Long term prognosis of patients with pediatric pheochromocytoma.

A third of patients with paraganglial tumors, pheochromocytoma and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127 and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy was performed in patients diagnosed <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1 and one patient each in RET, SDHA and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (p=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, p=0.001, SDHD vs others, p=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, 10 at initial diagnosis and another 6 during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, p<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine