Paraganglioma
Encyclopedia
A paraganglioma is a rare neuroendocrine neoplasm that may develop at various body sites (including the head, neck, thorax and abdomen). About 97% are benign and cured by surgical removal; the remaining 3% are malignant because they are able to produce distant metastases
. Paragangliomas are still sometimes referred to using older, obsolete terminology (for example as "chemodectomas" or "glomus jugularis", the latter not to be confused with glomus tumor
s of the skin).
s derived from the embryonic
neural crest
, functioning as part of the sympathetic nervous system
(a branch of the autonomic nervous system
). These cells normally act as special chemoreceptors located along blood vessels, particularly in the carotid bodies
(at the bifurcation of the common carotid artery
in the neck) and in aortic bodies
(near the aortic arch
).
Accordingly, paragangliomas are categorised as originating from a neural cell line in the World Health Organization
classification of neuroendocrine tumors
. 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 phaeochromocytomas, which however are chromaffine-positive.
(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. Paragangliomas may also occur in MEN
type 2A and 2B.
s 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
, neurofilament
and Neural cell adhesion molecule
; 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.
Paraganglioma-Pheochromocytoma Syndromes
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
. Paragangliomas are still sometimes referred to using older, obsolete terminology (for example as "chemodectomas" or "glomus jugularis", the latter not to be confused with glomus tumor
Glomus tumor
A glomus tumor is a rare benign neoplasm arising from the glomus body...
s of the skin).
Cellular origin and classification
Paragangliomas originate from chromaffin cells in paraganglia or chromaffin-negative glomus cellGlomus cell
A glomus cell is a peripheral chemoreceptor, located in the carotid bodies and aortic bodies, that helps the body regulate breathing. When there is a decrease in the blood's pH, a decrease in oxygen , or an increase in carbon dioxide , the carotid bodies and the aortic bodies signal the medulla...
s derived from the embryonic
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
neural crest
Neural crest
Neural crest cells are a transient, multipotent, migratory cell population unique to vertebrates that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia....
, functioning as part of the sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
(a branch of the autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
). These cells normally act as special chemoreceptors located along blood vessels, particularly in the carotid bodies
Carotid body
The carotid body is a small cluster of chemoreceptors and supporting cells located near the fork of the carotid artery ....
(at the bifurcation of the common carotid artery
Carotid artery
Carotid artery can refer to:* Common carotid artery* External carotid artery* Internal carotid artery...
in the neck) and in aortic bodies
Aortic body
In the human heart, the aortic body is one of several small clusters of chemoreceptors, baroreceptors, and supporting cells located along the aortic arch.-Function:...
(near the aortic arch
Aorta
The aorta is the largest artery in the body, originating from the left ventricle of the heart and extending down to the abdomen, where it branches off into two smaller arteries...
).
Accordingly, paragangliomas are categorised as originating from a neural cell line in the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
classification of neuroendocrine tumors
Neuroendocrine tumors
Neuroendocrine tumors are neoplasms that arise from cells of the endocrine and nervous systems. Many are benign, while some are cancers...
. 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 phaeochromocytomas, which however are chromaffine-positive.
Clinical presentation
Most paragangliomas are either asymptomatic or present as a painless mass. 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 phaeochromocytomas.Inheritance
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 SDHDSDHD
Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial , also known as succinate dehydrogenase complex subunit D , is a protein that in humans is encoded by the SDHD gene....
(previously known as PGL1), PGL2
PGL2
PGL2 is a gene that is one cause of familial paraganglioma, also known as glomus tumors. Its locus is at 11q13.1.-External links:*...
, and SDHC
SDHC (gene)
Succinate dehydrogenase complex subunit C, also known as succinate dehydrogenase cytochrome b560 subunit, mitochondrial, is a protein that in humans is encoded by the SDHC gene.- Gene :...
(previously PGL3) have been identified as causing familial head and neck paragangliomas. Mutations of SDHB
SDHB
Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial also known as iron-sulfur subunit of complex II is a protein that in humans is encoded by the SDHB gene....
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
Multiple endocrine neoplasia
The term multiple endocrine neoplasia encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign...
type 2A and 2B.
Pathology
The paragangliomas appear grossly as sharply circumscribed polypoid masses and they have a firm to rubbery consistency. They are highly vascular tumorVascular tumor
Vascular tumor may mean:* tumor of vascular origin, a growth formed from blood vessels; for example, hemangioma, Lymphangioma, hemangioendothelioma, Kaposi sarcoma, angiosarcoma, etc....
s 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
Adenoma
An adenoma is a benign tumor of glandular origin. Adenomas can grow from many organs including the colon, adrenal glands, pituitary gland, thyroid, prostate, etc. Although these growths are benign, over time they may progress to become malignant, at which point they are called adenocarcinomas...
; and meningioma.
With immunohistochemistry
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
, the chief cells located in the cell balls are positive for chromogranin
Chromogranin
Granin 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 :...
, synaptophysin
Synaptophysin
Synaptophysin also known as the major synaptic vesicle protein p38 is a protein that in humans is encoded by the SYP gene.-Genomics:...
, neuron specific enolase, serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, neurofilament
Neurofilament
Neurofilaments are the 10 nanometer intermediate filaments found specifically in neurons. They are a major component of the cell's cytoskeleton, and provide support for normal axonal radial growth...
and Neural cell adhesion molecule
Neural Cell Adhesion Molecule
Neural Cell Adhesion Molecule is a homophilic binding glycoprotein expressed on the surface of neurons, glia, skeletal muscle and natural killer cells...
; they are S-100 protein
S-100 protein
S-100 protein is a family of low molecular weight protein found in vertebrates characterized by two calcium binding sites of the helix-loop-helix conformation. There are at least 21 different types of S100 proteins...
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
Argentaffin
Argentaffin refers to cells which take up silver stain. Enteroendocrine cells are sometimes called "argentaffins", because they take up this stain....
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:-- Carotid paraganglioma (carotid bodyCarotid bodyThe carotid body is a small cluster of chemoreceptors and supporting cells located near the fork of the carotid artery ....
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 nerveVagus nerveThe vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...
and hypoglossal nerveHypoglossal nerveThe hypoglossal nerve is the twelfth cranial nerve , leading to the tongue. The nerve arises from the hypoglossal nucleus and emerges from the medulla oblongata in the preolivary sulcus separating the olive and the pyramid. It then passes through the hypoglossal canal...
. - Glomus tympanicum and Glomus jugulare: Both commonly present as a middle ear mass resulting in tinnitusTinnitusTinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
(in 80%) and hearing loss (in 60%). The cranial nerves of the jugular foramenJugular foramenThe jugular foramen is a large aperture in the base of the skull. It is located behind the carotid canal and is formed in front by the petrous portion of the temporal, and behind by the occipital; it is generally larger on the right than on the left side....
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". - 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 dysphagiaDysphagiaDysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
and hoarseness. - Pulmonary paraglioma: These occur in the lungLungThe lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
and may be either single or multiple.
- Other sites: Rare sites of involvement are the larynxLarynxThe larynx , commonly called the voice box, is an organ in the neck of amphibians, reptiles and mammals involved in breathing, sound production, and protecting the trachea against food aspiration. It manipulates pitch and volume...
, nasal cavity, paranasal sinuses, thyroidThyroidThe thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
gland, and the thoracic inlet, as well as the bladder in extremely rare cases.
External links
- Clinical Trial information for patients with Paraganglioma
- (Description with pictures)
- GeneReview/NIH/UW entry on Hereditary
- [http://rad.usuhs.edu/medpix/kiosk_image.html?mode=cow_viewer&quiz=no&pt_id=13796&imageid=54731#pic Carotid Paraganglioma] 3D-CT Angiogram
Paraganglioma-Pheochromocytoma Syndromes