Anatomy

The carotid body is a light-brown structure within the adventitial layer of the dorsal aspect of the CCA bifurcation. The vascular supply is from the carotid bifurcation, and the primary innervation is the carotid sensory branch of the glossopharyngeal nerve. This branch is also known as the carotid sinus nerve or the nerve of Hering.⁹ The carotid body is connected to the CCA bifurcation by a fibrovascular band called the ligament of Mayer. Embryologically, the carotid body may have constituents of both the third branchial arch mesoderm and neural elements of the neural crest ectoderm.¹⁰

Carotid bodies are part of a group of neuroepithelium-derived aggregates known as paraganglia. Tumors of these cells have also been known as paragangliomas, glomus tumors, and chemodectomas. Tumors of similar histology arise in several locations, including the ciliary body of the orbit, aortic-pulmonary paraganglia, carotid body (glomus caroticum), middle ear (glomus tympanicum), ganglion nodosum of the vagus nerve (glomus vagale), jugular body (glomus jugulare), and adrenal medulla (pheochromocytoma). Although most glomus tumors appear to be composed of nonchromaffin cells that are physiologically silent, some contain secretory granules that may secrete catecholamines similar to pheochromocytomas.¹⁰

Histology

Carotid body tumors consist of epithelioid cells grouped into cords or clusters, also known as Zellballen. Typically, the cells are polyhedral with granular cytoplasm (Fig. 353-1). The stroma is composed of a fine mesh of reticulin fibers.¹¹ Intertwined is a rich network of capillaries, giving the general appearance of a glomerulus. Several reports have detailed the chromaffin-positive nature of the secretory granules, indicating that the carotid body and tumors of it may be capable of secreting catecholamines such as norepinephrine and dopamine.^12,15

FIGURE 353-1 Photomicrograph of carotid body tumor showing the characteristic clusters of cells known as Zellballen, composed of octahedral cells in a glomerulus-like shape.

The angiogenic nature of carotid body tumors is a central issue in the pathophysiology of these lesions, and ultimately it dictates many aspects of their management. Vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) are expressed in carotid body tumors and may contribute to the extreme vascularity of these tumors.¹⁶

The influence of estrogens is another environmental factor that may accelerate the development of carotid body tumors. In high-altitude populations, carotid body tumors show a marked female preponderance, as high as 12 : 1,¹⁷ and even at sea level, the predominance of carotid body tumors in women is still apparent, at a ratio of 2 : 1.¹⁸ This suggests an interaction between hypoxic and estrogenic factors in the development of carotid body tumors. This interaction might occur at the level of VEGF or PD-ECGF synthesis, both of which are regulated by hypoxia as well as estrogen level.^19–22

Genetics

A genetic cause of carotid body tumors is highly suggested from examples of familial occurrence. In the sporadic form, the rate of bilateral tumor occurrence is 5%. An autosomal dominant expression of bilateral tumors, however, occurs in 32% of patients with a familial occurrence.^23,24 Comorbid cervical paragangliomas (glomus vagale, glomus jugulare) are relatively common in patients with carotid body tumors. Gardner and coworkers²⁵ reviewed 11 patients with carotid body tumors, 3 of whom had other head and neck paragangliomas.

Seminal genetic studies have indicated an increased expression of the oncogenes c-myc, bcl-2, and c-jun in most carotid body tumor specimens studied.²⁶ Wang and colleagues²⁷ suggested that the expression of the oncoprotein bcl-2 may deregulate apoptosis, thus suppressing programmed cell death, a critical step in the tumorigenesis of carotid body tumors.

Clinical Presentation

The most common manifestation of carotid body tumors is a palpable neck mass in the high cervical region. Less common initial presentations include cranial nerve deficits such as laryngeal dysfunction (hoarseness), difficulty swallowing, and unilateral tongue atrophy or weakness. These symptoms reflect the tumor’s proximity to the vagus and hypoglossal nerves. There have also been reports of patients who became symptomatic with Horner’s syndrome²⁸ or carotid sinus syndrome.²⁹

There is no reported sex predominance in carotid body tumors. Typically, diagnosis is between 30 and 60 years of age. The youngest reported patient was 7 years old.^30,32

Radiographic and Medical Evaluation

Cervical MRI with and without gadolinium can help differentiate carotid body tumors from other lesions that arise in the same region: carcinomas, enlarged lymph nodes, branchial cleft cysts, and leiomyomas.^29,33 MRI demonstrates a brightly enhancing, well-circumscribed mass at the cervical carotid bifurcation (Fig. 353-2). Magnetic resonance angiography can be useful by displaying the hypervascular nature of the tumor and the characteristic splaying of the ECA and ICA (Fig. 353-3).

FIGURE 353-2 A, Coronal magnetic resonance imaging with gadolinium enhancement of carotid body tumors can help surgical planning by demonstrating the cervical level of the carotid bifurcation as well as the superior and inferior extent of the tumor. B, Axial magnetic resonance imaging with gadolinium enhancement can help determine the Shamblin grade of the carotid body tumor (arrow) preoperatively.

FIGURE 353-3 Preoperative magnetic resonance angiogram of the cervical vessels showing characteristic splaying of the external and internal carotid arteries near the carotid bifurcation in larger tumors. Splaying is shown on both sides in a patient with bilateral carotid body tumors.

Angiography can help confirm the diagnosis. These tumors are extraordinarily vascular (Fig. 353-4). The ascending pharyngeal artery often provides most of the vascular supply, and the superior thyroid artery almost always provides a minority contribution. The blood supply of the tumor can also be derived from the ICA, vertebral artery, and thyrocervical trunk. If angiography is planned, a concomitant session to embolize the tumor can be coordinated. Studies have shown that preoperative embolization significantly reduces blood loss during resection of a carotid body tumor.^34,35

FIGURE 353-4 Digital subtraction angiography demonstrates a characteristic tumor blush at the carotid bifurcation. The carotid body tumor is typically fed by the ascending pharyngeal artery, with a smaller contribution from the superior thyroid artery.

An evaluation of the endocrine system may be warranted, particularly in patients who have elevated blood pressure or tachycardia. Clinicians must be aware of the potential comorbidity of a pheochromocytoma and that some carotid body tumors secrete catecholamines. In such patients, α-adrenergic blockade must be induced pharmacologically 2 weeks before surgery. Once this blockade is established, β-adrenergic blockade is recommended to control heart rate and cardiac arrhythmias.²⁹ Careful preoperative assessment of blood pressure may indicate the need for urine metanephrine analysis.

Characteristics of Tumor Growth

In an effort to assess the preoperative risks of tumor resection, Shamblin and associates³⁶ revised a classification scheme for carotid body tumors. Group I tumors are restricted to the space between the ICA and ECA. Generally, these tumors dissect easily from the surrounding structures. Neither the carotid vessels nor adjacent nerves travel through the tumor. Group II tumors partially involve the ECA and ICA but do not encase the arteries completely. Tumor involving the adventitia of the artery can still be dissected free. Finally, group III tumors totally encase the ICA and invade the adventitia into the muscularis. Dissecting group III tumors from the artery requires reconstruction or sacrifice of the ICA. In this challenging group, the superior laryngeal and hypoglossal nerves may traverse the tumor.

Metastasis

Most carotid body tumors are benign. They are problematic only in their local invasion of vascular and nervous structures and, occasionally, the oropharynx. Staats and coworkers³¹ reviewed 500 patients and found a 6.4% incidence of malignancy with local or distant metastases. Distant metastases have been reported in lymph nodes, bone, lung, liver, pancreas, thyroid, kidney, brain, and breast.^37–39

Surgical Treatment

Preoperative planning is critical to reduce morbidity in patients with carotid body tumors. As mentioned, a thorough medical evaluation is necessary, particularly to rule out endocrine abnormalities. Preoperative embolization helps reduce blood loss during resection, but diagnostic cerebral angiography is equally important for assessing collateral blood flow. In such cases, surgeons may anticipate intraoperative shunting to maintain adequate cerebral blood flow. We routinely use compressed spectral array electroencephalography (CSA-EEG) to monitor the patient’s cerebral function during resection. Therefore, intraoperative shunting is not routinely performed, even for large tumors; the need for shunting is based on changes in the CSA-EEG.

The initial incision primarily reflects the size and extent of the tumor. For example, a small group I tumor may be accessed through a transverse incision along a cervical skin crease, giving the best cosmetic result. Larger tumors with group II or III extension require a larger exposure to control the proximal and distal carotid artery for possible shunting. Here, an oblique incision along the medial border of the sternocleidomastoid muscle is indicated. As in a standard exposure for carotid endarterectomy, the common facial vein is ligated and cut to mobilize the jugular vein laterally. The hypoglossal and vagus nerves are identified. Frequently, the hypoglossal nerve may be displaced superiorly and posteriorly by the tumor⁸; consequently, care must be exerted during dissection of the superior aspect of the tumor to avoid damaging this nerve (Fig. 353-5). In the more challenging group III tumors, nerves may actually traverse the tumor, making dissection difficult and tedious. In rare cases, the vagus nerve can be involved with the tumor. Tumor invasion into the carotid arterial wall requires temporary occlusion with, or without shunting, to dissect the tumor and, if necessary, top patch the arterial wall defect with a graft.⁸

FIGURE 353-5 Intraoperative view of initial dissection and exposure of carotid body tumor, which splays the external and internal carotid arteries.

For large tumors that extend higher in the neck, or for patients who have a short or stocky neck, exposure of the more distal extracranial ICA is necessary. In these larger tumors, the possibility of prolonged carotid occlusion is more likely. Therefore, it is prudent to perform a temporary balloon test occlusion of the artery in these patients, or be prepared to use a carotid shunt intraoperatively.

In the high cervical exposure, the oblique incision is continued in a curvilinear fashion anterior to the tragus up to the root of the zygoma. Mobilization of the parotid gland is often necessary in these large carotid body tumors, so the temporoparotid fascia is incised along the posterior aspect of the parotid gland, and the parotid is retracted anteriorly and superiorly. Great care must be exercised in dissecting and preserving the lower division of the facial nerve, which is generally the superior-most limit of the exposure.

Then, more inferiorly, the stylohyoid and digastric muscles, as well as the stylomandibular ligament, must be divided to expose the more distal ICA and distal tumor. Resecting the styloid process here gives additional exposure of the distal ICA. The hypoglossal nerve can be traced back to where it traverses the ECA and ICA. To mobilize the hypoglossal nerve in the more superior dissection, the descendens branch should be cut. This avoids stretch injury to the main nerve trunk. Then the main nerve can be retracted anterior and superior to the primary tumor dissection. Following the tumor resection, sequential closure of the deep muscle and fascia layers gives the best postoperative functional result.

Patetsios and colleagues⁴⁰ reported that in their 30 years of experience with carotid body paragangliomas (29 patients with 34 tumors), complications included two arterial thromboses (7%), five permanent cranial nerve deficits (17%), and one death (3%). There were no strokes. Vascular reconstruction was necessary in eight cases (28%).

Preoperatively, the patient’s blood pressure should be monitored closely, particularly immediately after surgery. Labile blood pressure, presumed to be secondary to baroceptor failure from loss of carotid sinus function, has been reported after resection of a carotid body tumor.^41,42 Netterville and coworkers⁴² reviewed 30 patients with 46 carotid body tumors and found baroreceptor failure in 10 patients. Interestingly, first bite pain occurred in 10 of 25 patients assessed postoperatively.

The role of radiotherapy in managing carotid body tumors remains unclear. Radiotherapy is not used as the sole primary treatment of carotid body tumors, but it is the preferred therapy in recurrent or residual tumor with intracranial extension.^8,35,43 A retrospective study by Krych and coworkers⁴⁴ reported that in 33 patients with paragangliomas who were treated with external-beam radiotherapy or stereotactic radiosurgery, the 10-year tumor control rate was 92%. Radiosurgery may be useful for a metastasis or intracranial extension, however, no significant series of this relatively rare pathology has been reported to date. It has been shown that radiation therapy does not eradicate the tumor cells and probably exerts its major effects by inducing a vasculitis within tumor vessels.⁴⁵

Etiology

The exact cause of FMD is becoming better defined as we begin to understand the multifactorial pathology, with a spectrum of phenotypic expressions. Its prevalence in women is much higher than in men, with an approximate 9 : 1 ratio. Stanley and colleagues⁵⁹ suggested that progestin and estrogen play a role in the development of the disease because 94% of the patients they reviewed were women. Laboratory studies have demonstrated that sex hormones may contribute to the formation of FMD directly by local alterations of the vessel wall (endothelial proliferation, intimal thickening, and focal nodular thickening of the intima, media, and adventitia) or indirectly through an immune response.^60,63 However, in a case-control study of 33 patients, endogenous or exogenous sex hormones did not appear to play a role in the etiology of FMD, whereas cigarette smoking and genetics did appear to be linked to the development of FMD.⁶⁴ Mettinger’s familial analysis of patients with FMD suggests that is an inheritable dominant trait with limited penetrance in men.^65,66

Mechanical and anatomic features have also been evaluated in the development of FMD. Stanley and colleagues⁵⁹ implied that mechanical stresses on the vessel walls play a role in the development of FMD. Likewise, the disease appears to involve primarily arteries with a paucity of vasa vasorum, indicating that arterial wall ischemia may contribute to disease progression. Long-term follow-up of some cases has indicated definite progression of the disease in some patients with carotid FMD.⁵²

Clinical Presentation

Patients with cervical carotid FMD typically present in their 50s to 60s. On physical examination, about two thirds of symptomatic patients have a cervical bruit that is audible on ausculation.⁵⁶ Symptoms of cerebral ischemia have been reported in 18% to 56% of patients.⁶⁷ In such cases, the sequential arrangement of fibromuscular rings reduces blood flow while increasing turbulence within the vessel. In addition to ischemic symptoms, FMD has been associated with spontaneous carotid artery dissection,^68,69 aneurysm formation,^70,71 carotid-cavernous fistula,^72,73 and thromboembolism.⁵⁶ In Mettinger’s review of 284 patients with aortocranial FMD, a surprising 21% had associated intracranial aneurysms.⁶⁶

Angiographic Findings

In 1977, Osborn and Anderson⁵⁸ described the angiographic appearance of carotid FMD variants in a summary report. The classic angiographic appearance, present in the more than 80% of patients, is the “string of beads”—multiple, irregularly spaced arterial constrictions with normal or ectatic intervening segments. Angiographically, it is similar to stationary arterial waves or circular spastic contractions, although these show more regularly spaced constrictions with no associated dilated segments. The second variant is that of smooth, concentric tubular stenosis. Angiographically, this variant can be distinguished from Takayasu’s arteritis, which affects the proximal segments of the aortic branches. In contrast, FMD typically spares the origins. The third variant, termed atypical FMD by Houser and Baker,⁴⁸ usually involves one wall of the affected segment, creating a smooth or corrugated outpouching of the vessel.

Treatment

The treatment of the FMD should be tailored to the patient’s symptoms. Incidentally diagnosed FMD should be followed radiographically by noninvasive studies such as magnetic resonance angiography or carotid duplex ultrasonography. No convincing evidence suggests that the disease progresses as a rule, although notable exceptions have been reported. Therefore, asymptomatic patients should not be treated unless their disease progresses. In patients with an embolic presentation, antiplatelet medication such as aspirin, ticlopidine, or clopidogrel is recommended. Intervention is warranted in patients whose symptoms persist despite antiplatelet therapy.

A report by DeBakey’s group in 1968 described the surgical luminal dilation of the ICA in 12 patients and of the vertebral artery in 1 patient.⁷⁴ This report is interesting from a historical perspective, but it also documents intraluminal pressure at the proximal and distal ends of the affected segments in 2 patients. Before dilation, they found pressure before 25 and 50 mm Hg; after surgical treatment, there were no discernible gradients. These findings demonstrated that multiple tandem rings, as seen in FMD, significantly reduce arterial pressure and blood flow, although individual stenotic rings do not narrow the carotid artery significantly.

Contemporary treatment has used the endovascular techniques of balloon angioplasty and stenting for medically refractory cervical FMD lesions (Fig. 353-6). In the early 1980s, several reports documented the successful treatment of FMD by percutaneous balloon angioplasty.^75,79 By the mid-1980s, the limitations of this technology were revealed in reports of complications of percutaneous transluminal angioplasty of FMD, including dissection⁸⁰ and aneurysm formation.⁸¹ The transfemoral access route has significantly reduced the morbidity of endovascular procedures. Subsequently, endoluminal stenting, performed in coordination with angioplasty for cervical FMD, has become increasingly more prominent as the primary treatment method in medically refractory cases.

FIGURE 353-6 A, Lateral left internal carotid artery angiogram showing fibromuscular dysplasia in a 56-year-old woman who presented with left hemisphere transient ischemic attacks refractory to treatment with aspirin. B, Lateral angiogram after angioplasty and the deployment of a carotid stent.

(Courtesy of Barrow Neurological Institute, Phoenix, AZ.)

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