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

Abstract

Although pediatric pheochromocytomas and paragangliomas (PPGLs) are rare, they have important differences compared to those in adults. Unfortunately, without timely diagnosis and management, these tumors have a potentially devastating impact on pediatric patients. Pediatric PPGLs are more often extra-adrenal, multifocal/metastatic, and recurrent, likely due to these tumors being more commonly due to a genetic predisposition than in adults. This genetic risk results in disease manifestations at an earlier age giving these tumors time to advance before detection. In spite of these problematic features, advances in the molecular and biochemical characterization of PPGLs have heralded an age of increasingly personalized medicine. An understanding of the genetic basis for an individual patient’s tumor provides insight into its natural history and can guide clinicians in management of this challenging disease. In pediatric PPGLs, mutations in genes related to pseudohypoxia are most commonly seen, including the von Hippel-Lindau gene (VHL) and succinate dehydrogenase subunit (SDHx) genes, with the highest risk for metastatic disease associated with variants in SDHB and SDHA. Such pathogenic variants are associated with a noradrenergic biochemical phenotype with resultant sustained catecholamine release and therefore persistent symptoms. This is in contrast to paroxysmal symptoms (e.g., episodic hypertension, palpitations, and diaphoresis/flushing) as seen in the adrenergic, or epinephrine-predominant, biochemical phenotype (due to episodic catecholamine release) that is commonly observed in adults. Additionally, PPGLs in children more often present with signs and symptoms of catecholamine excess. Therefore, children, adolescents, and young adults present differently from older adults (e.g., the prototypical presentation of palpitations, perspiration, and pounding headaches in the setting of an isolated adrenal mass). These presentations are a direct result of genetic determinants and highlight the need for pediatricians to recognize these differences in order to expedite appropriate evaluations, including genetic testing. Identification and familiarity with causative genes inform surveillance and treatment strategies to improve outcomes in pediatric patients with PPGL.

The use of temozolomide in paediatric metastatic phaeochromocytoma/paraganglioma: A case report and literature review

“…PPGL typically present with signs and symptoms attributable to catecholamine excess, e.g. hypertension, flushing, sweating, headaches or palpitations ( 7 ). They may also present as an incidental finding on cross-sectional imaging or with symptoms of pain due to mass effect ( 8 ).…”

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“…Recurrences can be observed in up to 30% in the pediatric population (15). In rare cases, PPGL can occur in children in the setting of NF1; Carney triad (young females with no familial trait in whom 2 to 3 of the classical tumors [i.e., gastric GIST, pulmonary chondroma, PGL] develop); Carney-Stratakis syndrome (SDHx-related PPGL including GIST and PGL); or Pacak-Zhuang syndrome (young females with no familial trait in whom polycythemia develops at an early age, multiple PPGL and duodenal somatostatinoma, presence of somatic HIF2A mutation in tumors) (15). In patients with VHL, PHEO usually develops and can be bilateral (15) and associated with extra-adrenal PGL that can arise in a synchronous or asynchronous manner.…”

“…Pediatric pheochromocytomas (PHEOs) occur in children and adolescents having a mean age at diagnosis of approximately 11 years ( 15 ). The most common presenting symptoms are headache, diaphoresis, or palpitations ( 15 ).…”

“…Pediatric pheochromocytomas (PHEOs) occur in children and adolescents having a mean age at diagnosis of approximately 11 years ( 15 ). The most common presenting symptoms are headache, diaphoresis, or palpitations ( 15 ). Sustained hypertension is seen more often in about 93% of pediatric cases whereas paroxysmal hypertension is observed only in 7% of cases ( 15 ).…”

“…The most common presenting symptoms are headache, diaphoresis, or palpitations ( 15 ). Sustained hypertension is seen more often in about 93% of pediatric cases whereas paroxysmal hypertension is observed only in 7% of cases ( 15 ). Pediatric pheochromocytomas are most frequently hereditary (up to 80%) and multifocal as compared to their adult-onset PHEOs ( 15 ).…”