Paragangliomas

A paraganglioma is a rare neoplasm that can be found in the abdomen, thorax, and in the head and neck region. They are usually considered benign and complete surgical removal results in cure. However, in about 3% of cases they are malignant and have the ability to metastasize. Paragangliomas are still sometimes called glomus tumors (not to be confused with glomus tumors of the skin) and chemodectomas, but paraganglioma is the currently accepted and preferred term.

Presentation
Paragangliomas arise from the glomus cells, which are special chemoreceptors located along blood vessels that have a role in regulating blood pressure and blood flow. The main concentration of glomus cells are found are in the carotid body, located in the upper neck at the branching of the common carotid artery, and the aortic bodies, located near the aortic arch. The glomus cells are a part of the paraganglion system composed of the extra-adrenal paraganglia of the autonomic nervous system, derived from the embryonic neural crest. Thus, paragangliomas are a type of neuroendocrine tumor, and are closely related to pheochromocytomas. Although all paragangliomas contain neurosecretory granules, only about 1-3% have clinical evidence of oversecretion.

Paragangliomas are found predominantly in the abdomen (85%) and the thorax (12%), and only 3% are found in the head and neck region. Most occur as single tumors. When they occur in multiple sites they are usually found as a part of a heritable syndrome such as multiple endocrine neoplasia types II-A and II-B and SDH-related mutations.

Classification
According to the World Health Organization classification of neuroendocrine tumors, paragangliomas are classified as having a neural cell line of origin. In the categorization proposed by Wick, the paragangliomas belong to Group II.

Inheritance
Familial paragangliomas account for approx. 25% of cases, are often multiple and bilateral, and occur at an earlier age. Mutations of the genes SDHD (previously known as PGL1), PGL2, and SDHC (previously PGL3) have been identified as causing familial head and neck paragangliomas. Mutations of SDHB play an important role in familial adrenal pheochromocytoma and extra-adrenal paraganglioma (of abdomen and thorax), although there is considerable overlap in the types of tumors associated with SDHB and SDHD gene mutations.

Pathology
The paragangliomas appear grossly as sharply circumscribed polypoid masses and they have a firm to rubbery consistency. They are highly vascular tumors and may have a deep red color.

On microscopic inspection, the tumor cells are readily recognized. Individual tumor cells are polygonal to oval and are arranged in distinctive cell balls, called Zellballen. These cell balls are separated by fibrovascular stroma and surrounded by sustentacular cells.

By light microscopy, the differential diagnosis includes related neuroendocrine tumors, such as carcinoid tumor, neuroendocrine carcinoma, and medullary carcinoma of the thyroid; middle ear adenoma; and meningioma.

With immunohistochemistry, the chief cells located in the cell balls are positive for chromogranin, synaptophysin, neuron specific enolase, serotonin and neurofilament; they are S-100 protein negative. The sustentacular cells are S-100 positive and focally positive for glial fibrillary acid protein. By histochemistry, the paraganglioma cells are argyrophilic, periodic acid Schiff negative, mucicarmine negative, and argentaffin negative.

Clinical characteristics
Paragangliomas are described by their site of origin and are often given special names:


 * Carotid paraganglioma (carotid body tumor): Is the most common of the head and neck paragangliomas. It usually presents as a painless neck mass, but larger tumors may cause cranial nerve palsies, usually of the vagus nerve and hypoglossal nerve.


 * Glomus tympanicum and Glomus jugulare: Both commonly present as a middle ear mass resulting in tinnitus (in 80%) and hearing loss (in 60%). The cranial nerves of the jugular foramen may be compressed, resulting swallowing difficulty.  These patients present with a reddish bulge behind an intact ear drum.  This condition is also known as the "Red drum".  On application of pressure to the external ear canal with the help of a pneumatic ear speculum the mass could be seen to blanch.  This sign is known as "Brown's sign".


 * Vagal paragangliomas: These are the least common of the head and neck paragangliomas. They usually present as a painless neck mass, but may result in dysphagia and hoarseness.


 * Other sites: Rare sites of involvement are the larynx, nasal cavity, paranasal sinuses, thyroid gland, and the thoracic inlet, as well as the bladder in extremely rare cases.

Treatment
The main treatment modalities are surgery, embolization and radiotherapy.