1. Neuroblastoma

2. Neuroblastoma A tumor of postganglionic sympathetic neuroblasts
The sympathetic chain extends from the neck to the sacrum
The adrenal gland
Neurotransmitter- Catecholamines

4. Neuroblastoma - Epidemiology
Most common extracranial solid tumor
Incidence – 10/million per year
~10% of pediatric tumors
Peak age – 2-3 years
>90% cases before 5 years
Mostly sporadic – rare genetic associations
Most common neonatal tumor

5. Neuroblastoma - Genetics
Mostly sporadic – rare (2%) genetic associations (NF1, Hirschsprung, congenital central hypoventilation syndrome)
Mutations in ALK (tyrosine kinase)
Environment??

6. Neuroblastoma – Biology
Neuroblastoma is a tumor of undifferentiated (embryonal) neuroectodermal cells, derived from the neural crest
An aberration of normal differentiation
An abnormal response to normal neurotropic signals (TRK-A, NGF)
Spontaneous regression
Differentiation – Ganglioneuroma, ganglioneuroblastoma

7. Neuroblastoma – Clinical features I
Tumor originates from sympathetic ganglia/adrenal gland
Lymphatic and hematogenous spread
Metastases to bone, liver, bone marrow, skin
Most patients present with advanced disease (40% of all patients, 55% of patients over 1 year)

8. Neuroblastoma-Clinical features - II
Abdominal mass (65%)
Thoracic mass (Infants)
Bone pain
Fever
Weight loss
“Sick looking child”

10. Neuroblastoma – Clinical Features - III
Lower limb paresis – 20 to spinal epidural tumor (4%)
Severe diarrhea 20 to secretion of VIP (vasoactive intestinal peptide) (4%)
Horner syndrome - patients with cervical or upper thoracic sympathetic ganglia (1.7%)
Hypertension, flushing, sweating (0.2%)
Raccoon eyes
Pallor, bleeding diathesis (Bone marrow involvement)

11. Neuroblastoma
Raccoon eyes

12. Neuroblastoma – Clinical features - IV
Opsoclonus-Myoclonus syndrome
Acute cerebellar encephalopathy characterized by cerebellar ataxia, rapid and random eye movements (opsoclonus) and myoclonic jerks (2.8%)
Good oncological but poor neurological outcome

16. Laboratory Features Catecholamines (Dopamine, epinephrine, VMA, HVA)
Serum markers - LDH, ferritin, NSE (Neuron specific enolase)
Blood count (BM involvement)
Coagulation (Liver involvement)

17. Metabolism of Catecholamines

18. Pathology Small round blue cell tumor
Neuroblastic differentiation: From very
undifferentiated to differentiated
Degree of anaplasia – Shimada index
Biological parameters

21. Neuroblastoma biology II
N-MYC – Oncogene on chromosome 2 amplification – worse prognosis
DI (DNA Index= ploidy) – hyperdiploid – better outcome in infants
1p deletion – putative tumor suppressor genes – worse prognosis
17q gain – oncogene?

22. N-Myc amplification
Amplification – A localized genomic change that results in increased dosage of a gene or genes affected
Homogeneously staining regions (HSR’s) - are areas on the native chromosome with multiple kB copies of the region containing the amplified gene
Double minutes (DM) – Extrachromosomal fragments containing the amplified gene
>10 copies are associated with a worse prognosis

23. Mechanisms of N-myc amplification

24. N-MYC amplification- Homogeneously staining region

25. N-MYC amplification- Double minutes

26. Neuroblastoma- 1p deletion

27. Neuroblastoma - Staging
CT/MRI
MIBG (Meta-iodo-benzyl-guanidine)
Bone scan
Bone marrow aspirate and biopsy
Surgery

28. MIBG scan

30. Neuroblastoma - Staging
Stage
Tumor confined to organ of origin and completely resected I
Tumor extending beyond organ of origin, ipsilateral nodes+ II
Tumor crosses midline, contralateral nodes+
III
Metastatic disease IV
<1.5 year; metastases to liver, skin, BM
IV-S

31. Neuroblastoma - INSS Staging System
Stage 1- Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (nodes attached to and removed with the primary tumor may be positive)
Stage 2A – Localized tumor with incomplete gross resection; representative ipsilateral non-adherent lymph nodes negative for tumor microscopically
Stage 2B- Localized tumor with or without complete gross excision, with ipsilateral non-adherent lymph nodes positive for tumor’ enlarged contralateral lymph nodes must be negative microscopically
Stage 3 – Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement
Stage 4 – Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4s)
Stage 4s – Localized primary tumor (as defined for stage 1, 2A or 2B) with dissemination limited skin, liver, and or bone marrow (limited to infants<1 year)

33. International Neuroblastoma Staging System (INSS)1 4 2b 4S 3 2a

34. Age (<18m – favorable)
Prognostic Factors
Age (<18m – favorable)
Stage
Histology (Shimada)
Biology
N-MYC, DI, 17q+, 1p-

35. Neuroblastoma - Treatment
Risk adapted
Low risk NB – Minimal
therapy – excellent outcome
High NB – Intensive therapy – poor outcome

36. INRG – International Neuroblastoma Risk Group Classification System
Age
Stage
N-MYC status

37. Neuroblastoma -Protocol assignment by risk group
Study
Risk Group
DNA Ploidy
Shimada histology
N-MYC status
Age
INSS stage
Low risk
Low
Any
0-21 y 1
High risk
High -
Fav
Unfav
Non-Amp
Amp
<365/547 d
>365 d
>365
2A/2B
IM risk
High-risk
Intermediate
<365 d 3 4
>1 =1
<365 4s

38. Low/Intermediate risk Neuroblastoma
Watch and wait (No treatment=no toxicity)
Surgery- Minimize damage
Low intensity chemotherapy
Radiation – emergency only (rarely used)

39. Improving Survival for Stage 4 Neuroblastoma Patients > 1 Year of Age at Diagnosis
0.8
Childrens Cancer Group Data
Probability of Overall Survival
0.6
0.4
N = 675
0.2
N = 507
P < 0.001 1 2 3 4 5 6 7 8 9 10
Years from Diagnosis

40. Treatment – High Risk Neuroblastoma
Induction chemotherapy
Surgery
High dose chemotherapy with stem cell
rescue (Eradication of residual disease)
Radiation
Retinoic Acid
Immunotherapy

41. High-risk Neuroblastoma – Treatment Roadmap
█████ ███ ███ █ ██ ██
Induction Surgery Consolidation XRT Cis-RA Immunorx.
Chemotherapy ABMT Anti GD IL-2
GM-CSF
(Differentiation therapy)
Immunotherapy

42. Chemotherapy in Neuroblastoma
Platinum (Cis, carbo)
VP-16
Doxorubicin
Cyclophosphamide/Ifosfamide
Vincristine
Topotecan

43. High Dose Chemotherapy
Myeloablative doses
Eradication of tumor
Rescue with autologous stem cells
MEC
(Melphalan, etoposide, carboplatinum) BM
(Busulfan, Melphalan)

44. Neuroblastoma – Radiation Therapy
Local consolidation (In high-risk disease)
Massive hepatomegaly in infants with 4S
Cord compression?
Metastatic disease - palliation

45. Neuroblastoma – Differentiation therapy
Cis-retinoic acid (Roaccutane)
Induces differentiation of neuroblastoma cells in vitro and decreases proliferative capacity
Shown in randomized clinical trial to improve outcome

46. High-Dose, Pulse Retinoic Acid Induces Neuroblastoma Differentiation
Control
10 mM Retinoic Acid

48. Neuroblastoma – Immunotherapy
Anti GD-2 antibodies
Interleukin 2
GM-CSF

49. Accrual of 386
randomized patients
needed

50. COG-ANBL0032 Phase III 2/17/09 Status: DATA AND SAFETY MONITORING COMMITTEE
With ~61 % of accrual in, and ~ 2 year median follow up, the Immunotherapy arm shows:
Superior EFS (p = )
Superior OS (p = )

51. Neuroblastoma - Outcome
Stage I – 95% 5y EFS
Stage II – 90% 5y EFS
Stage III+IV – 10-40% 5y EFS
Stage IV-S - 95% 5y EFS

52. 4s Neuroblastoma NOT BONE Under 18 months Primary tumor stage I/II
Metastatic disease limited to:
Bone marrow(<10%)
Skin(Subcutaneous nodules)
Liver
NOT BONE

53. Bone and Bone Marrow

54. Neuroblastoma - Staging
Stage
Tumor confined to organ of origin and completely resected I
Tumor extending beyond organ of origin, ipsilateral nodes+ II
Tumor crosses midline, contralateral nodes+
III
Metastatic disease IV
<18months; metastases to liver, skin, BM
IV-S

55. 4s Neuroblastoma Spontaneous regression Cure with minimal therapy
Exception: Massive hepatomegaly in <2 months
(May require chemotherapy, RT)

56. Neuroblastoma – Spontaneous regression
Occurs mainly in 4s disease
But - may occur in all stages (overall ~ 10% of cases)
Screening studies detect a 2-fold increase in incidence of neuroblastoma compared to clinically detected cases
Cases detected in utero by ultrasound are being reported more frequently, and most are expected to resolve without treatment
Spontaneous maturation to ganglioneuroma is apparently less common, but there is little data

57. Neuroblastoma – Outcome by stage

58. MYCN Amplification Correlates With Poor Survival
in Infants with Stage 4 Neuroblastoma
P <
Schmidt, JCO 2000

59. Potential Therapy Radioactive MIBG Anti-GD2 antibodies Allogeneic BMT
Sequential auto-BMT x2-3
Rapid sequence induction
Early detection
Targeted therapy - ALK inhibition

60. Neuroblastoma - Screening
Rationale:
Poor results in advanced-stage tumors
Early stage – better outcome
Available tumor marker (CA)
Method
Universal screening by urinary CA at 6 months

61. Neuroblastoma Screening - Results
More early stage tumors
No increase in detection of advanced tumors
No improvement in overall cure
Do advanced tumors evolve from early stage less aggressive tumors?
Or are they rapidly evolving metastatic tumors that occur after 1 year of age?

62. Perinatal Neuroblastoma
Tumors discovered during routine antenatal ultrasound as adrenal masses
Differential diagnosis: Adrenal hemorrhage, pulmonary sequestration
Traditional approach: Surgery
Most tumors – stage 1, favorable histology, N-MYC non-amp
Postnatal MIBG scan. If positive:
Close observation; surgery for growing tumors
Excellent outcome

63. Neuroblastoma
A tumor of sympathetic neuroblasts that arises along the sympathetic chain and in the adrenal gland
Heterogeneous clinical behavior and prognosis
Different subtypes present different challenges