Pediatric Brain Tumors

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

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

3. 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?

4. 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.

5. 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

6. 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

7. 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

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

9. 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

10. 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.

11. 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.

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

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

14. Medulloblastoma • 20% of pediatric brain tumors • 40% of posterior fossa tumors

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

16. CP1150826-4

17. CP1150826-3

18. 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

19. 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

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

21. Extent of Resection by Type of Neurosurgeon Resection ____________ • Neurosurgeon ‹90% ›90% ________________________________ • General 18 57(76%) • Pediatric 6 60(91%) ________________________________ X2,p ‹0.02

22. Role of Irradiation • Effective • Dose to posterior fossa › 50 Gy

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

24. 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

25. 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

26. 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.

27. 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

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

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

30. CSF Dissemination

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

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

33. 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

34. 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

35. 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

36. 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

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

38. Ependymoma

39. Ependymoma

40. Ependymoma

41. 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

42. 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

43. 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

44. 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

45. 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

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

47. Pilocytic Astrocytoma

48. Pilocytic Astrocytoma

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

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