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H Ghayee, Internal Medicine/Endocrinology, UT Southwestern, Dallas, United States
B Havekes, Department of Endocrinology and Metabolism, Leiden University Medical Center, Leiden, Netherlands
E Corssmit, Department of Endocrinology and Metabolism, Leiden University Medical Center, Leiden, Netherlands
G Eisenhofer, Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine, University Hospital, Dresden, Dresden, Germany
S Hammes, Internal Medicine/Endocrinology, UT Southwestern, Dallas, United States
Z Ahmad, Internal Medicine/Endocrinology, UT Southwestern, Dallas, United States
A Tessnow, Internal Medicine/Endocrinology, UT Southwestern, Dallas, United States
I Lazurova, Department of Medicine, Faculty of Medicine, P. J. Safarik University, Kosice, Slovakia
K Adams, Reproductive Biology and Medicine Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
A Fojo, Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States
K Pacak, Department of Medicine, Faculty of Medicine, P. J. Safarik University, Kosice, Slovakia
R Auchus, Internal Medicine/Endocrinology, UT Southwestern, Dallas, 75390-8857, United States

Correspondence: Richard Auchus, Email: richard.auchus{at}utsouthwestern.edu

Abstract

Extra-adrenal pheochromocytomas, otherwise known as paragangliomas (PGLs), account for about 20% of catecholamine-producing tumors. Catecholamine excess and mutations in the genes encoding succinate dehydrogenase subunits (SDHx) are frequently found in patients with PGLs. Only 2% of PGLs are found in the mediastinum, and little is known about genetic alterations in patients with mediastinal PGLs, catecholamine production by these tumors, or their clinical behavior. We hypothesized that most mediastinal PGLs are associated with SDHx mutations, norepinephrine and/or dopamine excess, and aggressive behavior. The objective of this study was to characterize genetic, biochemical, and clinical data on a series of 10 patients with mediastinal PGLs. All 10 primary mediastinal PGL patients had germline SDHx mutations, 6 in SDHB and 4 in SDHD genes. Chest or back pain were the most common presenting symptoms (5 patients), and catecholamines and/or their metabolites were elevated in 7 patients. Additional tumors included head and neck PGLs in 4 patients, pheochromocytoma in 1 patient, and bladder PGL in another. Metastatic disease was documented in 6 patients (60%), and a concurrent abdominal mass was found in one patient. We conclude that mediastinal PGLs are strongly associated with SDHB and SDHD gene mutations, noradrenergic phenotype, and aggressive behavior. The present data suggest that all patients with mediastinal PGLs should be screened for SDHx gene mutations, regardless of age.