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 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. CP

17. CP

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
________________________________
General (76%)
Pediatric (91%)
X2, p ‹0.02

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

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

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 CP

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

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

52. Cerebellar Astrocytoma

53. 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

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

55. Cerebellar Astrocytoma

56. Cerebellar Astrocytoma

57. 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

58. 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

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

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

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

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

63. 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

64. 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

65. 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?

66. 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

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

68. Diffuse Pontine Astrocytoma

69. 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

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

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

72. 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.”

73. 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

74. 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.