Pediatric Brain Tumors

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Pediatric Brain Tumors

• Corey Raffel, M.D., Ph.D.
• Chief, Section of Pediatric Neurosurgery
• Nationwide Childrens Hospital
• Columbus, Ohio

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Brain Tumors in Children

• Oh, my God, my child/patient has a brain tumor!
• Depression!

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Brain Tumors in Children

• What are the symptoms and signs of brain tumors
  in children?
• What kinds of tumors are there and how are they
  treated?
• Is the outcome always so bad?

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Symptoms and Signs

• Headache. When to think about getting a scan.
• Easy, if headache is associated with neurologic
  symptoms or signs.
• Lethargy, personality change, clumsiness of hands
  or gait, diplopia, bradycardia, hypertension
• Papilledema! Must see the fundus.

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Symptoms and Signs

• Hard when associated neurologic signs are mild or
  absent.
• Nocturnal awakening with headache or headache at
  awakening in morning
• Vomiting associated with headache, often in the
  morning, often with temporary relief afterwards

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Symptoms and Signs

• Headache worsened by lying down, coughing,
  laughing, Valsalva
• Posterior location of the headache
• Distinct onset less than 6 months or distinct
  change in pattern of pre-existing headache
• Progressive worsening over time

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Symptoms and Signs

• Vomiting when associated with headache
• When occurs in the morning, but not later in the
  day
• When new, interfering with food intake

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Symptoms and Signs

• Seizures
• New onset seizure unassociated with fever
• Change in pattern of pre-existing seizures

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Symptoms and Signs

• In the infant, things are even harder.
• Loss of previously acquired motor milestones
• Accelerated head growth after a period of normal
  growth
• Feel for full fontanelle, separated sutures

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Imaging Studies

• These days, MR imaging is the modality of choice.
  Better at delineating tumors. No irradiation.
  Scan without and with contrast is best
• Quick MR scan? Axial T2-weighted images can be
  used as a screen. Quick and cheaper.

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Types of Tumors

• Brain tumors is children are not common, about 3
  cases per 100,000 children less than 15 years of
  age per year or about 1500 new cases per year.
  This means that about 1 in every 2700 such
  children will get a brain tumor.
• But brain tumors are common amongst types of
  tumors that children get, second only to leukemia
  in both incidence and mortality.

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Types of Tumors

• Will review the common tumor types, emphasizing
  presentation, treatment, and outcome.

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Medulloblastoma/PNET

• PNET describes morphologically related CNS tumors
• Unrelated to PNS PNET characterized by 11-22
  translocation
• Medulloblastomacerebellar PNET
• PNET terminology being abandoned

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Medulloblastoma

• 20 of pediatric brain tumors
• 40 of posterior fossa tumors

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Medulloblastoma

• Symptoms often those of hydrocephalus/raised
  ICP--headache, vomiting, diplopia
• Falling, incoordination
• Signs papilledema, EOM paresis, ataxia

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CP1150826-4
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CP1150826-3
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Role of Surgery

• First step in treatment is an operation
• Establish diagnosis
• Open CSF pathways
• Many, but not all, large studies show increased
  survival with radical tumor resection

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Surgical Approach

• Begin operation with goal of GTR
• Brainstem invasion may prevent reaching this goal
• Do not chase tumor into brainstem leave the
  carpet of tumor on floor of IV ventricle

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Role of Experience

• Experience of surgeon does play a role in degree
  of tumor resected
• This may effect outcome

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Extent of Resection by Type of Neurosurgeon

• Resection
  ____________
• Neurosurgeon 90 90
• ________________________________
• General 18 57(76)
• Pediatric 6 60(91)
• ________________________________
• X2, p 0.02

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Role of Irradiation

• Effective
• Dose to posterior fossa 50 Gy

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Outcome Radiation Dose
?50 Gy (15 pt)
Relapse-free survival ()
Plt0.01
lt50 Gy (43 pt)
Years (no.)
CP1150826-2
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Effects of Radiation

• Many studies show inverse relationship between
  age at irradiation and intellectual outcome
• Current trend is to decrease dose of radiation
  and add chemotherapy

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Neuraxis Irradiation

• A CCSG study suggested early failure in patients
  given chemotherapy and 27 Gy vs 36 Gy
• Late follow shows curves converging
• SIOP study shows no difference

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Role of Chemotherapy

• Studies from CCSG, POG, and SIOP all demonstrate
  increased survival in high-risk patients treated
  with adjuvant chemotherapy
• Active drugs include platinum, ENUs, cytoxan,
  etc.

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Role of Chemotherapy

• In a single institution study, the use of a
  three-drug regimen in high-risk patients resulted
  in a better overall survival than in the
  normal-risk patients treated with irradiation
  alone
• Recent European trial of chemotherapy alone in
  patients less than 3 years shows high survival

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Outcome Radiation Chemotherapy
Study group
Historical
Probability
Probability
Study group
Historical
Months post on study
Months post on study
CP1150826-1
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Prognostic Factors

• Age 2 years, poor prognosis
• CSF dissemination, poor prognosis
• Radical resection, good prognosis

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CSF Dissemination
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Histologic Markers

• Tumors can be divided into classical and
  anaplastic tumors.
• Patients with anaplastic tumors do worse
• Patients with large cell variant do worse

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Laboratory Studies

• Growth factors and receptors may be important in
  medulloblastoma growth
• IGFR-1
• trk/neurotrophins

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Laboratory Studies

• Sonic Hedgehog pathway important in at least some
  tumors
• Wnt pathway important in at least some tumors
• Notch2 may be important for growth, Notch1 may
  inhibit growth, of most tumors
• Simply says developmental pathways may be
  important

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Laboratory Studies

• Ptch pathway alterations associated with
  desmoplastic variant which may have an improved
  prognosis
• Increased expression of Notch pathway gene, Hes1,
  has been reported to have a worse prognosis in
  one study

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Ependymoma

• 6 of pediatric brain tumors
• 70 occur in the posterior fossa
• Hallmark on imaging is extension out of the
  foramina of the fourth ventricle into the CPA or
  cervical canal

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Medulloblastoma-Survival

• Current best 5-year survival rates are 70
• Not too bad!
• Survival tempered by cognitive deficits from
  irradiation
• Survival continues to fall after 5 years.
• We need radical, new treatments that are
  effective and eliminate use of radiation

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Ependymoma

• Signs and symptoms of hydrocephalus
• May be prominent vomiting from invasion of floor
  of fourth ventricle

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Ependymoma
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Ependymoma
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Ependymoma
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Ependymoma

• Treatment consists of radical resection
• No question that prognosis is greatly influenced
  by extent of resection
• Patients with radiographically confirmed GTR have
  greater than 80 five-year survival 20 or less
  for less than GTR

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Ependymoma

• Role of radiation therapy is not well
  established, but may be efficacious
• Stereotactic radiation may be effective, but may
  fail from dissemination in the face of local
  control
• Role of chemotherapy is not established

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Ependymoma

• Surgeon has a tremendous influence on progress
• Every attempt should be made to resect entire
  tumor
• Removal of tumor from floor of fourth ventricle
  is controversial, better prognosis vs major
  neurologic deficit

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Ependymoma

• Studies suggest small amount of residual disease
  does not effect prognosis
• Most surgeons do not chase tumor into the floor
  of the fourth ventricle

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Astrocytoma

• Symptoms and signs depend on location. Posterior
  fossa-symptoms and signs for hydrocephalus.
  Cerebral hemispheres-focal deficit, seizures.
• Tumor behavior depends on histology
• Tumor treatment depends on histology and location

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Cerebellar Astrocytoma

• Pilocytic astrocytoma
• Diffuse, grade II astrocytoma
• Grade III or IV astrocytoma in the cerebellum is
  rare in children

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Pilocytic Astrocytoma
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Pilocytic Astrocytoma
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Pilocytic Astrocytoma

• Surgical disease
• We try to remove all tumor
• But we do not chase tumor into cerebellar
  peduncle, brainstem

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Pilocytic Astrocytoma

• Post op scan clean, follow
• 6 month scan clean, may not need any further
  studies

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Cerebellar Astrocytoma

• Treatment for pilocytic astrocytoma is resection.
  A gross total resection is goal
• Controversy Immediate reoperation for residual
  tumor?

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Cerebellar Astrocytoma
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Cerebellar Astrocytoma

• Patients with grade II tumors and GTR do as well
  as patients with pilocytic tumors and GTR
• Role of radiation and chemotherapy for residual
  tumor in brainstem is unresolved

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Cerebellar Astrocytoma

• Diffuse, grade II astrocytoma
• Outcome relates to degree of resection
• Try for GTR
• Brainstem invasion prevents this

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Cerebellar Astrocytoma
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Cerebellar Astrocytoma
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Cerebellar Astrocytoma

• If postoperative scan shows residual tumor, only
  about 1/3 will show growth over next 10 years
• Reasonable to follow for symptoms and with scans,
  reoperate for progression

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Brainstem Tumors

• Called brainstem glioma, but not all tumors in
  the brainstem are the same.
• Symptoms and signs of brainstem dysfunction
  diplopia, swallowing problems, facial weakness,
  long track signs

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Focal Brainstem Astrocytoma

• Usually in midbrain, medulla, or cervicomedullary
• Dorsally exophytic into IV ventricle
• Account for 30

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Focal Brainstem Astrocytoma

• Pathology grade I, grade II astrocytoma,
  ganglioglioma
• Less often grade III or IV astrocytoma

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Focal Brainstem Astrocytoma

• Controversy about treatment
• Role of resection
• Role of radiation
• Role of chemotherapy

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Focal Brainstem Astrocytoma

• Subtotal resection may be effective
• Recommended for dorsally exophytic tumors

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Focal Brainstem Astrocytoma

• Role of surgery has yet to be defined
• Radical resection is a tour de force, but is it
  needed?
• Many reports of tumors that have remained stable
  for years with no treatment

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Treatment of Residual Tumor

• Controversy about role of chemotherapy
• No randomized prospective study
• No good study with adequate follow-up for this
  slow-growing tumor

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Focal Brainstem Astrocytoma

• Radical resection is possible, but at a cost
• True incidence of complications is not known
• Reported at least 50with tracheostomy and
  gastrostomy
• Is it worth it?

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Focal Brainstem Astrocytoma

• No rush to treat. Many are slow growing and
  cause few symptoms
• Stereotactic biopsy may be used to establish
  histology, if needed
• Treatment for documented growth and/or symptom
  progression

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Diffuse Pontine Astrocytomas

• Characteristic image, diffuse infiltration of the
  pons
• Unresectable
• No role for biopsy, as patients do poorly
  regardless of histology

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Diffuse Pontine Astrocytoma
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Diffuse Pontine Astrocytoma

• This is the tumor referred to as brainstem
  glioma
• Account for 70 of brainstem tumors
• Do not call others (focal brainstem tumors)
  brainstem gliomas because the prognosis is so
  different

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Diffuse Pontine Astrocytomas

• No controversy, 2 year survival is less than 5.
• What is needed is radical, new, effective therapy

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Diffuse Pontine Astrocytomas

• No effective treatment
• Conventional or hyperfractionated radiation are
  palliative
• No effective chemotherapy

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Conclusions

• Brain tumors in children are not common, but must
  be kept in mind for the child with headache or
  neurologic symptoms or signs. Subtle findings
  may be important.
• One perceives only what one actively seeks.

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Conclusions

• Outcome is not as bad as generally thought
• Pilocytic astrocytomas, grade II astrocytomas,
  gangliogliomas, choroid plexus papillomas,
  dermoid tumors all can be treated effectively
  with surgery alone
• Medulloblastoma, ependymoma, malignant germ cell
  tumors have greater than 70 long term survival
  with surgical resection, radiation therapy and
  chemotherapy

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Conclusions

• Irradiation is bad for the brain
• Current research directed at finding focused
  therapy based on what is known about the
  molecular biology of the different tumor types.