Many biological characteristics of tumors are not currently used in determining therapy; however, as clinical research matures, these characteristics may be found useful as therapeutic targets or as clinically important prognostic factors. Amplification of the MYCN gene is associated not only with deletion of chromosome 1p, but also gain of the long arm of chromosome 17 (17q), the latter of which independently predicts a poor prognosis. In contrast to MYCN gene amplification, the degree of expression of the MYCN gene in the tumor does not predict prognosis. However, high overall MYCN-dependent gene expression and low expression of sympathetic neuron late differentiation genes both predict a poor outcome of neuroblastomas otherwise considered to be at low or intermediate risk of recurrence. Other biological prognostic factors that have been extensively investigated include tumor cell telomere length, telomerase activity, and telomerase ribonucleic acid;[46,47] urinary VMA, HVA, and their ratio; dopamine; CD44 expression; TrkA gene expression; serum neuron-specific enolase level, serum lactic dehydrogenase level, and serum ferritin level. High-level expression of the MRP1 drug resistance gene is an independent indicator of decreased survival. The profile of GABAergic receptors expressed in neuroblastoma is predictive of prognosis regardless of age, stage, and MYCN gene amplification. Gene expression profiling may prove useful for prognosis prediction. Whole chromosome copy number changes do not predict recurrence, while segmental chromosome number changes do. In addition, response to treatment has been associated with outcome. The persistence of neuroblastoma cells in bone marrow during or after chemotherapy, for example, is associated with a poor prognosis.[53,54]
Unique Aspects of Neuroblastoma
Biologically discrete types of neuroblastoma
Based on biologic factors and an improved understanding of the molecular development of the neural crest cells that give rise to neuroblastoma, the tumors have been categorized into three biological types. These types are not used to determine treatment at this time; however, type 1 has a very favorable prognosis, while types 2 and 3 have poor prognoses.
Type 1: Expresses the TrkA neurotrophin receptor, is hyperdiploid, and tends to spontaneously regress.[55,56]
Type 2: Expresses the TrkB neurotrophin receptor and its ligand, has gained an additional copy of chromosome 17q, has LOH of 14q or 11q, and is genomically unstable.[55,56]
Type 3: Has a gain of chromosome 17q, loss of chromosome 1p, and the MYCN gene becomes amplified.[55,56]
Children whose tumors have lost a copy of 11q are older at diagnosis, and their tumors contain more segmental changes in gene copy number compared with children whose tumors show MYCN amplification.[57,58] Moreover, segmental chromosome changes not detected at diagnosis may be found in neuroblastomas at relapse. This suggests that clinically important tumor progression is associated with accumulation of segmental chromosomal alterations.