MSACL 2016 EU Abstract

Pediatric Reference Intervals of Plasma Free Normetanephrine, Metanephrine and 3-methoxytyramine: Application for Diagnosis of Neuroblastoma

Mirko Peitzsch (Presenter)
University Hospital Dresden

Authorship: Mirko Peitzsch1, Anke Pyper1, Julia Bruetting1, Anastasios Mangelis1, Elizabeth R Butch2, Elizabeth Lovorn2, Wayne Furman2, Graeme Eisenhofer1, Barry L Shulkin2 and Angela Huebner1
(1) University Hospital Dresden, Germany, (2) St Jude Children’s Research Hospital, Memphis, Tennessee, USA,

Short Abstract

Measurements of plasma free metanephrines, the O-methylated metabolites of catecholamines, provide superior sensitivity for diagnosis of pheochromocytoma, which we hypothesize, might also apply to neuroblastoma, the most common solid tumor of childhood deriving from neural crest progenitor cells. Therefore, age-adjusted pediatric reference intervals of metanephrines are established and their utility for diagnosis of neuroblastoma is shown with increases above the cut-offs in either one or both metabolites, methoxytyramine (96%) and normetanephrine (84%), indicating a diagnostic sensitivity of 100%. The present results indicate that measurements of plasma normetanephrine and methoxytyramine provide a potentially useful test for diagnosis of neuroblastoma.

Long Abstract


Neuroblastoma (NB), the most common extracranial solid tumor of childhood representing 8.5% of all malignancies in pediatric patients, derive from neural crest progenitors and like pheochromocytomas (PHEO) produce catecholamines. Because of a limited capacity for storage and secretion, catecholamines produced are largely metabolized within tumor cells. Catecholamine metabolites, therefore provide the mainstay for diagnosis, but continue to rely on measurements of homovanillic acid (HVA) and vanillylmandelic acid (VMA) in urine with limited sensitivity. Measurements of free metanephrines, the O-methylated metabolites of catecholamines, are well established to provide superior sensitivity for diagnosis of PHEO, which we hypothesize, might also apply to NB.


Concentrations of plasma free metanephrines and methoxytyramine were measured in two patient cohorts: 1. a patient cohort, without evidence of a catecholamine-producing neoplasm, including 211 girls and 191 boys, aged between 2 days and 18 years; and 2. additional 25 pediatric patients with confirmed diagnosis of NB.


Among the reference group cohort, concentrations of plasma free normetanephrine (NMN) and 3-methoxytyramine (MTY) were high in neonates up until six months of age, but thereafter decreased within the next several months to levels comparable to those of adults. In contrast, concentrations of plasma free metanephrine (MN) showed a reciprocal pattern with low concentrations in neonates, thereafter increasing during the first year to levels comparable to those of adults. Using this reference population to establish upper cut-offs, all children with NB had increases in either or both MTY (96%) and NMN (84%), indicating a diagnostic sensitivity of 100%. For the routinely used combination of VMA and HVA, diagnostic sensitivity was 94.4% (94.4% for HVA and 66.6% for VMA).


The dynamic reciprocal changes in plasma concentrations of NMN and MTY compared to MN during early childhood suggest underlying developmental changes in extra-adrenal and adrenal chromaffin tissue that must be considered in establishing pediatric reference intervals in catecholamine metabolites. With such reference intervals now at hand; the present results also indicate that measurements of plasma NMN and MTY provide a potentially useful diagnostic test for identification of patients with NB.

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