Carotid Body Tumors

Descriptions of surgery for carotid body tumors have existed for over 100 years. The early reports described significant complications, particularly mortalities secondary to intraoperative bleeding.[5, 6, 7]

In the United States, the earliest successful carotid body tumor resection was performed by Scudder in 1903.[5]

Even into the middle of the 20th century, resecting these tumors remained a problem because of the complications; Hayes Martin, in his textbook of head and neck tumors, recommended against resection of any tumor that is now considered a Shamblin type III (see Staging).[8]

Modern imaging and current surgical and vascular techniques have significantly improved the safety and success of this operation.

Frequency

Parasympathetic paragangliomas are rare, with a prevalence of 1-2 per 100,000 population.[9] Carotid body tumors (CBTs) constitute about 50-60% of head and neck paragangliomas.

Carotid body tumors (CBTs) can occur in children; however, carotid body tumors (CBTs) are considered to be a disease of middle age. The mean age of onset is reported to be 45 years.[10] Paragangliomas are inherited in 10-50% of cases. Age of onset in the hereditary group is typically younger, in the second to fourth decade.[11]

A retrospective study by Davila et al suggested that carotid body tumors also tend to appear at a younger age in patients with succinate dehydrogenase mutations (see Pathophysiology). In the study, of 183 patients with carotid body tumors, 18 patients underwent succinate dehydrogenase testing, with 17 found to be positive for mutations. The positive patients were diagnosed with tumors at a mean age of 38.0 years, compared with 50.3 years for patients without known mutations.[12]

About 5% of carotid body tumors (CBTs) are bilateral and 5-10% are malignant, but these rates are much higher in patients with inherited disease.[13, 14, 15] Familial tumors are found to be 5.8 times more common among patients who have carotid body tumors as compared with patients who have paragangliomas at other sites.

Interestingly, the male-to-female ratio differs in patients dwelling at high altitudes above 2,000 meters (1:8.3) than those patients dwelling at sea level (1:1.0-1.4).[16]

The only known risk factors are the presence of chronic hypoxic stimulation and the genetic predisposition.

Carotid body tumors (CBTs) are classified into sporadic, familial, and hyperplastic forms. The familial paraganglioma form is a genetically heterogenous entity; currently, 4 genes are identified. The first 3 genes encode the subunits of the enzyme succinate dehydrogenase complex, which is part of the Kreb's cycle. Paraganglioma (PG) syndrome 1, 3, and 4 occur because of mutations of the corresponding genes of the subunits D, C, and B.[17] PG syndrome 2 gene mutations are yet to be identified.

Defective succinate dehydrogenase has been postulated to cause an increase in the intracellular concentration of molecular hypoxia mediators and the vascular endothelial growth factor (VEGF) thus resulting in hyperplasia, angiogenesis, and neoplasia.[9]

In patients who lack a positive family history, germline mutations in the paraganglioma susceptibility genes are still possible via multiple causes, including genomic imprinting, reduced penetrance, or de novo mutations in the genes of the parental gametes.[17]  (Genetic testing is recommended in patients under age 40 years with a carotid body tumor (CBT) and in individuals with bilateral or multiple CBTs.[18] )

Chronic hypoxic conditions, such as patients living at high altitudes or those who have chronic obstructive pulmonary disease (COPD) or cyanotic heart problems, can overburden the carotid bodies and subsequently lead to hypertrophy, hyperplasia, and neoplasia of the chief cells.[17] This condition is seen in the hyperplastic type of carotid body tumors (CBTs). However, the mechanism by which reduced oxygen concentrations can lead to CB hyperplasia is unclear.

Carotid body tumors (CBTs) can be occasionally coupled with nonparaganglonic tumors in syndromes, including MEN type II, von Hippel-Lindau syndrome, and neurofibromatosis type 1.

A study by de Franciscis et al suggested that carotid body tumors have a neuroendocrine effect on arterial blood pressure. The study, on 17 patients with benign or malignant carotid body tumors, found that at admission, individuals with malignant carotid body tumors had higher blood pressure than did controls and that those with malignant tumors had higher blood pressure than did those with benign neoplasms. Moreover, the investigators determined that 10 days following resection of the tumors, all 17 patients showed significant reductions in blood pressure and in the level of matrix metalloproteinases.[19]

Carotid body tumors (CBTs) present most commonly as an asymptomatic palpable neck mass in the anterior triangle of the neck. They are slow-growing tumors that can remain asymptomatic for many years. The doubling time (TD) of carotid body tumors (CBTs), as estimated by Jansen et al using sequential imaging, was 7.13 years with a median growth rate of 0.83 mm/year.[20]

On examination, the mass is typically vertically fixed because of its attachment to the bifurcation of the common carotid (Fontaine sign). A bruit can be felt; however, the absence of a bruit does not rule out a carotid body tumor (CBT). Vagal body tumors are more cranially located and sometimes project into the lateral pharynx as a pulsatile mass.

Approximately 10% of the cases present with cranial nerve palsy with paralysis of the hypoglossal, glossopharyngeal, recurrent laryngeal, or spinal accessory nerve, or involvement of the sympathetic chain.[21] Carotid body tumors (CBTs) may, therefore, be associated with pain, hoarseness, dysphagia, Horner syndrome, or shoulder drop.

As the tumor enlarges and compresses the carotid artery and the surrounding nerves, other symptoms may also be present, such as pain, tongue paresis, hoarseness, Horner syndrome, and dysphagia.

Fever is an uncommon sign of carotid body tumor (CBT), although the literature has reported it as one of the causes of fever of unknown origin.[22] In cases of functional carotid body tumors (CBTs), symptoms similar to those of pheochromocytoma, such as paroxysmal hypertension, palpitations, and diaphoresis, are seen.

The carotid body is a small, reddish-brown, oval structure, located in the posteromedial aspect of the carotid artery bifurcation. The healthy gland measures 3-5 mm in diameter and weighs less than 15 mg on average.[23] The vast majority of the literature states that the gland is located in the adventitia near the carotid artery bifurcation. However, according to Maxwell et al, most surgeons experienced with carotid body dissection maintain that it is more peripherally located, within periadventitial tissue. This distinction is critical, as dissections in the deeper planes of the carotid artery are associated with higher risk for complications from vessel injury.[24]

The gland is highly vascular and receives its blood supply from feeder vessels running through the Mayer ligaments, primarily from the external carotid artery, typically the ascending pharyngeal artery. It is innervated by the Hering nerve, originating from the glossopharyngeal nerve about 1.5 cm distal to the jugular foramen.[25]

Check urinary catecholamines in patients who have any symptoms of a functional carotid body tumor. Routine assessment in all patients is common practice in many centers.

Various imaging studies can be used to confirm the diagnosis of carotid body tumor (CBT), starting with simple ultrasonography with color Doppler, which can assess the vascularity of the neck mass and can sometimes reveal a possibility of a carotid body tumor, although it is not the best imaging modality to detect these tumors.[2]

Computed tomography (CT) scanning of the head and neck is also helpful and typically reveals a hypervascular tumor located between the external and internal carotid arteries.

Magnetic resonance imaging (MRI) is considered to be the criterion standard for carotid body tumors, and the tumor has a characteristic salt and pepper appearance on T1-weighted image.

Magnetic resonance angiography (MRA) provides better insight into the vascularity of the tumor and its feeder vessels.[2] However, accurate diagnosis is usually based on angiographic criteria, which show the typical lyre sign. Angiography is also helpful for better visualization of the feeder vessels and is of utmost importance for high-risk tumors (Shamblin II or III) that need either embolization or a preoperative balloon occlusion test.

In patients who are suspected to have multiple small tumors, such as those with familial carotid body tumors (CBTs), performing a physical examination and supplementing it with imaging studies (including a CT, MRI, or metaiodobenzylguanidine [MIBG] scintigraphy) is essential. MIBG scans are quicker to perform than MRI and are also used in patients who are claustrophobic. The only issue with this scan is that it can only be used in patients who have functional tumors. In cases in which the tumor is nonfunctional, a better test is a pentetreotide scan, which uses a radiolabeled somatostatin analogue.

A study by Straughan et al indicated that preoperative imaging results showing a distance from the tip of the C2 dens to the superior aspect of the carotid body tumor of under 3 cm suggests an increased likelihood of perioperative cranial nerve injury. The study included 19 patients (20 carotid body tumor resections).[26]

Because of its classic radiographic and clinical picture of hypervascularity and location between the arteries, incisional biopsy of carotid body tumors (CBTs) is not indicated and should not be performed except in very unusual cases.[2] Inadvertent biopsy may lead to profuse bleeding and/or cranial nerve injuries.[27]

Fine-needle aspiration biopsy is helpful only if the diagnosis is unclear via imaging studies.

Carotid body tumors (CBTs) are highly vascular tumors composed of the following 2 cell types that are arranged in a pseudoalveolar pattern characteristic of paragangliomas known as "cell balls" (zellballen):[16]

• Type I cells, which are the chief cells that predominate in carotid body tumors (CBTs) and contain catecholamine-bound granules

• Type II cells, which are the sustentacular cells located at the periphery, are devoid of granules

Paragangliomas are classified into noninvasive, locally invasive, and metastatic types. Unfortunately, malignancy cannot be detected by routine histological findings and is only defined when the tumor metastasizes to regional lymph nodes or more distant sites.

Nuclear polymorphism, neurovascular invasion, high mitotic indices, and necrosis may be present in both benign and malignant carotid body tumors (CBTs).[16]

Shamblin describes 3 different types or stages of carotid body tumors. Type I consists of a small tumor that is easily dissected from the adjacent vessels in a periadventitial plane. Type II tumors are larger and more adherent and partially surround the vessel. Type III tumors are large and completely surround the carotid bifurcation.[28] As described, types II and III tumors are more likely to require carotid resection.

Radiotherapy as a primary modality of treatment for carotid body tumors (CBTs) has been heavily debated, because some investigators have found that these tumors are not radiosensitive and have reported regrowth after suppression. The tumors that are treated primarily with radiation are also difficult to resect afterwards because of radiation-induced fibrosis. Other investigators have reported no cure rates for patients who received radiation for their carotid body tumors (CBTs). The primary goal of radiotherapy is to slow or halt progression.

For these reasons, surgery is usually the treatment modality of choice for younger, healthier patients with carotid body tumors (CBTs), and radiotherapy is reserved for the elderly, patients who are poor surgical candidates, and selected individuals with multiple paragangliomas in whom resection may be highly morbid.

Patients with metastatic disease may be candidates for external beam radiation, chemotherapy, iodine-131 (131I)-MIBG therapy, or clinical trails. Consultations with the appropriate services, such as endocrinology, radiation oncology, and medical oncology, is necessary for these patients.[29]

Carotid body tumors (CBTs) are treated with either surgery or radiotherapy. When choosing treatment, consider the following factors: presence of other paragangliomas, bilateral carotid body tumors, the age and the health of the patient, and the patient's preference.[4]

In a study by Dorobisz et al of 49 carotid body paragangliomas (47 patients) managed with surgery, including 43 simple resections, treatment of 40 tumors (82%) was uneventful, with patients experiencing an uncomplicated postoperative period.[30]

Nonetheless, surgical treatment of carotid body tumors can be associated with significant morbidities, especially with large Shamblin III tumors (greater than 5 cm).[31] For this reason, patients who have poor medical conditions, elderly patients, or patients with recurrent tumors are usually treated with radiation therapy.

Preoperative evaluation is extremely important to avoid major surgical complications. The use of MRI and genetic testing in susceptible families have allowed earlier detection of multicentric tumors in many patients. Operative risk is directly related to the size and extent of the tumor.

Preoperative embolization is still controversial, although it has been used to decrease the risk of intraoperative bleeding, particularly in larger tumors.[32]  A study by Cobb et al indicated that presurgical tumor embolization provides no benefit in patients undergoing carotid body tumor (CBT) resection, finding no significant differences in mortality, cranial nerve injury, and blood loss between patients who underwent embolization and those who did not. Moreover, as evaluated following risk adjustment, embolization was associated with a greater length of stay.[33]

In contrast, a literature review by Texakalidis et al reported that in patients who underwent embolization prior to resection, intraoperative blood loss was significantly lower and operative time shorter than in those who did not. Moreover, the investigators found the length of stay to be similar between the two groups.[34]

Carotid body tumors are rarely associated with pheochromocytomalike symptoms, but checking urinary catecholamines, vanillylmandelic acid (VMA), and metanephrines is helpful and is routine in many centers.

Preoperative imaging is necessary to evaluate the extent of the disease and its multiplicity. If catacholamine levels are elevated, an evaluation for adrenal pheochromocytomas should be performed. If detected these tumors should be removed prior to the carotid surgery.

Carotid balloon test occlusion is performed in patients who are at a high risk of carotid resection due to the tumor’s involvement. In such cases, consultation with a vascular surgeon and a neurologist for intraoperative EEG monitoring may be necessary.

In addition to the above testing, discussion with the patient about the postoperative complications is extremely important; this includes the risks of cranial nerve injuries (IX, X, XI, XII), bleeding, infection, the possibility of a carotid bypass or vein grafts, stroke, and death.[35]

Embolization of carotid body tumors has been a controversial topic. It has been recommended by some surgeons when the size of the tumor exceeds 4 cm in size. Blood loss appears to be less with prior embolization of larger tumors. Bilateral arteriography can also be performed to delineate the vascularity of the tumor and to detect any tumors on the contralateral side.

A study by Zhang et al indicated that preoperative tumor embolization, carried out less than 48 hours before surgery, can significantly reduce blood loss, surgical time, and length of hospital stay in patients undergoing carotid body tumor resection. The investigators warned that embolization should be carried out only in vessels that can be subselectively catheterized and that do not permit contrast medium to freely reflux into the internal carotid artery. The study involved 32 patients, including 21 patients who underwent embolization and 11 who did not.[36]

In contrast, a literature review by Abu-Ghanem et al indicated that in carotid body tumor resection, preoperative embolization is no more effective than nonembolization in terms of estimated blood loss, length of surgery or of hospital stay, or risk of stroke, cranial nerve injury, or vascular injury.[37]

A study by Cobb et al also indicated that preoperative arterial embolization does not contribute to the safety of carotid body tumor resection. The investigators found that rates of mortality, cranial nerve injury, and blood loss did not significantly differ between patients in the study who underwent carotid body tumor resection alone and those who first underwent preoperative embolization.[38]

Effective communication between the surgeon and the anesthesiologist is of utmost importance throughout the surgery. Whether the patient is totally relaxed is the surgeon's preference. Some surgeons prefer paralysis to aid in muscle retraction and to facilitate the use of electrocautery. Others prefer the patient not be paralyzed, which, they feel, aids in the identification of the cranial nerves.

Different types of neck incisions have been described. The incision chosen is usually based on tumor size and extent. A horizontal incision in the mid neck affords excellent exposure both superiorly and inferiorly and typically provides excellent cosmesis. Some surgeons prefer an endarterectomy approach using a transverse cervical incision along the anterior border of the sternocleidomastoid. For larger tumors, many incisions have been described, including preauricular extension of the incision for tumors extending to the infratemporal fossa.

The most important step in tumor removal is superior and inferior control of the blood vessels. This includes identification of the internal jugular vein, common, and internal carotid arteries and placing vessel loops on each. (In a report on 11 patients with Shamblin II or III carotid body tumors, Spinelli et al described a surgical technique in which resection of the tumors from the internal carotid artery was performed bloodlessly by clamping the external carotid artery [at its origin and distal branches] but not the internal carotid artery.[39] )

In cases in which the tumor is not involving the hypoglossal and vagus nerve, these nerves should be exposed and followed cranially. Identification of the accessory and glossopharyngeal nerve is also performed; in certain cases, the digastric muscle must be sacrificed for better exposure.

The small feeder vessels, together with some branches from the external carotid artery, are ligated. Dissection between the external and internal carotid artery exposes the larger feeding vessels, including the ascending pharyngeal artery, which is the main feeding vessel most of the time. This is followed by a craniocaudal dissection of the tumor from the carotid vessels. In tumors that are identified intraoperatively as Shamblin type III, the plane of dissection can be found on either the dorsolateral side of the internal carotid or the ventrolateral side of the external carotid.

Dissection of the carotid body tumor is performed in the subadventitial plane using either loupes or microscope, as described by Gordon-Taylor. This is supplemented with the use of bipolar cautery, which limits blood loss and controls bleeding.

Any injury to the carotid vessel requiring clamping of the common or internal arteries needs temporary heparinization with a low risk of complications; this is often followed by vascular reconstruction. van der Mey reported that 65% of patients who had their internal carotid artery ligated had a stroke and that 25% of patients who passed their balloon occlusion test had a delayed stroke.[40]

During removal of the carotid body tumor, care should be taken once again to avoid injuring the nerves, especially the superior laryngeal nerve, which has been reported to be the most injured nerve during dissection. This nerve is frequently involved with tumor posteriorly. Ideally, it can be identified and dissected as it exits the vagus nerve and courses medially towards the larynx.

In the immediate postoperative period, the patient should be carefully observed for any complication of the procedure, including postoperative hemorrhage or late stroke. In patients who underwent vascular reconstruction, ICU admission is recommended, along with heparinization.

Patients should be closely observed for any local recurrence, although these are usually rare. If the patient has no morbidity from the initial surgery, contralateral tumors should also be resected. In patients with significant permanent morbidities to cranial nerves, radiation to the contralateral side might be considered. As always, a careful weighing of pros and cons must be done and presented to the patient. Operating on small tumors has a very low rate of complications and the long-term effects of radiation on younger patients is potentially a contraindication.

Careful subadventitial dissection of the tumor and control of the proximal and distal carotids minimizes vascular complications. Of note is that the size of the tumor and involvement of the carotid artery predict the vascular complication risks. The highest risk is observed in tumors larger than 5 cm and/or grade 3 by Shamblin classification. These patients with large tumors also have more frequent postoperative cranial nerve injuries.[28]

A study by Kim et al indicated that in carotid body tumor resection, for every 1 cm reduction in tumor distance to the skull base, the risk of a greater than 250 mL blood loss increases 1.8 times, and the risk of cranial nerve injury increases 1.5 times.[41]

The most commonly injured nerve is the superior laryngeal nerve. This nerve supplies the cricothyroid muscle and provides sensation to the supraglottic larynx. The patient postoperatively might suffer from some degree of aspiration and voice changes (inability to create high-pitched sounds).

Injury to the vagus nerve results in vocal cord paralysis with resultant hoarseness and increased aspiration risk. When combined with a superior nerve paralysis, as is the case with a high vagal injury, aspiration is a significant problem because the larynx not only does not function well but is also anesthetic. This may be compensated by the contralateral vocal cord over time. If the problem persisted, then vocal cord medialization procedures should be performed.

Speech and swallowing problems result from a hypoglossal nerve injury. If the nerve is accidentally cut, primary reanastomosis should be attempted first. If primary anastomosis fails, then other options include a greater auricular nerve graft.

Postoperative shoulder pain and weakness is typically a result of an accessory nerve injury. This results in significant disability for the patient.

First bite syndrome is another complication that occurs when the sympathetic supply to the ipsilateral parotid gland is severed. The resultant parotid gland has an unabated parasympathetic supply. To date, no successful treatment of this syndrome exists.

In cases of bilateral tumor excision with loss of the bilateral Hering nerves, patients experience labile blood pressure postoperatively, which is difficult to control medically. Concurrent excision of bilateral carotid body tumors should, therefore, be avoided, although staging the surgeries might help because of the compensation provided by the aortic receptors.