Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management

Abstract

Paragangliomas are rare neuroendocrine tumors derived from neural crest cells of the autonomic nervous system. Tumors occurring in the thorax, abdomen, and pelvis are usually derived from sympathetic paraganglia, which are associated with catecholaminemia, headaches, and resistant hypertension. Pheochromocytomas, arising from chromaffin cells of the adrenal medulla, are histologically similar to sympathetic paragangliomas and can have identical clinical presentations. In contrast to these tumors, skull base and head and neck region paragangliomas (SHN-PGs) are usually derived from parasympathetic paraganglia and rarely secrete catecholamines. These tumors can present in a variety of locations, most commonly arising from glomus Type I (chief) cells of the carotid body. Less commonly they arise in regions of the temporal bone including the middle ear (glomus tympanicum) and jugular fossa (glomus jugulare) (Fig. 1A), as well as along the length of the vagus nerve (glomus vagale) and in the nose and paranasal sinuses (sinonasal paraganglioma). 60,69,75,77,93,99 These tumors 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. 321Abbreviations used in ...

Initial experience with dual-lumen balloon catheter injection for preoperative Onyx embolization of skull base paragangliomas

“…19 These tumors are highly vascular, with upregulation of several angiogenesis factors. 9,11,21 Historically, early attempts at resection have been impeded by challenging anatomical tumor location, complex tumor anatomy, and robust tumor vascularity that causes excessive blood loss during resection. 4,15 Preoperative embolization was introduced in the 1970s.…”

Paraganglioma of the head and neck region, treated with radiation therapy, a Rare Cancer Network study

“…Some can be associated with cancer predisposing syndromes. Recently, a genetic mutation in the succinate dehydrogenase (SDH) gene complex has been associated with Inheritated Familiar Paraganglionic Syndrome and is suspected to be prevalent in at least 30% of cases …”

“…Although often benign hypervascular lesions, the tumors can metastasize to regional lymph nodes and distant organs. These malignant HNPGL can be found in 6%‐19% of cases with a male prevalence . Excellent survival rates can still be achieved when the spread is only to regional lymph nodes …”

“…Recently, a genetic mutation in the succinate dehydrogenase (SDH) gene complex has been associated with Inheritated Familiar Paraganglionic Syndrome and is suspected to be prevalent in at least 30% of cases. [1][2][3][4][5][6] Although often benign hypervascular lesions, the tumors can metastasize to regional lymph nodes and distant organs. These malignant HNPGL can be found in 6%-19% of cases with a male prevalence.…”

“…These malignant HNPGL can be found in 6%-19% of cases with a male prevalence. 1,2,7,8 Excellent survival rates can still be achieved when the spread is only to regional lymph nodes. 7 HNPGL treatment consists mainly of surgery, radiation therapy (RT) or the combination of both.…”