Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management.
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.
Departments of Neurological Surgery and.
Ibrahim
I
Hussain
Qasim
Q
Husain
Soly
S
Baredes
Jean Anderson
JA
Eloy
Robert W
RW
Jyung
James K
JK
Liu
D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010235:Paraganglioma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016634:Radiosurgery; D019292:Skull Base Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D013385:Succinate Dehydrogenase / Q000235:genetics; D009626:Terminology as Topic
D050976:Basic-Leucine Zipper Transcription Factors; D008565:Membrane Proteins; C067850:Myc associated factor X; D012333:RNA, Messenger; C548370:TMEM127 protein, human; D013385:Succinate Dehydrogenase