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Division of Endocrinology, Department of Internal Medicine, Southwesterm Medical Center, University of Texas, 5323 Harry Hines Boulevard, Suite Y-5.318, Dallas, Texas 75390-8857, USA¹ Reproductive Biology and Medicine Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA² Department of Endocrinology and Metabolism, Leiden University Medical Center, Leiden, The Netherlands³ Institute of Clinical Chemistry & Laboratory Medicine and Department of Medicine, University Hospital, Dresden, Germany⁴ Department of Medicine, Faculty of Medicine, P.J. afárik University, Koice, Slovak Republic⁵ Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

(Correspondence should be addressed to R J Auchus; Email: richard.auchus{at}utsouthwestern.edu)

^* H K Ghayee and B Havekes contributed equally to this work

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 germ line SDHx mutations, norepinephrine and/or dopamine excess, and aggressive behavior. The objective of this study was to characterize genetic, biochemical, and clinical data in a series of ten patients with mediastinal PGLs. All ten primary mediastinal PGL patients had germ line SDHx mutations, six in SDHB, and four in SDHD genes. Chest or back pain were the most common presenting symptoms (five patients), and catecholamines and/or their metabolites were elevated in seven patients. Additional tumors included head and neck PGLs in four patients, pheochromocytoma in one patient, and bladder PGL in another. Metastatic disease was documented in six 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.