Molecular Pathogenesis of Pheochromocytomas and Paragangliomash

General aspectsParaganglia are small neuroendocrine organs, that usually manifest as anatomically discrete bodies, the parenchymal cells of which are neural crest-derived, and produce catecholamines and various peptides. One group of paraganglia is aligned to the sympathoadrenal and the other to the parasympathetic autonomic nervous system.1,2 Sympathetic paraganglia are distributed along the pre- and paravertebral sympathetic chains and follow the sympathetic innervations of the pelvic and retroperitoneal organs. Their exact locations are somewhat variable, with the exception of the adrenal medulla and the organs of Zuckerkandl. Parasympathetic paraganglia are almost exclusively located in the region of the cranial and thoracic branches of the glossopharyngeal and vagal nerves. The principal glossopharyngeal paraganglia are the tympanic paraganglia, situated in the wall of the middle ear, and the carotid bodies (Figure 1). Neoplasms of the neuroendocrine cells found within the sympathetic or parasympathetic paraganglionic axes are designated pheochromocytoma and paraganglioma. The name pheochromocytoma – the Greek synonym of black colored tumor – is derived from the so- called chromaffi n reaction, resulting from oxidation of stored catecholamines. Adrenal tumors are usually referred to as pheochromocytomas (because of a positive chromaffi n reaction), whereas the extra-adrenal ones are alternatively designated extra-adrenal pheochromocytoma or paraganglioma, the latter name usually being reserved for parasympathetic or nonfunctional (i.e., non catecholamine-secreting) sympathetic tumors. Paraganglioma is also used to describe the parasympathetically aligned tumors. However, since these neoplasms are otherwise indistinguishable, and the chromaffi n reaction appeared to be a poor indicator of catecholamine storage, the terminology may be confusing. For this reason, in this thesis, all sympathicoadrenal neoplasms will be referred to as pheochromocytomas. Additional designations (e.g., nonfunctional, extra-adrenal, or malignant) will be used when appropriate. Neoplasms arising from parasympathetic paraganglionic tissues will be referred to as paragangliomas. In the literature, some of the latter may have been referred to as chemodectomas, glomus jugulare, or carotid body tumors.