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
 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#