Biochemical Diagnosis of Catecholamine-Producing Tumors of Childhood: Neuroblastoma, Pheochromocytoma and Paraganglioma

Abstract

Catecholamine-producing tumors of childhood include most notably neuroblastoma, but also pheochromocytoma and paraganglioma (PPGL). Diagnosis of the former depends largely on biopsy-dependent histopathology, but this is contraindicated in PPGL where diagnosis depends crucially on biochemical tests of catecholamine excess. Such tests retain some importance in neuroblastoma though continue to largely rely on measurements of homovanillic acid (HVA) and vanillylmandelic acid (VMA), which are no longer recommended for PPGL. For PPGL, urinary or plasma metanephrines are the recommended most accurate tests. Addition of methoxytyramine to the plasma panel is particularly useful to identify dopamine-producing tumors and combined with normetanephrine also shows superior diagnostic performance over HVA and VMA for neuroblastoma. While use of metanephrines and methoxytyramine for diagnosis of PPGL in adults is established, there are numerous pitfalls for use of these tests in children. The establishment of pediatric reference intervals is particularly difficult and complicated by dynamic changes in metabolites during childhood, especially in infants for both plasma and urinary measurements, and extending to adolescence for urinary measurements. Interpretation of test results is further complicated in children by difficulties in following recommended preanalytical precautions. Due to this, the slow growing nature of PPGL and neglected consideration of the tumors in childhood the true pediatric prevalence of PPGL is likely underappreciated. Earlier identification of disease, as facilitated by surveillance programs, may uncover the true prevalence and improve therapeutic outcomes of childhood PPGL. For neuroblastoma there remain considerable obstacles in moving from entrenched to more accurate tests of catecholamine excess.

Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension

“…Neuroendocrine neoplasms encompass a large diversity of epithelial and non-epithelial neoplasms differing for their incidence, localization, morphology, biology and available treatments. Despite these facts, these tumors share common characteristics, including the potential ability of hormones and biogenic amine production and secretion (1)(2)(3)(4). Pheochromocytoma (PHEO), paraganglioma (PGL) and neuroblastoma (NB) are non-epithelial neuroendocrine neoplasms arising from the adrenal medulla and ganglia of the sympathetic nervous system (SNS), which typically produce and secrete catecholamines (CATs; dopamine, DA, norepinephrine NE, epinephrine, E) (5).…”

Association of Fetal Catecholamines With Neonatal Hypoglycemia

“…In human adult β cells, dopamine has been found to decrease insulin secretion via dopamine type 2 receptors . Measurement of 3-methoxytyramine, a primary metabolite of dopamine, has been shown to increase the diagnostic sensitivity to detect catecholamine-producing tumors . Furthermore, in patients with elevated metanephrine and normetanephrine concentrations, an association with increased 3-methoxytyramine has been reported .…”

Tumor Volume of Onset and MYCN Amplification Predict Poor Prognosis in Patients with Neuroblastoma

“…At present, age of onset, INSS stage, histological type, degree of differentiation, and MYCN gene ampli cation have been recognized as risk factors for NB [14,15] . Urinary VMA and HVA levels, serum Fer, NSE, and LDH levels are considered to be characteristic tumor markers of NB, and these parameters are helpful for the initial diagnosis, therapeutic evaluation, and monitoring of the recurrence of NB [16,17] . In this study, age, INSS stage, Fer, NSE, and LDH were analyzed, and the results showed that all the above indicators were associated with the prognosis of NB.…”