Neuroblastoma is the most common extracranial solid tumor of childhood, with two-thirds of the cases presenting in children ages 5 or younger. These tumors originate where sympathetic nervous system tissue is present, within the adrenal medulla or paraspinal sympathetic ganglia. They are remarkable for their broad spectrum of clinical behavior, with some undergoing spontaneous regression, others differentiating into benign tumors, and still others progressing rapidly and resulting in patient death.
Patients with neuroblastoma are stratified into prognostic risk groups (low, intermediate, and high) that determine treatment plans. Risk variables include age at diagnosis, clinical stage of disease, tumor histology, and certain molecular characteristics, including the presence of the MYCN oncogene. Tumor histology is categorized as favorable or unfavorable, according to the degree of tumor differentiation, proportion of tumor stromal component, and index of cellular proliferation. It is well established that MYCN amplification is associated with rapid tumor progression and a poor prognosis, even in the setting of other coexisting favorable factors. Loss of heterozygosity (LOH) at chromosome arms 1p and 11q occurs frequently in neuroblastoma. Although 1p LOH is associated with MYCN amplification, 11q is usually found in tumors without this abnormality. Some recent studies have shown that 1p LOH and unbalanced 11q LOH are strongly associated with outcome in patients with neuroblastoma, and both are independently predictive of worse progression-free survival (PFS) in patients with low- and intermediate-risk disease. Although the use of these LOH markers in assigning treatment in patients is evolving, they may prove useful to stratify treatment.
Clinical stage of disease is based on the International Neuroblastoma Staging System (INSS) as follows:
• Stage 1 Localized tumor with complete gross excision, with or without microscopic residual disease; lymph nodes negative for tumor
• Stage 2A Localized tumor with incomplete gross excision; lymph nodes negative for tumor 2 – TRA45.37
• Stage 2B Localized tumor with or without complete gross excision, with ipsilateral lymph nodes positive for tumor
• Stage 3 Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration or by lymph node involvement
• Stage 4 Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as defined for stage 4S
• Stage 4S Localized primary tumor as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (marrow involvement less than 10%), limited to children younger than 1 year of age
The low-risk group includes patients younger than 1 year of age with stage 1, 2, or 4S with favorable histopathologic findings and no MYCN oncogene amplification. High-risk neuroblastoma is characterized by an age older than 1 year, disseminated disease, MYCN oncogene amplification, and unfavorable histopathologic findings.
In general, most patients with low-stage disease have excellent outcomes with minimal therapy, and with INSS stage 1 disease, most patients can be treated by surgery alone. Most infants, even with disseminated disease, have favorable outcomes with chemotherapy and surgery. In contrast, most children older than 1 year with advanced-stage disease die due to progressive disease, despite intensive multimodality therapy, and relapse remains common. Treatment of recurrent disease is determined by the risk group at the time of diagnosis, and the extent of disease and age of the patient at recurrence