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Kristin Goodkin
MSK- Head & Neck Surgery
Rotation #9
Paragangliomas of the Head and Neck

Head and neck paragangliomas, also referred to as glomus tumors, are rare, slow-growing neoplasms of paraganglionic tissues which comprise approximately 0.6% of all head and neck tumors. They are composed of epithelioid cell clusters, called Zellballen, which are separated by a fibrous and highly vascular stroma1. These clusters of cells have parasympathetic nervous system innervation and develop from migration of neuroectodermal tissue during fetal development and this tissue tends to mainly distribute itself along the distribution of the parasympathetic ganglia. This includes the carotid body, but also the middle ear (glomus tympanicum), vagal body (glomus vagale), jugular foramen (glomus jugulare, from the jugular ganglion), nasal cavity.2

Paragangliomas, on average, arise during the 4th and 5th decades of life, though can be seen within any age group.1 While they are most commonly unifocal, sporadic, and benign, 10% are bilateral, 10% are malignant, and approximately one-third are associated with inherited syndromes. Caucasian populations are most commonly and, while the male to female ratio is about equal in inherited types, women make up approximately 71% of all sporadic paragangliomas.3 Hereditary paragangliomas are most commonly associated with mitochondrial complex gene mutations in the succinate dehydrogenase (SDH) gene, located at chromosome 11q22-23, which causes endogenous hypoxia, leading to an increase in cellular proliferation and a decreases in the apoptosis of neural crest cells.4 Patients with the subtypes SDHB, SDHC, and SDHD and those with hereditary disease have a much higher rate of multiple tumors than those with sporadic tumors (approximately 30% vs 10%, respectively)1. SDHB and SDHC have autosomal dominant inheritance, while the SDHD gene comes from the paternal line, and therefore is only inherited from the father.2 Other conditions that put patients at higher risk for development of paragangliomas include neurofibromatosis type 1, multiple endocrine neoplasia types 2A and 2B (due to a germline mutation of the RET proto-oncogene), Carney-Statakis dyad, and von Hippel Lindau.3, 5

Benign and malignant paragangliomas are often difficult to distinguish histologically and therefore, malignancy of these tumors can only been diagnosed once local or distant metastases to other non-neuroendocrine tissues has occurred. When metastases do occur, they most commonly first appear in the nearby cervical lymph nodes and later can spread to the lung or liver.1 Those with SDHB mutations are at highest risk for malignant transformation.4

The most common location for head and neck paragangliomas is the carotid body, which make up 60-70% of all cervical paragangliomas.3 Carotid body tumors, also called chemodectomas or non-chromaffin paragangliomas, are found in the adventitia along the medial aspect of the carotid bifurcation.4 They are most commonly found in those residing at high altitudes, with some studies showing prevalence of head and neck paraganglioma at 1 in 10 in humans in high altitude areas compared to a prevalence of 1 in 500,000 or less in those living at low-altitude. The reason for this association is unclear, but is hypothesized to be related to the activation of hypoxia-inducible factor (HIF-1), transcription factors which control energy, erythropoiesis, and metabolism and aid in adaptation under hypoxic conditions.3

Normally, the carotid body functions as a chemoreceptor in the body, monitoring and responding to changes in arterial pH, PaO2, and PaO2 by transmitting information to the medulla in the brain and stimulating increases in sympathetic activity.4 Carotid body paragangliomas are characteristically slow growing, highly vascular, pulsatile (due to the vascularity as well as transmitted pulsations coming from the carotid arteries), and are only found to be malignant in 1-3% of cases.3 Carotid body paragangliomas are differentiated by the Shamblin Classification into three categories, which are determined by the tumor’s relationship to both the carotid arteries as well as the adjacent nerves. Type I tumors have no contact with the arteries and simply displaces them. Type II tumors have direct contact with both the internal and external carotids, with the superior laryngeal and hypoglossal nerves on top of the tumor surface. Lastly, Type III tumors encase the carotids.2

Other less common paragangliomas of the head and neck include those of the temporal bone, glomus tympanicum and glomus jugulare tumors. Glomus tympanic paragangliomas are typically associated with the tympanic branch of the glossopharyngeal nerve, known as the Jacobsen nerve, as well as a branch of the vagus nerve known as the Arnold nerve, which together form what is known as the tympanic plexus.1

Patient with paragangliomas are often asymptomatic and these masses often present incidentally on imaging studies for unrelated reasons.2 However, once the tumor grows large enough, certain symptoms may arise, depending on the location of the lesion. Carotid body lesions often present as a painless pulsatile mass, located at the angle of the mandible.1 Patients with a paraganglioma of the temporal bone often present with pulsatile tinnitus and/or progressive conductive hearing loss, though sensorineural loss may also occur if the tumor erodes through the otic capsule bone and begins to invade the inner ear. Facial nerve palsy can also occur with temporal bone paragangliomas, affecting up to 20% of patients. This occurs when the tumor invades and/or wraps around the facial nerve within the temporal bone Vagal paragangliomas often present with a painless, pulsatile posterolateral pharyngeal mass, hoarseness (resulting from vocal cord paralysis due to CN X palsy), and/or vagal neuropathy.2 Other, more serious, presentations due to the presence of a paraganglioma include hypoglossal nerve paralysis (characterized by declining articular, ipsilateral tongue atrophy, and deviation to the affected side), jugular foramen syndrome (dysphagia, aspiration, hoarseness, and SCM/trapezius weakness due to impingement upon cranial nerves IX, X, and XI), and Horner syndrome (ipsilateral ptosis, miosis, and anhidrosis due to tumor invasion of the sympathetic chain). 1, 3

Additionally, though a rare occurrence among head ; neck paragangliomas, all patients (and particularly young patients) with suspected paragangliomas must be asked about palpitations, episodic facial flushing, cardiac arrhythmias, or unexplained hypertension; all symptoms suggestive of a catecholamine-secreting paraganglioma.2 This is performed with a 24 hour urine collection for vanillylmandelic acid and metanephrine levels. An audiogram should be given to patients with a suspected glomus tympanicum or glomus jugulare, which may show conductive hearing loss if the tumor has invaded the middle ear. In contrast, if the inner ear has been invaded by tumor, the audiogram will show sensorineural hearing loss.1 Furthermore, all patients with confirmed paragangliomas should undergo genetic testing, particularly for the SDHx mutations listed above and if positive, other at-risk members of the patient’s family should then be screened in order to identify tumors early and minimize morbidity risks associated with treatment.5

On physical exam, it is extremely important to check that a patient’s cranial nerves are intact, paying close attention to the lower cranial nerves VII through XII.3 When auscultating a suspected paraganglioma, the patient should be instructed to undergo some form of exertion, such as jogging in place, because when exercise occurs, the pulsatile tinnitus of the vascular paraganglioma will become louder and faster to the listening clinician.1 A carotid body paragangliomas will be located at the carotid bifurcation and palpated along the anterior border of the sternocleidomastoid muscle and the tumor will be mobile in the horizontal plane, but immobile vertically.1

Imaging is essential for locating the extent of paraganglioma invasion. There is a role for both CT and MRI scans in the initial workup on paragangliomas.3 CT scans are extremely useful for looking at the bony structures of the temporal bone. MRI scans are additionally used to look for intracranial extension of tumors as they are useful when high soft tissue contrast resolution is needed and can delineate whether a paraganglioma has invaded the brainstem, cerebellum and/or cranial nerves. Both CTs and MRIs may show a “salt and pepper” speckled pattern within the tumor, that comes about in the presence of flow voids from the large number of blood vessels involved within the tumor.1 Carotid angiography is the gold standard of imaging for carotid bodies tumor because is can identify the typical characteristics of the mass, assess for intracranial circulation status, and also determine the impact of blood flow interruption through internal carotid artery via balloon occlusion test. However, due to its invasive nature, CT and/or MRI are still considered to be the choice for initial imaging to help assess the size of the tumor and its relationship to the skull base.4

While the use of fine-needle aspiration biopsy may be used to diagnose many tumors of the head and neck, it has no place in the diagnosis of paragangliomas due to its unreliability, as it rarely provides diagnostic data and poses a risk for bleeding, due to the highly vascular nature of the tumos. Open biopsies of paragangliomas are also contraindicated for diagnosis, again due to a significant risk for hemorrhage.2

Observation is generally used as a first line step in patients who are asymptomatic and/or are not surgical candidates, due to the fact that these tumors grow slowly at an average rate of 1mm per year and doubling time is between 4 and 14 years.6

Complete surgical removal is the definitive treatment of paragangliomas and only curative option available.6 However, due to the highly vascular nature of these tumors, profuse bleeding can complicate attempts at excision. Preoperative embolization with angiography can be used to help minimize surgical blood loss, particularly for vagal and jugulotympanic paragangliomas, though outcomes of preoperative embolization of carotid body tumors tend to be less significant.7 In additional to potential preoperative embolization, those with catecholamine-secreting paragangliomas must be pretreated before surgery with an alpha blocker, such as phentolamine. This is done to prevent a potentially life-threatening surge of catecholamine-induced hypertension during the procedure.1

Surgical resection of carotid body tumors is generally regarded as a safe procedure because it has a low risk of injury to the cranial nerves, assuming the tumor is no larger than 6-7cm and there is no extension of the tumor to the base of the skull.2 However, other paragangliomas arising from the lower cranial nerves are much more difficult to excise without conferring significant morbidity and the definitive need for surgery must take into account patient age, tumor size and location, and surgical risk regarding the number of nerves involved. Generally, paragangliomas of the lower cranial nerves are initially treated with observation and are followed with annual or biannual MRIs.7 The need for surgical intervention arises if the tumor shows significant growth over a short period of time or turns malignant and is associated with cervical lymph node or distant metastases.2

The most common complication resulting from surgical removal involves cranial nerve palsy or paresis of the jugular foramen nerves, including CN IX, X, and XI and patients must be monitored in the post-operative period for cranial neuropathies.2 Damage to these nerves can result in either temporary or permanent dysphagia, hoarseness, and even aspiration. Facial nerve palsy (CN VII) is another possible complication during tumor removal, Other potential issues include stroke and/or other CNS complications, particularly when interruption of the ICA without shunting and/or carotid ligation occurs intraoperatively.4 Postoperative monitoring for hypertensive episodes is additionally recommended for most patients.7

Individuals with bilateral carotid body tumors can be surgical candidates, though it is important to remove the tumors in staged operations at least a few months apart in order to minimize the risk of potential bilateral cranial neuropathies and/or cerebral circulation deficits.5 Typically, the smaller of the two masses is excised first in order to ensure removal can be accomplished without significant complications.4 One serious potential issue of removing bilateral carotid body tumors simultaneously is the potential for loss of carotid baroreceptor feedback in the setting of innervation loss of both carotid bodies, leading to hemodynamic instability and significant hypertension.5

While not a first line treatment, radiation therapy is also thought to play some role in the treatment of paragangliomas, as it can reduce tumor growth rates, but it does not usually completely eradicate the tumor itself, nor does is shrink the existing tumor.7 However, it can be useful to use in elderly patients, those at high risk for anesthesia or patients in poor health, as well as for those with tumors that are impossible to operate on in the setting of unavoidable nerve damage.6 However, the risk for radiation therapy potentially causing a secondary malignancy must be also weighed and this is why the modality is generally not recommended for use in younger patients.2 Furthermore, patients who require surgical resection after radiation can be problematic, as the radiation itself causes alterations in soft tissues as well as scarring and these challenges may result in more cranial nerve palsies postoperatively than if radiation had never been done at all.6

After treatment, a significant proportion of head and neck paraganglioma patients may develop persistent or recurrent tumors, with some studies showing a statistic in upwards of 31 percent with hereditary tumors most at risk.7 Furthermore, recurrences have been discovered as late as 20 years after surgical removal.6 Therefore, given the risk, patients should be followed with serial imaging yearly for surveillance in the long term.7

Bibliography

1. Oghalai JS. Chapter 65. neoplasms of the temporal bone ; skull base. in: Lalwani AK. eds. CURRENT diagnosis ; treatment in Otolaryngology—Head ; neck surgery. 3rd ed. New York, NY: McGraw Hill; 2012.
2. Shah JP, Patel SG, Singh B. Jatin shah’s head and neck surgery and oncology. Philadelphia, PA: Elsevier/Mosby; 2012.
3. Carty S, Young WF. Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology. In: Wen P, Loeffler JS, Lacroix A, eds. UptoDate. Waltham, MA: UptoDate; 2017.
4. Metheetrairut C, Chotikavanich C, Keskool P, Suphaphongs N. Carotid body tumor: A 25-year experience. European Archives of Oto-Rhino-Laryngology. 2016;273(8):2171–2179.
5. Moore MG, Netterville JL, Mendenhall WM, Isaacson B, Nussenbaum B. Head and neck paragangliomas: An update on evaluation and management. Otolaryngol Head Neck Surg. 2016;154(4):597-605. doi: 10.1177/0194599815627667 doi.
6. Fruhmann J, Geigl JB, Konstantiniuk P, Cohnert TU. Paraganglioma of the carotid body: Treatment strategy and SDH-gene mutations. European Journal of Vascular & Endovascular Surgery,. 2013;45(5):431-436.
7. Carty S, Young WF, Oh K. Paragangliomas: Treatment of locoregional disease. In: Wen PY, Loeffler JS, Lacroix A, eds. UptoDate. Waltham, MA: UptoDate; 2017.

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