Glomus jugulare tumors arise from adventitial chemoreceptor tissue in the jugular bulb. Although histologically benign, these tumors can be locally aggressive because of their proximity to the lower cranial nerves and major vascular structures. Traditional treatment involves microsurgical removal with or without endovascular embolization, but morbidity following total resection can result in injury to the facial and lower cranial nerves. Radiosurgery has recently emerged as a promising alternative to older therapeutic strategies for treatment of glomus jugulare tumors. This article reviews the latest benefits of radiosurgery and demonstrates how this modality represents an effective treatment option for glomus jugulare tumors with excellent tumor control and low risk for morbidity. In addition, this article will detail the role of minimally invasive sub-total resection of glomas jugulare tumors as a surgical complement to gamma knife therapy.
Paragangliomas (glomus tumors) are slow-growing, usually benign, highly vascular tumors of paraganglionic tissue. During embryogenesis, paraganglionic tissue is derived from the migration of neural crest cells in close association with the sympathetic nervous system. Within the head and neck these cell rests are predominantly distributed throughout the middle ear in close association with the Jacobson nerve (branch of cranial nerve [CN] IX) and the Arnold nerve (branch of CN X), the jugular foramen, vagus nerve, and carotid body. Tumors arising from paraganglionic tissue can be divided into adrenal paraganglioma (pheochromocytoma) and extra-adrenal paraganglioma. The term “branchiomeric paraganglioma” is used to describe extra-adrenal tumors arising from head and neck paraganglionic tissue. The presence of paraganglionic tissue associated with the Jacobson nerve was recognized as early as 1840. Guild coined the term “glomic tissue” to describe the vascularized ganglionic tissue along the adventitia of the jugular bulb and promontory. In 1945, Rosenwasser successfully removed a middle ear paraganglioma that he called a carotid body of the middle ear. Although frequently used, the term glomus is a misnomer and denotes the previously believed origin from specialized pericytes within arteriovenous complexes (glomus). Carotid and aortic bodies are the only two paraganglia known to function as chemoreceptors. Hence, the term chemodectoma is improperly used to designate paragangliomas. The most common head and neck paraganglioma is the carotid body tumor. Within the temporal bone two types of paragangliomas exist: glomus tympanicum and glomus jugulare or jugulotympanic paraganglioma (JTP). Glomus tympanicum arises from rests of paraganglionic tissue associated with Jacobson and Arnold nerves. Glomus jugulare is believed to arise from similar paraganglionic rests within the adventitia of the jugular bulb, intimately associated with CNs IX, X, and XI. The incidence of paragangliomas is estimated at 0.012%. No racial predilection has been noted and they commonly occur in the fourth and fifth decades of life. Multicentricity is seen in 3% to 10%. Familial paraganglioma, inherited as an autosomal dominant disorder with genetic imprinting through paternal transmission, occurs in 1/30,000 head and neck tumors. In contrast to the sporadic type, individuals affected by this rare condition develop multiple paragangliomas, often bilateral and at an earlier age. Multicentricity is seen in 30% of cases of familial paragangliomas. The most common association is a carotid body tumor and ipsilateral glomus tympanicum. Recent genetic studies found linkage to two distinct chromosomal loci, 11q13.1 (PGL 2) and 11q22.3-q23 (PGL 1). Germline mutations in the genes encoding for the three subunits of the mitochondrial complex II or succinate dehydrogenase (SDHD) (an essential component of Krebs cycle), SDHB, SDHC, and SDHD, have been recently found. Some reports suggested that the same pattern of mutations may be found in sporadic cases and other have disputed a common genetic alteration.
Paragangliomas spread through pathways of least resistance: air cell tracts, vascular channels, naturally occurring fissures, and foramina. Different patterns of intracranial spread, “dangerous triangles,” have been described. Paragangliomas can travel through the peritubal air cells into the petrous apex, petrous carotid artery, and middle cranial fossa, or through the hypotympanic air cell tract between the jugular bulb and carotid artery into the posterior fossa.
Malignant paragangliomas are rare and reported in 5% of cases. The diagnosis of malignancy is based on the confirmed presence of distant metastasis. Cellular criteria and invasiveness has not been established as a prerequisite for making the diagnosis of malignant paragangliomas. Paragangliomas may originate in the temporal bone and invade into the cerebellopontine angle (CPA).
Pathology
Paragangliomas contain two cell types: the chief cells and sustentacular cells. The chief cells possess secretory granules that contain catecholamines. They are derivatives of neural crest cells and belong to the diffuse neuroendocrine system (DNES). Cells that are members of the DNES are capable of secreting neurotransmitters and have similar cell receptors.
Despite the detection of catecholamine precursors in most paragangliomas, only 1% to 3% of head and neck paragangliomas excrete norepinephrine. Unlike adrenal paragangliomas (pheochromocytoma), extra-adrenal paragangliomas rarely produce epinephrine, because the rate-converting enzyme phenylethanolamine-N-methyl transferase is absent.
On light microscopy, chief cells form clusters (zellballen) embedded with support cells (sustentacular cells) within an abundant vascular stroma. Mitosis and capsular invasion have been described in the benign variant and are not considered determinant of malignant behavior. Unmyelinated nerve fibers may be seen.
Clinical manifestations
Paragangliomas may be sporadic or part of an inherited syndrome with an autosomal dominant mode of transmission with genetic imprinting. The hereditary form is characterized by a higher incidence of multicentricity and associated tumors. The genetic imprinting through paternal transmission seen in these tumors is reflected by the absence of phenotypic expression in offspring of females carrying the mutated gene, whereas inheriting a mutated copy from the father results in phenotypic expression with high penetrance.
Early-stage paragangliomas present with symptoms related to involvement of the middle ear cleft. Pulsatile tinnitus and conductive hearing loss are seen in 98% and 63%, respectively. Glomus tympanicum tends to spread through pathways of least resistance along the peritubal air cells, intrapetrous carotid artery, and petrous apex. Glomus jugulare presents with pulsatile tinnitus and cranial neuropathy. These neoplasms tend to spread trough the hypotympanic air cells tract, around the jugular bulb, inferior petrosal sinus, and carotid artery into the jugular foramen and posterior fossa. The jugular foramen syndrome may be seen in 50% of tumors. Involvement of CN IX has been reported in 4% to 43% of cases, CN X in 5% to 57%, CN XI in 4% to 43%, and CN XII in 7% to 43%. Glomus tympanicum is seen as a retrotympanic red mass on the promontory. Glomus jugulare presents as a middle ear mass when it erodes into the floor of the hypotympanum, and as an aural polyp if erosion of the tympanic membrane has occurred. Invasion of the middle ear results in conductive hearing loss. Of interest, paragangliomas encroach onto the ossicles but do not cause ossicular erosion. Pulsatile tinnitus is an indicator of the tumor hypervascularity. Brown sign (tumor blanching with positive pressure using pneumatoscopy) or Aquino sign (cessation of pulsations with compression of the ipsilateral carotid artery) may be seen. As tumor invades into deeper structures, additional lower cranial neuropathies, sensorineural hearing loss, vertigo, and pain may ensue. Extension of the tumor through the facial recess and retrofacial air cells may result in encasement of the facial nerve. Facial nerve involvement is present in 21% to 33%. In large tumors, Horner syndrome, facial hypesthesia, and diplopia may be seen due to extension into the carotid artery and intradural or extradural involvement of CN VI. In one study, posterior fossa involvement was seen in 50% of cases with jugular foramen syndrome and in 75% of cases with CN XII neuropathy.
It is prudent not to biopsy a vascular middle ear mass, because this may result in profuse bleeding or exsanguination if not properly controlled. An aberrant carotid artery or high-riding, dehiscent jugular bulb may present as a reddish or bluish mass in the hypotympanum and possibly masquerade as a glomus tumor.
In cases in which multicentricity is seen, an appropriate workup should include screening for other adrenal and extra-adrenal tumors and for familial type paragangliomas. A 24-hour urinary vanillylmandelic acid (VMA), plasma catecholamines, and urinary beta-metanephrine and normetanephrine may be obtained as part of the biochemical screening workup. History suggestive of labile hypertension, attacks of headache, anxiety, sweating, and flushing may suggest a catecholamine-producing tumor. Because of the rarity of functional head and neck paragangliomas, elevated plasma catecholamines should prompt the search for a pheochromocytoma, and perioperative alpha blockade may be indicated to avoid catecholaminergic crisis. Genetic screening is not widely available as a screening tool and remains confined to the research laboratory. A gadolinium-enhanced MRI of the head and neck is the gold standard modality to screen for multicentric paragangliomas.
Clinical manifestations
Paragangliomas may be sporadic or part of an inherited syndrome with an autosomal dominant mode of transmission with genetic imprinting. The hereditary form is characterized by a higher incidence of multicentricity and associated tumors. The genetic imprinting through paternal transmission seen in these tumors is reflected by the absence of phenotypic expression in offspring of females carrying the mutated gene, whereas inheriting a mutated copy from the father results in phenotypic expression with high penetrance.
Early-stage paragangliomas present with symptoms related to involvement of the middle ear cleft. Pulsatile tinnitus and conductive hearing loss are seen in 98% and 63%, respectively. Glomus tympanicum tends to spread through pathways of least resistance along the peritubal air cells, intrapetrous carotid artery, and petrous apex. Glomus jugulare presents with pulsatile tinnitus and cranial neuropathy. These neoplasms tend to spread trough the hypotympanic air cells tract, around the jugular bulb, inferior petrosal sinus, and carotid artery into the jugular foramen and posterior fossa. The jugular foramen syndrome may be seen in 50% of tumors. Involvement of CN IX has been reported in 4% to 43% of cases, CN X in 5% to 57%, CN XI in 4% to 43%, and CN XII in 7% to 43%. Glomus tympanicum is seen as a retrotympanic red mass on the promontory. Glomus jugulare presents as a middle ear mass when it erodes into the floor of the hypotympanum, and as an aural polyp if erosion of the tympanic membrane has occurred. Invasion of the middle ear results in conductive hearing loss. Of interest, paragangliomas encroach onto the ossicles but do not cause ossicular erosion. Pulsatile tinnitus is an indicator of the tumor hypervascularity. Brown sign (tumor blanching with positive pressure using pneumatoscopy) or Aquino sign (cessation of pulsations with compression of the ipsilateral carotid artery) may be seen. As tumor invades into deeper structures, additional lower cranial neuropathies, sensorineural hearing loss, vertigo, and pain may ensue. Extension of the tumor through the facial recess and retrofacial air cells may result in encasement of the facial nerve. Facial nerve involvement is present in 21% to 33%. In large tumors, Horner syndrome, facial hypesthesia, and diplopia may be seen due to extension into the carotid artery and intradural or extradural involvement of CN VI. In one study, posterior fossa involvement was seen in 50% of cases with jugular foramen syndrome and in 75% of cases with CN XII neuropathy.
It is prudent not to biopsy a vascular middle ear mass, because this may result in profuse bleeding or exsanguination if not properly controlled. An aberrant carotid artery or high-riding, dehiscent jugular bulb may present as a reddish or bluish mass in the hypotympanum and possibly masquerade as a glomus tumor.
In cases in which multicentricity is seen, an appropriate workup should include screening for other adrenal and extra-adrenal tumors and for familial type paragangliomas. A 24-hour urinary vanillylmandelic acid (VMA), plasma catecholamines, and urinary beta-metanephrine and normetanephrine may be obtained as part of the biochemical screening workup. History suggestive of labile hypertension, attacks of headache, anxiety, sweating, and flushing may suggest a catecholamine-producing tumor. Because of the rarity of functional head and neck paragangliomas, elevated plasma catecholamines should prompt the search for a pheochromocytoma, and perioperative alpha blockade may be indicated to avoid catecholaminergic crisis. Genetic screening is not widely available as a screening tool and remains confined to the research laboratory. A gadolinium-enhanced MRI of the head and neck is the gold standard modality to screen for multicentric paragangliomas.
Diagnosis
The role of neuroradiology in determining the origin, extent, and nature of the tumor is of paramount importance. Its role is not limited to the characterization of the lesion itself, but is essential in differentiating these lesions from vascular anomalies or temporal bone malignant neoplasms and in screening for other contralateral or ipsilateral lesions in cases of familial paragangliomas.
On high-resolution CT of the temporal bone, glomus tympanicum in its early phases appears as a well-circumscribed soft tissue mass localized on the promontory. The differential diagnosis of a soft tissue density confined to the promontory includes congenital cholesteatoma, persistent stapedial artery, and aberrant carotid artery. Radiographically, glomus jugulare tumors are associated with an irregular erosive enlargement of the jugular plate (floor of the hypotympanum) and the jugulocarotid spine, a pattern that is described as “moth-eaten.” Depending on their origin, these neoplasms extend through the skull base to involve the jugular foramen in its neural and vascular compartment and eventually progress intracranially through intra or extradural pathways or extracranially through cervical extension.
MR weighted images are superior to evaluate tumor vascularity, extension along neural foramina, and multicentricity. In addition, MR venography is helpful in ensuring intraluminal patency of the jugular vein and retrograde involvement of the venous system and the status of the contralateral venous system. On T1-weighted images, paragangliomas appear hypointense with a speckled appearance. On gadolinium-enhanced T1 images, early and pronounced enhancement is seen witnessing the hypervascular nature of the neoplasm. On T2-weighted images, paragangliomas are hyperintense, and when larger then 2 cm the serpentine flow void pattern is described as a “salt and pepper” appearance.
Paragangliomas exhibit an intense blush or a “bag of worm” appearance on angiography. MR angiography may substitute for four-vessel angiography as a tool to evaluate the vascularity of skull base tumors. Small vascular anomalies and blood feeders are better seen on conventional angiography, however. Four-vessel angiography is indicated if preoperative embolization is planned. The latter may decrease intraoperative blood loss and operative time.
Treatment
Classification Schemes
Different classification schemes have been described. The scheme advised by Fisch divides these lesions into four categories: type A, tumors limited to the middle ear; type B, tumors limited to the tympanomastoid compartment; type C, tumors involving the infralabyrinthine air cells tract and intrapetrous carotid canal and extending into the petrous apex; and type D, tumors with intracranial extension. The scheme described by Jackson and colleagues divides JTPs into four types: type I, small tumors involving the jugular bulb, middle ear, and mastoid; type II, tumors extending under the internal auditory canal that may have an intracranial extension; type III, tumors extending into the petrous apex with or without intracranial extension; and type IV, tumors extending beyond the petrous apex into the clivus or infratemporal fossa. The House ear group adopted the classification devised by Antonio De La Cruz. JTPs are considered tympanic when tumors are entirely confined to the mesotympanum, tympanomastoid when they extend beyond the limits of the mesotympanum without eroding the jugular plate, jugular bulb when the tumors are confined to the jugular foramen without involvement of the carotid artery or extension intracranially, carotid artery when the tumor involves the intrapetrous carotid artery, and transdural when the tumor extends intracranially. These classifications help guide the surgeon in the selection of the most appropriate approach to eradicate the disease.
Operative Management
Tympanic tumors may be completely excised by a transcanal approach. To ensure adequate exposure, the tympanic annulus is elevated circumferentially and left attached to the manubrium. The tumor is excised using cup forceps and hemostasis is obtained with hemostatic sealant or absorbable gelatin foam (Gelfoam). Tympanomastoid tumors are removed by a classic mastoidectomy with an extended facial recess approach. This approach can at times obviate the need to elevate a tympanomeatal flap. For jugular bulb tumors the mastoid-neck approach is used. Only after preoperative embolization has been achieved is a mastoidectomy performed. The mastoid tip is taken down along with the insertion of the sternocleidomastoid muscle. The posterior belly of the digastric is dissected free and reflected anteriorly to expose the great vessels. The jugular vein is ligated in the neck. The proximal sigmoid sinus is packed extraluminally and the anterior wall of the segment involved by the tumor is excised preserving the posterior dural surface of the vein intact. Bleeding from the inferior petrosal sinus is controlled by packing and the remainder of the tumor is removed. Some centers perform preoperative embolization of the inferior petrosal sinus to minimize intraoperative bleeding and facilitate neural microdissection. Facial nerve rerouting can often be avoided if a fallopian bridge technique is used to access the tumor. This technique involves the removal of the retrofacial and infralabyrinthine air cell tracts. Anatomic factors, such as an anteriorly displaced jugular bulb, may limit exposure. For carotid artery tumors the infratemporal fossa approaches described by Fisch provide adequate access. Detailing the surgical technique is beyond the scope of this discussion. Transdural involvement is addressed by different posterior fossa approaches. Paragangliomas involving the CPA are often extensive, and their treatment involves a combined extradural and intradural approach, which may or may not be a staged procedure. The transpetrous approach may be performed for complete tumor excision, with or without facial nerve rerouting, with or without a transcochlear approach, and with additional craniotomies designed as dictated by tumor extension. For tumors extending into the CPA without violating the otic capsule, a transsigmoid, retrolabyrinthine approach may provide adequate exposure of the upper compartment of the CPA. For lesions with inferior extension, a retrosigmoid approach, which may be combined with a far-lateral approach, may be needed. Lesions extending to the middle cranial fossa with preserved hearing may be removed using the subtemporal-retrolabyrinthine approach. These extensive operations are often associated with significant morbidity and increased operative time.
Conventional radiotherapy
Conventional fractionated external beam radiotherapy represents an alternative to surgery for paragangliomas and has been used as primary treatment in patients for whom surgery is contraindicated because of advanced age or other comorbidities. Radiotherapy has also been used as an adjuvant to surgery for patients who have large or unresectable tumors and as salvage treatment for residual disease. Glomus tumors are relatively radioresistant and tend to persist after radiotherapy, although control of tumor growth has been demonstrated. The effect of radiation on paraganglioma tissue is not well understood. Postirradiation histopathologic studies demonstrate variable amounts of perivascular fibrosis and increase in stromal connective tissue, but there is minimal effect on tumor cells themselves or catecholamine secretion after radiation. Nevertheless, long-term control of tumor growth can be obtained using radiotherapy.
Tumor control seems to be related to dose, with frequent recurrence reported at lower radiation doses. At higher doses, multiple studies have shown tumor control comparable to that obtained by surgery, with only rare progression, and similar or even lower rate of complication. One retrospective review of studies from 1965 to 1988 demonstrated long-term control rates after surgery alone, surgery and radiotherapy, and radiotherapy alone to be 86%, 90%, and 93%, respectively, with lowest complication rates in the radiotherapy group. Another review that included 582 patients from 24 series comparing surgery and radiotherapy demonstrated recurrence in 7% versus 8% and death in 2.5% versus 6%.
Unfortunately, radiotherapy is associated with risk for several significant long-term complications. To obtain an adequate dose of radiation to the tumor, normal tissue of the upper neck and skull base must be included in the radiation field. The temporal bone itself is exquisitely radiosensitive and is susceptible to osteoradionecrosis. Other reported complications of radiotherapy for glomus tumors include radiation-induced otitis, mastoiditis, altered taste sensation, alopecia, mucositis, dermatitis, cranial nerve palsy (such as facial weakness or hearing loss), brain necrosis, radiation-induced secondary malignancy, metastasis, cerebrospinal fluid leakage, and insufficiency of pituitary or hypothalamic function. For this reason, radiotherapy is not commonly used to treat glomus tumors. Elderly patients or patients for whom extensive surgery is contraindicated may benefit from a limited surgical procedure with adjuvant radiotherapy.
Radiosurgery
Over the past several years, radiosurgical techniques have emerged as a promising alternative to other therapeutic strategies for treatment of glomus jugulare tumors. Developed by Lars Leksell in 1951, radiosurgery is a refinement of traditional radiotherapy in which a large number of intersecting beams of radiation are focused directly on the tumor. This method allows for a steep drop-off in radiation dose around the tumor margin so that a large dose of radiation can be provided to the tumor while minimizing radiation exposure to adjacent tissues. Although glomus tumors are relatively radioresistant, they are otherwise ideal candidates for radiosurgical treatment, because they are well-demarcated on MRI, rarely invade the brain, are usually fairly small, and lie close to vital structures. Because the volume of irradiated tissue adjacent to the tumor is small, the rate of complications is also significantly lower than for conventional radiotherapy. Several studies have documented stability or reduction in tumor size after radiosurgery without new neurologic deficits. There are currently three techniques available for radiosurgery: gamma knife, linear accelerator (LINAC), and CyberKnife. A schematic of each of these is shown in Fig. 1 , and photographs of a gamma knife and a CyberKnife machine are shown in Fig. 2 .
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
