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 b ...

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 is a rare tumor of the adrenal medulla composed of chromaffin cells and is part of the paraganglioma (PGL) family of tumors, being defined as an intra-adrenal PGL. These neuroendocrine tumors can be sympathetic, where they relea ...

. They are rare tumors, with an overall estimated incidence of 1 in 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 ...

; 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 A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. ...

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 Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates ...

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 resp ...

SDHC Secure Digital (SD) is a proprietary, non-volatile, flash memory card format developed by the SD Association (SDA). Owing to their compact size, SD cards have been widely adopted in a variety of portable consumer electronics, including digi ...

(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 Compl ...

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. Before adulthood, a male child or adolescent is referred to as a boy. Like most other male mammals, a man's genome usually inherits an X chromosome from the mother and a Y chromosome from the fa ...

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 Max or MAX may refer to: Animals * Max (American dog) (1983–2013), at one time purported to be the world's oldest living dog * Max (British dog), the first pet dog to win the PDSA Order of Merit (animal equivalent of the OBE) * Max (gorilla) ...

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. See also * Solute carrier family The solute carr ...

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 or Sertoli cells) have been shown to be inv ...

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 Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, whe ...

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, lu ...

, 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 Immunohistochemistry is a form of immunostaining. It involves the process of selectively identifying antigens in cells and tissue, by exploiting the principle of Antibody, antibodies binding specifically to antigens in biological tissues. Alber ...

, 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 Synaptophysin, also known as the major synaptic vesicle protein p38, is a protein that in humans is encoded by the ''SYP'' gene. Gene The gene is located on the short arm of X chromosome (Xp11.23-p11.22). It is 12,406 bases in length and li ...

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 foun ...

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

neurofilament Neurofilaments (NF) are classed as Intermediate filament#Type IV, 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 mic ...

and

Neural cell adhesion molecule Neural cell adhesion molecule (NCAM), also called CD56, is a homophilic binding glycoprotein expressed on the surface of neurons, glia and skeletal muscle. Although CD56 is often considered a marker of neural lineage commitment due to its discover ...

; 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 enc ...

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 is a form of immunostaining. It involves the process of selectively identifying antigens in cells and tissue, by exploiting the principle of antibodies binding specifically to antigens in biological tissues. Albert Hewett ...

, the paraganglioma cells are argyrophilic, periodic acid Schiff negative, mucicarmine 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 peripheral chemoreceptor cells and supporting sustentacular cells situated at the bifurcation of each common carotid artery in its tunica externa. The carotid body detects changes in the composition of art ...

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 (CN X), plays a crucial role in the autonomic nervous system, which is responsible for regulating involuntary functions within the human body. This nerve carries both sensory and motor fibe ...

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 b ...

. ** Glomus tympanicum and Glomus jugulare, also known as jugulotympanic paraganglioma: Both commonly present as a middle ear mass resulting in

tinnitus Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...

(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 The accessory nerve, also known as the eleventh cranial nerve, cranial nerve XI, or simply CN XI, is a cranial nerve that supplies the sternocleidomastoid and trapezius muscles. It is classified as the eleventh of twelve pairs of cranial nerves ...

). 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 The internal carotid artery is an artery in the neck which supplies the anterior cerebral artery, anterior and middle cerebral artery, middle cerebral circulation. In human anatomy, the internal and external carotid artery, external carotid ari ...

(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 l ...

, hoarseness, or coughing with compression of the mass. * Pulmonary paraganglioma: These occur in the

lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...

and may be either single or multiple. * Other sites: Rare sites of involvement are the

larynx The larynx (), commonly called the voice box, is an organ (anatomy), organ in the top of the neck involved in breathing, producing sound and protecting the trachea against food aspiration. The opening of larynx into pharynx known as the laryngeal ...

, nasal cavity, paranasal sinuses,

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...

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 ...

s derived from the

embryo An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sp ...

nic

neural crest The neural crest is a ridge-like structure that is formed transiently between the epidermal ectoderm and neural plate during vertebrate development. Neural crest cells originate from this structure through the epithelial-mesenchymal transition, ...

, functioning as part of the

sympathetic nervous system The sympathetic nervous system (SNS or SANS, sympathetic autonomic nervous system, to differentiate it from the somatic nervous system) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous sy ...

(a branch of the

autonomic nervous system The autonomic nervous system (ANS), sometimes called the visceral nervous system and formerly the vegetative nervous system, is a division of the nervous system that operates viscera, internal organs, smooth muscle and glands. The autonomic nervo ...

). 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 chemorece ...

s located along blood vessels, particularly in the

carotid bodies The carotid body is a small cluster of peripheral chemoreceptor cells and supporting sustentacular cells situated at the bifurcation of each common carotid artery in its tunica externa. The carotid body detects changes in the composition of arte ...

(at the bifurcation of the

common carotid artery In anatomy, the left and right common carotid arteries (carotids) () are artery, arteries that supply the head and neck with oxygenated blood; they divide in the neck to form the external carotid artery, external and internal carotid artery, inte ...

in the neck) and in

aortic bodies The aortic bodies are one of several small clusters of peripheral chemoreceptors located along the aortic arch. They are important in measuring partial pressures of oxygen and carbon dioxide in the blood, and blood pH. Structure The aortic b ...

(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 list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...

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, lu ...

. 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. Gallium-68 DOTATATE PET/CT imaging modality may be used to confirm the presence of a paraganglioma.

Treatment

The main treatment modalities are

surgery Surgery is a medical specialty that uses manual and instrumental techniques to diagnose or treat pathological conditions (e.g., trauma, disease, injury, malignancy), to alter bodily functions (e.g., malabsorption created by bariatric surgery s ...

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 induced ...

and

radiotherapy Radiation therapy or radiotherapy (RT, RTx, or XRT) is a treatment using ionizing radiation, generally provided as part of cancer therapy to either kill or control the growth of malignant cells. It is normally delivered by a linear particle ...

. Treatment depends on a variety of factors, including patient symptoms, as well as tumor size and location.

Additional images

File:Carotid body tumour 2 low mag.jpg,

Micrograph A micrograph is an image, captured photographically or digitally, taken through a microscope or similar device to show a magnify, magnified image of an object. This is opposed to a macrograph or photomacrograph, an image which is also taken ...

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 In biochemistry, immunostaining is any use of an antibody-based method to detect a specific protein in a sample. The term "immunostaining" was originally used to refer to the immunohistochemical staining of tissue sections, as first described by ...

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
{{Authority control Endocrine neoplasia