ABSTRACT: Paragangliomas most commonly occur in the carotid body, jugulotympanic area, and vagus nerve but have also been reported in other areas of the head and neck. These tumors are highly vascular and characteristically have early blood vessel and neural involvement, making their treatment particularly challenging. Surgery has traditionally been the preferred method of treatment, especially in light of recent advances in technique. However, compared to radiation therapy, it can result in a higher incidence of cranial nerve dysfunction. Radiation therapy has the advantage of avoiding the increased morbidity of surgery while offering an equal possibility of cure. Part 1 of this two-part article focuses on techniques for diagnosing paraganglioma and the indications for and use of surgery as primary treatment. The complications commonly associated with surgery are reviewed, and strategies for rehabilitation of affected patients are presented.
Paragangliomas are highly vascular neoplasms arising embryologically from the paraganglia of neural crest origin and occurring most commonly in the head and neck region. Typically, paragangliomas manifest in the 5th or 6th decade of life,[1,2] predominantly in females.[3-6] A slowly enlarging neck mass and/or findings consistent with cranial nerve dysfunction are the hallmarks of presentation.
Part 1 of this two-part article addresses the etiology and epidemiology of paragangliomas, their diagnosis, and surgical approaches to treatment. Part 2, which will appear in next month's issue, describes the use of radiation therapy in management and offers an overall treatment algorithm.
Paraganglia are part of the diffuse neuroendocrine system, previously known as the amine precursor decarboxylate system, and have the potential to secrete neuropeptides and catecholamines.[7,8] Paragangliomas most commonly occur in the carotid body, jugulotympanic area, and vagal paraganglia (Figure 1), although they have also been reported in the larynx, orbit, thyroid,[ 11] tongue, nasal cavity, paranasal sinuses,[13,14] external auditory canal, and supratentorial locations.[16,17]
Risk factors include high altitude and, in 5% to 10% of cases,[18,19] a hereditary predisposition characterized by autosomal dominant genetic transmission with variable penetration[ 20] and paternal imprinting.[ 20-22] Multicentric tumors are common in familial cases (78% to 87% have multiple paragangliomas)[ 6,19] but also occur in 10% of sporadic cases. Such a presentation may result in refractory hypertension due to the loss of baroreceptive function after resection of bilateral carotid body tumors, whereas multiple tumors, including vagal or jugular paragangliomas, may result in multiple lower cranial nerve dysfunction.
Malignant paragangliomas are uncommon, and their diagnosis can only be confirmed by the presence of metastatic disease, usually within regional lymph nodes. There are no strict histologic criteria within the primary tumor to differentiate benign from malignant paragangliomas. Paragangliomas are highly vascular and characteristically associated with early involvement of blood vessels (carotid artery, jugular bulb) and neural areas (vagus, tympanic plexus), in addition to skull-base and potential intracranial extension.
These factors all contribute to the challenge of effectively treating these tumors. Traditionally, surgery has been the preferred method of treatment, especially with the evolution of more sophisticated skull-base approaches, safer embolization protocols, and advanced vascular bypass procedures. Postoperative cranial nerve dysfunction is anticipated in patients with larger tumors and skullbase involvement, making rehabilitative efforts the focus of care.
Radiation therapy was traditionally used to treat unresectable paragangliomas or tumors in elderly or debilitated patients. Advances in radiation oncology and increased experience with the treatment of head and neck paragangliomas have led to improved long-term tumor responses with acceptable complications from radiation treatment. Radiation represents a reasonable primary treatment option especially for locally advanced or multicentric tumors, which, if surgically resected, would result in undue morbidity.
Paragangliomas of the head and neck are rare tumors, accounting for only 0.012% of all tumors reviewed by the surgical pathology department of Memorial Sloan-Kettering Cancer Center between 1938 and 1975. The carotid body is the most common site of paragangliomas in the head and neck. Carotid body tumors, jugular paragangliomas, and tympanic paragangliomas account for 80% of all head and neck paragangliomas, with vagal paragangliomas accounting for another 5%. Nasal, orbital, laryngeal, and other paragangliomas occur much less frequently. Our review of 47 patients with 53 paragangliomas treated over a 10-year period (1990-2000) is consistent with the relative incidence of specific paragangliomas as reported by others (Tables 1-3).
Malignant paragangliomas are uncommon. The most important criterion of malignancy is documented lymph node or distant metastases, as- the histologic examination of the primary tumor is unreliable in establishing a malignant diagnosis. The prevalence of malignancy depends on the site of the primary tumor. Among the more common types of head and neck paragangliomas, vagal paragangliomas most likely are associated with the highest rate of malignancy (about 10%), with the regional lymph nodes and lungs being the most common sites of metastases.
Malignant carotid body tumors and jugulotympanic glomus tumors have been reported to occur in about 3% to 6% of cases.[30,31] Of head and neck paragangliomas, primary orbital and laryngeal tumors demonstrate the highest rate of malignancy (20% to 25% of cases). The most common sites of distant carotid body tumor metastases are the bones, lungs, and liver, while for jugulotympanic paragangliomas, the most common sites of metastases are the lungs, lymph nodes, liver, vertebrae, ribs, and spleen.
In a review of 43 cases of malignant carotid body tumors, Pacheco- Ojeda found that locoregional control requires resection of the pri- mary tumor and neck dissection followed by radiation therapy. The interval between primary resection and the appearance of a metastatic lesion may be long, ranging from 20 months to 20 years. Disseminated disease is relatively unresponsive to chemotherapy.
Paragangliomas are slow-growing tumors with a mean growth rate of 1.0 mm/yr and a median doubling time of 4.2 years. Jansen et al reported less growth in very small and very large paragangliomas compared to intermediate- size tumors, suggesting a biphasic growth pattern. The growth rate of metastases is slow, with a doubling time of 2,000 days.
Although all paragangliomas have the potential for releasing vasoactive substances such as catecholamines and dopamine,[29,36] only 1% to 3% produce associated clinical findings,[ 36,37] including excessive sweating, hypertension, tachycardia, nervousness, and weight loss. Laboratory screening tests, including 24-hour urinary metanephrine (normal value < 1.3 mg) and vanillylmandelic acid levels (normal = 1.8-7.0 mg), are frequently elevated 10 to 15 times normal in patients with actively secreting tumors.
Serum catecholamine levels, including serum norepinephrine and epinephrine, are also of value in the evaluation of patients. Because head and neck paragangliomas do not secrete epinephrine, an elevated serum epinephrine level is suggestive of a concurrent pheochromocytoma. Several reports have noted an association between pheochromocytoma and both familial and nonfamilial paragangliomas.[ 38-40] Paragangliomas may occur in patients with both type IIA (pheochromocytoma, medullary thy- roid carcinoma, and parathyroid hyperplasia) and type IIB (also includes mucosal neuromas) familial multiple endocrine neoplasia.
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