Paragangliomas are rare, slow-growing
tumors that frequently arise in the head and neck, with the carotid bodies and temporal bone of the skull base being the most common sites. These
neoplasms are histologically similar to
pheochromocytomas that form in the adrenal medulla and are divided into sympathetic and parasympathetic subtypes based on functionality. Skull base and head and neck region
paragangliomas (SHN-PGs) are almost always derived from parasympathetic tissue and rarely secrete
catecholamines. However, they can cause significant morbidity by mass effect on various cranial nerves and major blood vessels. While surgery for SHN-PG can be curative, postoperative deficits and recurrences make these lesions challenging to manage. Multiple familial syndromes predisposing individuals to development of
paragangliomas have been identified, all involving mutations in the
succinate dehydrogenase complex of mitochondria. Mutations in this
enzyme lead to a state of "pseudohypoxia" that upregulates various angiogenic, survival, and proliferation factors. Moreover, familial
paraganglioma syndromes are among the rare inherited diseases in which genomic imprinting occurs. Recent advances in gene arrays and transcriptome/exome sequencing have identified an alternate mutation in sporadic SHN-PG, which regulates proto-oncogenic pathways independent of pseudohypoxia-induced factors. Collectively these findings demonstrate that
paragangliomas of the skull base and head and neck region have a distinct genetic signature from sympathetic-based
paragangliomas occurring below the neck, such as
pheochromocytomas.
Paragangliomas serve as a unique model of primarily surgically treated
neoplasms whose future will be altered by the elucidation of their genomic complexities. In this review, the authors present an analysis of the molecular genetics of SHN-PG and provide future directions in patient care and the development of novel
therapies.