Glomus Tumors

Background

Glomus jugulare tumors are rare, slow-growing, hypervascular tumors that arise within the jugular foramen of the temporal bone. They are included in a group of tumors referred to as paragangliomas, which occur at various sites and include carotid body, glomus vagale, and glomus tympanicum tumors.


Glomus jugulare tumors occur predominantly in women in the fifth and sixth decades of life. Because of the insidious onset of symptoms, these tumors often go unnoticed, and delay in diagnosis is frequent. Because of the location and extent of involvement, glomus jugulare tumors present a significant diagnostic and management, as well as social, challenge.

Lateral view of the initial carotid arteriogram of a 20-year-old woman who presented in June 1970 with episodic hypertension, headaches, and palpitations. Urine catecholamine levels were elevated, and a pheochromocytoma was suspected. She underwent a negative exploratory laparotomy. She subsequently developed palsies of the IX, X, XI, and XII cranial nerves on the right side. A norepinephrine-secreting glomus jugulare tumor with intracranial and cervical extension was identified on radiologic and arteriographic imaging. Arrows delineate the tumor blush. The arrowhead demonstrates branch of the middle meningeal artery providing blood supply to the tumor. This branch was embolized.

History of the Procedure

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. In 1840, this tissue was first described by Valentin as ganglia tympanica. In 1878, Krause described the tissue as glandula tympanica. Guild was the first to note the similarity between these collections of tissue and the carotid body. He referred to them as glomus jugulare.

These structures also have been referred to as nonchromaffin paraganglia. The first description of glomus tumor as a hyperplastic glomus bodies was reported by Masson in 1924.


In 1945, Rosenwasser described the first patient diagnosed with glomus jugulare tumor.The patient survived until 1987. An association of glomus tumor with neurofibromatosis Type 1 (NF-1) has been described.
Vascular tumors of the middle ear had previously been reported, but Rosenwasser was the first to recognize the origin of these tumors from the glomus jugulare. He provided the first description of the surgical removal of a glomus jugulare tumor.

Problem

Glomus tumors of the temporal bone occur in the region of the jugular bulb and middle ear. These are rare, vascular, slow-growing tumors, and most are benign. Tumors that originate from the jugular bulb and may extend to involve the middle ear are referred to as glomus jugulare tumors.
Glomus tumors are also referred to as chemodectomas or nonchromaffin paragangliomas.

Paragangliomas are often found at other sites, including the middle ear (glomus tympanicum tumor), the carotid body (carotid body tumor), and the vagus nerve in proximity to the inferior (nodosum) vagal ganglion (glomus vagale tumor, glomus intravagale tumor). Affected sites that are much less commonly reported are the periaortic area, trachea, larynx, mandible, nose, ciliary ganglion, and fallopian canal. Optimal treatment of temporal bone glomus tumors remains controversial.

Epidemiology

Frequency

Glomus tumors occur with an estimated annual incidence of 1 case per 1.3 million people.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.

Etiology

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 more recently been referred to as the diffuse neuroendocrine system (DNES).

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.

Pathophysiology

Glomus tumors are encapsulated, slowly growing, highly vascular, and locally invasive tumors. Sen et al described histological structure of glomus tumors as a dense matrix of connective tissue among nerve fascicles.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.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.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.

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.

• 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

Presentation

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 and pulsatile tinnitus. 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 one 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 (pheochromocytomalike symptoms) produced by catecholamines, norepinephrine, or dopamine excreted by the tumor. 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.

Otoscopic examination reveals a characteristic, pulsatile, reddish-blue tumor behind the tympanic membrane that is often the beginning of more extensive findings (ie, the tip of the iceberg).
Audiologic examination reveals mixed conductive and sensorineural hearing loss. The sensorineural component tends to be more significant with larger tumors.

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 best 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.

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.

Differential diagnoses include the following:

• Chordoma
• Otitis Media
• Eosinophilic Granuloma (Histiocytosis X)
• Meningioma
• Schwannoma
• Neurofibroma
• Chondrosarcoma
• Carcinoma (primary and metastatic)
• Cholesteatoma
• Osteoma
• Otosclerosis
• Chronic mastoiditis
• Cholesterol granuloma
• Aneurysm
• Aberrant intrapetrous internal carotid artery
• Idiopathic hemotympanum
• Arterious malformation
• Prominent jugular bulb
• Persistent stapedial artery
• Lymphoma

Indications

See Surgical therapy for specific surgical indications.

Relevant Anatomy

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

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.

Contraindications

 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 radiosurgery, intratumoral injection of cyanoacrylate glue).

Glomus Tumors Workup

Staging

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.

• 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 Tumors Treatment & Management

  Medical Therapy

  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. 
  
  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.
  

  Surgical Therapy

  Surgery is the treatment of choice for glomus jugulare tumors. However, more recently, radiation therapy, particularly a gamma knife radiosurgery, has been shown to provide good tumor growth control with a low risk of treatment-related cranial nerve injury.
  
  
  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 growth, improvement of tinnitus and overall neurological status, as well as cranial nerve function. These results strongly suggest that gamma knife radiosurgery is becoming the treatment of choice for glomus tumors. 
  
  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.
  
  
  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.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.
  
  
  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 (see Pathophysiology) can be excised by a transmeatal or perimeatal approach.
  
  Type B tumors (see Pathophysiology) require an extended posterior tympanotomy.
  Type C tumors (see Pathophysiology) 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 (see Pathophysiology) need to be treated with a combined otologic and neurosurgical approach. An infratemporal approach with a skull base resection and a posterior fossa exploration are 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 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.
  
  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.However, a 2004 study by Prahbu showed that even complex glomus tumors can be managed surgically. 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.

  
  

  

  CT imaging demonstrates the extent of bony destruction (white and black arrows) by the tumor. The normal jugular foramen on the left (arrow head) is shown for comparison. The patient subsequently underwent surgical resection of the extracranial portion of this extensive tumor. The remaining intracranial portion was treated with radiation therapy (54 Gy). Follow-up evaluations, including imaging and laboratory investigations, demonstrated long-term control of both tumor growth and catecholamine production.

  
  

  Preoperative Details

  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.
  

  Intraoperative Details

  Surgical approach depends on the localization and extent of the tumor (see Pathophysiology). 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 are advisable in the attempt to remove the entire tumor.
  

  Postoperative Details

  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.
  

  Follow-up

  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

  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, secondary tumor development, pituitary-hypothalamic insufficiency, CSF leak, tumor growth, and radiation necrosis of bone, brain, or dura.
  

  Outcome and Prognosis

  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, a recent study showed a long-term reduced quality of life in patients with glomus tumors.
  
  The mortality rate is 6.2% among patients treated with radiation and 2.5% among those treated surgically. The overall mortality rate is 8.7%.
  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.
  

  Future and Controversies

  Surgery is the treatment of choice for glomus tumors, and its effectiveness will improve with intraoperative guiding and imaging systems.
  
  The cooperative work of neurosurgeons and neuro-otologists to surgically resect Fisch type A, B, and C tumors has proven to be of value. However, definitive optimal treatment of type D glomus jugulare tumor is still controversial.
  
  Because of its long-term effects on the bone and brain, radiation that is not stereotactically targeted is outdated. Radiosurgery with its influence on neuro-oncology must be proven useful in treatment of these slowly growing tumors. 
  
  Continued tumor growth and postsurgical damage to the lower cranial nerves are issues that still need to be successfully addressed.
  Recent genetic research on familial glomus jugulare tumors suggests future directions of treatment towards gene manipulation.