Glomus Jugulare Tumors

Most jugulotympanic paraganglia are located in the adventitia of the jugular bulb within the jugular foramen.[2]

The main blood supply is via the ascending pharyngeal artery from the external carotid artery (ECA) and branches from the petrous portion of the internal carotid artery (ICA). Larger glomus jugulare tumors may also have blood supply from other branches of the ECA, ICA, vertebral artery, and thyrocervical trunk.

The walls of the jugular foramen are formed anterolaterally by the petrous bone and posteromedially by the occipital bone. The canal follows an anterior, inferior, and lateral direction to exit the skull.

The posterolateral portion of the foramen (pars venosa) contains the jugular bulb, posterior meningeal artery, and cranial nerves X and XI. The anteromedial portion (pars nervosa) contains the inferior petrosal sinus and cranial nerve IX. The jugular bulb is situated between the sigmoid sinus and the internal jugular vein. The lower cranial nerves are situated medial to the medial wall of the jugular bulb. The inferior petrosal sinus enters the medial aspect of the jugular bulb via several channels anterior to cranial nerves IX, X, and XI.

Many important structures are in proximity to the jugular bulb, including the internal auditory canal, the posterior semicircular canal, the middle ear, the medial external auditory canal, the facial nerve (posterolaterally), and the ICA (anteriorly) within the carotid canal. At the extracranial end of the jugular foramen, the ICA, internal jugular vein, and cranial nerves VII, X, XI, and XII are within a 2-cm area.

The glomera jugulare, or glomus bodies, are small collections of paraganglionic tissue. They are derived from embryonic neuroepithelium in close association with the autonomic nervous system and are found in the region of the jugular bulb.[23]  Glomus tumors are encapsulated, slowly growing, highly vascular, and locally invasive tumors. Sen et al described the histologic structure of glomus tumors as a dense matrix of connective tissue among nerve fascicles.[24] These tumors tend to expand within the temporal bone via the pathways of least resistance, such as air cells, vascular lumens, skull base foramina, and the eustachian tube. They also invade and erode bone in a lobular fashion, but they often spare the ossicular chain.

Initially, the skull base erodes in the region of the jugular fossa and posteroinferior petrous bone, with subsequent extension to the mastoid and adjacent occipital bone (see the image below). Significant intracranial and extracranial extension may occur, as well as extension within the sigmoid and inferior petrosal sinuses. Neural infiltration is also common.

Lateral carotid arteriogram obtained 22 years after radiation therapy in a 20-year-old woman who presented in June 1970 with episodic hypertension, headaches, and palpitations.

The parenchyma of the paraganglia consists of 2 primary cell types. Type I cells are more common and are typically round with indistinct cell borders. Type II cells are smaller and irregularly shaped.

Metastases from glomus tumors occur in approximately 4% of cases.[12, 13] A reduction in the proportion of type II cells and a poorer staining of type I cells for s-100 and glial fibrillary acidic protein are reported to be correlated with an increased tumor grade. A metastatic lesion is distinguished from a multicentric lesion based on location. Metastases have been found in the lung, lymph nodes, liver, vertebrae, ribs, and spleen. Malignancy of the tumor probably is related to p53 and p16INK4A mutations.

Additional studies using immunohistochemical techniques revealed that malignant glomus tumors are characterized by the presence of MIB-1, p53, Bcl-2, and CD34.[25] Up to 4% of the tumors are functional and produce clinically significant levels of catecholamines, norepinephrine, or dopamine with symptoms mimicking a pheochromocytoma. Pheochromocytoma, parathyroid adenoma, and thyroid carcinoma have been reported in association with glomus jugulare tumors.[5]

The Glasscock-Jackson and Fisch classifications of glomus tumors are widely used. The Fisch classification of glomus tumors is based on extension of the tumor to surrounding anatomic structures and is closely related to mortality and morbidity.[26]

• Type A tumor - Tumor limited to the middle ear cleft (glomus tympanicum)

• Type B tumor - Tumor limited to the tympanomastoid area with no infralabyrinthine compartment involvement

• Type C tumor - Tumor involving the infralabyrinthine compartment of the temporal bone and extending into the petrous apex

• Type C1 tumor - Tumor with limited involvement of the vertical portion of the carotid canal

• Type C2 tumor - Tumor invading the vertical portion of the carotid canal

• Type C3 tumor - Tumor invasion of the horizontal portion of the carotid canal

• Type D1 tumor - Tumor with an intracranial extension less than 2 cm in diameter

• Type D2 tumor - Tumor with an intracranial extension greater than 2 cm in diameter

Glomus jugulare tumors originate from the chief cells of the paraganglia, or glomus bodies, located within the wall (adventitia) of the jugular bulb, and can be associated with either the auricular branch of the vagus nerve (Arnold nerve) or the tympanic branch of the glossopharyngeal nerve (Jacobson nerve). Paraganglia are small (< 1.5 mm) masses of tissue composed of clusters of epithelioid (chief) cells within a network of capillary and precapillary caliber vessels. The number seems to increase until the fourth decade of life and then seems to decline. Paraganglia develop from the neural crest and are believed to function as chemoreceptors. Based on the presence of catecholamines and neuropeptides, paraganglia are included in the amine precursor uptake and decarboxylase (APUD) system, which has been referred to as the diffuse neuroendocrine system (DNES).[5]

Although most paragangliomas are sporadic, they can be familial with autosomal dominant inheritance and incomplete penetrance. The development of tumors in familial cases is dependent on age and on the sex of the affected parent. The nonchromaffin paragangliomas have a familial tendency. Tumors rarely occur in people younger than 18 years, and as a result of suspected genomic imprinting, only children of males possessing the disease gene develop tumors. The gene responsible for hereditary paragangliomas has been localized to band 11q23.

Glomus tumors occur with an estimated annual incidence of 1 case per 1.3 million people.[27] Although rare, glomus tumors are the most common tumor of the middle ear and are second to vestibular schwannoma as the most common tumor of the temporal bone.

The female-to-male ratio is 3-6:1. Glomus jugulare tumors have also been noted to be more common on the left side, especially in females.

Most tumors occur in patients aged 40-70 years, but cases have been reported in patients as young as 6 months and as old as 88 years. Multicentric tumors are found in 3-10% of sporadic cases and in 25-50% of familial cases.[5]

Glomus jugulare tumors may grow slowly and produce cranial nerve palsies that, to a certain point, are benign and mostly cosmetic. However, despite this optimistic assessment, one study showed a long-term reduced quality of life in patients with glomus tumors.[8]

Prognosis has improved quite dramatically over the last decade, with a stroke rate of 0-3.5%, a cranial nerve injury rate of 5-39%, and overall mortality of 0-2.7%. With stereotactic radiosurgery treatment, 60% of the patients showed improvement of previous neurologic deficits, and tumor control was obtained in 91% of the patients.[28, 29]

Twenty years after treatment, the survival rate is 94%, and 77% of patients remain symptom free. In 1945, Rosenwasser described the first patient diagnosed with glomus jugulare tumor. The patient survived until 1987.[6]

Glomus jugulare are slow-growing tumors requireing long-term follow-up by an interprofessional team, which should include primary care physicians, neurosurgeons, otolaryngologists, and neuroradiologists as well as physical medicine and rehabilitation teams. Patients and their families should be well educated about their disease and the genetic screening of high-risk individuals in affected families has been advised to lower associated morbidity.[5]

The clinical course of temporal bone glomus tumors reflects their slow growth and paucity of symptoms. Often, a significant delay in diagnosis occurs, and tumors may be large when first identified.

The most common symptoms are conductive hearing loss (69%) and pulsatile tinnitus (55%).[3]  Other aural signs and symptoms are ear fullness, otorrhea, hemorrhage, bruit, and the presence of a middle ear mass. Significant ear pain is uncommon. Involvement of the inner ear produces vertigo and sensorineural hearing loss.

Cranial nerve involvement produces hoarseness and dysphagia. The presence of jugular foramen syndrome (paresis of cranial nerves IX-XI) is pathognomonic for this tumor, but it usually follows 1 year after the initial symptoms of hearing loss and pulsatile tinnitus. Less commonly, glomus tumors produce facial nerve palsy, hypoglossal nerve palsy, or Horner syndrome.

Headache, hydrocephalus, and elevated intracranial pressure may be produced by intracranial extension of the tumor. Ataxia and brainstem symptoms may also develop. Involvement of the dural sinuses may mimic sinus thrombosis.

In about 2-4% of cases, the first or leading symptoms are hypertension and tachycardia (pheochromocytoma-like symptoms) produced by catecholamines, norepinephrine, or dopamine excreted by the tumor.[3]  Also, somatostatin, vasoactive intestinal polypeptide (VIP), calcitonin, and neuron-specific enolase may be produced by the tumor. Other related symptoms include headache, perspiration, pallor, and nausea.[3]

Plain skull radiography may show enlargement of the lateral jugular foramen and fossa. Axial and coronal computed tomography (CT) scanning with thin sections are superior at demonstrating the extent of bone destruction. Magnetic resonance imaging (MRI) with gadolinium-diethylenetriamine pentaacetic acid (DTPA) contrast is the best imaging study for delineating tumor limits. Glomus tumors on T1- and T2-weighted MRI have characteristic soft tissue mixed intensity with intermixed high-intensity signals and signal voids (ie, salt and pepper appearance) representing fast flowing blood. A combination of CT scanning and contrast MRI is the imaging regimen of choice for glomus jugulare tumors.[5]

Unless carotid arteriography is necessary for preoperative evaluation and/or embolization, noninvasive techniques are preferred; however, for large tumors involving the internal carotid artery (ICA), preoperative carotid arteriography with cross-compression or trial balloon occlusion is recommended. The venous drainage systems also need to be carefully studied before sinus occlusion is carried out during surgical resection.

For tumors with large intracranial extension, vertebral arteriography is advised to exclude arterial feeders from the posterior circulation.

The Glasscock-Jackson and Fisch classifications of glomus tumors are widely used. Staging is as follows[26] :

• Type A - Tumor limited to the middle ear cleft (glomus tympanicum)

• Type B - Tumor limited to the tympanomastoid area with no infralabyrinthine compartment involvement

• Type C - Tumor involving the infralabyrinthine compartment of the temporal bone and extending into the petrous apex

• Type C1 - Tumor with limited involvement of the vertical portion of the carotid canal

• Type C2 - Tumor invading the vertical portion of the carotid canal

• Type C3 - Tumor invasion of the horizontal portion of the carotid canal

• Type D1 - Tumor with an intracranial extension less than 2 cm in diameter

• Type D2 - Tumor with an intracranial extension greater than 2 cm in diameter

Some cases require no treatment. Often, glomus jugulare tumors are diagnosed within the sixth or seventh decade of life and can be followed by imaging only and may not need surgical intervention.

A study from Vanderbilt University found that in the absence of brainstem compression or concern for malignancy, observation of  glomus jugulare tumors can be a viable initial management approach for elderly patients. Of 15 patients studied (80% female; median age, 69.6 yr), radiologic growth occurred in 5 patients. The median growth rate of the 5 enlarging tumors was 0.8 mm/yr (range, 0.6-1.6 mm/yr) using maximum linear dimension, or 0.4 cm3/yr (0.1-0.9 cm3/yr) with volumetric analysis. No deaths were attributable to tumor progression or treatment.[30]

Medical therapy may be indicated in some cases. Alpha-blockers and beta-blockers are useful for tumors secreting catecholamines. They are usually administered for 2-3 weeks before embolization and/or surgery to avoid potentially lethal blood pressure lability and arrhythmias. Successful treatment of pulmonary metastases with etoposide (VP-16) and cisplatin has been described. In a preliminary report, a somatostatin analogue (octreotide) has been successfully used for growth control of somatostatin receptor–positive tumors.[5]

Surgery is the treatment of choice for glomus jugulare tumors. However, radiation therapy, particularly stereotactic radiosurgery (eg, Gamma Knife surgery), has been shown to provide good tumor growth control with a low risk of treatment-related cranial nerve injury.[1, 17, 18, 19, 20, 31, 32, 33, 34]  Numerous studies of stereotactic radiosurgery have shown reduction or stabilization of tumor size and improvement in overall neurologic deficit.[1, 17, 18, 19, 20]  

The short- and intermediate-term risk of progression to nonserviceable hearing following stereotactic radiosurgery for jugular paraganglioma is low.  In a series of 85 patients who underwent SRA for the treatment of jugular paraganglioma, the Kaplan-Meier estimated rates of serviceable hearing at 1, 3, and 5 years following SRS were 91%, 80%, and 80%, respectively. Sixty percent of patients with pulsatile tinnitus who underwent SRS experienced varying levels of symptomatic improvement following treatment.[35]

A large retrospective, multicenter, international study analyzed the long-term outcome in 132 patients with primary radiation treatment or radiation after partial resection of a glomus tumor. The study found long-term successful control of the tumor growthi and mprovement of tinnitus and overall neurological status, as well as cranial nerve function.[36]

Of 22 patients with glomus jugulare tumors who underwent Gamma Knife surgery, neurologic status improved in 12 patients, 7 showed stable clinical condition, and 3 patients developed new moderate deficits. The average tumor volume was 7.26 cm3. Tumor volume following surgery was unchanged in 13 patients and was decreased in 8; tumor regrowth occurred in 1 patient. Tumor progression-free survival was 95.5% at 5 and 7 years.[37]

A German study of 32 patients who underwent stereotactic radiosurgery for glomus jugulare tumors showed that stereotactic linear accelerator (LINAC) radiosurgery achieved excellent long-term tumor control, along with a low rate of morbidity. According to the study, following LINAC stereotactic radiosurgery, 10 of 27 patients showed a significant improvement of their previous neurologic complaints, whereas 12 patients remained unchanged. No tumor progression was observed. Five patients died due to unrelated causes. Overall survival rates after 5, 10, and 20 years were 100%, 95.2% and 79.4%, respectively.[38]

In a study of 28 patients treated with radiosurgery and 2 patients with stereotactic radiosurgery, crude overall survival, tumor control, clinical control, and long-term grade 1 toxicity rates were 97%, 97%, 97%, and 13% (4/30), respectively. No statistically significant risk factor was associated with lower tumor control in the series. Univariate analysis showed a statistically significant association between patients having 1 cranial nerve (CN) involvement before radiosurgery and a higher risk of lack of improvement of symptoms (odds ratio 5.24, 95% confidence interval 1.06–25.97, P=0.043).[39]

Because resection of glomus jugulare tumors can be challenging due to their inherent vascularity, preoperative embolization of these tumors with ethylene vinyl alcohol (Onyx) has been proposed.[40] A study by Gaynor et al showed a dramatic reduction of blood loss and facilitation of surgical resection, but these results came at the price of a higher incidence of cranial nerve neuropathy.[40]

Because this tumor is rare and may present with various symptoms, surgery may be contraindicated for various reasons, including age and general physical condition. Surgical resection of the glomus tumor is relatively simple and complication free for type I tumors. Large tumors that affect the lower cranial nerves and extend beyond the petrous apex carry a significant risk of postoperative complications, especially in older patients. In these cases, other modalities of treatment should be considered (eg, embolization, radiation, Gamma Knife rardiosurgery, intratumoral injection of cyanoacrylate glue).

Ehret et al evaluated the effectiveness and safety of image-guided robotic radiosurgery (RRS) and reported overall local control of 99% after a median follow-up of 35 months and stated that 56% of patients experienced symptom improvement or recovered entirely after undergoing RRS.[15] Another study reported that quality of life analyses after RRS revealed no significant decline, while bodily pain significantly decreased.[41]

The surgical approach depends on the localization and extension of the tumor. Intraoperative monitoring including EEGs and somatosensory-evoked potentials (SSEPs) are routinely used.

Fisch type A tumors can be excised by a transmeatal or perimeatal approach. Type B tumors require an extended posterior tympanotomy.

Type C tumors require radical resection via a standard combined transmastoid-infratemporal or transtemporal-infratemporal approach with or without internal carotid artery (ICA) trapping, preceded by external carotid artery (ECA) embolization or superselective embolization. Intraoperatively, temporarily occlude the transverse or sigmoid sinus with EEG monitoring to determine whether vein bypass should be performed for total resection. Surgery leads to therapeutic success in about 90% of patients. Intratumoral injection of cyanoacrylate glue has been proposed to control bleeding.

Large type D tumors need to be treated with a combined otologic and neurosurgical approach. An infratemporal approach with a skull base resection and a posterior fossa exploration is the most advisable in attempting to remove the entire tumor. Partial resection of the tumor needs to be followed by radiation and follow-up MRI/CT scanning.

Radiation therapy and radiosurgery may be indicated. Both classic fractionated radiation therapy (40-50 Gy) and stereotactic radiosurgery (eg, Gamma Knife surgery) are successful in long-term control of tumor growth[31] and in decrease of catecholamine excretion in functional tumors; however, the short duration of observation after stereotactic radiosurgery does not allow for definite conclusions. Radiation treatment is advised as the sole treatment modality for elderly or infirm patients who are symptomatic, especially those with extensive or growing tumors.[5]

Gross total resection of some extensive tumors may be extremely difficult and may carry unwarranted risk. In such cases, radiotherapy may be indicated to treat residual tumor following subtotal resection.[9, 10] However, a study by Prahbu showed that even complex glomus tumors can be managed surgically.[42]

In a study of 51 patients with jugular foramen tumors who underwent less-aggressive surgical interventions to preserve neurovascular structures, overall tumor recurrence-regrowth-free survival, symptom-progression-free survival, and overall survival at 15 years were 78.9%, 86.8%, and 80.6%, respectively. The tumor recurrence-regrowth rate was 11.8%, swallowing function improved or stabilized in 96.1%, and facial function improved or stabilized in 94.1%. Overall neurologic status improved or stabilized in 90% of patients. In the study patients, the mean lesion size was 3.8 cm, and 43 cases (84.3%) were Fisch type D, including 37 cases (72.5%) of type Di1 and Di2. Thirty-seven cases (72.5%) were Glasscock-Jackson type III-IV. Gross-total resection and subtotal resection were achieved in 26 (51.0%) and 22 (43.1%) cases, respectively.[43]

(See the images below.)

A significant decrease of tumor vascular blush (arrows) following embolization of a norepinephrine-secreting glomus jugulare tumor with intracranial and cervical extension.

Content.

If routine screening for catecholamine is positive (3 times the reference range), alpha-blockers and beta-blockers are administered for 2-3 weeks before surgery and embolization. This helps to avoid blood pressure lability and arrhythmias. In emergent cases, 3 days of treatment is adequate.

Surgical approach depends on the localization and extent of the tumor. Fisch type A tumors can be excised by a transmeatal or perimeatal approach. Type B tumors require an extended posterior tympanotomy. Type C tumors require radical resection via a standard combined transmastoid-infratemporal or transtemporal-infratemporal approach with or without ICA trapping, preceded by external carotid artery embolization or superselective embolization. Surgery leads to therapeutic success in about 90% of patients. Treat large type D tumors with a combined otologic and neurosurgical approach. An infratemporal approach with a skull base resection and a posterior fossa exploration is advisable in the attempt to remove the entire tumor.[44]

Patients are usually in the sixth decade of life; therefore, careful monitoring of cardiac function is advisable, especially if a catecholamine secreting tumor was only partially resected.

Postoperative lower cranial nerve deficits need to be carefully diagnosed, and, when present, early rehabilitation is advocated.

Radiologic and, when indicated, endocrinologic monitoring for tumor growth or regrowth is indicated every 6 months to 1 year for 2 years and then, depending on the dynamics of the tumor behavior, every 2 years.

(See the images below.)

Lateral carotid arteriogram obtained 22 years after radiation therapy in a 20-year-old woman who presented in June 1970 with episodic hypertension, headaches, and palpitations.

Corresponding MRI of the tumor depicted in the previous image indicating no evidence of tumor growth over time.

Complications of surgery include death, cranial nerve palsies, bleeding, cerebrospinal fluid (CSF) leak, meningitis, uncontrollable hypotension/hypertension, and tumor regrowth.

Complications of radiation include ICA thrombosis, sigmoid sinus thrombosis, secondary tumor development, pituitary-hypothalamic insufficiency, CSF leak, tumor growth, and radiation necrosis of bone, brain, or dura.[5]

Toxicities of single-fraction stereotactic radiosurgery (SRS) include vertigo, nausea, and headache along with lower cranial neuropathies.[45]