BACKGROUND Children and adolescents with differentiated thyroid cancer (DTC) have a good prognosis and prolonged survival even when extensive regional disease or lung metastases are present at the diagnosis; very-long-term follow-up is needed to appreciate what, if any, impact the disease may exert on the ultimate outcome. METHODS We retrospectively reviewed the clinical course of 112 patients with DTC who registered at M. D. Anderson Cancer Center between 1944 and 1986, were younger than 20 years old at the time of diagnosis, and were followed for at least 10 years. Surgery alone or combined with radioactive iodine or radiotherapy was used for most cases. RESULTS At the time of most recent contact, 99 patients remained alive and 13 had died. The 99 patients had 25 +/- 0.9 years of available follow-up (mean +/- SEM) and were 41 +/- 0.9 years of age at time of last contact; one fourth had had recurrent disease at some point since diagnosis. Among the 13 patients who died, one died of complications from coexisting diabetes mellitus, and the cause of death was not clear in one other case. Two patients died of breast cancer 13 and 15 years after thyroid cancer diagnosis. In three cases, cause of death could be considered etiologically related to initial radiotherapy: one patient developed tracheal necrosis 26 years after diagnosis and died of upper airway complications, whereas another two patients developed sarcomas of the cervical region 22 and 29 years after thyroid cancer diagnosis. Lastly, six patients died of thyroid cancer 26 +/- 3.1 years after initial diagnosis (at age 40 +/- 2.1 years). Among these cases, one patient had invasive disease and lung metastases at diagnosis and died of progressive lung metastases after 36 years. The other five patients were initially seen with local/regional disease and developed lung and skeletal metastases after a 2- to 20-year disease-free interval. CONCLUSIONS Our findings support the clinical impression that children and adolescents with DTC live for many years regardless of apparent extent of disease at diagnosis or development of recurrence. Indeed, overall survival was 100% at 10 years even in patients with distant metastases. However, attention to these patients' clinical course beyond the first decade indicates that a small minority (5% to 7%) of patients eventually succumb to progressive disease and that a similar number develop possibly treatment-related lethal complications or second neoplasms. We suggest lifelong surveillance for all such patients.