Paragangliomas arise in specialized neural crest cells associated with segmental or collateral autonomic ganglia throughout the body.
Extra-adrenal paragangliomas occur most commonly in the head and neck region, usually involving the carotid bodies or glomus jugulare, and are observed less frequently in the mediastinum, retroperitoneum, lungs, duodenum, orbit, larynx, urinary bladder, and spinal cord paragangliomas.
Extra-adrenal phaeochromocytomas occur and may be referred to as paragangliomas, although this term is also used to describe vascular head and neck tumours, which most commonly develop at the carotid bifurcation. Pheochromocytomas are neoplasias of neural crest origin arising from the adrenal medulla.
Localization
adrenal paraganglioma (pheochromocytoma)
extra-adrenal paraganglioma
- carotid body paraganglioma
- jugulotympanic paraganglioma (glomus jugulare tumor)
- vagal paraganglioma (vagal body tumor)
- mediastinal paraganglioma (aortic body tumor, mediastinal aorticosympathetic paraganglioma)
- retroperitoneal paraganglioma
- vesical paraganglioma
- cephalic paraganglioma and cervical araganglioma (hean and neck paraganglioma)
- gangliocytic paraganglioma (duodenal, bronchial)
- cauda equina paraganglioma
- nasopharyngeal paraganglioma
- laryngeal paraganglioma
- orbital paraganglioma
- cardiac paraganglioma
- pulmonary paraganglioma (15166677)
- thyroid paraganglioma
Microscopic synopsis
architectural pattern
- zellballen pattern
- anastomosing trabecular pattern
- mixed pattern
- diffuse pattern (solid pattern)
- arcuate vascular network
- confluent tumor necrosis
cytological pattern
- argyrophilic cells
- pleomorphic paraganglioma (pleomorphic cells)
- gangliocytic paraganglioma (duodenal)
+/- hyaline globules
mitosis
+/- extensive local invasion
+/- extensive vascular invasion
Variants
pigmented paraganglioma (8491482)
oncocytic pheochromocytoma (11075859)
gangliocytic paraganglioma (15492999)
immature paraganlioma
paraganglioma with extensive gangliocytic differentiation (mixed pheochromocytoma and ganglioneuroma) (3181953, 10839612)
Functional classification
secreting paragngliomas (chromaffin-positive paragangliomas)
non-secreting paragngliomas (chromaffin-negative paragangliomas)
Immunochemistry
NSE + (100%)
chromogranin-A +
CD56+
synaptophysin+
neurofilament+
Leu-enkephalin + (76%)
Met-enkephalin + (75%)
somatostatin + (67%)
pancreatic polypetide + (51%)
VIP + (43%)
substance P + (31%)
adrenocorticotropic hormon + (28%)
calcitonin + (23%)
bombesin + (15%)
neurotensin + (12%)
CK- (cytokeratins -)
Ultrastructure
abundant dense core granules with an eccentric halo ("norepinephrine-type" granules)
Susceptibility syndromes
germline mutations may be detected in approximately 25% of unselected cases
von Hippel-Lindau disease (VHL)
multiple endocrine neoplasia type 2 (MEN 2)
phaeochromocytoma-paraganglioma syndrome
neurofibromatosis type 1
familial paraganglioma-GIST syndrome (15383933, 11857563)
Carney triad (paraganglioma, gastrointestinal stromal tumor (GIST), pulmonary chondroma)
SDH mutations
- Germline mutations in three of the succinate dehydrogenase (SDH, mitochondrial complex II) subunits (SDHD, SDHB and SDHC) cause susceptibility to head and neck paragangliomas, and may be found in approximately 20% of unselected patients.
- In addition, germline SDHD and SDHB mutations may cause phaeochromocytoma susceptibility with or without associated head and neck paragangliomas.
- Recent studies suggest that germline SDHD and SDHB mutations are an important cause of familial and isolated phaeochromocytoma. (dysregulation of hypoxia-responsive genes and impairment of mitochondria-mediated apoptosis)
References
Baysal BE. On the association of succinate dehydrogenase mutations with hereditary paraganglioma. Trends Endocrinol Metab. 2003 Dec;14(10):453-9. PMID: #14643060
Lack EE, Lloyd RV, Carney JA, Woodruff JM; Association of Directors of Anatomic and Surgical Pathology. Recommendations for reporting of extra-adrenal paragangliomas. Mod Pathol. 2003 Aug;16(8):833-5. PMID: 12920230
Lack EE, Lloyd RV, Carney JA, Woodruff JW; Association of Directors of Anatomic and Surgical Pathology. Recommendations for the reporting of extra-adrenal paragangliomas. The Association of Directors of Anatomic and Surgical Pathology. Hum Pathol. 2003 Feb;34(2):112-3. PMID: 12612877
Maher ER, Eng C. The pressure rises: update on the genetics of phaeochromocytoma. Hum Mol Genet. 2002 Oct 1;11(20):2347-54. PMID: 12351569