Pseudohypoxic pheochromocytomas and paragangliomas dominate in children

Objective Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that are associated with cancer predisposition syndromes in up to 80% of affected children. PPGLs can be divided into molecularly defined groups with comparable pathogenesis and biology: (1) pseudohypoxic, (2) kinase signaling, and (3) Wnt-altered. Methods We report the data of children and adolescents diagnosed with PPGL who have been registered with the German GPOH-MET registry since 1997. Results By December 2019, a total of 88 patients with PPGL were reported. Pheochromocytoma occurred in 56%, paraganglioma in 35%, and synchronous PPGLs in 9.1%. A total of 16% of patients presented with lymph node (5.7%) and distant metastases (10%). Median follow-up was 4.2 years (range 0-17.1). Overall and disease-free survival (DFS) were 98.6% and 54.0%, respectively. Local relapses, metastases, and subsequent PPGLs occurred in 11%, 4.5%, and 15% of patients. Germline mutations were detected in 83% of patients (51% in VHL, 21% in SDHB, 7.8% in SDHD, and one patient each in RET and NF1). One patient was diagnosed with Pacak-Zhuang syndrome. A total of 96% of patients presented with PPGL of the pseudohypoxic subgroup (34% TCA cycle-related, 66% VHL/EPAS1-related). In multivariate analyses, extent of tumor resection was a significant prognostic factor for DFS. Conclusions Most pediatric PPGLs belong to the pseudohypoxia subgroup, which is associated with a high risk of subsequent PPGL events and metastatic disease. Comprehensive molecular profiling of children and adolescents with newly diagnosed PPGLs will open new avenues for personalized diagnosis, treatment, and surveillance.