Name genes associated with familial neuroblastoma and germline mutations associated with NBL
Familial:
- ALK
- PHOX2B
Germline mutations associated with NBL:
- NF-1
- BWS/WT2
- p53
- Noonan
- deletion 1p36 or 1q14
Somatic changes with NBL
- 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
Classic pathology finding in BM in NBL
Homer-Wright rosette
Myoclonic jerking and random eye movements with cerebellar ataxia
- name, treatment, and outcomes
OMA syndrome
- treat with IVIG/steroids or plasmapharesis/ritux
- good tumor outcomes but poor long-term neurodevelopmental outcomes.
What % of tumors are MIBG avid and what is another option?
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
NBL vs other SRBCT
- Homer-rosette
- cohesive clumps of cells
- S100, CD56 and PGP9.5 on immunostaining
- CD99 negative - ewing’s is positive
- CD45 neg - positive in lymphoma
Principles of Low risk NBL therapy
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
Principles of Int risk NBL therapy
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
Principles of HR NBL therapy
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
INRG definition of MS
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
What is the Curie score?
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)
INSS vs INRG
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
Factors involved in INRG risk group assignment
INRG stage Age Histology Grade of differentiation Myc-N status 11q ploidy
divided into very low, low, intermediate and high risk groups
INRC response criteria
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
Minimum diagnostic criteria for NBL
Unequivocal pathologic diagnosis
Combination of bone marrow aspirate/trephine biopsy containing unequivocal tumor cells AND elevated HVA/VMA
What is the EFS and OS of LR, IR or HR?
Low: EFS > 90% (> 95%), OS 97%
Intermediate: EFS > 85% (80-95%), OS 96%
High: EFS 40-50%, OS 40-50%
what are adverse risk factors associated with NBL?
- low VMA to HVA ratio
- Myc-N amplification
- unfavourable INPC
- tumour segmental chromosome aberrations
- infants with tumour diploid DNA content
