Why age has independent prognostic significance in neuroblastomas. Evidence for intra-uterine development, and implications for the treatment of the disease.

In an unselected patient population consisting of all cases of childhood neuroblastomas in Denmark from 1943 to 1980, evidence was found for the theory that almost all childhood neuroblastomas are congenital, and that the age at diagnosis reflects the duration of the disease, whereas the clinical stage at diagnosis is a result of the growth rate of the tumor and the duration of the disease (i.e. age at diagnosis + up to 9 months). Furthermore, the age at diagnosis may be a measurement of the possibility of micrometastases in addition to the clinical extent of the tumor found at that time, and this may explain why age has independent prognostic significance in childhood neuroblastomas. From the concept that tumours develop by a series of changes from a conditioned to an autonomous state, the theory is consistent with the occasional observation of spontaneous regression of tumours in young infants, and the extremely rare observation of this phenomenon in older children. Since not only the tumor burden, reflected both in the clinical stage and the possibility of micrometastases, but also the proportion of cells resistant to antineoplastic drugs well increase with time, the tumour burden should be reduced as fast as possible with surgery and/or aggressive chemotherapeutic schedules if the disease is diagnosed in advanced stages or in patients older than 1 year of age with stage II disease, whereas surgical resection of the tumor appears to be sufficient treatment for stage I disease and stage II disease of infancy. A consequence of this theory that almost all childhood neuroblastomas are congenital is that screening procedures for the tumour should be carried out as shortly after birth as possible, the expected incidence of congenital neuroblastoma being 1 per 12-14,000 live births.