Paragangliomas (PGLs) are rare neuroendocrine tumors that arise in sympathetic and parasympathetic paraganglia and derive from neural crest cells. Malignancy is defined by presence of metastases, tumor spread in sites where chromaffin tissue is normally absent such as lymph nodes, liver, lungs, and bones. Malignant PGLs are extremely rare. The pathogenesis and progression of PGLs are very strongly influenced by genetics. A germline mutation in one of the susceptibility genes identified so far explains ~40% of all cases; the remaining 60% are thought to be sporadic cases. Sporadic as well as hereditary PGLs have been divided in two main clusters linked to two different signalling pathways: the first cluster contains all VHL-, SDHx-, and FH- mutated tumors and is associated to the activation of hypoxic pathway, while the second cluster contains all RET- , NF1-, MAX and TMEM127- mutated tumors and is associated to the activation of MAPK and mTOR (mammalian target of rapamycin) signaling pathways.
