Neuroblastoma

Question 1

Name genes associated with familial neuroblastoma and germline mutations associated with NBL

Answer 1

Familial:

• ALK
• PHOX2B

Germline mutations associated with NBL:

• NF-1
• BWS/WT2
• p53
• Noonan
• deletion 1p36 or 1q14

Question 2

Somatic changes with NBL

Answer 2

• whole chromosome gains vs segmental aberrations (whole better)
• MYCN (> 10 copies)
• ALK
• 17q (60%)
• 1p36 - associated with Myc-N
• 11q23
• 14q
• Telomerase mutations (ATRX only in adolescents and TERT)
• ARID1a/1b

Question 3

Classic pathology finding in BM in NBL

Answer 3

Homer-Wright rosette

Question 4

Myoclonic jerking and random eye movements with cerebellar ataxia
- name, treatment, and outcomes

Answer 4

OMA syndrome

• treat with IVIG/steroids or plasmapharesis/ritux
• good tumor outcomes but poor long-term neurodevelopmental outcomes.

Question 5

What % of tumors are MIBG avid and what is another option?

Answer 5

90%
FDG-PET scan recommended
–> PET scan
-> Technicium-99 bone scan can be used at diagnosis but not response as it remains positive for healing bone

Question 6

NBL vs other SRBCT

Answer 6

• Homer-rosette
• cohesive clumps of cells
• S100, CD56 and PGP9.5 on immunostaining
• CD99 negative - ewing’s is positive
• CD45 neg - positive in lymphoma

Question 7

Principles of Low risk NBL therapy

Answer 7

EFS/OS > 90%

• surgery is mainstay and complete resection not mandatory
• observation alone - COG study of < 6m old with localized adrenal tumors <3cm
• chemo/rads for life-threatening symp or relapse

Question 8

Principles of Int risk NBL therapy

Answer 8

EFS>85% oS>90%
Surgery - for biopsy
- delayed debulking but complete resection not needed

Chemo:

• 2-8 cycles with duration based on getting >50% reduction
• longer if unfav histology

rads only if emergent- ex. spinal cord compression

Question 9

Principles of HR NBL therapy

Answer 9

Induction:

• chemo 6 cycles
• harvest PBSC after 2 cycles
• surgery after 5 cycles

Consolidation
SCT: tandem
Ext. beam rads regardless of extent of resection (2160Gy)

Maintenance:
- Ch14.18 and isotretinoin

Question 10

INRG definition of MS

Answer 10

Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow. The primary tumor can be INSS stage 1, 2, or 3

MYC-N non-amplified
11q negative

*if last 2 are positive then high-risk disease

Question 11

What is the Curie score?

Answer 11

Score for assessing extent of MIBG avid disease.

Score > 2 is a negative prognostic factor for HR NBL (both upfront and in response to induction)

• EFS of HR-NBL is 15% with Curie >2 vs 45% < 2. (COG A3973)

Question 12

INSS vs INRG

Answer 12

INSS

• is based on surgical staging,
• 4S up to 12 m and primary tumor must be stage 1/2

INRGSS

• uses image-defined risk factors
• 4S up to 18m and primary can be stage 1/2/3

Question 13

Factors involved in INRG risk group assignment

Answer 13

INRG stage
Age
Histology
Grade of differentiation
Myc-N status
11q
ploidy

divided into very low, low, intermediate and high risk groups

Question 14

INRC response criteria

Answer 14

CR - MIBG negative, < 10mm of primary or LN

PR ->30% decrease in primary tumor, no new lesions, MIBG stable/improve, and 50% reduction in MIBG bone score
* note ANBL 0531 used 50-90% reduction in tumor volume as PR

Progressive disease: new lesion, growth of known lesion > 20%, increase in MIBG score by 1.25% or greater

Question 15

Minimum diagnostic criteria for NBL

Answer 15

Unequivocal pathologic diagnosis

Combination of bone marrow aspirate/trephine biopsy containing unequivocal tumor cells AND elevated HVA/VMA

Question 16

What is the EFS and OS of LR, IR or HR?

Answer 16

Low: EFS > 90% (> 95%), OS 97%

Intermediate: EFS > 85% (80-95%), OS 96%

High: EFS 40-50%, OS 40-50%

Question 17

what are adverse risk factors associated with NBL?

Answer 17

• low VMA to HVA ratio
• Myc-N amplification
• unfavourable INPC
• tumour segmental chromosome aberrations
• infants with tumour diploid DNA content