mas have a better overall prognosis, with OS greater than

90% compared with 60% to 70% for NGGCTs. Accord-

ingly, germinomas are commonly treated with 4 cycles of

chemotherapy (carboplatin/etoposide) followed by radio-

therapy to the tumor bed and whole ventricles, whereas

NGGCTs are generally treated with 6 cycles of chemo-

therapy (carboplatin/etoposide alternating with ifosfa-

mide/etoposide) and craniospinal radiotherapy in many

cases, although studies are examining whether radiother-

apy can be reduced in select patients with NGGCTs to

minimize toxicity associated with craniospinal radiother-

apy. (25)(26)

Craniopharyngioma

A craniopharyngioma is a suprasellar tumor arising from

the remnants of the Rathke pouch containing cystic and

solid components. Histologically, they are classiﬁed as

benign tumors and are divided into adenomatous and pap-

illary subtypes. Due to their location they can severely

impair visual, hormonal, and cognitive function. Optimal

treatment strategy for craniopharyngioma is controversial;

some centers perform a more aggressive primarily neuro-

surgical approach in an attempt to avoid radiotherapy, and

others perform an initial subtotal resection followed by

upfront radiotherapy. (27)

TUMOR PREDISPOSITION SYNDROMES

There are several germline mutations that predispose chil-

dren to speciﬁc types of childhood brain tumors in the

context of tumor predisposition syndromes. Knowledge of

these syndromes is important to the primary care physi-

cians who follow these patients longitudinally. In the child

who presents with a brain tumor, especially in the context

of other personal history of tumors, family history of

tumors at a young age, or characteristic dermatologic ﬁnd-

ings, it is important to consider further evaluation for

these cancer predisposition syndromes. Children with a

known family history of cancer predisposition syndromes

might require genetic screening for the presence of these

syndromes, and speciﬁc tumor surveillance if found to

harbor one of these mutations. Furthermore, the presence

of certain underlying syndromes may alter the choice of

therapy for the management of a brain tumor. (28)(29)

Table 4 summarizes selected germline syndromes associ-

ated with speciﬁc brain tumor types.

ACUTE AND EARLY EFFECTS OF TREATMENT

Although the treatment of different tumor types varies sig-

niﬁcantly, each of the commonly used treatment modali-

ties confers their own risks and acute toxicities.

Major risks of neurosurgery include bleeding, stroke,

infection, and damage to nearby structures, as well as

morbidity dependent on tumor location. For example, pos-

terior fossa syndrome affects an estimated 8% to 30% of

patients who undergo resection of large posterior fossa

tumors. Posterior fossa syndrome is characterized by a

combination of mutism or signiﬁcant language impair-

ment, with emotional lability and irritability or motor dys-

function occurring within 2 weeks of cerebellar injury.

Signs and symptoms can take months to resolve, and

unfortunately many are left with residual deﬁcits. (37)(38)

Patients with supratentorial tumors are at greater risk for

postoperative seizures and are often started on prophylac-

tic antiepileptic medications. Children with suprasellar

tumors are at increased risk for postoperative visual deﬁ-

cits and hormone dysfunction.

Radiotherapy treats tumors by directing high-energy

protons or photons at a tumor target to damage DNA.

Radiation is fractionated over several weeks to achieve a

total dose to the target. Photons are waves without mass,

meaning that when concentrated at a point to a certain

dose, they also deliver radiation “scatter” at a lower dose

on both the entrance and exit side of the wave. Protons

have mass, so the radiation is designed to “stop” within

the target tissue, releasing the highest amount of energy

at that point, minimizing the scatter that exits beyond the

target. Acute adverse effects of radiotherapy are mostly

due to the radiation absorbed in off-target tissues. With

both proton and photon radiotherapy, patients can develop

local skin reactions, which generally worsen over the treat-

ment period. Patients receiving intracranial radiotherapy

often experience headache or nausea. Craniospinal radio-

therapy can cause myelosuppression due to the dose

received by the vertebral body bone marrow and can harm

the growth plates of the vertebral bodies, resulting in loss

of adult height (worse in younger children). Proton radio-

therapy is becoming increasingly preferred over photon

radiotherapy, particularly for patients who require cranio-

spinal radiotherapy, because it avoids scatter to several

important anterior midline organs, such as the esophagus,

mediastinum, heart, breast tissue, and intestines. For

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patients receiving focal radiotherapy, proton therapy may

spare irradiation to important structures or result in a sig-

niﬁcantly smaller overall radiation ﬁeld, depending on

tumor location. Comparison plans showing the radiation

ﬁeld and dose for a proton plan versus a photon plan can

be helpful to evaluate relative advantages of proton over

photon based on the brain structures that would receive a

given dose with each plan. Primary limitations to the use

of proton therapy are the restricted number of proton

radiotherapy centers, requiring some patients to travel

long distances for therapy, as well as the relative cost of

treatment compared with photon radiotherapy.

A small percentage of patients might experience radia-

tion necrosis, especially in areas treated to high total doses

of radiation or that have been irradiated again. In some

cases, radiation necrosis is discovered based solely on imag-

ing ﬁndings, but symptomatic patients may require medical

management with corticosteroids or bevacizumab, or fur-

ther intervention such as surgery. Research is ongoing into

other strategies for treatment of radiation necrosis, such as

the use of laser interstitial thermal therapy. (39)

By targeting rapidly dividing cells, chemotherapy medi-

cines kill fast-growing tumor cells but also have off-target

effects on other cell types with high turnover rates, such

Table 4. Selected Tumor Predisposition Syndromes Associated with Childhood Brain Tumors

SYNDROME

GENES KNOWN

TO BE INVOLVED

BRAIN TUMORS

ASSOCIATED

OTHER ASSOCIATED

TUMOR TYPES

BRAIN TUMOR

SURVEILLANCE

Rhabdoid tumor

predisposition

SMARCB1, SMARCA4 Atypical teratoid rhabdoid

tumor

Extracranial malignant

rhabdoid tumors

Consider screening if age <5

y or symptomatic (30)

Gorlin PTCH1, SUFU Medulloblastoma (sonic

hedgehog subgroup)

Basal cell carcinomas PTCH1: Screen if symptomatic

SUFU: Consider screening if

age <5 y or symptomatic (30)

Familial

adenomatous

polyposis (Turcot

type 2)

APC Medulloblastoma,

astrocytoma,

ependymoma

Colon cancer, osteomas,

ﬁbromatosis, others

Screen if symptomatic (28)

Li-Fraumeni TP53 Glioma, medulloblastoma,

choroid plexus carcinoma

Sarcomas, adrenocortical

carcinoma, breast cancer,

others

Annual screening from birth

(31)

Neuroﬁbromatosis

type 1

NF1 Low-grade glioma, optic

glioma, astrocytoma

Malignant peripheral nerve

sheath tumor,

neuroﬁbroma, leukemia

Yearly clinical assessment and

ophthalmology; screen if

vision loss or other symptoms

of brain tumor (32)

Neuroﬁbromatosis

type 2

NF2 Schwannoma, meningioma,

astrocytoma,

ependymoma

Malignant peripheral nerve

sheath tumor,

neuroﬁbroma

Screen brain every 1–2 y and

spine every 2–3 y if age

>10 y or symptomatic (33)

Schwannomatosis SMARCB1 (mosaic

or hypomorphic)

LZTR1

Schwannoma, meningioma SMARCB1: malignant

peripheral nerve sheath

tumors, rarely other

rhabdoid tumors

LZTR1: other tumors

uncommon

SMARCB1: screen brain/spine

at diagnosis, every 2–3y

after age 10 y

LZTRI: screen brain/spine at

diagnosis, every 2–3 y after

age 15–19 y (33)

Germline

retinoblastoma

Rb Pineoblastoma, primitive

neuroectodermal tumor

Retinoblastoma,

osteosarcoma, others

Periodic brain MRI until age

5 y (34)

Simpson-Golabi-

Behmel

GPC3, GPC4 Medulloblastoma Wilms tumor,

hepatoblastoma,

neuroblastoma,

gonadoblastoma

No established guidelines,

screen if clinically indicated

Constitutional

mismatch repair

deﬁciency, Lynch

syndrome (Turcot

type 1)

MLH1, MSH2,

PMS2, MSH6

Astrocytoma, glioblastoma,

ganglioglioma,

meningioma,

medulloblastoma,

hemangioblastoma

Leukemia, gastrointestinal

tumors, others

Brain MRI every 6 mo from

time of diagnosis (4)

Tuberous sclerosis

complex

TSC1, TSC2 Subependymal giant cell

astrocytoma

Renal angiomyolipoma,

cardiac rhabdomyoma,

ﬁbroma, hamartoma

Surveillance brain MRI every

1–3 y until age 25 y (35)

Von Hippel Lindau VHL Hemangioblastoma Pheochromocytoma,

paraganglioma, renal cell

carcinoma

Screen brain/spine every 2 y

after age 8 y or if

symptomatic (36)

Brain tumor surveillance recommendations are created by consensus groups and change over time. The imaging modality of surveillance is

typically brain MRI with and without contrast. Many syndromes also include guidelines for screening for extra–central nervous system

tumors, not reviewed here. It is strongly recommended to refer to the most up-to-date guidelines when caring for a patient with a cancer

disposition syndrome and to refer families for genetic counseling when available. MRI=magnetic resonance imaging.

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as hair, gastrointestinal tract, and bone marrow. Alopecia,

although not painful or medically toxic, can be psychologically

difﬁcult for patients and parents. Nausea and vomiting affect

most patients and, especially when combined with mucositis,

contribute to poor appetite and weight loss during therapy.

Myelosuppression leads to anemia, thrombocytopenia, and

leukopenia. Children are supported with red blood cell and

platelet transfusions. Leukopenia causes immunocompro-

mise, making children more prone to opportunistic infec-

tions. Patients are maintained on pneumocystis prophylaxis

(trimethoprim-sulfamethoxazole is ﬁrst line) throughout treat-

ment and for at least 6 months after chemotherapy. Fever in

the oncology patient is a medical emergency, and neutropenic

patients with fever are admitted to the hospital for broad spec-

trum antibiotic therapy due to the risk of life-threatening

infection. Vaccine response is impaired during chemotherapy

and shortly after, so routine vaccinations should be deferred

during chemotherapy because development of antibodies

may be inadequate and live virus vaccines are strictly contrain-

dicated. However, immunocompromised children should still

receive yearl y inﬂuenza vaccination.

In addition to the shared toxicities of chemotherapy medi-

cines, individual chemotherapies carry drug-speciﬁcadverse

effects. Some commonly used chemotherapy medicines in

patients with pediatric brain tumor include vincristine (asso-

ciated with constipation, peripheral neuropathies, hypore-

ﬂexia, and jaw pain), cisplatin and carboplatin (associated

with renal toxicity and ototoxicity), and cyclophosphamide

(associated with hemorrhagic cystitis).

Novel targeted therapies have distinct mechanisms of

action from traditional chemotherapy and thus different

adverse effects. MEK inhibitors, for example, are known to

cause frequent dermatologic toxicity and gastrointestinal

adverse effects and also carry a risk of cardiac toxicity,

prompting frequent cardiac surveillance for patients

receiving therapy. TRK inhibitors, on the other hand, carry

an increased risk of weight gain and long bone fractures.

Immunotherapy medicines such as PD-1/PD-L1 inhibi-

tors activate the patient's immune system to better recog-

nize and attack tumor cells and thus present a different

array of toxicities. Patients taking immunotherapy medi-

cines are at increased risk for development of autoim-

mune disease and should be closely monitored for

autoimmune-mediated processes, including dermatitis,

thyroiditis, pancreatitis, and colitis.

FOLLOW-UP AND LATE EFFECTS

As advancements in treatment have improved the survival

rates of patients with pediatric brain tumors, pediatricians

are caring for more survivors with late effects of cancer

therapy. Figure 3 shows the multitude of late effects that

can impact patients treated for pediatric brain tumors. The

number and severity of late effects depend on many fac-

tors, including tumor location, age at treatment, treatment

modalities, and intensity of treatment.

Survivors of childhood brain tumors, especially those

who have received radiotherapy, are at high risk for neuro-

cognitive impairment. Studies have shown a decreased IQ

of approximately 10 to 15 points, with radiotherapy at a

younger age correlating to worse deﬁcits. The domains

most affected are executive function, processing, and

working memory. (40)

Cranial radiotherapy also signiﬁcantly increases the risk

of cerebrovascular disease, including stroke, moya-moya

syndrome, cavernomas, and aneurysms, which often man-

ifest years after therapy. The Childhood Cancer Survivor

Study showed that survivors of CNS malignancy had a

30× increased risk of stroke compared with a sibling con-

trol group. Stroke risk correlated with radiation dose and

increased over time from completion of therapy, with a

cumulative incidence greater than 1% in survivors of brain

tumors 10 years after treatment. The imaging ﬁndings of

radiation-induced vascular infarction can overlap with

those of tumor recurrence, so the cumulative risk over

time is important to consider when interpreting follow-up

imagining in survivors of brain tumor. (41) Concurrent

Figure 3. Potential late effects of chemotherapy and radiotherapy in the

treatment of childhood brain tumors. Even when therapy for brain tumors

results in cure and long-term survival, the late effects of therapy can be

signiﬁcant. Most organ systems throughout the body can experience late

effects related to the consequences of therapy. For this reason, it is impor-

tant that survivors of childhood brain tumors be followed lifelong for

screening and management of these late effects.

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hypertension and diabetes signiﬁcantly further increased

stroke risk, underscoring the importance of screening for,

and treating, these comorbidities in childhood cancer sur-

vivors. (42)

Patients who have had surgery or radiotherapy involv-

ing the hypothalamic-pituitary axis can experience endo-

crinopathies, including growth hormone deﬁciencies,

hypothyroidism, adrenal insufﬁciency, and sex hormone

deﬁciencies. Certain chemotherapy medications also con-

tribute to risk of infertility in survivors of cancer. Those

with hypothalamic injury from tumor, surgery, or radio-

therapy are at risk for hypothalamic obesity. (40)

Many survivors of childhood brain tumor experience

high-frequency sensorineural hearing loss as well.

Although it can occur in the acute phase of therapy, it can

also manifest as a late effect in children who have received

cisplatin chemotherapy or radiotherapy to structures in

the inner ear or auditory nerve. Otoprotective agents may

be used in select patients to decrease the risks of certain

patients receiving platin-based chemotherapy. Many of

these children require hearing aids and other accommoda-

tions long-term.

Unfortunately, even after surviving brain cancer, chil-

dren are at increased risk for a secondary malignancy. Cer-

tain chemotherapy agents, such as alkylating agents (eg,

cyclophosphamide, lomustine, temozolomide) and topo-

isomerase inhibitors (eg, etoposide) are known to pre-

dispose patients to secondary leukemia later in life.

Radiotherapy is also a risk factor for the development of a

secondary malignancy within the radiation ﬁeld. Underly-

ing genetic disorders, such as congenital mismatch repair

deﬁciency of p53 mutations, can further increase this risk.

In a study of more than 34,000 survivors of childhood can-

cer with median follow-up of 21 years, approximately 2% of

survivors died of secondary malignancies, accounting for

nearly 20% of late mortality in this cohort. However, all-

cause late mortality and rate of secondary malignancy in

cancer survivors has decreased over time due to efforts to

decrease the toxicity of therapy and improve survivorship

care. (43)

Brain tumor treatment also takes a toll on the psycho-

logical health of survivors, who report higher rates of

depression and lower rates of life satisfaction than their

peers. In addition, they are less likely to report having

close friends, being married, attending college, and being

employed. Even compared with other childhood cancer

survivors, survivors of childhood brain tumors have signif-

icantly poorer psychosocial outcomes. It is imperative for

providers to be aware of these disparities and refer

appropriately for mental health services, educational assis-

tance, and psychosocial support. (40)

FUTURE DIRECTIONS IN PEDIATRIC NEURO-

ONCOLOGY

Recent advances in pediatric neuro-oncology have

enhanced understanding of tumor biology and molecular

determinants of disease. Molecularly based clinical trials

will promote even greater knowledge regarding molecular

predictors of disease severity, response to therapy, and

molecularly based treatment strategies, helping to deﬁne

the role of novel targeted agents in pediatric neuro-oncol-

ogy (eg, MEK inhibitors, TRK inhibitors, SHH inhibitors).

Unanswered questions remain, such as whether these are

most effective as single agents, in combination with one

another, or in combination with cytotoxic chemotherapy.

Duration of treatment and duration of response once treat-

ment is suspended also remain to be determined, as well

as long-term adverse effects of their use in children.

Immunotherapy is another area of active research.

Immunotherapy approaches such as blinatumomab and

chimeric antigen receptor T cells drastically improved sur-

vival in relapsed acute lymphoblastic leukemia, and the

addition of antibody therapy in high-risk neuroblastoma

signiﬁcantly improved survival in this population. Resear-

chers hope that similar gains in survival might be seen

with the integration of immunotherapy in the treatment

of childhood brain tumors. Several different agents are

currently under investigation to enhance immune cell acti-

vation and function against brain tumors, including

agents such as PD-1 and PD-L1 inhibitors or CD47 inhibi-

tors. Chimeric antigen receptor T cells are also in clinical

trials for certain pediatric CNS malignancies expressing

speciﬁc targets. Vaccine studies for CNS tumors are also

being investigated.

Research is also ongoing to minimize morbidity associ-

ated with diagnosis and treatment of pediatric brain

tumors. Some studies are looking to decrease chemother-

apy and radiotherapy in tumor types with excellent sur-

vival outcomes, such as WNT-driven medulloblastoma and

CNS germ cell tumors. Research is also ongoing to inves-

tigate the utility of liquid biopsy as a minimally invasive

technique that might be used not only to make a diagno-

sis, but also to monitor response to therapy or detect early

relapse. (44) Liquid biopsy involves the isolation of circu-

lating tumor DNA or proteins from body ﬂuids such as

CSF, blood, or plasma, which could potentially decrease

the need for surgical interventions.

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CONCLUSIONS

Although pediatric neuro-oncology is a specialized and

rapidly evolving ﬁeld, patients often initially present to

their primary care pediatricians. It is essential for pediatri-

cians to be familiar with presenting signs and symptoms,

relevant physical examination ﬁndings, and acute manage-

ment of pediatric brain tumors. Knowledge of common

tumor types and their treatments, as well as acute and late

effects of therapy, is also important as pediatricians con-

tinue to follow these medically complex patients during

therapy and beyond as essential members of the neuro-

oncology team.

Summary

• Based on strong evidence, brain tumors are the

most common solid tumors in children and the

most common cause of childhood cancer death.

• Based on strong research evidence, patterns of

symptoms and physical examination ﬁndings at

presentation in a child with a brain tumor vary

with tumor location.

• Based on research evidence and consensus, brain

tumors are managed by a combination of surgery,

chemotherapy, or radiotherapy, depending on

tumor type, location, dissemination, and age.

• Based on research evidence as well as consensus,

the morbidi ty and mortality associated with child-

hood brain tumors are determined by many factors,

including tumor pathology, tumor genetics, ana-

tomica l location, and treatme nt.

• Based on strong evidence, treatment of childhood

brain tumors with radiotherapy and chemotherapy

places survivo rs at increased risk for neurocognitive

deﬁcits, neurovascular complications, endocrine

dysfunction, secondary malignancies, impaired

psychosocial functioning, and other late effects.

Acknowledgment

This work was funded by the Gordon Fellowship in Pedi-

atric Neuro-Oncology Celebrating Futures Fund.

References for this article can be found at

DOI: 10.1542/pir.2020-004499.

To view teaching slides that accompany this article, visit

10.1542/pir.2020-004499.

Childhood Brain

Tumors

Katherine C. Pehlivan, MD

Megan R. Paul, MD

John R. Crawford, MD

2,3

1. Department of Pediatrics, Division of Hematology-Oncology and Stem Cell Transplantaon, New York Medical College, Valhalla, NY

2. Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego and Rady Children's Hospital

3. Department of Neurosciences, University of California and Rady Children's Hospital, San Diego, CA

14 Pediatrics in Review

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1. An 8-year-old boy presents with early-morning vomiting, headache,

and increased clumsiness. On physical examination, vision and extraocular

movements are normal and there is no facial asymmetry or hemiparesis. The

physician wants to rule out a brain tumor. Based on his signs and

symptoms, which of the following is the most likely location of a brain

tumor in this patient?

A. Brain stem.

B. Pituitary gland.

C. Posterior fossa.

D. Spinal cord.

E. Suprasellar region.

2. A 10-year-old girl presents with abnormal gait and coordination.

She denies headache, back pain, nausea, or vomiting. On physical

examination she has left-sided facial palsy and right-sided hemiparesis. She

is diagnosed as having a brain tumor. Which of the following is the most

likely location of the brain tumor in this patient?

A. Brain stem.

B. Pituitary gland.

C. Posterior fossa.

D. Spinal cord.

E. Suprasellar region.

3. A 6-year-old boy is found on physical examination to have numerous

caf



e-au-lait spots on his trunk and axillary freckling. His gait and balance are

steady. This patient is at greatest risk for which of the following tumors?

A. Acoustic schwannomas.

B. High-grade gliomas.

C. Meningiomas.

D. Optic pathway gliomas.

E. Subependymal giant cell tumors.

4. A 2-year-old girl, who was diagnosed as having choroid plexus

carcinoma, has a family history of her father with osteosarcoma as a

teenager, a paternal aunt with breast cancer at 30 years of age, and a

paternal grandmother with adrenocortical carcinoma at 40 years of age. This

family is most likely to have which of the following associated conditions?

A. Familial adenomatous polyposis.

B. Li-Fraumeni syndrome.

C. Neuroﬁbromatosis type 1.

D. Neuroﬁbromatosis type 2.

E. Tuberous sclerosis.

5. A 15-year-old boy completed treatment for medulloblastoma with surgical

resection, craniospinal radiotherapy, and chemotherapy 5 years ago. At this

time, he is most at risk for which of the following conditions?

A. Bleeding.

B. Hyperthyroidism.

C. Immune suppression.

D. Neurocognitive dysfunction.

E. Visual defects.

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