Vascular Neoplasms

Paragangliomas comprise the most common class of benign vascular neoplasms of the neck. Paragangliomas arise from extra-adrenal paraganglionic cells derived from the neural crest.

Pathology

The paraganglion system denotes a collection of neuroectoderm-derived chromaffin cells in extra-adrenal sites. The system is vital as a source of catecholamines in fetal development, until the formation of the adrenal medulla.

Normal paraganglia contain two types of cells: type 1, chief cells or granular cells; and type 2, the supporting or sustentacular cells. Type 1 cells contain dense-core granules filled with catecholamines, a property that places them in the amine precursor and uptake decarboxylase (APUD) system. Type 2, or sustentacular cells, are elongated cells that closely resemble Schwann cells. Their function is not entirely clear. Tumors of paraganglia such as carotid body tumors contain both type 1 and 2 cells. Type 1 cells predominate and are arranged in an organized-nested pattern, known as Zellballen, surrounded by sustentacular cells in a fibrous stoma. These nests of Zellballen are illustrated in Figure 118-1. Type 1 chief cells tend to be polygonal shaped with abundant granular eosinophilic cytoplasm. They are peripherally surrounded by type 2 sustentacular cells that are difficult to identify by light microscopy and appear as spindle-shaped basophilic cells. Nuclear pleomorphism and cellular hyperchromatism are common in paragangliomas and should not be considered evidence of malignancy. Immunohistochemistry aids the diagnosis and differential diagnosis of these neoplasms. Type 1 cells stain positively with neuron-specific enolase, chromogranin A, and synaptophysin. Type 2 cells stain with S-100 and focally with glial fibrillary acidic protein.

Figure 118-1. Carotid paraganglioma. A, Coronal T2-weighted magnetic resonance (MR) image with suppression of fat (short tau inversion recovery, STIR) shows a hyperintense mass in the right neck with prominent internal vessels (flow voids). B, Axial postcontrast T1-weighted MR image reveals avid enhancement of the mass, which splays apart the internal and external carotid arteries (arrows). Note that the internal flow voids are again visualized. C, Frontal projection MIP (maximum intensity projection) image from neck MR angiogram shows presence of vessels between internal and external carotid arteries on the right, which are splayed apart. D, DSA (digital subtraction angiogram) frontal projection image following right common carotid artery injection demonstrates the tumor vasculature to a better advantage.

Nomenclature

The controversy over the proper nomenclature of paragangliomas has been confusing. Historically they have been referred to as glomus tumors, chemodectomas, and nonchromaffin tumors. The correct terminology of paragangliomas is based on location (i.e., carotid paragangliomas, jugulotympanic paragangliomas, and vagal paragangliomas), although the terms carotid body tumor, glomus tympanicum, and glomus jugulare still persist.

Other terms such as chemodectoma, glomus tumor, and nonchromaffin tumor are less accurate terms and should be avoided. Chemodectoma is an inaccurate term to describe all paragangliomas of the head and neck because the carotid body is the only known paraganglia of the head and neck that behaves as a chemoreceptor. The term glomus tumor more accurately describes benign cutaneous tumors arising from neuromyoarterial cells surrounding arteriovenous anastomoses. Designation as nonchromaffin tumor relates to histologic staining characteristics. An early histologic staining technique employing the chromaffin reaction failed to show the presence of catecholamines; paragangliomas were therefore described as nonchromaffin tumors. Newer techniques however have detected catecholamines in small quantities.⁸ The chromaffin reaction is a highly insensitive method on which to classify these tumors.⁹

Epidemiology

Approximately 90% of tumors arising from the paraganglion system are in the adrenal gland. These tumors are termed pheochromocytoma. The remaining 10% arise from extra-adrenal sites with 85% arising in the abdomen, 12% in the thorax, and the remaining 3% in the head and neck area.

The most common paraganglioma of the head and neck is the carotid body tumor, followed by jugulotympanic paragangliomas and vagal paragangliomas. Other sites include the larynx, nasal cavity, orbit, trachea, aortic body, lung, and mediastinum. It has been estimated that paragangliomas comprise 1 in 30,000 head and neck tumors.¹⁰ However, the true incidence of paragangliomas may be unknown because previous reports have confused paragangliomas with neuroendocrine tumors.¹¹ Further complicating an accurate estimate is the multicentricity of these tumors, particularly in familial paragangliomas.

Etiology

The etiology of paragangliomas appears to be multifactorial. Most paragangliomas are solitary. Multiple pheochromocytomas and paragangliomas are seen in familial syndromes, mainly multiple endocrine neoplasia types 2A and 2B. Other syndromes associated with paragangliomas are neurofibromatosis type 1 and von Hippel-Lindau disease, which is characterized by retinal angiomas and cerebellar hemangioblastomas. Carney’s triad demonstrates the association of paraganglioma, pulmonary chondroma, and gastric leiomyosarcoma.¹⁷

In addition to these associations, a syndrome of familial paragangliomas characterized by multiple paragangliomas, especially in the head and neck region, has been described and occurs in at least 10% of cases. The familial nature of carotid body tumors was first suggested by Chase in 1933 in his description of two sisters with carotid body tumors.¹⁸ Many developments have occurred recently in the characterization of the familial paraganglioma (PGL) syndromes including the genes and mutations involved and recommendations for the head and neck surgeon in managing these patients and their at-risk family members (Table 118-1). Genetic mutations responsible for the hereditary form of PGL have been identified in genes coding for succinate-dehydrogenase subunit D (SDHD), B (SDHB) and C (SDHC) genes, which map to chromosome 11, 1 and 1, respectively. Hereditary PGL syndrome has been classified genetically into four entities: PGL1, PGL2, PGL3, and PGL4. Germline mutations in SDHD, SDHB, and SDHC have been identified in PGL1, PGL4, and PGL3, respectively. The gene for PGL2 has not been identified.¹⁹ Individuals with hereditary paraganglioma syndrome have early onset of tumors and a higher frequency of bilateral and/or multiple tumors than do those with sporadic disease. Past reports suggested familial paraganglioma to be rare, although recent literature challenges this assertion and suggests the association of paragangliomas with germline genetic mutations is likely to be significantly higher, representing 17% of sporadic patients in one study¹⁹ and up to 28% to 40% in other studies.^20–22

Table 118-1 Screening Recommendations for Carriers of SDHB, SDHD, or SDHC Gene Mutations*

* Starts in early teens. Succinate-dehydrogenase subunits D (SDHD), B (SDHB), and C (SDHC).

From Drucker AM, Houlden RL. A case of familial paraganglioma syndrome type 4 caused by a mutation in the SDHB gene. Nat Clin Pract Endocrinol Metab. 2006;2(12):706-712 and Isik C, Erem C, et al. Familial paraganglioma. Eur Arch Otorhinolaryngol. 2006;263(1):23-31.

PGL1 is caused by mutations in the D subunit of the succinate dehydrogenase (SDH) gene and is the most common inherited genetic abnormality in families with a history of paragangliomas. All three syndromes follow an autosomal pattern of inheritance, but the inheritance pattern for PGL1 is autosomal dominant modified by genomic imprinting. Genomic imprinting in paragangliomas was described by van der Mey and colleagues after reviewing data from 15 large Dutch pedigrees.²³ The imprintable gene is transmitted in a mendelian manner, but the expression of the gene is determined by the sex of the transmitting parent. With paragangliomas, the gene results in the development of a tumor when it is paternally inherited. Offspring of male carriers were observed to demonstrate a 50% incidence of tumors, whereas children of female carriers never developed tumors. PGL1 is associated most commonly with head and neck tumors but also confers a risk for pheochromocytoma. It is estimated that 86% of individuals with a gene mutation will develop a tumor by age 50.²⁴ Gene mutations in SDHC are rare, with few families identified to date.

Of further interest is the development of a paraganglioma syndrome in head and neck patients due to the inheritance of mutations in the SDHB gene. Although the PGLs associated with mutations in SDHB are less common than their D subunit counterpart, mutations in this gene confer a higher risk for the development of extra-adrenal, catecholamine-secreting, and often malignant pheochromocytomas, making identification of these individuals crucial in management of the at-risk family members to ensure that proper screening for pheochromocytoma and other paragangliomas takes place. Several cases of renal cell carcinoma in carriers of these mutations have also been reported, and one case of papillary thyroid cancer has been documented in the literature.²⁴ The role of genetic counseling and testing in this population of patients cannot be overemphasized. Due to the apparent high rate of mutations in patients with a history consistent with sporadic paragangliomas, consideration of genetic counseling and testing should be given to every patient with a carotid body tumor or other paragangliomas.

Clinical Presentation and Diagnosis

The characteristic feature of carotid body tumors is slow growth rate, which is reflected clinically by the delay between the first symptoms and the diagnosis, which averages between 4 and 7 years. A carotid body tumor usually presents as a lateral cervical mass, which is mobile laterally but less mobile in the cranio-caudal direction because of its adherence to the carotid arteries. This physical finding has been called a positive Fontaine sign.²⁵ Alternatively, a carotid body tumor may present as a parapharyngeal mass. Many carotid body tumors are pulsatile by transmission from the carotid vessels or, less commonly, expand themselves, reflecting their extreme intrinsic vascularity. Sometimes a bruit may be heard by auscultation, but it can disappear with carotid compression. The consistency varies from soft and elastic to firm and these tumors are generally nontender. As they enlarge, progressive symptoms of dysphagia, odynophagia, hoarseness, and other cranial nerve (IX-XII) deficits appear. Carotid sinus syndrome syncope has been described in association with carotid body tumors.²⁶ The syndrome refers to a loss of consciousness accompanied with a reflex bradycardia and hypertension. Inciting stimuli include spontaneous movement of the head or following digital pressure applied to the tumor. Rarely, paraganglioma of the head and neck may present as a functional neuropeptide secreting tumor.

The capacity for catecholamine synthesis in head and neck paragangliomas, however, does not translate immediately to clinical findings. Although all paragangliomas have neurosecretory granules, only 1% to 3% are considered functional.²⁷ Glenner and coworkers first described a functional carotid body tumor secreting norepinephrine in 1962.⁹ Patients should be asked about signs and symptoms indicating elevated catecholamines. Complaints of headaches, palpitations, flushing, and perspiration should be evaluated. In these patients a 24-hour urine collection is examined for norepinephrine and its metabolites including vanillylmandelic acid (VMA) and normetanephrine. Alternatively, plasma metanephrine may be assessed. Excess epinephrine or metanephrine should prompt suspicion of an adrenal pheochromocytoma because head and neck paraganglioma lack the enzyme to convert norepinephrine to epinephrine (phenylethanolamine-N-methyltransferase). An abdominal CT scan should be performed to rule out a concomitant adrenal pheochromocytoma. α- and β-Adrenergic blocking is undertaken if a tumor is found to be functional preoperatively. This decreases the risk from sudden catecholamine release that may occur with tumor manipulation in surgery. Routine screening for urinary metanephrines and VMA and serum catecholamines is only indicated for multiple or familial paragangliomas or in the presence of catecholamine-related symptoms.²⁸

Multicentricity

The carotid body tumor is the most common paraganglioma in the head and neck, and the most frequent combination of multiple tumors is bilateral carotid body tumors. The overall incidence of multiple tumors is reported in the literature to be approximately 10%; some of these may be unrecognized familial genetic mutations. If a familial pattern is recognized, the incidence of multiple tumors is reported to be between 30% and 50%.

Malignancy

Cellular criteria for malignancy have not been established. Harrington and Dockerty²⁹ attempted to classify malignant tumors of the carotid body. Criteria for malignancy included mitoses with giant cells, nuclear pleomorphism, and capsular invasion. Using these criteria, 50% of the 20 tumors studied would be considered malignant. Batsakis³⁰ concurred that increased mitotic rate and capsular invasion should not be considered as determinants of malignancy. Other authors have hypothesized that all carotid body tumors demonstrate some degree of capsular invasion.³¹ Malignancy is determined by metastasis, which must be proven with biopsy, because paragangliomas may exhibit multicentricity. There are no histologic criteria for malignancy. In fact, previous reports have described metastatic carotid body tumors without mitoses.³² The diagnosis of malignancy should be made by evidence of spread to regional lymph nodes or distant sites^33,34 (most common being lung and bones).

Malignant paragangliomas have been reported in 6% of carotid body paragangliomas by Batsakis.³⁰ Accurate 5-year survival rates are not available because of the low malignancy rate of an uncommon tumor. Data from the National Cancer Data Base³⁵ suggest an overall 5-year survival rate of 60%. Distant metastases had a worse prognosis with a 5-year survival rate of 11.8%, while those with regional spread of disease fared much better with a 5-year survival rate of 78%.

Imaging Studies

Various diagnostic imaging modalities are available in the workup of carotid body tumors. Noninvasive duplex ultrasonography demonstrates a hypervascular mass and the tumor’s relationship to the carotid artery. Ultrasonography may also delineate any intrinsic carotid artery disease.

Computed tomography (CT) scanning with intravenous contrast demonstrates a hypervascular mass with avid contrast enhancement, similar to normal vessels, at the carotid bifurcation, splaying the internal and external carotid arteries. CT angiography may be performed to demonstrate the relationship of the carotid vessels to the enhancing neck mass.

MRI with gadolinium may be the most useful imaging study for evaluating carotid body tumors (see Fig. 118-1A and B) because it offers superior soft tissue contrast without the need for ionizing radiation compared with CT scanning. MRI is sensitive for tumors as small as 0.8 cm.³⁶ Paragangliomas larger than 2 cm in diameter typically demonstrate on T2-weighted images internal flow voids, dark lines, and dots that correspond to vascular structures. This is, however, not always present with carotid paragangliomas. Carotid body tumors demonstrate a characteristic lyre sign characterized as a bowing and displacing of the internal and external carotid arteries as shown in Figure 118-1B and C. Radiographic evaluation should be sufficient to make the diagnosis of carotid body tumor.

Carotid angiography has been replaced by MRI (including MR angiography, see Fig. 118-1C), but catheter angiography remains useful when preoperative embolization is necessary (see Fig. 118-1D). The use of preoperative embolization is controversial, but many authors have recommended its use for large tumors to decrease blood loss.³⁷ Preoperative embolization may also be used in those rare instances where a malignant carotid body may be suspected. If preoperative embolization is planned, surgery should be performed 24 to 48 hours following in order to avoid revascularization, edema, or local inflammation. Additionally, angiography with temporary balloon occlusion using clinical and electroencephalographic monitoring, combined with brain CT perfusion scanning, can provide specificity as to the tolerance of collateral cerebral circulation across the circle of Willis in select cases.

The high density of somatostatin receptors in paragangliomas provides for newer functional nuclear medicine imaging techniques including metaiodobenzylguanidine (MIBG) scanning and octreotide scanning. MIBG scanning uses I-131 labeled tracer, which is concentrated in intracellular storage vesicles of paragangliomas.³⁸ Octreotide scanning uses Indium-111 labeled somatostatin analog octreotide to diagnose primary tumors of the APUD system, as well as their metastases.³⁹ These functional imaging studies have been recommended as a possible screening test for familial paragangliomas for patients at risk.⁴⁰ They also allow the detection of additional tumors when malignant paraganglioma is suspected.⁴¹

Radiation Therapy

Carotid body tumors were originally thought not to be radiosensitive because the effects of radiation therapy were cytostatic but not cytotoxic. Radiation therapy for paragangliomas will arrest growth but not shrink tumor size. Furthermore, potential tumor regrowth following radiation therapy remains a possibility. Risks associated with radiation therapy for paragangliomas include carotid atherosclerosis, the risk of radiation-induced malignancy, and associated morbidity including mucositis.

Radiation oncologists at the University of Florida have described effective local control of 23 carotid and vagal paragangliomas using definitive radiotherapy.⁴⁵ In their study, 15 patients with 23 carotid or vagal paragangliomas were treated with radiotherapy between 1981 and 1995. Nineteen tumors were treated with radiation therapy alone, and four were treated with surgery and postoperative radiation therapy. For benign tumors, total doses ranged from 35 to 48.5 Gy. The two malignant tumors received 64.8 and 70 Gy, respectively. Follow-up ranged from 1.5 to 10 years. Local control was achieved in 96% of tumors at 5 years. Five-year disease-specific survival was 89%, with one patient dead of locally recurrent disease 5 years after radiation therapy. This patient had been previously treated with surgery and radiation therapy before treatment by the authors. Another patient died of atherosclerotic disease 13.5 years after radiation therapy. There were no patients with regional or distant failure following treatment. Complications reported by these authors included one patient experiencing a delayed transient CNS syndrome. No other complications were reported.

Valdagni and Amichetti reported 7 patients with 13 carotid body tumors treated with radiation therapy between 1968 and 1987.⁴⁶ Treatment consisted of radiotherapy alone for 10 tumors and surgery plus radiation therapy for 3 tumors. Total doses ranged from 46 to 60 Gy at 1.8 to 2.5 Gy per fraction. Follow-up ranged from 1 to 19 years. Local control was achieved in all patients. Acute side effects were minimal. No short or long-term toxicities were reported.

Even proponents of radiation therapy for carotid body tumors concur with surgical resection as the preferred modality of treatment for most lesions.⁴⁷ Definitive radiation therapy may be reserved for patients who are poor surgical candidates due to a debilitated medical condition and for locally advanced tumors where anticipated postoperative morbidity may preclude consideration for surgical resection. Adjuvant radiation therapy may be considered following surgery for malignant carotid body tumors for locoregional control.

Observation

Using sequential radiologic imaging, Jansen and colleagues⁴⁸ have estimated the median tumor doubling time for 20 carotid body tumors to be 7.1 years including 12 cases without detectable growth. Farr has estimated a growth rate for carotid body tumors, plotting tumor size against years of symptom duration, of 2 cm in 5 years.⁴⁹ A scan-and-wait policy may be considered for those patients who are not suitable candidates for surgery or radiation therapy. This highly select group of patients includes those individuals whose medical condition is so poor that both surgery and radiation therapy are contraindicated, or those patients of such advanced age that the carotid body tumor may have minimal impact on their life expectancy or quality of life. This group may also include those patients with malignant carotid body tumors with distant metastases where locoregional treatment would be only palliative in intent.

Clinical Presentation and Diagnosis

Vagal paragangliomas, like carotid body tumors, may present as a palpable neck mass that is more mobile in a lateral direction than a craniocaudal orientation. Paralysis of the ipsilateral true vocal cord or Horner’s syndrome, from involvement of the ipsilateral sympathetic chain, may be present as the tumor grows in size. True vocal cord paralysis may result in hoarseness with or without aspiration of liquids from glottic incompetence. Large tumors arising from the jugular ganglion may be associated with cranial neuropathies of IX, XI, and XII. Diagnostic imaging studies described previously in the chapter may demonstrate anterior displacement of the carotid artery from the tumor present in the posterior carotid sheath. Unlike carotid body tumors, the internal and external carotid arteries do not manifest a splayed configuration in vagal paragangliomas (Fig. 118-2).

Figure 118-2. Jugular paraganglioma. A, Axial computed tomography (CT) image with bone algorithm and window shows subtle bony erosions and widening of the left jugular foramen (arrows). B, Axial postcontrast CT image with soft tissue algorithm and window at a slightly lower level shows a densely enhancing mass just below the skull base on the left. C, Axial T2-weighted MR image in a different patient shows a hyperintense mass in the right jugular foramen (arrows) with internal flow voids. D, Coronal postcontrast T1-weighted magnetic resonance image shows enhancement of the mass with still noticeable internal vessels (“pepper”).

Management

The treatment strategies employed for carotid paragangliomas described in the previous section apply to the management of vagal paragangliomas as well. Most are treated by surgical resection, and the discussion pertinent to preoperative embolization described earlier is germane to vagal paragangliomas as well. Patients should be counseled preoperatively as to the fact that complete resection of the vagal paraganglioma typically necessitates sacrifice of the vagus nerve. The resultant ipsilateral true vocal cord paralysis may be addressed in the postoperative period as needed on the basis of the patient’s deficits. Vagal paragangliomas arising from the nodose ganglion are usually approached by a transcervical approach, whereas more superiorly located tumors of the jugular ganglion may require a combined transmastoid-transcervical approach, with possible craniotomy should there be intracranial extension. The necessity of carotid artery resection and repair is less common in vagal paragangliomas than their carotid artery counterparts. Indications for definitive radiation therapy or observation alone, which have been previously described for carotid paragangliomas, are applicable to vagal paragangliomas as well.