Infants with neuroblastoma (NBL) frequently present as stage 4s and overall, such patients have a good prognosis. However, not all survive, and neonates with hepatomegaly are particularly at risk. We therefore reviewed our 4s experience, the objective being to identify lethal patterns of disease progression. The specific aims of this work were (1) to develop a semiquantitative scoring system based on the severity of signs and symptoms that alone or in combination presaged a fatal outcome, and (2) to determine if early intervention could reverse life-threatening disease. Thirty-five patients were seen over a period of 50 years. The signs and symptoms of organ distress caused by hepatomegaly occurred in the lungs, kidneys, gastrointestinal tract (GI), the inferior vena cava (IVC), and the liver. A scoring scale reflecting organ compromise was developed, the scores ranging from 0 (0 compromise) to 10 (all 5 systems showing evidence of impairment). Scores were derived for 32 of 35 patients; 13 were 4 weeks old or under (neonates) when first seen, and 19 were aged 1-12 months (infants). Neonates were more likely than infants to develop increasing symptomatology (50% versus 25%) and were more likely to die when a score of 2 or more developed. None of the 6 neonates who did so survived despite treatment, compared with three of four infants. Early intervention is recommended: (1) for 4s neonates who develop a score of 1 and (2) for older infants with a score > or = 2.