TITLE: Paragangliomas
SOURCE: UTMB Dept. of Otolaryngology Grand Rounds
DATE: December 2, 1998
Resident Physician: Deborah P. Wilson, M.D.
Faculty Physician: Christopher Rassekh, M.D.
Series Editor: Francis B. Quinn, M.D.

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"This material was prepared by physicians in partial fulfillment of educational requirements established for Continuing Postgraduate Medical Education activities and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a interactive computer mediated conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of subscribers or other professionals and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion."


INTRODUCTION

Paragangliomas are generally benign, slow growing tumors arising from widely distributed paraganglionic tissue thought to originate from the neural crest. Paraganglia are distributed throughout the head and neck and superior mediastinum along the course of the major vasculature. Paraganglia are also found in the orbit, the larynx, and along the course of the vagus nerve.

Various terminology has been used in the past to describe these tumors based on their histopathologic and anatomical presentations. Glenner and Grimley’s classification scheme helped distinguish the adrenal paragangliomas from the extra-adrenal paragangliomas. The tumors are thus divided into adrenal paragangliomas or pheochromocytomas and extra-adrenal paragangliomas. The branchiomeric paragangliomas and intravagal paragangliomas are found in the head and neck and mediastinum1. Terms used in the past have included: glomus tumors, chemodectomas, carotid body tumors, and nonchromaffin tumors. Currently, the correct terminology is paraganglioma based on the anatomical location (e.g. carotid paraganglioma and jugulotympanic paraganglioma). Because the terms glomus tympanicum and glomus jugulare have persisted, they will be used to differentiate the jugulotympanic paragangliomas in this text.

HISTORY

The carotid body was first described by anatomist von Haller in 17432. Histiologic studies of the carotid body revealed glandular acini so the carotid body was renamed the carotid gland. In the early part of the 20th century, other structures were found throughout the body which were histologically similar to this carotid gland. The gland was renamed a vascular glomerulus or glomus. The term glomus today refers to any collection of specialized tissue. The term paraganglion was first used by histologist Kohn in the early part of this century to describe the carotid body3. This term was most appropriate as cells of the carotid body originate from the neural crest and migrate in close association with autonomic ganglion cells. Guild first described vascularized tisue in the dome of the jugular bulb and on the promontory of the middle ear and named it "glomic tissue" in 19414. In 1945, Rosenwasser reported a "carotid body tumor" of the middle ear and mastoid and the correlation between these tumors was made5.

ANATOMY AND FUNCTION OF PARAGANGLIA

Carotid bodies are located in the adventitia of the posteromedial aspect of the bifurcation of the common carotid artery. They are small pink ovoid structures that have been shown to have a chemoreceptor role by modulating respiratory and cardiovascular function in response to fluctuations in arterial pH, oxygen and carbon dioxide tension, and other chemical alterations. Their blood supply is primarily from the external carotid artery and sensory innervation is from the glossopharyngeal nerve.

Guild described the paraganglia of the temporal bone as ovoid, lobulated bodies measuring between 1-1.5mm in diameter6. On the average, there are three such bodies in each ear. These paraganglioma are usually found accompanying Jacobson’s nerve (from CNIX) or Arnold’s nerve(from CNX), or in the adventitia of the jugular bulb. Tumors of these paraganglioma are usually seen involving the mucosa of the promontory (glomus tympanicum) or the jugular bulb (glomus jugulare). The blood supply to jugulotympanic paragangliomas is the ascending pharyngeal artery via inferior tympanic and neuromeningeal branches. Numerous other arteries can contribute especially if the tumor is large or has intracranial extension.

Vagal paraganglia are small cell groups that rest within the perineurium of the vagus nerve. Their precise nerve supply has not been determined.

PATHOLOGY

All paragangliomas are closely related to one another and to pheochromocytomas of the adrenal gland. Their histiologic appearance is similar to the normal histology of the paraganglia. They consist of clusters of Type I or chief cells which are members of the amine precursor and uptake decarboxylase (APUD) family and Type II or sustentacular cells (modified Schwann cells). These two cell types are arranged into clusters with a core of chief cells surrounded by the sustentacular cells embedded in a fibrous stroma. The clusters of cells make up the histologic structure termed Zellballen. Nuclear pleomorphism and cellular hyperchromatism are common in paragangliomas and should not be considered evidence of malignancy. Malignancy can not be determined histologically but is reserved for the presence of local, regional or distant metastasis.

PARAGANGLIOMAS OF THE HEAD AND NECK

Paragangliomas are most commonly found in the head and neck. The most common cervical paraganglioma is the carotid paraganglioma (aka carotid body tumor). Paragangliomas can also involve the vagus nerve, the larynx, the orbit, and the nose and paranasal sinuses. Paragangliomas of the temporal bone include the jugulotympanic paragangliomas including the glomus tympanicum and glomus jugulare. For purposes of this discussion, we will separately discuss carotid paragangliomas, temporal bone paragangliomas and vagal paragangliomas.

CAROTID PARAGANGLIOMAS

Carotid paragangliomas are the most common paraganglioma of the head and neck comprising approximately 60% of the total. These tumors are rare and the incidence is not really known, although one study found only 60 paragangliomas in over 600,000 surgical specimens at one hospital (0.12 percent)7. They are thought to be more common in patients who live at high altitudes.

Carotid paragangliomas can occur at any age but the mean patient age is 45-50 years. Sex ratios vary but most authors report a higher incidence in females. They usually present as a slow growing painless neck mass located at the anterior border of the sternocleidomastoid muscle just lateral to the tip of the hyoid bone. They may bulge into the pharynx or extend upward into the neck (parapharyngeal area). Patients usually have noted the mass for several years, on average of 2-8 years. The patient may present with hoarseness, vocal cord paralysis, or dysphagia.

Multicentric paragangliomas occur in approximately 10% overall. About 20 % of paragangliomas are familial. If there is a family history of paragangliomas, the tendency for multicentricity is much higher - about 40-50%. The inheritance pattern for familial paragangliomas is autosomal dominant modified by genomic imprinting (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. Because of the autosomal dominant pattern of inheritance, it has been recommended that at risk individuals older than 16 -18 years of age be examined and screened with MRI every two years8. Others have described the use of octreotide scanning to search for multicentric tumors or to screen family members. Their value is still under investigation9.

On examination, the neck mass is mobile from side to side but not in a vertical direction. This is due to the tumor’s adherence to the carotid artery. The mass is frequently pulsatile and a bruit can be auscultated over the mass. The oral cavity should be carefully inspected as large paragangliomas can fill the parapharyngeal space and displace the oropharyngeal wall medially.

The patient should be questioned regarding any family history of paragangliomas. Remember that approximately 50% of familial paragangliomas are multicentric. Although the large majority of carotid paragangliomas are non-functional or non-secreting, any symptoms of catecholamine secretion of the tumor should be sought. These symptoms include palpitations, flushing, or labile or hard to control blood pressure. Measurement of 24 hour urinary vanillyl mandelic acid (VMA) and circulating catecholamines should be done. Some authors feel urinary screening is unnecessary in patients who give no evidence of a functioning tumor. However, if a secreting tumor is suspected and testing for abnormal catecholamine secretion is positive, an abdominal CT scan should be performed to rule out a concomitant adrenal pheochromocytoma. A patient with a symptomatic secreting tumor should be referred for anti-hypertensive therapy with appropriate alpha and beta blocking agents.

If the patient has a familial paraganglioma, he or she should be evaluated for one of the multiple endocrine neoplasm syndromes.

If a carotid paraganglioma is suspected, a fine needle aspiration should not be performed. Although the bleeding can be controlled with pressure, the diagnosis of paraganglioma is difficult to make on fine needle aspiration and the cytopathologist usually reports it out as non-diagnostic (mainly because of all the blood in the specimen). We had an interesting experience at our institution with a patient with a nasopharyngeal ulcer and a neck mass that seemed firm and mobile in both the horizontal and vertical plane. A fine needle aspiration was performed of the neck mass without complication and was reported as metastatic nasopharyngeal carcinoma. A subsequent CT scan revealed a mass that was characteristic for a carotid paraganglioma. The nasopharynx was biopsied and negative.

The initial radiographic study in evaluation for a carotid paraganglioma can either be a CT scan or an MRI. The diagnosis of a carotid paraganglioma is made by finding a mass arising from the carotid bifurcation which displaces the external and internal carotid arteries. The diagnosis is confirmed with arteriography by finding a characteristic tumor blush at the carotid bifurcation called the lyre sign. Carotid arteriography is also used to evaluate the adequacy of the carotid system. Both carotids should be studied to rule out multicentricity. Balloon test occlusion is performed to determine the patient’s ability to tolerate temporary carotid occlusion during surgery. Balloon occlusion coupled with xenon cerebral blood flow scanning can help predict how the patient would tolerate permanent carotid occlusion.

Most authors do not recommend preoperative embolization of tumors. Studies have shown that embolization does not appear to decrease the amount of blood lost at surgery. Additionally, some authors feel the embolization sets up a significant inflammatory response which makes the surgery even more risky.

There are currently three therapeutic options for patients with carotid paragangliomas. These include surgery, radiation therapy and observation.

Surgery is the mainstay of treatment for carotid paragangliomas. If the tumor is completely removed, the recurrence rate is about 10%. Preoperative considerations should include age, the medical condition of the patient, the size of the tumor and the multicentricity of the tumor. Tumor size is a very important indicator of operative morbidity. Shamblin and associates developed a classification scheme based on tumor size and difficulty of dissection. Group I tumors are small and easy to remove from adjacent vessels, group II tumors are medium sized but have an intimate attachment to the carotid artery that require dissection in a subadventitial plane, and group III tumors are large and have transmural invasion of the carotid artery that requires resection of the carotid with grafting10. McCaffrey found that carotid paragangliomas that measure greater than 5 cm carry an operative complication rate of 67% compared with those less than 5 cm which carry a risk of 14%7.

If the patient elects for surgical therapy, he or she should be properly informed of all risks. These historically have included an overall operative mortality of approximately 2-8%, a stroke rate of up to 20% and and a cranial nerve damage (mainly CN X and XII) rate of 40-50%. Netterville published a retrospective review of thirty patients with carotid paragangliomas. Sixteen patients had bilateral carotid paragangliomas for a total of 46 carotid paragangliomas. Twenty five patients elected to have surgical resection of their tumors. In his series 5 of the 25 patients had a permanent nerve palsy following resection (20%), Three of these nerve palsies were of the superior laryngeal nerve. Netterville also noted a significant number of patients suffering from baroreceptor failure (if bilateral - resulting in labile B/P and tachycardia postoperatively)) and "first-bite" syndrome (spasm of parotid myoepithelial cells from sympathetic dennervation to parotid) after the surgery. These conditions should be discussed with the patient preoperatively11. The patient should also be informed of the risk of significant blood loss requiring transfusion. The patient should be typed and crossmatched for six units of blood. Autologous blood donation should be considered. A vascular surgeon should be available in the event that carotid grafting is required.

Surgical resection is performed under general anesthesia. A skin incision is made 2cm below the mastoid tip curving anteriorly to the submental region. The marginal mandibular branch of CN VII is identified and preserved. The submandibular gland may be removed in the case of a large tumor. The hypoglossal nerve must be identified and preserved. The nerve is not usually encased if the tumor is small, but can be very difficult and tedious to trace with large tumors. All lymphoid tissue that overlies the tumor is removed. At this point proximal and distal control of the carotid artery is gained by placing vascular loops. The vagus nerve should be identified and dissected free. It is easiest to approach the tumor inferiorly and posteriorly in a subadventitial plane. The branches of the external carotid must be ligated as they are almost always completely encased with tumor. The tumor is rolled until it is just attached to the external carotid which requires ligation. Following tumor removal, hemostasis is achieved. The wound is irrigated, a suction drain is placed, and the skin closed.

Historically, carotid paragangliomas have been considered radioresistant. There have been a few studies that have shown good local control rates but others that have shown persistent disease in those paragangliomas treated with primary XRT 12,13. Radiation therapy is reserved for incompletely excised tumors (with intracranial extension), recurrent tumors, tumors that are very large, and for elderly patients or patients who are poor surgical candidates.

The mortality rate of untreated carotid paragangliomas is estimated to be 8% per year. For this reason, and because of the very slow growth rate of these tumors, some authors recommend observation alone. This is typically reserved for elderly patients or those that do not tolerate balloon test occlusion.

The malignancy rate of carotid paragangliomas is estimated to be between 2-10%. Malignancy is more common in familial paragangliomas. Again, there is no histologic criteria for malignancy. The diagnosis is made by evidence of spread to regional lymph nodes or distant sites (most common being lung and bones)

JUGULOTYMPANIC PARAGANGLIOMAS

Jugulotympanic paragangliomas are the second most common temporal bone tumor (after acoustic neuromas). The incidence of jugulotympanic paragangliomas is approximately 1:1,300,000. Unlike carotid paragangliomas, there is a definite female predominance in the incidence of jugulotympanic paragangliomas with a female to male ratio of 4:1. The median age of presentation is 50-60 years but the range is from 6 months to 88 years. There appears to be no ethnic or racial predilection. Like the carotid paraganglioma, the jugulotympanic paraganglioma has a sporadic and familial form. The familial form is associated with a higher incidence of multicentricity (approximately 25-50%). The incidence of a functional or secreting jugulotympanic paraganglioma is lower than the carotid paraganglioma, occuring in about 1-3%. The malignancy rate is less than 5%. Just like it’s carotid counterpart, there is no histologic distinction between benign and malignant lesions.

These tumors are very slow growing. They spread locally in a multidirectional fashion along pathways of least resistance within the temporal bone. The air cell tracts are the most important route of spread. Tumors have been noted to spread outside the temporal bone via the eustachian tube, vascular lumens, and neurovascular foramina including the internal auditory canal. Bone erosion is noted by distinct crescentic lucencies in the bone. The hypotympanum and carotid crest separating the internal carotid from the internal jugular vein at the skull base are two areas particularly susceptible.

The typical clinical course consists of slow continuous growth with few symptoms until the tumor has become far advanced. The patient usually presents with a complaint of pulsatile tinnitis. Other complaints may include aural fullness or hearing loss (usually conductive unless there has been labyrinthine erosion). Cranial nerve deficits may be seen with larger tumors. Deficits of cranial nerves IX and X are most commonly seen but CNs VII, VIII, XI, and XIII can also be affected. Otoscopic examination can be normal or a characteristic red or reddish-blue mass may be seen behind the tympanic membrane. Brown’s sign is described as blanching of the middle ear mass with positive pneumotoscopic pressure. The tumor may have grown through the tympanic membrane producing a vascular ear "polyp" which may bleed spontaneously.

The patient should be questioned regarding family history of paragangliomas or endocrine syndromes. Additionally, symptoms of a secreting tumor should be sought including difficult to control hypertension, tachycardia, tremors or vascular headaches. If there is any suspicion of a secreting tumor, a 24 hour urine collection should be obtained for VMA, metanephrine, nor-epinephrine and epinephrine. If these tests are found to be abnormal and because jugulotympanic paragangliomas are rarely secreting tumors (1-3%), an abdominal CT scan should be obtained to rule out a concomitant adrenal pheochromocytoma.

Evaluation should begin with air and bone conduction audiometry. Imaging studies should include both a fine cut CT scan of the temporal bone (with axial and coronal images) and an MRI. On CT scan, jugulotympanic paragangliomas characteristically show bone erosion around the jugular bulb and carotid artery. CT scanning also helps delineate the tumor relationship to the facial nerve, the cochlea and to the internal carotid artery. MRI scanning is helpful in evaluating intracranial and intradural extension, presence or absence of flow in the ipsilateral or contralateral sigmoid sinus, and to further define the relationship of the tumor to the internal carotid.

Four-vessel arteriography is helpful if surgical treatment is planned. Arteriography aids in the detection of multicentric tumors, identifies feeding vessels, allows for embolization of the external carotid artery blood supply to the jugulotympanic paraganglioma, identifies intrasinus and intravenous extension, and provides further information on the adequacy of flow in the contralateral sigmoid and/or internal jugular vein. Additionally, it allows for balloon occlusion testing if prior imaging suggests extensive involvement which may require carotid repair or resection.

There is no need for tissue biopsy as the diagnosis is easily made by the imaging findings.

Two classification systems have been described based on tumor size, petrous apex or carotid artery involvement and intracranial extension. Fisch’s classification system has four categories ranging from Type A tumors isolated to the middle ear cleft to Type D tumors with intracranial extension14. Glasscock and Jackson’s system divides the jugulotympanic paragangliomas into glomus tympanicum and glomus jugulare tumors. Each group is then further divided into four groups (I-IV) based on their size and further extension throughout the temporal bone15.

Decisions regarding management of these tumors can only be made after the extent of the tumor is defined. Unlike carotid paragangliomas, jugulotympanic paragangliomas are considered radiosensitive16. It should be understood that the goal of surgical treatment is the total or near-total removal of tumor while the goal of radiation therapy is the arrest of tumor growth. There is a considerable amount of controversy over the treatment of choice for jugulotympanic paragangliomas. Surgical risks include cranial nerve deficits, vascular injury and bleeding and cerebrospinal fluid leak (4%). Radiation risks include tumor regrowth, late-onset cranial nerve defects, and osteoradionecrosis of the temporal bone (studies have shown that the risk of ORN is low if the optimal dose of XRT of 35Gy/3weeks or 45Gy/4weeks is used) 17,18.

Most authors agree that the management of jugulotympanic paragangliomas should be individualized. For the most part, it is recommended that healthy, younger patients (<65 years - sorry Dr. Quinn) should consider surgical resection. Additionally, patients who have larger tumors that already have evidence of cranial nerve compromise are good candidates for surgery as they tend to compensate better than those without pre-existing cranial nerve deficits. Patients who are older than 65 years of age and have poor pulmonary function or other complicating medical conditions should consider primary radiation therapy.

For patients with multicentric tumors, careful consideration regarding therapy should be made as bilateral lower cranial nerve deficits can be devastating. Treatment should be directed towards the most life-threatening lesion first followed by observation/palliation of other lesions until the aftermath is clear.

Symptomatic patients with a secreting tumor require surgery to prevent the effects of the excess catecholamine secretion.

Preoperative planning includes educating the patient regarding all risks and alternatives. Risks should include the potential cranial nerve deficits and their consequences, need for further procedures to manage these conditions, and risk of significant blood loss. Consultations with a vascular surgeon and neurosurgeon should be made. The patient should be typed and crossmatched for blood. Autologous blood donation should be offered.

Preoperative embolization is controversial. Many authors recommend embolization of large glomus jugulare tumors 24-48 hours prior to surgical resection to decrease intraoperative blood loss while others feel the risks of embolization outweigh the benefits.

Surgical techniques differ depending on the size and extent of tumor growth.

Glomus Tympanicum

For glomus tympanicum tumors limited to the mesotympanum and hypotympanum (Fisch Type A) without involvement of the jugular bulb, a transcanal tympanotomy may be all that is required. For larger tumors that extend into the mastoid (Fisch Type B), a canal wall up mastoidectomy with extended facial recess approach is used. Larger tumors that extend beyond the middle ear or involve the jugular bulb are approached like glomus jugulare tumors.

Glomus Jugulare

Glomus jugulare tumors that are classified by Glasscock and Jackson as Class I and II or by Fisch as C1 or C2 can usually be resected with an extended facial recess approach. The posterior canal wall can be taken down if necessary for exposure. Dissection of the upper neck allows for identification and preservation of CNs X, XI, and XII as well as the great vessels.

For tumors that extend into or beyond the petrous apex, involve the horizontal carotid artery, or involve the foramen lacerum or cavernous sinus, (Glasscock and Jackson Class III and IV or Fisch C3 and C4 tumors) an infratemporal fossa approach is preferred. This approach allows the exposure necessary for distal control of the distal internal carotid artery. Again, dissection into the upper neck permits identification of the lower cranial nerves and control of the great vessels.

Tumors with intracranial extension (Fisch D1-3) may be resected with the infratemporal fossa approach. Retrosigmoid and/or suboccipital approaches may be necessary for tumors with extension into the posterior cranial fossa.

Patients are usually kept in the ICU overnight after infratemporal fossa surgery. If dysphagia is anticipated, a nasogastric tube should be placed. The remainder of the post-operative care is directed towards the cranial nerve deficits.

Post-operative radiation therapy should be considered in patients with residual tumor. These patients can also be observed with serial MRIs with XRT reserved for evidence of tumor growth.

Patients do require long-term follow-up after resection of jugulotympanic paragangliomas. Glomus tympanicum tumors typically require only routine otoscopic examination. For glonus jugulare tumors, a baseline MRI soon after resection then at regular intervals (e.g. 1, 5, 10 yrs) should be performed. The management of post-surgical recurrences or radiation failures is complicated and should be individualized based on the status of the cranial nerves and the location of the tumor.

INTRAVAGAL PARAGANGLIOMAS

Intravagal paragangliomas arise most commonly at the level of the nodose ganglion but may occur at any point along the course of the vagus nerve in the neck. The mean age at presentation is about 50 years of age. Intravagal paragangliomas are more common in females than males.

Intravagal paragangliomas usually present as a painless neck mass located behind the angle of the manible. The mass has typically been present for many years. Vagal paragangliomas can bulge into the pharynx and cause dysphagia. The patient may also complain of weakness of the tongue, hoarseness and/or Horner’s syndrome from tumor compression of cranial nerves IX, X or XII.

Imaging studies should include a CT scan and MRI to help delineate the relationship of the tumor to the bony and soft tissue structures. Angiography classically demonstrates a tumor blush and, instead of widening of the carotid bifurcation seen with a carotid paraganglioma, the vagal paraganglioma displaces the internal carotid artery anteriorly and medially.

Only one functional vagal paraganglioma has been reported. Intravagal paragangliomas are even more rare than other paragangliomas of the head and neck. Although they historically were thought to be rarely familial, Netterville recently performed a review of 46 patients treated over 20 years and found a family history of paragangliomas in 20%19.

Netterville’s group also found a multicentricity rate of 78% in patients with familial paragangliomas versus 23% in patients with sporadic paragangliomas19.

The malignancy rate for vagal paragangliomas is higher than for other paragangliomas in the head and neck. It is estimated in the literature to be around 18%.

Management of these lesions is complicated by their rarity and because they are frequently multicentric and bilateral. There is no agreement on the optimal treatment for intravagal paragangliomas. Proponents of surgery state that surgical resection is the treatment of choice because it offers a chance for complete tumor removal. Others propose non-surgical treatment saying that surgery is complicated by a very high rate of cranial nerve deficits. Radiation therapy has not been shown to be curative. It also has the risk of inducing osteoradionecrosis of the temporal bone.

In general, younger patients who tend to compensate better from cranial nerve deficits are offered surgical resection. Conservative management consisting of observation or palliative XRT is offered to elderly patients who have much more difficulty with swallowing rehabilitation after sacrifice of multiple cranial nerves. Other patients who would benefit from conservative management are those with bilateral vagal tumors or those with a pre-existing palsy of the contralateral CN X or XII.

Surgical resection is via a transcervical approach often combined with a lateral skull base approach depending on the extent of the tumor.

Post-operative care should be directed towards aggressive rehabilitation for cranial nerve defects. Netterville’s group sometimes performs primary medialization thyroplasty at the time of cranial nerve X sacrifice. Some patients had secondary medialization thyroplasty combined with arytenoid adduction. Facial nerve deficits were treated with eye precautions and gold weight implants and/or canthoplasty19.

OTHER PARAGANGLIOMAS OF THE HEAD AND NECK

Paragangliomas of the larynx, orbit and nose and paranasal sinuses tend to be locally aggressive. Laryngeal paragangliomas typically require wide local resection or partial laryngectomy. Orbital paragangliomas are particularly aggressive and rapid recurrence is common after local resection. Nasal paragangliomas usually require wide local excision. Radiation therapy has not been shown to be effective against paragangliomas of the larynx, orbit or nose16.


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