International Neuroblastoma Staging System
INSS combines certain features of the previously used POG and CCG systems [1,8] and has identified distinct prognostic groups.[1,8,9,10]
- Stage 1: Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (i.e., nodes attached to and removed with the primary tumor may be positive).
- Stage 2A: Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.
- Stage 2B: Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically.
- 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 (unresectable) or by lymph node involvement. The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.
- 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 (limited to infants younger than 18 months). Marrow involvement should be minimal (i.e., <10% of total nucleated cells identified as malignant by bone biopsy or by bone marrow aspirate). More extensive bone marrow involvement would be considered stage 4 disease. The results of the MIBG scan, if performed, should be negative for disease in the bone marrow.
Children's Oncology Group Neuroblastoma Risk Grouping
In North America, the COG investigated a risk-based neuroblastoma treatment plan that assigned all patients to a low-, intermediate-, or high-risk group based on age, INSS stage, and tumor biology. The relevant biological attributes of the tumor included MYCN status, International Neuroblastoma Pathologic Classification (INPC) histopathology classification, and tumor DNA index. The low-risk group was observed without further treatment unless the patient had life- or organ-threatening tumors. The intermediate-risk group received limited chemotherapy, additional surgery in some instances, and avoided radiation therapy. This study involved an overall reduction in treatment compared to prior treatment plans. The high-risk group was treated with aggressive chemotherapy, second-look surgery, high-dose chemotherapy with stem cell rescue, radiation therapy, and cis -retinoic acid. The outcome for the low- and intermediate-risk groups combined was an event-free survival and overall 3-year survival of 88% and 96%, respectively. There was no unexpected toxicity. These studies (COG-P9641 and COG-A3961) have established a new standard of care for children in North America with neuroblastoma.
Some controversies exist regarding the treatment of several small subsets of patients and the INSS staging system;[12,13,14] risk group assignment and recommended treatment are expected to mature as additional outcome data are analyzed. For example, the risk group for INSS stage 4, including patients aged 12 to 18 months was changed for patients with MYCN-nonamplified status in 2005.[15,16,17] Table 1 describes the risk group assignment criteria used to assign treatment in these studies.