The prognosis of neuroblastoma has improved over time:
The 5 year overall survival of all infants and children with neuroblastoma increased from 46% for those diagnosed between 1974 and 1989 to 71% for those diagnosed between 1999 abd 2005.
Important prognostic factors for neuroblastoma include the following (many prognostic factors overlap):
Age
- Age at diagnosis is an important prognostic factor.
- The majority of children diagnosed at 12 months or younger will survive.
- Children less than one year with localized tumors have a five year survival greater than 90%, whereas in older children with advanced disease the long term survival is less than 30%, even with intensive therapy.
- Younger patients do tend to present with earlier stage disease.
Site of Primary Tumor
- Adrenal primary tumors are more likely to be associated with unfavourable prognostic features (e.g. MYCN amplification) than non-adrenal or thoracic primary tumors.
- Adrenal tumors are also more likely to be associated with stage 4 disease., segmental chromosome abberations and elevated LDH levels.
Stage
Stage is an important predictor of outcome. Regional lymph node involvement is associated with a worse prognosis:
| Stage | 5 - 10 year Survival |
| 1 | Nearly all patients survive |
| 2 and 4S | 80% |
| 3 | 50 - 70% |
| 4 and over 1 year old | Only 5 - 10% |
Tumor histopathology
Favourable outcomes associated with:
- Higher degrees of neuroblastic maturation are associated with a better prognosis in stage 4 patients with no MYCN amplification .
- Neuroblastoma containing many differentiating cells (ganglioneuroblastoma) has a better prognosis
- Cystic neuroblastoma occurs in about 25% of fetal and neonatal neuroblastomas and has lower stage and a better prognosis
Unfavourable outcomes associated with:
- Mitosis and karyorrhexis.
- Shimada analyzed in CCG-3881 data and showed that unfavorable pathology was associated with advanced disease and less favorable outcome (except for Stage
I disease). - Undifferentiated NBL with MYCN protein expression has a very poor prognosis
Biological Features
Segmental chromosome changes:
- Segmental chromosome number changes predict for recurrent disease in infants with localized unresectable or metastatic neuroblastoma without MYCN amplification.
- For all patients with neuroblastoma a higher number of chromosome breakpoints is associated with advanced stage disease, advanced age at diagnosis and a worse outcome independent of MYCN amplification.
DNA Ploidy
- Flow cytometric techniques measure cellular DNA content or ploidy or cytogenetic
analysis of metaphase chromosomes. - A number of genetic abnormalities correlate with prognosis.
- Ploidy seems to override favorable clinical features.
- Hyperdiploid tumors do better than diploid tumors and respond better to chemotherapy. In infants with disseminated neuroblastoma, DNA ploidy accurately discriminated between good and poor responders to chemotherapy.
- MYCN gene amplification is more frequent in diploid than in hyperdiploid tumors.
MYCN Oncogene Amplification
- Genomic amplification of N-myc (or MYCN) is directly correlated with prognosis.
- MYCN amplification is defined as greater than 10 copies per diploid genome.
- Found in up to 25% of cases
- If MYCN oncogene is amplified, patients with stage 2, 3, 4 and 4S stage have a worse prognosis.
- MYCN amplification is only rarely detected in localized neuroblastoma.
- Amplification of the MYCN gene is associated with deletion of chromosome 1p and with gain in the long arm of chromosome 17 (17q).
ALK Mutations:
- Anaplastic lymphoma kinase (ALK) is a cell surface receptor tyrosine kinase, expressed at significant levels only in developing embryonic and neonatal brain.
- Germline mutations in ALK are the major cause of hereditary neuroblastoma.
- Somatically acquired ALK-activating mutations are found as oncogenic drivers in neuroblastoma.
- ALK mutations occur in 8% of neuroblastoma patients and are associate with significantly poorer survival in high-risk and intermediate-risk neuroblastoma.
- ALK mutations occur at the highest frequency (11%) in patients older than 10 years.
- In high, low and intermediate-risk groups of neuroblastoma, the frequency of ALK aberrations is 14%, 8% and 6%, respectively.
- Small molecule ALK kinase inhibitors such as crizotinib are being developed and tested in patients with recurrent and refractory neuroblastoma.
Risk grouping for patients with neuroblastoma stratifies them into different prognostic categories and survival is much better for low risk patients:
Low-risk group: 5-year survival rate is higher than 95%.
Intermediate-risk group: 5-year survival rate is around 90% to 95%.
High-risk group: 5-year survival rate is around 40% to 50%.
| INSS Stage | Age | MYCN Status |
Shimada Histology |
DNA Ploid |
Risk Group |
| 1 | 0- 21 yrs | Any | Any | Any | low |
| 2A/2B | <1 y ≥ 1-21 y ≥ 1-21 y ≥ 1-21 y |
Any Non-Amp Amp Amp |
Any Any Fav Unfav |
Any - - - |
Low Low Low High |
| 3 | <1yr <1yr ≥ 1-21 y ≥ 1-21 y ≥ 1-21 y |
Non-Amp Amp Non-Amp Non-Amp Amp |
Any Any Fav Unfav Any |
Any Any - - - |
Intermediate High Intermediate High High |
| 4 | <1y <1y ≥ 1-21 y |
Non-Amp Amp Any |
Any Any Any |
Any Any - |
Intermediate High High |
| 4S | <1 y <1 y <1 y <1 y |
Non-Amp Non-amp Non-amp Amp |
Fav Any Unfav Any |
> 1 = 1 Any Any |
Low Intermediate Intermediate High |
Patients who present with elevated serum ferritin levels tend to have a poor prognosis.
