CLINICAL REVIEW
David W. Eisele, MD, Section Editor
HEAD AND NECK PARAGANGLIOMAS William M. Mendenhall, MD,1 Robert J. Amdur, MD,1 Mikhail Vaysberg, DO,2 Charles M. Mendenhall, MD,3 John W. Werning, MD2 1
Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, Florida. E-mail:
[email protected]fl.edu 2 Department of Otolaryngology, University of Florida College of Medicine, Gainesville, Florida 3 Department of Radiation Oncology, Phoebe Putney Memorial Hospital, Albany, Georgia Accepted 13 May 2010 Published online 4 November 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.21524
Abstract: Background. The purpose of this study was to describe the natural history and optimal treatment for head and neck paragangliomas (PGs). Methods. Our methods were the review of the pertinent literature. Results. PGs are rare tumors seen most commonly in the head and neck. Approximately 90% are sporadic; the remainder are familial and related to mutations of the succinate dehydrogenase (SDH) gene complex. Most PGs are benign and slow growing; 6% to 19% are malignant, as evidenced by the development of metastases. PGs may be treated by complete resection or moderate-dose radiotherapy with a 90% likelihood of cure. The optimal radiotherapy dose is approximately 45 Gy/25 fractions/5 weeks. The treatment modality selected depends on the risk of complications. Due to their rarity, the optimal treatment for malignant PGs is unclear. Conclusion. PGs may be treated by either complete resection or radiotherapy with a high likelihood of success. Treatment depends on the location and extent of the PG and C the morbidity associated with treatment. V 2010 Wiley Periodicals, Inc. Head Neck 33: 1530–1534, 2011 Keywords: head and neck; paragangliomas; review
Paraganglia are derived from the embryologic neural crest and are found in vascular adventitia throughout the body.1 Head and neck paraganglia are associated with the parasympathetic nervous system and are present in a variety of locations, including the carotid body, vagus nerve, jugular bulb, and the tympanic branch of the ascending pharyngeal artery.1 It has been thought that the role of head and neck paraganglia is more likely sensory rather than secretory.1 In contrast, thoracic and abdominal paraganglia are associated with the sympathetic nervous system and secrete catacholamines.1
Correspondence to: W. M. Mendenhall C 2010 Wiley Periodicals, Inc. V
1530
Head and Neck Paragangliomas
Paragangliomas (PGs) are rare tumors thought to arise from paraganglia. Although they are found throughout the body, the majority arise in the head and neck. The sex distribution varies with the site; the majority of carotid body tumors are found in men, whereas for vagal PGs, a predominance is observed in women.1 The median age at diagnosis is approximately 50 years, with a wide range.2,3 PGs are rarely observed in children.4 PGs are usually benign and grow slowly, causing symptoms by compressing adjacent structures.1 Approximately 6% to 19% of PGs are malignant, as evidenced by the presence of regional and/or distant metastases.1 Malignancy cannot be determined based on the histologic appearance of the PG which resembles that of pheochromocytoma.1 Vagal PGs are among those most likely to metastasize. Approximately 1% to 3% of PGs exhibit biologic activity in that they secrete catecholamines.5 About 90% of PGs are sporadic; the remainder are found in those with a familial predisposition.1 Three known genes associated with PGs are succinate dehydrogenase (SDH) subunit D (SDHD), subunit B (SDHB), and subunit C (SDHC).1,6–10 The inheritance pattern may be autosomal dominant for some families; SDHD has a complicated inheritance pattern, where PGs develop only if the mutation is inherited from the father.1 Patients with familial PGs are more likely to present at a younger age, have multiple PGs, and have pheochomocytomas.1,6,9,11 Neumann et al6 reported that 50% of SDHB mutation carriers developed PGs by age 35 years and 77% by age 50 years; and that 50% of SDHD mutation carriers were diagnosed with PG by age 31 years and 86% by age 50 years. Familial head and neck PGs may Genetics.
HEAD & NECK—DOI 10.1002/hed
October 2011
Table 1. Familial head and neck paraganglioma syndromes. Paraganglioma type
Mutation
Parent of origin effect
Multifocality
Malignancy
Pheochomocytoma
1 2 3 4
SDHD Unknown SDHC SDHB
High Unknown Low Intermediate
High Unknown Low Intermediate
Low Unknown Low Intermediate
Intermediate Unknown No High
Abbreviations: SDHD, succinate dehydrogenase subunit D; SDHC, succinate dehydrogenase subunit C; SDHB, succinate dehydrogenase subunit B. Reprinted from Myssiorek et al8 2008, with permission from Elsevier.
be stratified into 4 syndromes as depicted in Table 1 by Myssiorek et al.8 Burnichon et al10 reported on 445 patients from 20 referral centers with head and neck, thoracic, abdominal, and/or pelvic PGs. Direct sequencing of the SDHB, SDHC, and SDHD genes was performed. Additionally, quantitative multiplex polymerase chain reaction of short fluorescent fragments and multiplex ligation-dependent probe amplification were used. SDH germline mutations were found in 220 patients (49%) by direct sequencing and 22 patients (5%) by quantitative multiplex polymerase short fluorescent fragments and multiplex ligationdependent probe amplification: SDHD, 130 patients (54%); SDHB, 96 patients (40%); and SDHC, 16 patients (6%). The relationships between the type of SDH mutation and various parameters are depicted in Table 2.
DIAGNOSTIC EVALUATIONS
Patients are evaluated by taking a history and performing a thorough physical examination. CT and/or MRI of the head and neck are used to define the location and extent of the PG and to detect synchronous PGs.12,13 Somatostatin receptor scintigraphy, such as octreotide imaging, may be used to detect additional PGs and to
Table 2. Relationship of SDH mutation and various parameters (242 patients). Parameters
SDHD
SDHC
SDHB
No. of patients Head and neck PG Thoracic, abdominal, and/or pelvic PG Multiple PGs Malignant PG
130 97.7% 16.1%
16 87.5% 12.5%
96 42.7% 63.5%
66.9% 3.1%
31.2% 0%
20.8% 37.5%
Abbreviations: SDH, succinate dehydrogenase; SDHD, succinate dehydrogenase subunit D; SDHC, succinate dehydrogenase subunit C; SDHB, succinate dehydrogenase subunit B; PG, paraganglioma. Reprinted as adapted from Burnichon et al10 2009, with permission from The Endocrine Society.
Head and Neck Paragangliomas
screen patients thought to be at risk for an SDH mutation.8,12 Patients who are at increased risk for harboring SDH mutations include those who have a family history of PGs, multifocal PGs, and age 40 years at diagnosis.9 The advantage of detecting SDH mutations is so that the patients may be screened and the PGs diagnosed while they are limited, so that the morbidity of treatment may be reduced. Additionally, siblings and children of SDH mutation carriers should be considered for genetic testing and, if found to harbor a mutation, screened for PGs. Neumann et al9 analyzed 598 unrelated patients with head and neck PGs entered into the European-American Paraganglioma Registry between 2001 and 2007. Germline mutations were detected in 183 patients (31%): SDHB, 63 patients (34%); SDHC, 26 patients (14%); and SDHD, 94 patients (52%). No risk factors were present in 272 patients (45%) and 15 patients (6%) had SDH mutations; 326 patients (55%) had 1 or more risk factors and 168 patients (52%) had SDH mutations. Multiple logistic regression analysis was used to evaluate the relationship between various parameters and the likelihood of having an SDH mutation (Table 3). Angiography may be useful if surgery is contemplated.12 Biopsy is usually not obtained prior to either surgery or radiotherapy (RT) because of the risk of bleeding.12 Table 3. Relationship between various clinical parameters and the likelihood of having a SDH mutation (598 patients). Clinical parameters Family history Previous pheochomocytoma Multiple head and neck PGs Age 40 y Male sex Malignant head and neck PG
Odds ratio
p value
37.85 10.86 10.61 3.99 3.46 2.10
