Once the tumor is identified, several key tests must be performed on the specimen in order to stratify the patient according to risk as outlined below.
There are three biological subtypes:
Type 1:
- Gains and losses of whole chromosomes
- Express the TrkA neurotrophin receptor
- Hyperdiploid
- Often regresses spontaneously
Type 2A
- Copy number alterations in portions of chromosomes
- Express TrkB neurotrophin receptor and its ligand
- Gained an additional copy of chromosome 17q
- Loss of heterozygosity of 14q or 11q
- Genomically unstable
Type 2B
- MYCN gene is amplified
- Gain of chromosome 17q
- Loss of chromosome 1p
- Expression of TrkB neurotrophin receptor and its ligand
The biological subtyping is used with clinical risk factors such as age and tumor stage to determine the "risk category of the tumor".
Shimada index
Hiroyuki Shimada et al developed a histologic classification system, which can be used as a prognostic indicator. Age is taken into account.
Classifies tumors as favorable or unfavorable
Favorable
- Stroma-rich, all ages
- Stroma poor, age 1-1.5 yr, differentiated, MKI <100
- Stroma poor, age < 1.5 yr, MKI <200
Unfavorable
- Stroma rich, all ages, nodular pattern
- Stroma poor, age > 5 yr
- Stroma poor, age 1.5-5 yr, undifferentiated
- Stroma poor, age < 1.5 yr, MKI > 200
Stroma- rich/stroma poor refers to presence or absence of Schwannian components
Differentiation refers to maturity of tumor
MKI is the mitosis-karyorrhexis index [number of mitoses (cell division) and karyorrhexis (degeneration of the nucleus) per 5,000 cells]
DNA index (DI)
DNA index refers to the amount of DNA in the tumor cell, which is prognostically important. DNA ploidy probably has the most prognostic significance in infants.
Hyperdiploid or near-triploid
- Whole chromosome gains without structural genetic aberrations
- Associated with localized tumors and favorable prognosis
- Respond better to chemotherapy
Aneuploidy or near diploid
- Associated with unfavorable prognosis
- Usually have other genetic aberrations (MYCN amplification, chromosomal losses, etc)
MYCN Amplification
MYCN is a normal oncogene (promotes cell division)
Amplification (increased copies) of MYCN is associated with advanced stages of disease and poorer outcome
Present in 25-35% of neuroblastoma
MYCN gene amplification is more frequent in near-diploid than in hyperdiploid tumors
Activating Mutations
- 6- 10% of NBL carry somatic ALK-activating mutations
- Additional 3 - 4% have a high frequency of ALK gene amplification
- The mutations lead to constitutive phosphorylation of ALK leading to dysregulation of cell signaling and uncontrolled proliferation of the ALK-mutant neuroblasts.
- Inhibition of ALK kinase is a potential target for therapy
Cytogenetics
Cytogenetic analysis of neuroblastoma cell lines has revealed other abnormalities.
Chromosome 1p (short arm of chromosome 1)
- Is a tumor suppressor gene (prevents amplification of MYCN)
- 1p deletions usually associated with MYCN amplification
- Found in 25-35% of neuroblastoma tumors
- Most commonly in patients with advanced disease.
Gains of chromosome 17q associated with more aggressive tumors
- Occurs in 60% of neuroblastomas
Deletion of 11q
- Present in approximately 35-45% of newly diagnosed tumors
- Rarely occurs in combination with MYCN amplification
- Associated with high risk disease because it is associated with older age, advanced stage, and unfavorable pathology
Neurotrophin Receptors
- Trk receptors = family of tyrosine kinases that regulate synaptic strength and plasticity in the nervous system
- Signal cell to differentiate
- A neurotrophin receptor, TrKA (a tyrosine kinase) expression associated with younger age at diagnosis, lower stage and absence of MYCN amplification
- High TrKA expression was associated with 86% 5 year survival and low TrKA expression with 14% survival.
