Epidemiology and Genetics

Approximately 90% of all paragangliomas arise in the adrenal gland and are called pheochromocytomas. Most (85%) extra-adrenal paragangliomas arise in the abdomen. Approximately 3% occur in the head and neck.²

Paragangliomas of the head and neck are rare, accounting for 0.012% of all tumors⁵ and 1 out of every 30,000 head and neck tumors.⁶ Carotid-body tumors tend to be equally distributed between men and women, whereas temporal bone and vagale tumors occur more often in women.^2,7–9 Some investigators suggest that higher altitudes and hypoxia may contribute to the development of carotid-body tumors.^10,11 Paragangliomas generally occur between ages 50 and 60,⁷ but may occur earlier in patients with a family history. Between 1% and 3% have endocrine activity that causes symptoms similar to pheochromocytomas or carcinoid tumors.¹² Although paragangliomas are normally benign, a small subset (10% or fewer) are malignant and metastasize.^8,13 They are multifocal in 10% to 20% of cases, although multifocality can be as high as 33% to 55% in familial cases.^9,14 Familial paragangliomas account for approximately 10% of all cases, and are much more likely to be multicentric and bilateral than sporadic tumors.³

Familial paragangliomas are inherited in an autosomal-dominant pattern, but display genomic imprinting with paternal inheritance, because the phenotype is expressed only when transmitted by the father.^2,3,15–17 The responsible gene is PGL, which codes for SDH, a mitochondrial enzyme complex that plays an important role in oxidative phosphorylation and intracellular oxygen sensing and signaling.¹⁸ Within these complexes are specific subunits coded for using three distinct genes: SDHB, SDHC, and SDHD. Genetic analysis has identified three different genetic types of paraganglioma: paraganglioma 1 (PGL1) 11q23, paraganglioma 2 (PGL2) 11q13, and paraganglioma 3 (PGL3).^19–22 PGL1 and PGL2 display the genetic imprinting pattern of inheritance, whereas PGL3 does not and is transmitted from either parent.^19,22 Paragangliomas occur in syndromes containing multiple tumors, including multiple endocrine neoplasia type II,²³ von Hippel-Lindau disease,²⁴ neurogenic disorders such as von Recklinghausen neurofibromatosis type I,²⁵ and Carney syndrome.²⁶

Anatomy

The carotid body is composed of multiple chemoreceptors located at the bifurcation of the common carotid artery, which are responsible for detecting changes in the partial pressures of oxygen and carbon dioxide in arterial blood. It is the most common location for head and neck paragangliomas, comprising between 60% and 70% of cases.³ The temporal bone is the next most common location. Tumors arising along the superior jugular bulb are referred to as glomus-jugulare tumors, whereas those from the tympanic (Jacobson nerve) nerve of cranial nerve IX or the auricular (Arnold nerve) nerve of cranial nerve X are called glomus-tympanicum tumors. The former runs along the tympanic canaliculus from the inferior petrous portion of the temporal bone between the jugular fossa and the carotid canal to the floor of the tympanic cavity. The Arnold nerve (X) runs from the jugular fossa laterally into the mastoid process. Glomus-vagale tumors may arise along the vagus nerve in any of three vagal ganglia, although usually from the most inferior (nodose) ganglia. Other possible sites include the ciliary ganglion, nasal cavity, larynx, trachea, periaortic region, and fallopian tubes.²⁷

Pathologic Conditions

Paraganglia are composed of two types of cells.² Type I, also called chief or granular cells, are part of the amino precursor and uptake decarboxylase system; they have catecholamine-containing granules and can be identified immunohistochemically by staining with neuron-specific enolase, chromogranin A, and synaptophysin. Type II, known as supporting or sustentacular cells, stain positive for S-1000 and glial fibrillary acidic protein.²

Nonchromaffin paragangliomas are notoriously hypervascular with well-defined edges and a pseudocapsule. Areas of necrosis or hemorrhage are not typically seen except in cases of malignancy.² Histologically, they appear benign with predominantly type I cells, but also type II cells and capillaries. They have nests of round, polygonal, or spindle-shaped epithelioid cells surrounded by an elaborate vasculature.²⁸ Nuclear atypia is variable and does not correlate with clinical behavior. Figure 23-1 shows the typical histologic appearance of a paraganglioma. Head and neck paragangliomas are almost always negative for chromaffin reaction, which is not sensitive enough to identify the small amounts of catecholamines they contain. Alternatively, immunohistochemical staining for neuron-specific enolase, chromogranin A, synaptophysin, and serotonin can be used to identify type I cells and S-100 and glial fibrillary acidic protein staining can identify type II cells.^2,28

FIGURE 23-1 • A, Hematoyxlin and eosin stain of a paraganglioma. Nested “Zellballen” arrangement of tumor cells with round to fusiform stippled nuclei and eosinophilic cytoplasm, surrounded by a fibrovascular stroma. B, S100 stain of paraganglioma: S100 immunostain highlights sustentacular cells surrounding tumor cell nests. C, Synaptophysin stain of paraganglioma. Diffuse, strong cytoplasmic synaptophysin staining supports the morphologic findings of this neuroendocrine neoplasm.

Malignancy is typically diagnosed clinically, as there are no established pathologic criteria for diagnosis. Attempts have been made to use mitoses, nuclear polymorphism, or capsular invasion to reliably predict metastatic potential.²⁹ Others have shown that most carotid-body tumors exhibit capsular invasion,³⁰ whereas some metastatic carotid-body tumors do not contain mitoses.³¹

Clinical Presentation

Carotid-body tumors generally present as a slow-growing, palpable neck mass at the bifurcation of the common carotid artery that has been present for several years.³² Other symptoms or signs may include neck discomfort, true-vocal-cord immobility that may result in hoarseness (from cranial nerve X involvement), tongue weakness and atrophy (from hypoglossal nerve XII involvement), or Horner syndrome (from involvement of the sympathetic chain).¹⁴ A very large mass may displace the soft tissue of the airway, resulting in airway symptoms like stridor extension into the parapharyngeal space that may rarely lead to dysphagia. Carotid sinus syndrome has also been reported, as in bilateral neck involvement.

Glomus-vagale tumors are less common than carotid-body tumors and appear more cephalad in the neck. They present as an upper lateral neck mass, often visible only intraorally, displacing the oropharynx anteromedially. Involvement of cranial nerves X and XII or Horner syndrome, as described in carotid-body tumors and accessory nerve weakness, are present in approximately 50% of cases.⁷

A paraganglioma involving the temporal bone may be a glomus jugulare or glomus tympanicum. Glomus-jugulare tumors, generally larger than glomus-tympanicum tumors, present with headache and skull-base destruction at the jugular bulb associated with involvement of cranial nerves IX through XI (jugular bulb syndrome). Advanced cases may extend into the posterior cranial fossa causing dysfunction of cranial nerves V through XII.

Glomus-tympanicum tumors usually arise in the tympanic cavity or floor of the middle ear, and are typically small and well circumscribed. They may appear as a blue or reddish lesion behind the tympanic membrane. The most common symptoms are progressive conductive hearing loss and pulsatile tinnitus.³³ Other symptoms include aural pressure or fullness, vertigo, and headache.

Routes of Spread

Most paragangliomas are benign, but may be locally destructive, invading into bone and displacing or invading adjacent soft tissue. Carotid-body paragangliomas may affect adjacent cranial nerves X and XII and the sympathetic chain. Temporal-bone paragangliomas may cause destruction of the temporal bone and posterior cranial fossa. They may extend medially to the internal auditory canal and involve cranial nerves VII and VIII. Laterally, they may progress to or through the tympanic membrane and appear as a middle-ear mass or a mass in the external auditory canal. It has been reported that 5% of temporal bone and 10% to 15% of carotid-body and vagale paragangliomas are malignant, determined clinically rather than histologically.^34,35 Malignant paragangliomas can spread to lymph nodes or distant sites. Caution must be taken to avoid confusing multifocality with metastases or extensive growth, cranial nerve involvement, or recurrence as a sign of malignancy.

Diagnostic Studies

Paragangliomas are often diagnosed presumptively by their typical radiographic appearance rather than by fine-needle aspiration (FNA) or open biopsy, which are associated with the risk of bleeding. Radiographic evaluation also details the extent of the lesion and its relationship to adjacent critical structures. Because paragangliomas are hypervascular, they typically appear as strongly enhanced and well circumscribed on magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT). If there is skull-base bone involvement, a high-resolution temporal bone CT will supplement the MRI in delineating tumor extent at the eroded jugular fossa (Fig. 23-2A and Fig. 23-2B) and through the numerous vascular channels and bony foramina.

FIGURE 23-2 • Computed tomography scan of a glomus jugulare showing enhancement and bony destruction (A and B), and magnetic resonance imaging scan of a glomus jugulare showing areas of both hyperintensity and hypointensity and extension into the posterior fossa (C).

MRI provides important information about tumors and adjacent soft tissues and vascular channels. Flow voids within tumors⁷ produce the characteristic “salt and pepper” appearance commonly seen on a T₂-weighted MRI sequence, representing areas of hemorrhage, slow-flowing blood, and tumor cells.³⁶ MRI is superior to CT in determining skull-base involvement, intracranial extension, dural sinuses, and encasement of the internal carotid artery and internal jugular vein,^7,37,38 although CT better determines middle- and inner-ear involvement and bony erosion of the jugular fossa or temporal bone.⁷ Figure 23-2C shows an MRI of a glomus jugulare.

Ultrasound has been used in the diagnosis of carotid-body or vagale tumors, but is of limited value for temporal-bone tumors and provides much less information than MRI. The classic appearance is that of a hypoechoic and heterogenous hypervascular lesion. For carotid-body tumors, splaying of the internal and external carotid artery may be seen.³⁹ A Doppler-flow study showing upward movement of intratumoral blood flow at the carotid bifurcation is diagnostic of a carotid-body tumor, whereas downward flow of a neck mass indicates a glomus vagale.⁴⁰

Angiography will confirm the hypervascularity of these tumors and also is an option to detect multifocality. Figure 23-3 shows a typical angiogram with intense tumoral vascularity and splaying of the internal and external carotid arteries.

FIGURE 23-3 • Angiogram of a carotid paraganglioma shows the intense vascularity of the tumor and splaying of the internal and external carotid arteries.

A family history of paragangliomas requires a more extensive radiographic workup because of the higher likelihood of multifocal disease. Because paragangliomas share similar histologic features with other neuroendocrine tumors, including somatostatin receptors, octreotide scintigraphy may be another way to detect multifocality (or metastases).^41,42 Radiolabeled metaiodobenzylguanidine, an analog of norepinephrine, is taken up and stored in the intracellular vesicles of neuroendocrine tumors and can be useful for diagnosing tumors of neuroendocrine origin, such as neuroblastoma,⁴³ pheochromocytoma,⁴⁴ and other paragangliomas.⁴⁵

Staging

There is no universally accepted staging system for carotid-body and glomus-vagale tumors, but several have been published for temporal-bone paragangliomas. Some authors have used the staging system proposed by McCabe and Fletcher.⁴⁶ The Glasscock-Jackson system is also available.⁴⁷ The classification by Fisch⁴⁸ is often used for surgical outcomes.

Standard Therapeutic Approaches

Radiation and surgery can be used as definitive treatment for paragangliomas. When the entire tumor cannot be removed, postoperative radiation is usually recommended. The decision of which modality to use is based on a number of factors such as patient age and overall health, and on the potential short-term and long-term risks of treatment complications. In general, surgery is preferred when complete resection is anticipated with a minimal surgical risk and in younger patients. This is especially so for early-stage, temporal-bone tumors, including middle-ear tumors and small-volume neck tumors that have a low attendant risk of permanent postoperative complications. Larger and locally invasive tumors may be treated with postoperative irradiation, or may be treated with primary radiotherapy because of potential cranial nerve or vascular injury associated with resection. When treated with irradiation, paragangliomas usually remain stable or may regress slowly, resulting in a persistent radiographic or palpable mass.⁴⁹ Hence local control is defined as the lack of tumor progression. Symptoms caused by the tumor often improve with radiation.

Simulation and Treatment Planning

Patients should be simulated in the supine position with arms at their sides and kept caudally to keep the shoulders from interfering with lateral treatment beams. If the lesion is high in the neck or temporal bone, a wedge-pair beam arrangement may be used. The head is placed in a neutral or slightly extended position and immobilized with an Aquaplast mask or other suitable device. Potential complications such as xerostomia can be avoided with ipsilateral beam arrangements because the contralateral neck does not require treatment. The head is hyperextended when using a wedge-pair for lesions in the temporal bone or high neck to avoid beam exit through the eye(s).

Intensity-modulated radiation therapy (IMRT) can provide a highly conformal dose distribution that decreases the dose to surrounding normal tissues (Fig. 23-4). These techniques can be especially important for glomus-jugulare and tympanicum tumors to spare the adjacent cochlea. Although the dose normally required for these tumors is moderate, minimizing the integral dose is an important goal to reduce these long-term risks. Acute toxicities can also be reduced by limiting the dose to oral cavity structures and salivary glands. Diagnostic information that can help in defining the gross tumor volume (GTV)⁶⁴ should be reviewed, including CT, MRI, and angiograms. The GTV encompasses the visible gross tumor on diagnostic imaging scans. The clinical target volume (CTV) only requires a small margin of approximately 0.5 cm to account for microscopic extension. Regional lymph-node spread is rare, so the regional nodes are not electively included in the target volume unless malignancy is suspected. The planning target volume (PTV), taken into account for set-up uncertainty and tumor motion, typically adds another 0.5 cm. If there is evidence of lymph-node spread (malignancy), the regional nodes are included in the CTV. The PTV may be extended slightly superiorly and inferiorly if the tumor extent is indistinct on the planning scan. Sensitive surrounding critical normal structures should be contoured to avoid exceeding normal-tissue tolerances, including the globes, brainstem, salivary glands, and bilateral cochleas.

FIGURE 23-4 • Intensity-modulated radiation therapy plan showing conformality of isodose curves around the planning target volume (red).

Moderate doses of 45 to 50 Gy at 1.8 to 2 Gy per fraction adequately control benign paragangliomas without exceeding the tolerances of adjacent neurologic and optic structures such as the spinal cord, brainstem, and optic chiasm. Local control appears to be reduced with doses lower than 40 Gy.⁶⁵

Little data exists on the adequate dose for malignant paragangliomas. These lesions tend to be locally aggressive with the potential for distant metastases, and higher doses are likely required. Generally, doses of 64.8 to 70 Gy at 1.8 Gy per fraction are used. At the University of Florida, malignant lesions are treated with a dose of 74.4 Gy at 1.2 Gy per fraction given twice a day. The treatment volume should include the primary tumor and the regional lymphatics.

Stereotactic Radiosurgery

The use of stereotactic radiosurgery (SRS) to treat temporal-bone tumors is increasing, because it can deliver a large dose of radiation in few fractions and minimize normal-tissue doses.^66–71 Treatment planning should again use contrast-enhanced CT, MRI, and angiography to help delineate tumor extent. A variety of doses ranging from 15 to 27 Gy in a single fraction have been published in the literature. It appears that 15 to 18 Gy in a single fraction adequately controls the disease and minimizes the risk of complications.^66–71

Outcomes

Results with any treatment approach are excellent. Table 23-1 and Table 23-2 show that the local control rates of selected patients treated with surgical resection and radiation are comparable, typically greater than 85% to 95%.⁷² Local control in radiation series is generally defined as lack of tumor progression after treatment. Although there is less data for carotid-body tumors, the available data suggests that control rates equal those for temporal-bone tumors. Valdagni and Amichetti reported on 7 patients with 13 carotid-body tumors treated with radiation and found 100% local control.⁷³ Verniers and colleagues reported a series including 17 carotid-body tumors, none of which recurred after radiotherapy, with a mean follow-up of 10 years.⁷⁴ In a series reported by Hinerman and colleagues, 18 patients with 25 carotid-body tumors or glomus-vagale tumors were treated with radiotherapy. The 15-year local control rate was 92%.⁷⁵

Because SRS is relatively new, less data on treatment outcomes is available and follow-up is shorter. Early results show excellent local control (Table 23-3). However, because this disease can have late failures, longer follow-up is needed to show results comparable to surgery or fractionated radiotherapy.

Treatment Toxicity

Table 23-4 shows surgical complications during the preceding two decades. Most surgical morbidity is related to cranial-nerve deficits, which can be either temporary or permanent. Other complications are related to wound infections or vascular damage. With appropriate selection and modern surgical and anesthesiologic methods, permanent cranial-nerve deficits are approximately 10% to 15%, and vascular injury is rare. Isolated X or XII deficits are well tolerated, and compensatory rehabilitation is available with good results when there are combined deficits.^72,76

Table 23-5 shows the reported treatment-related morbidity with radiotherapy. Cranial-nerve deficits and bone necrosis are occasionally seen after radiotherapy. Late radiation-induced malignancy, though possible, has not been reported. It is hoped that complication rates will continue to improve as imaging and radiation delivery technologies improve.