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.

Keywords: clinical presentation; diagnosis; genetics; metastatic; paraganglioma; pediatric; pheochromocytoma; therapeutic approach.

Figure 1

Catecholamines and metanephrines are derived from tyrosine by the enzyme tyrosine hydroxylase (TH), resulting in L-3,4-dihydroxyphenylalanine (L-DOPA). Aromatic L-amino acid decarboxylase (AACD) generates dopamine from L-DOPA. Dopamine β-hydroxylase (DBH) acts on dopamine to produce norepinephrine, followed by the enzyme phenylethanolamine N-methyltransferase (PNMT) to yield epinephrine. Norepinephrine and epinephrine are O-methylated by catechol-O-methyltransferase (COMT) to produce normetanephrine and metanephrine, respectively. The corresponding O-methylated metabolite of dopamine is 3-methyoxytyramine (3-MT). Metyrosine inhibits (red) TH. Glucocorticoids stimulate (green) PNMT.

Figure 2

Anterior maximal intensity projection (MIP) images of the ¹⁸F-FDG PET/CT (A) and ⁶⁸Ga-DOTATATE PET/CT (B) studies of a 10-year-old SDHB positive girl. She was diagnosed initially with metastatic disease at the age of 8 years. Her right paraaortic, retroperitoneal primary paraganglioma was surgically resected. On presentation to our institution, the progression of her disease was demonstrated by metastatic lesions in bone, lungs, and abdomen as shown in the images (A, B). The single red arrow on image (A) indicates the one lesion (abutting bowel) localized by ¹⁸F-FDG PET/CT that is not visualized by the ⁶⁸Ga-DOTATATE PET/CT. Similarly, all the additional lesions (transverse process of T4 spine, L2-L5 vertebral bodies, left ilium, and left and right iliac wings) localized by the ⁶⁸Ga-DOTATATE PET/CT (blue arrows) are not visualized by ¹⁸F-FDG PET/CT (B). This figure was adapted from the figure that was initially published as Figure 2 by Jha et al. (70).