title: Metastatic neuroblastoma confined to distant lymph nodes (stage 4N) predicts outcome in patients with stage 4 disease: A study from the International Neuroblastoma Risk Group Database.
abstract: OBJECTIVE
  The presence of distant metastases is one of the most powerful predictors of outcome in patients with neuroblastoma. However, the pattern of metastatic spread is not incorporated into current risk stratification systems. Small case series have suggested that patients with neuroblastoma who have metastatic disease limited to distant lymph nodes (4N disease) may have improved outcomes.
  
  
  METHODS
  We analyzed retrospective data from the International Neuroblastoma Risk Group database for patients diagnosed from 1990 to 2002. 4N patients were compared with the remaining stage 4 patients (non-4N), excluding those with missing metastatic site data.
  
  
  RESULTS
  In all, 2,250 International Neuroblastoma Staging System stage 4 patients with complete data were identified, of whom 146 (6.5%) had 4N disease. For 4N patients, event-free survival (EFS; 5-year, 77% ± 4%) and overall survival (OS; 5-year, 85% ± 3%) were significantly better than EFS (5-year, 35% ± 1%) and OS (5-year, 42% ± 1%) for non-4N stage 4 patients (P < .001). 4N patients were more likely to be younger (P < .001) and have tumors with favorable characteristics, including absence of MYCN amplification (89% v 69%; P < .001). In a multivariable analysis, 4N disease remained a significant predictor of outcome (hazard ratio for non-4N v 4N: 3.40 for EFS and 3.69 for OS). Within subgroups defined by age at diagnosis and tumor MYCN status, 4N disease was significantly associated with improved outcomes.
  
  
  CONCLUSIONS
  4N represents a subgroup with better outcome than that of other patients with metastatic disease. These findings suggest that the biology and treatment response of 4N tumors differ from other stage 4 tumors, and less intensive therapy should be considered for this cohort. Future exploration of biologic factors determining the pattern of metastatic spread is warranted.
authors.affiliation: Daniel A. Morgenstern and Meredith S. Irwin, Hospital for Sick Children and University of Toronto; Derek Stephens, Hospital for Sick Children, Toronto, ON, Canada; Daniel A. Morgenstern, Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, London; Andrew D.J. Pearson, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom; Wendy B. London, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA; Samuel L. Volchenboum and Susan L. Cohn, University of Chicago, Chicago, IL; Barbara Hero, University Children's Hospital, Köln, Germany; Andrea Di Cataldo, University of Catania, Catania, Italy; Akira Nakagawara, Chiba University School of Medicine, Chiba, Japan; Hiroyuki Shimada, University of Southern California at Los Angeles, Los Angeles; Katherine K. Matthay, University of California at San Francisco, San Francisco, CA; and Peter F. Ambros, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Morgenstern
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.forename: Derek
authors.initials: D
authors.lastname: Stephens
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Volchenboum
authors.forename: Barbara
authors.initials: B
authors.lastname: Hero
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Cataldo
authors.forename: Akira
authors.initials: A
authors.lastname: Nakagawara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.forename: Peter F
authors.initials: PF
authors.lastname: Ambros
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cohn
authors.forename: Andrew D J
authors.initials: AD
authors.lastname: Pearson
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Irwin
mesh_terms: D015331:Cohort Studies; D018572:Disease-Free Survival; D006801:Humans; D007223:Infant; D019656:Loss of Heterozygosity; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome