Paraganglioma

Paraganglioma
Digital subtraction arteriogram showing ipsilateral carotid body and jugular paragangliomas
Identifiers
ICD-9	237.3
ICD-10	Carotid: D44.6, Jugular: D44.7
Genetics
Gene	SDHD, SDHAF2, SDHC, SDHB, SDHA, VHL, RET, NF1
Locus	11q23.1, 11q13.1, 1q23.3, 1p36.13, 5p15.33, 3p25.3, 10q11.21, 17q11.2 (respectively with above)
Outside Resources
Radiopaedia	Paraganglioma

Overview

Paragangliomas are masses derived from the paraganglia, a group of non-neuronal cells that are associated with the sympathetic and parasympathetic nervous system.

History

These tumors historically were called "glomus tumors" when present in the head and neck. This term has fallen out of use due to potential confusion with other structures with similar names, such as glomus bodies.

Pathophysiology

Relevant Anatomy

The term "paraganglia" refers to a group of non-neuronal neuroendocrine cells derived embryologically from neural crest cells. There are paraganglia associated with the sympathetic nervous system comprised of chromaffin cells, and those associated with the parasympathetic nervous system comprised of glomus cells. The adrenal medulla is the largest collection of Chromaffin cells in the body. The paraganglia of the head and neck region are associated with the glomus cells of the parasympathetic nervous system.

The paraganglia are highly vascularized for the purposes of chemoreceptor sensitivity. Sympathetic paraganglia act as endocrine organs with systemic catecholamine release (such as the adrenal medulla, organ of Zuckerkandl, etc.). These paraganglia are a major source of catecholamines in early embryogenesis (assuming much function of the adrenal medulla). Parasympathetic paraganglia predominantly have more local effects on nerve endings, such as in the carotid body.

• 

  Target end-organs of the sympathetic nervous system.

• 

  Target end-organs of the parasympathetic nervous system.

Disease Etiology

Paragangliomas are a result of unregulated growth of paragangliar tissue. A majority of these masses arise from the carotid body just superior to the carotid bifurcation. Paragangliomas that arise from the area around the temporal bone are termed jugulotympanic paragangliomas. The term glomus tympanicum historically describes paragangliomas that arise from Jacobson's nerve (the tympanic branch of CN XI) - by definition these arise on the cochlea promontory and are confined to the middle ear and mastoid cavity. The term glomus jugulare was previously used to describe paragangliomas that arise along Jacobson's nerve or Arnold's nerve (the auricular branch of CN X), and involve the jugular bulb or skull base. These two terms have fallen out of favor and are more commonly described now collectively as "jugulotympanic" paragangliomas.

In rare instances these masses have been documented to metastasize, in what is termed a "malignant paraganglioma". Typical metastases are to the cervical lymph nodes but distant metastases to the bone, liver, and lung have also been described. Of note, syndromic paragangliomas are less often malignant compared to sporadic disease.

Epidemiology

The incidence of head and neck paragangliomas has been reported as 1 in 30,000 to 1 in 100,000. Approximately 10% of patients with head and neck paragangliomas will have multiple masses. As many as 25-35% of cases have been linked to hereditary conditions, typically Familial Paraganglioma Syndrome (see Genetics section below). There is an equal distribution of carotid paragangliomas in men and women, but jugulotympanic paragangliomas are six times more likely to be in women.

Genetics

There are several genetic syndromes associated with paragangliomas of the head and neck.

Genetic Syndromes Associated with Head and Neck Paragangliomas

Syndrome	Gene	Locus	Inheritance	Additional Findings
Paraganglioma Syndrome Type 1 (PGL1)	SDHD	11q23.1	AD, Maternal Imprinting	Pituitary adenoma, GIST, RCC
Paraganglioma Syndrome Type 2 (PGL2)	SDHAF2	11q13.1	AD, Maternal Imprinting	Pituitary adenoma, GIST, RCC
Paraganglioma Syndrome Type 3 (PGL3)	SDHC	1q23.3	AD	Pituitary adenoma, GIST, RCC
Paraganglioma Syndrome Type 4 (PGL4)	SDHB	1p36.13	AD	Pituitary adenoma, GIST, RCC
Paraganglioma Syndrome Type 5 (PGL5)	SDHA	5p15.33	AD	Pituitary adenoma, GIST, RCC
von Hippel-Lindau Syndrome	VHL	3p25.3	AD	Hemangioblastoma, retinal angioma, clear cell RCC, pancreatic neuroendocrine tumors, endolymphatic sac tumors
Multiple Endocrine Neoplasia type 2 (MEN-2)	RET	10q11.21	AD	Medullary thyroid carcinoma, Hyperparathyroidism
Neurofibromatosis Type 1 (NF1)	NF1	17q11.2	AD	Neurofibromas, cafe-au-lait spots, cognitive deficits, Lisch nodules

Histology

There are two predominant cell types seen on histologic sections of paragangliomas. Type I cells, also known as Glomus Cells, are comprised of secretory cells and make up a majority of the bulk of paragangliomas. Type I cells will stain positive for neuroendocrine markers such as chromogranin, synaptophysin, neuron-specific enolase (NSE), and CD56. Type II cells, also known as Sustentacular Cells, is comprised of Schwann-like satellite cells. Type II cells stain positive for S100 and occasionally glial fibrillary acidic protein (GFAP). Paragangliomas will arrange themselves in the same histologic morphology as normal paraganglia tissue, in what is described as the Zellballen configuration - an arrangement of clusters of Type I cells in a surrounding stroma of Type II cells.

• 

  Paraganglioma section at 20x demonstrating the Zellballen configuration.

• 

  Synaptophysin staining highlighting the Type I cells.

• 

  S100 staining highlighting the Type II cells.

Diagnosis

Patient History

Jugulotympanic paragangliomas classically present in the patient's fourth or fifth decade of life with progressive hearing loss and pulsatile tinnitus. This is often a slowly progressive, insidious loss of hearing with mass identification months to years after symptom onset. They may also have bloody otorrhea or vertigo. Depending on the extent of the disease at the time, the patient may have erosion into the adjacent skull base foramina and associated cranial neuropathy.

Carotid body paragangliomas typically present as a slow-growing painless lateral neck mass. In advanced disease, patients may have hoarseness from CN X involvement or decreased tongue mobility from CN XII involvement.

Physical Examination

Rising sun sign

Patients with a jugulotympanic paraganglioma may have a pulsatile red mass seen behind the medial tympanic membrane (known as the "Rising Sun Sign"). Due to the hypervascularity of these masses, they may blanch on pneumatic otoscopy (known as "Brown's sign").

Patients with carotid body paragangliomas will present with a painless mass in the lateral neck. Due to the attachment to the carotid vessels, this will be more mobile in a lateral direction than a cranial/caudal direction (known as "Fontaine's sign"). These masses are often pulsatile and will have an audible bruit on auscultation.

Patients with suspected paragangliomas may have cranial nerve deficits and should undergo a rigorous cranial nerve exam.

Laboratory Tests

Laboratory workup of paragangliomas should focus identifying whether the mass is a secretory paraganglioma by assessing for the presence of metanephrines and/or their metabolites:

• Urine metanephrines
• Urine vanillylmandelic acid (VMA)
• Urine homovanillic acid (HVA)
• Plasma metanephrines
• Plasma vanillylmandelic acid (VMA)
• Plasma homovanillic acid (HVA)

These are typically expensive tests that will need to be sent out. They may be bundled or separate orders based on your institution. This is important information for anesthesia purposes if you are planning a surgical resection. It is important to note that these masses should not be biopsied for tissue diagnosis if you suspect paraganglioma. They are extremely vascular and present a high risk for hemorrhage.

Imaging

Most paragangliomas of the head and neck are initially characterized on CT scan during the workup of a new neck mass. Paragangliomas will typically avidly enhance with contrast and have a delayed washout due to their rich capillary network. When the paraganglioma approaches the skull base, you may also see erosion of adjacent bone and involvement/compression of skull base foramina.

On MRI, paragangliomas will be T1 hypointense and T2 hyperintense, with a classic "salt and pepper" appearance on T1 imaging. This is due to the flow voids in the vascular network, with the "salt" describing the bulk of the mass and the "pepper" being the dark spots of the flow voids.

Angiography will demonstrate a classic "Lyre sign", in which the internal and external carotid arteries are splayed apart from the mass effect between them.

• 

  Carotid body tumor angiography with the internal and external carotid artery separated by mass effect.

• 

  A Lyre, for reference.

The extent of the mass, if in the carotid body, is often described by the Shamblin classification.

Shamblin Classification

Type I	Type II	Type III
Relatively small with minimal attachment to the carotid vessels	Somewhat larger with more extensive attachment to the carotid vessels	Large mass with complete encasement of the carotid vessels

Differential Diagnosis

Patients with paragangliomas, particularly in the jugulotympanic distribution, can present with the various eponymous jugular foramen syndromes:

Cranial Nerve Involvement in Skull Base Masses

Syndrome	CN IX	CN X	CN XI	CN XII	Sympathetics
Vernet Syndrome	✔	✔	✔
Collet-Sicard Syndrome	✔	✔	✔	✔
Villaret Syndrome	✔	✔	✔	✔	✔
Tapia Syndrome		✔	±	✔	±
Jackson Syndrome		✔	✔	✔
Schmidt Syndrome		✔	✔

There are several paraganglioma-associated syndromes that should be considered if the patient has any of the associated characteristic findings of each:

• von Hippel-Lindau (VHL) Syndrome
• Multiple Endocrine Neoplasia type 2 (MEN-2)
• Neurofibromatosis type 1 (NF1)
• Succinate Dehydrogenase-associated paraganglioma syndromes

In addition, the following diagnoses should be considered for patients with new neck masses:

• Schwannoma
• Arterio-Venous Malformation
• Metastatic Malignancy

Management

Medical Management

Not all patients require surgical intervention. For patients that are not interested in surgery, or are poor surgical candidates, observation is an acceptable option. These are slow-growing tumors at a typical rate of approximately 1 to 2 mm per year, with some patients exhibiting no growth at all. Many providers will opt for annual interval imaging studies to track the growth rate and assess whether the patient is developing new symptoms. Radiation therapy is also an option to limit the growth rate of head and neck paragangliomas.

Surgical Management

Surgical excision of paragangliomas can be challenging. The hypervascularity of the mass can result in significant intraoperative blood loss and obscuring of surgical planes. The close proximity of critical vascular and neural structures can also result in significant postoperative morbidity. Preoperative angiography with embolization 24 to 48 hours before surgery may decrease intraoperative bleeding and facilitate excision.

For carotid body paragangliomas, patients with a Shamblin Type I or Type II tumor are more amenable to surgical resection. Patients with a Shamblin Type III carotid body mass may require arterial bypass and resection, for which vascular surgery should be involved.

Traditionally, jugulotympanic paragangliomas were managed surgically with an infratemporal fossa approach. This is associated with significant postoperative morbidity including hearing loss and facial paralysis. Conservative measures are more favorable where possible for these patients. If there is intracranial extension of the mass, this often requires a combined approach with surgical removal of the middle ear and mastoid components and intracranial radiation.

Outcomes

Complications

Carotid body paragangliomas run the risk of injury to the internal carotid, external carotid, CN X, CN XII, superior laryngeal nerve, and sympathetic chain. Due to the intimate relationship with the carotid vessels these patients are at risk of intraoperative/postoperative ischemic stroke and death, particularly among those with a Shamblin Type III mass.

Prognosis

For patients that elect to observe these masses, there is typically minimal progression in symptoms on a yearly basis. In many cases, they will continue to grow slowly. In one study of 16 jugulotympanic paragangliomas managed by primary observation, primarily in elderly patients, there was minimal progressive compressive cranial neuropathy that patients typically compensated for well. In the absence of concerns for malignancy or intracranial involvement, these masses are typically safe to observe.