Mediastinal paragangliomas: association with mutations in the succinate dehydrogenase genes and aggressive behavior

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 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.

Figure 1

Imaging studies. (A) Chest MRI of patient 2 (coronal T1-weighted FOV three-plain localizing image; TR, 66.5 ms; TE, 1.5 ms) showing mediastinal mass. (B) Chest CT of patient 2 following i.v. contrast showing same paraganglioma. (C) Illustration of mediastinal compartments. The anterior mediastinum is defined as the space bordered by the sternum anteriorly and the ventral cardiac surface posteriorly, including the thymus and ascending aorta. The middle mediastinum is posterior to the anterior mediastinum and is bordered posteriorly by the anterior surface of the spine; the middle compartment includes the heart, esophagus, trachea, and major blood vessels. The posterior mediastinum is posterior to the anterior surface of the spine and contains the descending aorta, spine, and ribs. The superior mediastinum is defined by a horizontal line from the angle of Louis posteriorly to the spine as the inferior border and includes the thyroid, aortic arch, and superior parts of the esophagus and trachea. (D) MRI of patient 2 (sagittal T1-weighted images after gadolinium contrast; TR, 417 ms; TE, 13 ms) showing posterior mediastinal PGL. (E) Coronal [¹⁸F]FDG PET scan of patient 8, showing superior mediastinal PGL (arrow) plus additional lesions in the head, neck, and upper chest (arrowheads); axial CT-PET in (F) localizes mediastinal PGL near the aortic arch. (G) Coronal [¹⁸F]fluorodopamine PET scan of patient 8 shows localization of mediastinal PGL concordant with [¹⁸F]FDG PET (arrow), which was confirmed on axial CT-PET in (H).