Glomus tumor

Glomus tumor was also the name formerly used for a tumor now called a
paraganglioma.

A glomus tumor (also known as glomangioma, or nonchromaffin paraganglioma[1])

is a rare benign neoplasm, is a specialized arteriovenous anastomosis usually found
in the skin of the extremities.[2]:670 It arises from the glomus body, and was first
described at Mount Sinai Hospital in New York City.[3]

Research has indicated that there are at least four genetic mutations that lead to a
glomus tumor. If there is no underlying inherited condition, then the tumor is
considered "sporadic" or random. Mutations are masked when inherited through
mothers, which allows mutations to pass through a generation without making
themselves plainly obvious. [4]

Mortality/Morbidity

The most common adverse effect is pain, which is usually associated with solitary
lesions. Multiple tumors are less likely to be painful. In one report, a patient with
more than 400 glomus tumors had thrombocytopenia as a result of platelet
sequestration (ie, Kasabach-Merritt syndrome). Malignant glomus tumors, or
glomangiosarcomas, are extremely rare and usually represent a locally infiltrative
malignancy. However, metastases do occur and are usually fatal.

[edit]

Sex

Solitary glomus tumors, particularly subungual lesions, are more common in

females than in males. Multiple lesions are slightly more common in males.

[edit]

Age
Solitary glomus tumors are more frequent in adults than in others. Multiple glomus
tumors develop 10–15 years earlier than single lesions; about one third of the cases
of multiple tumors occur in those younger than 20 years. Congenital glomus tumors
are rare; they are plaquelike in appearance and are considered a variant of multiple
glomus tumors.

[edit]

Malignant glomus tumors

Malignant glomus tumors, histologically and/or clinically are exceedingly rare.

Criteria for the diagnosis of malignancy in glomus tumors are:[8]

Tumor size of more than 2 centimeters and subfascial or visceral location.

Atypical mitotic figures.

Marked nuclear atypia and any level of mitotic activity.

Pericytes of Zimmerman

[edit]

Treatment

Radiation therapy and surgery can be involved in the treatment of these tumors

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.1,2,3
This is an image 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. Image 1 shows a lateral view of the initial carotid
arteriogram. Arrows delineate the tumor blush. The arrowhead demonstrates a
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 1924.4

In 1945, Rosenwasser described the first patient diagnosed with glomus jugulare
tumor.5 The patient survived until 1987. An association of glomus tumor with
neurofibromatosis Type 1 (NF-1) has been described.6

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.

Frequency

Glomus tumors occur with an estimated annual incidence of 1 case per 1.3 million
people.7 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.8 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 Image 4). 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 (see Image 1).
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.9,10 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 CD34.11
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).

Treatment
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.

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. 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.2,3 However, a 2004 study by Prahbu
showed that even complex glomus tumors can be managed surgically.12

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.13

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.

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.1
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 1987.5

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.14

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.