A paraganglioma is a rare

neuroendocrine Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules (hormones) into the blood. In this way they bri ...

neoplasm A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

that may develop at various body sites (including the head, neck, thorax and abdomen). When the same type of tumor is found in the adrenal gland, they are referred to as a

pheochromocytoma Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred t ...

. They are rare tumors, with an overall estimated incidence of 1/300,000. There is no test that determines benign from

malignant tumors Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...

; long-term follow-up is therefore recommended for all individuals with paraganglioma.

Signs and symptoms

Most paragangliomas are asymptomatic, present as a painless mass, or create symptoms such as hypertension, tachycardia, headache, and palpitations. While all contain neurosecretory granules, only in 1–3% of cases is secretion of hormones such as catecholamines abundant enough to be clinically significant; in that case manifestations often resemble those of

s (intra-medullary paraganglioma).

Genetics

About 75% of paragangliomas are sporadic; the remaining 25% are hereditary (and have an increased likelihood of being multiple and of developing at an earlier age). Mutations of the genes for the succinate dehydrogenase,

SDHD Succinate dehydrogenase biquinonecytochrome b small subunit, mitochondrial (CybS), also known as succinate dehydrogenase complex subunit D (SDHD), is a protein that in humans is encoded by the ''SDHD'' gene. Names previously used for SDHD were ...

(previously known as PGL1),

SDHA Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the ''SDHA'' gene. This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respi ...

SDHC Secure Digital, officially abbreviated as SD, is a proprietary non-volatile flash memory card format developed by the SD Association (SDA) for use in portable devices. The standard was introduced in August 1999 by joint efforts between SanD ...

(previously PGL3) and

SDHB Succinate dehydrogenase biquinoneiron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein that in humans is encoded by the ''SDHB'' gene. The succinate dehydrogenase (also called SDH or Complex ...

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. Paragangliomas may also occur in

MEN A man is an adult male human. Prior to adulthood, a male human is referred to as a boy (a male child or adolescent). Like most other male mammals, a man's genome usually inherits an X chromosome from the mother and a Y chro ...

type 2A and 2B. Other genes related to familial paraganglioma are

SDHAF2 Succinate dehydrogenase complex assembly factor 2, formerly known as SDH5 and also known as SDH assembly factor 2 or SDHAF2 is a protein that in humans is encoded by the SDHAF2 gene. This gene encodes a mitochondrial protein needed for the flavina ...

, VHL, NF1, TMEM127, MAX and

SLC25A11 Mitochondrial 2-oxoglutarate/malate carrier protein is a protein that in humans is encoded by the ''SLC25A11'' gene. Inactivating mutations in this gene predispose to metastasic paraganglioma A paraganglioma is a rare neuroendocrine neoplasm t ...

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 cell A sustentacular cell is a type of cell primarily associated with structural support, they can be found in various tissues. * Sustentacular cells of the olfactory epithelium (also called supporting cells) have been shown to be involved in the phag ...

s. By light microscopy, the differential diagnosis includes related neuroendocrine tumors, such as

carcinoid tumor A carcinoid (also carcinoid tumor) is a slow-growing type of neuroendocrine tumor originating in the cells of the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut (jejunum, ileum, appendix, and cecum) a ...

neuroendocrine carcinoma Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung ...

, and

medullary carcinoma of the thyroid Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP"Thyroid and Parathyroid Cancers"in Pazdur R, ...

. With immunohistochemistry, the chief cells located in the cell balls are positive for

chromogranin Granin (chromogranin and secretogranin) is a protein family of regulated secretory proteins ubiquitously found in the cores of amine and peptide hormone and neurotransmitter dense-core secretory vesicles. Function Granins (chromogranins or sec ...

, synaptophysin,

neuron specific enolase Gamma-enolase, also known as enolase 2 (ENO2) or neuron specific enolase (NSE), is an enzyme that in humans is encoded by the ''ENO2'' gene. Gamma-enolase is a phosphopyruvate hydratase. Gamma-enolase is one of the three enolase isoenzymes found ...

, serotonin,

neurofilament Neurofilaments (NF) are classed as type IV intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring 10 nm in diameter and many micrometers in length. Together with microtubules (~25 nm) and mi ...

and Neural cell adhesion molecule; they are

S-100 protein The S100 proteins are a family of low molecular-weight proteins found in vertebrates characterized by two calcium-binding sites that have helix-loop-helix ("EF-hand-type") conformation. At least 21 different S100 proteins are known. They are en ...

negative. The sustentacular cells are S-100 positive and focally positive for

glial fibrillary acidic protein Glial fibrillary acidic protein (GFAP) is a protein that is encoded by the ''GFAP'' gene in humans. It is a type III intermediate filament (IF) protein that is expressed by numerous cell types of the central nervous system (CNS), including astro ...

. By

histochemistry Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to ant ...

, the paraganglioma cells are argyrophilic, periodic acid Schiff negative,

mucicarmine Mucicarmine stain is a staining procedure used for different purposes. In microbiology the stain aids in the identification of a variety of microorganisms based on whether or not the cell wall stains intensely red. Generally this is limited to micro ...

negative, and argentaffin negative.

Sites of origin

About 85% of paragangliomas develop in the abdomen; only 12% develop in the chest and 3% in the head and neck region (the latter are the most likely to be symptomatic). While most are single, rare multiple cases occur (usually in a hereditary syndrome). Paragangliomas are described by their site of origin and are often given special names: * Head and neck paraganglioma (HNPGL): There are various types of head and neck paraganglioma; they may have specialized names depending on the precise location. ** Carotid paraganglioma (

carotid body The carotid body is a small cluster of chemoreceptor cells, and supporting sustentacular cells. The carotid body is located in the adventitia, in the bifurcation (fork) of the common carotid artery, which runs along both sides of the neck. The ...

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 The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and righ ...

and

hypoglossal nerve The hypoglossal nerve, also known as the twelfth cranial nerve, cranial nerve XII, or simply CN XII, is a cranial nerve that innervates all the extrinsic and intrinsic muscles of the tongue except for the palatoglossus, which is innervated by ...

. ** Glomus tympanicum and

Glomus jugulare A paraganglioma is a rare neuroendocrine neoplasm that may develop at various body sites (including the head, neck, thorax and abdomen). When the same type of tumor is found in the adrenal gland, they are referred to as a pheochromocytoma. They ar ...

, also known as jugulotympanic paraganglioma: Both commonly present as a middle ear mass resulting in

tinnitus Tinnitus is the perception of sound when no corresponding external sound is present. Nearly everyone experiences a faint "normal tinnitus" in a completely quiet room; but it is of concern only if it is bothersome, interferes with normal hearin ...

(in 80%) and hearing loss (in 60%). The

cranial nerves Cranial nerves are the nerves that emerge directly from the brain (including the brainstem), of which there are conventionally considered twelve pairs. Cranial nerves relay information between the brain and parts of the body, primarily to and f ...

of the

jugular foramen A jugular foramen is one of the two (left and right) large foramina (openings) in the base of the skull, located behind the carotid canal. It is formed by the temporal bone and the occipital bone. It allows many structures to pass, including the ...

may be compressed, resulting swallowing difficulty, or ipsilateral weakness of the upper trapezius and sternocleiodomastoid muscles (from compression of the spinal accessory nerve). 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". A deficient bony plate along the tympanic portion of the internal carotid artery (aberrant ICA) is a normal variant and can be mistaken with glomus jugulare. * Organ of Zuckerkandl: A collection of paraganglia near the bifurcation of the aorta, comprising a small mass of neural crest-derived chromaffin cells. Serves as a common origin of abdominal paragangliomas. * Vagal paraganglioma: These are the least common of the head and neck paragangliomas. They usually present as a painless neck mass, but may result in

dysphagia Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a condition in its own right. It may be a sensation that suggests difficulty in the passage of solids or liq ...

and hoarseness. * Pulmonary paraganglioma: These occur in the lung and may be either single or multiple. * Other sites: Rare sites of involvement are the larynx, nasal cavity, paranasal sinuses,

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...

gland, and the thoracic inlet, as well as the bladder in extremely rare cases.

Diagnosis

Classification

Paragangliomas originate from paraganglia in chromaffin-negative

glomus cell Glomus cells are the cell type mainly located in the carotid bodies and aortic bodies. Glomus type I cells are peripheral chemoreceptors which sense the oxygen, carbon dioxide and pH levels of the blood. When there is a decrease in the blood's p ...

s derived from the embryonic

neural crest Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, per ...

, functioning as part of the sympathetic nervous system (a branch of the autonomic nervous system). These cells normally act as special

chemoreceptor A chemoreceptor, also known as chemosensor, is a specialized sensory receptor which transduces a chemical substance (endogenous or induced) to generate a biological signal. This signal may be in the form of an action potential, if the chemorecept ...

s located along blood vessels, particularly in the carotid bodies (at the bifurcation of the

common carotid artery In anatomy, the left and right common carotid arteries (carotids) (Entry "carotid"
in
aortic bodies (near the

aortic arch The aortic arch, arch of the aorta, or transverse aortic arch () is the part of the aorta between the ascending and descending aorta. The arch travels backward, so that it ultimately runs to the left of the trachea. Structure The aorta begins ...

). Accordingly, paragangliomas are categorised as originating from a neural cell line in the

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of ...

classification of

neuroendocrine tumors Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lun ...

. In the categorization proposed by Wick, paragangliomas belong to group II. Given the fact that they originate from cells of the orthosympathetic system, paragangliomas are closely related to

s, which however are chromaffin-positive.

Treatment

The main treatment modalities are surgery,

embolization Embolization refers to the passage and lodging of an embolus within the bloodstream. It may be of natural origin ( pathological), in which sense it is also called embolism, for example a pulmonary embolism; or it may be artificially indu ...

and radiotherapy.

Additional images

File:Carotid body tumour 2 low mag.jpg,

Micrograph A micrograph or photomicrograph is a photograph or digital image taken through a microscope or similar device to show a magnified image of an object. This is opposed to a macrograph or photomacrograph, an image which is also taken on a m ...

of a ''carotid body tumor'' File:Tumor Glomus Jugulare.jpg, Glomus jugulare tumor File:Ectopic functional paraganglioma (glomus jugulare) in a patient with VHL.jpg, Ectopic functional paraganglioma (glomus jugulare) in a patient with VHL. T2 weighted MRI at the same location demonstrates a high signal mass consistent with a paraganglioma. Extra adrenal paragangliomas can be found in VHL (arrow). File:Paraganglioma - s100 - very high mag.jpg, S100 immunostain highlighting the sustentacular cells in a paraganglioma File:Carotid Body Tumor.jpg, Digital subtraction arteriogram of carotid body tumor and jugular paraganglioma

References

External links

GeneReviews/NCBI/NIH/UW entry on Hereditary Paraganglioma-Pheochromocytoma Syndromes
k {{Central nervous system tumors Endocrine neoplasia