Abstract
Background
Malignant paragangliomas of the head and neck are very rare tumors of the neuroendocrine cells associated with the peripheral nervous system. There are limited data available to help guide treatment of these tumors and the role of radiation therapy (RT) is not well-defined. This article briefly reviews the pathology, clinical presentation, and treatment modalities of these tumors and reviews our institutional experience in treating this malignancy.
Patients and methods
From November 1993 through May 2005, 5 patients with 5 malignant paragangliomas of the jugular bulb and carotid body were treated with RT at the University of Florida to a median dose of 70 Gy at 1.8 Gy per fraction. Mean and median follow-up times are 12.8 years and 14.4 years, respectively.
Results
We were able to achieve significant disease-free intervals of > 10 years for 3 of 5 patients and > 5 years for 4 of 5 patients. Of the 2 patients who failed treatment, 1 recurred 7.3 years after the RT salvage treatment following combination surgery and RT at another institution, and 1 experienced distant metastasis 2.8 years after treatment without obvious recurrence of local disease.
Conclusion
Malignant paragangliomas are a very rare entity whose main treatment modality has yet to be well established. Overall, data concerning outcomes are sparse, but particularly data on the role of RT in the treatment of these difficult tumors. We recommend doses to 70 Gy at 2 Gy per once-daily fraction as an adjuvant treatment with surgery to both remove the source of disease and provide microscopic control. Patients with incompletely resectable tumors are treated with RT alone.
1
Background
Paragangliomas are rare, slow-growing, typically benign tumors of the paraganglia, which are clusters of neuroendocrine cells that are associated with the parasympathetic and sympathetic nervous system . Broadly speaking, they can be divided into one of two categories based on location: adrenal or extra-adrenal. When found within the adrenal medulla, they are referred to as pheochromocytomas. Within the extra-adrenal category, 70% can be found within the head and neck where they have been referred to as chemodectomas, nonchromaffin tumors, and glomus tumors . However, simply “paraganglioma” and the associated body location are the preferred term for the extraadrenal manifestations (e.g., carotid body paraganglioma).
Clinically, they can be further divided into benign or malignant and functional or nonfunctional disease, with the functional status referring to the ability of the tumors to secrete catecholamines. Malignancy is defined by clinical behavior – metastases – and not histologically . While most metastases in head and neck paragangliomas are confined to the regional lymphatics, distant metastases do occur, usually to the lung and bone . The likelihood of malignancy may also be affected by location, with 5% of temporal bone paragangliomas and 15% of carotid body/glomus vagale tumors usually found to be malignant . Their typical presentation depends on their location, and most symptoms are related to the mass effect that the tumor produces. Therefore symptoms can range from tinnitus, vertigo, and hearing loss in temporal bone tumors to a painless neck mass or cranial nerve deficits in carotid body and base-of-skull paragangliomas .
In the last decade, we’ve learned that the genetics involved in the familial forms of paragangliomas involve the subunits of succinate dehydrogenase (SDH) , VHL, RET, and NF1 . One 445-patient study of patients with paragangliomas published by Burnichon et al. found that 54% of individuals had a mutation in the SDH subunits B, C, or D . Among these, subunits B and D were significant for coinciding with a malignancy rate of 38% and 3%, respectively, and suggested phenotypic differences in the presentations of the disease ( Table 1 ). Neumann et al. found that individuals who are likely to have an SDH mutation are those who present before age 40 years, have a positive family history, have a previous pheochromocytoma, have multiple head and neck paragangliomas, and are male ( Table 2 ). SDHAF2 was recently shown to be associated with familial paragangliomas, although no connections to malignancy have been found . Burnichon and Neumann recommend screening paraganglioma patients, in varying degrees, for germline mutations .
| Parameters | SDHD | SHDC | SDHB |
|---|---|---|---|
| Number of patients | 130 | 16 | 96 |
| Head and neck PG | 97.7% | 87.5% | 42.7% |
| Thoracic, abdominal, and/or pelvic PG | 16.1% | 12.5% | 63.5% |
| Multiple PGs | 66.9% | 31.2% | 20.8% |
| Malignant PG | 3.1% | 0% | 37.5% |
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