Pseudohypoxic pheochromocytomas and paragangliomas dominate in children

Abstract

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) Wntaltered. 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 diagnosedPPGLs will open new avenues for personalized diagnosis, treatment, and surveillance.

Pediatric Metastatic Pheochromocytoma and Paraganglioma: Clinical Presentation and Diagnosis, Genetics, and Therapeutic Approaches

“…PPGLs are estimated to occur at an incidence of 0.57 per 100,000 person-years, of which, up to 20% of PPGLs are diagnosed in pediatric patients, at an average age of 11 years ( 19 , 22 , 23 , 27 ). Most pediatric patients are symptomatic (around 90%), and hypertension is the most common presentation of pediatric PPGL (64-93%), which causes pediatric hypertension in up to 1% of cases ( 7 , 8 , 22 ). Therefore, one should suspect PPGL in pediatric patients with sustained hypertension, with headache (39-95%), diaphoresis (90%), palpitations (53%), and signs/symptoms of mass effect or as an incidental mass (30%) ( Table 1 ) ( 8 , 11 , 22 ).…”

“…Accumulation of succinate results in impaired prolyl hydroxylation of HIF-2α, resulting in the pseudohypoxic expression pattern seen for these cluster 1A genes, as well as other epigenetic effects on gene expression ( 47 ). In addition to PPGLs, other tumors, including renal cell carcinoma (RCC), GIST, pituitary adenoma, pulmonary chondroma (as part of Carney triad, which also includes PGL and GIST), and papillary thyroid cancer, as well as thyroid nodules have been reported in patients with SDHx mutations or SDHC epimutation; estimated penetrance of RCC in SDHx carriers is 2-3% (mostly SDHB ), but 85% of GISTs diagnosed in childhood are related to SDHx mutations ( 4 , 7 , 48 ). No additional imaging is recommended to screen for these tumors in asymptomatic SDHx carriers ( 48 ).…”

“…In about 20% of cases, patients will have a de novo mutation; interestingly, a study of Spanish PPGL patients found a much higher de novo rate of 60% overall and 50% for the pediatric group, though the authors attributed this to sample size ( 29 , 54 ). VHL is the most common genetic cause of pediatric PPGL and tends to present the earliest at an average age of 11-12 years ( 4 , 5 , 7 , 8 , 22 ), in contrast to those syndromes arising from pathogenic variants in cluster 2 – specifically, MEN-2 (14-20 years) and NF1 (16-17 years); PCC may be the first manifestation of VHL disease ( 4 , 5 , 7 , 8 , 22 ). While screening recommendations for VHL may vary, PCC has been identified in a girl as young as 2 years, so measurement of blood pressure at each medical appointment and annual plasma free metanephrines or 24-hour urine fractionated metanephrines starting as early as 2 years but no later than 5 years has been proposed ( 54 ).…”

“…Additionally, decreased expression of dopamine β-hydroxylase or tyrosine hydroxylase can result in a dopaminergic or biochemically silent (non-secreting) phenotype, respectively, which may both be seen from mutations in cluster 1 genes ( 18 ). Pediatric PPGL is more often due to pathogenic variants in cluster 1 genes (particularly VHL , SDHx , and EPAS1 ; at least 57-80% of patients with pediatric PPGL when somatic variants are included) and is thus more likely to have a non-adrenergic (noradrenergic, dopaminergic, or non-secreting) biochemical phenotype (93% of pediatric patients without increased plasma metanephrine vs. 57% in adults, see Table 1 ) ( 2 , 4 , 5 , 7 ).…”

Adrenocortical Tumors and Pheochromocytoma/Paraganglioma Initially Mistaken as Neuroblastoma—Experiences From the GPOH-MET Registry

“…A male predominance is reported inconsistently. The average age at diagnosis ranges between 11 and 15 years (6)(7)(8). Most PCCs/PGLs in childhood and adolescence are hereditary in nature including von Hippel-Lindau (VHL) syndrome, hereditary paraganglioma syndromes due to variants of the SDHx gene, multiple endocrine neoplasia type 2 (MEN2) due to variants of the rearranged during transfection protooncogene (RET), and neurofıbromatosis type 1 (NF1) (6)(7)(8)(9).…”