Stage 4N Neuroblastoma (Metastatic disease confined to distant lymph nodes) has a better outcome than non-4N stage 4 disease: A study from the International Neuroblastoma Risk Group Database.

Background: The presence of metastatic disease is one of the most powerful predictors of poor outcome in patients with neuroblastoma. However, the pattern of metastatic spread is not part of current risk stratification systems. Small case series have suggested that patients with metastatic neuroblastoma limited to distant lymph nodes (4N disease) may have improved outcomes. Methods: Retrospective analysis of data from INRG database for patients diagnosed 1990–2002. 4N patients were compared to the remaining stage 4 patients (non-4N), excluding those with missing/inconsistent metastatic site data. Results: 2250 INSS stage 4 patients with complete data were identified, of whom 146 (6.5%) had 4N disease. Patients with 4N disease had significantly better outcomes than those with non-4N stage 4 disease (EFS 77%±4% v 35%±1%; OS 85% v 42%±1%; P<0.0001). 4N patients were more likely to be younger (P<0.0001)and have tumors with favorable characteristics, including absence of MYCN amplification (89% v 69%, P<0.0001), lower mean mitosis karyorrhexis index (P=0.0011), differentiating grade (21% v 8%, P=0.006) and favorable International Neuroblastoma Pathologic Classification (63% v 26%, P<0.0001). Insufficient cytogenetic data prevented analysis of associations between particular segmental chromosomal abnormalities and 4N/non-4N patterns of disease. In a multivariable analysis, 4N disease remained a significant predictor of outcome (hazard ratio for non-4N v 4N 3.40 for EFS, 3.69 for OS). Within subgroups defined by age atdiagnosis and tumor MYCN status, 4N pattern was significantly associated with improved outcomes. Conclusion: 4N represents a subgroup with better outcome than other patients with metastatic disease. These findings suggest that the biology and treatment response of 4N tumors differ from other stage 4 tumors, and that less intensive therapy should be considered for this cohort. Future exploration of biological factors (chromosomal aberrations, mRNA profiles and host factors) that determine the pattern of metastatic spread is warranted.