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Address reprint requests and correspondence: David Goldenberg, MD, Division of Otolaryngology—Head and Neck Surgery, Department of Surgery, Penn State Hershey Medical Center, 500 University Dr, Hershey, PA 17033.
Paragangliomas arise from an extra-adrenal paraganglionic cells, derived from the neural crest of the autonomic nervous system and make up the most common class of benign vascular neoplasms of the neck. PGLs of the head and neck originate most commonly from the paraganglia within the carotid body, the jugular foramen, the middle ear and the vagus nerve. Knowledge of the embryology, anatomy and genetics of these rare tumors is paramount to successful diagnosis and treatment of head and neck paragangliomas.
Paragangliomas (PGLs) arise from an extra-adrenal paraganglionic cells, derived from the neural crest of the autonomic nervous system and make up the most common class of benign vascular neoplasms of the neck.
Tumors in the thorax, abdomen, and pelvis are usually derived from sympathetic paraganglia, and are more often associated with catecholamine production.
On the other hand, head and neck region PGLs (HNPGLs) are most often benign, slowly progressing, derived from parasympathetic paraganglia and rarely secrete catecholamines.
Pheochromocytomas make up approximately 90% of tumors arising from the paraganglion system and the remaining 10% arise from extra-adrenal sites, with 85% arising in the abdomen, 12% in the thorax, and the remaining 3% in the head and neck area.
Day TA, Buchmann L, Rumboldt Z, et al: Head and Neck Surgery and Oncology. Year; 118: 1656-1662
PGLs of the head and neck originate most commonly from the paraganglia within the carotid body, the jugular foramen, the middle ear (tympanicum), and the vagus nerve (Figure 1).
Figure 1Common locations of paragangliomas of the head and neck.
Day TA, Buchmann L, Rumboldt Z, et al: Head and Neck Surgery and Oncology. Year; 118: 1656-1662
The carotid body, located in the adventitia of the posteromedial aspect of the carotid artery bifurcation, is a chemoreceptor that modulates respiratory and cardiovascular function in response to pH, oxygen, carbon dioxide tension changes.
Day TA, Buchmann L, Rumboldt Z, et al: Head and Neck Surgery and Oncology. Year; 118: 1656-1662
Low pH and low oxygen stimulate the carotid body to initiate an autonomic response to increase respiratory rate, heart rate, blood pressure, and cerebral cortical activity
Day TA, Buchmann L, Rumboldt Z, et al: Head and Neck Surgery and Oncology. Year; 118: 1656-1662
Moreover, carotid sinus syndrome syncope, which is a loss of consciousness and reflex bradycardia and hypertension, has been described to be associated with CBTs.
Day TA, Buchmann L, Rumboldt Z, et al: Head and Neck Surgery and Oncology. Year; 118: 1656-1662
However, some CBTs may be functional, which means they are able to synthesize catecholamines, and therefore may lead to symptoms such as heart palpitations, dizziness, headache, and hypertension.
Figure 2The bifurcation of the common carotid artery, demonstrating baroreceptors in the wall of the carotid sinus and chemoreceptors within the carotid body.
The right common carotid artery originates from the brachiocephalic trunk immediately posterior to the right sternoclavicular joint, whereas the left common carotid artery begins in the thorax as a direct branch of the arch of the aorta and passes superiorly to enter the neck near the left sternoclavicular joint.
At the bifurcation, the origin of the internal carotid artery is dilated. This dilation is the carotid sinus, which has receptors that monitor blood pressure.
The carotid body is another accumulation of receptors in the area of the bifurcation and is responsible for detecting changes in blood chemistry, particularly the oxygen content.
Pulsatile tinnitus is the most frequent symptom, and conductive hearing loss is seen with the progression of the tumor, which either causes impairment of ossicles vibration or invades bones behind the eardrum.
Upon further growth of these tumors, they can also invade the facial nerve, which can lead to facial paralysis or invade the hypoglossal nerve, leading to paralysis of the tongue
The jugular foramen is located in the floor of the posterior fossa, posterolateral to the carotid canal, and between the petrous temporal bone and occipital bone.
A complex canal of neurovascular structures in the skull base, the jugular foramen is divided into the pars nervosa (anteromedial) and the pars vascularis (posterolateral).
The pars nervosa contains the glossopharyngeal (IX) with Jacobson nerve and the pars vascularis contains the internal jugular vein, vagus nerve (X), and spinal accessory (XI).
They arise along Jacobson nerve (inferior tympanic nerve to branch of CN IX). These small-sized tumors become symptomatic as pulsatile tinnitus in most patients.
The tympanic membrane consists of 3 layers as follows: an outer (cutaneous), intermediate (fibrous), and inner (mucous) layer. A thickened fibrocartilaginous ring attaches the periphery of the tympanic membrane to the tympanic part of the temporal bone. A central concavity is produced by the attachment on its internal surface of the lower end of the handle of the malleus called the umbo of the tympanic membrane.
When tympanic PGL is present otoscopic examination may reveal a characteristic, pulsatile, reddish-blue tumor behind the tympanic membrane. The tympanic membrane may pulsate, if the PGL is touching the under surface of the intact eardrum. Anterosuperior to the umbo is the attachment of the rest of the handle of the malleus and at the most superior extent of this line of attachment is a small bulge in the membrane called the lateral process of the malleus.
The vagus nerve arises as a group of rootlets on the anterolateral surface of medulla oblongata just inferior to the rootlets arising to form the glossopharyngeal nerve (IX).
Within or immediately outside of the jugular foramen are the superior (jugular) and inferior (nodose) ganglia, which contain the cell bodies of the sensory neurons in the vagus nerve.
In contrast to HNPGLs, pheochromocytomas and sympathetic PGLs are more frequently seen in inherited cancer predisposition syndromes, such as multiple endocrine neoplasia Type 2, neurofibromatosis Type 1, and von-Hippel-Lindau disease.
although most HNPGLs arise sporadically. Mutations in genes coding for the succinate dehydrogenase (SDH) enzyme complex, have been found to be the most significant drivers of PGL tumorigenesis.
SDH is not only an important enzyme in the mitochondrial tricarboxylic acid cycle but also is a component of the electron transport chain and oxidative phosphorylation. Therefore, SDH is important in adenosine triphosphate generation.
owing to the accumulation of succinate and generation of reactive oxygen species. Moreover, the accumulation of succinate is associated with the depletion of fumarate, limited capacity to use oxidative phosphorylation for adenosine triphosphate production, accelerated cell proliferation and growth, and tumor development.
Genetic mutations responsible for the hereditary form of PGL syndromes have been identified in genes coding for SDH-subunit D, B, and C genes. Hereditary PGL syndrome has been classified genetically into 4 entities—PGL1-4.
Genes associated with SDHA, SDHB, SDHC, SDHD, and SDHAF2 are tumor suppressors that exhibit loss of heterozygosity, which in turn destabilizes the SDH complex and diminishes enzymatic activity.
SDHD mutations in head and neck paragangliomas result in destabilization of complex II in the mitochondrial respiratory chain with loss of enzymatic activity and abnormal mitochondrial morphology.
SDHA is a flavoprotein, SDHB, an iron-sulfur protein, which form the main catalytic domain. SDHC and SDHD are membrane-anchoring subunits of SDH that play a role in electron transport. Although these SDH proteins are components of the same complex, each mutation lead to differences in clinical phenotype.
Furthermore, it has been demonstrated that more egregious mutations, such as splice site and nonsense mutations, result in not only earlier onset but also increased risk of developing multiple HNPGLs and pheochromocytomas.
SDHB, which codes for subunit B of SDH complex, is also known as iron-sulfur subunit of mitochondrial complex II. In contrast to SDHD mutation carriers (PGL1) with more frequent multifocal PGLs, SDHB mutation carriers (PGL4) are more likely to develop malignant disease and possibly extraparaganglial neoplasias, including renal cell and thyroid carcinomas.
SDHC codes for SDH complex subunit C, which is an integral membrane protein found on chromosome 1. Mutations in SDHC are rarer than those of SDHB and SDHD and contrary to patients with PGL1 and PGL4, SDHC mutation carriers mostly present with benign, single HNPGs.
SDHAF2 (also referred to as SDH5) is a protein involved in the addition of flavin-adenine dinucleotide prosthetic group of SDHA. SDHAF2 mutations lead to SDH complex instability and reduction in enzymatic activity.
Within the SDH complex, SDHA is the largest gene, protein, and major catalytic subunit of the enzyme. However, SDHA mutations have only been recently described in small subsets of PGLs and pheochromocytomas (<3%).
Owing to the known genetic mutations related to HNPGLs, genetic testing for PGL is now an important part of diagnostic management and care for familial PGLs.
Disclosure
The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
References
Day TA, Buchmann L, Rumboldt Z, et al: Head and Neck Surgery and Oncology. Year; 118: 1656-1662
SDHD mutations in head and neck paragangliomas result in destabilization of complex II in the mitochondrial respiratory chain with loss of enzymatic activity and abnormal mitochondrial morphology.
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