Paragangliomas are tumours of the sympathetic and parasympathetic paraganglia.
While most paraganglioma are of parasympathetic origin and present as benign palpable masses of the neck, sympathetic paraganglioma are often secretory, presenting with symptoms related to excess catecholamines.
Such symptoms include hypertension, headache, palpitations, and diaphoresis.
Most sympathetic paraganglioma form within the adrenal medulla, the largest sympathetic paraganglia,and are commonly known as pheochromocytomas.
Sympathetic paragangliomas may present extra-adrenally, carrying a significantly higher risk of malignancy.
Extra-adrenal paraganglioma have an uniform distribution on either side of the midline. It extends from the middle ear region and base of the skull to the pelvic floor.
Paraganglia mediate fast adaptations to changes in the environment by a combination of :
A) Neural (norepinephrine release from postganglionic sympathelic neurons) and
B) Hormonal effects due to secretion of catecholamines (mainly epinephrine) from the adrenal medullae.
Extra-Adrenal Paraganglia -
Head and Neck Region
The location of head and neck paraganglia, which are close along the parasympathetic nervous system, makes them suited for a chemoreceptor role in reflex changes in respiratory and cardiovascular function in response to alterations in the composition of arterial blood.
- Paraganglia of the head and neck are closely aligned with the parasympathetic nervous system.
- These are often juxtaposed with branchial arch mesodermal derivatives.
- The largest, most compact collection of paraganglia is located on the medial aspect of the carotid bifurcation on each side of the neck.
- The average combined weight of the carotid bodies in adults is a little over 12 mg.
- Each carotid body is composed of lobules. These appear as compact lobules at low magnification. At higher power carotid body contain chief (or glomus type I) cells and sustentacular (glomus type II) cells.
- Immunostaining for chromogranin A clearly delineates the chief cells in small clusters or short cords.
- Staining for S-100 protein demonstrates the sustentacular cells at the periphery of cords and clusters of chief cells. This stain will also stain Schwann cells within the carotid body and other paraganglia.
- Carotid body enlargement and hyperplasia have been reported in some people living at high altitude and in a few patients with chronic hypoxemia under normobaric conditions.
Extra-Adrenal Paraganglia -
A) The sympathetic nervous system, with postganglionic neurons mediating effector responses via the neurotransmitter norepinephrine, and
B) The adrenal medullae, which synthesize and secrete the hormones epinephrine and some amount of norepinephrine.
Extra-Adrenal Paraganglia in this system are distributed along the paravertibral and para-aortic axis.
It extends from the neck down into the pelvis and are closely aligned with the sympathetic nervous system.
The adrenal medullae becomes the largest, most compact paraganglia following birth.
One of the extra-adrenal sites from which these tumors arise is from a collection of para-aortic, paraganglion cells around the origin of the inferior mesenteric artery. This collection of paraganglia was described in fetuses by Zuckerkandl in 1901 and has subsequently been referred to as the organ of Zuckerkandl. Zuckerkandl described these paraganglia as being multiple in majority of cases and referred to them as “aortic bodies”.
The diagnosis and management of these neoplasms differ somewhat from that of adrenal pheochromocytomas, but excellent results are often obtained by excision of these lesions.
During the first decade of life these paraganglia (organs of Zuckerkandl) undergo regression.
Vestiges are found at any age in adult life as small structures which resemble cells of the adrenal medulla.
Norepinephrine is the predominant catecholamine in extra-adrenal chromaffin cells.
The distribution of these paragangliomas parallels that of the sympathelic nervous system and they can arise anywhere from the pelvic floor (example: urinary bladder) to the neck.
An unusual location is the spinal canal, including cauda equine.
Within the abdomen, tumours can arise from vestiges of the organ of Zuckerkandl which histologically appear identical to chromaffin cells of the adrenal medulla.
Extra-adrenal paragangliomas of the abdomen range in size from 6 to 20 cm.
The tumour may show areas of necrosis and cystic degeneration on section.
These tumours histologically may resemble paragangliomas of the head and neck region with discrete small nests of cells (alveolar pattern or “Zellballen”). A broad anastomosing or trabecular pattern is more characteristic in these tumours.
Hemorrhage or congestion within the tumor may isolate thin trabeculae of cells which form perivascular pseudorosettes. The intricate vascular network is referred to as "endocrine-like", since most tumour cells are located or immediately adjacent to an endothelial-lined vascular lumen.
In some cases a trabecular or nested architecture is less evident, and tumour cells have a diffuse or solid growth pattern or rarely may show a spindle cell morphology.
On occasion, one may see intracytoplasmic hyaline globules as in pheochromocytomas (adrenal medullary paragangliomas). Rare cases contain copious melanin pigment.
It has been suggested that pheochromocytomas with an absence of sustentacular cells correlates with aggressive behavior.
Although a paucity or absence of sustentacular cells can occur in clinically malignant tumors, this is not an absolutely reliable indicator of malignancy, since it can also be found in some tumours which prove to be benign on follow-up.
An unusual but distinctive tumour is a paraganglioma of the urinary bladder. Paraganglioma of the Urinary Bladder
triad : A triad of gastric stromal sarcoma (most often with
epithelioid morphology), pulmonary chondroma and extra-adrenal
It is now recognized that at least 30% of these tumors are hereditary, caused by germline mutations of at least 10 genes
Hereditary pheochromocytomas and extra-adrenal paragangliomas arising in patients with different genotypes have characteristic distributions and biochemical profiles and different likelihoods of metastasis.
A wide spectrum of associated tumours including gastrointestinal stromal tumors, renal cell carcinomas, and pituitary adenomas is associated with newly discovered hereditary tumour syndromes.
Discoveries of new susceptibility genes and genotype-phenotype correlations have led to the realization that appropriate patient care requires a complete integration of clinical, genetic, biochemical, imaging, and pathology findings.
Ki67 and hTERT expression can aid in the distinction
between malignant and benign pheochromocytoma and paraganglioma.
Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extra-adrenal sympathetic paragangliomas including 38 malignant tumors. Endocr Pathol. 2005 Spring;16(1):23-32
Lack EE 1994 Pathology of adrenal and extra-adrenal paraganglia. Major problems in pathology. WB Saunders, Philadelphia, vol29.
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