Pediatric Brain Tumors Corey Raffel, M.D., Ph.D. Chief, Section of Pediatric Neurosurgery Nationwide Children’s Hospital Columbus, Ohio

Brain Tumors in Children “Oh, my God, my child/patient has a brain tumor!” Depression!

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?

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.

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

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

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

 Symptoms and Signs Seizures New onset seizure unassociated with fever Change in pattern of pre-existing seizures

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

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.

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.

Types of Tumors Will review the common tumor types, emphasizing presentation, treatment, and outcome.

Medulloblastoma/PNET PNET describes morphologically related CNS tumors Unrelated to PNS PNET characterized by 11-22 translocation Medulloblastoma=cerebellar PNET PNET terminology being abandoned

Medulloblastoma 20% of pediatric brain tumors 40% of posterior fossa tumors

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

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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

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

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

Extent of Resection by Type of Neurosurgeon ________________________________ General 18 57(76%) Pediatric 6 60(91%) X2, p ‹0.02

Role of Irradiation Effective Dose to posterior fossa › 50 Gy

Outcome Radiation Dose Relapse-free survival (%) 50 Gy (15 pt) Relapse-free survival (%) P<0.01 <50 Gy (43 pt) Years (no.) CP1150826-2

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

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

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, ENU’s, cytoxan, etc.

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

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

Prognostic Factors Age ‹2 years, poor prognosis CSF dissemination, poor prognosis Radical resection, good prognosis

CSF Dissemination

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

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

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

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

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

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

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

Ependymoma

Ependymoma

Ependymoma

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

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

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

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

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

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

Pilocytic Astrocytoma

Pilocytic Astrocytoma

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

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

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

Cerebellar Astrocytoma

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

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

Cerebellar Astrocytoma

Cerebellar Astrocytoma

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

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

Focal Brainstem Astrocytoma Usually in midbrain, medulla, or cervicomedullary Dorsally exophytic into IV ventricle Account for 30%

Focal Brainstem Astrocytoma Pathology: grade I, grade II astrocytoma, ganglioglioma Less often grade III or IV astrocytoma

Focal Brainstem Astrocytoma Controversy about treatment Role of resection Role of radiation Role of chemotherapy

Focal Brainstem Astrocytoma Subtotal resection may be effective Recommended for dorsally exophytic tumors

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

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

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

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

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

Diffuse Pontine Astrocytoma

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

Diffuse Pontine Astrocytomas No controversy, 2 year survival is less than 5%. What is needed is radical, new, effective therapy

Diffuse Pontine Astrocytomas No effective treatment Conventional or hyperfractionated radiation are palliative No effective chemotherapy

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.”

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

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.